SECTION 23 Disorders of the skin Section editor Ro

23.1 Structure and function of skin 5591 John A. M

23.1 Structure and function of skin 5591 John A. McGrath

ESSENTIALS Skin provides a mechanical and immunological barrier against the external environment, but has further roles in thermoregulation, me- tabolism, and the regulation of fluid balance, as well as being so- cially important in contributing to physical and chemical attraction between individuals. There are more than 1000 different skin diseases, although rela- tively few are commonly encountered in general medical prac- tice. However, several skin conditions can reflect a general medical problem such as a systemic infection, or a cutaneous manifestation of internal disease (e.g. patients with underlying malignancy, endo- crine disorders, or chronic inflammatory diseases). An understanding of skin structure and function is also important in dealing with the common clinical scenario of ‘skin failure’ resulting from adverse drug reactions, burns, or extensive trauma. Introduction The skin is the body’s largest organ. In a 70 kg individual, the skin weighs over 5 kg and covers a surface area approaching 2 m2. Structurally, skin consists of a stratified cellular epidermis (made of keratinocytes) and an underlying dermis of connective tissue (fibroblasts, collagens, elastic tissue, and ground substance) (Fig. 23.1.1). Below the dermis is a layer of subcutaneous fat, which is separated from the rest of the body by a vestigial layer of striated muscle. The skin also contains hair follicles, sweat glands, blood vessels, autonomic and sensory nerves, as well as pigment cells (melanocytes), antigen-​presenting cells (e.g. Langerhans’ cells), neuroendocrine (Merkel) cells, and some resident inflammatory cells (lymphocytes and mast cells). Origin of the skin The skin arises by the juxtaposition of two major embryological elements: the prospective epidermis, which originates from a sur- face area of the early gastrula, and the prospective mesoderm, which comes into contact with the inner surface of the epidermis during gastrulation. The mesoderm not only provides the dermis, but is essential for inducing differentiation of the epidermal structures, such as the hair follicle. The melanocytes are derived from the neural crest. While the skin develops in utero it is covered by a special layer, the periderm, which is unique to mammals. The periderm provides some protection to the newly forming skin, as well as having a role in the uptake of carbohydrate from the amniotic fluid. As skin matures in utero, physiological detachment of the periderm (into the amni- otic fluid) occurs by 24 weeks’ gestation. The embryonic dermis is at first very cellular, and at 6–​14 weeks three types of cell are present:  stellate cells, phagocytic macro- phages, and cells with secretory granules (either melanoblasts or mast cells). From weeks 14 to 21 fibroblasts are numerous and ac- tive, and perineural cells, pericytes, melanoblasts, Merkel cells, and mast cells can be individually identified. The various components of the skin that can be recognized postnatally start to appear at dif- ferent embryonic time-​points, for example, hair follicles and nails (9 weeks), sweat glands (9 weeks for the palms and soles, 15 weeks for other sites), and sebaceous glands (15 weeks). Touch pads become recognizable on the hands and fingers, and on the feet and toes, by 6 weeks, and reach their greatest development at 15 weeks. After this, they flatten and become indistinct. It is these areas that determine the pattern of the dermatoglyphs (fingerprints) that take their place. Structure of the skin Epidermis The normal epidermis is a terminally differentiated, stratified squa- mous epithelium composed of keratinocytes, which progressively move from attachment to the epidermal basement membrane to- wards the skin surface. This process normally takes about 40 days, but is accelerated in diseases such as psoriasis. The brick-​like shape of keratinocytes is provided by a cytoskeleton made of keratin inter- mediate filaments. As the epidermis differentiates, the keratinocytes become flattened as a result of the action of filaggrin, a protein com- ponent of keratohyalin granules, on the keratin filaments. Indeed, keratin and filaggrin comprise 80–​90% of the mass of the epidermis. The outermost layer of the epidermis is the stratum corneum, where the cells (now called corneocytes) have lost their nuclei and cytoplasmic organelles. The corneocyte has a highly insoluble 23.1 Structure and function of skin John A. McGrath

section 23  Disorders of the skin 5592 cornified envelope within the plasma membrane, formed by the cross-​linking of soluble protein precursors including involucrin and loricrin. The latter contributes 70–​85% of the mass of the cornified cell envelope, which also contains several lipids (fatty acids, sterols, and ceramides) released from lamellar bodies within the upper, living epidermis. Keratinocytes also generate hundreds of antimicrobial peptides that have important roles in innate and adaptive immune responses; most are small cationic peptides that can kill bacteria by binding to anionic components in microbe cell membranes. Human skin is also colonized by trillions of commensal micro- organisms, referred to as the skin microbiome, the nature of which is influenced by body site (e.g. dry or moist skin), gender, age, medi- cations, and diet. Host-​microbiome interactions are important in protective immune responses and perturbations in the microbiome may contribute to the pathogenesis of many skin diseases including acne vulgaris, psoriasis, and atopic dermatitis (eczema). Melanocytes are located within the basal layer of the epidermis (closest to the dermis). These are dendritic cells that distribute pack- ages of the pigment melanin (melanosomes) to surrounding kera- tinocytes, the process that gives skin its physical colour. The number of melanocytes does not differ much between white and black skin. Rather it is the nature of the melanin and the size of the melanosomes that account for the different appearance. Each melanocyte supplies melanin pigment to c.30–​40 surrounding keratinocytes. Another dendritic cell population within the epidermis is the Langerhans’ cell, which is of mesenchymal origin, and originates from bone marrow. Langerhans’ cells are antigen-​presenting cells that process antigens encountered by the skin to local lymph nodes, and thus have a key role in adaptive immune responses in the skin. Dermis Collagen is the major extracellular matrix protein, comprising 80–​ 85% of the dry weight of the dermis. Twenty-​eight different collagens have been identified in vertebrate tissue (distinguished by Roman numerals in the order of their discovery, from I to XXVIII), of which at least 12 are expressed in skin. The main interstitial dermal colla- gens are types I and III, whereas the principal basement membrane collagen (at the junction between the dermis and the epidermis, and around dermal blood vessels, nerves, and glands) is type IV. Triple-​helical collagen monomers polymerize into fibrils and fibres, which then become stabilized by the formation of complex intra and intermolecular cross-​links. Collagen fibres are extremely tough and provide skin with its tensile strength. Elastic fibres account for no more than 2–​4% of the extracellular matrix in the dermis, and consist of two components, elastin and microfibrils, which together give skin its elasticity and resilience. Elastic microfibrils are composed of several proteins, including fibrillin, that surround the elastin and can extend throughout the dermis in a web-​like configuration to the junction between the dermis and the epidermis. Collagen and elastic fibres are deposited by fibroblasts, mesen- chymal cells that show considerable embryonic heterogeneity and body site diversity, with various subpopulations of fibroblasts differ- entially contributing to skin homeostasis, wound healing, scarring, and formation of hair follicles. The dermis also contains several non​collagenous glycoproteins, including fibronectins, fibulins, and integrins, which are important components of the extracellular matrix, facilitating cell adhesion and cell motility. Between the dermal collagen and elastic tissue is the ground substance, made up of glycosaminoglycan/​proteoglycan macromolecules. These contribute only 0.1–​0.3% of the total dry weight of the dermis, but play a vital role in providing hydration, mostly via the high water-​binding capacity of hyaluronic acid. Indeed, about 60% of the total weight of the dermis is composed of water. Regional variations in skin anatomy The thickness of the living epidermis in normal human skin shows some variation with body site, and usually measures about 0.05–​ 0.1 mm, although it can be thicker in regions such as the palm and sole, where the stratum corneum can be up to 10 times thicker than in non​acral sites (Fig. 23.1.2). Likewise, the thickness of the dermis can differ considerably, from less than 0.5 mm on the eyelid to more than 5 mm on the back. There are two main types of human skin. Glabrous (non​hairy) skin is found on the palms and soles. It has a grooved surface with alter- nating ridges and sulci, giving rise to the fingerprints. Glabrous skin has a compact stratum corneum, encapsulated sense organs within the dermis, and a lack of hair follicles and sebaceous glands. By con- trast, hair-​bearing skin has both hair follicles and sebaceous glands, but lacks encapsulated sense organs. There is also wide variation be- tween body sites. For example, the scalp has large hair follicles that may extend into the subcutaneous fat, whereas the forehead has only small vellus hair-​producing follicles, although the sebaceous glands are large. The axilla is notable because it has apocrine glands in add- ition to the eccrine sweat glands that are found throughout the body. Skin renewal The epidermis can regenerate from a heterogeneous collection of keratinocyte stem cells that are located in small clusters in the basal interfollicular epidermis and, in particular, in the bulge region and other parts of hair follicles. Although morphologically similar to other keratinocytes, stem cells are associated with particular mo- lecular profiles. Some keratinocyte stem cells undergo symmetrical cell division to create transient amplifying cells which can proliferate Fig. 23.1.1  Histopathological appearance of normal human skin. This light microscopic image illustrates the structural features of the outer skin layers. BV, blood vessel; D, dermis; E, epidermis; M, melanocyte; SC, stratum corneum. Haematoxylin and eosin; scale bar  =  0.1 mm.

23.1  Structure and function of skin 5593 and divide a small number of times before undergoing terminal dif- ferentiation. Other keratinocyte stem cells can give rise directly to terminally differentiating cells (asymmetrical division). The key signals that influence symmetrical or asymmetrical division, the distinction between stemness and transient amplification, and the precise start/​stop signals for self-​renewal are not known, although Wnt and BMP (bone morphogenic protein) signalling are impli- cated. Stem cells in the bulge region have the capacity to migrate (e.g. to the base of the hair follicle in follicular regeneration), as well as to differentiate into diverse lineages (e.g. hair, sebaceous glands, or interfollicular epidermis). Mesenchymal stem cells can also reside within the dermis and fat, although the precise function of such cells in skin homeostasis or during wound healing has not been well es- tablished. Likewise, the renewal of many skin cells, including kera- tinocytes, might be possible by cellular differentiation from other stem-​cell sources such as bone marrow. Functions of the skin Skin provides a barrier against the external environment (Fig. 23.1.3). The cornified cell envelope and the stratum corneum re- strict water loss from the skin, while keratinocyte-​derived en- dogenous antibiotics (defensins and cathelicidins) provide an innate immune defence against bacteria, viruses, and fungi. The surface pH of human skin ranges from 4.3 to 5.3; skin pH is lower in people with darker skin because melanin biproducts are acidic. The epi- dermis also contains a network of about 2  ×  109 Langerhans’ cells, which serve as sentinel cells whose prime function is to survey the epidermal environment and initiate an immune response against microbial threats, although they may also contribute to immune tolerance in the skin. Within the dermis, there are approximately 20  ×  109 T-​lymphocytes, about twice the total number in periph- eral blood. Melanin in keratinocytes also provides some protection against DNA damage from ultraviolet radiation. An important function of skin is thermoregulation, and there is both a superficial and a deep vascular plexus; vasodilatation and vaso- constriction of these blood vessels helps regulate heat loss. Eccrine sweat glands, present in densities of 100–​600/​cm2, also play a role in heat control, and may produce approximately 1 litre of sweat per hour during moderate exercise. Secretions from apocrine sweat glands, which are mainly found in the axillae, contribute to body odour (pheromones). Skin lubrication and waterproofing is provided by sebum secreted from sebaceous glands: outpouchings of hair follicles. Subcutaneous fat has an important role in cushioning trauma, as well as in providing insulation and a calorie reserve. Fat also has an endocrine function, generating hormones such as leptin that con- tribute to regulation of appetite and metabolic energy control. Nails provide protection to the ends of the fingers and toes, and are im- portant in pinching and prizing objects. Skin also has a key function in synthesizing various metabolic products, such as vitamin D. Skin also contains motor and sensory nerves. The motor innerv- ation of the skin is autonomic, and includes a cholinergic compo- nent to the eccrine sweat glands, and adrenergic components to both the eccrine and apocrine glands, to the smooth muscle and the ar- terioles, and to the arrector pili muscle (attached to hair follicles). The sensory nerve endings are of several kinds; some are free, some terminate in hair follicles, and others have expanded tips. Failure of the skin Epidermis Loss of a functional epidermis has profound biological and clinical consequences involving the loss of water and electrolytes, cutaneous and systemic infection, and impaired thermoregulation. The clinical importance of an intact skin barrier has recently been highlighted by the discovery that many people with atopic dermatitis (and atopic dermatitis associated with asthma) have loss-​of-​function mutations in filaggrin (see OMIM 135 940), an important component of the cornified cell envelope. Loss of filaggrin leads to a defective skin barrier with increased transepidermal water loss (leading to skin dryness and itching) and an increased susceptibility to allergic sen- sitization and infection. Loss-​of-​function mutations in filaggrin, which might occur in up to 10% of the population, are also a major risk factor for systemic allergies and for nut allergy, emphasizing the importance of the skin as a portal for allergen presentation. As far as acquired epidermal failure is concerned, burns, trauma, and adverse drug reactions such as Stevens–​Johnson syndrome and toxic epidermal necrolysis (TEN, Lyell’s syndrome) can all lead to sig- nificant skin detachment and major metabolic imbalances. Stevens–​ Johnson syndrome can be considered a minor form of TEN, and involves less than 10% of body surface area skin detachment, with Fig. 23.1.2  Regional differences in skin anatomy. The physical differences in the structural composition of human skin at four different body sites (thigh, scalp, sole, and axilla) are depicted. Compared with thigh skin, the scalp has much larger hair follicles that extend deep into the subcutaneous fat, the sole has a thick stratum corneum, and the axilla has numerous eccrine and apocrine sweat glands.

section 23  Disorders of the skin 5594 an average reported mortality of 1–​5%, whereas toxic epidermal necrolysis is characterized by more than 30% skin detachment, and an average reported mortality of 25–​35%. Both conditions are char- acterized histologically by a rapid onset of keratinocyte cell death by apoptosis, a process that results in the separation of the epidermis from the dermis. There may be a pathophysiological role for inflam- matory cytokines and the death receptor Fas (TNF receptor super- family, member 6) and its ligand in the keratinocyte apoptosis during toxic epidermal necrolysis. Fas-​mediated keratinocyte apoptosis can be inhibited in vitro by antagonistic monoclonal antibodies to Fas, and by intravenous immunoglobulins, which have been shown to contain natural anti-​Fas antibodies. Other explanations of the pathophysi- ology of toxic epidermal necrolysis involve the drug interacting with major histocompatibility complex class I-​expressing cells to generate drug-​specific CD8 + cytotoxic T cells, which accumulate locally and release granzymes and perforin to kill keratinocytes. CD8 + T cells, natural killer (NK) cells, and NKT cells might also release granulysin, leading to keratinocyte death without the need for direct cell contact. Early recognition of toxic epidermal necrolysis leading to skin failure is, however, vital for optimal patient management. Dermis In normal skin ageing, and in photoageing (skin changes resulting from chronic sun exposure), there is reduced synthesis of inter- stitial collagens (type I  and III), and increased synthesis of en- zymes (matrix metalloproteinases) that break down dermal fibres. Paradoxically, there is an increase in elastin synthesis, although this functions poorly and contributes to the wrinkled, sagging appear- ance of aged skin. More specific insight into the consequences of the failure of particular dermal components, however, has been determined from the molecular characterization of genetic disorders such as Ehlers–​Danlos syndrome (EDS) and cutis laxa. Ehlers–​Danlos syn- drome represents a collection of six major disease groupings as- sociated with varying degrees of hyperextensible fragile skin and loose joints. There are several rarer variants of EDS, with patho- genic mutations reported in at least 18 different genes. Some sub- types may also be associated with catastrophic rupture of arterial blood vessels, the bowel, or the uterus. In some forms of EDS ab- normalities have been detected in type V collagen (OMIM 120 190) and tenascin X (a molecular organizer of connective tissue; OMIM 600 985), and in the vascular type of EDS, in type III collagen (OMIM 120 180). Further pathology has also been demonstrated in type I procollagen (OMIM 120 160) and in two enzymes, lysyl hydroxylase (EC 1.14.11.4; OMIM 153 454) and procollagen N-​ endopeptidase (EC 3.4.24.14; OMIM 604 539), involved in the for- mation of collagen fibres. Cutis laxa is clinically characterized by loose, sagging skin and, in some subtypes, by extracutaneous ab- normalities such as emphysema, and inguinal or umbilical hernias. Mutations in the gene encoding fibulin 5 (OMIM 604 580), a pro- tein involved in elastin fibrillogenesis, have been shown to underlie some, but not all cases of this disease. In some genetic diseases, such as focal dermal hypoplasia (Goltz syndrome, OMIM 305600), there is a near total failure to develop the dermis, which leads to outpouching of the subcutaneous fat into the overlying epidermis. This disorder results from mutations in an endoplasmic reticulum transmembrane protein, porcupine (see OMIM 300651), which normally activates key Wnt signal cascades needed to generate the dermis. Collectively, these rare genetic diseases highlight the significant clinical consequences of the failure of specific components of the dermis, and provide evidence for their important roles in the maintenance of normal, healthy skin. FURTHER READING Battie C, et al. (2014). New insights in photoaging, UVA induced damage and skin types. Exp Dermatol, 23 Suppl 1, 7–12. Gonzales KA, Fuchs E (2017). Skin and its regenerative powers: an alli- ance between stem cells and their niche. Dev Cell, 43, 387–401. Fig. 23.1.3  Function of human normal skin. The skin has several key biological roles, from the formation of a mechanical barrier, the stratum corneum, against the external environment, to providing a calorie reserve in the subcutaneous fat.

23.1  Structure and function of skin 5595 Lynch MD, Watt FM (2018). Fibroblast heterogeneity: implications for human disease. J Clin Invest, 128, 26–35. Malfait F, et al. (2017). The 2017 international classification of
the Ehlers-Danlos syndromes. Am J Med Genet Part C, 175C, 8–26. McGrath JA (2012). The structure and function of skin. In: Calonje E, et al. (eds) McKee’s pathology of the skin, pp. 1–31. Elsevier Saunders, Philadelphia. McGrath JA, Uitto J (2016). Anatomy and organization of human skin. In: Griffiths CEM, et al. (eds) Rook’s textbook of dermatology, pp. 2.1–2.48. Blackwell Publishing Ltd, Oxford. McLean WH (2016). Filaggrin failure – from ichthyosis vulgaris to atopic eczema and beyond. Br J Dermatol, 175 suppl 2, 4–​7. White KD, et al. (2018). SJS/TEN 2017: building multidisciplinary networks to drive science and translation. J Allergy Clin Immunol Prac, 6, 38–69.

23.10 Infections of the skin 5695 Roderick J. Hay

23.10 Infections of the skin 5695 Roderick J. Hay

ESSENTIALS A huge variety of different organisms exist on healthy skin, the normal microbiome. Under certain circumstances, microbes can actively in- fect the skin as a primary or secondary event in cutaneous or sys- temic disease. The most common causes of bacterial infection of the skin are Staphylococcus aureus or Group A streptococci. There are increasing reports of both hospital-​ and community-​acquired infection by methicillin-​resistant S.  aureus. Superficial infection that spreads laterally in the upper dermis or along the subcutaneous fascia is known as cellulitis. Complications of cellulitis include septicaemia or lymphoedema, hence it requires immediate antibiotic therapy. Mycobacterium tuberculosis remains a common skin infection in many tropical areas, and syphilis, leprosy, and leishmaniasis are im- portant skin infections in some parts of the world (see Section 8). Dermatophytosis, or ringworm, is caused by mould fungi that can digest keratin (keratinophilic). The diagnosis can be confirmed in the laboratory by examining scrapings or clippings of skin, hair, or nails mounted in potassium hydroxide. Pityriasis versicolor is mainly caused by Malassezia species: it is a chronic scaly condition in which the skin becomes either hyper or hypopigmented in the affected area; macules and scales join and may become confluent over the back and chest, less commonly elsewhere. Herpes simplex virus causes both acute as well as recurrent infec- tions, such as cold sores. Occasionally, in the immunocompromized patient these and other herpesvirus infections can disseminate, both to other parts of the skin as well as internally. Introduction The structure of the epidermis and its appendages such as hair and nails has been described elsewhere (see Chapters 23.1 and 23.13). The outer epidermis and the openings of the pilosebaceous units play host to a large diverse microbiome, the majority comprises bacteria such as micrococci, coryneform bacteria, and staphylo- cocci such as Staphylococcus epidermidis and Staphylococcus saprophyticus. These can achieve very high densities in excess of 4 log/​cm2. However, in occluded areas and other parts of the body, anaerobic bacteria such as brevibacteria or microaerophilic organ- isms including Propionibacterium acnes are also present. Generally, these do not cause disease unless their local environment is dis- turbed, for example, by occlusion or blockage of the sebaceous fol- licle, or if they find entrance to the bloodstream through an internal appliance such as a cannula. Also, these might cause disease in the presence of immunosuppression. S.  epidermidis, for instance, is a common pathogen in neutropenic patients. Other factors that play a role in determining surface populations include ultraviolet light exposure and the presence of skin disease. Fungi, apart from mem- bers of a single genus of lipophilic (fat metabolizing) yeasts called the Malassezia species, are not commonly carried on the skin surface. These are mainly found in the openings of sebaceous follicles. A mite species, Demodex folliculorum, is also found on the skin surface within hair follicles. Again, these organisms are normally in balance with the host and unless other conditions prevail, they do not cause disease. In addition to these microbes that are members of the resident skin microbiome, some bacteria can be temporarily carried as transient colonists of the skin. Examples include Staphylococcus aureus which colonizes the anterior nares, the axillae, or perineum in about 8–​25% of normal healthy individuals, depending on site. In addition, these bacteria or fungi can also colonize abnormal skin surfaces (e.g. pa- tients with psoriasis or atopic dermatitis often carry S. aureus on their skin lesions). Similarly, fungal species such as Candida albicans are occasionally carried on the skin surface (e.g. on the hands). The skin is therefore an ecological niche for a variety of microorganisms that, in turn, affect local environmental factors, such as pH. The skin can also be the focus for infections which are usually, but not invariably, caused by external pathogens. These are discussed under the heading of bacterial, fungal, viral, and ectoparasitic in- fections. The skin can also be affected by infections originating from other internal sites and carried via the bloodstream. Detailed accounts of diseases associated with particular organisms are also presented elsewhere in this book (e.g. for Mycobacterium leprae see Chapter 8.6.28 and for Treponema pallidum see Chapter 8.6.37). Cutaneous bacterial infections Bacteria commonly cause infection of the skin either as a primary event or secondary to some pre-​existing skin condition. The term 23.10 Infections of the skin Roderick J. Hay

section 23  Disorders of the skin 5696 ‘pyoderma’ is used to describe purulent infection of the skin caused by bacteria. The most common of these infections is the epidermal infection impetigo, but small abscesses such as boils or furunculosis can also result. The most common causes of pyoderma are S. aureus or group A streptococci. Uncommonly, but increasingly, both hospital-​ and community-​ acquired infection by methicillin-​resistant S.  aureus (MRSA) are being reported. Infections with community-​acquired methicillin-​ resistant staphylococci are more virulent; for example, they are more likely to require surgical intervention and many of these strains carry the Panton–​Valentine leukocidin (PVL) gene which enhances viru- lence; PVL-​positive staphylococci without resistant genes are also present with difficult to treat infections. Other forms of bacterial in- fection affecting deeper planes of the skin (e.g. dermis or subcuta- neous tissue), leading to cellulitis, are also seen regularly in clinical practice. Examples of secondary bacterial infection include sec- ondary infection of atopic dermatitis, Darier’s disease, or psoriasis. Impetigo This is a superficial infection confined to the epidermis caused by S.  aureus (see Chapter  8.6.4) or group A  streptococci (see Chapter 8.6.2), the cause depending, to some extent, on geography and climate. In temperate zones, the normal cause is S. aureus but in the tropics streptococci are more common; although in about 20% of cases these organisms can both be isolated from lesions, indicating a mixed infection. In most cases this is a primary infection but it might also be secondary to other skin conditions such as insect bites or scabies. Impetigo is common in primary care in temperate climates, its incidence accounting for about 20 per 1000 person years in the under 18 population, and it is among the top 50 most common of human diseases. However, it can also be found in other groups where close contact is likely (e.g. military recruits). It is more common in summer than winter. Pyoderma is more common in the tropics where it is often secondary to another skin disease such as scabies (see next). In most European countries and the United States of America, where S. aureus predominates, some cases present with blistering le- sions (bullous impetigo—​see next). S. aureus produces exfoliotoxins that cleave the human cell adhesion molecule desmoglein 1(Dsg1). This results in the formation of an epidermal bulla similar to the blister formation in pemphigus foliaceus where Dsg1 is the target of an autoantibody. Very extensive blistering occurs in the childhood infection staphylococcal scalded skin syndrome (SSSS). Production of exfoliotoxin A  is more associated with bullous impetigo and exfoliotoxin B with SSSS. Impetigo usually presents with itching or discomfort in the af- fected area, which becomes red and the surface glazed, with a golden-​ coloured serous ooze. As stated previously, S. aureus infections can also result in bullous lesions (bullous impetigo) (Chapter  8.6.4). Impetigo is most common in children and often develops on the face or trunk, but lesions can be found elsewhere. Infected lesions can also develop from localized wounds, or insect bites, or around areas where the carriage rate is high (e.g. near eczematous plaques, or close to the nose). Patients are generally well and usually show no systemic signs of infection, such as fever. Treatment consists of flucloxacillin or clindamycin, although, if the lesion is very localized, a topical antibiotic such as fusidic acid or mupirocin can be used (short term). Impetigo is contagious, particularly among children at school or in families, and therefore close contacts should be screened for infection. There is little evi- dence to support the use of antiseptics in primary treatment, how- ever logical. Hand washing, though, has been shown to reduce the risk of impetigo. If the lesions penetrate deeper into the dermis they appear as well defined but localized ulcers known as ecthyma. These occur, par- ticularly, in hot climates or where the site of infection is occluded by tight clothing. Ecthyma can also complicate other skin infections (e.g. chickenpox). It is treated with systemic antibiotics. Folliculitis and furunculosis S. aureus is the usual cause of a boil or furuncle which develops around an infected hair follicle. If the infection is restricted to the superficial part of a follicle the lesion is called folliculitis, whereas if it is deeper, a cutaneous abscess, boil, or furuncle develops. Folliculitis commonly presents in hair bearing areas such as in the beard area. Lesions are small, multiple, and pustular; with the earliest symptom often being itching. Folliculitis-​like lesions can also be caused by inflammatory tinea corporis and might also accompany ingrowth of curling hairs in the beard area (pseudofolliculitis) that traps skin commensal bacteria causing a papular or pustular response. A furuncle or boil usually starts as a solitary, tender, and inflamed nodule which, as it develops, points to form a pustular head. The patient might be febrile. Treatment is by incision to release pus followed by antibiotics (flucloxacillin or clindamycin). The most common sites for the formation of boils are the axillae or trunk areas, or even the face. Boils can develop at any age but there might a cluster of cases within the same household over several months, suggesting trans- mission within the family. Although it is frequently stated that re- current boils are indicative of underlying disease such as diabetes or immunosuppression, this is, in reality, unusual; it is more common that the individual is a bacterial carrier. Carriage of S.  aureus is common in atopics and history of atopy is therefore quite frequent in those with recurrent furunculosis. Severe and recalcitrant boils are often associated with a virulence determinant, Panton–​Valentine leucocidin, carrying strains of S. aureus. Lesions that resemble furuncles might appear in the axillae or groin associated with entrapment of commensals. This condition, known as hidradenitis suppurativa, is not associated with S. aureus, a useful clue to the diagnosis. Secondary scarring and recurrent attacks are common. There is little effective treatment for this condition (see Chapter 23.11). If several boils amalgamate, the large pustular mass is called a carbuncle. Sites of predilection include the neck. Cellulitis Superficial infection that spreads laterally in the upper dermis or along the subcutaneous fascia is known as cellulitis. The main cause is infection with Group A streptococci (also see Chapter 8.6.2), but other common causes include S. aureus. Cellulitis starts as a zone of spreading erythema and tenderness with other signs of inflam- mation such as increased surface temperature. With streptococcal infections the patient is often systemically unwell, with fever and chills. The main sites for infection are the face or the lower legs. Cellulitic infections affecting the dermis and upper subcutaneous tissue are sometimes known as erysipelas. Non​group A streptococci are also sometimes responsible.

23.10  Infections of the skin 5697 Complications include the development of septicaemia or en- croachment on adjacent structures such as the orbital cavernous sinus leading to thrombosis. Rare causes of the same syndrome include zygomycete fungi. Cellulitis requires immediate antibiotic therapy with an oral penicillin such as flucloxacillin or a macrolide antibiotic, and in systemically unwell patients with an intravenous regime. Recurrent attacks are also seen, particularly on the limbs and are often associated with lymphoedema. Management is dif- ficult as local antisepsis and improved drainage by themselves do not appear to prevent recurrences and long-​term oral penicillin V (phenoxymethylpenicillin) is often necessary for recurrent disease. However, in lower limb cellulitis there is an association with skin le- sions such as the cracks caused by athlete’s foot and treatment aimed to heal local skin defects (e.g. antifungals), is indicated. In the early phases, these infections are easily confused with early necrotizing fasciitis (see Chapter 8.6.2) where the surrounding ery- thema spreads slowly but the patient remains unwell and the over- lying skin becomes hypoaesthetic. Necrotizing fasciitis can be caused by group A streptococci but also by mixed bacterial infections after surgery or a compound fracture. The spreading erythema, dull ache, systemic reaction, and the reduction in overlying sensation should alert the physician. Surgical exploration is warranted, which then reveals a necrotic and oedematous reaction in the underlying dermis and deeper fascial planes. Treatment is by early surgical debride- ment, which is an essential part of management in addition to sys- temic broad spectrum antibiotics. Other bacterial skin infections Gram-​negative bacteria, such as a Pseudomonas species, can cause skin lesions. Most commonly these present as interdigital infec- tions of the feet. It occurs often in those whose occupations involve wearing heavy footwear or wet working conditions. The skin be- comes eroded and cracked; the toe web is also painful. If pseudo- monas is present, the edge of the lesions appears greenish. Often, Gram-​negative interdigital infection follows fungal infection (tinea pedis). Treatment with topical povidone-​iodine or 1–​2% acetic acid is useful, but sometimes the lesion flares up after treatment and this heralds the return of a dermatophyte infection. Gram-​negative folliculitis is a painful form of folliculitis pre- senting with small tender pustules on the trunk and limbs, some- times associated with fever. It is associated with bathing in whirlpool bathtubs contaminated with Gram-​negative bacteria (‘hot tub fol- liculitis’). Ecthyma gangrenosum is a necrotic ulcerative condition which is a manifestation of disseminated Pseudomonas infection in patients with Gram-​negative septicaemia, usually in the context of neutropenia. The lesions develop as nodules that evolve into raised plaques with a black necrotic centre. Tuberculosis of the skin and other
mycobacterial infections Mycobacterium tuberculosis is a rare cause of skin infection in most industrialized societies although it remains a regular infection seen in many tropical areas (see Chapter 8.6.26). With the increase in HIV and drug-​resistant tuberculosis, there have been increasing numbers of cases seen in recent years. Once common, cutaneous tuberculosis presents with several different clinical forms, all of which reflect the state of the host’s immunity and the route of in- fection to reach the skin, either through haematogenous spread, by direct spread from an underlying infected structure (e.g. lymph node or bone), or by direct inoculation into the skin. In immune individuals there are usually few organisms, which is described as paucibacillary. In other forms of infection, particularly in those who are immunocompromized, there are many organisms, which is described as multibacillary disease. The term tuberculid is used to describe skin lesions that do not contain viable organisms but that are associated with tuberculosis elsewhere. Usually, but not always, the pathogenesis is through an antigen-​mediated reaction (e.g. vasculitis). Examples include erythema nodosum and erythema induratum (Bazin’s disease), both of which are forms of vasculitis and which can, in some countries, be caused by tuberculosis among other causes. In papulonecrotic tuberculid, the rash is a reaction to disseminated and particulate antigen and, in some cases, viable bacteria are present. This can progress to infective forms of tuber- culosis such as lupus vulgaris. The main cutaneous forms of infection seen are tuberculosis verrucosa cutis, scrofuloderma, lupus vulgaris, and papulonecrotic tuberculid. The clinical and immunological features are seen in Table 23.10.1. Cutaneous tuberculosis is seen more frequently now with the spread of HIV/​AIDS. Non​tuberculous mycobacteria can also infect the skin. These include Mycobacterium chelonei and Mycobacterium fortuitum which can cause cold abscesses, often as a result of local skin in- jury, including needlestick injury or surgical or cosmetic proced- ures. Mycobacterium ulcerans is the cause of rapidly spreading skin ulceration or Buruli ulcer seen in tropical and semitropical areas, ranging from West Africa to south Australia. It is associated with Table 23.10.1  Cutaneous forms of tuberculosis Form Immune status/​organisms Clinical features Evidence of TB elsewhere Tuberculosis verrucosa cutis TB +ve No organisms Warty lesions on peripheries Slow spread No Scrofuloderma TB +ve or –​ve Organisms Purplish plaques over lymph node, often in neck Lymphadenopathy Lupus vulgaris TB +ve No organisms Plaques on face or trunk Heals with central scarring Risk of squamous cell carcinoma Uncommon Papulonecrotic tuberculid Usually TB –​ve. Seen in healthy and HIV +ve patients. Organisms Multiple papules, with central area of necrosis, limbs more than trunk Often other sites (e.g. lungs) TB, tuberculin test.

section 23  Disorders of the skin 5698 exposure to fresh water and a potential link with aquatic insects has been proposed. It is difficult to arrest the process with antibiotics and the most successful form of management is rifampicin and strepto- mycin plus surgical excision. Mycobacterium marinum is an infec- tion usually contracted from tropical fish kept in a fish tank (fish tank granuloma); however, naturally acquired infections are seen in the tropics, for example, in association with commercial fish-​ farming (Chapter 8.6.27). It presents with an area of localized pus- tular swelling, and granulomatous infiltration or ulceration, usually on a peripheral site such as a finger. In some cases there is local lymphadenitis (sporotrichoid spread). The main differential diagnosis is sporotrichosis or leishmaniasis. Treatment with a range of different antibiotics from minocycline to rifampicin has been used. Cutaneous fungal infections With the exception of infections due to Malassezia species, most fungal infections of the skin are extrinsic. The most common of these, dermatophytosis, is seen in all countries, whereas Malassezia infec- tions are more common in the tropics. Candida infections of the skin are less common, but are seen regularly as secondary skin infections. Cutaneous viral infections Certain viruses are capable of establishing infections of the epidermis and dermis, but, strictly speaking, there are no viral commensals of the skin. The main infections are the human papillomavirus (HPV) infections (warts) and herpes zoster and simplex. These infections are discussed in detail in Section 8. Table 23.10.2 outlines common HPV types and associated clinical patterns. Ectoparasitic infestations Demodex folliculorum, an acarid mite, is a commensal on normal skin, but there are also infestations due to ectoparasites—​scabies and pediculosis (lice). These are described in detail in Chapter 8.12. FURTHER READING Beyt BE Jr, et al. (1981). Cutaneous mycobacteriosis: analysis of 34 cases with a new classification of the disease. Medicine (Baltimore), 60, 95–​109. Daikos GL, et al. (1998). Disseminated miliary tuberculosis of the skin in patients with AIDS: report of four cases. Clin Infect Dis, 27, 205–​8. Fogo A, Kemp N, Morris-​Jones R (2011). PVL positive Staphylococcus aureus skin infections. Br Med J, 343, d5343. Grice EA, Segre JA (2011). The skin microbiome. Nat Rev Microbiol, 9, 244–​53. Koning S, et al. (2012). Interventions for impetigo. Cochrane Database Syst Rev, 1, CD003261. Schachner LA (2005). Treatment of uncomplicated skin and skin in- fections in the pediatric and adolescent patient populations. J Drugs Dermatol, 4 Suppl 6, S30–​3. Seal DV, Hay RJ, Middleton K (2000). Skin and wound infection: inves- tigation and treatment in practice. Martin Dunitz Ltd, London. Stanley JR, Amagai M (2006). Pemphigus, bullous impetigo, and the staphylococcal scalded-​skin syndrome. N Engl J Med, 355, 1800–​10. Table 23.10.2  Clinical patterns and common types of human papillomavirus Skin or mucosal infection HPV typea Common, plantar, mosaic warts 1, 2, 4 Plane warts 3, 10 Butcher’s warts 7 Bowen’s disease (some cases) 16 Epidermodysplasia verruciformis 3, 5, 8, 12, 36–​38, and others Condyloma acuminata (genital warts) 6, 11 Intraepithelial neoplasia (e.g. cervical dysplasia, bowenoid papulosis) 16 HPV, human papillomavirus. a Only commonly associated forms are shown.

23.11 Sebaceous and sweat gland disorders 5699 Ali

23.11 Sebaceous and sweat gland disorders 5699 Alison M. Layton

ESSENTIALS Cutaneous glands in humans include holocrine or sebaceous glands and merocrine or sweat glands. Merocrine glands are subdivided into apocrine, eccrine, and apoeccrine glands. Disorders of each of these cutaneous glands have been associated with disease. Apocrine glands in adults are found predominantly in the axillae and anogenital regions, with a few located in the ear canal (ceru- minous glands) and eyelids (Moll’s glands). Disorders associated with apocrine glands include hidradenitis suppurativa, Fox–​Fordyce dis- ease, bromhidrosis, trimethylaminuria, and chromhidrosis. Eccrine glands are the sweat-​producing glands of the skin. Many drugs and systemic diseases can influence the degree of sweating, such as thyroid disease, infection, carcinoid, and cholinergic drugs. In cystic fibrosis, the concentration of sodium chloride in sweat is increased. Sebaceous glands form part of the pilosebaceous unit and are found over the entire body surface, with the exception of palms and soles. They are under the influence of androgenic hormones. Acne is a common inflammatory skin disease often associated with significant psychosocial morbidity. Early effective intervention reduces emotional and physical scarring. An understanding of pathophysiology allows top- ical and systemic therapies to be combined logically to target therapy. Disorders of apocrine glands Apocrine glands are compound sweat glands with a secretory coil that extends deep through the dermis into subcutaneous tissue and drains via a long, straight secretory duct, into a hair follicle. Their function in man is not altogether clear, but in other mammals they are responsible for sexual attraction and scent production. This is re- sponsible for axillary and inguinal odour. The glands become larger and functionally active at puberty. The secretion is opalescent and malodorous. The glands are innervated by adrenergic fibres of the sympathetic nervous system. Hidradenitis suppurativa (HS) synonymous
with acne inversa Introduction This is a chronic, inflammatory, suppurative disease affecting apocrine-​gland bearing skin sites, including the axillae, groins, perineum, and/​or submammary area (in women). Hidradenitis suppurativa has a predilection for intertriginous regions, the ax- illae and inguinoperineal regions being the most commonly affected (see Figs. 23.11.1 and 23.11.2). The extent and severity of disease varies, most patients have more than one major site involved but some patients have relatively mild forms of the disease. It is a chronic disabling disease that generally progresses with time and frequently causes scarring, contractures, and significant morbidity for patients. Aetiology and epidemiology The aetiology of hidradenitis suppurativa is unclear; there is a female predominance with a ratio of 3:1 and it is associated with obesity and smoking. There is a significant risk of increased cardiovascular associated death in patients with hidradenitis suppurativa compared with controls, in keeping with high rates of smoking, type II dia- betes, hypertension and hyperlipidaemia. Hidradenitis suppurativa is associated with acne and pilonidal sinuses as well as Crohn’s dis- ease. The incidence in England is said to be around 1:600. Patients of African descent have been reported to have a higher prevalence than Europeans which might reflect the higher density of apocrine glands in black versus white skin. The age of onset ranges from 11 to 50 years, but it is very rare to see hidradenitis suppurativa before pu- berty or after the menopause. A familial form of the condition with autosomal dominance has been described. Specific bacteria (e.g. an- aerobic streptococci like Streptococcus milleri) have been reported in hidradenitis suppurativa and although cultures are frequently sterile, microbiological assessment allows treatment to be based on documented sensitivities. Pathogenesis Hidradenitis suppurativa was first described as a clinical entity in 1839 by Velpeau who described a patient with superficial abscesses in the axillary, perianal, and mammary regions. In 1854 Verneuil associated the suppurative condition with sweat glands. In 1922 the sweat glands were classified as apocrine and eccrine and it was suggested that hidradenitis was localized to the apocrine glands. Occlusion of the follicular infundibula is the initial event in patho- genesis and a defect of the terminal follicular epithelium is recog- nized. This is followed by inflammation of the apocrine glands and rupture of the follicles. The disease is sometimes referred to as acne inversa, reflecting the similarities to acne in terms of the follicular occlusion but the locations are inverse to acne and no increase in 23.11 Sebaceous and sweat gland disorders Alison M. Layton

section 23  Disorders of the skin 5700 sebum secretion is seen in hidradenitis suppurativa. A family his- tory of hidradenitis suppurativa is reported in up to 42% of cases and the condition can represent an autosomal dominant inheritance in some kindreds. Recent familial studies have reported heterozygous mutations in the γ-secretase genes PSEN1, PSENEN and NCTSN. In animal models alteration in the γ-secretase gene expression can re- sult in follicular occlusion. Clinical features A consensus approach suggests that three key elements are required to diagnose hidradenitis suppurativa. These include typical lesions, characteristic distribution, and recurrence. Typical primary lesions embrace painful and/​or tender erythematous papules, painful or tender abscesses, and inflamed discharging papules or nodules, dermal contractures, and rope-​like elevation of the skin and double-​ ended comedones. The groins and axillae are the most frequently affected sites. As a result of associated pain, purulent discharge, malodour and the involvement of sensitive and intimate areas, hidradenitis suppurativa can result in significant morbidity and impact on many aspects of quality of life. Diagnosis and differential diagnosis Some authors have based the diagnosis on several questions, including: Is there more than one inflamed lesion? Is the course chronic, are le- sions bilateral, and are lesions located to the primary milk line? Distinction from septic furunculosis can be difficult in the early stages. Clinical investigations The diagnosis is primarily a clinical one and diagnostic biopsy is rarely required. Microbiological culture might be helpful as might histological examination. Treatment Treatment is notoriously difficult. Many patients are smokers but smoking cessation does not universally result in improvement of hidradenitis suppurativa. Reducing friction and moist hot envir- onments, together with weight reduction and cotton clothing will help some patients. Laser hair removal can be beneficial in some patients. Localized inflammatory lesions benefit from intralesional injections using triamcinolone (5 mg/​ml). Small studies have shown a combination of oral clindamycin (300 mg twice daily) and rimfampicin (600 mg daily) is beneficial. Systemic antibiotics, including erythromycin 500 mg twice each day or minocycline 100 mg daily, are frequently used but topical clindamycin lotion is the only antibiotic that has been shown to be beneficial in a double-​blind, placebo-​controlled trial. Systemic steroids frequently produce improvement but recurrence is usual on withdrawal. Antiandrogen therapy alone as cyproterone acetate or in com- bination with ethinylestradiol has been used successfully in some women as has spironolactone; Finasteride, the 5-α reductase in- hibitor, has also been tried. Isotretinoin produces minimal benefit and the longer acting retinoid acitretin 25 mg daily has shown more promise. Ciclosporin A and tumour necrosis factor-​α (TNFα) in- hibitors have demonstrated improvement in refractory disease. Clinical trials using adalimumab, an IgG monoclonal antibody spe- cific for TNFα, and infliximab have produced good results in some patients. Good results have also been reported following radical surgical excision of involved areas with laying open of sinus tracts. More limited surgical intervention, consisting of unroofing abscesses and sinus tracts and leaving to heal with secondary-​intention have also proved effective in some patients. Non​ablative radiofrequency has also been used for certain stages of disease. Prognosis/​outcome Hidradenitis suppurativa is a chronic disabling disorder and has a tendency to progression with recurrent episodes of painful inflam- mation and resultant scarring. Patients frequently have to have time off work and negative impact on quality of life is significant. Fox–​Fordyce disease Introduction Fox–​Fordyce disease represents a papular eruption localized to apo- crine glands. Aetiology and epidemiology This is seen most frequently in females in a ratio of 9:1. It is most commonly seen around 13–​35  years and is rare outside this age range. There is no geographical influence or racial predilection al- though heat, humidity, and excessive sweating are often noted as exacerbating factors. Pathogenesis The histology reflects a keratin pug in the hair follicle infun- dibulum which obstructs the acrosyringium, resulting in apocrine anhidrosis. Rupture of the excretory duct then occurs, resulting in inflammation. Clinical features Light brown flesh-​coloured papules appear in areas of apocrine glands around the breasts, vulva, and axillae in females and may occur around the glans in males. The lesions are frequently itchy and inflamed. Treatment If symptomatic, electrodessication or hyfrecation of the irrit- able lesions will help. Other treatments advocated include topical clindamycin lotion, ultraviolet radiation, topical retinoids, oral contraceptives, and systemic retinoids. Bromhidrosis (synonymous with 
Bromihidrosis and body odour) Introduction Apocrine bromhidrosis is the most common form and should be discriminated from the less common eccrine bromhidrosis. Bacterial decomposition which liberates fatty acids will influence apocrine odour; this is most commonly from corynebacteria. Increased axillary pH might facilitate overgrowth of bacteria. In rare cases, bromhidrosis can become a significant chronic condi- tion which impacts negatively on the lives of certain individuals. Eccrine secretion is odourless when it is first excreted onto the surface of the skin but certain food substances (e.g. garlic,

23.11  Sebaceous and sweat gland disorders 5701 onion, curry, alcohol, and some drugs can cause eccrine bromhidrosis). Hyperhidrosis might contribute to apocrine bromhidrosis by encouraging a moist environment for overgrowth of bacteria. Aetiology and epidemiology This is considered a rare condition. Apocrine bromhidrosis is thought to be more common in black skin and, in Asian patients, might be associated with a family history. Males are more commonly affected which might reflect greater apocrine activity in males. Axillary bromhidrosis presents exclusively in puberty and is rare in older people; conversely, eccrine bromhidrosis is more common in childhood but can occur at any age. Clinical features A family history is common and an autosomal dominant pattern of inheritance has been described. Pathogenesis Human apocrine glands appears to be under sympathetic ner- vous control alongside peripheral mechanisms regulated by catecholamines. Treatment Deodorants that lower the skin’s pH will reduce the bacterial growth. Treatment of axillary bromhidrosis includes avoidance of relevant food substances, frequent washing, and local anti- bacterial substances. Surgical ablation of eccrine and apocrine glands can be beneficial in patients not helped by conservative approaches. Trimethylaminuria (TMAU) synonymous
with fish odour syndrome (FOS) Introduction Trimethylaminuria, also known as fish odor syndrome, is a psychologically disabling condition in which a patient emits a foul odour resembling that of rotting fish. Primary TMAU is most commonly caused by an inherited deficiency in flavin monooxygenase 3 (FMO3), the enzyme required for the metab- olism of trimethylamine (TMA), which is responsible for the odour found in sweat, urine, and breath. The disorder can cause profound psychosocial problems. While there is no cure, some simple treatment options can improve the quality of life of these patients. Aetiology Primary TMAU is caused by a deficiency in FMO3 resulting from an autosomal recessive inheritance. Under normal circumstances, dietary TMA precursors, such as choline, are ingested and then re- duced to TMA by colonic bacteria. The TMA passively diffuses and enters the enterohepatic circulation where it is removed and is oxi- dized by FMO3 into odourless compounds. Patients with primary TMAU lack adequate functional FMO3 and therefore experience an excess of foul-​smelling TMA. Primary trimethylaminuria accounts for most cases, but there also exists secondary or acquired trimethylaminuria where FMO3 might still retain varying degrees of functionality. Secondary cases can occur in the setting of excess dietary burden as occurred after therapeutic administration of choline for the treatment of Huntington’s chorea and Alzheimer’s disease. Hepatic disease might serve as another cause, as in viral hepatitis, and this has also been reported in chronic kidney disease. Fish odour syndrome has been described transiently in early child- hood when FMO3 levels are minimal and in the perimenstrual period when steroid hormones might have caused a reduction in FMO3 expression. Clinical investigations The diagnosis is made on the basis of the clinical presentation and urinalysis. Urine can be analysed for the concentration of both TMA and TMAO, and the results may be given as an oxidizing ratio based on the formula TMAO/​(TMAO + TMA) × 100%. A ratio of less than 84% should be observed in an affected in- dividual with two FMO3 inactivating mutations. Conversely, in- dividuals not affected with fish odour syndrome should have a ratio of greater than 92%. Many patients, in an attempt to reduce their odour, may have empirically tailored their diet to exclude TMA precursors, which could cause a false-​negative test result. Therefore, it is critical to ensure that adequate substrate has been ingested in order to allow for maximum sensitivity; this can be achieved by loading the patient with a 300 g marine fish meal. Genetic testing is available. Treatment considerations Once the diagnosis has been established, there are several poten- tially helpful treatment options; however, no single regimen seems universally efficacious and no systematic study has been performed to test the various recommendations. A  first step for the patient might be to wash frequently with an acidic soap (pH 5.5–​6.5). The patient should be informed that the malodour will intensify with hyperhidrosis, fever, stress, and exercise. Reduction or exclusion of TMAO from the diet might help; this is found in high concentration in marine fish. Foods with high con- centrations of choline include eggs, mustard seeds, chicken and beef, and raw soybeans. Oral activated charcoal has been shown to elevate oxidizing ratios to greater than 90%. Short courses of oral neomycin, metronidazole, and amoxicillin have been reported to be useful in some cases. The mechanism involves the destruction of gut bacteria, which are re- sponsible for the reduction of TMAO into TMA. Lactulose, which also acts in the alimentary canal, is another therapy that has dem- onstrated an ability to decrease urinary TMA. Patients should be offered psychological support. Complications Fish odour syndrome is often associated with significant psycho- social disturbances. Anxiety, social withdrawal, and depression can be an issue for these patients. Chromhidrosis Introduction Chromhidrosis represents a rare condition in which the apocrine sweat can be blue/​black, yellow, or green resulting from the secretion

section 23  Disorders of the skin 5702 of lipofuscins. The more oxidized lipofuscins appear deeper in colour and the lighter coloured lipofuscins might fluoresce. The onset of coloured sweat starts in puberty and resolves in old age as apocrine function regresses. The axillae are most frequently affected, although areolar and facial chromhidrosis have been re- ported. Topical capsaicin may be beneficial. Aetiology and epidemiology Apocrine chromhidrosis is more common in black than white popu- lations but facial chromhidrosis is described only in white skinned individuals. There is no sex predilection. Pathophysiology Lipofuscin is a yellow-​brown pigment normally found in the cyto- plasm of some cells. In chromhidrosis lipofuscins are found in a higher oxidative state or in higher numbers. It is unclear what causes the higher oxidative state. Pseudochromhidrosis represents a chem- ical on the surface of the skin that reacts with eccrine secretions, resulting in the colour transformation. Clinical presentation The sweat as just described, if coloured, and the yellow, green, or blue secretions fluoresce yellow under a Woods lamp in contrast to the dark brown and black secretions which do not. Disorders of eccrine glands Eccrine glands represent small tubular structures draining dir- ectly onto the skin surface. Up to four million sweat glands are present in all sites of the skin excluding mucous membranes, palms, soles, axillae, and forehead, the latter having the highest density. Sweat is formed by active secretion involving the so- dium pump. After tubular resorption of electrolytes and water the sweat becomes isotonic. Sweat contains sodium, potassium chloride, lactate, urea, and ammonia. The concentration of so- dium chloride in sweat is increased in cystic fibrosis. Sweat glands exhibit thermoregulatory control, the skin surface being cooled by evaporation. Eccrine glands are innervated by cholin- ergic fibres of the sympathetic nervous system and sweating can, therefore, be induced by cholinergic drugs and blocked by anti- cholinergic therapies. The preoptic hypothalamic sweat centre controls sweating centrally. Hyperhidrosis or excessive sweating Introduction Hyperhidrosis is an acutely embarrassing condition involving excess production of sweat and can manifest itself as generalized or local- ized disease. Aetiology and epidemiology The incidence rate is reported as 0.6–​1% in adolescents. Localized palmoplantar hyperhidrosis can occur in all races, but is 20 times more frequent in the Japanese than any other ethnic group. Both sexes can be affected. Hyperhidrosis might relate to underlying organic conditions and these should be considered as outlined in Box 23.11.1. Pathophysiology Generalized hyperhidrosis can develop as a consequence of auto- nomic dysregulation or might develop as a result of an underlying metabolic, malignant, or febrile disease. Palmoplantar hyperhidrosis can be inherited as an autosomal dominant disease. Clinical features Localized hyperhidrosis most commonly affects the palms, soles, and/​or axillae and usually begins in childhood or adolescence. Clinical investigations Potential underlying systemic disease should be considered as out- lined in Box 23.11.1 and appropriate investigations conducted for more generalized disease. Treatment Treatment of hyperhidrosis is not always successful. Practical ad- vice on appropriate cotton clothing, heat avoidance, and weight re- duction along with relaxation techniques and anxiolytics in selected cases might all prove helpful. Topical anticholinergic drugs can produce local benefits without causing systemic adverse effects. Topical 0.5% glycopyrrolate cream has been used with some success in gustatory hyperhidrosis associ- ated with diabetes. Box 23.11.1  Causes of generalized hyperhidrosis • Thermoregulatory triggers — Hot weather/​environment — Exercise • Infection — Fever/​nausea — Tuberculosis/​malaria/​brucellosis/​endocarditis, and so on • Metabolic/​hormonal — Thyrotoxicosis, acromegaly, diabetes, Cushing’s syndrome — Hypoglycaemia, alcohol intoxication, hyperpituitarism — Phaeochromocytoma — Menopause • Neoplastic — Lymphoma — Carcinoid — Carcinoma • Gustatory — Spicy/​hot foods or drinks • Neurological — Lesions of the sympathetic nervous system, cortex, basal ganglia, or spinal cord — Peripheral neuropathies — Familial dysautonomia (Riley–​Day) — Congenital autonomic dysfunction with universal pain loss — Cold-​induced profuse sweating • Drugs — Cholinergic drugs — Fluoxetine — Opiate withdrawal • Psychological — Anxiety — Fear

23.11  Sebaceous and sweat gland disorders 5703 Eccrine blocking agents work by impeding the delivery of sweat to the skin surface. Soaks using 3% formalin and 10% glutaraldehyde solution help pedal hyperhidrosis but they are irritant to other sites. Aluminium chloride is the most frequently used preparation for ax- illae and hands but is also irritant and damages clothes. Botulinum toxin A  injections produce blockade of neuronal acetylcholine release at the neuromuscular junction and in cho- linergic autonomic neurons. Intradermal injections can reduce sweating within 48 h and have lasting effects (eight months in the axillae and six months in palms). Injections can be safely repeated with good effect. Iontophoresis using tap water or anticholinergic drugs, such as glycopyrronium bromide, is very helpful for palmoplantar hyperhidrosis. A small, battery operated unit can be purchased for home maintenance. While atropine-​like drugs are effective for hyperhidrosis, ad- verse effects including dryness of the mouth, constipation, visual disturbances, and rarely glaucoma, hyperthermia, and convulsions may outweigh their benefits. Propantheline is the most frequently used preparation at 15 mg three times daily, increasing as tolerated to 150 mg daily. Calcium channel blockers such as diltiazem have helped some cases. Anxiolytic agents might be beneficial where there is psychological overlay. Clonazepam and amitriptyline have both been reported to help unusual localized hyperhidrosis. Surgical sympathectomy will result in anhidrosis. This is gen- erally performed endoscopically and is very successful in treating palmar, axillary, and craniofacial hyperhidrosis. Postoperative com- pensatory hyperhidrosis frequently ensues, particularly in warmer climates and, although usually mild, it can prove disabling. Axillary hyperhidrosis can be greatly helped by surgical excision of axillary glands. Hypohidrosis/​anhidrosis These rare problems may occur under the following conditions: • Abnormalities of the sweat glands: • Prematurity—​in neonates/​premature babies the sweat glands function poorly. • Ectodermal dysplasia—​this is a rare, inherited, X-​linked reces- sive disorder in which sweat glands are either absent or decreased. Boys have characteristic facies with abnormal teeth and hair and experience heat intolerance. See Chapter 23.3. • Heat stroke—​this is due to sweat gland exhaustion and repre- sents a medical emergency. It is seen most often in older people exposed to a hot climate. It may occur in the young during or after prolonged exercise. Patients present with headache, cramps, fa- tigue, confusion, and hyperthermia. This progresses to vomiting, hypotension, oliguria, metabolic acidosis, and hyperkalaemia. Morbidity is high if they are not cooled down immediately and given fluid and electrolyte replacement. • Abnormalities of the nervous system—​any abnormality in the sympathetic tract from the hypothalamus to peripheral nerves can result in anhidrosis. The symptoms of anhidrosis include heat in- tolerance, nausea, dizziness, tachycardia, and hyperthermia in hot environments. • Skin disease—​anhidrosis has been reported in several skin dis- eases including ichthyosis, psoriasis, lupus erythematosus, and morphoea and may be associated with Sjögren’s syndrome. A localized loss of sweating ability might be due to tuberculoid leprosy, syringomyelia, or diabetes mellitus. Miliaria This results from occlusion of the eccrine ducts leading to sweat retention. Typically, it occurs in hot, humid climates, and in all ages, particularly when excessive clothing is worn and excessive sweating occurs. It might also be seen in association with high fever. Depending on the level of ductal occlusion, the clinical picture can vary. • Miliaria crystallina results from ductal plugs in the stratum cor- neum and presents with vesicles of 1–​2  mm. The lesions are usu- ally non​symptomatic, and as they rupture desquamation of the skin occurs. • Miliaria rubra (prickly heat) reflects intraepidermal ductal ob- struction and occurs in 1:3 people exposed to hot climates. Itchy red papules typically occur at points of friction and flexures. Relief is usually gained quickly by cooling the skin. • Miliaria profunda relates to dermal ductal occlusion and presents with pale firm papules 1–​3 mm diameter. It is rare outside the tropics. Disorders of sebaceous glands and the pilosebaceous unit Sebaceous glands are an integral part of the pilosebaceous unit and are found over the entire body surface with the exception of palms and soles. The glands are multilobed and contain lipid filled cells. The lobules empty sebum into the upper hair follicle via a short duct. The sebum lubricates and waterproofs the skin and has some bactericidal and fungistatic activity. Free sebaceous glands are found in the eyelid (meibomian glands), mucous mem- branes (Fordyce’s spots), areolar, perianal, and genital skin. The hair follicle, the hair, the sebaceous gland, arrectores pilorum muscle, and (in certain regions) the apocrine glands make up the pilosebaceous unit. Sebaceous glands are under the influence of androgenic hor- mones especially dehydrotestosterone (DHT). Human sebaceous glands contain 5α-​reductase, 3β-​, and 17β-​hydroxysteroid dehydro- genase, which convert androgens to DHT. A surge of androgens at puberty is associated with the onset of acne in adolescence. Acne Introduction Acne is a polymorphic inflammatory disease of the pilosebaceous follicles, predominantly affecting the skin of the face and trunk. It is one of the most common skin diseases encountered by commu- nity physicians and dermatologists. Acne can present at any age, from neonates to mature adults, but is most prevalent and most se- vere during adolescence with 30% of teenagers requiring medical treatment. Aetiology/​epidemiology Acne is considered a disease of puberty but it is now starting earlier and lasting longer; earlier onset of puberty has been proposed as a cause

section 23  Disorders of the skin 5704 but earlier recognition might also lead to earlier age of presentation. Comedonal acne can be detected before any overt signs of puberty are detected and established acne starts at a younger age in girls than boys Post-​adolescent acne, both persistent and late-​onset, is more common in women than men. Peak prevalence occurs between the ages of 15 and 20 in all ethnic groups. Acne severity increases with age in both sexes. Pathogenesis The pathogenesis of acne relates to an increase in androgen-​ mediated sebum production, follicular hyperkeratosis, prolifer- ation of Propionibacterium acnes, and inflammation. There appear to be three phases in the development of acne: an innate immune response mediated by IL-​1α, followed by microcomedo formation, and then visible inflammation associated with a specific delayed-​ type hypersensitivity response. Hyperkeratinization of the sebaceous duct is mediated by IL-​1α and tumour necrosis factor-​α (TNF​α) from keratinocytes and T lymphocytes. The result is hyperproliferation of keratinocytes, re- duced apoptosis, and consequent hypergranulosis. The sebaceous follicle becomes blocked with dense keratin and so evolves the microcomedo, considered to be the precursor to both the non-​ inflammatory (blackheads/​whiteheads; Fig. 23.11.1) and inflam- matory lesions seen in acne. P. acnes colonize the skin surface and pilosebaceous ducts and bind to the Toll-​like receptor 2 (TLR-​2) on monocytes and neutrophils, leading to the induction of macrophage or keratinocyte secretion of IL-​12. This results in the differentiation of T cells, leading to the activation of Th 1 cells when they encounter their antigen in the dermis. Clinical features Acne lesions embrace inflammatory papules and pustules in most cases, but deeper inflamed lesions can present as acne nodules (Fig. 23.11.2). Non​inflammatory lesions present clinically as open and closed comedones (blackheads and whiteheads respectively). Scars which might represent an increase in collagen (hypertrophic and keloid scars) or a loss of collagen (atrophic scars) frequently occur in acne and are not necessarily related to the severity of the inflamed acne lesions. The patient might also develop persistent post-​inflammatory hyperpigmentation, although this is more common in patients with darker skin phototypes. Differential diagnosis Acne is generally easy to diagnose based on history and clinical pres- entation but several conditions should be considered in the differen- tial (Table 23.11.1) Comedones or comedonal-​like lesions can arise from drugs or cosmetics, as seen in pomade acne. Comedonal acne is also a characteristic feature of chloracne. Clinical investigations Clinical investigations are not usually required to make a diagnosis of acne but some cases might relate to underlying endocrinopathies. Table 23.11.2 summarizes conditions that may be implicated in acne and suggested investigations. Treatment Assessment of acne should include a thorough history, including details of family history, duration of acne, previous therapies, and response to treatments, along with careful physical examination. Most patients do not have an endocrine problem relating to their acne; however, polycystic ovary syndrome should be considered in women who have persistent/​late-​onset disease, particularly if this coexists with other signs of hyperandrogenism, such as hirsutism, irregular menses, or infertility. Cushingoid features, androgenic alopecia, acanthosis nigricans, and deepening of the voice might also reflect hyperandrogenism. These patients frequently have insulin resistance and are at increased risk of developing type 2 diabetes and possibly cardiovascular disease. Late-​onset adrenal hyperplasia can also trigger late-​onset acne in both sexes. Table 23.11.2 summarizes the investigations used to confirm or refute these diagnoses. Response to treatment can be slow and patients must be encour- aged to adhere to the chosen treatment regimen. Acne and scar- ring can result in significant psychological and social disability in Fig. 23.11.1  Inflammatory papular acne interspersed with closed, non-​ inflammatory lesions of the forehead. Fig. 23.11.2  Inflammatory nodular acne of the back with associated scarring.

23.11  Sebaceous and sweat gland disorders 5705 predisposed individuals (e.g. anxiety, depression, social isolation, and interpersonal difficulties). Topical therapies form the mainstay of treatment for mild to mod- erate acne. The choice of preparation will depend on the type of acne present (Table 23.11.3). Topical retinoids treat non​inflammatory and inflammatory acne. They reverse hypercornification and induce proliferation of the follicular epithelium, thus helping to ‘unplug’ the follicle. The less anaerobic conditions that result lead to a reduction in P. acnes. Given the central role of the microcomedo in the early development of both non​inflammatory and inflammatory lesions, most patients require a topical retinoid as part of their treatment regime. Retinoids are also now being considered for maintenance therapy. Skin irritation is a common side effect but is less problem- atic with the newer retinoids (topical isotretinoin and adapalene). Irritation is minimized by using lower concentrations for shorter durations. Topical retinoids are contraindicated in pregnancy. Benzoyl peroxide (BPO) is a powerful antimicrobial agent. It de- composes to release free oxygen radicals in the sebaceous follicles, which have bactericidal and anti-​inflammatory effects. BPO is ac- tive against fully sensitive and resistant strains of P. acnes. One high quality, randomized controlled trial demonstrated that BPO was as effective as oral oxytetracline and minocycline in mild/​mild to moderate acne. BPO is available alone in concentrations of 2.5–​ 10% and in combination with agents including hydroxyquinoline, erythromycin, and clindamycin. Lower concentrations are as ef- fective as 10% and less irritant. Infrequently an allergic contact dermatitis occurs. Benzoyl peroxide can bleach clothes and hair, so patients should be informed. Topical antibiotics both reduce P. acnes and are anti-​inflammatory through suppressing leucocyte chemotaxis and decreasing a propor- tion of proinflammatory free fatty acids and surface lipids. Topical erythromycin and clindamycin have been shown to be as effective as benzoyl peroxide in mild acne and are seemingly equally effective in treating moderate facial acne. As topical antibiotics drive bacterial resistance, they should be avoided as monotherapy over prolonged periods. Evidence supports a direct correlation between P. acnes resistance and failure to respond to oral antibiotic treatment. Resistance to erythromycin can be reduced by using a combination of erythro- mycin and zinc or erythromycin and benzoyl peroxide. Azelaic acid has some effect on inflamed acne lesions as it can re- duce the number of P. acnes. It can be irritant and, rarely, photosensi- tivity can occur. Nicotinamide gel represents an alternative topical anti-​inflammatory therapy; it has been shown to be as effective as 1% clindamycin gel and has the advantage of not promoting bac- terial resistance. Topical treatments can work synergistically when used in com- bination. Topical antibiotics and benzoyl peroxide are more ef- fective than benzoyl peroxide as a single therapy. When combined with zinc, topical erythromycin has increased therapeutic efficacy. When retinoids are used in combination with antimicrobial agents, the combination produces faster results and significantly greater re- ductions in acne lesions. Compliance might be enhanced by using combinations products. Current European Dermatology Forum evidence-​based guidelines advocate the use of novel fixed dose com- bination topical therapies for mild to moderate disease. Systemic therapy is used for moderate to severe acne, or mild to moderate acne associated with scarring or significant psychosocial disability and/​or failure to respond to topical treatment when it may be given in combination with topical therapy. Systemic anti- biotic therapy (Table 23.11.4) reduces the numbers of P. acnes and Table 23.11.1  Outlines conditions which could be considered in the differential of acne vulgaris Milia Plane warts Syringomas Adenoma sebaceum (angiofibromas) Ectopic sebaceous glands (Fordyce spots) Pilosebaceous naevoid disorders Favre-​Racouchot syndrome Birt-​Hogg-​Dube syndrome Sebaceous gland hyperplasia, adenoma, and carcinoma Sebaceous cysts and steatocystoma multiplex Lupus miliaris disemminatus facei Chloracne Aneiform eruptions related to drugs and cosmetics Acne keloidalis nuchae Keratosis pilaris Rosacea Pyoderma faciale Perioral dermatitis Folliculitis Gram negative Demodex Candida/​Malassezia folliculitis Folliculitis of the scalp Hidradenitis suppuritiva Miscellaneous causes of a papular facial rash Mimics of acne scarring Table 23.11.2  Investigating the underlying endocrine abnormalities implicated in acne Cause Investigations Polycystic ovary syndrome Day 1–​5 of menstrual cycle: Total and free testosterone LH/​FSH SHBG Ultrasonography of ovaries (not mandatory but may help to support the clinical impression) Congenital adrenal hyperplasia 17-​Hydroxyprogesterone DHEAS Cortisol levels Cushing’s syndrome Dexamethasone suppression test Gonadal or adrenal tumours Total and free testosterone DHEAS DHEAS, dehydroepiandrosterone sulphate; LH/​FSH, luteinizing/​follicle-​stimulating hormone ratio; SHBG, sex-​hormone binding globulin.

section 23  Disorders of the skin 5706 S. epidermidis and proinflammatory mediators in the microcomedo. It also modulates the host response to these stimuli. Patients with marked seborrhoea and truncal acne respond less well to anti- biotics. If oral antibiotics are to be incorporated into a regimen con- taining oral contraceptives, patients should still be warned about the possible decreased efficacy of the oral contraceptive, although, with the exception of rifampicin, there is currently no evidence to support the fact that commonly prescribed antibiotics either reduce blood levels and/​or the effectiveness of oral contraceptives. Based on efficacy, safety, and bacterial resistance, tetracyclines should be used in preference to other classes of antibiotics. Oxytetracycline needs to be taken 30 min pre-​food and not with milk to ensure adequate absorption. Second-​generation tetracyclines such as lymecycline (300–​600 mg/​day) and doxycycline (100–​200 mg/​day) may ensure better compliance and both have a better side effect profile than minocycline. Tetracyclines are contraindicated in children below 12 years of age and in pregnancy as they can affect dentition and re- sult in inhibition of skeletal growth in the fetus. The increasing incidence of P. acnes resistance to erythromycin and the link between erythromycin resistant P. acnes and reduced therapeutic response has resulted in the recommendation that erythromycin should be restricted. Erythromycin 1 g daily is the antibiotic of choice in pregnancy. Trimethoprim 200–​300 mg daily is a third-​line option for patients who have failed to respond to al- ternative antibiotics. Combining topical and systemic treatment aids more rapid effi- cacy and potentially reduces the length of exposure to antibiotics, so reducing the likelihood of emerging antibiotic resistance. Antibiotic resistant P. acnes were first detected in the United States of America in the late 1970s. The worldwide incidence of antibiotic resistant P. acnes has increased significantly over the last decade. Carriage of resistant P. acnes can result in reduced therapeutic response to anti- biotics. This is true for both erythromycin and tetracycline. To reduce emerging resistance, oral antibiotics should only be used for 6–​12 weeks in the first instance and only for as long as there is further clinical improvement. If the patient relapses after discontinuing the antibiotics, the same antibiotic should be restarted where possible. The addition of topical benzoyl peroxide can be used to try and eliminate resistant organisms. Hormonal therapies can help females with acne, whether or not their serum androgen levels are normal. They aim to reduce circu- lating androgen levels and/​or block androgen receptors. Possible options are oestrogens, androgen receptor blockers, or agents de- signed to decrease the endogenous production of androgens by the ovary or adrenal gland. The oestrogen component of oral contra- ceptives increases sex-​hormone binding globulin, thus decreasing free testosterone in healthy women. Oestrogens also decrease pro- duction of ovarian androgens by suppressing secretion of pituitary gonadotropins. The progestin component of oral contraceptives minimizes the risk of endometrial cancer. However, progestins like norethisterone have intrinsic androgenic activity so might aggravate acne. Drospirenone 3 mg combined with ethinylestradiol 30 µg has been shown to have a superior effect to a third generation-​combined pill. However, it is not licensed in the United Kingdom as a treatment for acne. Cyproterone acetate (CPA) has been shown to reduce sebum pro- duction and comedogenesis. CPA (2 mg) in combination with 35 mg ethinylestradiol has a licence for the treatment of severe acne in the United Kingdom and achieves significant improvement in 75–​90% of female patients. Treatment is frequently required for six months before a response is seen. The relative thromboembolic risk with co-​ cyprindiol is slightly higher than that linked to non-​antiandrogenic combined oral contraceptives but no higher than those containing third generation progestins. Spironolactone acts as an androgen receptor blocker and inhibits 5α-​reductase. In doses of 50–​100 mg twice daily, it reduces sebum Table 23.11.3  Topical therapies for acne: impact on aetiology Medication Inflammation Comedogenesis Reduction in
P. acnes Antimicrobials and antibiotics
BPO Erythromycin Clindamycin Dapsone ++ +++ +++ +++ + – +/– – +++ +++ +++ ++ Retinoids Tretinoin Isotretinoin Adapalene + + ++ +++ + ++ –​ –​ –​ Combination therapies Zinc and erythromycin BPO and erythromycin BPO and clindamycin BPO and adapalene Tretinoin and clindamycin +++ +++ +++ ++ ++ – + + ++ +++ +++ +++ +++ +++ ++ Others Azelaic acid ++ + ++ BPO, benzoyl peroxide. Table 23.11.4  Systemic antibiotics for acne—​dosage and adverse effects Drug Dosage Adverse effects Oxytetracycline 500 mg twice a day Rare onycholysis, photosensitivity, benign intracranial hypertension Erythromycin 500 mg twice a day Gastrointestinal upset, nausea, diarrhoea all fairly common Minocycline 100–​200 mg daily Headaches (dose dependent), pigmentary changes, autoimmune hepatitis/​lupus erythematosus-​like syndromea Doxycycline 100–​200 mg daily Photosensitivity (dose dependent) Lymecycline 300–​600 mg daily Fewer than minocycline Trimethoprim 200–​300 mg twice a day Rare hepatic/​renal toxicity agranulocytosis ANA, antinuclear antibody; LFT, liver function test; p-​ANCA, perinuclear antineutrophilic cytoplasmic antibody.a Advise, monitor LFTs, ANA, and p-​ANCA in ‘at risk’ patients or when treatment is prolonged (>6 months). Cyclines are contraindicated in pregnancy and in children below 12 years.

23.11  Sebaceous and sweat gland disorders 5707 production and improves acne. Side effects are dose-​related and in- clude potential hyperkalaemia, irregular menstrual periods, breast tenderness, headache, and fatigue. Although tumours have been re- ported in rodent models treated with spironolactone, this drug has not been directly linked with cancer in humans. There is a risk of feminization of a male fetus and thus pregnancy should be avoided. Isotretinoin is a synthetic form of vitamin A and is effective in severe inflammatory acne that has failed to respond to other treat- ments. Oral isotretinoin is the only agent that impacts on the four main aetiological factors driving acne. It is a lipid soluble drug, hence its absorption is enhanced when administered with food. Oral isotretinoin should not be combined with tetracyclines as both can lead to benign intracranial hypertension. Mucocutaneous prob- lems are the most common side effect of oral isotretinoin, including cheilitis, irritant dermatitis, and blepharoconjunctivitis. These side effects are dose dependent. Oral isotretinoin is a potent teratogen and women of childbearing age should not start therapy until a negative pregnancy test has been obtained, ideally two to three days prior to menstruation. Adequate contraception is essential for fertile, sexu- ally active females before, during, and up to five weeks post-​therapy. A  recent European directive recommends mandatory pregnancy testing prior to the start of treatment and five weeks post-​therapy and advocates monthly pregnancy testing throughout the treatment period. Baseline blood tests, including fasting lipids and liver func- tion, should be done before starting therapy and are recommended at one month, then three-​monthly throughout the treatment course. Adverse psychiatric events such as mood swings, depression, and suicidal ideation have been reported as possible idiosyncratic re- actions to isotretinoin and must be highlighted. Epidemiological studies have not demonstrated a definite causal relationship between psychological effects and isotretinoin, but the association of depres- sion with isotretinoin has not been satisfactorily investigated. Several small studies have trialled lasers, photodynamic therapy, and phototherapy with either clear blue or mixed blue-​red light/​ra- diation in inflammatory acne. Whereas some success has been re- ported, optimum regimes are still being assessed. Prognosis/​outcome Acne is a chronic inflammatory skin disease which can result in physical and emotional scarring. Treatment regimens should be adopted to address as many aetiological factors as possible to opti- mize treatment results. Special circumstances: Unusual acne variants Acne excoriée This occurs frequently in adolescent girls and young women. Patients pick their skin leading to inflammatory lesions. Treatment can be difficult, psychological problems should be investigated, and underlying acne lesions managed with standard acne treatment. Successful treatment with habit reversal has been reported. Dysmorphophobia This occurs in a small number of acne patients. The patient’s percep- tion of their acne is disproportionate to their physical signs. There is often associated depression and/​or obsessional neurosis. The acne should be treated in the standard fashion and psychiatric collabor- ation is important. Drug-​induced acne This is well recognized. Corticosteroids are the most common of- fenders. Steroid acne has a monomorphic appearance and consists of non​inflammatory and inflammatory lesions. Other drugs im- plicated include anticonvulsants, lithium, and the novel epidermal growth factor receptor (EGFR) inhibitors currently used for solid tumours. Cosmetic acne Various cosmetic ingredients induce comedones, in particular lanolins, petrolatum, and certain vegetable oils. Hair pomades can produce a monomorphic, low-​grade acne. Infantile acne This is rare but can result in scarring if left untreated. Patients de- velop inflammatory lesions, particularly on the cheeks, usually after three months of age. These can evolve into deep-​seated nodules and sinus tracts. Treatment is similar to adult acne, but tetracyclines should be avoided due to the risk of discoloured teeth. Topical ther- apies and/​or oral erythromycin (125 mg twice daily) or trimetho- prim (100 mg twice daily) can be used safely. Gram-​negative folliculitis This occurs as a complication of any long-​term topical or oral antibiotic therapy. It is characterized by sudden onset of multiple pustules, often localized periorally and perinasally. This results from overgrowth of Gram-​negative organisms including Escherichia coli, proteus, pseudo- monas, and klebsiella. The offending antibiotic should be stopped and changed to oral trimethoprim or ampicillin. Oral isotretinoin gener- ally produces a more rapid and permanent response. Acne conglobata This is an uncommon severe form of acne characterized by acne nodules, interconnecting sinuses, grouped comedones, and ex- tensive scarring. Treatment is difficult and the problem usually runs a chronic course. Isotretinoin is usually the preferred therapy. Concomitant short courses of antibiotics and oral steroids might be required to control acute exacerbations. Acne fulminans This is rare, most frequently affecting adolescent boys. Acute erosive inflammatory lesions occur predominantly on the trunk. Associated systemic symptoms including fever, weight loss, arthralgia, and my- algia are evident. The aetiology is uncertain, but the presence of microscopic haematuria, erythema nodosum, increased response to P. acnes antigen on skin tests, and depressed response to intradermal purified protein derivatives are in favour of an abnormal immuno- logical response. Oral prednisolone is the treatment of choice fol- lowed by the cautious introduction of systemic isotretinoin. Several cases of acne fulminans have been triggered by anabolic steroids and testosterone. Pyoderma faciale This disorder is more common in adult women and often occurs in the context of emotional stress. These patients are not systemically unwell but the appearance of the disorder often adds considerably

section 23  Disorders of the skin 5708 to the stress. Treatment with prednisolone reducing over four to six weeks and the daily application of moderate to potent topical steroid for one week will help. Isotretinoin should be introduced after one week, and, if tolerated, can be gradually increased. SAPHO This is the acronym for synovitis, acne, pustulosis, hyperostosis, and osteitis in which a group of overlapping joint diseases occur in conjunction with palmoplantar pustulosis and, less frequently, with psoriasis, acne, and inflammatory bowel disease. Complications and comorbidities The main complications that arise from acne relate to subsequent physical and emotional scarring. Post-​inflammatory erythema or pigment changes may also result in visible abnormalities that are cosmetically unacceptable to patients. Acne scarring is a common consequence of acne and can occur, albeit mildly, in up to 90% of patients. A delay in appropriate acne management is more likely to result in significant scarring. Scarring commonly follows deep-​seated inflammatory lesions, but can also occur as a result of more superficial inflamed lesions in scar-​prone patients. Scars might show increased collagen (hypertrophic scars and keloids) or be associated with loss of collagen (i.e. atrophic scars). Psychosocial effects of acne Studies have shown that many acne patients experience shame (70%), embarrassment and anxiety (63%), lack of confidence (67%), impaired social contact (57%) and significant problems with un- employment. When compared to other serious organic diseases, acne patients describe levels of social, psychological, and emotional problems as great as those reported with chronic disabling diseases such as asthma, epilepsy, back pain, arthritis, and diabetes. Clinical depression has been demonstrated in acne patients and the preva- lence of active suicidal ideation is higher in acne patients than re- ported in the general population. The psychological impairment does not necessarily correlate with the clinical severity of disease. It has been suggested that the depressed acne patient should be as- sessed for suicide risk. Conclusions and the future Acne is a common inflammatory skin disease often associated with significant psychosocial morbidity. Early effective intervention pre- vents emotional and physical scarring. Understanding of patho- physiology allows topical and systemic therapies to be combined logically to target the individual aetiological factors. Research into the pathogenesis has defined acne as a T-​cell mediated dermatosis. The possibilities for using immunomodulatory therapies and spe- cific anti-​inflammatory treatments are open to further develop- mental research studies and controlled trials. In theory, a TLR-​2 antagonist, IL-​1α antagonist, and cytokine therapy could be possible candidates for future acne treatment. Other possibilities include in- sulin sensitizing agents, 5α-​reductase type 1 inhibitors, and possibly new anti-​inflammatory agents such as lipoxygenase inhibitors. FURTHER READING Burns T, et al. (eds) (2016). Rook’s textbook of dermatology, 9th edition. Blackwell Science, Oxford. Lee RA, et al. (2015). Treatment of hidradenitis suppuritiva with bio- logic medications. JAAD, 73 (5 Suppl 1), S82–8. Nast B, et  al. (2016). European evidence-​based (S3) guidelines for the treatment of acne. J Eur Acad Dermatol Venereol, 30(8), 1261–8. National Institute for Health and Care Excellence (NICE) (2014). Acne Vulgaris: Clinical Knowledge Summary. http://​cks.nice.org.uk/​ acne-​vulgaris Thiboutot D, et al. (2018). Practical Management of acne for clinicians. An international consensus from the Global Alliance to Improve Outcomes in Acne. JAAD, 78(2), S1–S23. e1. Zouboulis C, Katsambas A, Kligman A (2014). Pathogenesis and treat- ment of acne and rosacea. Springer, Berlin.

23.12 Blood and lymphatic vessel disorders 5709 Pe

23.12 Blood and lymphatic vessel disorders 5709 Peter S. Mortimer and Roderick J. Hay

ESSENTIALS Bleeding into the skin may occur for local reasons or as part of a sys- temic disorder. The distribution of lesions is important: widespread lesions suggest a systemic problem, whereas regional lesions suggest that local factors predominate. Widespread flat purpura without erythema should prompt a search for underlying haematological abnormalities such as platelet disorders. Larger (>1 cm) areas of purpura or bruising usually result from coagulation dysfunction. Palpable purpuric lesions, or those with a blanching component, suggest an associated inflammation as can be seen with vasculitis. In patients with acute peripheral ischaemia, it is important to ex- clude embolism. A pressure ulcer (decubitus ulcer, bedsore, pressure sore) is due to localized injury to the skin and/​or underlying tissue as a result of pressure alone, or in combination with shear and/​or fric- tion. The presence of moisture, particularly relevant in an incontinent patient, leads to a macerated (and therefore more vulnerable) skin. Faecal soiling results in chemical damage to the skin. Acute deep venous thrombosis (see Chapter  16.16.1) may be silent but usually results in skin erythema and limb oedema. Consequences of post-​thrombotic vein damage include further deep venous thrombosis, superficial thrombophlebitis, oedema, skin changes, and eventually ulceration. Approximately 70% of leg ulcers are venous in origin; the other 30% resulting from coexistent arterial disease, diabetes, and other skin disease. Most ulcers occur in the gaiter region at or above the level of the malleoli, where the per- sistently elevated ambulatory venous pressure has an adverse effect on the upstream capillary microcirculation. Nearly half of all venous ulcers are associated with deep vein valvular incompetence, usually secondary to previous deep venous thrombosis, while the remainder result from incompetence of the superficial or communicating veins (primary varicose veins). Introduction Vasculogenesis represents the formation of new blood and lymph- atic vessels from endothelial precursors which share an origin with haemopoietic precursors. This process is not confined to the embryo. Adult bone marrow-​derived haemopoietic cells extravasate around nascent vessels and stimulate growth of resident vessels by releasing angiogenic factors. These cells can also function as haemangioblasts, producing both haemopoietic and endothelial progenitors that give rise to new blood vessels (probably not lymphatic vessels). Angiogenesis is the growth of blood vessels through a process of sprouting and remodelling from existing vessels. The lymphatic system develops differently as most lymphatics differentiate from veins. Both blood and lymphatic vessels are crucial for organ growth in the embryo, as witnessed by mutations in some of the key genes in programming for cardiovascular and lymphatic development. For example, deletion of FLT4 (VEGFR3, vascular endothelial growth factor receptor 3, the gene most responsible for lymphangiogenesis) leads to defects in blood vessel remodelling and embryonic death at mid-​gestation, indicating an early blood vascular function. The formation of blood and lymphatic vessels is a complex process con- trolled by numerous genes and molecular players. For example, members of the Notch family drive the arterial gene programme; the orphan receptor COUP-​TF11 regulates venous specification; and PROX1 commits venous endothelial cells to lymphatic lineage. The vascular endothelial growth factor (VEGF) family of proteins seem most important for vascular and lymphatic endothelial cell sprouting, whereas platelet-​derived growth factor (PDGF) and the angiopoietins are responsible for subsequent remodelling, matur- ation, and stability of the newly formed vessels. Close links exist between vessels and nerves; for example, axon-​guidance signals such as ephrins and semaphorins allow vessels to navigate to their targets. Skin has been one of the most investigated tissues for under- standing mechanisms of (lymph) angiogenesis, largely because it is so accessible. Angiogenesis is reactivated physiologically during wound healing and repair. In some circumstances—​for example, malignancy—​the (lymph) angiogenesis activation becomes excessive and harmful so promoting the tumour growth and facilitating metastatic spread. Conversely, in arterial ischaemia the angiogenic switch is insuf- ficient, preventing revascularization and healing of skin ulcers. In recent years, angiogenesis promoters and inhibitors have served as therapeutic targets. For example, the anti-​VEGF antibody bevacizumab conveys survival benefit in the treatment of meta- static colorectal, breast, and lung cancer when combined with 23.12 Blood and lymphatic vessel disorders Peter S. Mortimer and Roderick J. Hay

section 23  Disorders of the skin 5710 conventional chemotherapy but not as a monotherapy. One side ef- fect is impaired wound healing. Cutaneous manifestation of blood vessel disorders As the main organ interacting with the environment, the skin vas- culature has to be adaptive. The blood supply has a generous re- serve to meet the requirements of wounding and repair as well as thermoregulation. Skin disorders invariably involve the vasculature, if only because inflammation drives an increase in blood (and lymph) flow. A rash is red (erythema) because of an increase in blood flow. Surface pres- sure, by emptying the compressible venules and veins and reducing capillary inflow, will blanch the skin. Purpura represents extrava- sation of red cells from microvessels into the dermis and cannot be blanched. Simple purpura is not raised, but if it is associated with inflammatory changes of the blood vessels (vasculitis), the mass of cells and oedema makes the purpura palpable. More extensive release of red cells into the skin and subcutis (haemorrhage) will result in a bruise (ecchymosis). Differences between purpura and bruising are simply a matter of degree or depth of haemorrhage. The cause may be due to: thrombophilia; excessive intravascular pres- sure; weakness of the blood vessel wall or surrounding stroma (as seen with steroid therapy). Petechiae are pinpoint lesions of purpura (<2 mm diameter). Gravitational forces, by increasing venous and consequently capillary pressure, are likely to make purpura more evident in the lower limbs. Telangiectases (named from Greek words meaning ‘end’, ‘vessel’, and ‘extension or dilatation’) are chronically widened capillaries or small vessels. They appear on the skin and mucous membranes as small, dull red, linear, stellate, or punctate markings. Telangiectases (telangiectasias) represent expansion of pre-​existing vessels without any obvious new vessel growth (angiogenesis). Unfortunately, clinical appearance may vary greatly according to the site, depth, and type of blood vessel involved. For example, the macular (flat) telangiectases seen in scleroderma, generalized essential telangiectasia, and port-​ wine stain are produced by dilatation of the postcapillary venules of the uppermost vascular plexus in the dermis. The common raised cherry angioma (Campbell de Morgan spot) is produced by spher- ical and tubular dilatations of capillary loops in the dermal papillae. Telangiectases are discussed in more detail next. Angiokeratomas (as seen in Fabry’s disease and the more common, harmless scrotal angiokeratoma) have the ultrastructure of collecting venules that contain valves and are dark red to black in colour. A spider angioma (spider naevus) represents high flow filling of surface capillaries by a single feeding dilated arteriole which, if blanched, will obliterate the whole spider naevus. The cutaneous le- sions of hereditary haemorrhagic telangiectasia represent small ar- teriovenous anastomoses. Mottling (marbling) of the skin is a physiological response to cold. Vasoconstriction to the skin results in desaturation of the slow flowing blood, leading to bluish (cyanotic) discoloration overlying the polygonal plexus of superficial venules and veins; warming re- stores normal flow and colour. If a similar reduction in flow occurs for pathological reasons, for example, intravascular thrombosis in antiphospholipid syndrome or vasculitis in polyarteritis nodosa, the mottling is fixed and broken up in pattern (livedo reticularis). Necrosis of the skin occurs following vascular occlusion due to intravascular coagulation, vasculitis, emboli, hyperviscosity syn- dromes, or vessel wall thickening. Purpura Simple macular purpura/​petechiae Bleeding into the skin may occur for local reasons or as part of a systemic disorder (Box 23.12.1). Widespread flat (macular) pur- pura without erythema (no associated inflammation) should prompt a search for underlying haematological abnormalities such as platelet disorders. Larger (>1 cm) areas of purpura with or without ecchymoses usually result from coagulation dysfunction. The distribution of lesions is important: widespread lesions sug- gest a systemic problem, whereas regional lesions suggest that local factors predominate. For example, purpura confined to the lower limbs would suggest venous hypertension (acute following a deep venous thrombosis (DVT) or chronic from long-​standing varicose veins); purpura in chronically sun damaged skin, such as the backs of hands and forearms in older people result from weakness in the supporting collagen of the dermis, particularly in those on steroids; eyelid purpura occurs acutely with raised intravascular pressure from coughing/​vomiting or chronically with systemic amyloidosis (panda sign, Fig. 23.12.1). Box 23.12.1  Causes of simple purpura/​ecchymoses • Platelet disorders — Thrombocytopenia (in isolation or with myeloproliferative disorders) — Abnormal platelet function/​antiplatelet drugs (aspirin, chemotherapy) — Thrombocytosis • Coagulation disorders — Haemophilia and other clotting factor deficiencies — Drugs (anticoagulants) — Thrombophilia (protein C and S deficiency) — Disseminated intravascular coagulation and purpura fulminans — Liver disease (decreased clotting factor synthesis) • Microvascular occlusion — Dysproteinaemias (e.g. hypergammaglobulinaemic purpura) — Cryoproteinaemias — Emboli (cholesterol, oxalate, fat, myoma, septic) — Sickle cell disease • Mechanical — Chronic sun damage (‘senile’ purpura) — Corticosteroids — Scurvy — Amyloid — Inherited collagen disorders (Ehlers–​Danlos, pseudoxanthoma elasticum) — Easy bruising syndrome/​pinch purpura/​’bite’/​exercise purpura • Raised intravascular pressure — Coughing, vomiting, Valsalva manoeuvre — Tourniquet — ‘Stasis’ from chronic venous disease (varicose veins, post-​ thrombotic syndrome) and dependency syndrome

23.12  Blood and lymphatic vessel disorders 5711 Palpable purpura Palpable purpuric lesions, or those with a blanching component, suggest an associated inflammation. Care should be taken to evaluate new purpura as old lesions may show secondary inflammatory changes. Palpable purpura suggests vasculitis or some degree of vessel damage. In dysproteinaemic purpura, hypergammaglobulinaemic purpura, and cryoproteinaemia, a range of purpura may develop from macular purpura to larger necrotic lesions depending upon the size and type of blood vessel involved. Distribution may be widespread or limited to colder or more de- pendent peripheries (lower legs). Larger vessel involvement may produce cutaneous necrosis or livedo reticularis. Vasculitis Vasculitis refers to inflammation and necrosis of any blood vessel (Box 23.12.2; also see Chapter 21.10.2). Minor inflammation of a capillary (capillaritis) may simply increase permeability, resulting in only purpura, whereas involvement of arteries and veins will af- fect tissue perfusion. Vasculitis may be local or systemic, primary, or secondary. Many systemic vasculitides have a cutaneous compo- nent. That cutaneous component will usually be a palpable purpura with multiple lesions distributed symmetrically and usually worse in the lower limbs. More severe inflammation from neutrophil in- filtration will often manifest with pustule formation on top of the purpura. Necrosis of the lesion will produce a small black eschar after a few days. More extensive necrosis and punched out ulceration will ensue. ‘Vasculitic’ is a term inappropriately used to describe focal nec- rotic skin lesions that result from small infarcts due to micro- vascular occlusion. To understand the cause and guide treatment, a skin biopsy is essential in order to distinguish an inflamma- tory vasculitis responsive to systemic steroids from a vasculitis with marked fibrinoid wall changes where steroids are unlikely to be helpful. Other investigations that should be performed include measurement of complement (C4), antiphospholipid antibodies (which cause microvascular thrombosis and a sec- ondary vasculitis), antiendothelial cell antibodies (AECA), and antineutrophilic cytoplasmic antibodies (ANCA), as well as serological tests for connective tissue disorders and screening for distant infection. Microvascular occlusion/​cutaneous necrosis Microvascular occlusion may occur for several reasons (Box 23.12.3). While purpura can be the only clinical manifestation, the usual consequences are focal areas of necrosis secondary to failed perfusion, such as the digital finger tip infarcts seen in scleroderma. Disturbances in blood rheology may arise from aggregation of blood contents. Alternatively, the fault may lie with the endothelial wall or lack of blood vessel conformation. If vascular occlusion is extensive or involves larger ves- sels, then well-​demarcated areas of skin are infarcted and a black eschar forms. Terminal vessel involvement will cause peripheral gangrene. Purpura fulminans results from Fig. 23.12.1  Amyloid (panda sign). Box 23.12.2  Working classification of systemic vasculitis Small vessel vasculitis • Henoch–​Schönlein purpura • Essential mixed cryoglobulinaemia • Waldenström’s hypergammaglobulinaemia • Vasculitis associated with systemic lupus erythematosus and other connective tissue disorders and antiphospholipid syndrome • Urticarial vasculitis • Septic vasculitis • Eosinophilic vasculitis • Drug-​induced • Reactive leprosy • Bowel-​associated dermatosis–​arthritis syndrome (BADAS) • Fungal infection of vessels (immunocompromized) • Behçet’s disease Larger vessel vasculitis • Polyarteritis nodosa — Systemic (including microscopic polyarteritis) — Cutaneous limited • Granulomatous vasculitis — Granulomatosis with polyangiitis (formerly Wegener’s) — Churg–​Strauss allergic granulomatosis • Giant cell arteritis — Temporal — Takayasu’s Box 23.12.3  Disorders of microvascular occlusion Intravascular • Platelet plugging (myeloproliferative disorders) • Cryoprecipitates (cryoglobulinaemia, cryofibrinogenaemia, cold agglutins) • Emboli (cholesterol, crystals, septic) • Sickle cell disease Vessel wall • Raynaud’s disease • Scleroderma, rheumatoid arthritis, dermatomyositis • Fibrinoid vasculopathy/​atrophie blanche

section 23  Disorders of the skin 5712 extensive vascular occlusion, the most important cause of which is meningococcaemia. Livedo reticularis Livedo (Box 23.12.4; also Fig. 23.12.2) describes a reticulate network of slow blood flow in the deep skin vascular plexus. When fixed and broken up in its pattern it is always pathological, usually representing thrombosis or vasculitis. In areas of livedo where perfusion is most compromised, purpura and necrosis will occur. Erythema ab igne is a hyperpigmented fixed mottling resulting from prolonged application of heat to the skin. It occurs from sit- ting too close to a fire or from the use of heat pads applied for pain relief. Arterial and peripheral ischaemic disorders Arterial disease will generally compromise skin perfusion only in its advanced stages. Nevertheless, it may present with a dusky red to blue discolouration of skin in the peripheries (hand or foot) or frank ulceration. If the ischaemia is marked, limb elevation above heart level causes skin pallor, while dependency results in delayed but exaggerated hyperaemia. In such circumstances, a history of cardiovascular risk factors, intermittent claudication, and rest pain should be sought. A gross general rule is that arterial disease will cause foot ulceration particularly at sites of pressure including be- tween the toes, whereas venous disease will cause leg ulceration (see next). If peripheral pulses cannot be palpated, simple assessment of peripheral arterial pressure can be undertaken by measuring the ankle brachial pressure index or toe pressures. Arterial pressure in the foot or ankle vessels should be the same or slightly greater than in the arm. If lower limb pressure is less than 80% of the arm, then arterial disease should be considered. Measurements can be unreli- able in diabetes where calcification of the arterial wall prevents oc- clusion by the sphygmomanometer cuff and a false high reading may be obtained. Toe pressures are more reliable in such circumstances. Significant arterial disease demanding investigation is un- common when the foot pulses are easily palpable. Covert arterial disease may manifest with a reduction in oxygen delivery from an- aemia, cardiac dysrhythmias, or any circumstances where cardiac output is reduced. In patients with acute peripheral ischaemia it is important to ex- clude embolism. Thromboangiitis obliterans (Buerger’s disease) may be difficult to distinguish from atherosclerosis. Rarer causes of ischaemia include external arterial compression (popliteal en- trapment or a cervical rib), dissecting or thrombosed aneurysms, ergot poisoning, intra-​arterial injections, coagulation disorders, and vasculitis. Management of atherosclerosis includes correction of underlying cardiovascular risk factors where possible. The vast majority of pa- tients with arterial disease die from medical comorbidities, such as myocardial infarction. Small vessel calcification (calciphylaxis) Calcification of arteries is common, but when it affects small ar- terioles, as occasionally happens with hyperparathyroidism, par- ticularly in chronic renal failure, it results in complete vascular occlusion of dermal arterioles (Fig. 23.12.3). Surrounding an area of skin infarction there is extensive livedo reticularis, as well as sub- cutaneous induration from fat necrosis. The pathogenesis is unex- plained. Uraemia and hyperphosphataemia are often more obvious Box 23.12.4  Livedo reticularis • Vasculitis (large vessel) — Polyarteritis nodosa — Mixed cryoglobulinaemia • Antiphospholipid syndrome • Sneddon’s syndrome (livedo with cerebrovascular accident) • Calciphylaxis • Disseminated intravascular coagulation and thrombophilia Fig. 23.12.2  Livedo reticularis. Fig. 23.12.3  Calciphylaxis.

23.12  Blood and lymphatic vessel disorders 5713 than hypercalcaemia. Women are more often affected. An X-​ray will reveal extensive vessel calcification and a skin biopsy will dem- onstrate calcium replacing dermal vessels. The prognosis is poor and treatment unsatisfactory. The management of any renal failure and normalization of the calcium phosphate product are essen- tial. Parathyroidectomy is only indicated if hyperparathyroidism is proven. Thromboangiitis obliterans (Buerger’s disease) This appears a distinct condition, usually in young men who are heavy smokers. The aetiology is unknown, but antiendothelial cell antibodies can be present in high titre in active disease. Pathological examination shows that the arterial walls are invaded by inflam- matory cells with changes being segmental or focal and resulting in thrombosis. Nerves and veins may be involved and fibrosis oc- curs in the later stages. Pain is usually the presenting feature because of muscle or nerve ischaemia or thrombophlebitis. Claudication of the foot is especially characteristic. Ulceration or gangrene de- velops early, especially around the sides of the nails or tips of digits. Recurrent superficial or deep venous thrombosis is also common. The proximal pulses (e.g. brachial or popliteal), are usually present while the distal pulses are absent. The erythrocyte sedimentation rate (ESR) and C-​reactive protein (CRP) levels are usually raised, antiendothelial cell antibodies are often present, and arteriography is usually diagnostic (normal proximal vessels but multiple stenoses and occlusions in distal vessels with collateralization). The differ- ential diagnosis is early-​onset atherosclerosis, embolism, diabetic vasculopathy, and connective tissue disorders. Strict abstinence from smoking is essential. Infusion of a prosta- cyclin analogue has been shown to be effective, but medical treat- ment is otherwise unhelpful and referral to a vascular surgeon is recommended. Sickle cell disease Perimalleolar, painful leg ulcers develop in association with sickle cell disease. While the ulceration may be attributed to sickling of erythrocytes causing microvascular occlusion and skin infarction, similar ulcers have been reported in other forms of chronic haemo- lytic anaemia. Low, steady state levels of haemoglobin, intensity of haemolysis, and sickle cell anaemia with thalassaemia genotypes ap- pear associated with ulceration. Leucocyte adhesion may initiate occlusion episodes in a manner similar to venous ulceration (in the same site); indeed, gravitational factors or venous disease may contribute to non​healing of sickle cell ulcers. Secondary infection may also discourage healing, particu- larly in tropical climates. Treatment is unsatisfactory. Spontaneous healing may occur after some weeks irrespective of intervention; otherwise, bed rest and local compression may be necessary. Raynaud’s phenomenon/​syndrome Raynaud’s phenomenon is defined as episodic digital ischaemia occurring in response to cold, emotional stimuli, or vibration. It is characterized by sequential colour changes:  white—​blue—​red. Pallor is essential for the diagnosis but may be short-​lived and be succeeded by prolonged cyanosis, making distinction from acro- cyanosis difficult. Raynaud’s phenomenon may be primary (idio- pathic), when it is referred to as Raynaud’s disease, or secondary to a range of diseases, most notably connective tissue disorders. Perniosis/​acrocyanosis (cold injury) Chilblains (perniosis) are localized, tender, red, and often itchy le- sions which may blister or ulcerate. They occur as an abnormal re- sponse to cold. Perniosis of fingers and toes can be associated with cryoglobulinaemia, myelodysplastic disorders, lupus erythematosus (‘chilblain’ lupus), and anorexia or malnutrition. In contrast to per- ipheral (acral) chilblains, perniosis can occur overlying extensive subcutaneous fat (e.g. thighs), because the skin is more vulnerable to cold as a result of insulation by the fat. Acrocyanosis is a persistent bluish mottled discoloration of the skin, usually over hands and feet. Unlike Raynaud’s phenomenon where digital artery vasoconstriction occurs, it arises due to dila- tation of small venules resulting in extremely slow venous flow fol- lowing physiological vasoconstriction of arteriolar inflow in response to cold. The backs of the hands and fingers look blue and puffy (from oedema). While connective tissue disorders, antiphospholipid syn- drome, neuropathies, and cryoglobulinaemia should be considered, the vast majority of cases are constitutional. Frostbite is the result of acute freezing of tissues including the blood vessels. Hands, feet, ears, nose, and cheeks are most often af- fected. After the initial pain, the affected part becomes pain-​free and the skin becomes shiny and white. Reperfusion injury occurs on warming with necrosis of tissue. Long-​term scarring and abnormal autonomic nerve responses may occur. Trench or (cold) immersion feet are similar, but the tissues do not freeze. Vascular occlusion results in tissue necrosis and neuropathic changes. The syndrome is not uncommon in the homeless popula- tion living in the United Kingdom. Erythromelalgia (erythermalgia) This is a condition of painful red extremities in which the sensation of burning is induced by warmth. Patients will complain of intolerable burning relieved only by dunking their feet in cold water or wrapping in towels kept in the freezer. There is consequently a danger of cold immersion injury. The term erythermalgia was introduced to sep- arate primary cases (erythermalgia) from those (erythromelalgia) secondary to underlying disorders such as thrombocythaemia and other myeloproliferative disorders. The fundamental cause is now known to be a fault in sodium channels discovered by identifying mutations in the gene SCN9A, which encodes the voltage-​gated so- dium channel NaV1.7. Mutations alter channel gating behaviour in a manner that increases nociceptive neuron excitability. Cooling re- duces the threshold of activation of the abnormal sodium channels. Although fundamentally a neuropathy, involvement of skin blood vessels results in persistent vasodilatation. Treatment with carba- mazepine and similar drugs acting on sodium channels can help. Complex regional pain syndrome (reflex sympathetic dystrophy, causalgia, Sudeck’s atrophy) This is a syndrome of chronic pain with altered or heightened sen- sation, hyperhidrosis, and swelling. Allodynia is characteristic. The increased blood flow combined with a reluctance to use the limb (movement triggers pain) results in deep redness of the skin and swelling. Increased blood flow is an important diagnostic feature of early complex regional pain syndrome and can often be dem- onstrated on a three-​phase bone scan. Treatments include graded physical therapy and neuropathic pain relief.

section 23  Disorders of the skin 5714 Arteriovenous fistulae Persistent arteriovenous shunts cause local venous hypertension and skin changes as a result. Arteriovenous fistulae consist of direct connections between large arteries and veins and are always pathological. Congenital forms result from a failure of embryo- logical differentiation. Acquired forms are almost always traumatic and, if large, can cause significant cardiovascular effects. Increased warmth of the skin together with signs of increased venous pres- sure result (e.g. varicose veins). A palpable thrill and murmur on auscultation may be detected. Duplex ultrasonography is the in- vestigation of choice. Embolization may be the best therapeutic option. Pressure ulcers A pressure ulcer (decubitus ulcer, bedsore, pressure sore) is due to localized injury to the skin and/​or underlying tissue as a result of pressure alone or in combination with shear and/​or friction. The presence of moisture, particularly relevant in an incontinent patient, leads to a macerated, and therefore more vulnerable, skin. Faecal soiling results in chemical damage to the skin. Sustained pressure occurs most commonly when an individual is debilitated or paralysed and therefore cannot move to relieve pres- sure. Neurological deficit predisposes to a lack of movement or a lack of sensory feedback to pain, as well as impaired autonomic con- trol. Observations on patients with amyotrophic lateral sclerosis, a condition in which pressure sores are rarer, suggest a role for ciliary neutrophic factor. Defective collagen synthesis may be promoted in anaesthetic skin as well as by certain drugs such as corticosteroids. Other factors contributing to the development of pressure ulcers in- clude arterial ischaemia, hypotension, dehydration, malnutrition, cachexia of cancer, prolonged pyrexia, hypermetabolic states, and hypoalbuminaemia. Patients undergoing extracorporeal circulation are particularly at risk. Different classifications exist, but that of the National Pressure Ulcer Advisory Panel is simple to use. Stage I is non​blanchable ery- thema over a bony prominence; stage II partial thickness loss of dermis; stage III is ulceration into subcutaneous fat; stage IV is ex- posure of muscle, bone, or joint. Deep sores will often result in more necrosis of fat or muscle than skin, so a cavity wound with under- mined edges occurs. Prevention should involve recognition of the at-​risk patient. Several risk scales exist with the Norton scale being the best known. All at-​risk patients should have a pressure-​relieving mat- tress in addition to frequent repositioning. Static support systems mould around the patient so distributing pressure over a greater area, while dynamic support systems vary the pressure distribu- tion by, for example, the use of air-​fluidized and low air loss beds. The lateral position must be avoided and nursing in the prone position is advised. Any medical conditions should be controlled and the nutritional status assessed; spasticity should be relieved where possible. When pressure is relieved, necrotic tissue will sep- arate naturally but eschar is best removed surgically. In principle, wounds heal best when moist and clear of infection and when exudate is absorbed away from wound surfaces. The choice of dressing depends upon the stage and state of the wound. Surgical debridement is necessary for removal of necrotic tissue and radical excision with reconstruction may be needed for extensive cavity wounds. Venous disorders Chronic venous disease Veins are responsible for venous return. Muscles in the calf and foot compress and empty veins thereby lowering venous pressure. Valves prevent the reflux of blood. Valve failure results in min- imal respite from high venous pressures during exercise. Venous pressure at the ankle is normally 70–​100 mm Hg dropping to 0–​ 30 mm Hg on exercise and remaining at approximately 55 mm Hg while sitting. Long periods spent sitting with legs dependent, reduced exercise levels, and obesity encourage venous hyperten- sion with sustained pressures of 50–​100 mg Hg. Venous reflux due to valve failure will result from inherent vein or valve weak- ness in primary varicose veins, or damage to veins usually from deep venous thrombosis. Persistently elevated venous pressure af- fects capillary pressure and endothelial function that results in a complex train of events which adversely affects skin viability in the gaiter region. The clinical consequences are varicose veins, oedema, haemosiderin skin pigmentation, varicose eczema, lipodermatosclerosis, and ulceration signs that are used for the CEAP Classification (class, aetiology, anatomy, pathophysiology) of chronic venous disease (CVD). Deep venous thrombosis (DVT), post-​thrombotic syndrome, and venous obstruction Acute deep venous thrombosis (DVT) may be silent but usually re- sults in skin erythema and limb oedema. Iliac vein thrombosis may be easily missed on compression ultrasonography but should be sus- pected if whole limb swelling is associated with a mottled erythema. Post-​thrombotic (postphlebitic) syndrome complicates 50–​75% of DVTs. The more proximal the deep venous thrombosis, the greater the risk. Consequences of post-​thrombotic vein, and particularly valve, damage include further deep venous thrombosis, superficial thrombophlebitis, oedema, skin changes, and eventually ulceration. Lipodermatosclerosis and prominent perforating veins are characteristic skin changes. Lipodermatosclerosis refers to a com- bination of skin and subcutaneous changes seen with chronic con- gestion, due to venous or lymphatic hypertension. Fat inflammation (panniculitis) combined with phlebitis and dermatitis results, over time, in fat atrophy and fibrosis which manifests as hardening and retraction of the skin, leading to the appearance of an inverse champagne-​bottle shape to the gaiter region. The most common cause of deep vein obstruction is deep venous thrombosis but non​thrombotic causes include iliac vein compres- sion from pelvic tumours or aneurysms, tumours, or aneurysms compressing the deep femoral vein, and a Baker’s cyst may com- press the popliteal vein. Abdominal obesity interferes with venous drainage, particularly in the sitting position. Retroperitoneal fibrosis can obstruct the iliac veins. Superficial thrombophlebitis Thrombosis in a superficial vein usually develops because of slow flow within a varicose vein. Pain, heat, and tenderness over a palp- able nodule or cord is characteristic. Cellulitis may extend for

23.12  Blood and lymphatic vessel disorders 5715 some distance, sometimes making distinction from infection dif- ficult. In the absence of any varicose veins, superficial thrombo- phlebitis usually occurs from trauma due to an intravenous cannula with or without extravasation of an irritating substance (e.g. chemotherapeutic agent). When recurrent or widespread, consider- ation should be given to the possibility of a thrombophilic state such as protein C or S deficiency, antiphospholipid syndrome, Behçet’s syndrome, or underlying cancer (thrombophlebitis migrans). Mondor’s disease is diagnosed when palpable tender cords de- velop around the axilla, breast, or chest wall. Such cords, which may represent thrombosed veins or lymphatics, may ‘bowstring’ across the axilla (axillary web syndrome) and extend down the arm, cre- ating a ‘guttering’ effect with the limb outstretched. Leg ulcers Approximately 70% of leg ulcers are venous in origin; the other 30% result from coexistent arterial disease, diabetes, and rarer skin disorders (Box 23.12.5). Most ulcers occur in the gaiter re- gion, at or above the level of the malleoli, where the persistently elevated ambulatory venous pressure has an adverse effect on the upstream capillary microcirculation. The consequent changes to the microvasculature and interstitium result in a failure of wound healing after trauma. Nearly half of all venous ulcers are associ- ated with deep vein valvular incompetence, usually secondary to previous DVT, while the remainder results from incompetence of the superficial or communicating veins (primary varicose veins). Community surveys suggest an overall prevalence of 0.2% of the population with the highest rates in older women. Once treated, up to 72% can recur. Capillary congestion conveys a bluish erythema to the skin often with purpura and oedema. Over time, the purpura turns to a brown ‘rust’ discoloration due to haemosiderin deposition. Scratching (due to ‘varicose’ eczema) or other trauma will lead to skin break- down. Once ulceration has occurred, wound exudation will further damage surrounding skin, promoting more skin inflammation (ec- zema/​dermatitis) and necrosis. Underlying oedema will further fuel the exudation process. Indeed, leg oedema is an invariable associ- ation of a venous ulcer and always a sign of inadequate treatment. The ‘congestion’ resulting from the venous hypertension and oe- dema can cause a persistent redness to the skin resembling cellulitis from which clinical distinction can be difficult. The diagnosis of a venous ulcer is essentially clinical. Venous du- plex Doppler ultrasound examination can be normal in obese pa- tients who spend long periods in a chair, whereupon ‘functional venous hypertension’ occurs. Nevertheless, venous duplex Doppler is essential for identifying ulcers due to surgically correctable superficial venous incompetence. Arterial ischaemia can be ex- cluded by measuring the ankle brachial pressure index, although it is unreliable in diabetes and other circumstances where compres- sion by a sphygmomanometer cuff is not possible due to arterial wall calcification. Falsely high readings may be obtained and arterial duplex Doppler may be needed. Sensory testing is always important in dia- betic patients, not just because impaired sensation can lead to ul- ceration but also because compression therapy applied unwittingly may contribute to ulceration. Any ulcer with a raised border or one that does not respond to therapy should undergo biopsy to exclude malignancy. First-​line therapy for venous ulceration is compression therapy and exercise. The concept is to reduce venous pressure, particularly during walking, by improving calf muscle pump function and by opposing gravitational venous reflux. Exercise and movement are to be encouraged and preferred to rest. Long periods spent sitting and standing are discouraged, but when resting the leg(s) should be ele- vated, ideally with the ulcer just above heart level, to ensure the max- imum reduction in venous pressure. Falling asleep in a chair with the legs elevated on a stool is of no use. Obesity should be tackled effectively. Heart failure must be controlled, as right-​sided failure further elevates leg venous pressures. Severe anaemia should be cor- rected, although chronic leg ulcers will result in a degree of chronic anaemia. Graduated, multilayer, high-​compression bandage regimens cap- able of sustaining compression for a week at a time should be the first line of treatment. In general, it is treatment of the leg rather than the wound that is important. Nevertheless, eczema and exudation must be controlled. Antibiotics, topical or oral, are of no value unless there is clear evidence of clinical infection or if streptococci are colonizing Box 23.12.5  Cutaneous necrosis • Venous disease — Stasis, congenital, post-​thrombotic • Coagulation defects — Disseminated intravascular coagulopathy — Purpura fulminans — Protein C and S deficiency, antithrombin III deficiency • Infection — Viral, gas gangrene, Buruli ulcer, tuberculosis, leprosy, swimming pool granuloma, Meleney’s anaerobic ulcer, synergistic gangrene, streptococcal, superficial or deep fungus, syphilis, yaws, leishman- iasis, Haemophilus ducreyi, Fusobacterium ulcerans • Blood disorders — Hyperviscosity, dysglobulinaemia, sickle cell anaemia, spherocytosis, polycythaemia • Vasculitis • Pyoderma gangrenosum • Vasculopathy — Arterial disease, Buerger’s disease — Antiphospholipid syndrome — Raynaud’s disease — Calciphylaxis • Emboli • Metabolic — Hyperhomocysteinaemia • Venoms (snake and spider bites) • Neuropathic — Leprosy, diabetes • Drugs — Anticoagulants — Ergot — Chemotherapy infusions — Illicit drugs • Malignancy (or paraneoplastic) — Melanoma, squamous cell carcinoma, Kaposi’s sarcoma, leu- kaemia, secondary deposits • Physical damage from contact

section 23  Disorders of the skin 5716 the ulcer. Beneath the compression, a simple low adherent wound dressing is advisable. Foot ulcers It is unusual to see ulcers of purely venous origin below the line of the edge of the shoes, although atrophie blanche/​livedoid vasculopathy (Fig. 23.12.4) can occur on the foot. Vasoconstriction operates more powerfully in the feet than the legs and it is here that the earliest effects of arterial insufficiency or neuropathy manifest. Pressure or friction points suffer first. In populations who do not wear pro- tective shoes, the foot is prone to infection. It was previously thought that microangiopathic arteriolar occlusion disease was responsible for the tissue necrosis in the diabetic foot. Tissue necrosis and ul- ceration are now believed to result from narrowing and occlusion of the main arteries of the leg below the knee, complicated by septic oc- clusive vasculitis of the terminal arteries. Consequently, correction of the occlusive artery disease by angioplasty and the infection by aggressive antibiotic treatment and debridement are recommended. Telangiectasis Telangiectases (Box 23.12.6) are chronically expanded capillaries or small venules. They usually appear in the skin as spidery red lines, as on the facial cheeks, but can be punctate, as in hereditary haemor- rhagic telangiectasis (HHT), or be flat red macules as seen in the mat telangiectasis of scleroderma. Telangiectases represent enlargement of pre-​existing vessels without any apparent angiogenesis (con- versely angiomas imply a vascular malformation due to an anomaly of embryological development or alternatively a form of tumour). Secondary telangiectases Telangiectases commonly represent the effect of wear and tear on the skin and are particularly frequent on ageing, light-​exposed skin. Atrophy of the skin and the resulting lack of dermal support to the microvasculature will result in telangiectases, as may follow smoking and ultraviolet (UV) radiation. Prolonged vasodilatation may be followed by permanent telangiectases as in rosacea. Varicose veins are frequently the cause of telangiectases of the leg where an arborizing pattern may result. The colour of the telangiectases depends on the calibre of the dilated venule. Large dilatations (<1 mm) are dark blue and palpable. The smallest (0.1 mm), most superficial telangiectases are red and barely empty when the leg is raised. Telangiectases around the lower border of the ribs are virtually physiological in older age groups. There are increasing reports of telangiectases associated with calcium channel blocking drugs. Connective tissue disorders The presence of telangiectases is an important diagnostic sign in lupus erythematosus, dermatomyositis, scleroderma, and overlap syndromes. Nailfold telangiectases can usually be seen with the naked eye, but an ophthalmoscope will reveal fewer but larger, tortuous capillaries often with haemorrhage. Scleroderma results in mat telangiectases which can mimic the telangiectases of HHT both in appearance and distribution (face and hands), but in heredi- tary haemorrhagic telangiectasis they are more obvious on mucous membranes. Telangiectases can occur with cutaneous mastocytosis and angiotropic (intravascular) lymphoma. Spider naevi (arterial spider, spider angioma) Spider telangiectases occur in up to 15% of a normal population and are even more common in children and pregnant women. They are char- acteristically found in liver disease of which they may be a presenting sign. A relationship to high oestrogen levels has been suggested. The main vessel of the spider is an arteriole. The high blood flow fills the capillaries radiating from the vessel. Occlusion of the ar- teriole with a pin head blanches the whole lesion; refilling occurs first from the arteriole and is pulsatile. Spider naevi are only seen above heart level (e.g. upper body). Cherry angiomas (Campbell de Morgan spots) These are common in middle age, but disappear in extreme old age. They can be confused with petechiae when small and flat because they do not blanch. Larger angiomas are raised and dome-​ shaped. They have no known medical associations. Fig. 23.12.4  Atrophie blanche represented by red dots (enlarged tortuous capillaries) between which are areas of white scarring. Box 23.12.6  Elangiectasia Secondary • Prolonged vasodilatation (e.g. rosacea, varicose veins) • Photoageing (sun damage, smoking) • Spider naevi • Radiotherapy • Topical steroids • Connective tissue disorders (scleroderma, lupus erythematosus, dermatomyositis) • Mastocytosis • Cutaneous lymphoma Primary • Vascular birthmarks (e.g. port-​wine stain) • Hereditary haemorrhagic telangiectasia • Ataxia—​telangiectasia • Generalized essential telangiectasia

23.12  Blood and lymphatic vessel disorders 5717 Venous lakes (phlebectasia) Greatly dilated, thin-​walled venules occur on the face, lips, and ears of older patients. Because they contain desaturated blood, venous lakes are dark blue to black and can be confused with melanoma until compressed and emptied. Rosacea and flushing Rosacea is a diagnostic term applied to a spectrum of abnormal- ities in the skin and eyes. Cutaneous features include persistent redness of exposed skin (usually the face) with telangiectases, flushing, oedema, erupting small inflammatory papules (pimples) and pustules, and, in chronic cases, hypertrophy of the sebaceous glands with fibrosis (rhinophyma). Ocular changes occur in more than 50% of patients and range from the common blepharitis and conjunctivitis to the rare, sight-​threatening keratitis. The onset is usually between 30 and 50 years old and more common in women and in patients with fair skin. Ambient heat, alcohol, sunlight, hot drinks, spicy food, and stress appear to exacerbate the condition. The use of topical fluorinated steroids and tacrolimus can trigger a rosacea-​like eruption. Persistent central facial erythema is the most common feature. Telangiectases are prominent and, together with inflammation, cause the red complexion. Appearances may mimic the ‘butterfly’ rush of lupus erythematosus, but a skin biopsy will confirm the presence of ectatic capillaries (and lymphatics) in the dermis. Inflammation may be minimal but, if present, is usually follicular (folliculitis). Photo (sun) damage and oedema frequently coexist. Flushing is usually provoked by ambient temperature, alcohol, hot or spicy food, menopause, or anxiety. Prolonged episodes of severe flushing accompanied by sweating, flushing, sweating not limited to the face, and associated systemic symptoms such as diarrhoea, wheezing, headache, or palpitations should prompt investigation for carcinoid syndrome, phaeochromocytoma, or mastocytosis. Treatment of the erythema and flushing component of rosacea is difficult. A therapeutic six-​week trial of antiacne-​type antibiotics (e.g. oxytetracycline 500 mg twice daily or metronidazole 200 mg twice daily) is worthwhile to resolve any underlying inflammation contributing to symptoms. Such first-​line treatment usually works well for any papules or pustules. If telangiectases are prominent, laser therapy can be helpful. Because relapse of rosacea is common, avoidance of exacerbating factors, such as alcohol, is advised and topical metronidazole cream has proved effective. Perioral dermatitis is a persistent erythematous eruption con- sisting of tiny papules and pustules primarily distributed around the mouth. It occurs predominantly in younger women and is associ- ated with the use of topical steroids. Indeed, the steroid potency as- sociates with risk of disease and it is important to stop steroid usage. Response to treatment with four weeks of oral tetracycline is usually excellent. Topical tetracycline and topical metronidazole can also be effective. Primary telangiectases Hereditary haemorrhagic telangiectasia (HHT, Osler–​Rendu–​ Weber disease) Hereditary haemorrhagic telangiectasis is an autosomal dominant disorder characterized by epistaxis, cutaneous telangiectases, and visceral arteriovenous malformations (AVMs). Mutations in at least two genes are responsible. Endoglin (ENG) on chromosome 9 is the gene for HHT1, where there is a higher preva- lence of cerebral and pulmonary arteriovenous malformationss, while activin receptor-​like kinase 1 (ACVRL1 or ALK1) on chromo- some 12 causes HHT2 which has a milder, later onset phenotype with an increased number of hepatic arteriovenous malformationss. ENG and ALK both encode a homodimeric integral membrane glycoprotein which is the surface receptor for TGF​β. Recurrent epistaxis is usually the presenting symptom at, or just after, puberty but onset may begin in childhood. Telangiectases are punctate, or sometimes papular, and most commonly seen on the lips, mucous membranes, and fingers. They represent micro- vascular arteriovenous anastomoses causing the visible dilatation of postcapillary venules. Lesions occur on the nasal septum, naso- pharynx, and throughout the gastrointestinal tract where they may be demonstrated by endoscopy or magnetic resonance angiography, but not by barium studies. Pulmonary arteriovenous malformationss cause dyspnoea, cyanosis, and clubbing and are seen on chest X-​ray. Liver enlargement and cirrhosis can occur (HHT2). An association with juvenile polyposis has been described. The diagnosis is based on family history and clinical phenotype. Molecular genetic testing de- tects mutations in 60–​80% of individuals. Prenatal testing is available. In mild cases, no treatment is usually needed except the control of any anaemia, possibly including iron replacement. Tranexamic acid, by regulating the ALK1/​endoglin pathway, may be beneficial in some patients. Symptomatic skin or mucous membrane lesions can be destroyed by cautery or laser. Recurrent nasal bleeding and pul- monary arteriovenous malformationss may demand more extensive surgery or embolism approaches. Antibiotic prophylaxis is recom- mended for dental and invasive procedures. Ataxia-​telangiectasia (Louis-​Bar syndrome) Ataxia-​telangiectasia syndrome is a rare recessive disease with pleio- tropic involvement of nervous and lymphoid systems caused by mu- tations in the ataxia-​telangiectasia-​mutated (ATM) gene. Defective excision repair of DNA damaged by ultraviolet (UV) light, γ, or X-​rays is responsible. The syndrome presents with telangiectases, progressive cerebellar ataxia, combined immuno- deficiency, and a marked susceptibility to cancer. A  diminished level, or absent, IgA is characteristic. Telangiectases may be present as early as the second year and first appear on the bulbar conjunctiva and subsequently on the ears, eyelids, and the butterfly area of the cheeks. Bleeding is un- common. Recurrent sinus and pulmonary infections are frequent and may dominate the clinical picture. X-​ray investigation should be restricted. The laboratory diagnosis relies on increased serum α-​fetoprotein levels and cellular sensitivity to ionizing radiation. Molecular, genetic, and prenatal testing for the presence of the ab- normal ATM gene is available. No proven treatment exists. Antioxidants such as vitamin E and α-​lipoic acid are recommended. Intravenous immunoglobulin ap- pears to reduce the number of infections. Vascular birthmarks Vascular birthmarks usually develop during childhood and are therefore naevoid in origin (naevus is Latin for ‘maternal impression’

section 23  Disorders of the skin 5718 or ‘birthmark’). Many, possibly all, birthmarks represent clones of genetically altered cells arising from mosaicism during somatic mu- tation. It is important to distinguish between haemangiomas and vascular malformations, although it may prove difficult on clinical grounds. Haemangiomas are proliferative blood vessel tumours, whereas vascular malformations represent structural defects arising from vascular development. Vascular malformations can be high flow (arterial or arterio- venous fistulas) or low flow (capillary, venous, lymphatic, or mixed) types. In general, vascular malformations possess no endothelial proliferation, are present at birth, and do not involute. Port-​wine stain (naevus flammeus) These are characterized clinically by persistent macular erythema from birth, and pathologically by ectasia of superficial dermal capil- laries. Port-​wine stains have a greatly diminished density of perivas- cular nerves. Associated eye and brain abnormalities occur in 8–​15% of port-​wine stains on the head and neck. The most significant ocular problem is glaucoma, particularly if the eyelids are involved. The Sturge–​Weber syndrome represents involvement of the leptomenin- geal vasculature giving rise to epilepsy and neurological deficit. Klippel–​Trénaunay syndrome The association of a port-​wine stain with tissue overgrowth and vein abnormalities usually affecting one hindquarter is termed the Klippel–​Trénaunay syndrome. The port-​wine stain is present from birth with excessive longitudinal bone growth occurring during childhood. Increased limb girth suggests soft tissue overgrowth. Vein abnormalities, particularly aberrant veins such as the lateral thigh vein (embryological remnant), progress from puberty. Lymphatic abnormalities (lymphoedema and lymphangioma) are not un- common. Sometimes the whole of one side of the body is affected with hemihypertrophy. There is a high rate of thrombosis involving both superficial and deep veins. Venous ulceration may occur. The differential diagnosis includes the Parkes Weber syndrome in which limb hypertrophy is associated with multiple arteriovenous anastomoses. The Proteus syndrome is highly variable (protean) in its clinical presentation. Mandatory general criteria include mosaic distribution of lesions, a progressive course, and a sporadic occur- rence. Connective tissue naevi are pathognomonic and epidermal naevi, tissue overgrowth, lipodystrophy, and vascular malforma- tions (including lymphatic) may occur. Mutations in PTEN may be present. The Proteus-​like syndrome is undefined and refers to the presence of significant clinical features falling short of diagnostic criteria. The Servelle–​Martorell syndrome encompasses vascular malformations associated with limb hypoplasia (shortening). Cutis marmorata (reticulate vascular naevus) This is a combined capillary and venous birthmark form of livedo reticularis. Appearances are very similar in that a fixed mottled or marbled look to the skin results from an uneven perfusion and slow flow in the venous component. Atrophy of skin and subcutaneous tissue makes the reticulate pattern even more livid. Limbs are most commonly involved, in which case hypoplasia of underlying bones may occur. A range of other abnormalities can occur including glau- coma, macrocephaly, and cardiac abnormalities. Because of natural improvement with time, treatment is rarely needed. Blue rubber bleb naevus syndrome The most typical lesions are small, compressible, blue to purple rub- bery nodules occurring anywhere on the body surface as well as on lips, mouth, and penis and within the gastrointestinal tract where they frequently bleed. The resulting anaemia may be profound. Other organs including the lung and the central nervous system may be involved. Nodular blue lesions under the tongue are charac- teristic. Onset is usually during childhood but may be in adult life. Once developed, lesions persist for life. Treatment is directed at con- trolling bleeding and anaemia. Maffucci’s syndrome (dyschondroplasia with haemangiomas) Despite the name, the soft, bluish cutaneous protrusions are not haemangiomas but small venous malformations. They persist and may grow into large lesions resembling a bunch of red grapes. Hard nodules arising from the bones, especially on the hands and feet, represent enchondromas which are radiologically translucent. Bone growths are delayed and pathological fractures occur with slow re- covery. Deformity of the hands and feet may be gross. Malignancy is common, particularly chondrosarcoma but also angiosarcoma and ovarian cancer. Dyschondroplasia can occur without the vascular malformations (Ollier’s disease). Patients require careful follow-​up with imaging or biopsy of any lesions that enlarge or cause symptoms. Angiokeratoma corporis diffusum (Fabry’s disease) Angiokeratomas are characterized clinically by the presence of dark red to black, flat to slightly raised, vascular lesions which are most commonly seen on the scrotum where they are harmless. Histology reveals superficial vascular ectasia (expanded capillaries) with an overlying increase in surface keratin and so they represent capillary malformations rather than haemangiomas. Anderson–​Fabry disease should be considered when lesions are clustered as small telangi- ectatic spots between the umbilicus and the knees. This is an X-​linked disorder (MIM 301 500) in which deficiency of lysosomal hydrolase and galactosidase leads to deposition of globotriaosylceramide in cells throughout the body. It causes severe, painful neuropathy with progressive renal, car- diovascular, and cerebrovascular dysfunction and early death. The surface angiokeratomas affect both skin and mucous membranes and usually appear shortly before puberty. Lesions can be up to 4 mm across but do not blanch on pressure due to the presence of red cells trapped within the ectatic capillaries. Their persistence distinguishes the lesions from purpura. Skin biopsy will confirm an angiokeratoma. The finding of albuminuria or haematuria and, more specifically, ‘mulberry-​like’ cells in the urinary sediment sug- gests a diagnosis of Fabry’s disease, but the finding of decreased X-​galactosidase A  in plasma or isolated leucocytes is diagnostic. Disease causing mutations in the GLA gene can be found in all af- fected individuals and in most carriers. Vascular tumours Infantile haemangioma Usually appearing in the first year of life, these common haemangi- omas characteristically have an initial proliferative and then a later

23.12  Blood and lymphatic vessel disorders 5719 involutional phase. Although previously known as a ‘strawberry’ naevus or haemangiomas, the terms strawberry, capillary, and cav- ernous have been abandoned for the preferred superficial, deep, and mixed haemangiomas. Over 60% will develop on the head and neck. The principal features distinguishing infantile haemangiomas from vascular malformations are that they are not present at birth and that they undergo spontaneous resolution. Few associations exist, but posterior fossa brain abnormalities may occur as in the PHACE(S) syndrome (posterior fossa malformations, haemangiomas, arterial anomalies, coarctation of the aorta and other cardiac defects, eye abnormalities, and sternal abnormalities). Lumbosacral haemangi- omas can be a marker of spinal dysraphism. Glomus tumour (glomangioma) Glomus cells are modified smooth muscle cells found in glomus bodies which are believed to function as temperature receptors. Solitary glomus tumours are characteristically found in finger tips and in nail beds and are exquisitely tender. Multiple glomangiomas can be familial. Pyogenic granuloma (lobular capillary haemangioma) Pyogenic granuloma is a misnomer. Neither pyogenic nor granu- lomatous, the lobular capillary haemangiomas are benign vascular tumours that represent excessive production of granulation tissue usually in response to injury. Bleeding can be profuse and persistent. They can be indistinguishable clinically from amelanotic melan- omas and should be treated by excision biopsy, although curettage will suffice if confident of the diagnosis. Kaposi’s sarcoma Kaposi’s sarcoma (KS) is a multifocal tumour characterized by dysregulated angiogenesis, a proliferation of spindle cells, and ex- travasation of inflammatory cells and erythrocytes. Human herpes- virus 8 appears causal. Kaposi’s sarcoma is the most common cancer in HIV-​infected individuals and in sub-​Saharan Africa. There are four clinically distinct subsets of Kaposi’s sarcoma: (1) classic forms, as described originally by Kaposi, are found mainly in older men. Red to purple lesions appear on the feet and spread proximally. Usually flat patches (like purpura or purple stain) or slightly raised lesions can progress to plaques or nodules. Limb oedema (lymphoedema) fre- quently coexists. The characteristic colour, slow development, and multifocal distribution should suggest the diagnosis. (2) Endemic Kaposi’s sarcoma is found in equatorial Africa. Crops of cutaneous vascular lesions develop, usually on the lower limbs, associated with gross oedema, lymphadenopathy, and sometimes visceral involvement. (3)  Iatrogenic forms result from immunosuppres- sion in transplant patients and after cytotoxic chemotherapy. Both systemic and cutaneous involvement occurs. (4) HIV-​associated Kaposi’s sarcoma occurs most commonly in homosexual men where dark red to purple stains may appear rapidly and occur any- where on the skin surface or mucous membranes, particularly in the soft palate. Skin biopsy is characteristic, demonstrating a proliferation of jagged, irregular lymphatic-​like vascular channels lined by a single layer of bland endothelial cells. An inflammatory infiltrate is as- sociated with red cell extravasation and haemosiderin deposition (explaining the purple to brown skin discoloration on blanching). A  network of bland spindle cells develops. Staining for HHV-​8 should be positive in all tumour cells. HIV testing should be under- taken. The differential diagnosis would include causes of purpura, venous disease (lower limb only), and angiosarcoma. No treatment may be required in asymptomatic indolent classical forms. Superficial radiotherapy is rapid and effective for localized diseases. Cases related to AIDS may regress with HAART (highly ac- tive antiretroviral therapy). Doxorubicin, bleomycin, and vincristine chemotherapy is widely regarded as first-​line treatment, although liposomal anthracyclines have also proved effective in advanced dis- ease. A reduction of immunosuppressant therapy will often resolve lesions in transplant patients, but this is not always possible without jeopardizing the transplant. Sirolimus inhibits the progression of dermal Kaposi’s sarcoma in kidney transplant recipients while pro- viding effective immunosuppression. Angiosarcoma (lymphangiosarcoma) This is a malignant vascular tumour arising from both vascular (and lymphatic) endothelium which occurs in three settings: (1) as a pri- mary event on the face, scalp, or neck usually in older people; (2) as- sociated with lymphoedema (although best described following mastectomy (Stewart–​Treves syndrome)) lymphangiosarcoma can occur in any long-​standing lymphoedema); and (3) postirradiation. In all types of (lymph) angiosarcoma, the first sign may be a bruise. Dark red to black plaques and nodules appear, spreading rapidly. Oedema and haemorrhage are common. The diagnosis is through skin biopsy. Defining the limits of the tumour is difficult and imaging is unhelpful. Consequently, wide excision, if possible, is the only treatment and the prognosis is poor. Lymphatic disorders The lymphatic system has long been a neglected area of medicine largely because, lymphoma excepting, it has not produced any life-​ threatening diseases nor has the technology been available to indi- cate the contribution of lymphatics to pathology. See Section 16 for further descriptions of lymphatic disease. The recent discovery of specific genes and proteins, however, has catapulted lymphatic biology onto the research agenda of cancer spread, infection and inflammation, asthma, organ transplant rejec- tion, and lymphoedema. The lymphatic system is essentially a drain, returning to the blood circulation protein and fluid unwanted by the tissues. This com- pletes the extravascular circulation of fluid and protein and main- tains tissue volume homeostasis. Lymph drainage is also an essential part of the body’s immune defence. Cells such as extravasated leuco- cytes and activated antigen-​presenting cells enter the initial lymph- atics and are transported to lymph nodes where specific immune responses to foreign materials are generated. Lymphatic capillaries are thin-​walled vessels but capacious and potentially larger than nearby blood capillaries. Lymphatic capil- laries absorb protein and fluid from the interstitial space and initiate lymph drainage and hence are referred to as ‘initial lymphatics’. They drain into downstream ‘collecting lymphatics’ which, unlike initial lymphatics, possess a smooth muscle layer and valves. Intermittent changes in tissue pressures, external to initial lymphatics, are mainly responsible for lymph absorption and transport. Lymph within

section 23  Disorders of the skin 5720 collecting lymphatics, however, is propelled forward by mural smooth muscle contraction with valves preventing backflow. Lymphangiogenesis Lymphatic vessels were discovered before the blood circulation, but the first growth factors and molecular markers specific for lymph- atics were discovered only 15 years ago. The gene PROX1 commits endothelial cells from a venous to a lymphatic phenotype. Vascular endothelial growth factor (VEGF) C and D and their receptor VEGFR3 are mainly responsible for lymphatic vessel sprouting and growth. Subsequently, a signal transduction system is responsible for lymphatic endothelial cell growth, migration, maturation, and survival. Lymph sacs appear at six to seven weeks in embryos with lymph- atic endothelial cells sprouting from embryonic veins in the jugular and perimesonephric areas under the influence of VEGFC. From here they migrate to form primary lymph sacs and the primary lymphatic plexus. Antibodies to cell surface markers LYVE1, VEGFR3, podoplanin (D2-​40), and PROX1 enable distinction be- tween blood and lymphatic endothelial cells. Lymphoedema A failure of lymph drainage causes a build-​up of protein and fluid within the tissues (lymphoedema). When this occurs in the skin and subcutis the tissues become swollen and undergo character- istic changes. An increase of intralymphatic pressure (lymphatic hypertension) results in enlargement of the dermal initial lymph- atics. If compliance permits, distended lymphatics bulge like blisters on the skin surface (lymphangiectasia), leading to leakage of lymph fluid (lymphorrhoea). If disruption to lymph drainage involves the lymphatics draining the intestinal lacteals, then rerouting/​backflow of chylous lymph can result in leaking of milky chyle from the skin surface, particularly after a fatty meal. Chronic distension of dermal lymphatics and accumulation of protein-​rich fluid within the skin results in a cobble stone appear- ance to the skin (papillomatosis) and a build-​up of surface keratin (hyperkeratosis). This combination of features is referred to as ele- phantiasis (Fig. 23.12.5) because of its resemblance to elephant skin. In tropical medicine and parasitology, the term elephantiasis is syn- onymous with lymphoedema resulting from filarial infection, but elephantiasis skin changes can occur with any form of lymphoedema irrespective of cause. If left untreated, elephantiasis progresses to marked fibrosis with little evidence of pitting oedema. Most swelling with lymphoedema occurs in the more compliant subcutis. Fat and fibrous tissue accumulates as much as protein-​rich fluid. Indeed, the pathology of lymphoedema is complex involving proliferation of inflammatory cells, adipocytes, fibroblasts, and blood vessels (angiogenesis). Lymphoedema is also discussed in Chapter 16.18. Infection and lymphatic failure Recurrent infection (e.g. tinea pedis, cellulitis) is a common event in lymphoedema. It is likely that disturbances to the trafficking of im- munologically active cells, such as lymphocytes and dendritic cells, compromise tissue immunosurveillance, but the exact mechanism is not known. Lymphatic vessels participate in the regulation of an in- flammatory response through their role in transport of lymphocytes to and from lymph nodes. Migration of dendritic cells is mediated in part by the chemokine receptor CCR7, with lymphatic vessels ex- pressing the ligand CCL21. Lymphangitis The lymphatic system has evolved in humans as a host defence mech- anism. Noxious agents and predators such as bacteria, if not dealt with at the point of entry to the host, access the lymphatic system. Lymphatic vessels, together with adjoining lymph nodes, effectively act as a second line of defence preventing further onward spread and limiting systemic involvement (e.g. septicaemia). Lymphangitis represents inflammation of the lymphatic collectors and is clinically seen as tender red streaks spreading up the limb cor- responding to the inflamed vessels. Inflammation of downstream lymph nodes, known as lymphadenitis, manifests with painful, tender, swollen glands. Lymphangitis is not easily seen in the pres- ence of oedema and a more diffuse erythema is observed, making distinction from cellulitis impossible. Cellulitis (erysipelas, acute inflammatory episodes, dermatolymphangioadenitis) Cellulitis can result from the impaired local host defence mech- anism associated with lymphatic insufficiency but, conversely, can damage lymph drainage routes and cause lymphoedema. A vicious cycle of recurrent cellulitis and worsening swelling can arise. In one epidemiological study, 64 (29%) of 218 patients identified with lymphoedema had suffered at least one attack of cellulitis within the previous 12  months with 16 (8%) experiencing more than three episodes. Any patient with recurrent attacks of cellulitis in the same leg almost certainly has compromised lymph drainage in that leg. Unlike conventional cellulitis (in an immunocompetent site), the first sign of illness is usually constitutional upset with flu-​like symptoms, fever, rigors, or vomiting. Only some hours later may a blotchy rash, pain, and increased swelling appear with Fig. 23.12.5  Elephantiasis resulting from underlying lymphoedema. Elephantiasis refers to the thickened skin with papillomatosis and hyperkeratosis.

23.12  Blood and lymphatic vessel disorders 5721 the diagnosis becoming clear. The typical advancing border of a spreading cellulitis is not seen with lymphoedema. Streptococcal infection is considered the likely culprit, but it is unusual to be able to isolate an organism. A  consensus document on the management of cellulitis in lymphoedema emphasizes the need to correct risk factors (e.g. skin wounds, dermatitis, tinea pedis), and the need for longer courses of antibiotics as insufficient treatment will often result in early relapse of cellulitis. When attacks occur more than twice a year, prophylactic antibiotics are indicated, such as penicillin V (phenoxymethylpenicillin) 500 mg daily. Prophylaxis for two years is recommended, although it is not unusual for cellulitis to recur as soon as antibiotics are discontinued suggesting relapse rather than the development of a new infection. In such circumstances, lifelong prophylaxis is suggested. Tropical lymphoedemas Lymphatic filariasis Adenitis and lymphangitis are major acute manifestations of lymphatic filariasis. Two events may present in a similar manner. ‘True’ filarial adenolymphangitis is caused by the death of the adult worm, whereas acute dermatolymphangioadenitis (ADLA) is equivalent to cellulitis/​lymphangitis secondary to bacterial infection (usually streptococcal). Recurrent ADLA/​cellulitis is a major risk factor for progression to elephantiasis. Treatment with diethylcarbamazine (DEC) has no effect on the outcome of ADLA, but scrupulous attention to skin hygiene and/​or prophy- lactic penicillin significantly reduces the number of attacks. Podoconiosis Similar secondary lymphoedema is seen, together with ADLA, in podoconiosis, a chronic reaction to certain soil types seen in those going barefoot in some tropical regions (e.g. Ethiopia). Tumour metastasis Lymphatic spread is the preferential route of metastasis for most human cancers, with sentinel lymph node assessment as the most important prognostic indicator in, for example, melanoma and vulval and penile cancers, where growth factor stimulation of lymphatic vessels enhances lymphatic metastasis. Melanoma cells expressing VEGFC induce local lymphangiogenesis at the tumour margin. Some evidence exists to suggest that lymphatic endothe- lium actively attracts certain cells, by secreting chemokines such as CCL21 whose receptor CCR7 is expressed on some tumour cells. Lymph containing VEGFC stimulates downstream lymphatics to di- late and facilitate spread of clumps of tumour cells. Carcinoma erysipeloides (carcinoma telangiectatica) Carcinoma erysipeloides (Fig. 23.12.6) manifests clinically with a fixed erythematous patch or plaque resembling cellulitis/​erysipelas but without fever. The inflamed area may show a distinct raised com- ponent due to palpable infiltrated lymphatics and oedema. Congenital lymphatic malformations Lymphangioma Simple sustained dilatation of otherwise normal lymphatic vessels is termed lymphangiectasia, but when lymphatics are distended due to structural abnormalities of a tumour-​like nature the term lymphangioma is best used. The most important feature of all con- genital lymphangiomas is that they are not part of the normal lymph conducting system. Lymphangioma circumscriptum, as the name implies, is localized to an area of skin, subcutaneous tissue, and sometimes muscle. It consists of lymph (and sometimes blood) filled vesicles which bulge on the skin surface (Fig. 23.12.7). The lymphangiomas may resemble blisters or may take on a more warty appearance and be mistaken for viral warts, except they can leak lymph fluid. There may or may not be swelling depending upon extension into deeper tissues, but pitting oedema is absent. The term ‘circumscriptum’ may be misleading because deeper compo- nents may be extensive, making surgical excision difficult. Although lymphangioma circumscriptum is usually evident at or soon after Fig. 23.12.6  Carcinoma erysipeloides indicating infiltration of breast carcinoma within dermal lymphatics. Usually associated with local oedema because of lymphatic obstruction. Fig. 23.12.7  Cutaneous lymphangioma as demonstrated by lymph blisters on skin surface.

section 23  Disorders of the skin 5722 birth, it may present later. Radical surgery offers the only chance of cure, but a conservative approach with simple electrocautery to cor- rect the weeping (lymphorrhoea) is advised. Diffuse lymphangioma indicates a more extensive malformation which may involve an entire hindquarter. Limb swelling may be due either to lymphoedema or to gross dilatation of abnormal lymphatic channels, while skin surface lymphangiomas may coexist with blood vascular malformations. Diffuse lymphangiomas may form part of the Klippel–​Trénaunay syndrome with limb and tissue overgrowth. If the lymphangioma involves underlying bone, osteoid tissue may resorb leading to pathological fractures (Gorham’s disease). Maffucci’s syndrome consists of diffuse, multiple haemoly­ mphangiomas accompanied by severe deformities of bone and cartilage. Cystic hygroma (cystic lymphangioma) Cystic hygromas are large lymph cysts considered remnants of primitive lymph sacs, which is why they are found most often in the neck, groin, or retroperitoneum. Although usually present at birth, some present in adulthood after a local disturbance stimu- lates lymph absorption. if large, a cystic hygroma may interfere with breathing or swallowing. Episodes of infection occur in 25% of both cystic hygromas and lymphangiomas. Cystic hygromas are strik- ingly translucent. Repeated aspiration, sclerotherapy, or excision are treatment options. Acquired lymphatic abnormalities Acquired lymphangiectases (acquired lymphangioma) Acquired or secondary lymphangiectases arise following damage to previously normal deep lymphatic vessels. Obstruction to drainage leads to back pressure and dermal backflow with subsequent dila- tation of upper dermal lymphatics. They develop most often in genital skin where they are easily mistaken for warts, but weeping of lymph distinguishes one from the other. Persistent leakage of lymph can be mistaken for urinary incontinence. They occur following cancer treatment (lymphadenectomy or radiotherapy) and scarring processes. Traumatic lymph cysts (lymphoceles) and fistulae Lymphatics severed by accidental trauma or surgery normally col- lapse and block with fibrin. If lymph continues to leak, it collects in the tissues forming a large pseudocyst or lymphocele (often wrongly called a ‘seroma’). Should the lymphocele burst through the over- lying wound, then a fistula with continuous lymph leakage can occur. Most lymphoceles resolve spontaneously with or without re- peat aspiration. Chylous reflux/​intestinal lymphangiectasia Chyle is lymph-​rich in chylomicrons. The word chylous means juice and the milky whiteness comes from fat absorbed from intestinal lacteals. It is important to recognize that fluid in the lacteals is only white after a meal containing free fat; patients on a low-​ or non-​ fat diet have clear fluid in their lacteals. Chyle, like lymph, can es- cape into peritoneal (chylous ascites), pleural, or pericardial cavities, joints, vagina (chylous colporrhoea), or external genitalia as well as refluxing into a lower limb with chyle leaking from the skin. Where chyle refluxes is entirely dependent on the position of incompetent lymphatics or the site and degree of any obstruction to normal lymph flow. Primary chylous reflux arises from congenitally incompetent megalymphatics (lymphangiectasia with valve incompetence) or lymphatic hypoplasia when lymph/​chyle is forced to reroute. Secondary (acquired) reflux is almost always caused by thoracic duct obstruction caused by filariasis, malignant disease, or trauma (accidental or surgery). Treatment involves reducing chyle produc- tion by following a strict, no fat diet supplemented with medium chain triglycerides and extra vitamins. When chyle cannot pass through the lacteals, cisterna chyli, and thoracic duct as usual, it refluxes back into the villi and diffuses back through the intestinal mucosa into the lumen of the bowel. The dis- tended intestinal lacteals are termed intestinal lymphangiectasia. A steady loss of protein, fat, and fat-​soluble vitamins causes weight loss, steatorrhoea, diarrhoea, and a hypoproteinaemic oedema (protein-​losing enteropathy). Intestinal lymphangiectasia usually occurs from a failure of lymphatic development in genetic forms of lymphoedema, but can rarely be acquired following radiotherapy. Lymphatic tumours The understanding of benign and malignant lymphatic tumours has been limited owing to a lack of specific lymphatic markers. Lymphangiosarcoma Lymphangiosarcoma is the only known malignant disease of lymph- atics. Although well known for its association with postmastectomy lymphoedema (Stewart–​Treves syndrome), it is a rare but serious complication of any chronic lymphoedema irrespective of cause. Red-​brown or purple discoloration, like a bruise, appears in the skin. Nodules or raised plaques may appear later and oedema deteriorates. Limits are poorly defined and progression is rapid. Radical surgery, if per- formed early, may offer cure. Kaposi’s sarcoma The phenotype of the endothelial cells of Kaposi’s sarcoma may be as much lymphatic as blood vascular, but its origins may lie with a primitive cell capable of either differentiation. It can arise in long-​ standing lymphoedema or indeed cause lymphoedema. FURTHER READING Angiogenesis/​lymphangiogenesis Alitalo K, Tammela T, Petrova TV (2005). Lymphangiogenesis in de- velopment and human disease. Nature, 438, 946–​53. Carmeliet P (2005). Angiogenesis in life, disease and medicine. Nature, 438, 932–​6. Calciphylaxis Weeniq RH, et al. (2007). Calciphylaxis: natural history, risk factor analysis and outcome. J Am Acad Dermatol, 56, 569–​79. Buerger’s disease Olin JW, Shih A (2006). Thrombangiitis obliterans (Buerger’s Disease). Curr Opin Rheumatol, 18, 18–​24.

23.12  Blood and lymphatic vessel disorders 5723 Sickle cell disease Clare A, et al. (2002). Chronic leg ulceration in homozygous sickle cell disease: the role of venous incompetence. Br J Haematol, 119, 567–​71. Erythromelalgia Waxman SG, Dib-​Hajj S (2005). Erythermalgia: molecular bases for an inherited pain syndrome. Trends Mol Med, 11, 555–​62. Pressure ulcers National Pressure Ulcer Advisory Panel (2016). NPUAP Pressure Injury Stages. http://​www.npuap.org/​resources/​educational-​and-​ clinical-​resources/​npuap-​pressure-​injury-​stages/​ Venous disorders Eklöf B, et  al. (2004). Revision of the CEAP classification for chronic venous disorders: consensus statement. J Vasc Surg, 40, 1248–​52. Palfreyman SJ, et al. (2006). Dressings for healing venous leg ulcers. Cochrane Database Syst Rev, 3, CD001103. Foot ulcers Prompers L, et  al. (2007). High prevalence of ischaemia, infection and serious comorbidity in patients with diabetic foot disease in Europe:  baseline results from the Eurodiale Study. Diabetologia, 50, 18–​25. Rosacea Powell FC (2005). Clinical practice:  rosacea. N Engl J Med, 352, 793–​803. Vascular birthmarks Berry SA, et  al. (1998). Klippel–​Trénaunay syndrome. Am J Med Genet, 79, 319–​26. Biesecker LG, et al. (1999). Proteus syndrome: diagnostic criteria, differ- ential diagnosis, and patient evaluation. Am J Med Genet, 84, 389–​95. Garzon MC, et al. (2007). Vascular malformations: part I. J Am Acad Dermatol, 56, 353–​70. Garzon MC, et al. (2007). Vascular malformations: part II: associated syndromes. J Am Acad Dermatol, 56, 541–​64. Vascular tumours Stallone G, et  al. (2005). Sirolimus for Kaposi’s sarcoma in renal-​ transplant recipients. N Eng J Med, 352, 1317–​23. Lymphatic disorders Browse NL, Burnand KG, Mortimer PS (2003). Diseases of the lym- phatics. Arnold, London. Moffat CJ, et  al. (2003). Lymphoedema:  an underestimated health problem. QJM, 96, 731–​8. Website NCBI. GeneTests. http://​www.ncbi.nlm.nih.gov/​sites/​GeneTests/

23.13 Hair and nail disorders 5724 David de Berker

23.13 Hair and nail disorders 5724 David de Berker

ESSENTIALS Nails grow continuously throughout life, except after exceptional physiological or traumatic events when they are shed. All other less disruptive influences result in changes in the colour, thickness, tex- ture, and growth of nails, and may also affect the periungual tissues. The most common local diseases affecting the nail are psoriasis, fungal nail infections, periungual eczema, and viral warts. Trauma is a common cause of changes in toenails. Looking at the nails is an important part of the general examination, since changes such as clubbing or splinter haemorrhages can indicate systemic disease. Hair growth in a healthy person is determined by body site, gender, and age. Within these parameters there are accepted norms. Disease can affect hair growth by direct action on the fol- licle or by indirect effects sustained through generalized physio- logical disturbance. Clinicians might be asked to assess specific diseases of the scalp with implications for hair growth, or specif- ically to address pathological patterns of hair growth where there may be underlying systemic disease. Common diseases of the scalp include psoriasis, eczema, fungal infection, alopecia areata, and the scarring alopecias. Telogen effluvium is the most common hair problem related to general medical or surgical upset, char- acterized by variable shedding of hair about 6–​10 weeks after a period of significant physiological disturbance. Where scalp hair loss presents in association with increased hair on the body or at sites associated with masculinity (hirsutism), a pathological source of androgen should be sought. A reduction in scalp hair is a normal part of ageing in both sexes. Disorders of the nails The nail grows from the matrix and is supported by the nail bed until it reaches the free edge. At the proximal and lateral margins, it is em- bedded in the nail folds. Local and systemic diseases can alter the ap- pearance and function of all four structures (Fig. 23.13.1). The most common local diseases affecting the nail are psoriasis, fungal nail infections, periungual eczema, and viral warts. Tumours other than viral warts are rare. They include squamous cell carcinoma and ma- lignant melanoma. Systemic diseases manifested in the nail include cardiovascular, respiratory, and gastrointestinal diseases leading to clubbing; vascular phenomena (e.g. splinter haemorrhages, cyan- osis) and changes in nail growth as a result of general metabolic fac- tors influencing nail matrix function. Psoriasis Psoriasis affects 1.5–​3% of the population, and nail involvement is found in up to 90% of patients at some time. Clinical features The most common manifestations are pitting, onycholysis, ‘oily spots’, transverse ridging of the dorsal surface, splinter haemorrhages, and subungual hyperkeratosis. Pits represent surface defects in the nail due to foci of psoriatic epithelium (Fig. 23.13.2). Onycholysis is sep- aration of the nail from the nail bed arising because psoriasis of the 23.13 Hair and nail disorders David de Berker Nail bed Lateral nail fold Cuticle Nail plate Cuticle Proximal nail fold Nail matrix Distal interphalangeal joint Lunula Fig. 23.13.1  Anatomy of the normal nail.

23.13  Hair and nail disorders 5725 nail bed reduces adherence of the nail. Subungual hyperkeratosis is thickening of the skin of the nail bed with psoriatic scale that cannot be lost because of the overlying nail. An oily spot is psoriasis in the nail bed. It is termed ‘onycholysis’ if it extends to the free edge. These signs might allow diagnosis of psoriasis at other sites. Even in the presence of obvious psoriasis elsewhere, fungal infection should be sought if the nail features are not typical, because treatable infection can be superimposed and might warrant active therapy. Treatment Using local therapy, pitting can be concealed with lacquers, or may respond to a potent topical corticosteroid applied over 2–​3 months to the proximal nail fold. Severe pitting and other changes might occasionally justify a trial of injection of triamcinolone acetonide, 0.1 ml of 2.5–​5 mg/​ml, into the proximal nail fold, with preliminary local anaesthetic. Onycholysis is difficult to manage and is made worse by trauma and picking. Patients should avoid leverage at the free edge by keeping the nails short and by wearing gloves during wet or dirty work. Debris caught beneath the nail should be removed with a soft nail brush. Excavation with a pointed tool (a common cleaning technique) makes the condition worse. Topical calcipotriol or potent corticosteroid ointment can be helpful and needs to be applied under the free edge at night. Clipping the nail back to the point of separation from the nail bed can facilitate treatment of nail bed psoriasis with topical therapy. Occlusion of the nail with tape is also advocated. Systemic therapy (e.g. methotrexate, ciclosporin, acitretin, or biologics) and psoralen plus ultraviolet A (UVA) can help and might remove the need for inconvenient local treatments. Fungal nail infection The prevalence of fungal nail disease is up to 13% in urban areas in developed countries, but less than 1% in rural Democratic Republic of Congo. It largely affects toenails associated with enclosed foot- wear; raised humidity probably explains the difference between European and African prevalence rates. The principal pathogens are dermatophyte fungi, which infect skin and nail; Trichophyton rubrum and Trichophyton interdigitale are the most common (see Chapters 8.7.1 and 23.10). The non​dermatophyte fungi (e.g. Fusarium sp., Scopulariopsis brevicaulis) and yeasts (e.g. Candida spp.) are uncommon pathogens. Onychomycosis is more common in damaged nails. Tinea pedis often coexists between the fourth and fifth web space or as a moccasin infection (a diffuse, scaling fungal infection affecting the sole of the foot). Clinical features Onychomycosis presents in one of four patterns (Fig. 23.13.3). Classic onychomycosis is where the nail thickens, becomes yellow, and is undermined by subungual hyperkeratosis. It may involve just the distal and lateral margins of the nail or be throughout, being named distal, lateral, subungual, or total dystrophic onychomycosis, respectively. Superficial white onychomycosis (Fig. 23.13.4) is rela- tively more common in children and is the variant best treated with topical therapy. Proximal white subungual onychomycosis may pre- sent with a white proximal nail plate and no destruction in the early stages of the disease; this pattern is more common in patients who are immunosuppressed (e.g. organ transplant recipients, those with (a) (b) Fig. 23.13.2  (a) Psoriasis with pitting of the nail and splinter haemorrhages in the nail bed. (b) Psoriasis with marked subungual hyperkeratosis. (b) (a) (d) (c) Fig. 23.13.3  Four most common variants of onychomycosis: (a) distal lateral onychomycosis; (b) total dystrophic onychomycosis; (c) superficial white onychomycosis; (d) proximal white subungual onychomycosis.

section 23  Disorders of the skin 5726 HIV infection). Candida spp. are most commonly found colonizing the damp undersurface of an onycholytic fingernail, where warmth and humidity are common in affected individuals (e.g. caterers). There might also be factors influencing local or systemic immunity (e.g. peripheral ischaemia, Raynaud’s, and diabetes mellitus). Diagnosis Mycological confirmation should normally be obtained before starting systemic antifungal therapy. A large sample of discoloured nail plate, with underlying soft debris, is required for a reliable re- sult; this is best taken using heavy-​duty nail clippers. Infection can be confirmed through definite identification on microscopy, with identification of the fungus through subsequent culture. Microscopy alone is indicative, but not conclusive as the fungus can be non​viable or already treated. Polymerase chain reaction can also be used to type the fungus, but is at risk of detecting clinically irrelevant antigen in the absence of viable pathogen. The importance of making a clear diagnosis before treatment is greatest where systemic therapy is ad- vocated. Both of the main agents have been reported to cause severe reactions, such as Stevens–​Johnson syndrome and toxic epidermal necrolysis. Drug interactions are a particular risk with itraconazole. Treatment Terbinafine and itraconazole are systemic therapies for dermato- phyte onychomycosis. Terbinafine is slightly more effective than itraconazole in dermatophyte infections, but possibly less effective against Candida spp. Topical therapy is usually less effective than systemic therapy, being of most value in superficial or mild distal infections. Avulsion is usually warranted only in non​dermatophyte ­infections or when systemic therapy is ineffective or contraindicated. Relapse can be diminished by vigorous treatment of local tinea pedis and avoidance of trauma through correction of orthopaedic abnor- malities and the wearing of broad-​fitting footwear. Nails in systemic disease Clubbing This is a classic sign of various disorders (Box 23.13.1), but is seen in some healthy people. It is usually more obvious on the fingers than the toes; increased longitudinal curvature and loss of the angle between the nail at its proximal margin and the nail fold is seen. This margin is ‘boggy’ or fluctuant. There may be associated cyanosis if clubbing is caused by cyanotic heart disease or certain pulmonary diseases. Classic changes of geometry change the angle (Lovibond’s angle) at the junc- tion of the proximal nail fold and nail plate. Normally, this is less than 160 degrees, but in clubbing it increases to become more than 180 degrees. Clinically, this corresponds to the loss of a window visible be- tween the dorsal aspects of corresponding contralateral fingers when held against each other (Schamroth’s sign). Prominent clubbing can be part of hypertrophic pulmonary osteoarthropathy (HPOA) where hypertrophy of the upper and lower extremities resembles that seen in acromegaly, with additional pseudoinflammatory painful changes of the large limb joints with associated radiological and neurovascular changes. Secondary HPOA is typically associated with lung car- cinoma, mesotheliomas of the pleura, and, less commonly, bronchi- ectasis. Primary HPOA is associated with mutations in the HPGD and SLCO2A1 genes which are involved in prostaglandin metabolism and prostaglandin transmembrane transport, respectively. The diagnostic features of clubbing are shown in Fig. 23.13.5. Splinter haemorrhages These represent blood escaping from the longitudinal capillaries in the nail bed beneath the nail (Fig. 23.13.2a). They can have a local or systemic cause. The most common causes are trauma (e.g. manual labour) and nail psoriasis, in which nail bed vessels are more nu- merous and fragile. Significant systemic causes are uncommon; they include infarction of the vessels (e.g. microemboli in endocarditis) and vessel damage related to other causes of vasculitis. The likelihood of a systemic dis- order is greater when there are associated nail fold infarcts than when nail bed changes are found in the absence of nail dystrophy. Nail fold vessels They might become prominent with dilatation, tortuosity, and haemorrhage. This can be associated with increased length and a ragged appearance of the cuticle. These changes are seen in con- nective tissue diseases, in particular systemic sclerosis, dermato- myositis, and systemic lupus (see Chapter 23.7). Beau’s lines Any severe illness can lead to a transverse arcuate depression on each nail, often most prominent on the thumbs. Because the average Fig. 23.13.4  Superficial white onychomycosis affecting the big toe and the third toe. Involvement of the upper surface of the big toe is exacerbated by the overlapping second toe. Box 23.13.1  Systemic causes of clubbing • Idiopathic/​congenital • Cardiovascular — Congenital cyanotic heart disease — Infective endocarditis • Respiratory — Bronchiectasis — Bronchial carcinoma — Empyema — Fibrosing alveolitis • Gastrointestinal — Liver disease — Inflammatory bowel disease — Malabsorption

23.13  Hair and nail disorders 5727 rate of fingernail growth is 2–​4 mm per month, the position of the line indicates the approximate date of onset of the original illness. A milder event may produce just a pale transverse line in the nail (see Mee’s lines, next). Thyroid disease Localized separation of the nail from the nail bed (onycholysis) is sometimes seen in thyrotoxicosis. In hypothyroidism, nail thickening is more common. A form of clubbing termed ‘thyroid acropachy’ occurs in Graves’ disease. Koilonychia (spooning of the nails) This is occasionally seen in iron deficiency anaemia. It is common in the big toes of normal babies and infants, and has been reported in mechanics performing oily work. Rickshaw pullers tend to develop traumatic toenail koilonychia. Acquired colour changes None of the classic variants of white transverse bands or zones repre- sent firm clinical signs. The three main signs reflect vascular changes within the nail bed, unlike the fourth which represents abnormal nail production (Table 23.13.1). Terry’s nail A white nail bed obscures the lunula and extends to the distal 2–​ 3 mm of the nail bed, where there is a red-​brown appearance. This is sometimes associated with cirrhosis, in which setting it was origin- ally described; it is also seen in normal ageing. Uraemic half and half nail This is similar to Terry’s nail, but only 50% of the proximal nail bed is involved and associated with uraemia in some instances. Muehrcke’s bands These are thin, transverse white bands seen usually within the prox- imal part of the nail bed, but which move distally to some degree. They appear sensitive to blood albumin levels and can be reversed if it is normalized. This association is not invariable and there is some overlap with the appearance of Mee’s lines where the change is in the nail plate and not the nail bed. Mee’s lines These are transverse bands resembling Muehrcke’s bands but the white change appears within the nail plate rather than the nail bed. This re- flects a period of abnormal nail production that usually corresponds to (b) (a) 160

180 Schamroth’s window open in normal digit Phalangeal depth ratio Nail-fold angles Normal Clubbed Clubbed Normal Schamroth sign Normal B A C D Clubbed A B C D Schamroth’s window closed in the clubbed digit DPD IPD DPD IPD Fig. 23.13.5  Diagnostic features of clubbing. (a) The normal angle between the nail plate and the proximal nail fold is less than 160 degrees, increasing to greater than 180 degrees in clubbing. If the depth of the finger is measured at the interphalangeal joint (interphalangeal finger depth, IPD), it is greater than the depth as measured at the edge of the proximal nail fold (distal interphalangeal finger depth, DPD) in a normal finger. In clubbing it is the reverse. (b) When two contralateral fingers are apposed on their dorsal surfaces, a diamond-​shaped window is revealed in normal fingers, bordered by the proximal nail fold and proximal nail (Schamroth’s window). This is lost in clubbing. Table 23.13.1  Systemic causes of nail discolouration Nail colour Location Causes Yellow Nail plate Yellow nail syndrome White Nail bed Hypoalbuminaemia Brown Nail bed Chronic renal disease Blue Nail bed Mepacrine Lunula Wilson’s disease Red Lunula Congestive cardiac failure, rheumatoid arthritis

section 23  Disorders of the skin 5728 some form of poisoning. The most common is therapeutic poisoning in the form of chemotherapy, but criminal poisoning with arsenic has been detected by this sign. Associations between acquired nail colour changes, drugs, and systemic disease are listed in Table 23.13.1. Disorders of the hair Hair arises from follicles distributed almost universally over the body surface, within the skin. In some areas it becomes dark and relatively thick in diameter such as in the axillae, groin, and beard. On the scalp it is variably pigmented and of moderate bore. On the rest of the body it is generally pale, fine, and termed vellus hair. Vellus hair is short. Length is determined by the period of growth of any single hair before the hair follicle transforms out of the growth phase (anagen) and into the resting phase (telogen), during which the hair is shed and the follicle gradually returns to the growing phase. The characteristics of scalp disease, features of follicular change, and hair shaft morphology can all be assessed by the use of a dermatoscope, which when used on the scalp is referred to as trichoscopy. Follicles that have an anagen phase of 1000 days or more will grow hair far longer than those where it is limited to 60 days and this re- flects the situation for the scalp and eyebrow, respectively. If scalp hair follicles were grafted to the eyebrow, they would retain their scalp identity and the person would grow extremely long eyebrows! Scalp psoriasis Scalp psoriasis can present in isolation. Equally, where signs else- where are equivocal, scalp changes should be sought to explore and clarify the diagnosis. Typically, there are zones of redness with mod- erate demarcation and variable amounts of scale. Scale can be either light and yellow or composed of dense, adherent white material that exposes pin point bleeding of the scalp when picked off. There is a predilection for the margins of the scalp, the creases behind the ears, and within the external auditory canal. There is rarely marked hair loss, but when inflammation is intense there may be shedding and, if associated with prolonged periods of dense scale, scarring can occur. Diagnosis can be confirmed by scalp biopsy where the main differ- ential is with eczema or discoid lupus erythematosus. The main local scalp diseases, including psoriasis, as well as systemic diseases and treatments affecting hair growth are shown in Box 23.13.2. Treatment Patients mainly complain of itch, scale that drops onto clothing, and the appearance within the hair line. Itch can be relieved short term by washing with tar-​based shampoos, but this does little more than wash away the surface scale and only provides a weak antipruritic dose of tar coupled with the detrimental irritant effects of shampoo. It does not address the underlying inflammatory process. Alcohol-​ based steroid preparations delivered through a nozzle are popular because they leave no residue on the hair and are easy to apply. However, the alcohol can sting in the cracked inflamed skin and the barrier function of the diseased skin is further compromised by the solvent properties of the alcohol. The most effective local treatments entail making a mess of the hair in order to treat the scalp as for psor- iasis elsewhere. This can include thick emollient based products con- taining tar, salicylic acid, and coconut oil massaged carefully into the scalp and left overnight before washing out. An overnight shower cap can protect the pillow and enhance the emollient effect on the scalp. Vitamin D-​based products, topical steroid as foam, gel or shampoo, and dithranol can all be used on the scalp. Systemic therapies used for widespread psoriasis also help the scalp, while phototherapy provides less benefit as the scalp is photoprotected by hair. Eczema Scalp eczema This is usually part of atopic eczema and will be found with a typical history and appearance of the disease elsewhere (see Chapter 23.6). The treatments are as for the skin, with an emphasis on avoidance of irritants (use conditioner in place of shampoo and avoid alcohol-​ based topical products), the use of some emollient (ideal with short hair, but otherwise use steroids in lotion or cream base), and some steroid creams, gels, or foams. Allergic contact scalp dermatitis This can present acutely, typically in connection with paraphenylenediamine (PPD) in hair dyes. Less aggressive presentations are with allergy to ingredients in other hair cos- metics. Paraphenylenediamine allergy can be sufficiently florid as to appear as an acute cellulitis of the scalp, descending onto the forehead. There may be significant reversible hair shedding in the after- math of such an episode. The allergen is determined by patch testing (see Chapter 23.6). Irritant scalp dermatitis This presents with gradual widespread scalp itch, dryness, and light scale with only slight inflammation. It is usually due to excess use of shampoo in someone who has a low threshold for skin irritancy—​ which can be part of atopy or acquired with age and loss of sebum. Seborrhoeic dermatitis of the scalp This is also termed pityriasis capitis. It barely itches, but presents as scaling or as ‘heavy dandruff’. Redness and scale affect the nasolabial folds, eyebrows, sternum, and sometimes interscapular skin. In the Box 23.13.2  Local scalp diseases and systemic diseases and treatments affecting hair growth The main local scalp diseases affecting hair growth are: • Psoriasis • Eczema • Fungus • Alopecia areata • Scarring alopecia: lichen planopilaris and discoid lupus erythematosus Systemic diseases/​treatments affecting hair growth are: • Telogen effluvium • Endocrine:  androgen secreting pathologies, hypopituitarism, hypo/​ hyperthyroidism, hypoparathyroidism, acromegaly, hyperprolactina­ emia, Cushing’s syndrome • Iron deficiency • Malnutrition • Severe chronic illness • Genetic syndromes • Drugs (e.g. antimitotic, anticoagulants, oral contraceptives)

23.13  Hair and nail disorders 5729 scalp it might be difficult to distinguish from psoriasis, with light, yellow, slightly greasy scale. Overgrowth of normal skin malassezia yeasts plays a part in the disease and management can be directed at reducing the concentration of this yeast on the skin and scalp with antifungal shampoos containing azoles or selenium sulphide. Topical hydrocortisone can reduce the inflammatory component. Fungal scalp disease Fungus can primarily affect the hair shaft, or the scalp, or both. Where the scalp is heavily involved, it can respond either mainly with scaling or with inflammation, with some common ground between both presentations. An intense inflammatory response can produce a raised, oedematous boggy mass known as a kerion. This is usually found in children in contact with farm animals or pets where the zoophilic fungi Trichophyton verrucosum or Microsporum canis are encountered. Transmission between hu- mans is of anthropophilic fungi where the inflammatory response is usually less. Patterns include discoid areas of hair loss, diffuse scale, diffuse pustules, kerion formation or a scalp with little scale and inflammation, and hairs that snap at the scalp surface revealing a ‘black dot’ of residual hair shaft. Changing urban patterns of fungal scalp disease means that this variant due to Trichophyton tonsurans is now the most common in western medicine. Diagnosis is by scalp scraping and hair pluck for mycology. A differential diag- nosis can be sought by scalp biopsy, but this is seldom necessary in a child. Treatment is with systemic griseofulvin, itraconazole, or terbinafine. All are effective, but griseofulvin requires longer treat- ment and has more side effects. However, in many countries it is the only systemic agent licensed in children who are the most common sufferers. Contact tracing within the extended family is important to try to prevent relapse through reinfection. Infectivity in the early phases of treatment can be reduced with use of antifungal sham- poos. A kerion can give rise to long-​term scarring hair loss, due to the intensity of the inflammation. Alopecia areata The classic pattern of alopecia areata is with small discoid areas (‘areata’) of hair being shed in a scattered distribution on the scalp or body. The eyebrows, and lashes are also commonly affected and the beard area in men. Hair loss might progress through a phase where there are residual white hairs (being lost last) followed by a smooth scalp with retained normal hair follicle openings and no apparent inflammation (Fig. 23.13.6). Scalp biopsy reveals a T-​lymphocyte inflammatory process engulfing the dermal papilla of the hair fol- licle. This autoimmune attack on the follicle arises in genetically sus- ceptible people. It which switches off anagen, leading to shedding of hair. This attack is not always overwhelming and some follicles might continue to produce small, short-​lived, slightly dystrophic hairs with partial pigmentation. These are known clinically as ‘ex- clamation mark’ hairs because they are distally thicker and more pigmented than they are proximally. Details of the residual follicular openings and exclamation mark hairs are best detected using a dermatoscope (Fig. 23.13.7). Typically, no tests are needed to estab- lish the diagnosis. Where all the hair on the scalp is lost, the clinical pattern is re- ferred to as alopecia totalis, which can extend to all hair throughout the body, known as alopecia universalis. The likelihood of spontan- eous regrowth of hair is between 60 and 80% for small ‘areata’, but 10% or less for extensive patterns. There is a statistical association with autoimmune thyroid disease. Treatment Treatment might suppress the immune attack on the follicle for as long as therapy is maintained, but any clinical response is prone to relapse once treatment is stopped. Topical (lotion, gel, foam, shampoo), locally injected, and sys- temic steroids can all be used, with greater efficacy in proportion to penetration and concentration of steroid. Local side effects of atrophy become prominent with time. The side effects of systemic steroid mean that this is not a good long-​term treatment choice. Topical immunotherapy is the term applied to the other main treat- ment option where the patient is sensitized to either diphencyprone or squaric acid dimethylbutyl ester. These chemicals are then ap- plied to the affected scalp at regular intervals to provoke an allergic contact dermatitis. Hair might grow in response to this in 50–​60% of patients, with less than 20% in more extensive patterns of loss. Relapse after treatment is common. These chemicals have no license for medical use and there are problems with sensitization of medical Fig. 23.13.6  Alopecia areata with smooth non​scarred scalp retaining normal skin markings. Fig. 23.13.7  Scalp dermoscopy illustrates exclamation mark hairs within the affected area and normal follicular openings distinguishing it from a scarring alopecia.

section 23  Disorders of the skin 5730 staff and contamination of work areas, which limits acceptance. Wigs, hair pieces, and psychological support can be very helpful and are not to be underestimated. Scarring alopecia Lichen planopilaris (LPP) and discoid lupus erythematosus (DLE) These are two of the more common forms of scarring alopecia. Lichen planopilaris is characterized by perifollicular purplish discoloration and scale. The interfollicular skin can be normal. Meanwhile, discoid lupus erythematosus has a more coarse pattern of scale and is more likely to affect the scalp between follicles. Where hairs have been lost, the follicles might be plugged with scale (Fig. 23.13.8). Both condi- tions can leave scarring which appears as multiple hairs aggregated within one follicular opening and loss of normal follicle openings in adjacent scalp. With time, these areas might become smooth, hypo or hyperpigmented. Both conditions may have signs elsewhere to help confirm the clinical diagnosis (see Chapters  23.5 and 23.7). Confirmation of the diagnosis is by scalp biopsy with testing for immunofluorescence. False positive immunofluorescence can be a problem on the scalp. Serological tests are done to exclude systemic lupus erythematosus or in preparation for systemic medication. Treatment Both conditions can be progressive and irreversible and hence short-​ term early treatment with systemic steroid can be justified as a means of containing active disease before establishing a less toxic regimen for maintenance. Systemic hydroxychloroquine and acitretin are common options in this order for discoid lupus erythematosus and ciclosporin is an option for lichen planopilaris. Doses can be min- imized by coincident, locally injected, or topical potent steroid. Sun avoidance can be important for some discoid lupus erythematosus patients where photo-​exacerbation is noted. Systemic diseases and hair changes Telogen effluvium (TE) is the most common hair problem related to general medical or surgical upset. It is characterized by pronounced shedding of hair about 6–​10 weeks after a period of significant physiological disturbance such as major blood loss, high fevers, or a period of active inflammatory bowel disease. The patient might not make the association with recent illness and such clues need to be actively sought when someone presents with hair loss. Anagen effluvium describes a more acute pattern where a toxic event im- mediately switches off the hair follicle. The typical example of this is cancer chemotherapy, where treatment is often directed at prolif- erative cells, inadvertently including those of the dermal papilla of the hair follicle. Other drugs such as retinoids, some anticonvulsants, and proges- togens might contribute to hair loss. The list is much longer, but the data to support commonly cited drugs, such as statins, hormone re- placement therapy, and atenolol are less clear. Treatment This entails looking for any active contributing inflammatory or other systemic precipitating factor and correcting it. The iron status might have some independent relevance and should be maintained within the normal range. Usually, the hair will return to normal. The exception is when the individual is of an age where normal patterns of balding are evolving. In this instance, they might find that the hair pattern returns one or two grades down the line of age-​related patterned balding. Where scalp hair loss presents in a woman with increased hair on the body or at sites associated with masculinity (hirsutism), a pathological source of androgen should be sought. The history is extremely important in terms of establishing the time course of change and whether the problem is part of a familial pattern. Disturbed menses will increase the index of suspicion of a definable endocrine cause. In someone with recent alteration of menses and evolving male-​type hair changes, the concern is of an androgen se- creting tumour. Where there is a family history and problems have been established over years, often since puberty, the diagnosis is more likely to be polycystic ovary disease. Both can be screened by checking the free testosterone levels. Where this is elevated, further endocrinological, and possibly gynaecological assessment is war- ranted. The rash of secondary syphilis can cause a patchy pattern of hair loss scattered over the scalp like numerous ‘glades in a wood’. FURTHER READING Disorders of the nails Baran R, et al. (eds) (2012). Baran & Dawber’s diseases of the nails and their management, 4th edition. Wiley-​Blackwell, Chichster. Daniel CR 3rd, Zaias N (1988). Pigmentary abnormalities of the
nails with emphasis on systemic diseases. Dermatol Clin, 6, 305–​13. de Berker D (2009). Clinical practice: fungal nail disease. N Engl J Med, 360, 2108–​16. de Vries AC, et al. (2013). Interventions for nail psoriasis. Cochrane Database Syst Rev, 1, CD007633. Dehesa L, Tosti A (2012). Treatment of inflammatory nail dis- orders. Dermatol Ther, 25, 525–​34. Eisman S, Sinclair R (2014). Fungal nail infection:  diagnosis and management. BMJ, 348, g800. Fig. 23.13.8  Dermoscopy of scalp discoid lupus erythematosus with inflammation, perifollicular scale, and waxy change in the scarred areas with loss of follicular openings.

23.13  Hair and nail disorders 5731 Epstein E (1998). How often does oral treatment of toenail onycho­ mycosis produce a disease-​free nail? Arch Dermatol, 134, 1551–​4. Hershko A, et al. (1997). Yellow nail syndrome. Postgrad Med J, 73, 466–​8. Lencastre A, Lamas A, Sá D, Tosti A (2013). Onychoscopy. Clin Dermatol, 31, 587–​93. Myers KA, Farquhar DR (2001). The rational clinical examination. Does this patient have clubbing? JAMA, 286, 341–​7. Tosti A, Piraccini BM, Lorenzi S (2000). Onychomycosis caused by nondermatophytic molds: clinical features and response to treat- ment of 59 cases. J Am Acad Dermatol, 42, 217–​24. Disorders of the hair Fuller LC, et  al. (2003). Diagnosis and management of scalp ring- worm. BMJ, 326, 539–​41. Gupta AK, Drummond-​Main C (2013). Meta-​analysis of random- ized, controlled trials comparing particular doses of griseofulvin and terbinafine for the treatment of tinea capitis. Pediatr Dermatol, 30, 1–​6. Harrison S, Sinclair R (2002). Telogen effluvium. Clin Exp Dermatol, 27, 389–​5. Mason AR, et  al. (2013). Topical treatments for chronic plaque
psoriasis of the scalp:  a systematic review. Br J Dermatol, 169, 519–​27. Messenger AG, et al. (2012). British Association of Dermatologists’ guidelines for the management of alopecia areata. Br J Dermatol, 166, 916–​26. Mubki T, et al. (2014). Evaluation and diagnosis of the hair loss pa- tient: part II. Trichoscopic and laboratory evaluations. J Am Acad Dermatol, 71, 431.e1–​431.e11. Price VH (2006). The medical treatment of cicatricial alopecia. Semin Cutan Med Surg, 25, 56–​9. Rosenfield RL (2005). Clinical practice: hirsutism. N Engl J Med, 353, 2578–​88. Schmidt TH, Shinkai K (2015). Evidence-​based approach to cutaneous hyperandrogenism in women. J Am Acad Dermatol, 73, 672–​90. Sperling LC, Solomon AR, Whiting DA (2000). A new look at scarring alopecia. Arch Dermatol, 136, 235–​42.

23.14 Tumours of the skin 5732 Edel O’Toole

23.14 Tumours of the skin 5732 Edel O’Toole

ESSENTIALS A variety of tumours, both benign and malignant, are found in skin. Benign skin lesions, such as seborrhoeic keratoses and skin tags, are often just a cosmetic nuisance, but some benign skin lesions can be a component of diseases with serious medical consequences (e.g. neurofibromatosis or LEOPARD syndrome). Exposure to ultraviolet light is a major factor leading to the devel- opment of both benign lesions (e.g. melanocytic naevi) and most skin cancers. Changes in dress style, increased travel abroad, use of sun tanning salons (sunbeds), and the depletion of the ozone layer have all contributed to increased exposure to ultraviolet light. Skin cancer is the most common human cancer and its incidence continues to increase. It most commonly affects older, fair-​skinned individuals who have had either acute intermittent exposure to ultra- violet light or chronic ultraviolet light exposure. Organ transplant re- cipients have a 200-​fold increased risk of squamous cell carcinoma. About 2% of patients who develop skin cancer have a genetic predis- position, for example, Gorlin’s syndrome in basal cell carcinoma and familial melanoma syndromes in malignant melanoma. Mutations in the PTCH gene cause Gorlin’s syndrome, and loss of heterozygosity at that locus is also present in most sporadic basal cell carcinoma. Non​melanoma skin cancer is rarely fatal, but can cause a lot of morbidity. Malignant melanoma is a deadly skin cancer which is the second most common cancer (excluding non​melanoma skin cancer) in young women. Over the last 20 years, its incidence has been increasing faster than any other cancer, with an approximate doubling of rates every 10 years in countries with largely white popu- lations. Early detection and excision of melanoma is the best way to reduce mortality, as there is no curative treatment for metastatic malignant melanoma. Benign skin tumours Benign non​melanocytic tumours Seborrhoeic keratosis Seborrhoeic keratoses are probably the most common benign skin tumour. These lesions are usually found on the trunk in older individuals. Clinical features The classic seborrhoeic keratosis is a dry, brown, warty plaque with a ‘stuck-​on’ appearance (Fig. 23.14.1). There is large variation in colour, including pale and darker lesions which may even simu- late malignant melanoma. The sudden appearance of multiple seborrhoeic keratoses accompanied by the development of a malig- nancy is known as Leser–​Trélat sign. Treatment If the lesion is definitely a seborrhoeic wart the patient can be re- assured. As the lesions are a cosmetic nuisance, patients may request treatment which can include cryotherapy or curettage. Sebaceous hyperplasia Sebaceous hyperplasia is a common benign tumour of the sebaceous glands usually occurring in middle age. The lesions are usually 2–​ 3 mm, skin-​coloured, or yellow papules with central umbilication from which a small amount of sebum can be expressed. Treatment is usually not needed, but if requested for cosmetic reasons, curettage or gentle cautery are appropriate. Extensive sebaceous hyperplasia may be responsive to low-​dose isotretinoin or laser therapy. Sebaceous adenoma Sebaceous adenomas are also derived from the sebaceous glands. Tumours present as a yellow, smooth papule, or nodule usually on the face or neck and are associated with Muir–​Torre syndrome. This is an autosomal dominant disorder, caused by mutations in the mis- match repair genes, MLH1 or MSH2, with an increased tendency to visceral cancers, particularly colorectal carcinoma. Skin tags Skin tags are extremely common, flesh-​coloured, pedunculated skin lesions that usually occur in the flexures, particularly the neck and axillae. There is some correlation with obesity. Treatment can in- clude cryotherapy or snip excision. Epidermoid cyst An epidermoid cyst consists of a sphere of stratified squamous epi- thelium buried within the dermis. These cysts occur mainly on the face, neck, and chest and have a predilection for the genitalia, where they frequently calcify. A common presentation is a dermal nodule 23.14 Tumours of the skin Edel O’Toole

23.14  Tumours of the skin 5733 with a small pore (punctum) on the surface. The cyst wall can rup- ture into the dermis, causing an intense inflammatory response fol- lowed by suppuration which may require antibiotics and/​or incision and drainage. If the lesion is bothersome to the patient, it may be surgically excised. Milia Milia present as 1–​2 mm white papules, most commonly on the thin skin of the periorbital region in an adult female. Histologically, the lesions are small epidermoid inclusion cysts. A 20 gauge needle can be used to extract milia. Pilar cyst Pilar (trichilemmal) cysts occur on the scalp, where they present as smooth, firm, mobile nodules with overlying hair. A punctum is not usually present and inflammation rarely occurs. Histologically, these cysts differ from epidermoid cysts in having the squamous epithelial lining without the granular layer. Surgical excision can be performed if required. Dermatofibroma The dermatofibroma is a common dermal tumour usually occurring on the limbs. There is sometimes a history of an insect bite or other trauma. The lesions are firm, pink-​brown papules that may involute with time. Xanthogranuloma This is a benign tumour of histiocytic cells which occurs predom- inantly in infancy and early childhood and typically regresses spon- taneously. The characteristic clinical appearance is of reddish yellow papule(s) which enlarge up to 1 cm diameter and evolve into yellow-​ brown plaques and macules. Resolution occurs over months or years to leave small atrophic scars. Visceral involvement might occur in the lung, liver, spleen, testes, pericardium, gastrointestinal tract, and kidney, as well as in the eye. Histologically, the lesions show a mixed dermal infiltrate with histiocytes, lymphocytes, eosinophils, and other cells. A typical feature is the presence of giant cells with a wreath-​like arrangement of nuclei, the Touton giant cell. Benign melanocytic tumours Freckles Freckles (ephelides) are brown macules that occur on sun-​exposed areas, particularly the nose and the arms, in fair-​skinned individ- uals. The lesions often fade in winter. Solar lentigo The solar lentigo is a brown patch occurring on sun-​exposed skin that results from UV exposure. Multiple symmetric, hyperpigmented patches on the face, arms, and dorsa of the hands are typical. Lentigines-​associated syndromes Extensive lentigines at a young age might indicate underlying gen- etic disorders such as xeroderma pigmentosum (see Chapter 23.9), Carney’s (atrial cutaneous myxomas, lentigines, blue naevi, endo- crine disorders, and testicular tumours) or LEOPARD (lentigines, electrocardiographic conduction defects, ocular hypertelorism, pul- monary stenosis, genital abnormalities, retardation of growth, and deafness) syndromes. Acquired melanocytic naevi (moles) Melanocytic naevi are benign tumours of melanocytes, and are also known as moles. Aetiology, genetics, and pathogenesis Acquired naevi tend to first appear and increase in number during childhood, reaching their maximum in early adulthood. There is some evidence that the number of acquired naevi might be related to UV exposure. Fair-​skinned individuals and white people who live close to the equator have more acquired naevi than nonwhite popu- lations. Naevi commonly darken or enlarge during pregnancy sug- gesting a degree of sex hormone responsiveness. Correlation in sex and age-​adjusted naevus density in adolescence is higher in mono- zygotic twins than dizygotic twins suggesting a definite additional genetic effect. About 2% of the UK population have the atypical mole syndrome, which is associated with an increased risk of mel- anoma. Mutations in the BRAF gene, a serine/​threonine kinase in- volved in the mitogen-​activated kinase pathway, are present in about 80% of melanocytic naevi and might contribute to melanocytic hyperproliferation. Clinical Acquired melanocytic naevi appear and change in the childhood, teenage, and early adult years. As a rule, new melanocytic naevi do not appear after the age of 40 years. Junctional naevi are usu- ally flat, uniformly pigmented macules that appear in childhood. Histologically, nests of naevus cells appear at the dermoepidermal junction. Compound naevi are, usually, slightly elevated pig- mented papules. They may have a smooth or papillomatous (a) (b) Fig. 23.14.1  Seborrhoeic warts are often multiple and may be deeply pigmented (a) or light brown (b).

section 23  Disorders of the skin 5734 surface (Fig. 23.14.2a). Compound naevi usually increase in size during adolescence. Nests of naevus cells are found both at the dermoepidermal junction and in the dermis. Intradermal naevi are seen mainly after adolescence. These are skin-​coloured, dome-​ shaped papules that most frequently occur on the face. A  halo naevus is a clinical variant with a ring of depigmentation around an otherwise normal mole (Fig. 23.14.2b). A blue naevus usually occurs on the limbs. It appears blue-​grey because the pigmentation is deep in the dermis. A Spitz naevus usually presents as a vascular-​ looking papule on the face in children. Atypical (dysplastic naevi) are usually more than 5 mm in diameter, have a macular compo- nent, and an indistinct margin, sometimes with background ery- thema. Recognition of atypical naevi is important as individuals with five or more atypical naevi, naevi in unusual locations (scalp, buttocks, dorsum of feet, and iris) and 100 or more naevi more than 2 mm in diameter (atypical mole syndrome) are at increased risk of developing malignant melanoma. Treatment The malignant potential of individual naevi is low, therefore prophy- lactic excision of acquired melanocytic naevi to prevent transform- ation into melanoma is not advised. Excision of naevi is advocated where it is not possible to clinically exclude a diagnosis of melanoma. Complete excision and histological examination is advocated even when moles are removed for purely cosmetic reasons. Although the clinical differentiation of atypical naevi from melanoma is dif- ficult, it can be facilitated by regular surveillance, automated digital imaging systems, and dermoscopy. Removal of an atypical mole is only necessary if melanoma is suspected. Congenital melanocytic naevi Clinical Congenital melanocytic naevi (CMN) are proliferations of nested melanocytes that are present at birth. The term is also used to de- scribe histologically and clinically identical lesions that appear in diameter in infancy. Small CMN (<1.5 cm in diameter) are seen in 1–​2% of neonates, intermediate-​sized lesions (1.5–​20 cm) in 0.6%, and large and giant CMN (>20 cm) in about 0.02%. Giant CMN may also be known as ‘bathing suit naevi’ because of their distribu- tion. The lesions are tan, brown to dark brown patches or plaques at birth. They may have a smooth, nodular, or verrucous surface which might be hair-​bearing. Patients with large CMN are at increased risk of developing melanoma within the CMN, in the central nervous system, and elsewhere. Treatment Most small and intermediate CMN can be managed by routine surveillance. The lifetime risk of malignant melanoma in a patient with a large CMN is about 7%. Parents should be instructed on proper sun avoidance and sun protection techniques including use of sunscreen and use of high-​weave, sun-​protective clothing. Many specialists recommend partial or complete excision of large CMN. This might require multiple surgical procedures, tissue expansion, and/​or grafting. Other surgical options include cur- ettage, dermabrasion, or laser surgery to remove the superficial naevus cells. Premalignant lesions Solar keratosis Solar keratoses (also known as actinic keratoses) are erythematous scaling lesions between 2 and 10 mm in diameter, seen in fair-​skinned individuals on areas of maximal sun exposure such as the face, ears, dorsum of the hands, forearms, and lower legs. Histologically, these lesions show dysplasia of the basal keratinocytes. The estimated risk of transformation into squamous cell carcinoma (SCC) is very low, approximately 1% per annum. Some small lesions resolve spontan- eously, particularly with photoprotection. Treatment options include cryotherapy, topical diclofenac, ingenol mebutate, 5-​fluorouracil, or imiquimod, a topical immune modifier. Bowen’s disease Bowen’s disease (squamous cell carcinoma in situ) presents as an asymptomatic, enlarging, erythematous, scaly plaque. Approximately 5% progress to invasive squamous cell carcinoma. Bowen’s disease affecting the glans penis is called erythroplasia of Queyrat. Bowen’s disease might be misdiagnosed as tinea, psoriasis, or discoid eczema. Biopsy of a typical lesion shows full-​thickness dysplasia of the epidermis. Treatment can include cryotherapy, top- ical 5-​fluorouracil, topical imiquimod, or photodynamic therapy. (a) (b) Fig. 23.14.2  (a) Benign compound naevus with papillomatous surface. (b) Halo naevus showing an area of depigmention around a benign mole. The mole might eventually regress completely leaving a depigmented patch, which will eventually repigment.

23.14  Tumours of the skin 5735 Malignant skin tumours Non​melanocytic Basal cell carcinoma Introduction Basal cell carcinoma (BCC) is the most common cancer in humans, which typically occurs in areas of chronic sun exposure. Basal cell carcinomas are usually slow-​growing and rarely metastasize. Aetiology The most common factor involved in the pathogenesis of basal cell carcinoma is exposure to ultraviolet light (UV). Fair-​skinned individ- uals who burn easily and tan poorly are at greatest risk of developing basal cell carcinoma. Both cumulative lifetime UV exposure and intermittent intense sun exposure are risk factors. Other sources of UV include sunbeds and psoralen ultraviolet A (PUVA) for psoriasis. Other environmental factors leading to the development of basal cell carcinoma include ionizing radiation given for benign conditions (e.g. acne, tinea capitis) and arsenic ingestion. Organ transplant re- cipients have a 10-​fold increased risk of basal cell carcinoma. Genetics Several genetic syndromes of increased susceptibility to basal cell carcinoma have been described. The most significant is Gorlin’s syndrome (naevoid basal cell carcinoma syndrome) which is char- acterized by the appearance of basal cell carcinomas before the age of 20, an autosomal dominant family history, palmar/​plantar pits, odontogenic keratocysts, and bilamellar calcification of the falx cerebri. Mutations are present in the human PTCH gene, the human homologue of the drosophila patched gene Ptch1. Ninety per cent (90%) of sporadic nodular basal cell carcinomas have loss of hetero- zygosity at chromosome 9q21-​q31, where the PTCH gene is located and 70% of nodular basal cell carcinomas have detectable PTCH gene mutations. This gene negatively regulates the hedgehog signalling pathway, which is important in epithelial cell growth during hair follicle development, and an inactivating mutation allows uncon- trolled hedgehog signalling. Activating mutations in the SMO gene (smoothened) similarly allow for unregulated hedgehog signalling in basal cell carcinoma. About 40% of basal cell carcinoma have UV-​induced transition mutations in TP53. Polymorphisms in genes activated by exposure to UV, such as reactive oxygen species (GST, CYP450) or DNA repair (xeroderma pigmentosum), are also sig- nificantly associated with risk of basal cell carcinoma development. Pathology The major histological patterns of basal cell carcinoma are nodular, micronodular, superficial, and morphoeic. The nodular type is characterized by well-​defined islands of basaloid cells with well-​ defined peripheral palisading. The superficial type has foci of tu- mour extending from the epidermis into the papillary dermis. The morphoeic subtype has tumour islands of varying size with sur- rounding fibrosis. Epidemiology Basal cell carcinoma most commonly occurs in white, fair-​skinned individuals and rarely occurs in darker skin types. Although it more commonly occurs in men, the incidence of basal cell carcinoma con- tinues to rise in women because of increased UV exposure due to changes in dress and lifestyle, including ‘sun holidays’ and use of sunbeds. Prevention The most important risk factor is cumulative lifetime UV exposure. Avoidance of exposure to UV radiation is encouraged. Helpful preventive measures include avoidance of midday/​afternoon sun, wearing a broad-​brimmed hat during outdoor activities, and using sunscreens with sun protection factor (SPF) of 15 or greater (see Chapter 23.9). Patient education about the appearance of new le- sions to maximize early detection should be encouraged. Clinical features Approximately 50% of basal cell carcinomas occur on the head and neck, 30% on the upper trunk, and the remainder elsewhere. The clinical variants include nodular/​nodulocystic, morphoeic, superfi- cial, and pigmented basal cell carcinomas. The nodular subtype rep- resents about 60% of basal cell carcinomas and presents as a small, pink nodule, with a translucent, pearly appearance with telangi- ectasia (Fig. 23.14.3a). As the lesion enlarges, central ulceration can occur (‘rodent ulcer’). Although slow-​growing, if neglected, these tumours can enlarge and extend deeply, causing significant damage to eyelids, nose, or ears. Superficial basal cell carcinoma accounts for about 20% of such carcinomas and is more commonly found on the trunk and extremities. Typically, the lesion is a slightly scaly, pink plaque with a threadlike, translucent, raised border. Multiple lesions might be present. Melanin pigmentation can occur in both superficial and nodular basal cell carcinomas, giving a pigmented variant which is more common in individuals with dark skin (a) (b) Fig. 23.14.3  (a) Basal cell carcinoma in a common location, nasal aspect of the nasolabial fold. Note the surface crusting and telangiectasia. (b) Pigmented basal cell carcinoma.

section 23  Disorders of the skin 5736 (Fig. 23.14.3b). Morphoeic (infiltrative) basal cell carcinomas pre- sent as an indurated, ivory plaque, often resembling a scar. The name is derived from its resemblance to a plaque of localized scleroderma (morphoea). This variant is notable for its tendency to extend be- yond the apparent clinical borders and a high local recurrence rate after treatment. Differential diagnoses of nodulocystic basal cell carcinoma to consider include intradermal naevi and rarer tumours derived from appendageal structures. Clinical investigation Dermoscopy (a magnifying device with or without polarizing light) can be used to refine the clinical diagnosis of basal cell carcinoma. Features include arborizing telangiectasias, leaf-​like areas, foci of ul- ceration, blue/​grey globules, and large blue/​grey ovoid nests. A small shave or punch biopsy is usually sufficient to confirm the diagnosis and histological subtype of basal cell carcinoma. Treatment Treatments are influenced both by tumour factors (the size, site, margin, and subtype of the basal cell carcinoma) and patient fac- tors (such as age, coexisting illnesses, e.g. bleeding diathesis, anti- coagulant therapy, or susceptibility to bacterial endocarditis), access to specific treatments locally, and patient preference. Options for superficial basal cell carcinoma include topical imiquimod, which has largely replaced 5-​fluorouracil, and cryotherapy. Nodular basal cell carcinoma can be treated by curettage and cautery or simple excision. Morphoeic or nodular basal cell carcinomas in high-​risk sites ideally should be treated with Mohs’ micrographic surgery, which is performed in stages with examination of the histological margins, but wide excision can be performed if this is not available. Photodynamic therapy may be useful for thin basal cell carcinomas at cosmetically difficult sites. Radiotherapy can be useful in older patients where surgery is not feasible. With appropriate patient selection, the treatments just described will give cure rates exceeding 95%. Patients who have had one basal cell carcinoma have a 20% risk of developing a further basal cell car- cinoma over the following five years. It is likely that over the next 5–​10 years, further basal cell car- cinoma tumour suppressor genes will be identified. Clinical trials of oral vismodegib, a small molecule inhibitor of smoothened, showed antitumour activity in inoperable basal cell carcinoma and Gorlin’s syndrome. Other small molecule inhibitors of the hedgehog pathway might be used routinely in the future, either systemically or topically. Squamous cell carcinoma (SCC) Squamous cell carcinoma is the second most common form of skin cancer and usually occurs on sun-​exposed areas in older individuals. Aetiology, genetics, pathogenesis, and pathology Squamous cell carcinoma is a malignant tumour of epidermal kera- tinocytes. Its development is multifactorial, involving both gen- etic predisposition and environmental factors. Most squamous cell carcinomas occur on sun-​exposed areas (head and neck, dorsum of hands). Individuals with type I and II skin types (who burn easily) are at greatest risk. Africans with oculocutaneous albinism, who have lost their protective melanin, also have an increased risk of squamous cell carcinoma. The amount of chronic cumulative sun exposure is a major risk factor for squamous cell carcinoma. The highest incidence of squa- mous cell carcinoma worldwide is in Australia, a country with a large white population and year-​round sunshine. Absorption of UVB by DNA in skin keratinocytes induces unique mutations at the site of pyrimidine dimers. Ultraviolet B (UVB) irradiation also leads to the activation of cell cycle checkpoint controls and apoptotic pathways. The repair and/​or elimination of such apoptotic and mutated cells from the epidermis by ‘gatekeeper genes’ such as TP53 is important, as clonal proliferation of mutated cells may eventually lead to cancer development. Mutations in TP53 are found in up to 90% of squamous cell carcinomas. Mutations in HRAS, KRAS, p16INK4a and p14ARF, as well as hypermethylation without mutation, have also been docu- mented in squamous cell carcinoma. Exome sequencing has recently identified inactivating mutations in NOTCH1/​2 in cutaneous squa- mous cell carcinoma. The Notch pathway is an important regulator of differentiation, epidermal barrier formation and inflammation. Finally, mutations in HRAS, KRAS, and KNSTRN, which encodes a kinetochore protein, have also been demonstrated in squamous cell carcinoma. UVA also plays a role in squamous cell carcinoma car- cinogenesis through DNA damage, modulation of protein kinase C, and immunosuppression. There is evidence that human papillomavirus (HPV) might play a causal role in the condition (Chapter 8.5.19). Epidermodysplasia verruciformis (EV), a rare inherited disorder with a high risk of squa- mous cell carcinoma is associated with susceptibility to infection with specific HPV types, called ‘EV types’, including the oncogenic HPV-​5. Organ transplant recipients are highly susceptible to HPV infection, particularly warts, and have a c.200-​fold risk of squamous cell carcinoma compared to the immunocompetent population. Up to 80% of transplant squamous cell carcinomas have detectable EV-​ type HPV DNA. HPV E6 and E7 proteins functionally inactivate TP53. Azathioprine and UVA radiation have recently been shown to generate oxidative DNA damage which may be a further risk factor in organ transplant recipients. Other documented risk factors include arsenic ingestion and exposure to chemical carcinogens such as polycyclic aromatic hy- drocarbons found in soot and tar (a historical example of this is squamous cell carcinoma of the scrotum in chimney sweeps). Other conditions predisposing to squamous cell carcinoma include chronic ulcers (known as Marjolin’s ulcer), recessive dystrophic epi- dermolysis bullosa (an inherited blistering disease which heals with extensive scarring), skin damage from ionizing radiation, thermal injury, and lymphoedema. Chronic infection and chronic inflam- mation, such as discoid lupus erythematosus, erosive lichen planus, and lichen sclerosus et atrophicus, also increase the predisposition to squamous cell carcinoma. Mutations in nucleotide excision re- pair genes in xeroderma pigmentosum causing defective DNA repair result in a 1000-​fold increased risk of skin cancers (both non-​ melanoma and melanoma). Epidemiology The incidence of squamous cell carcinoma has doubled over the last 40  years. The British Association of Dermatology estimates that there are 25 000 new cases of squamous cell carcinoma in the United Kingdom annually, representing about one-​quarter of non-​ melanoma skin cancers. Men are affected 2 to 3 times more than women probably because of outdoor occupations, less protective

23.14  Tumours of the skin 5737 clothing, and a greater lifetime cumulative UV radiation exposure. The success of organ transplantation and immunosuppression has also contributed to the increased incidence of squamous cell carcinoma. Prevention Recommendations include photoprotection against UVA and UVB, patient education about warning signs, regular skin examination, and treatment of actinic keratoses. Systemic chemoprevention with oral retinoids may be an option for high-​risk patients (e.g. organ transplant recipients with multiple squamous cell carcinomas). Clinical features The classical squamous cell carcinoma is a pink, keratotic papule or nodule (Fig. 23.14.4) appearing on the head and neck regions on sun-​damaged skin. Surface changes may include ulceration, crusting, scaling, or the presence of a cutaneous horn. As the lesion progresses, it will become nodular and/​or ulcerated. These lesions are frequently tender to compression. Squamous cell carcinoma of the lip generally occurs on the vermilion border of the lip in men with a background of actinic cheilitis (the lower lips are scaly, ir- regularly pigmented, and atrophic). Squamous cell carcinoma of the anogenital region can present with pruritus, a palpable lump, or ero- sion. A full skin examination and palpation of regional lymph nodes is important. The common differential diagnoses of squamous cell carcinoma include keratoacanthoma, hypertrophic actinic keratosis, verruca vulgaris, and basal cell carcinoma. Clinical investigation In most patients, the clinical diagnosis of squamous cell carcinoma is confirmed by excision and histopathology. Where there is diag- nostic doubt, a small biopsy will confirm the diagnosis. Treatment Simple excision with a 4 mm margin of normal surrounding skin is adequate treatment for most low-​risk squamous cell carcinoma. High-​risk tumours (>2 cm in diameter, depth more than 4 mm, lo- cated on ears, lip, nose, or scalp, poorly differentiated, desmoplastic histology, perineural invasion, or subcutaneous invasion and recurrent tumours) should be removed with a margin of 6 mm or ideally using Mohs’ micrographic surgery. Selected small, low-​risk squamous cell carcinomas can be treated with curettage and cau- tery or cryotherapy after a confirmatory biopsy. Radiotherapy can be used for non​resectable tumours. Prognosis The 5-​year cure rate after simple excision of squamous cell carcinoma is 92%. The overall risk of metastasis from squamous cell carcinoma is in the range of 2–​5%. High-​risk squamous cell carcinomas have the greatest risk of metastasis. Chronically immunosuppressed pa- tients also have an increased rate of metastasis. The overall five-​year survival after regional metastasis is just 25%. In addition, patients are at risk of developing a second primary skin cancer. Within five years, 12% cent of patients will have developed a new squamous cell carcinoma, 43% a new basal cell carcinoma, and 2% a malignant melanoma. It is likely that over the next 5–​10 years, the use of genomic and proteomic technology will identify new therapeutic targets in cuta- neous and metastatic squamous cell carcinoma. Cyclo-​oxygenase-​2 inhibitors and antioxidants (e.g. green and black tea compounds), might be potentially useful as chemopreventative agents in pa- tients with multiple actinic keratoses. There will be more aggressive management of patients with high-​risk squamous cell carcinoma, including sentinel lymph node mapping. If a role for HPV in squa- mous cell carcinoma development is validated, there may be ran- domized clinic trials of vaccination against EV-​type HPV in high-​risk groups such as organ transplant recipients. The use of sirolimus, an mTOR inhibitor, instead of calcineurin inhibitors or azathioprine in transplant immunosuppression regimes may reduce the incidence of post-​transplantation cancer. Keratoacanthoma Keratoacanthoma is a clinically and genetically distinct subtype of squamous cell carcinoma. A nodule with a central keratin crater develops rapidly over several weeks, stabilizes in size, and then spontaneously resolves over several months. Histologically and clin- ically (apart from the history), it is difficult to distinguish from a well-​differentiated squamous cell carcinoma. There are minimal mi- toses or cellular atypia. Ferguson Smith syndrome is an autosomal dominant disorder presenting with multiple keratoacanthomas at a young age, recently found to be caused by mutations in the trans- forming growth factor receptor β 1 gene (TGFBR1). Hundreds of eruptive keratoacanthomas occur in the Grzybowski variant. Keratoacanthomas are also found in Muir–​Torre syndrome. Melanocytic tumours Malignant melanoma Malignant melanoma (MM) is a melanocyte-​derived tumour located predominantly in the skin, but also found in the eyes, leptomen- inges, and oral, genital, and rectal mucous membranes. Melanoma accounts for only 4% of all skin cancers, but causes about 80% of skin cancer-​related deaths worldwide. Aetiology, genetics, pathogenesis, and pathology The development of malignant melanoma is multifactorial. Risk factors include fair skin phenotype (blonde/​red hair, freckles easily, blue eyes), blistering sunburn in childhood or adolescence, history Fig. 23.14.4  Squamous cell carcinoma presenting as a nodule with central keratinization on the forehead.

section 23  Disorders of the skin 5738 of excessive UV exposure, greater than 100 melanocytic naevi, greater than five atypical/​dysplastic naevi, personal or family his- tory of malignant melanoma, and changing moles. The presence of the atypical mole syndrome (also known as familial atypical mole melanoma syndrome) or xeroderma pigmentosum increases the risk by 500–​1000-​fold. More than 60% of melanomas arise de novo (no pre-​existing lesion). The genetics of inherited cancers are further discussed in Chapter 5.3. BRAF mutations occur in 70% of melanomas arising in intermit- tently sun-​exposed sites. The receptor tyrosine kinase gene, KIT, is mutated in 20% of acral and mucosal melanomas. Melanocortin 1 receptor variants that cause red hair and freckling are associ- ated with a small increase in melanoma risk (two–​threefold) and an increased risk of melanoma with BRAF mutations. There are probably at least three other genes which underlie predisposition to familial melanoma. The most common is a gene on chromo- some 9, CDKN2A, which codes for p16INK4a, an inhibitor of the cyclin-​dependent kinases 4 and 6. In the United Kingdom, 50% of families with three or more melanoma cases have CDKN2A muta- tions, but only 12% of families with two or fewer cases. The second is the CDK4 gene. A rare, dominant activating mutation in this gene renders it insensitive to p16 inhibition. The third is p14ARF, a second product of the CDKN2A locus. Very rare deletions of this gene have been shown to underlie susceptibility to melanoma and neural tumours. Recent exome sequencing of 14 metastatic melanoma tumours has revealed a novel melanoma oncogene, TRRAP, which is part of a complex regulating the transcriptional activity of TP53 and c-​Myc, and a new tumour suppressor gene, GRIN2A, encoding a glutamate receptor. Melanoma might also occur as a second tumour in familial retinoblastoma and in the Li–​Fraumeni syndrome (associated with sarcomas, brain, and breast tumours). Histologically, a malignant melanoma is an asymmetric le- sion consisting of single or nested melanocytes in the epidermis (pagetoid spread), appendageal structures, and dermis. The tumour melanocytes do not mature as they descend into the dermis. The dis- tribution of melanin is irregular and the melanocytes display atypia and mitoses. An initial radial growth phase (melanocytes prolifer- ating in the epidermis and papillary dermis) is followed by a more aggressive vertical growth phase with more extensive spread deep into the dermis. Epidemiology Malignant melanoma is the most serious type of skin cancer and is primarily a disease of white individuals. It rarely occurs in black and Asian individuals. There were 15 906 new cases of malignant mel- anoma in the United Kingdom in 2015 and about 2459 melanoma related deaths (Cancer Research UK statistics). In the age group 20–​ 39, melanoma is the second most common cancer (excluding basal cell carcinoma and squamous cell carcinoma). The incidence of mel- anoma increases with age with a peak in the fifth decade. Prevention The general public should be encouraged to avoid sunburn and other excessive UV exposure. At risk individuals should use sun- block and wear protective clothing and take vitamin D supple- mentation if levels are suboptimal (see Chapter 23.9). Healthcare professionals and patients should be educated about the features of early malignant melanoma as early detection of thin melanoma is the best method of reducing mortality. Clinical features The major clinical characteristic of melanoma is a changing mole. The seven-​point checklist is useful. Major features (2 points each) are change in size, irregular colour, and irregular shape, while minor features (1 point each) are inflammation, oozing, change in sensa- tion, and diameter 7 mm or less. Suspicion of melanoma is greater for lesions scoring 3 points or more. The mnemonic ABCDE is also used which stands for asymmetry, border irregularity, colour varie- gation, diameter more than 6 mm, and evolving (changing). Four major clinicopathological variants of malignant melanoma have been identified. Superficial spreading melanoma represents about 70% of melanomas and occurs most commonly on the legs in women and on the trunk in men (Fig. 23.14.5a). It presents as a flat, pigmented lesion with variegation in colour and an irregular border. Nodular melanoma accounts for about 15–​20% of melan- omas and presents as a papule or nodule on the trunk (usually in men) or limbs. There is frequently a history of rapid growth. This variant is more likely to be amelanotic (no pigmentation) and there might be a delay in diagnosis (Fig. 23.14.5b). Lentigo maligna, also known as Hutchinson’s melanotic freckle, occurs on the head and neck of older people who have been heavily exposed to sunlight. These are slow-​growing in situ melanomas (Fig. 23.14.5c) with the potential to progress to invasive melanoma (lentigo maligna mel- anoma) and metastasize. Acral lentiginous melanoma occurs on palmoplantar skin (Fig. 23.14.5d) or the nail bed. It occurs in all races and therefore does not appear to be caused by exposure to the sun. A tendency to delayed diagnosis gives this variant a poor prognosis. At presentation, 10% of cutaneous melanomas will have metasta- sized. The primary lesion might regress, leaving a hypopigmented patch, or the primary can be non​cutaneous. Although systemic me- tastasis is predominantly to the lung, liver, brain, and bone, lesions can arise anywhere including bowel, kidney, and muscle. Localized skin metastasis is also common. Differential diagnosis Atypical naevi, deeply pigmented seborrhoeic warts, and pigmented basal cell carcinoma might all simulate melanoma. Dermoscopy can be helpful in discriminating between melanocytic and non-​ melanocytic lesions. Features of malignant melanoma include a broadened pigment network, multiple colours, a blue-​white veil, pseudopods, and peripheral black dots and globules. Clinical investigation The diagnosis should always be based on a full-​thickness excisional biopsy down to fat with a margin of 2 mm of normal skin around the lesion. Sentinel lymph node (initial draining lymph node) bi- opsy (SLNB) with selective complete clearance of regional nodes is now performed in many centres for lesions of AJCC Stage IB or above. Patients with AJCC Stage IIB melanoma or higher will require a CT scan of brain/​chest/​abdomen/​pelvis or a PET scan depending on local preference. Molecular profiling for BRAF muta- tions on the primary tumour is also offered in many centres in the United Kingdom for patients with stage IIB melanoma or more at initial diagnosis.

23.14  Tumours of the skin 5739 Treatment The definitive treatment of localized disease is wide excision of the tu- mour with a normal skin margin of 0.5 cm for in situ melanoma (con- fined to the epidermis), 1 cm minimum and up to 2 cm for tumours with a Breslow’s thickness of 1–​2 mm and 2–​3 cm for thicker lesions. Completion lymphadenopathy can be considered for people whose SLNB shows micro-​metastases. Lymph node dissection is offered to individuals with palpable lymph nodes or nodal disease detected on imaging. NICE guidelines currently suggest offering dabrefinib or vemurafenib, potent inhibitors of BRAF, for treatment of BRAF V600 mutation-​positive unresectable or metastatic melanoma. Complications of treatment include the development of keratoacanthomas, caused by paradoxical activation of the MAP Kinase pathway. Ipilimumab (an antibody against cytotoxic T-​lymphocyte-​associated antigen 4 [CTLA-​4]) is currently offered as a second-​line treatment in patients with unresectable or metastatic melanoma. Limited metastatic disease can also be managed with excision or carbon dioxide laser ablation. Extensive recurrent disease in a limb can be treated with isolated limb perfusion with melphalan or electrochemotherapy. Prognosis Breslow’s thickness is the distance from the granular layer to the deepest level of the tumour and is the most important prognostic factor in malignant melanoma. Patients with lesions confined to the epidermis (melanoma in situ) have an approximate five-​year survival rate of 100%; those less than 1 mm, 95–​100%; between 1 and 2 mm, 80–​ 96%; between 2.1 and 4 mm, 60–​75%; and lesions of more than 4 mm in depth, 50%. If a single lymph node is involved the five-​year survival is 45%, if two lymph nodes are involved, the survival rate is 28%, but this rate drops to 9% if more than four lymph nodes are involved. The me- dian survival time following metastasis is between 5 and 16 months. It is likely that over the next 5–​10 years, immunotherapy might provide hope for those patients with metastatic disease. In patients with advanced melanoma, combined treatment with ipilimumab and nivolumab (an antibody against the programmed death 1 [PD-​ 1] receptor) produced an objective response in 53% of patients. Clinical trials combining BRAF and MEK inhibitors also show promise. Tyrosine kinase inhibitors targeting KIT mutations are in clinical trials for acral and mucosal melanoma. Advances in gen- omic technology should provide new targets for investigation. Other cutaneous malignancies Cutaneous lymphoma Cutaneous lymphomas are rare lymphoproliferative disorders of the skin, mainly of T-​ or B-​cell origin. The most common cutaneous lymphoma is mycosis fungoides (MF), a T-​cell lymphoma. (a) (c) (b) (d) Fig. 23.14.5  Malignant melanoma: (a) superficial spreading melanoma with variegation in colour and irregular margin, (b) amelanotic (no pigment) nodular melanoma, (c) invasive nodular melanoma arising in a lentigo maligna; and (d) acral lentiginous melanoma on the sole.

section 23  Disorders of the skin 5740 Aetiology, genetics, pathogenesis, and pathology Clonal lymphocyte proliferation has been ascribed to viral infection, chromosomal alterations, overexpression of oncogenes, or environ- mental toxins. Chromosomal aberrations associated with cutaneous T-​cell lymphoma include losses on chromosomes 1p (38%) and 17p (21%) and gains on chromosomes 4/​4p, 18, and 17q/​17. These loci contain two well-​known tumour suppressor genes, TP53(17p) and PTEN(10q). A recent study identified recurrent alterations in the TNFR2 pathway in addition to other genes regulating T-​cell survival and proliferation affecting more than a third of patients with my- cosis fungoides and Sézary syndrome. Biopsy of a patch or plaque lesion in MF shows prominent atypical lymphocyte invasion of the epidermis (epidermotropism), forma- tion of intraepidermal collections called Pautrier’s microabscesses, and a band-​like infiltrate in the papillary dermis. The clonal nature of the lymphocyte infiltration can be confirmed by demonstration of rearrangement of the TCRB gene by polymerase chain reaction. However, clonal T-​cell populations are also found in inflammatory dermatoses. Immunohistochemistry shows that the lymphocytic in- filtrate expresses T-​cell antigens (CD2, CD3, CD4, CD5) with loss of CD7 and CD26. Mycosis fungoides most commonly occurs in the fourth to fifth decade and is approximately twice as common in black individuals as it is in white individuals. Clinical features Mycosis fungoides—​the typical clinical presentation of MF is with brownish-​red patches and plaques. Some lesions may have an an- nular or serpiginous configuration and poikiloderma (telangi- ectasia, pigmentation, and atrophy), particularly on the breasts and buttocks. Some patients will progress to develop thicker plaques and tumours. Widespread erythroderma with ulcerated tumours is the final stage of the disease. Other clinical variants that may have the immunophenotypic features of MF include granulomatous slack skin disease, follicular mucinosis, and large plaque parapsoriasis. Sézary’s syndrome—​this is part of the spectrum of MF and is characterized by generalized erythroderma (‘red man’) with scaling and pruritus, lymphadenopathy, and circulating atypical lymphoid cells (Sézary cells) which have cerebriform nuclei (usually >1000 atypical lymphocytes/​mm3). Adult T-​cell leukaemia/​lymphoma—​this is a high-​grade CD4-​ positive lymphoproliferative disorder associated with infection with human T-​lymphotropic virus 1 (HTLV-​1). It is most common in Japan and in the Caribbean and in immigrants from these regions. The cutaneous manifestations include patches, plaques, and tu- mours. Atypical lymphocytes (clover leaf cells) are commonly seen in the peripheral blood. Extracutaneous manifestations include lymphadenopathy, hypercalcaemia, splenomegaly, pulmonary infil- trates, and opportunistic infections. B-​cell lymphoma—​cutaneous B-​cell lymphoma usually presents as grouped dermal nodules, sometimes in an annular configuration. These generally progress slowly and remain confined to the skin. Other inflammatory skin disorders may simulate MF including psoriasis, eczema, and parapsoriasis. Clinical investigation A  clinical diagnosis of MF is confirmed by a skin biopsy. Initial histology can be subtle and several biopsies might be required to see the histological features of MF. Initial clinical investigation of a newly diagnosed patient with MF should include a thorough his- tory (looking for systemic symptoms such as fever, weight loss, night sweats) and examination (looking for lymphadenopathy or hepatosplenomegaly). Routine investigations should include full blood count/​blood film, liver function tests, lactate dehydrogenase (an indicator of tumour load), and HTLV-​1 antibodies. If lymph node enlargement is present, a lymph node aspirate/​biopsy should be performed. Patients with an elevated lactate dehydrogenase (LDH), abnormal full blood count, or rapidly progressive disease should have a staging CT of chest, abdomen, and pelvis and bone marrow biopsy. Treatment Potent topical corticosteroids are usually the initial treatment for limited patch or plaque stage cutaneous T-​cell lymphoma (CTCL). Topical nitrogen mustard is also effective in adults with patch or plaque stage disease but application is time-​consuming. Superficial (patch stage) disease also responds well to narrowband UVB, but psoralen ultraviolet A  (PUVA) is better for plaque stage disease. Combined treatment with α-​interferon improves the duration of response. Total skin electron beam therapy is a further option. Bexarotene, a synthetic retinoid-​X receptor agonist, is a promising new therapy for cutaneous T-​cell lymphoma with response rates of up to 70%, even in tumour stage disease. Bexarotene-​related tox- icity includes marked hypertriglyceridaemia and hypercholesterol- aemia. Photopheresis and denileukin diftitox are other options for more advanced disease. Patients with resistant early stage disease or advanced disease should be offered entry into clinical trials where available. Prognosis Patients with early stage disease have a similar life expectancy to their peers. Patients presenting with tumours or erythroderma have a 10-​year survival of approximately 40% (tumour-​node-​metastasis (TMN) Stage III or higher). Poor prognostic factors include presen- tation with extensive thick plaques, tumours, or erythroderma, a late age of onset, or folliculotropic histology. There are many newer agents in development/​trials directed at receptors, tumour-​specific genes, or signalling pathways. These in- clude alemtuzumab, a humanized anti-​CD52 antibody that targets a cell surface antigen expressed on normal and malignant T cells, individualized dendritic cell-​based vaccines, depsipeptide, a histone deacetylase inhibitor molecule (in Phase I-​II clinical trials), topical tazarotene, and allogenic haematopoietic stem cell transplant. Other targets include PI3K isoforms, CTLA4 and NF-​κB processing. Leukaemic infiltrates Leukaemic infiltrates of skin are known as leukaemia cutis. Leukaemia cutis is most commonly associated with myeloid subtypes of leu- kaemia, particularly acute monocytic or myelomonocytic leukae- mias, but might also herald the transformation of myelodysplastic syndrome to leukaemia. It is less commonly associated with lymph- atic leukaemia. The most characteristic lesions of leukaemia cutis are red-​brown to violaceous papules, nodules, and plaques which may be purpuric from thrombocytopenia. The lesions might localize to sites of skin trauma or surgical scars. A granulocytic sarcoma (or chloroma) presents as a rapidly growing, firm nodule that at times

23.14  Tumours of the skin 5741 has a green hue. This tumour is usually associated with acute myeloid leukaemia, and the greenish colour is related to myeloperoxidase in the granulocytes. Leukaemia cutis is usually an indicator of ad- vanced disease. If there is diagnostic doubt, immunophenotyping of a skin biopsy may be helpful. Cutaneous metastases Skin metastases usually occur at a late stage of disease and indicate a poor prognosis. The most common skin tumour to metastasize to the skin is malignant melanoma. Frequent visceral primary sites that metastasize to skin include breast, stomach, lung, uterus, colon, kidney, prostate gland, and ovary. Metastases from other organs are transferred via lymphatic or haematogenous spread and this occurs in about 3% of cancer cases. The presenting lesions are often rather inflammatory in appearance (Fig. 23.14.6). The most common pres- entation is isolated or multiple nodules. Intra-​abdominal metastasis may produce an umbilical nodule, known as Sister Mary Joseph’s nodule. The primary cancer is often ovarian or gastric and this may be the presenting sign. Metastases from renal cell carcinoma are often very vascular. In breast carcinoma, metastases can pre- sent as inflammatory plaques resembling erysipelas (carcinoma erysipeloides). Breast cancer can also cause dermal oedema which resembles orange peel (peau d’orange). Rarely, infiltrative breast cancer metastases can cause scarring alopecia. The presenting lesion is usually excised to confirm the diagnosis. Immunohistochemistry can be performed with tumour-​specific markers to confirm the pri- mary source. Paget’s disease Paget’s disease of the nipple is the presenting feature of about 2% of breast cancers, usually intraductal carcinoma. It occurs most fre- quently in the fifth or sixth decade. Early changes might be very minimal (e.g. only a very small amount of nipple discharge). An erythematous plaque subsequently develops over the nipple and areola which may simulate eczema. The main differential diagnosis is nipple eczema, which is almost always bilateral. A biopsy will con- firm the diagnosis. Langerhans cell histiocytosis Langerhans cell histiocytosis is a rare disease of unknown aetiology, but characterized histologically by a proliferation of Langerhans cells expressing CD1a and CD207, and with the presence of Birbeck granules on electron microscopy. The clinical presentation varies with the nature of organ involvement and whether it is single system or multisystem disease. Skin, bone, and lymph node are the most common sites of involvement, but other systems include liver, lung, gastrointestinal, endocrine, nervous system, and haematological. The characteristic skin presentation is the presence of greasy scales on the scalp, reminiscent of seborrhoeic dermatitis. On the trunk, the lesions are discrete, yellow-​brown, scaly papules, often with areas of purpura. Ulceration in the flexures and groin is a common presen- tation in adults. The disease is discussed in detail in Chapter 22.3.9. FURTHER READING Agar NS, et al. (2004). The basal layer in human squamous tumors har- bors more UVA than UVB fingerprint mutations: a role for UVA in human skin carcinogenesis. Proc Natl Acad Sci U S A, 101, 4954–​9. Ananthaswamy HN, et al. (1997). Sunlight and skin cancer: inhibition of p53 mutations in UV-​irradiated mouse skin by sunscreens. Nat Med, 3, 510–​14. Chapman PB, et al. (2011). Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med, 364, 2507–​16. Dajee M, et al. (2003). NF-​κB blockade and oncogenic Ras trigger in- vasive human epidermal neoplasia. Nature, 421, 639–​43. Euvrard S, et al. (2012). Sirolimus and secondary skin-​cancer preven- tion in kidney transplantation. N Engl J Med, 367, 329–​39. Fan H, et  al. (1997). Induction of basal cell carcinoma features in transgenic human skin expressing Sonic Hedgehog. Nature Med, 3, 788–​92. Goudie DR, et al. (2011). Multiple self-​healing squamous epithelioma is caused by a disease-​specific spectrum of mutations in TGFBR1. Nat Genet, 43, 365–​9. Gudbjartsson DF, et al. (2008). ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma. Nat Genet, 40, 886–​91. Hussussian CJ, et al. (1994). Germline p16 mutations in familial mel- anoma. Nat Genet, 8, 15–​21. Landi MT, et al. (2006). MC1R germline variants confer risk for BRAF mutant melanoma. Science, 313, 521–​2. Marsden JR, et al. (2010). Revised UK guidelines for the management of cutaneous melanoma 2010. Br J Dermatol, 163, 238–​56. Morton DL, et al. (2006). Sentinel-​node biopsy or nodal observation in melanoma. N Engl J Med, 355, 1307–​17. Motley R, et al. (2002). Multiprofessional guidelines for the manage- ment of the patient with primary cutaneous squamous cell car- cinoma. Br J Dermatol, 146, 18–​25. National Institute for Health and Care Excellence (NICE) (2015). Melanoma: assessment and management. NICE guideline [NG14]. http://​www.nice.org.uk/​Guidance/​NG14 O’Donovan P, et al. (2005). Azathioprine and UVA light generate mu- tagenic oxidative DNA damage. Science, 309, 1871–​4. Pho L, Grossman D, Leachman SA (2006). Melanoma genetics: a re- view of genetic factors and clinical phenotypes in familial mel- anoma. Curr Opin Oncol, 18, 173–​9. Prickett TD, et al. (2009). Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nat Genet, 41, 1127–​32. Fig. 23.14.6  Erythematous nodule on abdomen. This was a cutaneous metastasis from breast carcinoma.

section 23  Disorders of the skin 5742 Stacey SN, et al. (2009). New common variants affecting susceptibility to basal cell carcinoma. Nat Genet, 41, 909–​14. Stern RS, et al. (1984). Cutaneous squamous-​cell carcinoma in pa- tients treated with PUVA. N Engl J Med, 310, 1156–​61. Su F, et  al. (2012). RAS mutations in cutaneous squamous-​cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med, 366, 207–​15. Teh MT, et  al. (2005). Genomewide single nucleotide poly- morphism microarray mapping in basal cell carcinomas un- veils uniparental disomy as a key somatic event. Cancer Res, 65, 8597–​603. Telfer NR, Colver GB, Morton CA (2008). British Association of Dermatologists: guidelines for the management of basal cell car- cinoma. Br J Dermatology, 159, 35–​48. Thompson JF, Scolyer RA, Kefford RF (2009). Cutaneous melanoma in the era of molecular profiling. Lancet, 374, 362–​65. Ungewickell A et al. (2015). Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2. Nat Genet, 47, 1056–​60. Von Hoff DD, et al. (2009). Inhibition of the hedgehog pathway in ad- vanced basal-​cell carcinoma. N Engl J Med, 361, 1164–​72. Wang NJ, et al. (2011). Loss-​of-​function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma. Proc Natl Acad Sci USA, 108, 17761–​6. Wei X, et  al. (2011). Exome sequencing identifies GRIN2A as fre- quently mutated in melanoma. Nat Genet, 43, 442–​6. Wolchok JD, et al. (2017). Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med, 377, 1345–56.

23.15 Skin and systemic diseases 5743 Clive B. Arc

23.15 Skin and systemic diseases 5743 Clive B. Archer and Charles M.G. Archer

ESSENTIALS Dermatology is most interesting where it overlaps with general in- ternal medicine. Skin lesions can be part of a systemic disease (e.g. in sarcoidosis or systemic lupus erythematosus), or they may be a manifestation of an underlying disease or process as in the case of acanthosis nigricans, which can be associated with either an underlying adenocarcinoma in older patients, or with insulin re- sistance and sometimes overt diabetes mellitus in younger obese patients. Sarcoid can affect the skin in numerous ways, including erythema nodosum, nodular sarcoid lesions, multiple papules, and larger plaques, particularly on thenose, a site at which the skin changes are frequently perniotic in appearance (lupus pernio, scar sarcoidosis, and rarely angiolupoid sarcoid). Diabetes mellitus can also affect the skin in a myriad of ways, with more common forms including granuloma annulare, necrobiosis lipoidica, diabetic dermopathy, cutaneous infections, and the con- sequences of neuropathy. Liver disease can affect the skin by causing pruritus, pigmenta- tion (grey or jaundice), vascular changes (spider naevi), porphyria cutanea tarda, dryness, and hair/​nail alterations. Renal disease may affect the skin by causing pruritus, pigmentary changes, dryness, and calciphylaxis, and use of immunosuppression can lead to an increase in malignancy in some cases. Common associations of pyoderma gangrenosum include in- flammatory bowel diseases (ulcerative colitis and Crohn’s disease), rheumatoid arthritis, and other rheumatological disease, haemato- logical malignancies, and monoclonal gammopathies. The non​infectious granulomatous disorders of the skin in- clude sarcoidosis, granuloma annulare, and necrobiosis lipoidica. Granulomatous diseases caused by bacterial infections (e.g. tubercu- losis and leprosy) and fungal infections are discussed in Chapter 23.10 and Section 8. Sarcoidosis and the skin Sarcoidosis has been defined as ‘a disease characterized by the for- mation in all or several affected organs or tissues of epithelial cell tubercles, without caseation, although fibrinoid necrosis may be pre- sent at the centre of a few, proceeding either to resolution or to the conversion of the epithelial cell tubercles into hyaline fibrous tissue’. Other changes present to a varying degree include partial or com- plete suppression of tuberculin and other intradermal cell-​mediated immune responses, and an elevated serum calcium level. The Kveim test, which was positive in most active cases, is no longer available. Aetiology Many infectious agents have been put forward as the potential cause of sarcoidosis, but cultures have been negative and responses to anti-​ infective treatments have been disappointing. A polymerase chain reaction (PCR) study revealed the presence of various subtypes of mycobacterial DNA in 16 of 20 cases of cutaneous sarcoidosis, but the significance of these and other findings are unclear. Genetic fac- tors may be important, HLA type, for example, seeming to influence the pattern of the disease rather than determining its occurrence. The prevalence of sarcoidosis in developed countries is greater than 10 per 100 000 population, but an apparent increased inci- dence in the last 50 years is probably due to improved methods of detection. Clinical features Skin lesions occur in about 30% of patients with systemic sarcoid- osis, but cutaneous sarcoidosis can occur without systemic disease. Significant pulmonary disease can be asymptomatic and the extent of skin involvement does not correlate with the extent of systemic disease. The specific skin lesions of sarcoidosis arise from a dense accu- mulation of epithelioid granulomas in the dermis or subcutis and can be of variable morphology. Erythema nodosum (Fig. 23.15.1) is a non​specific clinical feature of early or acute sarcoidosis without the characteristic sarcoidal granulomas (see Chapter 23.7). Nodular sarcoid lesions are often annular and reddish-​brown or violaceous in colour. There may be multiple papules and larger plaques, par- ticularly on the nose, a site at which the skin changes are frequently perniotic in appearance (lupus pernio) (Fig. 23.15.2). Skin lesions can affect pre-​existing scars (the Koebner or isomorphic phenom- enon), sometimes referred to as scar sarcoidosis. A rare but char- acteristic telangiectatic form of sarcoidosis, angiolupoid sarcoid, affects women, almost always on the sides of the nasal bridge, on 23.15 Skin and systemic diseases Clive B. Archer and Charles M.G. Archer

section 23  Disorders of the skin 5744 the adjacent cheek or below the eyebrows. Sometimes the nodular lesions are solely subcutaneous, and erythrodermic and lichenoid sarcoidosis are unusual morphological forms. Sarcoidosis is more common in black skin and in African-​ Americans; typical lesions include annular lesions on the nose (Fig. 23.15.3), hypopigmented macules and papules, keloid-​like lesions, ulcerative, verrucous, and large nodular forms. Erythema nodosum is uncommon in black skin. In white skin the colour of the lesions ranges from yellowish to the livid violaceous colour which is most marked in lupus pernio. The epidermis is rarely affected and scarring is unusual except in the papular and annular forms. Differential diagnosis The differential diagnosis includes lupus vulgaris, a cutaneous form of tuberculosis, syphilis, and tuberculoid leprosy (see Chapter 23.10). These can usually be distinguished on histology. Other common disorders with granulomatous histology include granuloma annulare, rosacea, and Crohn’s disease. Sarcoid-​like reactions in a scar should be distinguished from a foreign body reaction. A granulomatous sarcoidal reaction to any pigment of a tattoo may occur, either alone or accompanied by other signs of sarcoidosis. Clinical investigation A skin biopsy is usually required to show the characteristic granu- lomatous histology. However, a patient with erythema nodosum and bilateral hilar lymphadenopathy may not require histological con- firmation of the erythema nodosum (a form of panniculitis) for the diagnosis of acute sarcoidosis to be acceptable. A  chest X-​ray should be performed in all cases. Angiotensin-​ converting enzyme (ACE) is produced by sarcoidal granulomas and serum ACE is raised in about 60% of patients with systemic Fig. 23.15.1  Erythema nodosum, with painful bruise-​like lesions on the shins. Fig. 23.15.2  Sarcoidosis, showing the violaceous lesions of lupus pernio on the nose. Fig. 23.15.3  Sarcoidosis on the nose of a man of Afro-​Caribbean origin.

23.15  Skin and systemic diseases 5745 sarcoidosis. However, serum ACE can be elevated in tuberculosis, diabetes mellitus and alcoholic liver disease, and is often normal in localized sarcoidosis of the skin. Serum calcium should be checked, as an increased level may lead to renal failure. Less spe- cifically, the erythrocyte sedimentation rate (ESR) is usually raised, with a slight anaemia, neutropenia or lymphopenia, and hypergammaglobulinaemia in over 50% of patients. An ECG is re- quired to exclude cardiac involvement. Pulmonary function tests might be indicated and computed tom- ography of the chest is helpful to define lung involvement. Hand radiographs may show cystic changes in chronic disease, usually when there are clinical abnormalities in the fingers. The most specific investigation was the Kveim test, in which sarcoidal tissue from the spleen of an affected individual was injected intradermally to produce an epithelioid cell granulomatous reaction. A positive response was the development of a reddish papule at two to three weeks. Excision at six weeks showed the confirmatory hist- ology. However, this test is no longer used because of the infective risk of injecting human tissue. See Chapter 18.12 for further details of investigation of the patient with suspected sarcoidosis. Treatment Limited cutaneous sarcoidosis can resolve spontaneously, so a con- servative approach to treatment is often adopted. Papular and sub- cutaneous skin lesions may settle spontaneously but lupus pernio tends to persist. Superpotent topical corticosteroids are usually tried and can be helpful. Intralesional triamcinolone is often effective, care being taken to inject deeply to avoid atrophy of the skin. In some types of cutaneous sarcoid (e.g. lupus pernio), cosmetic camouflage advice is useful. Other local therapies reported to be beneficial have included cryotherapy, radiotherapy, PUVA (psoralen ultraviolet A) in hypopigmented and erythrodermic sarcoidosis, pulsed dye laser in lupus pernio, and topical tacrolimus. Commonly used systemic therapies include oral corticosteroids, pulsed intravenous corticosteroids, methotrexate, and azathioprine. The most frequent indications for systemic treatment include symp- tomatic pulmonary disease, ocular disease not responding to local corticosteroids, disfiguring skin disease or lymphadenopathy, hypercalcaemia, liver disease with significant dysfunction or hep- atomegaly, other organ involvement such as myocardial disease, nervous system disease or renal disease, myopathy or myositis, and thrombocytopenia. See Chapter 18.12 for further details of treat- ment of the patient with sarcoidosis. Prednisolone is usually prescribed at 30–​40 mg daily and re- duced over about two months to a maintenance dose of prednis- olone 15 mg on alternate mornings. Treatment may be necessary for about six months, and azathioprine is often introduced for its immunosuppressive and steroid-​sparing effects. Intravenous pulsed methylprednisolone (e.g. 1 g/​week for two months, has been ef- fective in patients with severe systemic disease). Methotrexate is often an effective systemic agent, usually pre- scribed as a weekly oral dose (e.g. 7.5–​25 mg weekly), with careful monitoring. The response of sarcoidosis to other drugs has been vari- able, including ciclosporin, chlorambucil, allopurinol, isotretinoin, thalidomide, and minocycline. Diabetes mellitus and the skin Skin disorders in individuals with diabetes mellitus include dia- betic dermopathy, the most common skin disorder associated with diabetes, cutaneous infections, the consequences of diabetic neur- opathy, acanthosis nigricans (related to insulin resistance), necro- biosis lipoidica, and probably generalized granuloma annulare. Anogenital pruritus in diabetes mellitus may be caused by candid- iasis or streptococcal infection, but diabetes is not a proven cause of generalized pruritus. See Chapter 13.9.1 for further discussion of diabetes. Diabetic dermopathy (diabetic shin spots) This occurs in about half of the patients with diabetes, men being more commonly affected than women. Diabetic dermopathy is thought to be due to microangiopathy and possible neuropathy. Reddish oval macules and slightly scaly plaques are seen on the shins, forearms, thighs, and over bony prominences, later evolving into brownish atrophic scars, the brown pigment being due to haemosiderin deposition. The presence of these lesions has been suggested to correlate with other internal complications of diabetes including retinopathy, nephropathy, and neuropathy. Granuloma annulare Granuloma annulare (GA) is a reaction pattern in the skin with a well-​established morphology and natural history, although the aetiology and pathogenesis are unclear. Several potential antigenic trigger factors have been suggested. There is an association between granuloma annulare and diabetes mellitus but this is seen uncom- monly. Granuloma annulare can occur at any age but most patients are under 30  years old, women being affected more frequently than men. Localized granuloma annulare is the most common form and pre- sents as reddish collections of papules which form annular lesions, with palpable edges, often over the knuckles (Fig. 23.15.4) and on the elbows. Other areas of the skin may be involved and a diffuse or generalized pattern occurs uncommonly. In the generalized pat- tern, there are numerous skin-​coloured or erythematous, slightly palpable coalescing papules, arranged symmetrically on the trunk and limbs. Annular lesions may be violaceous in colour and itching is often a feature of the generalized form. Perforating (referring to extrusion of material through the epidermis) and subcutaneous granuloma annulare are uncommon patterns, the latter sometimes being difficult to distinguish from rheumatoid nodules. It is reasonable to exclude diabetes mellitus in patients with granuloma annulare, but this probably occurs in only about 5% cases of localized GA, rising to about 20% in the generalized form. The association of granuloma annulare with diabetes mellitus is de- batable, however, and some relatively small studies have not shown a definite association. The distinction from necrobiosis lipoidica, more strongly associated with diabetes mellitus, is usually made histologically but granuloma annulare and necrobiosis lipoidica can occur in the same patient. The sporadic occurrence of granuloma annulare and its tendency to remit spontaneously makes it difficult to assess the efficacy of treatment and in many cases no treatment is needed. Spontaneous

section 23  Disorders of the skin 5746 remission would occur in about 50% of patients within 2 years but recurrence, usually at the same sites, occurs in 40%. Potent topical corticosteroids might hasten resolution of localized granuloma annulare and intralesional triamcinolone can be effective if treatment is required. Cryotherapy has also been used. PUVA seems to be effective for generalized granuloma annulare. Other treatments reported to be of benefit include retinoids, ciclosporin, local injections of low-​dose recombinant interferon-​γ, and topical imiquimod or tacrolimus. However, better clinical studies are re- quired in what is a sporadic disorder. In one clinical trial of gener- alized granuloma annulare treated with oral potassium iodide, the active drug had no advantage over placebo. Necrobiosis lipoidica The precise pathogenesis of necrobiosis lipoidica is unknown, but impaired vascularity of the microcirculation is considered to play a role. Necrobiosis lipoidica has been reported in monozygotic twins. The occurrence of diabetes mellitus in up to 60% patients who have necrobiosis lipoidica was probably overestimated previously in ter- tiary referral populations. Necrobiosis lipoidica might precede the development of diabetes in about one in 10 individuals. However, it does not occur exclusively in diabetes, and the term necrobiosis lipoidica diabeticorum is no longer used. It can occur at any age but usually develops in young adults and in early middle age. There is a female to male ratio of 3:1. Only about 0.3% patients with diabetes mellitus will have necrobiosis lipoidica. Necrobiosis lipoidica occurs as reddish-​yellow shiny plaques on the shins, with atrophy and telangiectasia (Fig. 23.15.5), but early lesions are less obvious. Lesions may ulcerate and a chronic course is usual. In most cases, lesions are bilateral, and they are similar in appearance, whether occurring in diabetic or non​diabetic patients. The differential diagnosis includes granuloma annulare, in which there is less necrobiosis on histology. The yellowish appearance may resemble xanthomatous lesions but this will be distinguished on histology. Necrobiotic xanthogranuloma is a rare disease in which red-​orange or yellowish indurated plaques occur on the trunk and periorbital regions, associated with systemic lesions and a mono- clonal gammopathy. Treatment with a superpotent topical corticosteroid under poly- thene occlusion is effective in settling the active inflammatory pro- cess of necrobiosis lipoidica, but the chronic atrophic changes are not reversible and the lesions persist. Early treatment is therefore re- commended. Intralesional triamcinolone has been used with good effect, and some dermatologists use perilesional triamcinolone to prevent extension of the process centrifugally. Short courses of pred- nisolone have been reported to arrest the process but are usually not required. Psoralen and ultraviolet A (PUVA) using a topical psoralen have been beneficial, as has excision and grafting in severe cases. Other treatments which have been tried in the past with limited success include nicotinamide, clofazimine, pentoxifylline, ciclosporin, mycophenolate mofetil and, more recently, infliximab. Promising results have been obtained with thalidomide, antimalarial drugs and, most recently, ultraviolet A1 phototherapy. Cutaneous infections in diabetes mellitus Skin infections due to Staphylococcus aureus and group A  Streptococcus haemolyticus are common in diabetes mellitus. Infections with boils (furuncles), carbuncles (with multiple sinuses), and styes were more common before insulin and antibiotics became available, and good skin care, especially of the feet and lower legs, is essential to help prevent cellulitis. Uncommonly, diabetics are prone to soft tissue infections with a mixture of organisms, some- times referred to as non​clostridial gas gangrene or bacterial syner- gistic cellulitis/​gangrene, probably a form of necrotizing fasciitis. Well demarcated red areas on the legs and feet of older diabetics do Fig. 23.15.5  Necrobiosis lipoidica, showing reddish-​yellow atrophic plaques on the shins. Fig. 23.15.4  Granuloma annulare, showing an annular dermal lesion on the dorsum of the hand.

23.15  Skin and systemic diseases 5747 not necessarily indicate cellulitis or erysipelas, and this is sometimes referred to as erysipelas-​like erythema. Candida albicans infections of the mouth, nail folds, genitals, and intertriginous zones (skinfolds) are common in diabetes. A  high glucose level in the saliva seems to be related to the increased preva- lence of oral candidosis. Recurring candida infection is thought to be the cause of an increased prevalence of phimosis in diabetic men. Diabetic neuropathy Older patients with diabetes mellitus are at risk of developing a peripheral neuropathy with mixed sensory and motor nerve in- volvement. Good foot care is essential to prevent the formation of indolent painless perforating ulcers, particularly at pressure points (e.g. from footwear or the bed). The ulcer is usually punched out and often occurs on the sole of the foot in the middle of a cal- losity. Diabetic ulcers are usually due to a combination of factors including microangiopathy, neuropathy, and an increased tendency to infection. Acanthosis nigricans and insulin resistance Acanthosis nigricans, in which there is hyperpigmentation and hyperkeratosis of the flexures (e.g. a velvety appearance in the ax- illae), exists in two forms. In the absence of obesity, acanthosis nigricans (Fig.  23.15.6) may be an important clinical sign of an underlying adenocarcinoma (e.g. carcinoma of the stomach). The changes of acanthosis nigricans in younger obese patients, in which the nape of the neck and antecubital fossae are often involved, are as- sociated with insulin resistance (hyperinsulinaemia) and sometimes overt diabetes mellitus. There are considered to be two syndromes of insulin resistance, type A occurring in hyperandrogenic women due to a genetic defect affecting insulin receptor function, and type B in older women with signs of immunological dysfunction. Acanthosis nigricans has been reported in response to exogenous insulin. Other skin disorders associated with diabetes mellitus Diabetic bullae Various forms of diabetic blisters occur, presenting as appar- ently spontaneous lesions mostly on the feet and hands. A  typ- ical subepidermal blister occurs on a non​inflamed base and heals without scarring in a few weeks. Skin reactions to insulin (insulin allergy) Insulin may cause immediate or, more commonly, delayed reac- tions in the skin. A delayed reaction usually begins after two weeks as an itchy nodule at the site of the injection. It lasts for days before healing, with hyperpigmentation and sometimes scarring. Insulin lipodystrophy is rare. Atrophic lesions at the sites of in- sulin injections reflect localized fat atrophy which usually persists. Vitiligo Vitiligo occurs more frequently in patients with diabetes mellitus, a prevalence of about 5% being reported in late-​onset diabetes. Wet gangrene of the foot This is a late manifestation of diabetic microangiopathy, non-​ diabetic atherosclerotic patients tending to develop a dry form of gangrene due to large vessel disease. Liver disease and the skin Numerous systemic diseases may affect the liver and some of these will have cutaneous features (e.g. as occurs in sarcoidosis). The predominant dermatological features and dermatoses associated with liver diseases are discussed here. For a full discussion of liver disease, see Section 15. Pruritus in liver disease Generalized pruritus is the most common symptom associated with liver disease. It may precede the onset of jaundice and may be a feature of hepatitis. Itching is most prominent in primary biliary cirrhosis, sclerosing cholangitis, and other forms of biliary tract obstruction, being less of a problem in alcoholic cirrhosis, autoimmune chronic active hepatitis, and haemochromatosis. Improvement in hepatic itching by drugs which block the action of opiates suggests that en- dogenous opiates may be important in the mechanism of itching. Treatment is directed at the underlying cause (e.g. drug with- drawal in drug-​induced cholestasis, surgery for mechanical bil- iary obstruction). Antihistamines are usually ineffective. Other approaches have included cholestyramine, rifampicin, and various forms of phototherapy. Pigmentary changes in liver disease Jaundice is first seen in the sclerae before it becomes generalized. Carotenaemia and drugs, including mepacrine, can also cause yellowing of the skin. A grey hyperpigmentation may occur in chronic liver disease of any cause. There might be a yellowish tinge due to associated jaun- dice. The pigmentation is usually more prominent on sun-​exposed sites, including the face with perioral and periorbital accentuation. Pigmentation sometimes localizes to the palmar creases, and men Fig. 23.15.6  Acanthosis nigricans, showing hyperpigmentation and hyperkeratosis of the axillary skin.

section 23  Disorders of the skin 5748 sometimes have increased pigmentation of the areola in association with gynaecomastia. Vascular changes in liver disease Some of the recognized vascular changes in liver disease are non-​ specific, including spider naevi (spider telangiectases/​spider angi- omas) and palmar erythema. Finger clubbing, thought to be due to increased digital pulp blood flow and dilation of arteriovenous anas- tomoses, occurs in about 15% of patients with cirrhosis. Hair, nail, and collagen changes in liver disease The body hair is often thinned and men tend to develop a female pubic hair pattern, due to increased production and decreased me- tabolism of oestrogens, associated with decreased production and increased metabolism of testosterone. Extensive loss of scalp hair might be due to zinc deficiency. Nail colour changes include diffuse white colour, proximal white colour, and distal reddish-​pink colour, and white bands. Nail plate changes include clubbing, and flattened nails or koilonychia, associ- ated with poor nutrition or altered iron metabolism. Striae occur in both sexes, especially on the lower abdomen, thighs, and buttocks. Porphyria cutanea tarda Porphyria cutanea tarda (PCT) is associated with chronic liver disease. In this form of porphyria, there is photosensitivity with blisters, scar- ring, milia (small epidermal cysts), and hyperpigmentation on sun-​ exposed areas (e.g. dorsa of hands and forearms) with hypertrichosis of the face (e.g. the temples). See Chapters 12.5 and 23.9. Lichen planus The cause of most cases of lichen planus is unknown but lichen planus has been reported in primary biliary cirrhosis, usually following treatment with penicillamine, and in chronic active hepatitis. Hepatitis C virus has also been associated with lichen planus. Uncommon skin disorders Capillaritis of the skin has also been reported in chronic active hepa- titis and primary biliary cirrhosis. Other skin disorders include pityriasis lichenoides, pyoderma gangrenosum, the Gianotti–​Crosti syndrome, and the signs of zinc deficiency. Renal disease and the skin The skin and renal system may be affected by the same disease pro- cess. This occurs in various forms of collagen diseases and vasculitis (see Chapter 23.7), in hereditary syndromes such as Fabry’s disease (angioma corporis diffusum) and nail-​patella syndrome, and in metabolic diseases, including calcific arteriolopathy (calciphylaxis) and primary systemic amyloidosis. Here we concentrate on the cutaneous signs of chronic renal failure, with discussion of re- cent findings in calcific arteriolopathy and nephrogenic fibrosing dermopathy. Uraemic pruritus Generalized severe pruritus occurs in about one-​third of pa- tients with renal failure, with many more patients experiencing less troublesome pruritus. In one study, up to 85% of patients on haemodialysis suffered from pruritus, the haemodialysis seeming to provoke the itching in two-​thirds of them. There seems to be a correlation between pruritus and predialysis plasma urea levels, but a less obvious relationship between itching and dry skin (xerosis) and secondary hyperparathyroidism. The mechanism of pruritus is complicated, since a reduction in uraemia often does not improve the itching, and pruritus is unusual in acute renal failure. Uraemic neuropathy affects about 60% of patients with renal failure or on long-​term haemodialysis and may play a role in uraemic pruritus. The incidence of uraemic pruritus has been reported to be decreasing, which in part may be due to the use of more sophisti- cated techniques and equipment for dialysis. In dialysis, lowering the magnesium concentration of the dialysate has been reported to be helpful. In intractable itching, emollients and ultraviolet B (UVB) radiation are reported to be the most effective therapy. Other treat- ments have included UVA (without psoralen), cholestyramine, acti- vated charcoal, and erythropoietin therapy. Pigmentary changes in chronic renal failure Anaemia presenting as pallor is an early and common sign of chronic renal failure, resulting from reduced haemopoiesis and in- creased haemolysis. A  greyish-​brown discolouration develops in many cases, due to deposition of melanin. Increased nail pigmen- tation, usually confined to the distal nail, occurs in a proportion of patients. This distal brown or reddish colour, combined with a prox- imal white appearance gives rise to the term ‘half and half’ nails, a distinctive pattern seen in about 10% of patients with renal failure. Purpura due to mild thrombocytopenia or more marked platelet dysfunction is common and may be partly corrected by dialysis. Urea frosting, in which crystalline urea is deposited on the skin, is now exceedingly rare. Renal transplantation and the incidence of skin cancer The incidence of skin cancers in patients who have received a renal transplant is above that of the general population, and patients often have numerous viral and dysplastic lesions on their skin, some of which will become malignant. The incidence of basal cell carcinomas (BCCs) rises in a linear fashion from the date of transplantation, but the increase in the incidence of squamous carcinomas (SCCs) rises in an exponential fashion. Sun exposure does play a major aetio- logical role in these immunosuppressed patients, as in the non-​ transplanted population. There is a high incidence in Australia with a mean non​melanoma skin cancer (NMSC) incidence of 28.1%, with a maximum incidence of 47.1% in patients immunosuppressed for more than 20 years. The same group from Queensland noted that white patients at highest risk for developing NMSC have blue or hazel eyes, have spent a longer time living in a hot climate, and are more likely to have a pretreatment SCC. See Chapter 23.14. Sun avoidance advice is important in all potential renal transplant patients and should be encouraged among the general population. Calcific arteriolopathy (calciphylaxis) Calcific arteriolopathy (calciphylaxis, calcific uraemic arteriolopathy or CUA) is a disorder in which patients, usually with renal failure, de- velop large painful areas of ulceration. These can be distal involving the limbs, or can be proximal causing large areas of ulceration on the breasts, abdomen, and buttocks.

23.15  Skin and systemic diseases 5749 Recent studies have shown that the calcification is not the same as that seen in patients with skin necrosis, and the term calciphylaxis is considered inaccurate. CUA indicates the site of the calcification and the usual clinical state of the patients. However, CUA has been reported in patients with minimal or no renal failure, hence the author’s preferred use of the term calcific arteriolopathy. In addition to renal failure, the other major risk factors include female gender, white race, diabetes mellitus, obesity, and warfarin and the clotting disorders such as protein C and protein S deficiency. It has also been shown that the use of calcium salts and vitamin D in chronic renal failure is a risk factor. A direct role of hyperparathyr- oidism in the development of calcific arteriolopathy is not proven, the disease having been described in the presence of a normal parathormone level. The usual presentation of calcific arteriolopathy is of areas of ul- ceration on the legs, buttocks, abdomen, or breasts which are painful and may be extensive. Livedo reticularis around the ulcers may be present. Acral ulceration can also occur, causing autoamputation. The differential diagnosis is any cause of ulceration, especially vas- culitis, in which livedo reticularis may also be present. Increasing awareness of the condition is allowing the diagnosis of calcific arteriolopathy at an earlier non​ulcerative stage, before the subcuta- neous indurated plaques develop into ulcers. The diagnosis of calcific arteriolopathy is usually by biopsy, the histology showing calcification of the media of small arterioles in the skin. This is associated with a brisk intimal proliferation, sometimes with fibrin thrombi visible in the lumen. Other types of vascular cal- cification are seen in chronic renal failure. The calcification seen in calcific arteriolopathy is no longer thought to be a passive process. The calcium deposited is hydroxyapatite, which is the same as seen in bone. This is different from the compounds found in other types of calcification. If calcific arteriolopathy is diagnosed at the non​ulcerative stage there is some evidence for the use of oral prednisolone at a dose of 30–​50 mg mane for up to eight weeks. If ulceration is already pre- sent, debridement of the necrotic tissue is sometimes recommended and use of antibiotics to prevent overwhelming sepsis is important. Adequate pain control is another important management measure. The outcome is poor, with a mortality of about 60% for proximal disease and about 20% for distal disease, usually from overwhelming sepsis. Since there is such a high mortality, the approach should be to aim for prevention. The control of the hyperphosphataemia is thought to be fundamental to this. Phosphate binders are used, with some evidence showing that the non-​calcium-​containing binders are better. Parathyroidectomy has been found to be useful in the control of calcific arteriolopathy in some series but not in others. Nephrogenic fibrosing dermopathy Nephrogenic fibrosing dermopathy (NFD) is a recently reported fi- brotic disease occurring in patients with renal disease. Nephrogenic fibrosing dermopathy was initially reported in patients with estab- lished renal failure, either on dialysis or having had a transplant, but it has since been reported in patients with chronic renal insuffi- ciency not requiring renal replacement therapy. An association with the intravenous injection of gadolinium-​based radiocontrast media has been suggested. The clinical presentation of this rare disorder is of plaques of indurated skin on the extensor surfaces of the limbs, and scleral involvement has been described. The limbs are affected in a sym- metrical manner with skin-​coloured papules coalescing to form brawny plaques with a ‘peau d’orange’ appearance, occasionally with swelling of the hands and feet. Patients may complain of pain, prur- itus, and causalgia. Most patients do not have systemic involvement, but when this is present the disease may be rapidly fatal. The histology shows an increase in dermal collagen with a paucity of inflammatory cells. There is mucin deposition with abundant eo- sinophilic spindle cells in the upper dermis that stain for CD34. The disease that nephrogenic fibrosing dermopathy is most similar to is scleromyxedema, but the relative sparing of the face in nephrogenic fibrosing dermopathy and the lack of a paraprotein allows the dis- eases to be separated on clinical grounds. The mainstay of treatment is improvement of the renal function but transplantation is not guaranteed to cure the disease. Treatments such as plasmapheresis, topical calcipotriol under occlusion, PUVA, and oral steroids have been tried, but the results are difficult to as- sess, since an improvement in renal function is itself an effective form of therapy. Other systemic diseases and the skin Pyoderma gangrenosum Pyoderma gangrenosum (PG) is an uncommon, non​infectious neutrophilic dermatosis commonly associated with underlying sys- temic disease. Several clinical variants of pyoderma gangrenosum have been described, including ulcerative, pustular, bullous, and vegetative forms. An immune-​mediated process is thought to play an important pathogenetic role, with about 50% of patients having an associ- ated systemic disease. Common associations include inflammatory bowel diseases (ulcerative colitis and Crohn’s disease), rheumatoid arthritis and other rheumatological disease, haematological malig- nancies, and monoclonal gammopathies. A characteristic presentation of pyoderma gangrenosum be- gins with small tender papules or pustules that evolve into painful ulceration with typical undermined violaceous edges (Fig. 23.15.7). Lesions can be solitary or multiple. Healing usu- ally occurs with an atrophic cribriform scar (i.e. having several small holes within it). Associated symptoms include fever, mal- aise, myalgia, and arthralgia. Bullous pyoderma gangrenosum is often associated with myeloproliferative disorders. Vegetative or superficial granulomatous pyoderma gangrenosum may have superficial and deep components and is not usually associated with any systemic disease. The diagnosis of pyoderma gangrenosum is made by recognizing the characteristic clinical features and by excluding other causes of ulceration. A biopsy across the edge of a lesion, depending on the type of pyoderma gangrenosum, will show a neutrophilic infiltrate, but at best the histology is ‘consistent with’ as opposed to ‘diagnostic of’ the condition. Many effective treatments for pyoderma gangrenosum have been reported, the precise choice depending on disease severity as well as on the presence of an underlying systemic disease. For early or mild disease, topical therapy with a superpotent corticosteroid or tacrolimus, along with good wound care, may be sufficient. Intralesional triamcinolone may also be effective.

section 23  Disorders of the skin 5750 For more severe cases or PG resistant to topical therapy, oral pred- nisolone has been the mainstay of treatment. Other treatments in- clude pulsed intravenous corticosteroids, minocycline, dapsone, and immunosuppressants such as azathioprine or ciclosporin. Ciclosporin is usually effective at a dose of less than 5 mg/​kg per day. Methotrexate has been used for patients with underlying in- flammatory bowel disease and, more recently, infliximab and other biological agents have been effective. Less commonly used treat- ments include plasmapheresis, intravenous immunoglobulin, and thalidomide. Behçet’s disease Behçet’s disease is a multisytem disease that is defined by the pres- ence of oral aphthosis with at least two of the following:  genital aphthae, synovitis, posterior uveitis, cutaneous pustular vasculitis, or meningoencephalitis, in the absence of inflammatory bowel dis- ease or autoimmune diseases. It typically affects young adults and is uncommon in northern Europe and the United States of America, but common in Middle Eastern and Japanese populations. Here we focus on cutaneous manifestations, but see Chapter 19.11.10 for a full discussion of Behçet’s disease. Behçet’s disease was named after the Turkish dermatologist who described the multisystem disease. The pathogenesis is unclear, but there may be a genetically determined response to an infec- tious agent. Biopsies of early aphthae or of lesions of pustular vas- culitis show a leukocytoclastic vasculitis, although late lesions are lymphocytic. The clinical course of Behçet’s disease is variable, although patients typically have oral aphthae with any combination of genital aphthae, cutaneous pustular vasculitis, ocular lesions, or arthritis. Only pus- tular vasculitis and erythema nodosum-​like nodules should be used to satisfy diagnostic criteria, although a variety of skin findings (e.g. pyoderma gangrenosum-​like lesions) may be present in patients with Behçet’s disease. Posterior uveitis is the only ocular criterion for the diagnosis of Behçet’s disease, but there are other ophthal- mological manifestations. The posterior uveitis in Behçet’s disease is due retinal vasculitis and may result in blindness. The musculoskel- etal involvement in Behçet’s disease is an asymmetrical, migratory, non​erosive oligoarthritis, mimicking rheumatoid arthritis. Many neurological manifestations may occur, but only meningoencephal- itis is considered to be a diagnostic criterion. Vascular involvement in Behçet’s disease may affect arteries and veins, leading to aneur- ysms or occlusions that are sometimes fatal. The diagnosis of Behçet’s disease should be suspected in any pa- tient with recurrent and extensive oral aphthosis. Other causes of aphthosis such as inflammatory bowel disease, as well as lesions that mimic aphthae such as herpes simplex virus infection, must be ex- cluded. The diagnosis should also be considered in young patients with deep venous thrombosis, particularly in the absence of other risk factors or thrombophilia. A positive pathergy provocation test, read at 24–​48 h, may further support the diagnosis. Aphthae may be treated with topical or intralesional cortico- steroids, topical tacrolimus, or with viscous lidocaine (lignocaine). Oral colchicine may also be used to treat mucocutaneous manifest- ations, although this option might be limited by gastrointestinal intolerance and requires monitoring for neutropenia. Dapsone in combination with colchicine has also been used successfully. Thalidomide may be effective in this situation but is becoming in- creasingly difficult to prescribe for women because of the risks to the fetus. Behçet’s disease with manifestations other than mucocutaneous involvement may be treated with systemic corticosteroids, although this may not control severe ocular, neurological, or non​vasculitic vascular disease. Immunosuppressive agents such as ciclosporin, azathioprine, and methotrexate have been used for patients with se- vere Behçet’s disease. Xanthomas There are different forms of xanthoma. Eruptive xanthomas of the skin, often on the buttocks and limbs, may develop in patients with hyperlipoproteinaemia in association with diabetes mellitus. Control of the hyperlipoproteinaemia and diabetes usually leads to resolution of the yellowish papules. See Chapter 12.6 for more de- tailed discussion. Crohn’s disease and the skin Periorificial granulomatous lesions sometimes occur in Crohn’s dis- ease. Perianal abscesses and multiple fissures with fistulae occur in about a quarter of patients. Anal tags which are oedematous or have granulomatous histology are common. Oral Crohn’s disease pre- sents as a thickened corrugated appearance of the oral mucosa and lips. Granulomatous cheilitis may precede other features of Crohn’s disease. Cutaneous Crohn’s disease may also affect sites not in continuity with the bowel, and reactive dermatoses associated with Crohn’s dis- ease include oral aphthae, erythema nodosum (see Chapter 23.7), and pyoderma gangrenosum (see next), a neutrophilic derma- tosis. Other skin diseases are rarely associated with Crohn’s disease, and it can be difficult to distinguish perianal Crohn’s disease from hidradenitis suppurativa. Fig. 23.15.7  Pyoderma gangrenosum, showing ulceration with a characteristically undermined edge on the lower leg.

23.15  Skin and systemic diseases 5751 Thyroid disease and the skin Thyroid disease is discussed in detail in Chapter 13.3.1. However, there are several cutaneous manifestations of both hypothyroidism and hyperthyroidism. Skin features associated with hypothyroidism in- clude pale and cold extremities, absence of sweating, puffy oedema of hands and face, eczema craquele and pruritus, xanthomatosis (sec- ondary to hyperlipidaemia), coarse sparse hair, brittle/​striated nails, purpura/​ecchymoses, punctuate telangiectasia on arms and finger- tips, and delayed wound healing. Features associated with hyper- thyroidism include soft and dry skin, palmar erythema, flushing, increased sweating, fast nail growth, pruritus and urticaria, pretibial myxoedema, acropachy, and diffuse addisonian hyperpigmentation. Pruritus without a rash Pruritus associated with systemic disease has been dealt with else- where within this chapter, but individuals presenting with itch in the absence of skin disease, should be carefully assessed. It can some- times be difficult to distinguish secondary changes associated with excoriation from primary skin disease. However, detailed history (including drug history) and thorough systemic examination are crucial. Routine initial investigations might include renal function, full blood count with differential and haematinics, thyroid func- tion, and liver function, with consideration of other investigations dependent on the clinical findings, such as chest radiograph, HIV testing, and screening for malignancy. FURTHER READING Archer CB (2008). Dermatological aspects of internal medicine. In: Archer CB (ed) Ethnic dermatology—​clinical problems and skin pigmentation, pp. 110–​25. Informa Healthcare, London. Barham KL, et al. (2004). Vasculitis and neutrophilic vascular reac- tions. In: Burns T, et al. (eds) Rook’s textbook of dermatology, 7th edition, pp. 49.1–​49.46. Blackwell Science, Oxford. Carroll R, et al. (2003). Incidence and prediction of non-​melanomatous skin cancer post-​renal transplantation:  a prospective study in Queensland, Australia. Am J Kidney Dis, 41, 676–​83. Durupt F, et al. (2008). Successful treatment of necrobiosis lipoidica with antimalarial agents. Arch Dermatol, 144, 118–​9 Euvrard S, Kanitakis J, Claudy A (2003). Skin cancers after organ trans- plantation. N Engl J Med, 348, 1681–​91. Finucane KA, Archer CB (2005). Dermatological aspects of medi- cine: recent advances in nephrology. Clin Exp Dermatol, 30, 98–​102. Gawkrodger DJ (2004). Sarcoidosis. In: Burns T, et al. (eds) Rook’s text- book of dermatology, 7th edition, pp. 58.1–​58.24. Blackwell Science, Oxford. Graham RM, Cox NH (2004). Systemic disease and the skin. In: Burns T, et al. (eds) Rook’s textbook of dermatology, 7th edition, pp. 59.1–​ 59.75. Blackwell Science, Oxford. Heinzerling L, et al. (2008). Insulin allergy: clinical manifestations and management strategies. Allergy, 63, 148–​55. Johns CJ, Scott PP, Schonfled SA (1989). Sarcoidosis. Annu Rev Med, 40, 353–​71. Jorizzo JL (1986). Behçet’s disease: an update based on the 1985 inter- national conference in London. Arch Dermatol, 122, 556–​8. Kukreja T, Petersen J (2006). Thalidomide for the treatment of refrac- tory necrobiosis lipoidica. Arch Dermatol, 142, 20–​2. Li N, et al. (1999). Identification of mycobacterial DNA in cutaneous lesions of sarcoidosis. J Cutan Pathol, 26, 271–​8. Mailler-​Savage EA, Adams BB (2008). Exogenous insulin-​derived Acanthosis nigricans. Arch Dermatol, 144, 126–​7. Morgan AJ, Schwartz RA (2008). Diabetic dermopathy: a subtle sign with grave implications. J Am Acad Dermatol, 58, 447–​51. Radakovic S, et al. (2010). Dramatic response of chronic ulcerating necrobiosis lipoidica to ultraviolet A1 phototherapy. Photodermatol Photoimmunol Photomed, 26, 327–​9. Sarkany RPE, et  al. (2004). Metabolic and nutritional disorders. In: Burns T, et al. (eds) Rook’s textbook of dermatology, 7th edition, pp. 57.1–​57.124. Blackwell Science, Oxford. Scadding JG, Mitchell DN (eds) (1985). Sarcoidosis, 2nd edition, pp. 1–​12. Chapman & Hall, London. Shimanovich I, et  al. (2008). Necrobiosis lipoidica in monozygotic twins. Arch Dermatol, 144, 119–​20. Sterling JC (2004). Virus infections. In: Burns T, et al. (eds) Rook’s text- book of dermatology, 7th edition, pp. 25.1–​25.83. Blackwell Science, Oxford. Wells RS, Smith MA (1963). The natural history of granuloma annulare. Br J Dermatol, 75, 199–​205. Young AW Jr, et al. (1973). Dermatologic evaluation of pruritus in pa- tients on haemodialysis. N Y State J Med, 73, 2670–​4.

23.16 Cutaneous reactions to drugs 5752 Sarah Wals

23.16 Cutaneous reactions to drugs 5752 Sarah Walsh, Daniel Creamer, and Haur Yueh Lee

ESSENTIALS Adverse reactions to medications are common and important cause of iatrogenic illness. Severe cutaneous adverse drug reactions in- clude toxic epidermal necrolysis, Stevens–​Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, and acute gen- eralized exanthematous pustulosis, which together constitute 2% of all adverse drug reactions and may be life-​threatening. Less severe drug-​induced skin reactions such as exanthems, urticaria, lichenoid drug rashes, and fixed drug eruptions are more common, sometimes termed benign cutaneous adverse reactions, and generally resolve without sequelae. Drugs may also cause adverse events due to alteration of the normal function of the skin or its appendages. This may take the form of photosensitivity, abnormal pigmentation, or disrupted growth of hair or nails. The field of adverse drug reactions is changing constantly with the advent of new targeted therapies, particularly in the domain of on- cology. Reaction patterns in the skin resulting from these new agents include pustular eruptions, palmoplantar erythrodysaesthesia, and eruptive keratoacanthomas. Ascribing culpability to a particular drug when an adverse reac- tion has occurred requires careful assessment of the drug history, including latency, notoriety, and the reaction pattern in the skin. The most important first step in the management of any adverse drug re- action is cessation of the culprit drug or drugs. In vivo or in vitro tests are of limited use because, for most drugs, the antigenic molecule, hapten, or metabolite is not known or available. Introduction Adverse reactions to medications are common and are an important cause of iatrogenic illness. While only 2% of all drug-​induced skin reactions are severe, they may all cause considerable morbidity for the patient affected, and can have medicolegal and health economic consequences. In addition, cutaneous adverse reactions to a medi- cation may influence the patient’s future adherence to prescribed therapy. Assessment of the patient with a suspected cutaneous adverse drug reaction is important both in the acute phase of illness—​so that the offending drug can be stopped—​and for the long-​term well-​ being of the patient, so that the drug implicated and all related agents can be avoided in future. Careful documentation of the conclusions of such assessment, and any testing performed, is paramount to avoiding inadvertent re-​exposure. Assessment of drug causality is rendered difficult by the following principles which underpin adverse reactions to medications: • Almost any drug can cause any rash • Unrelated drugs might cause similar eruptions • The same drug might cause different patterns of eruption in dif- ferent patients • Some drug reactions can resemble specific skin diseases such as eczema, acne, or lichen planus making it difficult to distin- guish between idiopathic skin disease and a drug-​induced phenomenon Drug-​induced skin disease can be classified as follows: a. Drugs causing alteration of normal skin function b. Drugs causing exacerbation of an existing dermatosis c. Benign drug-​induced skin disease:  exanthems, urticaria/​ angioedema, lichenoid reactions, fixed drug eruption, pruritus. These are sometimes referred to as benign cutaneous adverse reactions (BCAR) d. Severe drug-​induced skin disease: acute generalized exanthema- tous pustulosis (AGEP); drug reaction with eosinophilia and systemic symptoms (DRESS); Stevens–​Johnson syndrome/​toxic epidermal necrolysis (SJS/​TEN); and generalized bullous fixed drug eruption (GBFDE). These are sometimes referred to as se- vere cutaneous adverse reactions (SCAR) Clinical approach to drug causality The identification and withdrawal of the culprit drug is key to the management of all adverse drug reactions. Clinical assess- ment of drug causality relies on a comprehensive drug history 23.16 Cutaneous reactions to drugs Sarah Walsh, Daniel Creamer, and Haur Yueh Lee

23.16  Cutaneous reactions to drugs 5753 and recognition of the morphology and type of adverse reaction. Causality reasoning relies on two broad principles: a. Latency of the particular reaction pattern b. Epidemiological risk of certain drug/​drugs groups in causing a particular reaction. This is sometimes referred to as the notoriety of the drug (e.g. allopurinol is a high notoriety drug for Stevens– Johnson Syndrome). Latency Recognition of the different morphology and types of adverse reac- tions is essential as these reactions have varying latencies between the administration of the drug and the onset of the reaction (Table 23.16.1). For example, urticaria and angioedema are immediate re- actions which occur typically within 1–​6 hours of drug exposure whereas exanthematous eruptions, Stevens–​Johnson syndrome (SJS)/​toxic epidermal necrolysis (TEN) and drug hypersensitivity reactions are delayed reactions with latencies of 1 week, 5–​28 days, and 2–​8 weeks, respectively. Drugs that are taken within the latency period are considered potential culprits for inciting the reaction. Epidemiological risk The risk of inciting a particular drug reaction differs between drugs with some being high-​risk for a specific reaction. These drugs are summarized in Table 23.16.1. Information regarding such epi- demiological risk is largely derived from pharmacovigilance reports, disease registries, and published literature. For example, most SJS/​ TEN can be attributed to a few high-​risk drugs, such as allopurinol, carbamazepine, phenytoin, co-​trimoxazole, oxicam non​steroidal anti-​inflammatory drugs (NSAIDs), nevirapine. With the help of a drug exposure time-​line, a list of possible culprit drugs can be compiled (Fig. 23.16.1). In a patient who de- velops toxic epidermal necrolysis, the latency period from drug initiation to onset of symptoms is typically 5–​28 days. A complete drug exposure history is taken from the patient and annotated. Allopurinol and paracetamol best fits the temporal sequence. Between the two, allopurinol is the more likely causative drug due to its high epidemiological risk. The rest of medications are un- likely; aspirin and enalapril are long-​term medications, omeprazole was stopped seven weeks prior to onset of disease, the latency period of frusemide is too short to cause Stevens–​Johnson syn- drome/​ toxic epidermal necrolysis and amoxicillin was started after the onset of symptoms. Diagnostic testing Skin testing and in vitro testing are available for the evaluation of hypersensitivity reactions; however, these tests have an overall low sensitivity and are not routinely available in most centres. Choice of tests is dependent on the suspected immune mechanism underlying the drug reaction. Skin testing (i.e. prick, intradermal, and patch testing) is usually performed four weeks to six months after the resolution of the reaction. Prick and intradermal tests are useful for immediate hypersensitivities such as urticaria, angioedema, and ana- phylaxis. Protocols have been standardized for some drug classes such as β-​lactams, neuromuscular blocking agents, and iodinated contrast. However, for most drugs, test reagents, and concentrations have not been sufficiently validated. Patch tests and intradermal testing with delayed readings on the other hand may be useful for the evaluation of delayed hypersensitivity reactions such as drug exanthems, acute generalized exanthematous pustulosis, drug reac- tion with eosinophilia and systemic symptoms, and Stevens–​Johnson syndrome (SJS)/​toxic epidermal necrolysis. Validated concentrations of the drug are applied on the patient’s back in special test chambers and are left in place for 48 hours. Readings of these tests are per- formed at three and five days after the application of test chambers. In vitro tests such as basophil degranulation tests, lymphocyte proliferation, cytokine secretion, and cytotoxicity assays are avail- able mainly in research centres with a interest in drug allergies. Positive basophil degranulation tests indicate the presence of spe- cific IgE on the surface of basophils and are useful in the evaluation of immediate hypersensitivity reactions. Lymphocyte proliferation, cytokine secretion, and cytotoxicity assays are typically used for the evaluation of delayed reactions. Their use remains limited to the do- main of research at the present time. Despite being the gold standard to confirm or exclude a drug al- lergy, provocation testing should not be taken lightly. A risk-​benefit analysis needs to be undertaken. It should never be performed in patients with severe cutaneous adverse reactions, high-​risk patients with severe comorbidities such as severe asthma, cardiac disease, or in patients who are unlikely to need the drug in the future. Drugs causing alteration to normal skin function Pigmentary change Alteration of the skin’s normal colour might be seen in response to medication. This can occur in either a localized or a generalized pat- tern, though the former is more commonly recognized. Common causes of drug-​induced skin pigmentation include melasma, the mid-​brown discolouration seen on the upper lip and peripheral part of the face, particularly in female patients taking the oral contracep- tive pill. Amiodarone and minocycline characteristically produce a grey facial pigmentation in susceptible individuals. Several mechanisms are proposed for the process of drug-​induced skin pigmentation, though none are definitively accepted. The drug, or a metabolite thereof, may be deposited in the dermis or epidermis, causing dyspigmentation. This process may require, or be enhanced by, environmental ultraviolet light, causing it to predominate in sunlight-​exposed sites. This has been suggested to contribute to the pathogenesis of amiodarone dyspigmentation. Alternatively, it has been proposed that melanin production might be enhanced, with or without an increase in the number of melanocytes. This is likely to be the mechanism for increased pigmentation in melasma. Photosensitivity Drug-​induced photosensitivity can be classified as phototoxic or photoallergic (Box 23.16.1). Phototoxic reactions resemble severe sunburn, and occur 5–​15 hours following exposure to the drug, and subside quickly on withdrawal. Phototoxic reactions demon- strate a dose-​response relationship both to the drug and to sunlight. Photoallergic reactions are more insidious and difficult to diagnose. This reaction pattern occurs after exposure to normal levels of ultra- violet (UV) light and are not dose-​dependent. Withdrawal of the drug may not result in immediate resolution of photosensitivity, but may linger on for months or years following discontinuation of the culprit drug. The morphology of a photoallergic rash is usually

section 23  Disorders of the skin 5754 Table 23.16.1  Summary of clinical features, latency and common inciting drugs of cutaneous adverse reactions SJS/​TEN DRESS AGEP GFBDE Fixed drug eruption Drug Exanthem Urticaria/​ angioedema Clinical features Purpuric macules, atypical targets, blisters, erosions, and sheet-​like detachment Maculopapular exanthema, exfoliative dermatitis, pustules, facial oedema Multiple pinpoint pustules on background of erythema Multiple large dusky plaques, bulla, skin detachment with normal intervening skin Round/​oval erythematous /​ dusky plaques, occasionally bullous Macules and papules, confluent erythema Wheals and flare, perioribital and lip oedema Differential diagnosis GBFDE, SSSS GVHD, acute cutaneous lupus, autoimmune blistering diseases, post-​infectious EM Viral infections Drug exanthem Lymphoma Hypereosinophilic syndromes Pustular psoriasis SSSS SJS/​TEN in GBFDE Post-​infectious EM Viral exanthem Chronic spontaneous urticarial, physical urticaria Latency period 5–​28 days 2–​8 weeks 1–​12 days Few hours to 3 days Few hours to 3 days 5–​14 days Within 1–​6 hours High-​risk drugs Allopurinol, phenytoin, carbamazepine, lamotrigine, phenobarbital, infective sulphonamides, oxicam NSAIDS, nevirapine Allopurinol, anti-​ infective sulphonamides, phenytoin, carbamazepine, minocycline, vancomycin Penicillin, quinolones, pristinamycin, sulphonamides, antimalarials, terbinafine, diltiazem Co-​trimoxazole NSAIDs β-​lactams Allopurinol Co-​trimoxazole, tetracyclines, NSAIDS, doxycycline, paracetamol β-​lactams NSAIDs Sulphonamides Fluoroquinolones β-​lactams Neuromuscular blocking agents Local anaesthesia AGEP, acute generalized exanthematous pustulosis; DRESS, drug reaction with eosinophilia and systemic symptoms; EM, erythema multiforme; GBFDE, generalized bullous fixed drug eruption; GVHD, graft-​versus-​host disease; NSAIDs, nonsteroidal anti-​inflammtory drugs; SJS, Stevens–​Johnson syndrome; TEN, toxic epidermal necrolysis; SSSS, staphylococcal scalded skin syndrome.

23.16  Cutaneous reactions to drugs 5755 eczematous, but lichenoid, bullous, urticarial, and purpuric variants are described. Nail disorders The growth and appearance of finger and toenails can be altered by drugs. Specifically, chemotherapeutic drugs may interfere with normal nail growth, resulting in changes to the pigmentation or the texture of the nail. Leuconychia (white nails) may be caused by cyclo- phosphamide, doxorubicin, or vincristine. Onycholysis describes sep- aration of the nail plate from the nail bed; any cytotoxic agents may cause this by toxicity to the nail matrix. Photo-​onycholysis is a specific form of the disorder described with minocycline, whereby UVA ex- posure is required in combination with the drug to cause onycholysis. Hair disorders Drugs might interfere with any of the phase of the hair cycle, produ- cing hair loss (Box 23.16.2). A simple illustration of the hair cycle is included in Fig. 23.16.2. The latency of onset of hair loss following introduction of the medication will depend on the part of the hair cycle with which the drug interferes. Cytotoxic drugs interfere with anagen, or the growth phase of the hair cycle, thus hair loss is dra- matic and occurs within one to two weeks of drug exposure. Drugs which interfere with the telogen or resting phase of the hair cycle produce a more insidious form of hair loss which occurs gradually over months following drug initiation. Onset of reaction Latency period Toxic epidermal necrolysis – 8 wks Aspirin Enalapril Omeprazole Allopurinol Paracetamol Furosemide Amoxicillin Drug exposures – 6 wks – 4 wks – 2 wks 2 wks Fig. 23.16.1  Drug time-​line analysis. Box 23.16.1  Drugs causing photosensitive eruptions Phototoxic reactions Amiodarone NSAIDs Chlorpromazine Tetracyclines Photoallergic reactions NSAIDs Sulphonamides Sulphonylurea Thiazide diuretics Statins Box 23.16.2  Drug-​induced hair disorders Alopecia Acitretin and isotretinoin (retinoids) Anticoagulants B blockers Cytotoxic drugs Gold salts Interferon Lithium Statins Tacrolimus Hirsutism/​hypertrichosis Anabolic steroids Corticosteroids (topical and systemic) Ciclosporin Danazol Minoxidil Oral contraceptive pill Penicillamine Phenytoin Tamoxifen Verapamil

section 23  Disorders of the skin 5756 Excessive growth of hair may be a troublesome adverse effect of a medication. Hirsutism is the term used to describe excess hair growth in a male-​pattern distribution, such as the development of facial hair in women. Hypertrichosis is the growth of hair in quantities greater than would be normal for an individual of that age, sex, and ethnicity. Phenytoin and ciclosporin may cause hirsutism in certain individuals. The therapeutic potential of minoxidil to produce hypertrichosis was noted in early trials of this drug as an agent to lower blood pressure; this has subsequently been exploited with the development of topical solutions of minoxidil which are used to treat baldness. Drugs exacerbating existing skin complaints Certain medications can exacerbate or precipitate idiopathic skin complaints. These are summarized in Box 23.16.3. Withdrawal of the medication may in part resolve the problem, but often supple- mentary treatment is required. Benign drug-​induced skin disease (BCAR) Simple drug exathems Exanthems are the most common type of drug reaction in the skin, and typically have a latency of seven days or fewer following first exposure to the culprit medication. The morphology of the rash may vary, consisting of macular or maculo-​papular erythema. A  morbilliform (measles-​like) eruption is also recognized. The distribution is usually generalized, with the exact proportion of the body surface area (BSA) involved varying from case to case. The mucous membranes are spared. Any drug can provoke an exanthem, but, in practice, common causes include antibiotics (penicillins, sulphonamides, cephalosporins, carbopenams), anti- convulsants (phenytoin, carbamazepine), and quinine-​containing medications. Identification of the culprit medications using these interrogative techniques is imperative to preventing inadvertent re-​exposure to the drug. The adverse reaction should be clearly conveyed to the pa- tient, documented in the patient notes, and communicated to the primary care physician. The reaction should also be reported to the appropriate pharmacovigilance agency in that country, for example, the Medicines and Healthcare products Regulatory Authority (MHRA) in the United Kingdom. Most simple drug exanthems respond to application of a potent topical steroid such as mometasone fuorate ointment once a day for five to seven days, with antihistamines being taken orally. Urticaria and angioedema These two conditions may be considered to be idiopathic, but can exist in a drug-​induced form. Urticaria is characterized by the ap- pearance of transient, pruritic, erythematous weals in the skin; angioedema described sudden, dramatic soft tissue swelling, most noticeable in the head and neck area. Urticaria/​angioedema may be a cutaneous manifestation of anaphylaxis to a drug, and thus prompt medical attention is required. Common drugs which cause urticarial eruptions, or which exacerbate pre-​existing idiopathic chronic urti- caria are listed in Box 23.16.4. Treat­ment consists of identification and withdrawal of the culprit medication, and administration of combination antihistamine therapy. Lichenoid drug eruption (LDE) These eruptions are so named as their clinical appearance resembles that of lichen planus, with its purplish flat-​topped Anagen Catagen Telogen Growth phase Transitional phase Resting phase Hair Growth Cycle Fig. 23.16.2  The hair growth cycle. Box 23.16.3  Drugs exacerbating existing skin conditions Acne Androgens (in women) Corticosteroids (oral and topical) Ciclosporin EGFR receptor antagonists (e.g. cetuximab) Lithium Oral contraceptive pills (particularly progesterone only) Phenytoin Eczema Calcium channel blockers Statins Diuretics Alcohol Retinoids—​acitretin, isotretinoin Calcium channel blockers—​nifedipine, amlodipine Psoriasis ACE inhibitors Alcohol Antimalarials (chloroquine, mepacrine) B blockers Corticosteroids Lithium Rosacea Corticosteroid (oral or topical) Alcohol Box 23.16.4  Drugs causing urticaria/​angioedema Antibiotics—​particularly penicillin given by parenteral route Drugs acting on the angiotensin pathways—​ACE inhibitors and angio- tensin receptor blockers (ARBs) Non​steroidal anti-​inflammatory drugs (NSAIDs)—​aspirin, diclofenac, naproxen Opiate anagesics—​codeine, morphine Antimalarials—​quinine, chloroquine, hydroxychloroquine, mepacrine Rifampicin Sulphur-​containing drugs

23.16  Cutaneous reactions to drugs 5757 polygonal papules. However a lichenoid drug eruption may have an atypical distribution, and will usually be resistant to topical therapies which alleviate idiopathic lichen planus. Lichenoid drug eruptions may be caused by several different agents (Box 23.16.5). Following withdrawal of the culprit medication, resolution of lichenoid drug eruption may take some time, oc- casionally even months, differing from simple exanthems in this respect. Pronounced post-​inflammatory hyperpigmenta- tion might also be seen following resolution of lichenoid drug eruption. Fixed drug eruption (FDE) Fixed drug eruption describes a specific reaction pattern in the skin, the pathogenesis of which is poorly understood. It consists of one or multiple inflammatory, erythematous macules, sometimes with a blistering centre, appearing at diverse sites on the body. The typical sites are the torso, the hands, feet, face, or genital skin. The pecu- liarity of fixed drug eruption is that on re-​exposure to the culprit medication, the eruption recurs at exactly the same sites as the pre- vious exposure. While fixed drug eruption is largely self-​limiting, re- covery can be accelerated by the application of topical steroid to the affected area. Post-​inflammatory hyperpigmentation may remain. Although any drug may cause a fixed drug eruption, more common culprits are listed in Box 23.16.6. Severe cutaneous adverse drug reactions Adverse cutaneous drug reactions differ in clinical features and prognosis with the most severe, life-​threatening reactions col- lectively termed as severe cutaneous adverse reactions (SCARs) (Fig. 23.16.3). These reactions include Stevens–​Johnson syndrome (SJS)/​toxic epidermal necrolysis (TEN), drug reaction with eosino- philia and systemic symptoms (DRESS), and acute generalized ex- anthematous pustulosis, and are summarized in Table 23.16.1. These reactions are life-​threatening and the mortality rate of such reactions ranges from 5% in DRESS to more than 40% in TEN. Previously thought to be idiosyncratic and unpredictable, recent advances have shown a pharmacogenetic association with certain drug-​induced SCARs (Table 23.16.2). Stevens–​Johnson syndrome/​Toxic epidermal necrolysis Stevens–​Johnson syndrome and toxic epidermal necrolysis are rare conditions; the incidence of toxic epidermal necrolysis is estimated to be one to two cases per million per year. Both conditions repre- sent a disease spectrum, and are classified according to the extent of body surface area detachment with epidermal detachment of less than 10% body surface area being classified as SJS, cases with greater than 30% as toxic epidermal necrolysis and those between 10 to 30% as SJS-​TEN overlap. The terms erythema multiforme (EM) and SJS have been historically linked and thought to be part of the disease process but it is now known that EM can be distinguished from SJS/​ TEN based on clinical pattern (EM presents with typical targets which are well-​defined papules with 3 different zones of erythema distributed peripherally, as opposed to atypical targets in SJS/​TEN which are flat erythematous/​purpuric macules with blisters distrib- uted centrally) and aetiology (EM is typically post-​infectious versus drugs in SJS/​TEN). The process is immune-​mediated and involves interactions be- tween drug-​specific T cells, drugs, and HLA molecules with the sub- sequent release of cytotoxic mediators, such as granulysin. This leads to the pathologic hallmark of widespread keratinocyte apoptosis The clinical presentation of SJS/​TEN is acute and may be preceded by constitutional symptoms of fever, malaise, upper respiratory tract symptoms, followed by the onset of a painful rash characterized by purpuric macules, target-​like lesions, vesicles, bullae, and sheet-​like detachment. Mucosal surfaces including the conjunctiva, oral and anogenital regions are affected in more than 90% of cases. Following the active phase of detachment which typically lasts 1 week from the onset of symptoms, the detachment stops with subsequent re-​ epithelialization of the skin. Consequent to this ‘acute skin failure’, there is a loss of the barrier, thermoregulatory and homeostatic function of the skin resulting in excess fluid loss, hypothermia, sepsis, and prerenal failure. In severe cases, multiorgan failure and death can occur. Mortality ranges from 10% in SJS to more than 40% in TEN. A prognostic scoring SCORTEN consisting of seven clinical and biochemical markers are useful to predict outcome (Table 23.16.3/​Table 23.16.4). Supportive care remains the mainstay of treatment and pa- tients should be managed in specialized referral centres. The cul- prit drug should be immediately discontinued. Although various immunomodulatory treatments such as corticosteroids, intravenous immunoglobulins, and ciclosporin have been proposed, none has been validated in controlled studies. Long-​term sequelae affecting the skin and eyes such as dyspigmentation, corneal scarring, and blindness can profoundly impact the quality of life in survivors. Drug reaction with eosinophilia and systemic
symptoms (DRESS) Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-​induced hypersensitivity syndrome (DIHS), is characterized by cutaneous eruption that is associated with internal organ involvement, prolonged latency from drug initiation, chron- icity, and relapsing nature. Box 23.16.5  Causes of lichenoid drug eruptions Antimalarials—​quinine, chloroquine, hydroxychloroquine, mepacrine Aspirin ACE inhibitors and angiotensin receptor blockers Calcium channel blockers Gold Lithium Methyldopa NSAIDs Penicillamine Thiazide diuretics Sulphoylureas Box 23.16.6  Causes of fixed drug eruptions Antibiotics—​penicillin, metronidazole, sulphonamides, tetracyclines Aspirin Dapsone NSAIDs Oral contraceptive pills Phenytoin

section 23  Disorders of the skin 5758 The cutaneous eruption is polymorphous and may present with an maculopapular exanthematous reaction, target-​like lesions, pur- pura, pustules, or generalized exfoliative dermatitis. This is often accompanied by prominent facial oedema, eosinophilia, atyp- ical lymphocytosis, and lymphadenopathy. Organ involvement predominantly affects the liver and kidneys, but other systemic com- plications such as arthralgia, myositis, pneumonitis, myocarditis, and pericarditis are known to occur. Unlike other cutaneous adverse reactions, the clinical course in DRESS may be prolonged, lasting Fig. 23.16.3  (a) SJS/​TEN overlap with sheet-​like detachment with spots and atypical targets. (b) Confluent erythema in a DRESS patient requiring ICU care. (c) GBFDE: Scattered dusky plaques and bulla. (d) AGEP: Multiple pinpoint pustules on erythematous base. AGEP, acute generalized exanthematous pustulosis; DRESS, drug reaction with eosinophilia and systemic symptoms; GBFDE, generalized bullous fixed drug eruption; ICU, intensive care unit; SJS, Stephen–​Johnson syndrome; TEN, toxic epidermal necrolysis. Table 23.16.2  Pharmacogenetics of human leukocyte antigen associated severe cutaneous adverse reactions Drug HLA allele Hypersensitivity reaction Ethnicity Abacavir B57:01 DRESS Caucasian Allopurinol B58:01 SJS/​TEN Han Chinese, Caucasians Carbamazepine B15:02 A31:01 A31:01 SJS/​TEN SJS/​TEN DRESS Han Chinese, Indian, Thai, Malay Caucasian Caucasian, Han Chinese Dapsone B13:01 DRESS Chinese DRESS, drug reaction with eosinophilia and systemic symptoms; SJS, Stevens–​Johnson syndrome; TEN, toxic epidermal necrolysis. Table 23.16.3  SCORTEN prognostic scoring system for toxic epidermal necrolysis Independent prognostic factors Weight Age >40 years 1 Cancer/​haematological malignancy 1 Body surface area involved at day 1 >10% 1 Serum bicarbonate level <20 mmol/​litre 1 Serum glucose level >14 mmol/​litre 1 Serum urea level >10 mmol/​litre 1 Heart rate >120 beats/​min 1 These values were derived from multivariate analysis of 23 variables in 165 patients with toxic epidermal necrolysis (TEN). Each positive criterion is given a score of 1; the correlation between SCORTEN and mortality is shown in Table 23.16.4. Adapted from N. Fouchard et al. (2000). SCORTEN: A Severity-​of-​Illness Score for Toxic Epidermal Necrolysis. Journal of Investigatory Dermatology, 115, 149–​53. Copyright 2000, with permission from The Society for Investigative Dermatology.

23.16  Cutaneous reactions to drugs 5759 weeks to months despite culprit drug withdrawal. Reactivation of viruses of the herpes family such as human herpes virus 6 (HHV6), cytomegalovirus (CMV), and Epstein-​Barr virus (EBV) have been recognized and may denote a more chronic and severe clinical course. The mortality of DRESS is about 5–​10%. Long-​term auto- immune sequelae such as autoimmune thyroid disease, vitiligo, and alopecia areata have been reported in survivors. Treatment consists of drug withdrawal and supportive therapy. To date, no controlled studies on treatment of drug reaction with eosinophilia and systemic symptoms exist. Both potent topical and systemic corticosteroids have been used in its treatment with the latter being widely used in patients with systemic involvement. There is a theoretical risk of worsening of existing viral reactivation with systemic corticosteroids and judicious tapering of corticoster- oids should be done to prevent a flare-​up of disease. Acute generalized exanthematous pustulosis (AGEP) The clinical hallmark of acute generalized exanthematous pustulosis (AGEP) is the presence of numerous pinpoint pustules overlying background of erythema or erythematous lesions. These lesions may initially arise in the intertriginous areas before becoming general- ized. This is frequently accompanied with facial oedema, pruritus, fever, and peripheral neutrophilia. Organ involvement occurs in about 20% of cases, typically involving the liver and kidney. The reac- tion is self-​limiting with a good prognosis, with mortality occurring in less than 5% of cases. Resolution is characterized by post-​pustular desquamation and occurs typically within two weeks of the onset of reaction. Supportive treatment is the mainstay of treatment since it is self-​limiting. Although widely used, topical and systemic cortico- steroids have not been shown in controlled studies to modify the clinical course of the disease. Generalized bullous fixed drug eruptions (GBFDE) Generalized bullous fixed drug eruptions are rare, extensive vari- ants of fixed drug eruptions. Unlike typical fixed drug eruption, the lesions consist of large erythematous/​purpuric patches with bulla and erosions and involve a larger proportion of the body surface area. Due to the extensive nature and the presence of skin detach- ment, it is often misdiagnosed as SJS/​TEN. In distinction from SJS/​ TEN, constitutional symptoms are less common and there are dif- ferences in clinical morphology such as absence of atypical targets, purpuric spots, minimal mucosal involvement as well as the pres- ence of normal intervening skin between lesions. A history of pre- vious recurrent episodes is common and the extent of disease may be progressive with each subsequent attack. Traditionally thought to confer a better prognosis than SJS/​TEN, a recent study has shown that the prognosis is similar to SJS/​TEN of the same body surface area detachment, with an average mortality of 20%. Nonetheless, it is important to distinguish GBFDE from SJS/​TEN as the implicated drugs in GBFDE have a shorter latency of hours to 3 days compared to the typical 5–​28 days in SJS/​TEN. In cases with extensive skin involvement, GBFDE should be managed similarly to SJS/​TEN in specialized units with care focused on supportive treatment and im- mediate withdrawal of culprit drug. Cutaneous adverse reactions induced
by targeted anticancer therapies Conventional chemotherapy typically acts on disrupting the specific phases of the cell cycle in actively dividing malignant cells. Their side effects are well-​recognized and typically occur in tissues with rapid turnover of cells such as hair follicles and mucosal surfaces, leading to alopecia and mucositis. Other reactions vary depending on the type of chemotherapy. Pigmentary changes can occur with bulsulphan and 5-​fluorouracil. Nail dystrophies, including ridging and onycholysis, can occur in patients receiving taxanes. Extravasation injuries may occur due to leakage of intravenously ad- ministered chemotherapy, such as anthracyclines, vinca alkaloids, paclitaxel, and cisplatin, leading to erythema and necrosis in severe cases. Hand-​foot syndrome or palmoplantar erythrodysaesthesia, which is characterized by erythema, oedema, blistering and scaling of the palms and soles, can occur with treatment of cytarabine and 5-​fluorouracil. The rest of this section focuses on targeted therapies which are novel anticancer drugs directed against the molecular abnormalities involved in the pathogenesis of neoplastic transformation and me- tastases. Newer agents are constantly being approved and, to date, approved targeted therapies include epidermal growth factor re- ceptor (EGFR) inhibitors, KIT and BCR-​Abl inhibitors, multikinase inhibitors, RAF inhibitors, and more recently, immunomodulatory agents that antagonize CTLA4 as well as PD1. Skin toxicities are not uncommon as many of such target molecules are also highly ex- pressed in the skin. EGFR inhibitors (e.g. gefitinib, erlotinib,
cetuximab, panitimumab) Papulopustular reactions are the most common adverse reactions affecting up to 90% of patients in trials and arise early in the course of treatment. They develop mainly on the seborrhoeic areas of the head and trunk and are characterized by follicular pustules and pap- ules, resembling acne vulgaris and rosacea. Xerosis or skin dryness is common, often resulting in fissuring of fingers and toes. Nail fold paronychia are described in 10–​20% of patients. Hair changes in- clude both scarring and non​scarring alopecia as well as trichomegaly of the eyelashes which can result in corneal erosions and ulcerations. KIT, BCR-​Abl, and PDGF inhibitors
(e.g. imatinib, nilotinib, dasatinib) Imatinib is the prototypical drug in this class and is used in the treatment of chronic myeloid leukaemia and stromal tumours. Facial oedema is one of the most observed adverse reaction and Table 23.16.4  Mortality rates depending on SCORTEN severity score SCORTEN Mortality rate Odds ratio 0–​1 3.2 1 2 12.1 4.1 3 35.3 14.6 4 58.3 42

5 90 270 Adapted from N. Fouchard et al. (2000). SCORTEN: A Severity-​of-​Illness Score for Toxic Epidermal Necrolysis. Journal of Investigatory Dermatology, 115, 149–​53. Copyright 2000, with permission from The Society for Investigative Dermatology.

section 23  Disorders of the skin 5760 can be mistaken for angioedema. Maculopapular and generalized exfoliative dermatitis may also occur. Pigmentary changes con- sisting of both hyper and hypopigmentation can occur in up to 40% of patients. Rare cases of SJS/​TEN have been reported with imatinib. Multikinase inhibitors (e.g. sorafenib, sunitinib) Sorafenib is FDA approved for the treatment of renal cell and hepatocellular carcinoma and targets RAF, VEGF, FLT-​3, C-​KIT, and RET tyrosine kinases. The targets of sunitinib are VEGFR, PDGFR as well as c-​KIT, RET, and FLT 3 receptor tyrosine kinase. The most common side effect is the hand-​foot syndrome, which affects up to 70% of patients. This is characterized by skin thickening localized to pressure areas. Other reactions include facial erythema and nail splinter haemorrhages. RAF inhibitors (e.g. vemurafenib, dabrafenib) The most clinically significant adverse reaction is the development of keratoacanthomas and squamous cell carcinoma. This adverse reaction is abrogated with the concurrent use of MEK inhibitors. Other reactions observed in trials include keratosis pilaris-​like reac- tions, cysts, photosensitivity, and pruritus. MEK inhibitors The adverse reactions associated with MEK inhibitors (e.g. trametinib) are similar to those of EGFR inhibitors and include papulopustular rash, dry skin with fingertip fissuring as well as paronychia. Anti-​CTLA 4 Antibodies CTLA-​4 (Cytotoxic T-​lymphocyte-​associated protein 4)  is a sur- face molecule found on various lymphocyte subtypes and it acts as a brake on immune activation. The use of CTLA-​4 antibodies (e.g. ipilimumab, tremelimumab) results in a proliferation of T lympho- cytes with antitumour response and has been approved for the treatment of metastatic melanoma. However, this can lead to imbal- ances in immunologic tolerance and can lead to collateral damage in normal tissues, resulting in inflammatory or autoimmune side effects. Dermatologic adverse reactions associated with anti-​ CTLA4 molecules include diffuse maculopapular eruptions, usually developing one to two weeks after initiation of treatment, pruritus, and vitiligo. Anti PD-​1 Anti PD-​1 (Programmed cell death-​1) is another immune-​ checkpoint inhibitor. Dermatological adverse reactions include maculopapular eruptions (the most common) as well as other reac- tions such as bullous disorders like bullous pemphigoid. FURTHER READING Barbaud A, et al. (2001). Guidelines for performing skin tests with drugs in the investigation of cutaneous adverse drug reactions. Contact Dermatitis, 45, 321–​8. Bastuji-​Garin S, et al. (1993). Clinical classification of cases of toxic epideraml necrolysis:  Stevens-​Johnson syndrome and erythema multiforme. Arch Dermatol, 129, 92–​6. Chung WH, et  al. (2004). Medical genetics:  a marker for Stevens-​ Johnson syndrome. Nature, 428, 426. Kardaun SH, et al. (2013). Drug reaction with eosinophilia and sys- temic symptoms (DRESS): an original multisystem adverse drug re- action. Results from the prospective RegiSCAR study. Br J Dermatol, 169, 1071–​80. Lipowicz S, et al. (2013). Prognosis of generalized bullous fixed drug eruption:  comparison with Stevens-​Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol, 168, 726–​32. Macdonald J, et  al. (2015). Cutaneous adverse effects of targeted therapies. Part I: inhibitors of the cellular membrane. J Am Acad Dermatol, 72, 203–​18. Macdonald J, et al. (2015). Cutaneous adverse effects of targeted ther- apies. Part II: inhibitors of intracellular molecular signalling path- ways. J Am Acad Dermatol, 72, 221–​36. Mockenhaupt M, et al. (2008). Stevens-​Johnson syndrome and toxic epidermal necrolysis: assessment of medication risk with emphasis on recently marketed drugs. The EuroSCAR study. J Invest Dermatol, 128, 35–​44. Roujeau JC, Stern R (1994). Severe adverse cutaneous reactions to drugs. N Engl J Med, 331, 1272–​85. Sassolas B, et al. (2010). ALDEN, an algorithm for assessment of drug causality in Stevens-​Johnson syndrome and toxic epidermal necrolysis: comparison with case-​control analysis. Clin Pharmacol Ther, 88, 60–​8. Sekula P, et al. (2013). Comprehensive survival analysis of a cohort of patients with Stevens-​Johnson syndrome and toxic epidermal necrolysis. J Invest Dermatol, 133, 1197–​204. Sidoroff A, et al. (2001). Acute generalized exanthematous pustulosis (AGEP)—​a clinical reaction pattern. J Cutan Pathol, 28, 113–​9.

23.17 Management of skin disease 5761 Rod Sinclair

23.17 Management of skin disease 5761 Rod Sinclair

ESSENTIALS Topical therapy employs a vehicle (ointments, creams, lotions, gels) to deliver an active ingredient to the skin, to provide a protective bar- rier, or to hydrate and moisturize the skin. There are many types of topical treatments, including (1) antipruritics (e.g. calamine), are used to relieve itching; (2) keratolytics (e.g. salicylic acid, urea) are used to remove hyperkeratotic skin; (3) tars act by reducing the thickness of the epidermis; (4) corticosteroids have anti-​inflammatory and im- munosuppressive effects that are useful in treating many skin dis- orders; (5) calcipotriol (an analogue of 1,25-​dihydroxycholecalciferol) reduces epidermal proliferation and is used in local treatment of plaque psoriasis; (6) calcineurin inhibitors for eczema and other dis- eases; (7) retinoids influence immune function and have some anti-​ inflammatory activity and are used in acne; (8), immunomodulatory drugs such as imiquimod for some human papillomavirus infections, superficial basal cell carcinomas, and other diseases; (9)  medical therapies such as diclofenac cream and inguenol mebutate for ac- tinic keratosis and superficial basal cell carcinoma; (10) antiseptics (e.g. benzoyl peroxide, chlorhexidine); (11) antifungal agents; (12) sunscreens; (13) anaesthetics/​analgesics; (14) hair growth promoting agents such as minoxidil and topical prostaglandin analogues such as bimatoprost and stemoxydine. Other dermatological treatments include phototherapy (e.g. for psoriasis), photodynamic therapy (e.g. for actinic keratosis), and cryotherapy (e.g. for viral warts). Systemic therapies include oral ret- inoids, cytotoxics, and immunosuppressants. A major advance in the treatment of skin diseases has been the development of biological therapies as effective interventions for psoriasis, psoriatic arthritis, pemphigus vulgaris, urticaria, atopic dermatitis, and alopecia areata. General principles of therapy Topical therapy employs a vehicle to deliver an active ingredient to the skin, to provide a protective barrier, or to hydrate and moisturize the skin. Compliance and adherence Non​compliance to the clinician’s instructions is an important con- sideration in the treatment of dermatological disease where patients are asked to apply sticky and unpleasant preparations. The incidence has been estimated at around 30%. Helping patients to understand their disease encourages them to follow instructions from their medical attendant. Patient involve- ment in the decision making process can be helpful in building rap- port when dealing with a chronic problem like psoriasis or atopic dermatitis. Compliance is affected by the cost of medication, so a clear indica- tion of the likely duration, cost, and quantities needed for adequate treatment should be given, especially if the patient is financially disadvantaged. When prescribing topical preparations, it is important to provide patients with sufficient quantities. Full body coverage requires 40 g of a cream and slightly less if applying an ointment. Dermatological vehicles Dermatological vehicles are composed of one or more of the fol- lowing ingredients: powders (e.g. zinc oxide, starch, calamine, or talc); liquids (e.g. water, alcohol, glycerol, or propylene glycol); oils, greases, or waxes (e.g. peanut oil, castor oil, liquid paraffin, white and yellow soft paraffin, wool fat, hard paraffin, beeswax, or poly- ethylene glycols (macrogols)). These ingredients are combined to produce ointments, creams, gels, powders, lotions, paints, tinctures, and pastes. Ointments Ointments consist of oils, greases, or waxes and have little or no water. They are generally greasy, but can be rendered water miscible if an emulsifying agent is included. They have emollient, protective, and occlusive properties. Greasy ointments can be sticky and dif- ficult to remove, and are often not well received by patients. Non-​ greasy ointments such as macrogol ointment consist of polyethylene glycols and are water-​soluble. They spread well on the skin and wash off with water. Ointments are not prone to mould or bacterial growth and therefore do not require the addition of preservatives. 23.17 Management of skin disease Rod Sinclair

section 23  Disorders of the skin 5762 Creams Creams contain ointment and water, stabilized by an emulsifying agent. The stability and the drug-​carrying ability of these finely balanced emulsions are dependent on the pH of the creams, the type and amount of emulsifying agents used, and the chemical properties of the active ingredients. Lotions Lotions are liquid preparations. They may be aqueous or alcoholic solutions, suspensions, or emulsions. They are easily spread, have a cooling effect, and a low risk of irritation to the skin. They are often used to deliver a thin layer of powder to the affected surface over a large or hairy area. Shake lotions such as calamine lotion tend to evaporate quickly, providing a cooling effect, but leaving a layer of powder on the skin. Gels Gels are water-​miscible, viscous preparations which contain no oil. They contain a gelling agent such as tragacanth, gelatin, or hydroxypropyl cellulose, together with a solvent such as glycerol, propylene glycol, or alcohol, and a preservative. Gels form a durable film which stays on the skin surface longer than a water-​miscible cream. They are suitable for the delivery of water-​soluble drugs. Additives Preservatives Preservatives are added to products with high water content (e.g. creams, lotions, and shampoos) to inhibit the growth of moulds or bacteria and prevent spoilage. All preservatives are capable of pro- ducing irritant or allergic contact dermatitis. Absorption enhancers Several chemical agents can be added to the vehicle base to enhance percutaneous absorption of certain drugs. These agents include pro- pylene glycol, dimethyl sulfoxide (DMSO), cetrimide, and sodium lauryl sulphate. Antioxidants Antioxidants are sometimes added to topical preparations to in- crease the stability of formulations that are susceptible to oxidation. These agents act either by reacting with free radicals and blocking oxidation by competing for oxidation (reducing agents), or by enhancing the action of other antioxidants. Emulsifiers Emulsifiers are added to stabilize complex ingredients, vehicles, and additives. For water-​based preparations, the issue of ion compati- bility must be considered when emulsifiers are selected. Vehicle choice The vehicle is a critical factor in the effectiveness of all topical therapies. Some vehicle-​related key factors which may influ- ence therapeutic outcome in topical therapy are water/​lipid mis- cibility, occlusive properties, and durability. The following guide can be used in the selection of an appropriate vehicle or base for a particular use. Creams and ointments are the most commonly used bases and the selection usually depends on the degree of hydration of the skin, as well as cosmetic factors. Creams are generally used on normal or moist skin. They are cosmetically acceptable for use on the face, and are suitable for use in the flexures and for application to large areas. However, some creams can be drying if the skin is already very dry. The preservatives in creams can also cause contact dermatitis in some patients. Ointments are generally used when the skin is dry, when enhanced absorption is required (ointments are generally more effective than creams), and when avoidance of preservatives is desirable. Lotions are generally used on wet surfaces, for example, wet rashes (soaks or wet dressings) and oral mucosa (mouthwashes), or on hairy areas, for example, scalp, axillae, and pubic area. Gels are used as alternatives to lotions in hairy areas and where a drying effect is beneficial; and this applies especially to gels with an alcoholic base such as use in the treatment of acne. Gels or lotions containing alcohol should not be applied to excoriated or abraded skin, as they will sting. Pastes are used for occlusion and protection, and where substan- tive effects are required, allowing the drug to stay in contact with the skin for prolonged periods. They are also used in the application of an irritant drug to a limited area of skin (e.g. dithranol or a high con- centration of salicylic acid). Moisturizers Moisturizers can be categorized into emollient, humectant, and occlusive (see Table 23.17.1). Excessive soaking in water damages the waterproof seal on the skin, allowing a net water loss and dehy- dration. The best time to apply a moisturizer is immediately after a handwash or a bath. Emollients are preparations of emulsified oils and fatty acids, which replace the natural oils in the stratum corneum. These mol- ecules are incorporated into the epidermal structure, repairing the epidermis and providing a humidifying barrier to loss of water from between the cells of the keratin layer, which is the main source of loss, as well as from the skin surface, thereby increasing the water-​ holding capacity of the skin. Humectants contain chemicals that attract and retain water due to their hygroscopic or osmotic properties. They act by causing a migration of water from the epidermis to the skin surface as well as trapping water on its way out. Occlusive preparations provide an external physical barrier over the skin surface to prevent transepidermal water loss, at the same time replacing the natural oils in the stratum corneum. They are Table 23.17.1  Types of moisturizers Emollient Humectant Occlusive Aqueous cream Urea 10% cream White soft paraffin 50% in liquid paraffin Sorbolene cream Glycerol 10% cream White/​yellow soft paraffin Peanut oil 5% cream Olive oil 10% cream

23.17  Management of skin disease 5763 very effective but are greasy and often not cosmetically acceptable to patients. Topical antipruritics Calamine Calamine is zinc carbonate or zinc oxide powder mixed with a small amount of ferric oxide, which gives it its pink colour. It is a mild astringent and antipruritic, and is used as a soothing and protective application in dusting powders, creams, lotions, and ointments. Camphor This is a white, crystalline ketone, which acts as a mild topical anal- gesic and a counterirritant. It is readily absorbed from all surfaces and systemic adverse effects such as nausea, dizziness, headache, and breathing difficulties may occur. Menthol Menthol is a crystalline substance obtained from mint oils or pre- pared synthetically. When applied topically, it will dilate blood ves- sels and cause a cooling and analgesic effect. It is used in creams and ointments to relieve itching in pruritus. However, it has the potential to cause allergic reactions and contact dermatitis, and may sting if applied to broken skin. Keratolytics Keratolytics are used to remove hyperkeratotic skin in conditions such as dermatitis, seborrhoeic dermatitis, ichthyosis, psoriasis, palmoplantar keratoderma, warts, and acne. Salicylic acid and benzoic acid Salicylic acid and benzoic acid are keratolytic agents with mild bac- teriostatic and antifungal properties. They are both mild irritants and can themselves cause dermatitis. Salicylic acid has been used topically as a 2–​10% cream or oint- ment for hyperkeratotic dermatitis, although concentrations as high as 50% have been used in palmoplantar keratoderma. A 2% alcoholic lotion is used in acne to unblock comedones. It can be combined with liquor picis carbonis (LPC) in the treatment of psoriasis and dermatitis or with sulphur in the treatment of ich- thyosis. Salicylic acid 30% in mineral oil is used to remove scale from the scalp. For warts, a 10–​15% paint or a 20–​72% paste can be used. Benzoic acid 6% can be used with 3% salicylic acid (Whitfield’s ointment) for treating fungal infection of the skin, but specific targeted antifungal treatments are more effective (see Chapter 23.10). Urea Urea is a mild bactericidal keratolytic agent and promotes hydration of the skin by increasing the ability of the epidermis to absorb water. It is used as a 10% cream for moisturizing, or a 20–​60% soak solution for the treatment of hyperkeratotic dermatitis. Propylene glycol Propylene glycol is a keratolytic agent with some bactericidal and fungicidal properties. A 40–​60% solution applied under occlusion can be used to clear scaling skin in hyperkeratotic eczema. Tars Introduction Tars act by reducing the thickness of the epidermis and are used for the treatment of psoriasis, dermatitis, seborrhoeic dermatitis, and dandruff. Their efficacy is enhanced when ultraviolet B (UVB) therapy is given after application of the tar. Controversies exist in relation to the potential carcinogenic and teratogenic effects, and to the increased risk of carcinogenicity with concurrent use of tar ap- plication and ultraviolet (UV) therapy. Long-​term treatment with high concentration tar preparations is not encouraged. Coal tar Coal tar is obtained from bituminous coals at high temperature. It has anti-​inflammatory, antipruritic, and mild antiseptic proper- ties. Crude coal tar 0.5–​5% is included in creams, ointments, pastes, shampoos, and soaps, often in combination with salicylic acid. Coal tar solution (liquor picis carbonis or LPC), which is a 20% solution of coal tar in alcohol, is used in concentrations of 3–​12%. Coal tar may cause skin irritation and photosensitivity, but hypersensitivity reactions are uncommon. Preparations stain clothing and skin and have a mild odour, which may affect compliance. Pine tar Pine tar is obtained from the destructive distillation of the wood of trees belonging to the Pinaceae family. It has antipruritic prop- erties, but does not have the anti-​inflammatory properties or photosensitizing potential of coal tar. It is included in a variety of proprietary preparations as solutions, cleansing bars, gels, and bath oils. Ichthammol Ichthammol is a black, viscous liquid with a strong odour, consisting of a destructive distillation product of bituminous schist or shale to- gether with ammonium sulphate. It has a mild antibacterial effect and is used in chronic dermatitis. It is a mild skin irritant. It is in- cluded in proprietary preparations for the treatment of dermatitis, psoriasis, and acne. Ichthammol 2% in glycerol lotion has been used for the treatment of ear psoriasis. Dithranol Dithranol is a yellow to orange powder of synthetic trihydroxy­ anthracene. When used in topical preparations, its strength starts at 0.05 or 0.1% and gradually increases to 3% as required. Strengths as high as 6% have been used in severe cases. It has anti-​inflammatory properties. It stains skin and many fabrics and surfaces. Liquid par- affin may be used to remove dithranol products from the skin. Dithranol reduces proliferation of the epidermis by inhibiting en- zyme metabolism and reducing mitotic turnover. As it is irritant to mucosal surfaces, inflamed skins, and other delicate skin areas, it should not be used on the face, groin, and perilesional skin. Patients with fair skin are more sensitive. Concomitant use of coal tar may reduce its irritating effect. Dithranol can be localized to the plaques by application in Lassar’s paste. Application of white soft paraffin to the perilesional areas may provide further protection. Dithranol is better absorbed through plaques of psor- iasis than normal skin. There are two methods of dithranol

section 23  Disorders of the skin 5764 treatment:  low-​strength, long-​contact therapy and high-​strength, short-​contact therapy. It is also used in the treatment of alopecia areata. While its mode of action is unknown, it is not effective unless skin irritation is produced. Dithranol preparations have many problems with stability, which decreases with the strength of the preparations. Addition of sali- cylic acid, ascorbic acid, or oxalic acid as an antioxidant stabilizes dithranol products and prevents discolouration and inactivation. White soft paraffin appears to be the most stable base, while cream bases are least stable. Dithranol must be protected from light and should be supplied in appropriate light-​occlusive containers. Topical corticosteroids The naturally occurring hydrocortisone has anti-​inflammatory and immunosuppressive effects, which are useful in treating many skin disorders. Modifications of the hydrocortisone molecule have pro- duced a large number of agents with varying anti-​inflammatory po- tency, which may be used systemically or topically. The potency of topically applied corticosteroids is ranked ac- cording to clinical effectiveness and potential for adverse effects (see Table 23.17.2). Adverse effects consist of loss of dermal collagen (leading to skin atrophy, striae, fragility, and easy bruising), telangi- ectasia, and perioral dermatitis. Penetration of corticosteroid to the dermis is greater on the face, the scrotum, and where conditions mimic application under oc- clusion (i.e. flexures and intertriginous areas). The use of the more potent corticosteroids on these sites therefore carries greater risk of local damage and should be avoided. With greater potency, there is increased risk of rebound on withdrawal and of tachyphylaxis. Absorption of more potent agents applied to large areas might cause suppression of the hypothalamic-​pituitary axis and other usual complications associated with systemic corticosteroid administration. Topical corticosteroids should not be used on a patient where the diagnosis is uncertain. For example, patients may use topical cor- ticosteroids for years on a groin rash where the diagnosis is tinea cruris, which is curable with correct treatment. It is common for patients to express reluctance to use topical cor- ticosteroids because of misconceptions about the risks of their use. Suggested potencies and preparations for intermittent use of topical corticosteroids for chronic dermatoses are: • face and flexures (hydrocortisone 1%) • trunk (betamethasone valerate 0.02%, triamcinolone acetonide 0.02%) • elbows/​knees and palms/​soles (betamethasone dipropionate 0.05%, mometasone 0.1%, methylprednisolone aceponate 0.1%) Potent corticosteroids should be avoided on the face. However, more potent corticosteroids may be used intermittently for up to two weeks. The greater the potency the greater the risk of local adverse effects, particularly perioral dermatitis. Calcipotriol Calcipotriol is an analogue of 1,25-​dihydroxycholecalciferol, the active form of vitamin D. It shares with the vitamin affinity for an intracellular receptor, combination with which reduces epidermal proliferation and inhibits interleukin 1 (IL-​1) and T-​cell function. It is used topically as an ointment or cream in local treatment of plaque psoriasis. Adverse effects include erythema and irritation. The the- oretical possibility of hypercalcaemia, renal calculi, and ectopic cal- cification due to absorption is not a practical problem unless it is applied to large areas of inflamed skin. It should not be used on the face or flexures. Calcineurin inhibitors Both pimecrolimus and tacrolimus can be formulated as topical agents. They have anti-​inflammatory activity similar to a class I or class  II topical corticosteroid and are used in atopic dermatitis, seborrhoic dermatitis, lichen planus, vitiligo, and psoriasis. Both agents can be used on the face with minimal risk of aggravating ros- acea or inducing perioral dermatitis. The United States Food and Drug Administration (FDA) mandated that topical pimecrolimus packaging would be required to carry a ‘black box’ warning regarding the potential increased risk of lymph node or skin malignancy. Topical tacrolimus is formulated extemporaneously as a 0.1% ointment for use on the body or 0.03% ointment for use on the face. Retinoids The term vitamin A refers to a group of compounds that are neces- sary for cellular differentiation, organ development, and production of the visual pigment in the retina. These compounds also influence immune function and have some anti-​inflammatory activity. Tretinoin creams in concentrations ranging from 0.025 to 0.1% can be used for acne and sun damage. Acne sufferers can experi- ence some erythema, dryness, and irritation, which can be managed by decreasing the frequency of application or discontinuing the preparation. Patients with sun-​damaged skin react more vigorously to topical tretinoin, and its use should be titrated for the individual patient, starting with a daily application for 10 min before washing off. The duration of application can be increased until the preparation is eventually left on overnight. The best results in the treatment of sun damage are not seen until the preparation has been used for six months but include improvement in texture, reduction of pigmentation, removal of Table 23.17.2  Classification of potencies of topical corticosteroids Class I—​mild Hydrocortisone 0.5–​1% Hydrocortisone acetate 0.5–​1% Class II—​moderate Alclometasone dipropionate 0.05% Betamethasone valerate 0.02, 0.05% Triamcinolone acetonide 0.02, 0.05% Class III—​potent Betamethasone dipropionate 0.05% Betamethasone valerate 0.1% Methylprednisolone aceponate 0.1% Mometasone furoate 0.1% Triamcinolone acetonide 0.1% Class IV—​very potent Clobetasol 0.05%

23.17  Management of skin disease 5765 superficial solar keratoses, and effacement of small wrinkles. Topical isotretinoin and adapalene are used in acne and may also cause drying, erythema, burning, and photosensitivity, but generally these symptoms would be less than with tretinoin. Tazarotene can be used for acne, psoriasis, and sun-​damaged skin. It is available as a cream or gel in concentrations of 0.05% or 0.1%. It is drying on the skin and should be used together with a moisturizer. Antiseptics Benzoyl peroxide Benzoyl peroxide has mild keratolytic, antiseptic, and bleaching properties. It is used in the treatment of acne as a 2.5–​10% gel. Its antiseptic properties are probably the result of its oxidizing effect. Bleaching of clothing may occur where it is in contact with the agent. As irritation is common, caution is needed when applying it near the eyes and other mucosal surfaces. The irritation usually resolves on continued use. Chlorhexidine Chlorhexidine is a bisbiguanide antiseptic that is commonly used in topical preparations with or without cetrimide. It is used as the acetate, gluconate, or hydrochloride in sprays, creams, gels, so- lutions, dressings, and powders in concentrations ranging from 0.02 to 5%. Chlorhexidine salts may cause skin reactions, irritate mucosal surfaces, and interrupt wound healing. Discolouration of the teeth, tongue, and the buccal cavity associated with chlorhexidine mouth- wash or oral gel has been reported. Cetrimide Cetrimide is a quaternary ammonium antiseptic with surfactant properties. It has been used alone or with chlorhexidine in topical preparations in concentrations ranging from 0.1 to 3%. Skin sensi- tivity can occur, particularly with repeated and prolonged applica- tions. Application to mucosal surfaces should be avoided. Povidone-​iodine Povidone-​iodine is an iodine complex which has antibacterial, antifungal, and antiviral properties. It is used in mouthwash/​gar- gles, skin cleansers, and antiseptic creams, ointments, solutions, and paints, in concentrations ranging from 5 to 14%. It is also used in some antiseptic swabs and wound dressings. It can cause skin irri- tation and is absorbed via damaged skin. Application over a large, broken skin surface is not recommended. Triclosan Triclosan is a bisphenol antiseptic agent commonly used in medi- cated soaps and topical preparations in concentrations of up to 2%. It is a mild irritant and allergic contact dermatitis has been reported. Antifungal agents Topical application of antifungal agents is effective for superficial cu- taneous infections but is not for those involving hair or nails. There are many agents used in this way. Imidazole derivatives bifonazole, clotrimazole, econazole, miconazole, and ketoconazole have a broad spectrum of antifungal activity achieved by inhibition of ergosterol synthesis and consequent disruption of the fungal mem- brane. After topical application they efficiently reach keratinocytes but there is no appreciable systemic absorption. Topical imidazole preparations can be irritating but local sensitization is uncommon. Tolnaftate is a thiocarbamate active against dermatophytes but not Candida species. Its mode of action is unknown. Terbinafine is an allylamine, which inhibits ergosterol synthesis at an earlier stage than the azoles. It is fungicidal for dermatophytes, and is also active against pityrosporum species, but less clearly useful against Candida species. Nystatin and amphotericin are polyenes active against Candida species but not dermatophytes. Various other compounds such as undecenoic acid and the keratolytics benzoic acid and sali- cylic acid are used to treat tinea. Amorolfine is a morpholine with a broad spectrum, which inhibits ergosterol synthesis at different sites to other antifungals. It is used as a lacquer painted onto abraded nails once or twice weekly for 6–​12 months to treat onychomycosis. Sunscreens Sunscreen active agents work by either absorbing or reflecting UV radiation. Absorbent sunscreen chemicals act mainly in the UV range, whereas reflectants provide a barrier against UV, visible light, and infrared radiation. A list of the commonly used sunscreen agents is included in Table 23.17.3. Most sunscreen products combine agents that absorb in the ultra- violet B (UVB) range (wavelengths 290–​320 nm) with agents that absorb in the UVA range (wavelengths 320–​360  nm) to provide broad-​spectrum coverage. Many products also include a reflectant, such as titanium dioxide, which increases the protection but can give the skin a white appearance. Zinc oxide is used as a physical sun bar- rier for the protection of the ears and nose, which often receive high sun exposure. Primary prevention is an important part of the public approach to management of skin cancer. Reduction of sunlight exposure in child- hood is critical, but protection during adulthood is also important. It has been suggested that the entire spectrum of ultraviolet radiation (UVR) (i.e. 290–​400 nm), contributes to risk of skin cancer, so pro- tection should be broad-​spectrum in the UVR range. The primary approach is natural protection, involving the use of good quality clothing and hats while outdoors, seeking shade where possible, and avoiding the sun around the middle of the day. Reflected radiation may result in people receiving a high dose of UVR even when they are in the shade, and this needs to be accounted for when a canopy is being designed to reduce UVR exposure. Sunscreens are an adjunct to natural protection, not a substitute for it. Table 23.17.3  Commonly used sunscreen chemicals Physical blockers (reflectants) Zinc oxide, titanium dioxide, talc, red petrolatum UVB absorbers Salicylates—​octyl salicylate, homosalate Cinnamates—​octyl and isoamyl p-​methoxycinnamate Camphor derivatives—​4-​methylbenzylidene camphor Aminobenzoates—​p-​aminobenzoic acid (PABA), padimate-​O (octyl dimethyl PABA), methyl anthranilate UVA absorbers Benzophenonesa—​benzophenone-​6, oxybenzonea Dibenzoylmethanes—​dibenzoylmethane, avobenzone (butylmethoxydibenzoylmethane) a Benzophenones absorb in the UVB, UVA, and UVC ranges.

section 23  Disorders of the skin 5766 Sun protection factor (SPF) is a laboratory-​derived figure classi- fying the relative potency of the different products. Because of the many variables determining the actual dose of UVR received (e.g. time of day, time of year, cloud cover, reflection, adequacy of ap- plication), it is not a figure which can be translated easily into the degree of protection afforded when used under normal conditions outdoors. The SPF number applies to the ability of a sunscreen product to reduce predominantly the UVB range of the solar spectrum. There is relatively little increase in protection for large increases in SPF number after SPF15 (Table 23.17.4). Other topical therapies Antihistamines Topical antihistamines are poorly absorbed and not effective in the treatment of most skin conditions. Systemic H1 receptor antagonists should be considered when indicated. Emulsifying ointment Emulsifying ointment is a mixture of paraffin and emulsifying wax. It can act as a detergent or soap substitute and is particularly useful for patients with contact dermatitis in which the offending chemical is not known. Lanolin Lanolin (wool fat) is a purified anhydrous waxy substance obtained from the wool of sheep. It is used in creams and ointments to provide skin penetration properties. Lanolin is capable of absorbing about 30% of water, and hydrous lanolin is used as an ointment base. It is known to cause skin sensitivities. However, most lanolin-​related sensitivities are found to be caused by residues of pesticide and de- tergent used on sheep. Removal of these impurities reduces the inci- dence of sensitization markedly. Podophyllum Podophyllum has an antimitotic action and is used in the treat- ment of warts. A combination of podophyllum resin and salicylic acid as a paint or ointment is used in the treatment of plantar warts. Podophyllotoxin 0.5% paint is used for anogenital warts. Podophyllum should not be used during pregnancy or in children. Topical anaesthetics and analgesics Most local anaesthetic agents are well absorbed through mucous membranes and damaged skin but absorption through intact skin is poor. However, a eutectic mixture of lidocaine and prilocaine can produce effective surface analgesia of intact skin prior to minor medical or surgical procedures, and this effect is enhanced by occlu- sion. Lidocaine is used in several products for use on oral and other mucosal surfaces and ulcers. Choline salicylate is used as a local an- algesic for oral lesions. Zinc oxide Zinc oxide is a mild astringent used as a soothing and protective ap- plication in dusting powders, pastes, ointments, creams, and lotions, often combined with ingredients such as coal tar, ichthammol, sali- cylic acid, calamine, or castor oil. Common topical preparations containing zinc oxide include cala- mine cream and lotion, zinc cream, ointment, and paste, Burow’s emulsion, and zinc and castor oil ointment. Zinc oxide reflects UV radiation and is used in sunscreen preparations. Fluorouracil Fluorouracil cream is used to remove superficial solar keratoses. It is used for a period of three weeks on the face and on the arms and legs for four to six weeks, although times may vary. It causes severe chemical irritation with erythema and crusting, but heroic patients who complete a course reap significant benefits. Some irritation is needed for the preparation to be effective. It may cause some photosensitivity. If added potency is required, tre- tinoin can be applied along with the fluorouracil, as the two act synergistically. Diclofenac sodium 3% Diclofenac gel is a topical non​steroidal anti-​inflammatory medica- tion that is approved for the topical treatment of actinic keratosis. It is applied twice daily to the affected areas as a field treatment for 60–​90 days. In contrast to fluorouracil, diclofenac generally only produces mild skin irritation. Ingenol mebutate Ingenol mebutate is an extract of the Australian milkthistle. Its mech- anism of action involves both direct cell necrosis and immune medi- ated inflammation. It is used in the treatment of actinic keratosis: on the face and scalp in a 0.015% concentration; on the trunk and ex- tremities a 0.05% gel is applied for two consecutive days. Significant erythema swelling, crusting, flaking, and scaling may occur. Imiquimod Imiquimod (1-​(2-​methylpropyl)-​1H-​imidazo[4,5-​c]quinolin-​4-​ amine) is an immune response modifier that binds to the toll-​like receptors 7 and 8. The drug has many actions including modulation of antigen presenting cell function and consequent enhancement of effector T-​cell activity. It is used topically in the treatment of external genital warts, but has no direct antiviral activity. It is also used in the treatment of actinic keratosis and superficial basal cell carcinoma (BCC). Inflammatory reactions can be a problem. Complementary medicines in topical therapy Aloe vera Extract from aloe vera has been used in a variety of creams, oint- ments, gels, lotions, and shampoos. It has been suggested that aloe vera gel is useful for the treatment of mild burns and to Table 23.17.4  Erythemal UVB reduction by SPF number SPF number % Reduction % Penetration   2 50 50   4 75 25   8 87.5 12.5 16 93.75 6.25 32 96.88 3.13 64 98.44 1.56

23.17  Management of skin disease 5767 promote wound healing as a result of antiseptic, anaesthetic, anti-​ inflammatory, antipruritic, and moisturizing properties. While recent clinical studies have provided mixed findings about its effectiveness in the treatment of frostbite, wound healing, and cuts, its topical use appears to be non​toxic. Tea tree (melaleuca) oil Oil from the leaves of the tea tree Melaleuca alternifolia has trad- itionally been used for cuts, burns, and insect bites. It contains various terpene oils and sesquiterpenes. It may also contain cineole, which is known to be a skin irritant. The antiseptic effect of tea tree oil is largely due to the presence of terpinen-​4-​ol. This is added to various commercial preparations. There are many in vitro studies demonstrating the antibacterial and antifungal effects of melaleuca oil. However, its antimicrobial ac- tivity is concentration dependent and clinical studies have not ad- equately demonstrated its effectiveness in the treatment of acne and skin infections such as tinea. Phototherapy Phototherapy involves treating patients with ultraviolet (UV) light of three types. These are shown next. Narrowband UVB (311 nm) The adverse effects of this treatment seem to be few. Carcinogenesis has not so far been demonstrated; however, lag times for the devel- opment of skin cancer are prolonged. Remission seems to be shorter than seen with psoralen ultraviolet A (PUVA) therapy, but the lack of long-​term problems indicates that it should be the first-​line form of phototherapy in most patients. Broadband UVB (290–​320 nm) This is a tried and tested therapy, having been used for more than 80 years. It has not been shown to be carcinogenic. It is often com- bined with tar therapy for added efficacy. Psoralen and ultraviolet A (PUVA) (320–​400 nm) Ultraviolet A light source is administered following pretreatment with a psoralen drug, usually methoxypsoralen 0.6 mg/​kg orally, 2 h before UVA. Adverse effects include nausea and photosensitivity. Long-​term use causes skin atrophy, lentigines and, after cumulative high dose, the incidence of squamous cell carcinoma is greatly in- creased. Long-​term studies are still in progress, but it appears to also cause a small but definite increase in the incidence of melanoma. In the management of psoriasis, both PUVA and narrowband UVB are made more efficacious by pretreatment with acitretin. Continuation of acitretin during a course of phototherapy reduces the cumulative dose needed for clearing the psoriasis and lengthens the duration of post-​treatment remissions. Patients taking psoralens to photosensitize themselves take the drug 2 h before phototherapy. They remain photosensitive to a decreasing extent for 24 h, so while on these drugs they must protect themselves generally from natural UV light, including the wearing of suitable eye protection. A typical course of photo- therapy, either PUVA or narrowband UVB, for plaque psoriasis may involve three treatments a week for 6–​8 weeks. Patients need to stand unaided in the phototherapy apparatus for periods of up to 10 min. Claustrophobia is a relative contraindication for phototherapy. Photodynamic therapy Photodynamic therapy (PDT) is used to treat actinic keratosis, Bowen’s disease, and superficial basal cell carcinoma. It involves the application of a photosensitizing cream to the target lesion fol- lowed after a few hours application of intense red light to the skin. During this time the drug is selectively modified and concentrated in diseased cells while largely clearing from normal tissue. The drug remains inactive until exposed to light. When applied, the light energy, delivered to the cancer site, chemically activates the active metabolite and creates a toxic form of oxygen which destroys the cancerous and precancerous cells with minimal damage to healthy cells. Most PDT treatment can be performed on an outpatient basis. Principal side effects of PDT include a skin sensitivity to light for a few hours following treatment. Inflammation can occur after treat- ment. The reaction can be painful while the light is on (5–​10 min) and local anaesthetic may be required in some cases. Cryotherapy Cryotherapy is very useful in the treatment of solar keratoses, super- ficial basal cell carcinoma, viral warts, small seborrhoeic keratoses, and small skin tags (acrochordons). A firm diagnosis is needed prior to consideration of cryotherapy. Liquid nitrogen is the preferred cryogen. The method of appli- cation of the nitrogen is somewhat immaterial as the damage to the tissue is determined by the depth of the resultant ice ball and the thaw time. Nitrogen is usually applied with a cotton-​tipped ap- plicator or sprayed on with a cryotherapy gun. After cryotherapy, patients may be alarmed at the blistering reaction. If they are fore- warned they are less likely to be anxious. Systemic therapy Oral retinoids Isotretinoin (13-​cis-​retinoic acid) is a stereoisomer of all-​trans-​ retinoic acid, which probably acts by conversion to it but has less toxicity. It is given orally in the treatment of cystic acne. Like all vitamin A analogues it is teratogenic, but in contrast to acitretin relatively rapid elimination permits the safe initiation of pregnancy from one to two months after stopping the drug. Adverse psychiatric events such as mood swings, depression, and suicidal ideation have been reported as idiosyncratic reactions to isotretinoin. Acitretin has been used orally in the treatment of psoriasis and disorders of keratinization such as severe ichthyosis. It is necessary to avoid pregnancy for two years (three years in the United States of America) after stopping acitretin. More recent potent synthetic analogues known as arotinoids (adapalene and tazarotine) differ more markedly in structure from retinoic acid. They bind to retinoic acid receptors with different

section 23  Disorders of the skin 5768 affinities for the different subtypes. Future developments may pro- duce agents with selective activity and consequent reduced toxicity. All systemic retinoids have substantial toxicity potentially manifested as: • cheilitis • dryness of nose, eyes, and face • scaling of palms and soles and softening of nails • loss of hair • joint and muscle pain and headache • hypertriglyceridaemia • hypercholesterolaemia and reduced high-​density lipoprotein cholesterol • photosensitivity Most significantly, they are teratogenic and must not be used in women who may conceive. Because of prolonged retention of etretinate in the body, pregnancy should be prevented for two years after the drug is ceased (three years in the United States of America). A similar caution applies to acitretin since it is in part metabolized to etretinate. Comprehensible, practical advice on the need and means for fertility control is essential. Cytotoxics and immunosuppressants Corticosteroids Oral corticosteroids have an important role in management of many skin conditions. They are the mainstay of therapy in autoimmune blistering disease and most life-​threatening dermatoses. While ef- fective in atopic dermatitis, most cases can be managed with topical therapy. While also effective in psoriasis, their use in this condition is contraindicated due to the potential for severe rebound on dose reduction. Chronic stable plaque psoriasis may be converted in to generalized pustular psoriasis following discontinuation of oral steroid. Azathioprine Azathioprine is converted in the body to 6-​mercaptopurine, an in- hibitor of purine synthesis and an immunosuppressant. It also has potent anti-​inflammatory properties. It is used alone or in combin- ation with other agents, usually corticosteroids. Toxicity is mainly due to bone marrow suppression, although this is less than with agents such as cyclophosphamide. Estimation of serum levels of thiopurine methyltransferase (TPMT) help predict the risk of myelotoxicity. Gastrointestinal upset is common and may necessi- tate discontinuation of therapy. Cyclophosphamide Cyclophosphamide is a nitrogen mustard analogue which is con- verted to the active metabolite in the body where it exerts its im- munosuppressant effects by interfering with DNA synthesis and function in B and T cells. It may be a more effective immunosuppres- sant than azathioprine, but this is associated with greater toxicity. Ciclosporin Ciclosporin is a potent inhibitor of T-​cell activation and prolifer- ation. It is variably absorbed after oral administration and exten- sively metabolized predominantly by CYP3A4, an isoform of the hepatic cytochrome P450 enzymes. Standard doses for psoriasis are in the range of 3–​5 mg/​kg. Use of high doses should be guided by monitoring of blood levels. The main toxicity is partially reversible renal impairment and hypertension. Its place in dermatology is in the treatment of a wide variety of inflammatory conditions such as psoriasis, atopic dermatitis, lichen planus, and bullous pemphigoid, but the difficulties in its use and the reversibility of benefit on ceasing administration markedly limit the circumstances warranting its use. Methotrexate Methotrexate is an inhibitor of dihydrofolate reductase. It is well ab- sorbed after oral dosing of up to 25 mg/​m2. It is not metabolized to any extent and elimination depends on renal excretion, so caution and perhaps dosage adjustment is needed in the presence of renal impairment. Toxicity due to bone marrow depression and mucositis is less likely in dermatological applications than when higher doses are used, but regular monitoring with blood counts is necessary. Prolonged intake leads to hepatic fibrosis and this requires liver function to be included in the monitoring. Liver biopsy is neces- sary for early detection and characterization of this complication, but whether this is justified and how often it should be performed is controversial. Methotrexate is valuable in treatment of severe unresponsive psoriasis. Hydroxyurea Hydroxyurea blocks pyrimidine synthesis. It causes much more short-​term bone marrow depression than methotrexate, necessitating frequent blood counts. Thalidomide Thalidomide is not generally available but is an inhibitor of tumour necrosis factor and has found a use in several inflammatory condi- tions despite its significant risks. Bleomycin Bleomycin has antitumour, antibacterial, and antiviral activity. It binds to DNA, causing strand scission and elimination of pyridine and purine bases. Intralesional injections are used in the treatment of unresponsive warts, although it can be extremely painful. The mechanism of ac- tion is not known. Biological treatments See Chapter 23.5 for an account of the currently used biological agents in the management of psoriasis. Many other potential uses have emerged and it seems likely that this will continue to develop. Anti-​CD20 antibody is currently approved for the management of various forms of B-​cell lymphoma, but reports are also appearing of their use in pemphigus vulgaris, paraneoplastic pemphigus, epi- dermolysis bullosa acquisita, dermatomyositis, and graft versus host disease, as well as other disorders. Off-​label reported uses of the tumour necrosis factor-​α (TNFα) antagonists have included the treatment of hidradenitis suppurativa, pyoderma granulosum, cuta- neous sarcoidoisis, cutaneous Crohn’s disease, Wegener’s vasculitis, autoimmune blistering diseases, Behçet’s disease, graft-​versus-​host disease, and others, although there appears to be differences in ac- tivity between the specific TNFα antagonists. IL-​12/​IL-​23 pathway inhibition is increasingly being recognized as a potentially useful

23.17  Management of skin disease 5769 therapy for psoriasis. There are many other emerging biological therapies, resulting in a rapidly progressing and exciting area of therapeutics. Antimicrobial agents Topical administration favours development of resistance in skin flora (particularly if given long term) and is prone to cause hypersensitivity in the patient. It can be an extremely valuable ap- proach, but should thus be cautiously employed with these caveats in mind. Mupirocin Mupirocin is a valuable topical antibiotic which is not used system- ically. It is active mainly against Gram-​positive aerobes, including most strains of staphylococci and streptococci. However, the emer- gence of high-​level mupirocin resistance in methicillin-​resistant Staphylococcus aureus (MRSA) has been reported. Topical mupirocin is used in the treatment of bacterial skin in- fections such as impetigo and infected dermatitis. Non​macrogol based formulations are used intranasally to eradicate staphylococcal carriage. Tetracyclines Tetracycline itself has a very broad spectrum, but acquired resist- ance is common in many species of organisms. Modifications of the basic molecule has produced many drugs, including doxycycline and minocycline, which have longer half-​ lives and greater potency on a weight basis but do not differ appre- ciably in spectrum and exhibit cross-​resistance. All tetracyclines cause some gastrointestinal symptoms and may lead to photosensitivity. They damage enamel of unerupted teeth and should not be given to children under 12 years. They should be avoided in pregnancy for the same reason but also because of the rare occurrence of hepatic necrosis in pregnant women. Except for doxycycline and minocycline they are excreted renally, and may accumulate in renal failure and further aggravate renal impairment. Minocycline is particularly prone to cause dizziness and ataxia but such symptoms can occur with others of the group and they can rarely cause benign intracranial hypertension. Minocycline in par- ticular can cause abnormal pigmentation of mucosae and of tissues, including scars. As with all broad-​spectrum antibiotics, overgrowth of resistant organisms occurs, particularly fungi in the case of tetracyclines. Tetracyclines are frequently used in the treatment of acne where, like other antibiotics, they probably act by suppressing proliferation of Propionibacterium acnes. The rationale for use in rosacea is uncer- tain. Tetracyclines also have anti-​inflammatory effects, mediated by inhibition of neutrophil chemotaxis and phagocytosis and suppres- sion of granuloma formation, and possibly a direct effect on vascular endothelium, which may be beneficial in a variety of skin conditions. Erythromycin Erythromycin is a macrolide active against Gram-​positive organ- isms and some anaerobes. It is used both topically (as a 2% gel or solution) and systemically in the treatment of acne and rosacea. This antibiotic is suitable for use in pregnancy. Clindamycin Clindamycin is active against P. acnes. It is used topically as a lotion or gel in acne and rosacea. Oral administration carries a risk of pro- ducing pseudomembranous colitis. Metronidazole Metronidazole is active against anaerobes but not P. acnes. It is ad- ministered topically in rosacea but the mode of its action is un- known, although there is some evidence that metronidazole is effective against the demodex mite. Dapsone and sulphapyridine Dapsone, a sulphone used for the treatment of leprosy, and sulphapyridine, a sulfonamide, are used in dermatology for anti-​ inflammatory effects in a variety of inflammatory skin conditions. Dapsone is of specific value in dermatitis herpetiformis and is used in such non​infective inflammatory conditions as pyoderma gangrenosum, pemphigus, and bullous pemphigoid. Dapsone, in the doses employed, causes a considerable incidence of haemolysis (especially in patients with glucose-​6-​phosphate dehydrogenase (G6PD) deficiency), methaemoglobinaemia, and rash. Rarer ad- verse consequences are blood dyscrasias, severe skin reactions, hepatitis, fever, and malaise, which may occur alone or as part of a generalized hypersensitivity reaction. Antifungal agents Systemic antifungals are used to treat deep-​seated infections and those involving nails and hair. The imidazole, ketoconazole was the first orally active azole but has been largely superseded by the triazoles (itraconazole and fluconazole) due to the rare occurrence of liver damage, inhibition of androgen synthesis, and interactions with many drugs due to inhibition of the cytochrome P450 3A4 pathway. The triazoles are absorbed after oral administration. Both are effective against Candida species, but itraconazole is more active against filamentous fungi. Terbinafine, an allylamine, is well absorbed when given by mouth and concentrates in the stratum corneum, including the nail bed. Gastrointestinal disturbance occurs in approximately 5% of patients and rare adverse effects include hepatitis, toxic epidermal necrolysis, blood disorders, and a reversible loss of taste. Griseofulvin was the first orally effective agent against dermato- phytes. It is less effective than the azoles and allylamines but is much cheaper. It is poorly soluble and absorption is assisted by prepar- ations with very small particle size or by ingestion with a fatty meal. It is taken up by keratinocytes and exerts a fungistatic action in the stratum corneum which continues in hair and nails. It must be given for sufficient time for the quiescent but viable spores in the keratin to be shed. It is inactive against Candida species. Antimalarial agents Chloroquine and hydroxychloroquine are used as immunomodulating agents in lupus erythematosus and other con- nective tissue disorders. Their mode of action in these diseases is unknown. The most alarming adverse effect is a dose-​related

section 23  Disorders of the skin 5770 permanent retinopathy, and regular monitoring by an optometrist or ophthalmologist is necessary. They are category D drugs and their use should be avoided in pregnancy. Antiviral agents Aciclovir is an analogue of guanosine that is phosphorylated prefer- entially by herpes simplex viral thymidine kinase to then inhibit the DNA polymerase. It can be administered topically or systemically by oral or intravenous routes. When taken orally, it is poorly and vari- ably absorbed. Its prodrug, valaciclovir, is its L-​valyl ester which is much better absorbed after hydrolysis, resulting in higher and more reliable blood levels of aciclovir and permitting less frequent dosing. Famciclovir is a prodrug of penciclovir, which has the same mode of action as aciclovir. Penciclovir is also administered topically. They are all generally well tolerated. Antiandrogens These have a role in hirsutism, androgenic alopecia, and in acne. They should all be avoided in pregnancy. Spironolactone Spironolactone is a potassium-​sparing diuretic which, independent of that property, is a weak antagonist of androgen receptor binding and an inhibitor of androgen biosynthesis. Spironolactone should not be administered to patients with renal failure due to the potential for potassium retention. The patient’s potassium status should be checked prior to commencing therapy and on an annual basis thereafter. Cyproterone acetate Cyproterone acetate is a synthetic corticosteroid with progestational and antiandrogen actions. The latter is due to competition at the dehydrotestosterone receptor and, at high doses, to inhibition of an- drogen synthesis. It may be used in the treatment of hirsutism and paradoxically of alopecia of the androgenetic type. Finasteride Finasteride inhibits the conversion of testosterone to dehydrotesto­ sterone by the type 2 5α-​reductase enzyme, which is present on hair follicle cells, thus reducing the influence of androgens. Consequently, it has a role in androgenetic alopecia in men since it does not alter the effect of androgen on the testes and hypothalamic-​pituitary function. Minoxidil Minoxidil was initially developed as a vasodilator antihypertensive medication. Its systemic use to treat hypertension is limited by tachycardia, fluid retention, and the undesired stimulation of hair growth. Minoxidil is used as a local application to the scalp where it acts as a non​specific hair growth stimulant, probably by prolonging the anagen phase. This persists only while treatment is continued. Topical prostaglandin analogues Eye drops used for the treatment of glaucoma containing the pros- taglandin analogue bimatoprost or ophthalmic prostaglandins such as latanoprost and travaprost were unexpectedly found to promote eyelash growth. Bimatoprost was subsequently approved as a cos- metic drug for the darkening and lengthening of eyelashes. It has also been investigated for the treatment of scalp hair loss and other prostaglandin analogues such as stemoxydine are used in shampoos, conditioner, and scalp serums to promote hair growth. Biologics Biologics are medicines extracted from or semi-​synthesized from biological sources. Gene based biologics are used to treat a variety of dermatological conditions including psoriasis, psoriatic arth- ritis, pemphigus vulgaris, atopic dermatitis, urticaria, and alopecia areata. Custom-​designed monoclonal antibodies and fusion pro- teins to tumour necrosis factor-α, Interleukin 12, Interleukin 23, and Interleukin 17 have become established treatments for psoriasis. Interleukin 2 receptor binders were used to treat metastatic mel- anoma, but have been largely superseded by B-​Raf inhibitors such as vemurafenib, debrafenib, and, MEK inhibitors such as trametinib, CTLA-​4 inhibitors such as ipilimumab, and phosphatidylserine-​ targeting immunotherapy agents (anti-​PD-​1 antibodies) such as bavituximab. The sonic hedgehog signalling pathway targeting agent vismodegib is used to treat advanced basal cell carcinoma, Rituximab, an anti-​CD20 antibody has been shown to induce long-​ term remission in pemphigus vulgaris. Omalizumab, and anti-​ IgE antibody has been used to treat chronic idiopathic urticaria. Multiple new biologic agents are currently undergoing clinical trials for the treatment of atopic dermatitis, lupus erythematosus, Merkel cell carcinoma, alopecia areata, autoimmune blistering disease, and a host of other inflammatory and neoplastic skin diseases. Management of skin failure Erythema multiforme, Stevens–​Johnson
syndrome, toxic epidermal necrolysis These disorders represent a spectrum ranging in severity from rela- tively benign erythema multiforme to life-​threatening toxic epi- dermal necrolysis. Erythema multiforme is usually secondary to infection (mainly herpes simplex) and presents with target lesions particularly on the hands and feet. It can be more generalized, with mucosal involvement. Stevens–​Johnson syndrome and toxic epi- dermal necrolysis are both, in most cases, caused by drugs (Box 23.17.1). They are considered to be a continuum, with clinical fea- tures ranging from atypical targetoid lesions with blisters and severe mucosal involvement in Stevens–​Johnson syndrome to widespread detachment of full-​thickness epidermis, confluent erythema, and skin tenderness in toxic epidermal necrolysis. See also Chapter 23.16. There is a mortality rate of up to 20% even with appropriate man- agement in toxic epidermal necrolysis, but this was much higher several years ago. Most fatalities in patients with toxic epidermal necrolysis are the result of sepsis. If Stevens–​Johnson syndrome or toxic epidermal necrolysis is suspected, then hospital admission is essential. Patients with toxic epidermal necrolysis should be ad- mitted to a burns unit. All drugs should be stopped.

23.17  Management of skin disease 5771 Treatment consists of fluid and electrolyte replacement; main- tenance of body temperature; adequate pain relief; early treatment of infection; debridement where needed; and treatment of mucosal surfaces, especially the eye, where there is a 30% long-​term mor- bidity. The role of oral corticosteroids is controversial, but if they are to be given they need to be started early, in high doses, and should be given for short periods of time. Ciclosporin and other approaches have been reported in some recent articles to be effective. Some studies have suggested that intravenous immunoglobulin (IVIG) may be of benefit, but others have disputed this. Staphylococcal scalded skin syndrome Children and neonates are most susceptible. They present with ir- ritability and raised temperature, along with skin tenderness and a scarlatiniform eruption, leading to superficial crusting initially in the flexures and around body orifices and then becoming general- ized. Treatment is with supportive measures and di/​flucloxacillin 2 g (children: 25–​50 mg/​kg up to 2 g) orally, six-​hourly. Corticosteroids are contraindicated. Meningococcal septicaemia A preceding, viral-​like illness is followed by petechial lesions plus transient urticarial, macular, or papular lesions. The petechiae have a ‘smudged’ appearance and are raised with pale greyish centres. There is associated fever and there may be signs of meningitis. For further information on management, see Chapter 8.6.5. Exfoliative dermatitis (erythroderma) These terms are applied to any inflammatory skin disease that affects more than 90% of the body surface. The cause is not found in 10% of patients. The most common causes are dermatitis, psoriasis, drugs, lymphoma, pityriasis rubwra pilaris, and Norwegian (crusted) sca- bies. There are profound metabolic disturbances which mean that rapid diagnosis and inpatient management are needed. These dis- turbances include hypothermia, fluid loss, protein and electrolyte imbalance, and haemodynamic changes. Any suspected drug should be withdrawn. Treatment is directed at the underlying cause but oral corticosteroids are effective for cases due to dermatitis or drugs. FURTHER READING Dermatology Expert Group (2009). Therapeutic guidelines: dermatology version 3, 3rd edition. Therapeutic Guidelines Limited, Melbourne. Lebwohl MG, et al. (eds) (2006). Treatment of skin disease: comprehen- sive therapeutic strategies, 2nd edition. Mosby Elsevier, Philadelphia. Price CJ, Sinclair RD (2008). Fast facts: minor surgery, 2nd edition. Health Press, Oxford. Rakel RE, Bope ET (2009). Conn’s current therapy. Elsevier Science, Philadelphia. Williams HC, et al. (eds) (2008). Evidence-​based dermatology, 2nd edi- tion. BMJ Books, London. Box 23.17.1  Drug-​induced rashes Drugs that commonly cause serious reactions • Allopurinol • Anticonvulsants • NSAIDs • Sulfa drugs • Bumetanide • Captopril • Furosemide • Penicillamine • Piroxicam • Thiazide diuretics Drugs less likely to cause skin reactions • Digoxin • Diphenhydramine hydrochloride • Aspirin • Aminophylline • Prochlorperazine • Ferrous sulphate • Prednisone • Codeine • Tetracycline • Morphine • Regular insulin • Warfarin • SSRIs NSAIDs, non​steroidal anti-​inflammatory drugs; SSRIs, selective serotonin reuptake inhibitors.

SECTION 24 Neurological disorders Section editor: Christopher Kennard 24.1 Introduction and approach to the patient with neurological disease   5775 Alastair Compston and Christopher Kennard 24.2 Mind and brain: Building bridges between neurology, psychiatry, and psychology   5778 Adam Zeman 24.3 Clinical investigation of neurological disease   5781 24.3.1 Lumbar puncture  5781 R. Rhys Davies and Andrew J. Larner 24.3.2 Electrophysiology of the central and peripheral nervous systems  5785 Christian Krarup 24.3.3 Imaging in neurological diseases  5802 Andrew J. Molyneux, Shelley Renowden, and Marcus Bradley 24.3.4 Investigation of central motor pathways: Magnetic brain stimulation  5817 K.R. Mills 24.4 Higher cerebral function   5821 24.4.1 Disturbances of higher cerebral function  5821 Peter J. Nestor 24.4.2 Alzheimer’s disease and other dementias  5830 Jonathan M. Schott 24.5 Epilepsy and disorders of consciousness   5860 24.5.1 Epilepsy in later childhood and adulthood  5860 Arjune Sen and M.R. Johnson 24.5.2 Narcolepsy  5882 Matthew C. Walker 24.5.3 Sleep disorders  5886 Paul J. Reading 24.5.4 Syncope  5896 Andrew J. Larner 24.5.5 The unconscious patient  5901 David Bates 24.5.6 Brainstem death and prolonged disorders of consciousness  5908 Ari Ercole, Peter J. Hutchinson, and John D. Pickard 24.6 Disorders of the special senses   5913 24.6.1 Visual pathways  5913 Sara Ajina and Christopher Kennard 24.6.2 Eye movements and balance  5922 Michael Strupp and Thomas Brandt 24.6.3 Hearing loss  5931 Linda Luxon 24.7 Disorders of movement   5937 24.7.1 Subcortical structures: The cerebellum, basal ganglia, and thalamus  5937 Mark J. Edwards and Penelope Talelli 24.7.2 Parkinsonism and other extrapyramidal diseases  5946 Elisaveta Sokolov, Vinod K. Metta, and K. Ray Chaudhuri 24.7.3 Movement disorders other than Parkinson’s disease  5956 Bettina Balint and Kailash Bhatia 24.7.4 Ataxic disorders  5976 Nicholas Wood 24.8 Headache   5987 Peter J. Goadsby 24.9 Brainstem syndromes   6006 David Bates 24.10 Specific conditions affecting the central nervous system   6010 24.10.1 Stroke: Cerebrovascular disease  6010 J. van Gijn (revised by Peter M. Rothwell) 24.10.2 Demyelinating disorders of the central nervous system  6026 Alasdair Coles and Siddharthan Chandran 24.10.3 Traumatic brain injury  6042 Tim Lawrence and Laurence Watkins 24.10.4 Intracranial tumours  6048 Jeremy Rees 24.10.5 Idiopathic intracranial hypertension  6054 Alexandra Sinclair

24.11 Infections of the central nervous system   6060 24.11.1 Bacterial infections  6060 Diederik van de Beek and Guy E. Thwaites 24.11.2 Viral infections  6082 Fiona McGill, Jeremy Farrar, Bridget Wills,
Menno De Jong, David A. Warrell, and
Tom Solomon 24.11.3 Intracranial abscesses  6097 Tim Lawrence and Richard S.C. Kerr 24.11.4 Neurosyphilis and neuro-AIDS  6100 Hadi Manji 24.11.5 Human prion diseases  6109 Simon Mead and R.G. Will 24.12 Disorders of cranial nerves   6120 Robert D.M. Hadden 24.13 Disorders of the spinal cord   6127 24.13.1 Diseases of the spinal cord  6127 Anu Jacob and Andrew J. Larner 24.13.2 Spinal cord injury and its management  6135 Wagih El Masri(y) and Michael Barnes 24.14 Diseases of the autonomic nervous system   6150 Christopher J. Mathias and David A. Low 24.15 The motor neuron diseases   6166 Tom Jenkins, Alice Brockington, and Pamela J. Shaw 24.16 Diseases of the peripheral nerves   6176 Robert D.M. Hadden 24.17 Inherited neurodegenerative diseases   6197 Swati Sathe 24.18 Disorders of the neuromuscular junction   6295 David Hilton-Jones and Jacqueline Palace 24.19 Disorders of muscle   6304 24.19.1 Structure and function of muscle  6304 Michael G. Hanna and Enrico Bugiardini 24.19.2 Muscular dystrophy  6310 Kate Bushby and Chiara Marini-Bettolo 24.19.3 Myotonia  6328 David Hilton-Jones 24.19.4 Metabolic and endocrine disorders  6334 David Hilton-Jones and Richard Edwards 24.19.5 Mitochondrial disease  6343 Patrick F. Chinnery and D.M. Turnbull 24.20 Developmental abnormalities of the central nervous system   6350 Chris M. Verity, Jane A. Hurst, and Helen V. Firth 24.21 Acquired metabolic disorders and the
nervous system   6368 Neil Scolding 24.22 Neurological complications of systemic disease   6376 Neil Scolding 24.23 Paraneoplastic neurological syndromes   6384 Jeremy Rees 24.24 Autoimmune encephalitis and Morvan’s syndrome   6393 Camilla Buckley and Angela Vincent SECTION 24  Neurological disorders

ESSENTIALS Clinical neurology uses conversation, detailed questioning, and dis- cussion, observation, structured examination, and selective investi- gation to formulate the patients’ problems into an anatomical and pathological framework. The competent neurologist identifies and probes relevant components of the history, reliably elicits the phys- ical signs, knows which investigations are necessary and relevant, appreciates the most likely underlying diagnosis and mechanism of disease, and communicates relevant information to the patient ac- curately, intelligibly, and sensitively. This system has evolved over sev- eral centuries, during which much knowledge has accumulated on structure and function in health and disease, the reliability of physical signs and laboratory investigations, and the nosology of disease. The neurological history Although patients usually start with an account of what troubles them most, the neurologist prefers a history of the components in the order in which they occurred. However, much can be gleaned from listening to the patient without interruption for a few minutes. It may then take some time to establish the chronology of the symp- tomatology. The first task is to assess the core symptoms and how they cluster. The neurologist asks enough questions to try and determine a likely anatomical localization and aetiology based on the temporal sequence of events. For example: a reported episode of difficulty with speech refers to a disturbance of language (aphasia) or articu- lation (dysarthria); there are motor or sensory deficits in a ‘heavy’ limb; alterations of sensation are positive (tingling and paraesthesia) or negative (numbness) symptoms; a disturbance of bladder func- tion suggests neurological or urological disease; and double vision actually refers to diplopia or altered acuity. Some questions reflect the peculiarities of neurological anatomy; it may surprise the pa- tient complaining of impaired vision on the right that the symptom is in fact unaltered by sequential closure of either eye—​because it is hemianopic—​or that awareness of temperature and the appreciation of pain may be disturbed in the ‘good’ leg in some forms of spinal cord disease (the Brown–​Séquard syndrome). Once the individual symptoms have been accurately defined, they can be grouped; from this follows an interpretation of their anatomical basis, suggesting the involvement of one or more sites. Recognition of these patterns is fundamental to interpretation of the neurological history and this synthesis directs attention to specific components of the subsequent examination. It is easy to conclude that the patient with cognitive impairment has disease of the cere- bral cortex, but a more detailed history will, in addition, indicate whether this is diffuse or focal and reflects involvement of the dom- inant or non​dominant hemispheres and the frontal, temporal, or parietal cortices. Incoordination of more than one motor skill (eye movement, speech, the limbs, and balance) necessarily indicates involvement of brainstem–​cerebellar connections. The pathology causing a hemianopic field defect lies above and that resulting in lower cranial nerve palsies below the tentorium. The combination of motor and sensory symptoms in limbs with altered sphincter function indicates spinal cord disease; for the male patient with an unreliable bladder, the significance of linking urgency and fre- quency to impotence and constipation may seem strange. In turn, the coexistence of diffuse distal symmetrical motor and sensory symptoms, shoulder and pelvic girdle weakness, or ocular, bulbar, respiratory, and upper limb weakness steers the thinking towards peripheral nerve, primary muscle, and neuromuscular junction dis- ease, respectively. The time course of the onset of the symptomatology helps to deter- mine the possible underlying pathology. As a generalization, abrupt events are vascular or electrical in origin, subacute symptoms are demyelinating or inflammatory, and symptoms that develop slowly suggest structural deficits or degeneration. The subsequent course of the symptoms also assists in identifying the underlying pro- cess: self-​limiting events are often vascular; paroxysmal symptoms tend to be electrical or demyelinating, depending on their duration; and progressive syndromes are compressive or degenerative. The circumstances surrounding the development of the symptoms may be suggestive of a particular pathophysiology: trauma, preceding infection, drug exposure, or pregnancy alerts the observer to struc- tural, demyelinating, toxic, and venous thrombotic mechanisms, respectively. Although it can be dangerous for the beginner, but nevertheless important to recognize, are the inconsistencies of ex- aggeration, mismatch between the severity of symptoms and altered 24.1 Introduction and approach to the patient with neurological disease Alastair Compston and Christopher Kennard

SECTION 24   Neurologica l disorder 5776 function, and the anatomical impossibilities that usually feature in non​organic neurological disease. Together, these pattern recogni- tions are the stuff of neurological diagnosis. The neurological examination Examination of the patient with neurological disease needs to be structured and organized without exhausting the patient and exam- iner through obsessive attention to irrelevant detail. Conclusions on likely localization from the history are essential to focus the exam- ination to the most likely relevant areas. In fact, the neurological examination is often used to confirm or refute the diagnosis which has been formulated on the basis of the history. However, much can be learned by astute observation without formal assessment. Gross defects of cognition do not need to be confirmed by reciting tele- phone numbers in reverse or assembling lists of former prime minis- ters, defects of speech will usually be evident in conversation, many neurological diagnoses are immediately apparent from the patient’s gait and movement disorders can be observed while taking the his- tory. That said, it is best routinely to adopt a basic core examination and do things in order because the detection of one abnormality will determine the interpretation of another. It takes only a few minutes for the experienced and adequately equipped examiner to confirm that corrected visual acuity is normal in each eye, there is no gross field defect, and the optic fundi are normal. Although more detailed assessment will sometimes be ne- cessary, a full range of smooth following (pursuit) eye movements in the horizontal and vertical planes can rapidly be established: this will detect obvious ophthalmoplegia and can be supplemented by cover testing of each eye during fixation on the examiner’s nose, and rapid gaze refixations from right to left—​very few significant defects of eye movement will escape this rapid screen. Movement of the lower face during forced eye closure, voluntary elevation of the palate, and rapid protrusion or side-​to-​side movement of the tongue take a few seconds to observe and effectively cover all the lower cra- nial nerves. It is rarely necessary to test the sense of smell or hearing, and a tuning fork is most useful for establishing that deafness is con- ductive and therefore probably not relevant. Before moving to the limbs, it is worth testing neck flexion in patients where the history suggests muscular or neuromuscular disease. A sufficient routine examination of the arms would start with posture (outstretched in supination with the eyes open and then closed):  a quick look for selective muscle wasting and fascicula- tions; tone in flexion–​extension and supination–​pronation at the elbow and wrist, respectively; strength in flexion and extension at the elbow and wrist, spreading the fingers, and abduction of the thumb; coordination during movement between the patient’s nose and examiner’s finger (or both hands if there is gross incoordination to avoid accidental ocular injury); and the tendon reflexes. This will take the experienced examiner less than a minute. It may be neces- sary to establish specific patterns of muscle weakness: global loss affecting the hand in cortical disease; selective involvement of ex- tensor groups in upper motor neuron disease; the patterns of C5 to T1 nerve root lesions; diffuse distal weakness of both extremities in peripheral neuropathy; and the subtle distinctions between radial, median, and ulnar neuropathies, and C7, C8, and T1 root lesions, re- spectively. Detailed sensory examination of the arms rarely achieves more than can be learned from establishing that crude protective sense (recognition of a sharp pin) or discrimination (position sense and the ability to distinguish two points or perform a simple task such as manipulating a button) is intact. Although this may involve some rearrangement of clothing, it otherwise takes almost no time to swipe the abdominal reflexes in passing, before examining the legs. Here, the structured motor examination is as for the arms, although increased tone is more easily detected by lifting the relaxed leg from the couch at the thigh, and testing internal and external rotation at the hip. Characteristic patterns of weakness are the involvement of flexors at all joints and eversion at the ankle in upper motor neuron lesions, the usual dif- fuse symmetrical distal involvement in peripheral neuropathy at a time when the hands may be normal, and difficulty in distinguishing injury of the lateral popliteal nerve from an L5 to S1 root lesion (in which the ankle jerk is lost) in the context of unilateral foot-​drop. Proximal weakness is best detected by watching the patient walk, and the calf muscles are normally so strong as to be untestable ex- cept with the patient standing. As in the arm, coordination can be assessed only once the degree of weakness has been established. Tendon reflexes in the legs may be brisk in isolation and often spread, so that, in an upper motor neuron lesion, when one is tapped several may respond—​and in either leg. Even non-​neurologists rarely forget to elicit the plantar responses. Sensory examination of the legs tends to be more reliable for protective than for discriminative sensation. In mapping a sensory level, it is best to move from the relatively anaesthetic to the normal zone, noting the band of hypersensitivity that usually exists at the boundary. It is a matter of fact that many patients confuse the exam- ination by exaggeration or elaboration of physical signs; this most commonly affects power, with the usual clues being a mismatch between the ability to walk and findings on formal assessment of muscle strength (or vice versa), and simultaneous contraction of agonist and antagonist muscles. Sensory testing is subjective and so necessarily vulnerable to inaccurate reporting, but confirming that a sensory level is present both on the abdomen and back, and on the same side on each, with a slightly higher level on the trunk, is a simple manoeuvre that may yield surprising discrepancies in the patient with non​organic deficits. The overall purpose of the history and examination is to assess where and through what mechanism structure and function have been affected. Detection of these patterns becomes routine for the experienced neurologist, but the process represents more than just a ritual of clinical neurology. From anatomical localization follows a formulation of likely mechanisms and pathological conditions underlying the patient’s symptoms and signs. Investigation of neurological disease The investigation of patients with neurological disease was revolu- tionized in the early 1970s with the introduction of computed tom- ography. Before then, only the most primitive structural details of the central nervous system could be detected by demonstrating in- directly the shape and placement of the ventricles and blood vessels, and usually at some discomfort to the patient. Function in the cen- tral nervous system and peripheral nervous system was measured using neurophysiological techniques. Disruption of the blood–​brain

24.1  Introduction and approach to the patient with neurological disease 5777 barrier and immunological activity in the central nervous system were assessed through analysis of the cerebrospinal fluid. Investigation still does not replace clinical assessment but, as the chapters that follow make clear, it is now possible to detect structural changes in most parts of the brain and spinal cord at high resolution; to distinguish many pathological appearances at these sites on the basis of differences in the magnetic resonance signals; to map func- tion within regions of interest using changes in blood flow and the use of metabolic substrates; to show variations in efferent and af- ferent electrical activity in the central nervous system and peripheral nervous system; and to detect an increasing range of soluble medi- ators of normal and pathological function in the cerebrospinal fluid. Taken together, these laboratory investigations still do no more than supplement clinical assessments and, in one sense, the high expect- ations of diagnosis make for additional difficulties in interpreting neurological illness when the images are normal, compared with the era when authoritative statements from neurologists could never be validated and necessarily went unchallenged. The value of many routine investigations lies in confirming nor- mality and endorsing abnormalities already strongly suspected on clinical grounds. Given the increasing sensitivity of techniques for brain imaging, altered appearances that are not necessarily of patho- logical significance and genuine lesions that are not relevant in the particular clinical context need to be interpreted with common sense. Overall, the trend has been for the pendulum to swing from diagnosis without adequate laboratory evidence to diagnosis made in defiance of clinical intuition. Even when an imaging abnormality has been identified, its nature may require clinical discussion in order to resolve the most likely pathological substrate—​the distinc- tion between ischaemic and inflammatory tissue often proving diffi- cult and not all neoplastic tissue being easily identified as such. The management of neurological disease The first issue that confronts the doctor looking after a person with neurological disease is when to discuss and name the diagnosis. Most wait until there is sufficient clinical or laboratory evidence to rule out misdiagnosis; telling people that they have a condition when they do not is bound to cause distress and has landed some special- ists in the law courts. However, excessive caution and avoidance of discussion can be equally damaging, and there are many more pa- tients who harbour bitterness over delay in learning the true nature of their illness than those who wish that they had not been told so soon, or at all. Most individuals cope extremely well even with the prospect of conditions that are known to be life-​threatening or have a poor prognosis for disability. Advice may be needed on alterations in lifestyle resulting from neurological disease (e.g. driving in epi- lepsy, and the use of drugs in pregnancy). There is a basic human need to know why a thing has happened and most patients enquire about causation but, naturally, the uppermost question is whether symptoms can be treated, or the natural history of disease usefully modified. The chapters that follow document specific treatments for par- ticular conditions, but judgement is often required when deciding whether to deploy these remedies, depending on age, significance of the symptoms for the individual, level of disability, security of the diagnosis, adverse effects, and the patient’s own views. Drug treat- ment may be used, on an intermittent or regular basis, to suppress symptoms; for example, intravenous methylprednisolone to reduce inflammation, anticonvulsants to suppress epilepsy, γ-​aminobutyric acid agonists to deal with spasticity or anticholinesterases to enhance transmission at the neuromuscular junction. Pharmacological op- tions also exist for interfering with the mechanism of disease, again on an intermittent or routine basis (e.g. the use of triptans to re- lieve migraine or the replacement of dopamine in Parkinson’s dis- ease). In other situations, the rationale of treatment is to modify the underlying disease process; for example, by suppressing inflam- matory processes in acute post-​infectious polyneuritis using intra- venous γ-globulin, treating patients with multiple sclerosis using β-​interferon, and using immunosuppressants such as methotrexate and cyclophosphamide in polymyositis and vasculitis, respectively. Many other illustrations could be given, confirming that the age-​old witticism concerning the therapeutic nihilism of clinical neurology is at best now only of historical interest and was always generally rather ill-​informed. Beyond the present pharmacological achieve- ments in drug treatment lie many opportunities for improving handicap and disability through the use of rehabilitation, which ­increasingly assumes centre stage in the management of neuro- logical disease through attention to the person with impairments in a particular social and cultural setting rather than focusing on the pathophysiology of disease in an individual void. For the future, there is the prospect of enhanced regeneration in the context of dis- eases ­affecting the central nervous system and peripheral nervous system, restoring structure and function, and thereby both limiting and repairing the damage.

23.2 Clinical approach to the diagnosis of skin di

23.2 Clinical approach to the diagnosis of skin disease 5596 Vanessa Venning

ESSENTIALS As in most medical specialties, the diagnosis of skin disease relies on careful history taking, and a thorough examination, supported in some cases by appropriate investigation. Astute physicians will also be aware that management outcomes are improved by taking account of the impact of skin disease on patients’ lives, whether through discomfort, disfigurement, or disability. This chapter, how- ever, is chiefly concerned with aspects of history taking and examin- ation that inform the diagnostic process. History taking There are certain key points in the history of skin disease that should be specifically elicited, and these are summarized in Box 23.2.1. These should include a description of the events surrounding the onset of skin lesions: when and where the eruption started, and how it progressed. Neoplasms are likely to be relatively asymp- tomatic and persistent, whereas inflammatory disorders can itch, scale, or ooze, and frequently fluctuate. The rapidity of fluctuation is helpful; urticaria and eczema are both intensely itchy, but are dis- tinguished by the fluctuation of the individual lesions of urticaria over hours, rather than days or weeks as in eczemas or psoriasis. The site of onset might also give a clue to the diagnosis and cause of a rash. The history should include an enquiry into general health, both past and present, and of skin disease, including specific enquiry about the personal and family history of psoriasis and the atopic disorders eczema, asthma, and hay fever. If more than one house- hold member is affected this might indicate heredity or contagion. Occupation, travel, or residence abroad, leisure activities, and hobbies might indicate exposure to the sun, irritant or sensitizing chemicals, or infections. Many patients will already have tried top- ical treatment before presentation, either self-​medicated or phys- ician prescribed, and the response to these, whether beneficial or adverse, can be helpful in diagnosis. Drug-​induced skin disease is important, and a full history of drugs taken for other disorders is essential. Examination Dermatology differs from other specialties because the disease is visible to the naked eye, and the lesions can also be touched and palpated. However, it is necessary to know what to look for and to understand what is seen and felt. To examine the skin properly the patient should ideally be undressed, and examined in a good light, preferably daylight. Distribution Before concentrating on the appearance of the individual lesions, much can be deduced from their distribution. The distribution of lesions in many common dermatoses is so characteristic that it fre- quently aids diagnosis. In some diseases, the pattern might reflect regional variations in skin structure (e.g. acne vulgaris favours areas rich in pilosebaceous units, such as the face and upper torso). Other disorders are distributed according to exposure to external causative agents (e.g. points of contact with irritants/​allergens or sun exposure) (Fig. 23.2.1). Gravity and stasis underpin the distribution of varicose eczema on the lower legs. The sluggish blood flow of stasis also favours immune-​complex deposition, and explains the frequency of vasculitis lesions on the lower legs (Fig. 23.2.2). In other instances the factors affecting distribution are not necessarily fully understood but, nonetheless, observation of the distribution can be crucial to diagnosis. Is the skin disease localized or generalized? Is it symmetrical? What specific sites are involved? It is important to examine not only the skin itself, but also the hair and nails, and the mucous membranes (particularly inside the mouth). Symmetry Although the basis for the body symmetry of rashes is not fully understood, the presence or absence of symmetry serves as a useful pointer in diagnosis. Rashes showing bilateral symmetry are frequently suggestive of endogenous skin disease. The most common inflammatory dermatoses—​atopic eczema and psoriasis, having a strong hereditary component in their pathogenesis—​are regarded as endogenous or constitutional dis- eases, and both show striking symmetry in the distribution of 23.2 Clinical approach to the diagnosis
of skin disease Vanessa Venning

23.2  Clinical approach to the diagnosis of skin disease 5597 their lesions (Fig. 23.2.3). Symmetry is not confined to the major heritable skin diseases; several skin diseases are regarded as re- actions to underlying triggers. Although these might not have a genetic basis, they behave like intrinsic disorders and, as such, frequently show symmetry. Examples of these are most drug eruptions, viral exanthema, erythema multiforme provoked by a cold sore or other trigger, and dermatitis herpetiformis (the rash of gluten sensitivity). By contrast, rashes and lesions caused by exogenous factors such as the random behaviour of a biting insect, contact with allergenic or irritant substances, or with infections like bacterial impetigo are commonly, but not necessarily, asymmetric. A foot dermatitis that affects only one foot should prompt investigation for fungal infection. Site Certain conditions have a predilection for characteristic sites, and knowledge of the favoured sites is diagnostically important. Psoriasis favours the extensor surfaces of elbows and knees, and also affects the scalp, nails, and gluteal cleft. By contrast, atopic eczema favours the flexures (Fig. 23.2.3b), for example, antecubital and pop- liteal fossae, and other sites. This distinguishes it from seborrhoeic eczema, which prefers the scalp and ears, central face (eyebrows, nasolabial folds), mid chest, and groins. Lesions provoked by sunlight predominate on exposed skin (e.g. skin cancers, idiopathic or drug-​induced photosensitive rashes, lupus erythematosus). In some sun-​induced rashes there might be a sharp cut-​off under clothing, or sparing of shielded sites (e.g. under the chin and behind the ears). Contact derma- titis to airborne pollens, such as those of the Compositae family (Fig. 23.2.1), or volatile allergens such as epoxy resin glues, will not spare these shielded sites, but might show a similar cut-​off at the collar. The distribution of some important diseases is shown in Fig. 23.2.4. Morphology Many skin diseases have characteristic lesion morphology, although scratch marks, ulceration, and secondary infection can modify the appearance. A good light is essential, and a hand lens is helpful. Touch and palpation give important information about the thick- ness, depth, consistency, and tenderness of lesions, and whether the surface is rough or smooth. Ideally, a primary lesion should be sought for deciding lesion type, one that has not been damaged by picking, scratching, or prior application of creams or anything else likely to eradicate important clues. To aid the clear and unambiguous description of lesions, certain terms are used, the most important of which are listed in Table 23.2.1. The lesion type, colour, and surface characteristics should be recorded, the aim being to try to glean as much information as possible about the underlying pathology. Redness (erythema) Fig. 23.2.1  Eczema confined to exposed skin. In this case, it is resulting from contact dermatitis to an airborne allergen (Compositae pollen), but a similar cut-​off under clothing can occur with photosensitivity. Box 23.2.1  Outline of dermatological history • History of present skin condition — Duration — Site of onset — Details of spread or enlargement — Does it fluctuate or persist? — Provoking or aggravating factors — Symptoms (e.g. itch, burning, soreness, pain, bleeding, weeping, oozing, blisters, odour) — Impact on quality of life • Past history of skin disorders • Past and present general medical history — Ask specifically about asthma and hay fever • Family history — Ask specifically about eczema, asthma, and hay fever (the atopic disorders), and psoriasis • Social history — Occupation, travel, and leisure activities — Particularly enquire about sun exposure and burning episodes • Medication used to treat present skin condition — Topical or systemic — Physician prescribed or over the counter • Drugs taken for other disorders — Allergies to medication, or contact allergens Fig. 23.2.2  These purpuric lesions are palpable rather than flat, indicating vasculitis. The distribution on the lower legs is common.

section 23  Disorders of the skin 5598 resulting from vasodilatation of the upper dermal vasculature will blanch on pressure, and indicates inflammation. If purpuric lesions are present, attention should be paid to whether they are entirely flat (macular) or are palpable, the latter indicating a more profound degree of vascular pathology than mere leakage, and sig- nifies the presence of vasculitis (Fig. 23.2.2). The presence and nature of scale is a physical sign of great im- portance. Keratin is the principle protein product of the epidermis, and constitutes up to 90% of the stratum corneum. Any disease, whether inflammatory, infective, or neoplastic, that affects the epidermis will disrupt keratin production, resulting in scaliness. The importance given to scale is indicated by the large number of synonyms used by dermatologists to describe it (scaly, keratotic, hyperkeratotic, keratinized, warty, verrucous). Scale can be par- ticularly thick and loosely adherent in psoriasis, making it ap- pear light in colour (silvery scale), or is sometimes dense and compacted. Very acute inflammation of the epidermis will also result in ves- iculation and oozing, as in the case of acute eczemas and superfi- cial bacterial infections, or might result in an influx of neutrophils leading to pustule development in bacterial and candidal infec- tions, and in some forms of psoriasis. The presence of epidermal signs (scale, vesicles, ooze, pustules) indicates that the pathology is chiefly or solely superficial, and differentiates these diseases from those that are chiefly dermal. Deep-​seated dermal or sub- cutaneous inflammatory or neoplastic infiltrates are more likely to form lumps or swellings, which can distort the epidermis from below, but may not actually disrupt it, so that the surface is more likely to be smooth with skin markings preserved. This distinction between epidermal and dermal diseases is not of course absolute, and many disorders affect both, but this artificial separation helps to focus the examiner on the question: Where is the pathology? The appearance of some lesions might be so characteristic that occasionally they permit an immediate confident diagnosis, an ex- ample being lichen planus when present in its most typical form, with shiny, flat-​topped, mauve-​coloured papules with surface white streaks (Wickham’s striae). Other lesion types might not permit immediate diagnosis, but are still sufficiently distinctive as to be a useful starting point for a differential diagnosis, an example being vesicles and bullae (blisters). Common causes of blisters include burns, acute eczemas, viral infections such as Herpes spp., and in- fection with Staphylococcus aureus (bullous impetigo). Rarer causes of blisters include erythema multiforme, immunobullous diseases (e.g. pemphigoid, pemphigus), and some porphyrias. Lesion shape and grouping Additional diagnostic clues are afforded by the lesion shape and the way they are grouped. Distinctive lesion shapes are annular, target-​ shaped, and linear. Annular lesions imply inflammation spreading out centrifu- gally from a central focus, with clearance in the centre. This pat- tern is characteristic of dermatophyte fungus infection of skin (tinea corporis or ringworm; Fig. 23.2.5), which, being a superfi- cial infection, is accompanied by subtle scaling, particularly at the margin. Granulomas in the dermis form a characteristic ring in granuloma annulare. These lesions are palpable, but the overlying epidermis is smooth. Reactive erythemas frequently assume an an- nular shape (also known as annular or toxic erythema; Fig. 23.2.6). The margin is red, slightly elevated, and can be very slightly scaly. Annular erythemas evolve at a variable rate; the slow enlargement of erythema chronicum migrans (the eruption of early Lyme disease) occurs at a rate of a few centimetres per day, rather than over hours, and eventually fades within a few weeks. Reactivation of inflamma- tion at the centre of annular erythema produces target lesions char- acteristic of, but not exclusive to, erythema multiforme. The close clustering of individual lesions into groups is some- times distinctive. The grouping of vesicles in herpes simplex (Fig.  23.2.7) is so characteristic that other diseases which show (a) (b) Fig. 23.2.3  Both atopic eczema and psoriasis show classical epidermal signs (scaliness), but have different distributions. Symmetry is characteristic of many endogenous skin diseases. (a) Extensive psoriasis. The symmetry of psoriatic lesions may be dramatic and striking. (b) Itchy, scaly, inflamed skin in a symmetrical flexural pattern. This is typical of atopic eczema.

23.2  Clinical approach to the diagnosis of skin disease 5599 Cosmetic, medicament, and clothing Make-up Necklace Deodorants Otitis externa Mouth Rubber gloves Jean buttons Shoe: chrome rubber dyes Pruritus ani Discoid lesions can be in any distribution but they tend to be symmetrical and coin-sized Interdigital Genitalia Axillary folds Hands Nickel ear-rings a m e z c e cie o h rr o b e S a m e z c e cip o t A a m e z c e tc a t n o C Erythema multiforme Discoid eczema Eyes Feet seib a c S ytivitis n e s o t o h P si m r o fite p re h sitita m re D Nipples Wrists Psoriasis Mouth Genitalia a e s o r sisairytiP s u n alp n e h ciL Fig. 23.2.4  Distribution of common skin diseases.

section 23  Disorders of the skin 5600 similar lesion grouping are referred to as herpetiform (e.g. derma- titis herpetiformis). The grouping of lesions within a dermatomal distribution is seen in shingles, and reflects reactivation of the varicella–​zoster virus from dorsal root ganglia. In some conditions, a scratch or other injury localizes lesions in a linear fashion because the lesions have a predilection for dam- aged skin. This is known as the Koebner phenomenon, and is seen in psoriasis, lichen planus, and warts. Other lesions are roughly linear because they follow linear anatomical structures (e.g. super- ficial thombophlebitis and ascending lymphangitis). The shape of many congenital hamartomas might be determined by the migra- tion of skin cells during embryogenesis, or from genetic mosaicism. Lesions might be roughly linear in shape, or assume bizarre patterns of lines and whorls (Blaschko’s lines, named after the dermatologist who described the patterns in epidermal naevi). Brushing against the foliage of phototoxin-​containing plants in sunlight produces painful linear lesions with blisters (phytophotodermatitis) and long-​ lasting streaks of pigmentation. Very straight-​edged lines and rec- tilinear shapes might raise the suspicion of artefactually induced lesions (dermatitis artefacta). Special investigations Although it is frequently possible to diagnose a rash or lesion from its appearance, in some cases additional investigations are required. Table 23.2.1  Terminology of skin lesions Lesion Definition Description Macules Flat (non​palpable) lesion Minimal changes in surface markings or texture; may merely be areas of redness, purpura, or melanin Papules and plaques Papules are small, circumscribed, palpable raised lesions Plaques are larger diameter palpable lesions, often resulting from the confluence of papules Palpable lesions may arise either from thickening of the epidermis, or from infiltration/​oedema of the upper dermis, or a combination Nodules Circumscribed palpable masses, usually >1 cm Usually consist of infiltrating cells (inflammatory or neoplastic) filling the dermis and/​or subcutaneous tissue Cysts Circumscribed palpable lesions containing fluid or semisolid material Clinically resemble nodules, but are fluid filled rather than solid (unlike vesicles and blisters, which are superficial, unlined, and contain visible fluid) Vesicles and bullae (blisters) Visible accumulations of fluid Vesicles are small, bullae are >1 cm; they frequently coexist Urticaria or wheal Angio-​oedema Urticaria is dermal oedema (can be any size) Angio-​oedema is deep-​seated dermal oedema extending into subcutaneous tissue Petechiae and purpura Leakage of blood in the skin, which does not blanch on pressure Petechiae (pinhead size) Purpura (a few mm diameter) Ecchymosis (larger haemorrhagic areas) Fig. 23.2.5  Fungal infection (tinea corporis). By contrast with the endogenous diseases, this eruption is asymmetrical. The annular shape is typical. Dermatophyte fungus infections are usually very superficial, so the epidermal sign of scaliness is marked. Fig. 23.2.6  Annular erythema (reactive or toxic erythema). The annular shape may suggest a fungal infection, but the overlying epidermis is smooth or only slightly scaly, indicating that the pathology lies chiefly in the dermis. The margins of these rings are elevated by dermal infiltration with inflammatory cells and oedema.

23.2  Clinical approach to the diagnosis of skin disease 5601 Skin scrapings for fungal mycelia Scales removed by gentle scraping with a scalpel blade are treated with potassium hydroxide to clear keratin and other obscuring debris, and examined by light microscopy for fungal hyphae. Culture on a suitable medium identifies the fungal species. Biopsy Biopsy is indicated in the evaluation of skin tumours, in the case of rashes in which there is clinical uncertainty, or when it is essen- tial to document the diagnosis before treatment (e.g. lymphomas). The lesion or area of rash chosen for biopsy should be reasonably representative, and not be modified by scratching, picking, sec- ondary infection, or treatment. The standard procedure is to re- move a small ellipse of skin, including some underlying fat, under local anaesthesia. A punch biopsy of 4 mm diameter is frequently sufficient and convenient in a clinic setting, but is less suitable for evaluating deep pathology such as panniculitis. Small lesions (e.g. papules, small nodules, and blisters) can be entirely excised within a small ellipse. Complete excision is preferable to an in- cisional biopsy for the evaluation of tumours. If a blister is to be biopsied, this should be a recent one (no more than 24 h old), so that the blister depth can be judged before epithelial regener- ation takes place. For standard histopathology the skin is placed in formalin. Dermoscopy The dermoscope is a hand-​held instrument with a powerful halogen beam that illuminates and magnifies (10×) intraepidermal and some subepidermal structures, including the superficial vascular plexus. A smear of water, alcohol, or mineral oil applied to the surface of the lesion eliminates surface reflections and make the horny layer more translucent. Dermoscopy is principally used as a non​invasive tool for the evaluation of melanocytic lesions by assessing the pattern of the pigmentary network, certain features of which correlate with malignancy. It is also useful for assessment of other non​pigmented skin tumours, such as haemangiomas and basal cell cancers, and has an increasing use in the evaluation of non​neoplastic conditions, for example, for visualizing the mites in suspected scabies. Immunofluorescence tests Immunofluorescence tests using fluorescein-​labelled antibodies can detect skin-​bound immunoglobulins or complement, and are used in the diagnosis of the immunobullous diseases such as pemphigus, pemphigoid, and dermatitis herpetiformis (see Chapter 23.4). The direct immunofluorescence test requires a skin biopsy frozen im- mediately in liquid nitrogen, and detects immunoreactants already bound to antigenic components of the patient’s skin. The indirect test is performed using patient serum or blister fluid incubated with a substrate of normal skin or other epithelia before the application of a fluorescein-​tagged antiglobulin. The indirect test is used to detect circulating antibodies directed against skin antigenic components. Woods light examination Examination of the skin with an ultraviolet A lamp (360 nm, Wood’s light) can help to accentuate pale areas, for example, the symmet- rical irregular areas of depigmentation in vitiligo (see Chapter 23.8) or the hypopigmented ash-​leaf macule of tuberous sclerosis (see Chapter 24.17). It can also demonstrate green fluorescence in some fungal infections of hair (e.g. Microsporum canis), or pink fluores- cence in teeth and urine indicating porphyrin accumulation. FURTHER READING Coulson IH, Cox NH (2010). Diagnosis of skin disease. In: Burns T, et al. (eds) Rook’s textbook of dermatology, pp. 5.1–​6.1. Blackwell, Oxford. Fig. 23.2.7  Grouping of vesicles typifies herpes simplex virus infection.

23.3 Inherited skin disease 5602 Thiviyani Marutha

23.3 Inherited skin disease 5602 Thiviyani Maruthappu and David P. Kelsell

ESSENTIALS Considerable advances in our understanding of inherited skin diseases have been made over the last decade as a result of high throughput sequencing technologies including next generation sequencing and whole exome sequencing. The genetic basis of a myriad of monogenic epidermal disorders and syndromes including blistering diseases, ichthyoses, palmoplantar keratodermas, and the ectodermal dysplasias have now been elucidated. However, most patients referred from primary care to the dermatology clinic will be seeking treatment for a few common skin disorders such as psor- iasis, eczema, and acne. The genetic basis of these disorders is rather more complex, but progress has been made through genome-​wide association studies, which, for example, have linked susceptibility variants in the gene for filaggrin (FLG) to atopic eczema, and IL23R and many other immune-​related genes to psoriasis. Several genes have also been identified that predispose to malignancies of the skin including p16 (CDKN2A) and CDK4 in melanoma. Not only have these breakthroughs allowed a greater understanding of the patho- logical basis of skin diseases, but they have also highlighted novel targets for therapeutic development. Structure of the epidermis To understand inherited skin disease, it is first necessary to understand the basic biology of the epidermis and associated basement membrane zone. The basic structure of the epidermis is illustrated in Fig. 23.3.1. The epidermis is a stratified squa- mous epithelium consisting predominantly of keratinocytes. The remaining small percentage of intraepidermal cells includes resi- dent melanocytes, Langerhans’ cells, and migratory leucocytes. The keratinocyte undergoes a process of terminal differentiation resulting in the stratum corneum, the critical component for the barrier function of the epidermis. The highly insoluble stratum corneum consists of a cornified envelope enclosing keratin microfibres separated by a highly lipid-​rich intercellular layer. This lamellated lipid is the predominant component of the bar- rier, and is secreted into the extracellular space from membrane-​ coating granules synthesized in the stratum granulosum. The epidermis is separated from the underlying dermis by a complex basement membrane zone. The basement membrane zone When studied ultrastructurally, the basement membrane zone of the epidermis contains four distinct layers: • the basal cell membrane of the basal keratinocyte, which contains electron-​dense adhesion plaques called hemidesmosomes • the electron-​lucent lamina lucida, which is traversed by anchoring fibrils • the electron-​dense lamina densa • within the sublamina densa region, the lamina fibroreticularis contains distinct anchoring structures called anchoring fibrils, which insert into the lamina densa and loop around bundles of connective tissue collagens The hemidesmosome Although the morphology of this organ ultrastructurally resembles that of the desmosome, there are clear differences in biochemical composition. Two major hemidesmosomal proteins were initially identified by the characterization of autoantibodies arising in bul- lous pemphigoid, an autoimmune mechanobullous disease of late adult life. The proteins are known as bullous pemphigoid antigen 1 (dystonin (DST); 230 kDa) and bullous pemphigoid antigen 2 (COL17A1; 180 kDa). Bullous pemphigoid antigen 2 has been iden- tified as a unique transmembrane collagen, type XVII, which has an extracellular domain containing the immunodominant epitope of bullous pemphigoid. Bullous pemphigoid antigen 1, like plectin, a further component of hemidesmosomes, is a member of the plakin family of proteins. Plakins have been thought to contribute to plaque structures within the hemidesmosome; other members of the plakin family include desmoplakin, envoplakin, and periplakin, and are found associated with the desmosome. Plectin and bullous pemphigoid antigen appear to interact with keratin intermediate filaments as they course towards the hemidesmosome, and bind them into the hemidesmosome structure, acting as a protein clamp. This appears to provide a stable link between the intermediate filament cytoskeleton and the basement membrane zone. Basal keratinocytes also express 23.3 Inherited skin disease Thiviyani Maruthappu and David P. Kelsell

23.3  Inherited skin disease 5603 several integrins, which are members of a superfamily of receptors for extracellular matrix proteins. The major hemidesmosomal in- tegrin is α6β4 integrin, although other aspects of the basal cell mem- brane express α6β1, α5β1, α3β1, ανδ, and α2β1 integrins. The lamina lucida appears to contain a complex of laminin mol- ecules, particularly laminins 5 and 6. It is thought that laminin 5 is the major component of the anchoring filament. The lamina densa is constructed of a meshwork of interacting type VII collagen, from which arises the anchoring fibrils of the basement membrane com- plex, which are made of aggregates of antiparallel dimers of type VII collagen. Keratins The cytoskeleton of all epithelial cells contains several filamentous systems, including actin, microfilaments, microtubules, and inter- mediate filaments. The protein family that is characteristic of the intermediate filaments of all epithelial cells are the keratins. Keratin polypeptides are segregated by two-​dimensional gel electrophor- esis into acidic and basic polypeptides. Fifty-​four keratin genes have been identified expressed in epithelial cells and/​or the hair follicle: 28 belong to the type I group and 26 to the type II group. The type II keratin gene family encodes the basic keratin polypeptides, and the type I family the acidic keratin polypeptides. Each keratin gene is expressed in a body-​site and cell-​type specific manner (e.g. KRT9 is only expressed in the suprabasal layer of the palmoplantar epidermis and KRT6, KRT16, and KRT17 are rapidly induced in response to injury in stratified epithelia). The keratin genes are clustered in two chromosomal regions of the human genome:  the type I  keratins mapping to 17q12-​q21, and the type II keratins to 12q11-​q13. A keratin intermediate filament consists of both type I and type II keratin. The fundamental building block of a keratin filament is a heterodimer of a type I and type II keratin comprising four hel- ical regions separated by non​helical linking regions, with non​helical head and tail domains. These heterodimers aggregate in a complex antiparallel fashion to form the intermediate filaments, which an- chor to both hemidesmosomes and desmosomes to provide stability to the cell and ensure its integrity. In addition to keratin mutations associated with human disease, in vitro and transgenic models of keratin genes harbouring mutations have shown that there are critical regions for filament assembly, particularly the helix initiation and termination motifs. The amino terminal head domain of type II keratins mediates interaction with desmosomes but the function of the tail domain remains unclear. Desmosomes Desmosomal proteins form a complex structure at the interface be- tween adjacent epithelial cells. The desmosomal plaques of electron-​ dense material run along the cytoplasm parallel to a junctional region in which three ultrastructural bands can be seen. The plaques contain plakoglobin (which is also found in adherens junctions and is thought to be important in cell signalling), desmoplakin, and plakophilin 1.  In addition, the desmosomal cores are en- riched with calcium-​binding glycoproteins called desmogleins and desmocollins. These are the adhesive proteins of the desmosome, and are similar to the classical cadherins in their general structure, with five extracellular repeats that contain Ca2+-​binding sites, a single transmembrane region, and a cytoplasmic domain. To date, seven human desmosomal cadherins have been iden- tified, clustered in the chromosomal region 18q11-​q12. The cyto- plasmic domain has binding sites for plakoglobin, plakophilin 1, and desmoplakin, linking them to the intermediate filaments. Desmoglein 1 has been identified as the dominant target antigen for the autoimmune bullous disease pemphigus foliaceus, and desmoglein 3 is the target antigen for pemphigus vulgaris. Gap junctions Gap junctions provide a mechanism for synchronized cellular re- sponses to a variety of intercellular signals by regulating the diffusion of small molecules (<1 kDa) such as metabolites and ions between the cytoplasm of adjacent cells. Connexins are the major proteins of gap junctions and are encoded by a large gene family. All connexins have four transmembrane domains and two extracellular loops, with the N-​ and C-​termini located in the cytoplasm. Connexins assemble into hexameric hemichannels (termed connexons) in the endo- plasmic reticulum, and are then transported into the lipid bilayer of the plasma membrane. A connexon then docks with a connexon of an adjacent cell to form a dodecameric aqueous channel, the gap junction. These cluster together in macromolecular complexes of several hundred channels. Connexons can form either homotypic or heterotypic channels, with various channel types having distinct molecular permeabilities. Most connexins have wide tissue distribu- tion. Those expressed in the skin include connexin 26, 31, and 43. Disease associations with the aforementioned structural proteins have provided a molecular classification of disease to complement the classical morphological description of hereditary blistering diseases and disorders of keratinization, some of which are described next. Epidermolysis bullosa Genetic analysis of the heterogeneous group of mechanobullous disorders has facilitated enormous progress in understanding the function of proteins involved in the basement membrane at the dermoepidermal junction, and the role of keratins in the cyto- skeleton (Table 23.3.1). The clinical phenotypes of epidermolysis bullosa correspond to different levels of skin separation within the basement membrane zone or basal keratinocyte, identified Keratin filaments Desmosome Gap junction Nucleus Hemidesmosome Lamina lucida Lamina densa Anchoring filaments Anchoring plaque Anchoring fibrils Cornified cell envelope e.g. loricrin Suprabasal keratinocytes e.g. desmoglein 1, desmoplakin, keratins (1, 6a, 6b, 9, 10, 16, 17) Basement membrane e.g. laminins (1,5,6), type IV collagen Dermis e.g. type VII collagen Basal keratinocytes e.g. keratins (5,14) plectin, α6 β4 integrin Fig. 23.3.1  A schematic representation of the epidermis indicating its organization, important structures, and site of expression of several skin disease-​associated proteins.

section 23  Disorders of the skin 5604 via electron microscopic examination. All cases of epidermolysis bullosa are atrophic skin disorders characterized by the blistering of mucocutaneous sites following minor trauma, and are classified according to a combination of laboratory and clinical criteria. Epidermolysis bullosa simplex In epidermolysis bullosa simplex, skin tissue separates at the level of the basal keratinocyte, with or without the aggregation of keratin intermediate filaments. This is the most common form of epi- dermolysis bullosa, and is usually inherited in an autosomal dom- inant fashion. Blister formation occurs in the basal keratinocytes, which may show aggregates of keratin filaments. Mutations in the genes encoding the basal cell-​specific keratins 5 (KRT5; OMIM 148040) and 14 (KRT14; OMIM 148066) plus in the gene encoding the ubiquitination-associated protein KLHL24 have been found to underlie epidermolysis bullosa simplex, probably leading to the cytoskeletal weakness that results in the tendency for cells to rupture on pressure. Three types of the disease are described next, and clin- ical pictures are shown in Fig. 23.3.2. Epidermolysis bullosa simplex Weber–​Cockayne The soles and palms are mainly affected, but other sites can also be involved, although rarely. The blistering occurs from infancy (with walking), and is exacerbated by heat and ameliorated by cold. The blisters heal without scarring. Epidermolysis bullosa simplex Koebner The blisters are widespread on the scalp, trunk, arms, and legs, in addition to the palmoplantar areas. These cases might represent autosomal recessive inheritance. Nail dystrophy, oral blisters, and dental caries are common. Epidermolysis bullosa simplex Dowling–​Meara (herpetiform epidermolysis bullosa simplex) The blistering can be very severe, and is potentially fatal in infancy. The blisters occur in groups on an erythematous bed, which heals without scarring, but hyperpigmentation and milia formation can occur. Patchy keratoderma develops in later life. Junctional epidermolysis bullosa In junctional epidermolysis bullosa, the epidermis separates from the dermis at the lamina lucida of the basement membrane zone. Most mutations lie within genes encoding the three polypeptide subunits of laminin 5 (LAMA3, OMIM 600805; LAMB3, OMIM 15010; LAMC2, OMIM 150292). Clinically, the disease has been subdivided into two main categories:  Herlitz (lethal) and non-​ Herlitz (non​lethal) forms. Herlitz junctional epidermolysis bullosa Blistering and erosions are present at birth, and become widespread as the skin is so fragile that it peels away on contact. The resulting lesions are slow to heal and tend to persist, becoming infected. The oropharyngeal mucosa is involved, often making feeding difficult. If the infant survives for a few months, typical crusted lesions will be seen on the nose, mouth, and jaw, and across the rest of the skin in patches. The teeth have abnormal enamel and are lost easily, as are the nails. Infants usually die from overwhelming infection. Non-​Herlitz junctional epidermolysis bullosa Patients show generalized skin fragility and blistering, but the mucosae are less severely affected. The lesions heal leaving atrophic scars (generalized atrophic benign epidermolysis bullosa). Poor hair and tooth development is seen, and the nails are dystrophic. Large hyperpigmented patches are also present. Dystrophic epidermolysis bullosa In both the recessive and dominant forms of dystrophic epiderm- olysis bullosa, skin separation occurs below the dermoepidermal region at the level of the anchoring fibrils, and a large number of mutations have been discovered in the type VII collagen gene (COL7A1; OMIM 120120) that encodes the constituent protein of the anchoring fibrils. Scarring and dystrophy are prominent features in addition to skin fragility and blistering. Severe generalized recessive dystrophic epidermolysis bullosa This is the most severe form of dystrophic epidermolysis bullosa, and is very disabling in view of the deformities produced by scar- ring. Blisters are present at birth and recur readily at sites of trauma, especially the hands, feet, neck, shoulders, and sacrum. They heal slowly, with scarring and milia formation producing a mitten-​like deformity of the hands, and clubbed feet. The severe oral lesions lead to microstomata, and the inability to protrude the tongue or open the mouth. Poor dentition leads to feeding problems. Scalp blistering and scarring brings permanent hair loss, eye involvement gives corneal erosions and opacities, and general physical develop- ment is retarded. Oesophageal and perianal strictures lead to dif- ficulty in swallowing, and constipation. Although children often survive into adult life, multiple squamous cell carcinomas can de- velop in the chronically scarred skin and progress rapidly. Dominant dystrophic epidermolysis bullosa The skin is less fragile than in recessive dystrophic epidermolysis bullosa, and blistering is much more difficult to provoke, so that it tends to be localized to bony prominences: knees, elbows, hands, and feet. Localized scarring with milia can replace the nails. Other areas, such as the oral and anal regions, are much less affected. Hemidesmosomal epidermolysis bullosa Rarer forms of epidermolysis bullosa result from inherited defects in three hemidesmosomal components: plectin mutations in epiderm- olysis bullosa simplex with muscular dystrophy (PLEC1; OMIM Table 23.3.1  Genetics of epidermolysis bullosa Type of epidermolysis bullosa: site of blistering Genetic defect Associated disorder Simplex: basal cells Keratin 5 Keratin 14 KLHL24 Hemidesmosomal: basal cells/​ lamina lucida Plectin Integrin α6 Integrin β4 Type XVII collagen Muscular dystrophy Pyloric atresia Junctional: lamina lucida Laminin α3 Laminin β3 Laminin γ2 Dystrophic: sublamina densa Type VII collagen

23.3  Inherited skin disease 5605 601282), type XVII collagen mutations in generalized atrophic be- nign epidermolysis bullosa (COL17A1; OMIM 113811), and α6β4 integrin mutations in epidermolysis bullosa with pyloric atresia (ITGB4; OMIM 147557). Diagnosis and management of blistering in childhood Early diagnosis is key to the management of the disease and the prognosis. The diagnosis of a baby born with blisters is often difficult on clinical grounds, so diagnosis will rest on electron microscopy of a shave skin biopsy. Immunohistochemistry is likely to be indi- cative in recessive cases of gene knockout, the diagnostic reagents being LH7.2 antibody to type VII collagen, and GB3 antibody to laminin 5. There is no specific treatment for any form of epiderm- olysis bullosa, so management centres on wound care, the avoidance of physical trauma, and general physical and psychological support. Specialist nurses can advise on nursing babies with silk-​covered dressing pads, and the use of Vaseline gauze dressings. Oral hygiene and dental care needs to be lifelong. A high-​calorie and high-​fibre diet is essential to improve growth. Gastrostomy feeding can also help maintain body weight in children unable to eat. Finger and hand contractures require splinting at night and regular surgical re- lease by an expert surgeon. Now that the genetic basis of epiderm- olysis bullosa has been identified, prenatal diagnosis by DNA-​based techniques, and gene therapy by ex vivo techniques are actively being explored. Active areas of research into treatments for recessive dystrophic epidermolysis bullosa include allogeneic haematopoi- etic cell transplantation and induced pluripotent stem cells (iPSCs) with the ability to deliver collagen VII locally into chronic wounds. Ultimately, gene-​correction using viral vectors to reintroduce wild-​ type collagen VII into recessive dystrophic epidermolysis bullosa cells could provide a long-​term therapeutic strategy. Hailey–​Hailey disease and Darier’s disease The genetic bases of these rare autosomal dominant intraepidermal blistering diseases are mutations in the genes for calcium pumps:  ATP2C1 (OMIM 604384)  in Hailey–​Hailey disease, and (a) (b) (e) (g) (h) (f) (c) (d) Fig. 23.3.2  Clinical photographs of the different forms of epidermolysis bullosa. (a) and (b) a patient with dystrophic epidermolysis bullosa; (c) the hand of an infant with Herlitz junctional epidermolysis bullosa; (d) blister on the foot of a patient with epidermolysis bullosa simplex; (e) baby with epidermolysis bullosa simplex Dowling–​Meara; (f) baby with Herlitz junctional epidermolysis bullosa; (g) baby with dystrophic epidermolysis bullosa; (h) intraepidermal blister from a Weber Cockayne epidermolysis bullosa simplex patient. Skin section stained with Richardson’s stain.

section 23  Disorders of the skin 5606 ATP2A2 (OMIM 108740) in Darier’s disease. Darier’s disease typ- ically presents in the mid teenage years, with small pink and brown papules with greasy scale, and might distribute in a seborrhoeic pat- tern. However, the pattern and severity of the disease can be highly variable. Histology shows characteristic clefts in the epidermis, and dyskeratotic cells. Peeling skin syndrome Peeling skin syndrome describes a group of autosomal recessive dis- orders that present with mild superficial peeling, which can either be generalized (PSS1) or restricted to acral (palms and soles) sites (PSS2-​4). Typically presenting in childhood, affected sites may ex- hibit erythema, inflammation, or more rarely, vesiculation. PSS1 can be caused by mutations in corneodesmosin gene (CDSN; OMIM 602593) or in the calpastatin gene (CAST; OMIM 616295) where it is associated with leukonychia, acral punctate keratoses, cheilitis, and knuckle pads. The acral form of the disorder can be caused by mutations in TGM5 (OMIM 603805), CHST8 (OMIM 610190), and CSTA (OMIM 184600). The condition can be aggravated by heat, humidity, and exposure to water. Treatment includes regular appli- cation of emollients and avoiding the aforementioned triggers. Ichthyoses Ichthyoses manifest as dry, rough skin, with persistent scaling over most of the body, which can resemble fish scales (ichthys, Greek: fish). Congenital ichthyosis can be bullous, or associated with other abnormalities (ichthyosiform syndromes). Ichthyosis can be acquired in later life as a result of drugs such as hypocholesterolaemic agents, chronic hepatic disease, lymphoma, and other malignancies, thyroid disease, chronic renal or hepatic failure, and malabsorption. When an individual’s ichthyosis has improved in adult life and then worsened in late adult life, it is sometimes difficult to be absolutely sure whether a patient has a congenital or an acquired ichthyosis. Progress in the understanding of the molecular and cellular biology of the ichthyoses will aid in establishing their classification and po- tential treatment. Autosomal dominant ichthyosis vulgaris This, the most common form of ichthyosis, is associated with atopic eczema in up to 50% of individuals. The condition improves in teen- agers and young adults, and often worsens again with age. The clin- ical features present with dryness and scaling in the neonatal period, and become progressively more obvious in childhood. Scales are small, flaky, or brown, and are most pronounced on the extensor aspects of the arms and lower legs. Facial involvement is often min- imal, although patients might have dandruff and increased mark- ings on the palms and soles. Hyperlinearity of palm creases might be seen in addition to keratosis pilaris occurring in a symmetrical distribution on the upper arms, thighs, and buttocks. It is usually very well-​tolerated symptomatically, with only the dryness and roughness being a problem. Treatments have therefore been aimed at removing the keratotic-​retained stratum corneum with keratolytic agents such as salicylic acid or 1–​5% lactic acid, other hydroxy acids, or buffered urea creams. Histopathology shows hyperkeratosis, with a diminished or absent granular cell layer, but otherwise very little abnormality at both the light and ultrastructural levels. This disease appears to be inherited in an autosomal dominant manner; however, there is variable penetrance, and difficulties in as- certainment. Loss-​of-​function mutations in FLG, the gene-​encoding filaggrin (filament aggregating protein), underlie ichthyosis vulgaris (OMIM 135940). Filaggrin plays a role in the differentiation of the epidermis and the formation of the skin barrier. X-​linked recessive ichthyosis This disorder is much less common than the autosomal dominant form, and predominantly affects the male children of female car- riers. The scaling is usually absent for the first week of life, but pro- gressively increases; it tends to be prominent on the arms, thighs, and lower legs, and very large adherent brown scales may involve the flexures and the face. On ultrastructural examination the granular cell layer and keratohyalin granules appear normal. The molecular basis of this form of ichthyosis was determined from observations of low urinary oestriol secretion in the third trimester of pregnancy, and reduced steroid sulphatase activity. Subsequently, the steroid sulphatase gene was mapped to the X chromosome (STS; OMIM 300747), and disease-​associated mutations in this gene have been identified in the vast majority of patients. Steroid sulphatase mutations lead to the abnormal breakdown of cholesterol sulphate in the stratum corneum lipids, resulting in reduced epidermal bar- rier function and and increased stratum corneum thickening. A small proportion of patients will have the additional mani- festations of Kallman’s syndrome (KAL1; OMIM 308700), with hypogonatropic, hypogonadal, and neurological abnormalities. These result from contiguous gene defects, usually a large deletion on the short arm of the X chromosome encompassing the steroid sulphatase locus. Bullous ichthyosiform erythroderma
(epidermolytic hyperkeratosis) This is a rare autosomal dominant ichthyosis. There is mild erythroderma at birth, and blisters and peeling can occur at sites of minor trauma. Large areas of denuded skin are often apparent after a difficult birth. In infancy, a yellow-​brown hyperkeratosis develops, particularly at the sites of joint flexure, with cobblestone keratoses present on the hands, feet, and trunk. Ridged scale can accumu- late in skin creases, which are highly susceptible to bacterial and/​or fungal infection, leading to a pungent body odour. Histologically, there is lysis and clumping of the keratin fila- ments in the granular layer of the epidermis. Intercellular spaces are often apparent because of the rupture of suprabasal keratinocytes. Immunohistochemical studies have revealed the specific aggrega- tion of the suprabasal keratins of the epidermis, keratins 1 and 10. Subsequently, mutations in either KRT1 (OMIM 139350) or KRT10 (OMIM 149080) have been shown to underlie the disease in many patients. Mutations in KRT9 (OMIM 607606) have been shown to underlie a form of bullous ichthyosiform erythroderma limited to the palms and soles. Superficial epidermolytic ichthyosis This is a more rare form of bullous ichthyosis. Neonatal disease is much milder, with episodic superficial blistering occurring throughout childhood, sometimes into adulthood. The blisters occur mainly on the flexures, lower limbs, and abdomen. At these sites, a rippled grey hyperkeratosis can occur. Plate-​like scaling and

23.3  Inherited skin disease 5607 focal peeling (mauserung phenomenon) are usually found. There is an absence of palmoplantar keratoderma and erythroderma. Mutations in the gene encoding another suprabasal keratin, KRT2 (OMIM 600194), have been identified as the basis of this condition. This type II keratin is expressed in many of the higher suprabasal keratinocytes. Lamellar ichthyosis Lamellar ichthyosis is a severe form of autosomal recessive congenital ichthyosis characterized by severe hyperkeratosis and the formation of large, often brownish-​coloured plate-​like scales over the whole body surface, including the face, with some flexural accentuation. The scales are present at birth, and might appear as a carapace-​like sheet over the body of the newborn (collodion babies), which then sheds. Bathing suit ichthyosis is a rare variant of lamellar ichthyosis in South African black patients, where the scale is centrally distributed on the trunk, upper limbs, scalp, and neck. Mutations in the genes encoding transglutaminase 1 (TGM1; OMIM 190195), a lipid trans- porter (ABCA12; OMIM 607800), ichthyin (ICHYN; OMIM 609383), and arachidonate lipoxygenase 3 (ALOXE3; OMIM 607206) and 12 (ALOX12B; OMIM 603741) underlie both lamellar ichthyosis and non​bullous congenital ichthyosiform erythroderma (see next). Non​bullous congential ichthyosiform erythroderma Although these patients have a severe generalized autosomal re- cessive ichthyosis, and present as collodion babies, this condition differs from lamellar ichthyosis by the presence of generalized erythroderma, which contributes to the characteristic facies and ectropion. This also produces problems with temperature and fluid control. The scaling is often finer and more brawny than in lamellar ichthyosis, and inflammation and parakeratosis are additionally found on histopathology. Netherton’s syndrome Netherton’s syndrome is a severe autosomal recessive disorder which can result in infant mortality due to fluid/​protein loss and infection, and is characterized by ichthyosis with erythroderma and trichorrhexis invaginata (hair-​shaft abnormalities often termed ‘bamboo hair’). Scanning electron microscopy of patients’ hair often also reveals torsion nodules, pili torti, and trichorrhexis nodosa. Light microscopy can show invagination of the hair cuticle into the cortex. Mutations in the gene SPINK5 encoding LEKTI, a serine protease inhibitor, underlie Netherton’s syndrome. Sjögren–​Larsson syndrome Sjögren–​Larsson syndrome is inherited as an autosomal recessive trait, and is particularly prevalent in northwestern Sweden (1 in 10 000), occurring less frequently elsewhere. The syndrome char- acteristically includes ichthyosis, spastic diplegia, and mild-​to-​ moderate developmental delay. The skin disease presents as mild erythroderma at birth, with scaling developing in the first few months, which persists particularly on the face and limbs. In the flex- ures, neck, and periumbilical folds, an orange/​brown lichenification overlaid with hyperkeratosis is a characteristic feature. In early life, neurological defects including upper motor neurone defects of the limbs, learning difficulties, and often ocular abnormalities (spots on the retina) are observed. Histologically, the affected skin displays orthohyperkeratosis, acanthosis, and papillomatosis. The genetic defect has been shown to be in the fatty aldehyde dehydrogenase gene (FALDH; OMIM 609523), which affects essential fatty acid metabolism. Ichthyosis prematurity syndrome This recessive ichthyosis has a higher prevalence in Norway and Sweden (OMIM 608649). It manifests with complications at mid-​ trimester leading to premature birth. The babies are born with thick desquamating skin and atopic features. Mutations in the FATP4 gene underlie this condition and is associated with defective very long chain fatty acid metabolism. Harlequin ichthyosis Harlequin ichthyosis is the most severe and often lethal form of re- cessive congenital ichthyosis. Infants born with this condition have hard, thick skin covering most of their bodies. The skin forms large diamond-​shaped plates separated by deep fissures that restrict move- ment. These skin abnormalities also affect the shape of the eyelids, nose, lips, and ears. The severely compromised skin barrier func- tion in neonates leads to increased transepidermal water loss and impaired thermoregulation, and they are more susceptible to infec- tion. In addition, the tightened skin can cause breathing difficulties leading to respiratory failure. Supportive treatment and oral retinoid therapy can enable Harlequin infants to survive the neonatal period, surviving children and adults may display dry erythematous skin and sparse hair, resembling non​bullous congenital ichthyosiform erythroderma. Mutations in the ABCA12 gene encoding an ATP-​ binding cassette (ABC) transporter (OMIM 607800) are found in almost all Harlequin ichthyosis cases. Keratodermas The inherited keratodermas are characterized by the presence of thickened skin on the palms and soles. Palmoplantar skin is uniquely adapted to withstand weight bearing and friction, so the stratum corneum is much thicker (hyperkeratotic) than the rest of the epi- dermis. The keratodermas can be classified clinically according to the pattern of thickening on the palm and sole skin. Three distinct clinical patterns have been observed: • diffuse—​the hyperkeratotic thickening is evenly and symmet- rically distributed over the palm and sole, usually manifesting at birth • focal—​hyperkeratotic plaques develop particularly at sites of weight bearing and friction; these are usually plaque-​like callosites or linear thickening (striate keratoderma) • punctate—​multiple bead-​like keratoses that pepper the palmoplantar skin The keratodermas can have autosomal recessive or dominant in- heritance, and may occur in syndromes. They can be further subgrouped into: • simple—​palmoplantar involvement only • complex—​associated with lesions of non​volar skin, hair, teeth, nails, and sweat glands (including ectodermal dysplasias) • syndromic—​associated with abnormalities in other organs, inclu­ ding deafness, cancer, cardiomyopathy, and adrenal insufficiency

section 23  Disorders of the skin 5608 They can also be classified biologically by their underlying genetic defects (see Fig. 23.3.3 and Tables 23.3.2 and 23.3.3). This branch of the genodermatoses is genetically heterogeneous, with mutations in genes encoding keratins, desmosomal proteins, connexins, prote- ases, and a water-​channel protein. Diffuse facies (PPK) Simple—​diffuse epidermolytic palmoplantar keratoderma This condition is characterized by epidermolytic hyperkeratosis with keratin filament clumping in suprabasal keratins. This auto- somal dominant disease presents with symmetrical thickening giving a cracked, crocodile skin-​like surface resulting from the underlying epidermolysis, which starts in early infancy. Most epidermolytic PPK pedigrees are linked to the type I keratin cluster on chromosome 17q12-​q21, and disease is because of mutations in the palmoplantar-​specific keratin 9 (KRT9; OMIM 607606), the majority clustering in the helix initiation domain of the protein. However, epidermolytic palmoplantar keratodermas can also be associated with mutations in the type II keratin 1 (KRT1; OMIM 139350). Simple—​diffuse non​epidermolytic palmoplantar
keratoderma (NEPPK) Non​epidermolytic PPK is also inherited as an autosomal dominant trait, and is often difficult to distinguish from epidermolytic PPK because of the inconsistent finding of epidermolysis by electron mi- croscopy in epidermolytic palmoplantar keratodermas. There is a uniform waxy yellow thickening over the palms and soles, which can spread onto the dorsum of the hands and wrists, with a sharp cut-​off. It is commonly aggravated by secondary fungal infection, (a) (b) (d) (c) Fig. 23.3.3  Clinical photographs of: (a) bullous ichthyosiform erythroderma (BIE) and three types of keratoderma: (b) focal palmoplantar keratoderma (PPK) associated with a keratin 16 mutation; (c) striate palmoplantar keratoderma associated with a desmoglein 1 mutation; and (d) constriction around the digit from an individual with Vohwinkel’s syndrome associated with mutation in the gene-​encoding connexin 26 (GJB2; OMIM 121011).

23.3  Inherited skin disease 5609 which might require intermittent oral antifungal agents. These often improve the keratoderma. Some families have disease linked to 12q11-​q13. A single family has a mutation in the variable head do- main of keratin 1; however, in most non​epidermolyic palmoplantar keratodermas families, fine mapping of the 12q11-​q13 locus has ex- cluded abnormalities of the type II keratin genes. Complex—​erythrokeratoderma variabilis Erythrokeratoderma variabilis is a rare autosomal dominant skin dis- ease characterized by diffuse PPK and transient figurate red patches at various sites of varying severity. Germline mutations in connexin 31 (GJB3; OMIM 603324) and in the 3-ketodihydrosphingosine reductase (KDSR; OMIM 617526) have been identified in the af- fected members of some erythrokeratoderma variabilis families. Focal keratoderma Most focal palmoplantar keratodermas are characterized by the presence of discoid lesions, and the majority can be regarded as complex PPKs as they are often associated with abnormalities of hair, nails, teeth, and glands. Simple—​striate PPK This focal palmoplantar keratoderma is characterized by the pres- ence of distinctive linear streaks on the palms and soles, and over the ventral aspects of the fingers extending onto the palms. The le- sions are often more extreme on the feet. Variable nail and hair in- volvement with fragility or splitting is seen. Mutations in the genes for two desmosomal proteins: desmoglein 1 (DSG1; OMIM 125670; 18q11-​12) or desmoplakin 1(DSP; OMIM 125647; 6p21) have been described, which result in a hemizygous gene knockout leading to haploinsufficiency of the gene product. Keratin 1 mutations have also been reported. Complex—​pachyonychia congenita type 1/​focal PPK with
oral mucosal hyperkeratosis This clinical overlap syndrome presents in childhood with nail changes (pachyonychia). Typically, a subungual hyperkeratosis pro- duces a trumpet-​shaped nail, especially on the thumb, first finger, and toes. The sole lesions consist of painful callosities over weight-​ bearing areas; less prominent callosities occur on the palms. The gingival mucosa shows milky hyperkeratosis. Nutmeg-​grater-​like follicular keratoses also occur. Variable fragility and blistering can be associated with severe pain on walking. Milder nail involvement may present as splinter haemorrhages. The pathological finding of epidermolytic hyperkeratosis with keratin filament clumping sug- gests that keratin gene mutations underlie this disorder; this was confirmed by the identification of mutations in the genes encoding keratin 6A (KRT6A; OMIM 148041) and keratin 16 (KRT16; OMIM 148067) in affected individuals from multiple families. Complex—​pachyonychia congenita
type 2/​steatocystoma multiplex The palmoplantar keratoderma might be very limited, although pachyonychia nail changes present early. Multiple epidermal cysts and steatocysts are seen. Woolly scalp hair, fuzzy eyebrows, and natal teeth are also common features. The finding of keratin clumps in skin bearing keratin 17, particularly the hair follicle’s deep outer root sheath, suggested KRT17 (OMIM 148069)  as the candidate gene, and autosomal dominant mutations have been extensively de- scribed. Mutations in KRT6B (OMIM 148042) have also been iden- tified. The resulting pathology varies from keratin cysts, vellus hair cysts, and oil-​filled cysts. Complex—​Papillon–​Lefevre syndrome This focal palmoplantar keratoderma is inherited in an autosomal recessive manner, and is marked by associated severe periodon- titis and secondary ulceration, with opalescent oral mucosae. The inflammatory lesions often result in pocket formation seen patho- logically. Mutations in cathepsin C, a lysosomal protease, have been shown to underlie this disorder. It is postulated that cathepsin C may Table 23.3.2  Genetics of diffuse palmoplantar keratoderma (PPK) Type of diffuse PPK Associated disorder Genetic defect EPPK (epider-​molytic PPK) Keratin 9 NEPPK (non​epidermolytic PPK) Umbilical hyperkeratosis Keratin 1 NEPPK Diffuse Nagashima-​type NEPPK Aquaporin 5 Serpin B7 Syndromic NEPPK (Naxos disease) Woolly hair and cardiomyopathy Plakoglobin Desmoplakin Vohwinkel’s syndrome Sensorineural deafness Connexin 26 Ichthyosis Loricrin Erythrokeratoderma variablis Generalized erythroderma Connexin 31 KDSR Clouston’s syndrome Alopecia, nail dystrophy, sensorineural deafness Connexin 30 and connexin 30.3 Hypohidrotic ectodermal dysplasia Erythroderma, impaired sweating, hair and nail abnormalities Plakophilin 1 Mal de Meleda Olmsted syndrome Hyperhidrosis and perioral erythema Palmoplanter keratodema and perioroficial keratosis SLURP-​1 TRPV3 NEPPK, non​epidermolytic palmoplantar keratoderma. Table 23.3.3  Genetics of focal palmoplantar keratoderma (PPK) Type of focal PPK Associated disorder Genetic defect Focal NEPPK Follicular and orogenital hyperkeratosis Keratin 16 Focal NEPPK (tylosis) Oesophageal cancer, oral and follicular hyperkeratosis iRhom2 Pachyonychia congenita type 1 Nail dystrophy and oral lesions Keratin 6a Keratin 16 Pachyonychia congenita type 2 Epidermal cysts, nail dystrophy, and oral lesions Keratin 6b Keratin 17 Striate PPK Desmoglein 1 Desmoplakin Keratin 1 Papillon–​Lefevre Cathepsin C Oculocutaneous tyrosinaemia Photophobia, corneal ulceration, and mental retardation Tyrosine aminotransferase NEPPK, non​epidermolytic palmoplantar keratoderma.

section 23  Disorders of the skin 5610 be important in the processing of key structural proteins, such as keratins, in the epidermis. Simple—​punctate PPK This is inherited as an autosomal dominant trait and presents with a uniform bead-​like hyperkeratosis over the palms and soles with secondary broader areas of hyperkeratosis in weight-​bearing areas. They can appear clinically similar to acquired punctate keratoses, but are more uniform, appear earlier in life, and have a positive family history. Both acquired and inherited forms are associated with malignancies. Rarer porokeratotic forms exist. Mutations in the AAGAB gene (OMIM 614888) have been found to underlie this disease. Syndromic keratodermas (multiple phenotypic) PPK and deafness Several families with palmoplantar keratoderma and sensorineural deafness have been described. This might be due to a mutation in a single gene expressed in all affected tissues, or cosegregation of two distinct gene mutations. One such disorder is Vohwinkel’s syndrome; a mutating palmoplantar keratoderma with constric- tions developing around the fingers, leading to autoamputation. Autosomal dominant mutations in the genes encoding the gap junction protein connexin 26 (GJB2; OMIM 121011) have been described in families with Vohwinkel’s syndrome, and other forms of palmoplantar keratoderma and sensorineural deafness. There is a genotype–​phenotype correlation between the site of the GJB2 mutation and the severity of the keratoderma and ex- tent of the hearing impairment. Mutations in the gene for loricrin (LOR; OMIM 152445), a cornified cell-​envelope component of the stratum corneum, have also been identified in individuals affected with a variant form of Vohwinkel’s syndrome that is as- sociated with ichthyosis. In addition, palmoplantar keratoderma and deafness have also been associated with mutations in mitochondrial DNA. PPK and cancer Focal non​epidermolytic PPK and oesophageal cancer (Tylosis with oesophageal cancer –​TOC) Two large pedigrees from the United Kingdom and smaller pedigrees from the United States of America, Spain, Finland and Germany have been studied in which a focal non​epidermolytic palmoplantar keratoderma with oral hyperkeratosis segregates with a high lifetime risk of squamous cell carcinoma of the oesophagus (up to 95% by age 65 years). The cutaneous phenotype is completely penetrant by puberty. Gain-​of-​function mutations in the gene encoding the in- active rhomboid protease, iRhom2 (RHBDF2; OMIM 148500) have been determined as the underlying cause in all described cases. The autosomal dominantly inherited mutation is associated with dysregulated EGFR signalling, which has been postulated to con- tribute to carcinogenesis in these patients. Huriez disease (sclerotylosis) This is an autosomal dominant disease characterized by PPK, nail changes, and scleroatrophy of the distal extremities. Around 15% of individuals develop aggressive squamous cell carcinomas in their thirties and forties. It is proposed that the scarring resulting from skin fragility predisposes to the carcinomas. The Huriez disease gene has been mapped to chromosome 4q23. PPK, woolly hair, and cardiomyopathy Diffuse non​epidermolytic PPK with arrhythmogenic ventricular cardiomyopathy (which leads to heart failure and arrhythmias) can result from recessive or dominant mutations in the gene for either desmoplakin (DSP; OMIM 125647) or plakoglobin (JUP; OMIM 173325), two major proteins of the desmosome. It is now known that affected individuals may present with cardiac features, cutaneous features or both, and these studies have alerted dermatologists to the possible covert cardiac problems that may occur in patients with palmoplantar keratoderma and woolly hair. Triple A syndrome In triple A or Allgrove’s syndrome, individuals have ACTH-​resistant adrenal insufficiency, achalasia, and alacrima with palmoplantar keratoderma. This disease has been mapped to 12q13, and muta- tions in a novel gene, AAAS (OMIM 605378), have been identified. The predicted protein is a WD repeat-​containing protein that might play a role in signalling, and RNA processing and transcription. Ectodermal dysplasias There are a many ectodermal dysplasias, in which abnormal- ities of the skin, hair, teeth, nails, and/​or sweating are seen. The clinical classification is unsatisfactory, but might become more transparent when the genetic basis of a significant number of these complexes has been classified. Two major subgroups in- clude hidrotic and non​hidrotic ectodermal dysplasia. The con- cept of dysplasia in these diseases is developmental rather than premalignant. Hidrotic ectodermal dysplasia (Clouston’s syndrome) Hidrotic ectodermal dysplasia is characterized by nail dystrophy with thick, slow-​growing, discoloured, short nails. Diffuse palmoplantar keratoderma is variable, but may be severe and spread to knuckles and finger joints. Scalp hair is sparse, fine, pale, and brittle, with thin eyebrows and sparse body hair. The disease is inherited as an auto- somal dominant trait. Mutations in connexin 30 encoded by GJB6 (OMIM 604418) underlie this condition. Keratosis, ichthyosis, deafness syndrome In this condition, a severe extensive and progressive erythrokera­ toderma is associated with sensorineural hearing loss and vascular- izing keratitis. Fatal cases have been reported. Missense germline mutations in the genes encoding connexin 26 (GJB2; OMIM 121011) and 30 (GJB6; OMIM 604418) have been found. Ectodermal dysplasia/​skin fragility syndrome This very rare inherited disorder presents with erythema at birth and skin blistering resulting from fragility, and is associated with nail dystrophy, palmoplantar keratoderma, and hair loss. It was initially confused with epidermolysis bullosa. It was found to be histologically associated with increased intercellular spaces and desmosomal ab- normalities, which led to the discovery of plakophilin 1 mutations (PKP1; OMIM 601975) in sporadic cases.

23.3  Inherited skin disease 5611 Hypohidrotic ectodermal dysplasia This X-​linked recessively inherited disease is characterized by a loss of sweat glands, causing absent or reduced sweating (hypohidrosis), and total or partial loss of teeth. Patients may be very uncomfortable on exertion and are heat intolerant. The teeth are characteristically conical and the mouth dry. In severe forms the facial appearance is altered, with saddle nose, sunken cheeks, and sparse, dry, fine, short hair with absent eyebrows. The disease maps to Xq12-​13.1 and is caused by mutations in the gene for ectodysplasin anhidrotic protein (EDA; OMIM 300451). An autosomal recessive form results from mutations in the ectodysplasin receptor (EDAR; OMIM 604095). Recent advances and possible future developments Major advances in our understanding of the genetic basis of several rare diseases such as ichthyoses, keratodermas, and blistering dis- orders have occurred in the last decade. What has become clearer is that vast herterogeneity exists and that mutations in different pro- teins can cause similar clinical manifestations (e.g. Vohwinkel’s syn- drome can result from mutations in either connexin 26 or loricrin). The study of rare, monogenic disease has also improved our under- standing of the molecular basis of more common skin diseases. For example, loss-​of-​function mutations in ADAM17 and EGFR both result in severe skin inflammation as well as inflammatory bowel disease, highlighting the importance of these pathways in inflamma- tory responses, such findings also have important therapeutic impli- cations beyond the scope of skin disease. FURTHER READING Akiyama M (2006). Harlequin ichthyosis and other autosomal re- cessive congenital ichthyoses:  the underlying genetic defects and pathomechanisms. J Dermatol Sci, 42, 83–​9. Blaydon DC, et al. (2011). Inflammatory skin and bowel disease linked to ADAM17 deletion. N Eng J Med, 365, 1502–​8. Blaydon DC, et  al. (2013). Mutations in AQP5 encoding a water-​ channel protein cause autosomal dominant diffuse nonepidermolytic palmoplantar keratoderma. Am J Hum Genet, 93, 330–​5. Brooke MA, Nitoiu D, Kelsell DP (2012). Cell-​cell connectivity: desmo- somes and disease. J Pathol, 226, 158–​71. Fine JD, et al. (2014). Inherited epidermolysis bullosa: updated recom- mendations on diagnosis and classification J Am Acad Dermatol, 70, 1103–​26. Has C. (2017). The “Kelch” surprise: KLHL24, a new player in the pathogenesis of skin fragility. J Invest Dermatol, 137, 1211–2. Hu Z, et al. (2000). Mutations in ATP2C1, encoding a calcium pump, cause Hailey–​Hailey disease. Nat Genet, 24, 61–​5. Kere J, et al. (1996). X-​linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nat Genet, 13, 409–​16. Knöbel M, O’Toole EA, Smith FJ (2015). Keratins and skin disease. Cell Tissue Res, 360, 583–​9. Laird DW (2006). Life cycle of connexins in health and disease. Biochem J, 394, 527–​43. Lefevre C, et al. (2003). Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2. Hum Mol Genet, 12, 2369–​78. Lefevre C, et al. (2004). Mutations in ichthyin a new gene on chromo- some 5q33 in a new form of autosomal recessive congenital ichthy- osis. Hum Mol Genet, 13, 2473–​82. Maruthappu T, Scott CA, Kelsell DP (2014). Discovery in genetic skin disease: the impact of high throughput genetic technologies. Genes, 5, 615–​34. McGrath JA, Mellerio JE (2006). Epidermolysis bullosa. Br J Hosp Med (Lonod), 67, 188–​91. Mikkola ML (2007). p63 in skin appendage development. Cell Cycle, 6, 285–​90. Oji V, Traupe H (2006). Ichthyoses:  differential diagnosis and mo- lecular genetics. Eur J Dermatol, 16, 349–​59. Oji V, et al. (2006). Bathing suit ichthyosis is caused by transglutaminase-​ 1 deficiency: evidence for a temperature-​sensitive phenotype. Hum Mol Genet, 15, 3083–​97. Rajpopat S, et al. (2011). Harlequin ichthyosis: a review of clinical and molecular findings in 45 patients. Arch Dermatol, 147, 681–​6. Sakuntabhai A, et al. (1999). Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease. Nat Genet, 21, 271–​7. Comment in: Nat Genet, 21, 252–​3. Smith FJ, et  al. (2006). Loss-​of-​function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet, 38, 337–​42. Takeichi et al. (2017). Biallelic Mutations in KDSR Disrupt Ceramide Synthesis and Result in a Spectrum of Keratinization Disorders Associated with Thrombocytopenia. J Invest Dermatol, 137, 2344–53. Toomes C, et al. (1999). Loss-​of-​function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nat Genet, 23, 421–​4. Uitto J, Richard G (2004). Progress in epidermolysis bullosa: genetic classification and clinical implications. Am J Med Genet C Semin Med Genet, 131C, 61–​74. Webber BR, Tolar J (2015). From marrow to matrix: novel gene and cell therapies for epidermolysis bullosa. Mol Ther, 23, 987–​92.

23.5 Papulosquamous disease 5621 Christopher E.M.

23.5 Papulosquamous disease 5621 Christopher E.M. Griffiths

ESSENTIALS Papulosquamous diseases are characterized by well-​demarcated areas of papules and scale, typically on an erythematous back- ground. The differential diagnosis includes psoriasis, lichen planus, mycosis fungoides, discoid lupus erythematosus, eczema/​dermatitis, drug eruptions, tinea, pityriasis versicolor, secondary syphilis, and pityriasis rosea. The presence of significant pruritus is a useful marker to help with the differential diagnosis:  lichen planus and discoid eczema are typically pruritic, whereas others, such as psoriasis, are less so. The distribution is also key to diagnosis, with psoriasis often showing characteristic symmetrical involvement of the extensor surfaces, scalp, and nails. Histology can be essential to reach a diagnosis and plan an appropriate approach to management. The most common form of psoriasis is chronic plaque psoriasis, which often first affects the scalp. The nails are affected in about 50% of cases. There is no cure. Topical corticosteroids and vitamin D3 analogues (e.g. calcipotriol) are the most commonly used treatment worldwide. Phototherapy and photochemotherapy can be effective. Systemic treatments, including biological therapies, are only required in the most refractory cases. Lichen planus is characterized by purple (violaceous) flat-​topped polygonal papules that vary in size, most commonly on the flexor aspects of the wrists, the lower back, and the ankles. About 50% of patients have involvement of the mucous membranes. The skin dis- ease is usually self-​limiting. Psoriasis Psoriasis is one of the most common and easily identifiable inflam- matory skin diseases. In Western Europe its prevalence is estimated at 2%, but is higher in parts of Scandinavia (e.g. the Faroe Islands, where it reaches 5%). Worldwide, the disease is rare in Inuit, Native American, Japanese, and Afro-​Caribbean people, and has been estimated to affect just 0.3% of the general population in China. There is no evidence that the incidence of the disease is chan- ging, by contrast with the year-​on-​year increase in atopic derma- titis. Overall, the sex incidence is equal, the mean age of onset is 20 years and in 75% of cases the disease begins before the age of 40 years. Psoriasis starts earlier in females than males, indicating hormonal influences. Late-​onset disease (type II), first presenting after the age of 40 years, reaches a peak of onset between the ages of 55 and 65 years. There appears to be no association with either social class or diet. Early-​onset, type I psoriasis is familial; one-​third of patients have a first-​degree relative with the disease. It is apparent that this form of psoriasis is genetically predetermined and polygenic. At least 47 psoriasis susceptibility loci have been identified worldwide. The most robust association is with the MHC class I allele HLA-​C06:02, which contributes up to 50% of the risk in patients with psoriasis. No gene or gene product has thus far been definitively associated with psoriasis. Type II psoriasis is not associated with HLA-​C06:02, and may be a separate disease. Twin studies underscore the importance of an interaction be- tween environment and genotype for the expression of psoriasis, and concordance is 72% in monozygotes. Environmental triggers in gen- etically susceptible individuals include: β-​haemolytic streptococcal tonsillitis/​pharyngitis; physical and psychological stress; HIV infec- tion; drugs including β-​blockers, non​steroidal anti-​inflammatories, lithium, antimalarials; and alcohol. Clinical features The most common form of psoriasis, chronic plaque psoriasis, or psoriasis vulgaris, accounts for 90% of cases. The characteristic fea- tures are well-​circumscribed red plaques covered with silvery-​white scales. These occur most commonly on the extensor aspects of the knees and elbows, the lower back, and scalp (Figs. 23.5.1 and 23.5.2), although any skin surface may be affected. Plaques are frequently strikingly symmetrical, varying in diameter from less than 1 cm to more than 10 cm. Individual plaques are dynamic, such that in ac- tive disease a plaque may clear from the centre to leave an annular or gyrate configuration that to the uninitiated could be misdiagnosed as tinea corporis. Various phenotypes of psoriasis exist: Guttate psoriasis Named from the Latin guttata, meaning a droplet. This form clas- sically occurs two to three weeks after streptococcal pharyngitis or tonsillitis, and is the most common presentation in childhood (Fig. 23.5.3). Onset is acute, with a predominantly centripetal 23.5 Papulosquamous disease Christopher E.M. Griffiths

section 23  Disorders of the skin 5622 distribution of small (<1 cm diameter) papules. This form of psor- iasis is frequently self-​limiting. Erythroderma Total skin involvement by psoriasis is known as erythroderma, al- though this term is also used for any inflammatory skin disease affecting more than 90% of the skin’s surface area. Other diseases producing erythroderma include atopic dermatitis, lichen planus, drug eruptions, and cutaneous T-​cell lymphoma. Erythroderma, particularly in older people, can lead to fluid loss, hypocalcaemia, impaired thermoregulation (both hypo-​ and hyperthermia), and high-​output cardiac failure. Generalized pustular psoriasis Generalized pustular psoriasis (GPP), also known as Von Zumbusch disease, is an acute onset of painful red plaques studded with small sterile pustules. This form of psoriasis is usually precipitated by in- fection or acute withdrawal of either systemic glucocorticosteroids or, on occasion, high-​potency topical corticosteroids, leading to a re- bound pustular flare. The patient is systemically unwell, with pyrexia and influenza-​like symptoms. Recent evidence indicates that gener- alized pustular psoriasis is more akin to the autoinflammatory dis- eases and should more accurately be termed generalized pustulosis, rather than as a variant of chronic plaque disease. It has been linked to a genetically determined deficiency in interleukin-​36 receptor antagonist. Flexural psoriasis Flexural psoriasis (psoriasis inversa) pertains to a form that involves the groins, axillae, and inframammary regions. Psoriasis at these sites loses many of the characteristic clinical features, in that it is shiny, non​scaly, and bright red, but retains the characteristic clear demarcation between involved and uninvolved skin. Sebopsoriasis This form of psoriasis occurs in the seborrhoeic sites of the nasolabial folds, eyebrows, scalp, post-​auricular region, and Fig. 23.5.1  Plaques of psoriasis. Fig. 23.5.2  Widespread chronic plaque psoriasis. Fig. 23.5.3  Guttate psoriasis.

23.5  Papulosquamous disease 5623 presternum. At times it may be difficult to distinguish from seborrhoeic dermatitis. Scalp The scalp is often the first and sometimes the only site to be affected by psoriasis. Paradoxically, it may be the most difficult form of psoriasis to treat. The lesions vary from typical plaques to involve- ment of the entire scalp, with encroachment of scales along the hair shafts, a process known as tinea amiantacea (Fig. 23.5.4). Rarely do the lesions extend beyond the hairline. Alopecia may at times be a consequence. Koebner phenomenon The appearance of psoriasis at sites of recent trauma or pressure to the skin, such as under a tight waistband, is known as the iso- morphic or Koebner phenomenon. Although not unique to psor- iasis (it occurs also in lichen planus, viral warts, sarcoid, and vitiligo) it is a clinical marker of active, progressive disease. Nails Approximately 50% of patients with psoriasis have characteristic clinical involvement of any one or up to all the finger and toe nails. The involvement of the skin of the fingers by psoriasis, and the pres- ence of psoriatic arthritis, predispose to nail disease. The clinical fea- tures range from thimble-​like pitting of the nail plate, to onycholysis (separation of the nail from the nail bed), oil spots (orange discol- ouration of the nail bed), and disabling nail dystrophy (Fig. 23.5.5). Patients are frequently concerned about nail disease, and may re- quest treatment for this aspect of psoriasis alone. Co-​morbid diseases Chronic plaque psoriasis is associated with several co-​morbid con- ditions, which include: Inflammatory bowel disease Ten per cent (10%) of patients with inflammatory bowel disease, particularly Crohn’s disease, have concomitant psoriasis. Palmoplantar pustulosis Now believed to be a condition separate from psoriasis, palmoplantar pustulosis has been reclassified as a co-​morbid condition. Yellow sterile painful pustules occur on the palms and soles, fading to brown scaled lesions. Up to 25% of patients have coexistent chronic plaque psoriasis. This is a disease of middle-​aged women (female:male ratio 9:1), and more than 95% are current or previous smokers. There is an association with thyroid disease. There is no association with HLA-​C*06:02. Psoriatic arthritis This seronegative inflammatory arthritis occurs in more than 25% of patients with psoriasis. Most cases present either concomitantly with or after the first signs of skin disease, but on occasion (<10%) the arthritis predates psoriasis. Five clinical phenotypes of psoriatic arthritis exist: asymmetrical distal interphalangeal arthritis (most commonly and classically); oligoarthritis; polyarthritis; spondyl- itis; and arthritis mutilans (Fig. 23.5.6). A characteristic, perhaps pathognomonic, radiological feature is the presence of enthesitis—​ inflammation of a tendon sheath, particularly the Achilles. The immunogenetics of psoriatic arthritis are different from those of psoriasis, implying that the underlying pathogenic mechanisms are separate. Metabolic syndrome Emerging evidence suggests that patients with psoriasis have an increased incidence of the metabolic syndrome, particularly the components of diabetes mellitus, central obesity, hypertension, Fig. 23.5.4  Scalp involvement by psoriasis, showing tinea amiantacea. Fig. 23.5.5  Psoriatic nail dystrophy.

section 23  Disorders of the skin 5624 hyperlipidaemia, and coronary artery disease. It is currently un- known whether these signs are a consequence of psoriasis per se or of chronic inflammation, as is the case with arthritis. Indeed weight gain can be a precursor of the development of psoriasis and the pres- ence of psoriatic arthritis significantly increases the risk of cardio- vascular disease. Psychosocial aspects Psoriasis is associated with significant impairment of quality of life. Studies have shown that this is equivalent to or worse than other chronic diseases, including chronic obstructive airways disease, dia- betes mellitus, and ischaemic heart disease. There is a significant association with clinical anxiety, depression, suicidal ideation, and stigmatization. Worry about the chronicity of psoriasis may produce resistance to therapy. Histology The classical histology of psoriasis comprises epidermal keratino- cyte hyperproliferation and thickening of the epidermis (acanthosis) accompanied by loss of markers of differentiation (e.g. keratins 1 and 10), loss of the granular cell layer, and parakeratosis of the stratum corneum. The epidermis also contains microabscesses (of Munro) and collections of neutrophils (micropustules of Kogoj (Fig. 23.5.7)). There is, at times, a significant inflammatory infiltrate com- prising predominantly T lymphocytes, with localization of CD8 + T cells in the epidermis and CD4 + T cells in the dermis. Dilated blood vessels are prominent in the dermis. Pathogenesis For many years it was believed that psoriasis was a disease primarily of keratinocytes, and that the inflammatory infiltrate was a sec- ondary phenomenon. Current understanding of psoriasis is that it is an immune-​mediated inflammatory disease. Components of the innate and adaptive immune responses play important roles in pathogenesis. CD8 + T cells within plaques are clonal, and most T cells are positive for cutaneous lymphocyte-​ associated antigen. It is believed that in the case of streptococcal pharyngitis there is stimulation and subsequent expansion of T cells, which cross-​react with components of keratin in the epi- dermis. The central importance of T cells to the psoriatic pro- cess has been confirmed by the efficacy of T-​cell targeted drugs including ciclosporin, an interleukin 2 (IL-​2) diphtheria fusion toxin that is cytolytic for activated T cells, and biological therapies. Natural killer and natural killer T cells also participate in the psori- atic process. Plaques of psoriasis contain a predominance of Th1 cytokines, including interferon-​γ, IL-​2, and IL-​23. By contrast, atopic derma- titis is primarily a Th2-​cytokine-​driven disease. This is confirmed by observations that atopic dermatitis is relatively rare in patients with psoriasis. Cytokines and chemokines of the innate immune response, including tumour necrosis factor-​α (TNFα), are also Fig. 23.5.6  Psoriasis with psoriatic arthritis. Fig. 23.5.7  Histological section of psoriasis showing epidermal acanthosis, elongation of rete ridges, and inflammation.

23.5  Papulosquamous disease 5625 present in plaques of psoriasis, and the demonstrated efficacy of biological agents targeted to TNFα, IL-​17 A, and IL-​23 has under- scored the key role of these cytokines in the pathogenesis of psoriasis. Indeed, psoriasis is now considered a prototypic IL-​17 disease. Angiogenesis is an underinvestigated area in psoriasis, but there is compelling evidence for significant vascular proliferation and angio- genesis in the dermis, and this is associated with the overexpression of vascular endothelial growth factor produced by epidermal keratinocytes. Research on the pathogenesis of psoriasis is hindered by the ab- sence of an animal model for the disease: psoriasis occurs in no other animal but humans. The most reliable model for psoriasis is xenotransplantation, which involves transplantation of biopsies of uninvolved, clinically symptomless skin from patients with psoriasis onto the flanks of immunodeficient mice. Mice treated topically with imiquimod can develop an inflammatory dermatosis virtually indistinguishable from psoriasis. Management General principles The management of psoriasis, as with any other chronic skin dis- ease, involves a biopsychosocial approach and an understanding of the individual patient’s expectations of therapy. At present there is no cure. In the United Kingdom, 80% of patients with psoriasis can, with the use of topical agents, be treated adequately in pri- mary care. Patients should be educated about psoriasis (e.g. it is not caused by diet, and is neither contagious nor neoplastic). An understanding of how psoriasis interferes with a patient’s daily ac- tivities, and the psychosocial disability associated with anxiety and depression, are key aspects of the consultation. Indeed, cognitive behavioural therapy is often a useful adjunctive management tool. Lifestyle management such as weight loss, smoking cessation, re- duction in alcohol intake, and exercise have all been shown to con- tribute to improved control of the disease. Environmental triggers of psoriasis should be ascertained, such as underlying infection, including streptococcal pharyngitis/​tonsillitis, and drug triggers. Up to 20% of patients with psoriasis may enter spontaneous remis- sion for varying periods of time, but in most cases it is a persistent and lifelong disease. In all cases, the liberal use of emollients is important. Topical ther- apies are aimed at directly reducing the epidermal keratinocyte pro- liferation or the inflammatory mediators that drive the epidermal changes. Topical therapies Vitamin D3 analogues A major advance in the topical treatment of psoriasis in the past 30 years has been the introduction of vitamin D3 analogues. These include calcipotriol, calcitriol, and tacalcitol. All vitamin D3 ana- logues directly inhibit keratinocyte proliferation, but also switch intraplaque cytokines from a Th1 to a Th2 profile. Calcipotriol and calcitriol are applied twice daily, whereas tacalcitol is used once daily. Local side effects include the irritation of uninvolved skin, and if used over an extensive body surface area, a risk of hypercalcaemia. The combination of calcipotriol with betamethasone valerate in a once-​daily preparation is the most commonly prescribed, active topical therapy in the United Kingdom. This enhances efficacy and reduces irritation. Topical corticosteroids Worldwide, topical corticosteroids are still the predominant therapy for localized chronic plaque psoriasis. If used appropriately, they can be a valuable component of the armamentarium. Medium-​ and high-​potency topical corticosteroids in ointment formulation are the most effective, but should be used for no more than two weeks on a continuous basis, and not on the face or in the flexures. Higher potency steroids carry an increased risk of rebound flare on with- drawal. To minimize complications various innovative regimens are employed, such as weekends-​only usage, combination with non-​ steroidal drugs such as calcipotriol, and tapering to less potent top- ical steroids. Calcineurin inhibitors The calcineurin inhibitor tacrolimus, although approved only for the treatment of atopic dermatitis, has an advantage over topical cor- ticosteroids in that it does not produce skin atrophy. It is effective for the treatment of facial and flexural psoriasis. Dithranol Dithranol (formerly anthralin) has been one of the main topical treatments for psoriasis for many years. The mechanism of action is via an inhibitory effect on mitochondria. Dithranol is applied once daily, usually in a short-​contact (30–​60 min) outpatient regimen. Significant skin irritation, and staining of involved and uninvolved skin, clothing, and furniture nowadays limits dithranol to inpatient and day-​treatment centre usage. The Ingram regimen is the com- bination of dithranol with ultraviolet B (UVB) phototherapy. With the advent of vitamin D3 analogues the use of dithranol has declined significantly over the past 25 years. Coal tar Coal tar has been a standby of treatment for psoriasis for over 100  years; the classical psoriasis treatment, the Goeckerman regimen, involves a combination of crude coal tar with UVB photo- therapy. Dissatisfaction with the cosmetic aspects of crude coal tar, in addition to skin irritation and folliculitis, has considerably re- duced its use as a routine outpatient therapy, and it is mostly limited to day-​treatment centre or inpatient management of psoriasis. Phototherapy Broadband and narrowband UVB Natural sunlight has been used for centuries for the treatment of psoriasis. The Dead Sea, because of its salinity and the abundant UV radiation, is a popular destination for psoriasis patients. The most effective wavelength of UV radiation for psoriasis is in the narrow- band (311–​313 nm) range. Narrowband UVB phototherapy is an effective treatment for psoriasis, and is superior to traditional broadband UVB photo- therapy. UVB phototherapy is performed as an outpatient procedure following determination of the minimal erythema dose, based on an individual patient’s skin phototype. Twenty-​five year follow-​up studies have not demonstrated significant increases in either mel- anoma or non​melanoma skin cancers in patients receiving narrow- band UVB phototherapy.

section 23  Disorders of the skin 5626 Photochemotherapy Psoralen UVA (PUVA) photochemotherapy is a combination of an ingested psoralen photosensitizer (8-​methoxypsoralen or 5-​ methoxypsoralen), followed by exposure to UVA. This is one of the most effective treatments available for psoriasis. Apart from imme- diate side effects, which include nausea, headache, sunburn, and photosensitivity, there is a significant risk of premature skin ageing (photodamage) and non​melanoma skin cancer, particularly in those who have received a cumulative dose of 1000 mJ/​m2 or 250 treat- ments. Side effects are reduced to some extent by bath PUVA, which involves immersion in a dilute aqueous solution of psoralen for 30 min before UVA exposure. PUVA patients should wear spectacles with plastic lenses, and avoid natural sun exposure on the day of treatment. Because of the complexities of treatment and significant skin cancer risk, the use of PUVA in psoriasis treatment has declined significantly in recent years. Systemic therapies Only a minority of psoriasis patients require therapy with systemic agents; most can be managed with topical therapies. However, some patients have disease that is too extensive, unstable, inflammatory, or recalcitrant for topical therapies, and thus phototherapy or sys- temic therapy is indicated. Methotrexate Methotrexate is a folic acid antagonist that inhibits DNA synthesis and thus cell replication; it also has T-​cell suppressive activities. Methotrexate is the gold standard systemic therapy. Very few trials of the efficacy of methotrexate have been performed. Approximately 40% of patients achieve at least a 75% improvement in clinical se- verity as measured by the psoriasis area severity index (PASI). Methotrexate is prescribed orally, and increasingly subcutaneously, in a once-​weekly dose following a 2.5 mg test dose. Doses range from 7.5 to 25 mg per week, dependent on clinical response. Folic acid 1–​5 mg daily is added to prevent stomatitis and anaemia, and to reduce gastrointestinal side effects. Psoriasis patients receiving methotrexate require careful monitoring; they appear to have an increased risk of hepatotoxicity compared with rheumatoid arthritis patients pre- scribed the drug. Traditionally, hepatotoxicity from methotrexate was assessed by liver biopsy; however, serum assay of the amino propeptide of collagen III has been shown to be a reliable measure of hepatic fi- brosis, thereby obviating the need for liver biopsy in most patients. The use of pharmacogenetics may optimize the use of methotrexate by identifying individuals susceptible to hepatotoxicity and bone marrow suppression, and those likely to achieve a clinical response. Retinoids Oral retinoids (vitamin A derivatives) have been used in the treat- ment of psoriasis for over 30 years. The original third-​generation retinoid used for psoriasis, etretinate, has been superseded by its natural metabolite acitretin. Monotherapy with acitretin is nor- mally commenced at a dose of 10–​25 mg daily. Systemic retinoids are particularly effective for the treatment of the erythrodermic and pustular variants of psoriasis. As they are not immunosuppressive, retinoids have a role in the treatment of those psoriasis patients who are HIV-​infected or have cancer, particularly non​melanoma skin cancer following PUVA. Caution must be exercised when considering acitretin in women of childbearing potential, because of significant teratogenicity. Women should avoid pregnancy for up to two years (United Kingdom) or three years (United States of America) after completing acitretin treatment. Adverse psychiatric events, such as mood swings, de- pression, and suicidal ideation, have been reported as possible idio- syncratic reactions to the related retinoid isotretinoin. Retinoid toxicities are similar to those occurring with hypervitaminosis A, and can include mucocutaneous side effects including sticky skin, alopecia, and cheilitis. Osteoporosis, hyperlipidaemia, and pseudotumour cerebri may occur. Combining acitretin with PUVA (Re-​PUVA) significantly enhances the response to PUVA but is nowadays rarely used. Ciclosporin Ciclosporin is a highly effective, short-​term therapy for moderate to severe psoriasis. It inhibits the activation of T cells as a con- sequence of blockade of cytoplasmic calcineurin phosphatase. Ciclosporin therapy is used for psoriasis at doses between 2.5 and 5 mg/​kg per day, usually for no more than 12 weeks. Intermittent short-​course therapies are recommended because of the association of long-​term continuous ciclosporin therapy with nephrotoxicity and hypertension. Unlike methotrexate or acitretin, ciclosporin is not teratogenic, thus it is the only systemic therapy that can be used in pregnancy. In those patients who have received significant PUVA, there is an increased risk of non​melanoma skin cancer. Patients may have other side effects, including hypertrichosis, gum hyperplasia, and paraes- thesia. Long-​term continuous therapy with ciclosporin is used on occasion at a daily dosage of 3–​4 mg/​kg, but regular monitoring of glomerular filtration rate is required. Ciclosporin has been used in combination with acitretin, low-​dose methotrexate, and the newer biological agents. Fumaric acid esters A commercially available mixture of four fumaric acid esters (fu- marates) has been used to treat psoriasis in Europe for at least 50 years. They are hindered by several subjective side effects, mainly gastrointestinal in nature, including abdominal cramps, diarrhoea, nausea, and flushing. Lymphopenia (disconnected from efficacy) has recently become a concern because of the risk of progressive multifocal leucoencephalopathy. Other systemic therapies Less frequently used second-​tier systemic agents include hydroxycarbamide, mycophenolate mofetil, sulphasalazine, and leflunomide. Few randomized controlled trials are available to con- firm their effectiveness. Biological agents A major advance in the management of patients with moderate to severe psoriasis has been the introduction of biological agents. These are defined as recombinant molecules designed from the genetic sequence of existing living organisms, and are often similar or iden- tical to proteins produced by humans. They include fusion proteins, recombinant proteins, and monoclonal antibodies, and have been in common use for diseases such as rheumatoid arthritis and Crohn’s

23.5  Papulosquamous disease 5627 disease. There are several biological agents licensed currently for the management of moderate-​severe psoriasis; these block cytokines TNFα, IL-​12/​IL-​23, and IL-​17 A. Cytokine-​blocking agents Etanercept Etanercept is a human recombinant p75 TNF receptor/​Fc fusion protein that binds TNF and is self-​administered subcutaneously at doses from 25 to 50 mg twice weekly. At the lower dose, 34% of pa- tients achieve PASI 75 at 12 weeks, and at the higher dose 49% of pa- tients achieve this level of improvement. In addition to its beneficial effects on psoriasis, etanercept, in common with other TNF antag- onists, is an effective treatment for psoriatic arthritis. Infliximab Infliximab, a chimeric monoclonal antibody, binds to and neutral- izes the activity of TNFα. It is given as a 5 mg/​kg intravenous in- fusion, with three loading infusions at 0, 2, and 6 weeks, and then subsequently at 8-​week intervals. Infliximab is a highly effective, rapid-​acting biological therapy in that more than 80% of patients achieve PASI 75 by 10 weeks. It can be used long term, and at 1 year 61% of patients maintain PASI 75 with a regular 8-​week infusion. Infliximab is also effective for psoriatic arthritis. Adalimumab Adalimumab, a fully human anti-​TNFα monoclonal antibody, is self-​administered subcutaneously with an initial loading dose of 80 mg followed by 40 mg at week 1 and subsequently on alternate weeks. Twenty-​four weeks of treatment with adalimumab signifi- cantly improves psoriasis, 54% of patients achieving PASI 75; psori- atic arthritis is improved also. TNFa antagonist monitoring Because of the role of TNFα in granuloma formation, infections such as tuberculosis, histoplasmosis, and deep fungal infections require careful monitoring with appropriate tuberculosis screening before starting therapy. Other reported serious adverse effects with TNF antagonists include demyelination, exacerbation of pre-​existing cardiac failure, development of lupus, enhanced risk of soft-​tissue infections, and the potential development of non​melanoma skin cancer in patients who have received significant PUVA. Prospective pharmacovigilance under the auspices of national registries is of importance for ascertaining the true risk of biological therapies. Ustekinumab Ustekinumab, a fully human monoclonal antibody directed to the shared p40 subunit of IL-​12 and IL-​23 is self-​administered subcuta- neously at 0 and 4 weeks and 12 weekly thereafter at a dose of 45 mg or 90 mg. Twelve weeks of treatment significantly improves psor- iasis, 70% of patients achieving PAS1 75, response is maintained with continuous therapy to five years. Secukinumab Secukinumab is a fully human anti-​IL17A self-​administered sub- cutaneously at a dose of 300 mg weekly for the initial four weeks followed by four-​weekly administration thereafter. Results to date with this biological therapy and the newly licensed ixekizumab anti-​IL17A are impressive with up to 70% of subjects achieving PASI 90 and close to 40% of patients achieving complete clearance (PASI 100). Biosimilars As the patents on the original ant-​TNF biologic therapies expire, a new generation of biosimilar drugs has started to enter the market. These are the biosimilars, so-​called because they are similar to pre- viously authorized biotherapeutics in quality, efficacy, and safety. Furthermore, they are cheaper to produce. Oral small-​molecules These target intracellular signalling pathways. Currently only one such agent is approved for use in the United Kingdom, namely apremilast, a phosphodiesterase E4 inhibitor which achieves a PASI 75 in approximately 40% of patients with psoriasis. It is dosed at 30 mg twice daily with minimal monitoring required. Apremilast is also effective for psoriatic arthritis. Lichen planus Lichen planus is a relatively common benign skin disease, estimated to account for 1.2% of new patients presenting to dermatology de- partments. It is slightly more common in women and, although occurring at all ages, most commonly presents between the ages of 40 and 50 years. The familial incidence has been quoted as 11%, implying genetic susceptibility. The underlying aetiology is un- known; however, several drugs (gold, methyldopa) can produce a lichenoid reaction that is at times almost indistinguishable from li- chen planus. In parts of Europe, including Italy and Spain, hepatitis C infection is associated with lichen planus, but this has not been noted in patients from northern Europe, the United Kingdom, and the United States of America. There is no consistent MHC associ- ation, although HLA A3 and HLA A5 have been linked. The clinical features are highly characteristic in that lichen planus is characterized by purple (violaceous) flat-​topped polygonal pap- ules that vary in size (Fig. 23.5.8). The surface of the papules has a fine tracery of white lines known as Wickham’s striae. Lichen planus can occur at sites of excoriation or scars: the Koebner phe- nomenon (Fig. 23.5.9). Annular lesions are seen, particularly on the penis. Although lichen planus can affect any skin surface, it most Fig. 23.5.8  Typical flat-​topped polygonal papules of lichen planus.

section 23  Disorders of the skin 5628 commonly occurs on the flexor aspects of the wrists, the lower back, and the ankles. Hypertrophic lesions occur most commonly on the anterior shins, and involvement of the hair follicles of the scalp (li- chen planopilaris) can produce significant scarring alopecia. Resolution of lesions can lead to significant post-​inflammatory hyperpigmentation, particularly in black and Asian skin. Approximately 50% of patients have involvement of mucous membranes, most commonly the buccal mucosa, where the ap- pearance is of a lacework of white streaks. Oral involvement can be significant, with painful erosions. In the absence of cutaneous manifestations, oral lichen planus may present solely to dentists. The skin lesions are classically highly pruritic, but can be variable in pattern and morphology, including hypertrophic, atrophic, fol- licular, annular, and linear forms. Involvement of the nails occurs in approximately 10% of cases, and when present can be pathogno- monic. The most common changes are longitudinal ridges caused by thinning of the nail plate, but adhesion between the dorsal nailfold, causing destruction of the lateral aspect of the nail (pterygium), is characteristic (Fig. 23.5.10). Chronic oral ulceration as a conse- quence of lichen planus can lead to the development of squamous cell carcinoma. Lichen planus and lichenoid drug eruptions are characterized histologically by thickening of the epidermis (acanthosis) and hypokeratosis, in which the basal layer of the epidermis is dam- aged, producing colloid bodies that may be clumped. Rete ridges of the epidermis are irregular and flattened, giving a saw-​tooth appearance, and a band-​like infiltrate of lymphocytes hugging the dermal–​epidermal junction is a characteristic feature. Hyperpigmentation is due to pigmentary incontinence. At times, complete separation of the epidermis from the dermis may result in blister formation. Treatment The cutaneous disease is usually self-​limiting, with 85% of cases clearing spontaneously within two years. Oral lichen planus and scarring alopecia are difficult to treat, but local skin lesions can be treated with high-​potency topical corticosteroids (e.g. clobetasol propionate 0.5%). Sometimes systemic corticoster- oids or other immunosuppressant agents, such as ciclosporin, are required. Phototherapy, either PUVA or narrowband UVB, and a variety of immunosuppressant therapies including methotrexate, azathioprine, and thalidomide, have also been used. Oral mucous membrane disease can be treated with topical corticosteroids such as triamcinolone in a carmellose and gelatine paste that adheres to mucous surfaces, clobetasol propionate ointment, or fluticasone propionate asthma inhaler spray directed to the lesions. Ciclosporin oral rinse has also been used effectively for the treatment of oral li- chen planus. Other papulosquamous diseases Numerous other disorders can present with a papulosquamous phenotype, including mycosis fungoides (see Chapter  23.14), dis- coid lupus erythematosus (see Chapter  23.7), eczema/​derma- titis (see Chapter  23.6), drug eruptions (see Chapter  23.16), tinea (Chapter 23.10), pityriasis versicolor (Chapter 23.10), secondary syph- ilis (Chapter 8.6.37), and pityriasis rosea. Pityriasis rosea Most cases of pityriasis rosea occur between the ages 10 and 35 years, and onset is often seasonal. In many cases it is likely to be viral in aetiology, and various herpes viruses have been impli- cated. In addition, a prolonged pityriasis rosea-​like rash can occur in association with various drugs (e.g. angiotensin-​converting en- zyme inhibitors and hydroxychloroquine). Histology may show epidermal hyperplasia, spongiosis, and focal parakeratosis, with a superficial dermal infiltrate of lymphocytes, histiocytes, and occa- sional eosinophils. Most patients with pityriasis rosea present initially with one plaque (herald patch), and then after several days many smaller plaques appear on the trunk, neck, and extremities, and sometimes other sites. In Africans, the lesions tend to be more papular. The plaques themselves are pink, with a fine peripheral scale and a well-​ defined and sometimes elevated margin. The scaling usually forms a ring (collarette) at the outer edge of the lesion, with its free edge inwards. Lesions are arranged with the long axes running in parallel Fig. 23.5.9  Lichen planus with linear Koebner response. Fig. 23.5.10  Nail dystrophy from lichen planus, with pterygium.

23.5  Papulosquamous disease 5629 to the ribs, resulting in a characteristic ‘Christmas tree’ distribution pattern. Lesions typically evolve over a few weeks, with subsequent spontaneous resolution. As secondary syphilis can mimic pityriasis rosea so closely, testing for syphilis is advised. The classical disease is self-​limiting, and no treatment is usually required. FURTHER READING Burden AD, Kirby B (2016). Psoriasis and related disorders. In: Griffiths CEM, et al. (eds) Rook’s textbook of dermatology, 9th edition, Ch. 35. Wiley-​Blackwell, Oxford. Eisen D (2003). The clinical manifestations and treatment of oral li- chen planus. Dermatol Clin, 21, 79–​89. Gelfand JM, et al. (2006). Risk of myocardial infarction in patients with psoriasis. JAMA, 296, 1735–​41. Griffiths CEM, Barker JNWN (2007). Pathogenesis and clinical fea- tures of psoriasis. Lancet, 370, 263–​71. Helliwell PS, Taylor WJ (2005). Classification and diagnostic criteria for psoriatic arthritis. Ann Rheum Dis, 64 Suppl 2, ii3–​8. Krueger JG, Bowcock A (2005). Psoriasis pathophysiology: current concepts of pathogenesis. Ann Rheum Dis, 64 Suppl 2, ii30–​6. Menter A, Griffiths CEM (2007). Current and future management of psoriasis. Lancet, 370, 272–​84. Piguet V, et  al. (2016). Lichen planus and lichenoid disorders. In: Griffiths CEM, et al. (eds) Rook’s textbook of dermatology, 9th edition, Ch. 37. Wiley-​Blackwell, Oxford. Tsoi LC, et al. (2015) Enhanced meta-​analysis and replication studies identify 5 new psoriasis susceptibility loci. Nature Commun, 6, 2001. Valdimarsson H, et  al. (1995). Psoriasis:  a T-​cell-​mediated auto- immune disease induced by streptococcal superantigens? Immunol Today, 16, 145–​9.

23.6 Dermatitis eczema 5630 Peter S. Friedmann, Mi

23.6 Dermatitis/ eczema 5630 Peter S. Friedmann, Michael J. Arden- Jones, and Roderick J. Hay

ESSENTIALS Eczema is a characteristic pattern of skin inflammation that has many subtypes, with some induced by external factors such as ir- ritants or skin sensitizers. Atopic eczema is due partly to a genetic susceptibility, which programmes altered immune responses and skin physiology, together with reactions to exogenous allergens and microbes, but several eczema patterns do not appear to have ex- ternal causes. The key points in the recognition of eczema are that the skin is red- dened, may be thickened as a result of the inflammatory infiltrate and oedema, and the affected areas have ill-​defined margins that break up into tiny red papules. Acute or severe eczema bubbles, blisters, and weeps. The distribution of the rash may be diagnostic, both of the type of eczema and the key causal factors. Management requires identification and avoidance of provoking factors. The inflammation is treated with topical steroids of different potencies, supplemented with moisturizers. Newer therapies include topical calcineurin antagonists, with a range of systemic therapies being used to control the most severe types of disease. Introduction The term eczema is used to describe a pattern of skin inflam- mation characterized clinically by ill-​defined areas of redness (erythema) made up of tiny individual papules (bumps). At the edges of eczema lesions the individual papules often become vis- ible, which accounts for the lack of sharp definition (Fig. 23.6.1). Eczemas are characteristically very itchy. Microscopically, ec- zematous inflammation shows infiltration of T lymphocytes in both the dermis and epidermis, and the generation of oedema in the dermis, but also particularly in the epidermis. The oedema separates the epidermal cells from each other like the air spaces in a sponge (called spongiosis), but the oedema may coalesce into blisters, giving the appearance of a bubbly surface; these may leak or rupture producing serous oozing and crusting. There are many different types of eczema, some with known causation and others remaining cryptic. Classification There is no completely accepted classification of eczema, but it can be helpful to group eczemas in relation to what is known of their aeti- ology: those with mainly exogenous causation, often called dermatitis rather than eczema, and those with no known external causes (en- dogenous eczemas) (Box 23.6.1). The exogenous eczemas are never- theless the consequence of interactions between external factors and host susceptibility, which may be largely genetically determined. Contact dermatitis/​eczema This form of dermatitis/​eczema is induced by external agents of dif- ferent physicochemical types:  substances with irritant properties that are not immunogens, those that induce T-​cell-​mediated allergic contact sensitivity, and ultraviolet light. Irritant contact dermatitis Aetiology/​pathogenesis Irritants are substances that inflict toxic damage on the epidermis. There are many types of irritant, but from a practical point of view they can be classified as surfactants (soaps/​detergents), solvents (petrol, paraffin, oils), caustics (acids, alkalis, chemicals such as phenol), and miscellaneous chemicals that include non​anoic acid and dithranol (used in the treatment of psoriasis). Irritants vary greatly in their potency and hence the level of exposure required to induce an inflammatory response in skin. Individuals also vary greatly in their intrinsic resistance or susceptibility to the effects of irritants. A single exposure to mild irritants such as soaps and de- tergents is often insufficient to cause a clinically apparent irritant ef- fect, which usually requires multiple exposures having a cumulative effect. The general effect of irritants is a perturbation of the epidermal microenvironment, which is detected as a danger signal. This re- sults in the activation of essential components of the innate immune response. Keratinocytes produce a variety of cytokines, including interleukin (IL)-​8, IL-​18, and tumour necrosis factor-​α; epidermal Langerhans’ cells become activated and up to 30% may migrate 23.6 Dermatitis/​eczema Peter S. Friedmann, Michael J. Arden-​Jones, and Roderick J. Hay

23.6  Dermatitis/eczema 5631 into the dermis; the dermal microvasculature expresses increased levels of the adhesion molecules ICAM1, E-​selectin (ELAM1), and VCAM1; and there is infiltration of lymphocytes and often neutro- phil leucocytes. Repeated exposure may augment the microscopic response until it becomes clinically apparent inflammation. Most of the changes resulting from cumulative irritant insult are indistin- guishable from those that follow the specific immunologically me- diated process of allergic contact dermatitis. Epidemiology Irritant dermatitis is a major occupational skin disease. A survey in Sweden indicated that of 16 600 people who responded to a ques- tionnaire about hand eczema, 11% had experienced eczema in the last year. Thirty-​five per cent (35%) of cases were irritant hand ec- zema, 19% allergic contact dermatitis, and 22% atopic hand eczema. In northern Germany, a large study from 1990 to 1999 examined compensation claims for occupational skin disease. The annual incidence of occupational irritant dermatitis was 4.5 cases per 1000, compared with 4.1 cases per 10 000 of allergic contact dermatitis. Under most circumstances the hands are the body site most likely to come into contact with irritants. One notable exception is the napkin area of infants, which may be in prolonged contact with alkaline (ammoniacal) urine or faecal material, and can develop irritant napkin dermatitis as a result. The rash is erythematous with poorly defined margins, ac- companied by scaling or fissures, and if more severe or acute, by eczematous blisters. The dorsa of the hands are usually more se- verely affected than the palmar surfaces, which probably reflects the thicker stratum corneum permeability barrier of the palms (Fig. 23.6.2). Once an irritant dermatitis has been initiated it seems to require very little and only occasional exposure to irritants to maintain a chronic dermatitis. Many patients who try to protect themselves by wearing rubber gloves find that when the hands become sweaty inside the gloves, this actually irritates and aggra- vates the dermatitis. Those with a past or present history of atopic eczema are sig- nificantly more susceptible to developing irritant dermatitis from surfactants and solvents. This may reflect an impaired stratum cor- neum barrier and/​or summation/​synergism of the irritant effects and low-​level subclinical inflammation of atopic eczema. Treatment The most important principle is avoiding further contact with irri- tants. The medical treatment is as for other eczemas, as outlined in ‘Treatment of atopic eczema’later on in this chpter. Allergic contact dermatitis Aetiology Contact hypersensitivity is an acquired immune response in which T lymphocytes recognize and react to the causative molecules. Contact allergens are mostly small xenobiotic molecules, although under some circumstances proteins can act as contact sensitizers. Several factors are involved in determining whether an individual will develop contact sensitivity to a given molecule. These include the intrinsic immunogenicity of the chemical, the dose to which the individual is exposed, and the individual’s susceptibility to sensitization. Fig. 23.6.1  Poorly defined margins of eczema. Box 23.6.1  Classification of eczema Exogenous Contact dermatitis • Irritant • Allergic • Photoinduced Atopic eczema Seborrhoeic eczema/​dermatitis Photodermatitis Endogenous Asteatotic eczema; dyshidrotic eczema; varicose eczema Fig. 23.6.2  Dorsal hand involvement in dermatitis.

section 23  Disorders of the skin 5632 Sensitizing potency of chemicals Of the thousands of chemicals in the environment, some are clearly highly potent immunogens capable of sensitizing everyone, while others may be defined as moderate, weak, or even non​sensitizers. For small molecules to become recognizable by the T-​cell receptor, they have first to act as haptens, which become bound to protein carriers. The hapten–​carrier complex will be processed by den- dritic antigen-​presenting cells such as epidermal Langerhans’ cells. Processing involves loading haptenated peptides into the major histocompatibility molecules (mainly MHC class II, but in some in- stances also Class I) on the surface of the antigen-​presenting cell. The sensitizing potency of chemicals is generally proportional to their protein-​binding reactivity. Some compounds (haptens) are intrinsically protein reactive, others (prohaptens) are con- verted to protein-​reactive metabolites through the actions of phase I xenobiotic metabolizing enzymes such as the cytochrome P450 family. The overall phenotype of xenobiotic detoxification systems, including P450 and other antioxidant systems, may be an important contributor to an individual’s susceptibility to sensitization. They may either detoxify reactive compounds and prevent immunogen- icity, analogous to high acetylator status and resistance to drug al- lergy, or, possibly through the failure of normal detoxification, may generate protein-​reactive immunogenic intermediates. Lessons from experimental work The use of 2,4-​dinitrochlorobenzene (DNCB) as an experimental contact sensitizer in healthy human volunteers has revealed that the human immune system obeys very reproducible dose-​response relationships. Groups of individuals received different sensitizing doses of DNCB (62.5–​1000 µg) on a 3 cm diameter circle of forearm skin. In proportion to the log of the sensitizing dose, there was a classical sigmoid dose-​response curve for the proportion of indi- viduals showing clinical sensitization, as detected by positive elicit- ation challenges applied four weeks later, with 100% being sensitized by 500 µg or more. Furthermore, as the sensitizing dose increased, there was a log-​linear increase in the strength of the response to the elicitation challenge; in other words, as the sensitizing dose in- creases on a log scale, so proportionately more people are sensitized, and to a greater extent. For a chemical to induce allergic contact sensitization it must penetrate the stratum corneum. Most sensitizers are lipophilic and hence penetrate readily, but metals such as nickel, cobalt, and chromate are water soluble. Hence a major factor in augmenting sensitization by metals is mechanical penetration of the stratum cor- neum, as in body piercing. The induction of contact sensitization involves the activation of hapten-​specific T cells, which undergo clonal expansion resulting in the establishment of immunological memory. The next time the sensitizer is in contact with the skin it will be recognized by the memory T cells, which respond by releasing interferon-​γ and other proinflammatory cytokines. This recruits other T cells to the site in a non-​antigen-​specific fashion. The combination of cells and cyto- kines generates the oedema and swelling accompanied by itch that is characteristic of allergic contact dermatitis. Individual susceptibility Very little is known of how individual susceptibility is controlled. There are clearly individuals who develop contact sensitivity to environmental substances more easily than others. Thus individuals who developed contact sensitivity to three or more unrelated chem- icals could be sensitized experimentally by 2,4-​dinitrochlorobenzene to a much greater degree than individuals with no pre-​existing con- tact allergy. Individuals with only one contact sensitivity were inter- mediate in reactivity. These differences are not qualitative, but reflect the high-​responder end of the normal distribution of responsive- ness. The corollary of this is that there is a low-​responder end of the normal distribution—​individuals who appear resistant to the spon- taneous development of contact sensitivities, and who give the lowest responses to any given sensitizing dose of 2,4-​dinitrochlorobenzene. There do not appear to be any major human leukocyte antigen as- sociations with increased susceptibility to contact sensitization. As indicated here, one level at which susceptibility may be determined is that of intermediate metabolism, which can either detoxify or gen- erate reactive intermediates. A second level, which has been shown at least with regard to nickel sensitivity, is the fundamental control of immunological tolerance, mediated by regulatory T lymphocytes. Prevalence Allergic contact sensitization and dermatitis are common; about 10% of women are sensitive to nickel. The total prevalence of contact dermatitis among the population of many countries is estimated at between 6 and 11%. The incidence of occupational contact derma- titis has been estimated to be around 0.5–​1.9 cases per 1000 full-​time workers per year (Chapter 10.2.1). Clinical features of allergic contact dermatitis Allergic contact dermatitis can vary from a low-​grade minor nuisance—​the pierced earlobes that become mildly inflamed and itchy if the earrings are left in for too long—​to catastrophic and disabling acute blistering and weeping with severe oedema of the sites to which the sensitizer was applied. The key points in diagnosis are the recognition that the inflammatory process is eczematous in nature, and that the distribution on the body raises the suspicion that there is an exogenous source. Thus contact dermatitis from nickel in the metal studs and buttons of denim jeans has a character- istic distribution around the lower abdomen and hips (Fig. 23.6.3). However, in strongly sensitized individuals nickel in most metal ob- jects, such as money, keys, cutlery, and door handles, can transfer from the fingers to other places, resulting in ill-​defined eczematous Fig. 23.6.3  Allergic contact dermatitis to nickel.

23.6  Dermatitis/eczema 5633 areas on the face and abdomen. The relationship of these distant areas to contact sensitivity may be much less obvious. Common sensitizers in everyday products include metals; dyes (paraphenylenediamine and other azo dyes) used for ha ir and clothing; preservatives (often formaldehyde releasers, as well as methyl-​ or chloromethyl-​isothiazolinone) found in many personal products; rubber accelerators found in rubber gloves and glue/​ce- ment used in shoe manufacture; colophony, extracted from pine resin and used to facilitate adhesion, as in the rubbery adhesive of sticking plasters, but also in mascara and felt-​tipped pens; and fra- grances used in personal and domestic products. Confirmation of causality Contact allergens are applied to the skin of the back in patch tests. Patients are normally screened by an initial application of 40 substances (some individual, others as mixtures of a class) re- ferred to as the European standard battery. These compounds have been selected by the International Contact Dermatitis Research Group and the European Environmental and Contact Dermatitis Research Group because they represent the groups of the most fre- quent sensitizers. The patch tests are applied on aluminium disc chambers held in place with hypoallergenic adhesive tape for 48 h, after which the chambers are removed and the skin assessed. Each compound or mixture is used at the highest concentration that does not normally induce a non​specific irritant reaction. Many centres read the patch tests a second time at 72 or 96 h after appli- cation; this is said to reduce the number of false-​positive tests that may result from irritant effects, and may detect responses that are slower to evolve. The final interpretation of causality depends not only on the pres- ence of a positive patch test, but also on the demonstration of rele- vance in terms of the person actually being exposed to the culprit, and it making contact with them in the areas where there is clinical dermatitis. The use of patch tests in elucidating the presence of con- tact allergy in patients with hand dermatitis is of great importance, as there may be major implications for the person in terms of their occupation. Treatment The general approach is first to identify the causal agent(s) through careful history taking, examination, and patch tests, and then avoid it. The treatment of the eczematous inflammation is summarized in ‘Treatment of atopic eczema’ later on in this chapter. Atopic dermatitis/​eczema Definitions The atopic state is defined when an individual’s immune system re- sponds to certain antigens by producing antibodies of the IgE class rather than the IgG class. There is considerable disagreement among dermatologists, paediatricians, and allergists over how best to define atopic eczema/​dermatitis. Dermatologists define it as a diffuse sym- metrical eczematous eruption that is characterized by onset in early life (infancy or childhood), and typically affects flexural sites such as the antecubital and popliteal fossae, and the hands and face. There is characteristically a personal and/​or family history of allergic syn- dromes of asthma or rhinitis. The main point of controversy is whether it is found only in in- dividuals who are atopic. Among European dermatologists, atopic dermatitis is classified as extrinsic (associated with IgE-​mediated allergies of mucosal systems) or intrinsic (usually of onset in adult life and not associated with the formation of allergen-​specific IgE or clinical mucosal allergies). The extrinsic type accounts for around 80–​95%, and the intrinsic type for 5–​15% of cases of atopic eczema. Incidence, prevalence, and natural history of atopic eczema/​dermatitis Over the last 40 years there has been a steady increase in the frequency of the atopic state and all the associated allergic syndromes of eczema, asthma, and rhinitis. While assessments for different national groups vary somewhat, it is now estimated that one-​third of the population of the Western World is atopic. In the United Kingdom, up to 15% of children will develop atopic eczema by the age of 12 years. The maximum incidence is during the first two years of life. Atopic ec- zema is usually the first of the atopic syndromes to develop, whereas asthma comes later, and rhinitis last—​a sequence that has been called the atopic march. There are several patterns to the natural history, the most common being early onset and spontaneous remission during childhood. Atopic eczema affects up to 0.5% of the adult population. In some of these, the eczema has been present from early childhood, while in others it recurs after a period of remission. Clinical features The distribution of atopic eczema varies with age. In pre-​crawling infants, it is often a diffuse symmetrical erythema with dryness af- fecting the head and neck, torso, and even the limbs. Once a baby starts crawling, the eczema is usually distributed on the extensor surfaces of the arms, knees, and ankles, all of which are in phys- ical and frictional contact with the floor surface on which the child is crawling. As the child becomes ambulatory, the eczema tends to be distributed in the flexural areas, particularly the antecubital and popliteal fossae (Fig. 23.6.1). In some adults, the eczema may be localized predominantly or exclusively to the head, neck, and upper chest, a pattern possibly re- lated to the distribution of the saprophytic skin microbe Malassezia. In addition to the flexural pattern, there is a pattern comprising circular or discoid patches of eczema, sometimes called nummular (coin-​shaped), scattered on the torso and limbs. This pattern is not well associated with allergic sensitization (Fig. 23.6.4). The extent of skin involvement is one of the indicators of the overall severity, others being the degree of redness, the presence of weeping/​oozing and crusting, as well as the presence of excoriation. The main symptom of eczema is itch, which can be very intense; a child can work itself into a complete frenzy of scratching, which can be almost as distressing for the parents/​carers because of the diffi- culty of relieving the symptom. Pathogenesis of atopic eczema The pathogenesis of atopic eczema is still remarkably obscure. There is clearly genetic programming of susceptibility, with the atopic state being determined in a polygenic manner. Twin studies show that in monozygotic twins there is a 75% concordance rate, while it is only 21% in dizygotic twins. However, what causes the susceptibility to become manifest as disease is unknown. Many

section 23  Disorders of the skin 5634 observations have been made of abnormalities in the physiological functions of the skin and the immune system, but it is not clear how they fit together. The dominant hypothesis is that the atopic state is primarily a dysregulation of the immune system, in which characteristics of the fetal immune system aimed at avoiding immune rejection between the mother and fetus somehow fail to mature into the adult im- mune responses designed to give protection against the extrauterine world. Thus in the fetus, T-​helper cells differentiate towards the Th2 phenotype (Chapter 4.3). Following delivery, as the postnatal in- fant is colonized by microbes and exposed to endotoxin-​producing pathogens, there is a change in the drivers of T-​cell differentiation, resulting in the redirection of T-​helper cells towards the Th1 pheno- type. Lack of exposure to endotoxins from enteral pathogens is re- garded as a major factor in the increase in the incidence of the atopic phenotype; the so-​called hygiene hypothesis. So in early postnatal life, the immune response of atopic individuals is directed via the Th2-​derived cytokines IL-​4, -​5, and -​13 to generate IgE, causing the activation of mast cells and eosinophils. This pattern of immune re- sponse correlates with the development of clinical atopic allergies, but it is not clear what causes the orientation to either the skin or mucosae. Additional factors that may contribute to the altered immune response include constitutive overproduction of prostaglandin E2 and IL-​10 by monocyte-​macrophages, which favours Th2 dif- ferentiation. There is also evidence of constitutive overactivity of the cAMP-​degrading enzyme phosphodiesterase 4. This results in the attenuation of intracellular signalling mediated via cAMP, but the consequences of this on the immune system or skin are not yet known. Three main alterations have been detected in the skin itself. The first suggests an impaired contribution to innate immune re- sponses. Thus, atopic eczematous skin produces decreased quan- tities of the antimicrobial peptides β-​defensins, which have homologies with chemokines such as IL-​8. This appears crucial in the increased susceptibility of atopic eczematous skin to infection by a range of microbes (see ‘Microbes’, next). The second alteration is the observation of a strong genetic association with mutations in the filaggrin gene. Filaggrin is a crucial component involved in the formation of the stratum corneum permeability barrier. This finding has not been confirmed in all populations studied, but it raises the important concept that altered permeability of the epi- dermis may be a primary factor in the development of atopic ec- zema. The third observation is that the skin of atopic dermatitis sufferers is actually able to help programme the adaptive T-​cell-​ mediated immune response towards the Th2 bias that character- izes atopics. When a previously unencountered immunogen such as the experimental contact sensitizer 2,4-​dinitrochlorobenzene is delivered to the immune system via the epidermal route, the sub- sequent T-​cell response to 2,4-​dinitrochlorobenzene is strongly Th2 orientated. This is in marked contrast to the T-​cell response of non​atopics after topical exposure to 2,4-​dinitrochlorobenzene, in which case a nearly pure Th1 response is generated. A key factor in the epidermal capacity to direct the T-​cell response appears to be the production of thymic stromal lymphopoietin (TSLP) by the atopic epidermis. This cytokine activates dendritic cells to drive T cells towards the Th2 type. The current working hypothesis is that atopic eczema, like other forms of eczematous inflammation, is a T-​cell-​mediated inflamma- tion. However, the range of cells and mediators contributing to the pathogenesis is more complex than for other types of eczema. Thus, at the microscopic level, atopic eczema is characterized by the infil- tration of CD4 + T cells, and eosinophils. In acute lesions, degranu- lated mast cells can be seen. A factor thought to be of importance is the presence of IgE on the epidermal Langerhans’ cells. Antigen-​ specific cell-​bound IgE is thought to facilitate the presentation of very low levels of antigen to T cells, so-​called antigen focusing. Atopic eczema is regarded as multifactorial; some of the recognized triggering or aggravating factors include airborne and dietary aller- gens, microbial colonization and infection, emotional factors, and climatic factors (temperature and humidity). There are probably other as yet unrecognized factors. Role of allergy There are two sides to allergy in atopic eczema: the demonstration of allergic sensitization by skin tests, and the ascertainment of the clinical significance of allergy in the provocation of an individual’s eczema. There is clear evidence that immunological sensitization, reflected by the presence of specific IgE, occurs not only early in life, but even in utero. The pattern of allergen-​specific IgE changes during the first two years of life from predominantly food-​directed to air- borne allergen-​directed IgE. Allergy to environmental airborne and/​or food allergens is an im- portant triggering factor in some, but not all individuals. There are major difficulties in determining which patients have clinically sig- nificant allergies contributing to driving the eczema. Different types of allergic response can be demonstrated with skin tests. Thus im- mediate, type I, weal and flare responses can be elicited by prick tests in 80–​95% of people with eczema. If allergens are administered by intradermal challenge, up to 30% will exhibit both immediate and late phase (6–​12 h) responses. If allergens are administered by ap- plication as patch tests, depending on whether or not the stratum corneum permeability barrier is breached by prior stripping with cellophane tape, eczematous responses that replicate the clinical and histological features of eczema can be generated in up to 80% Fig. 23.6.4  Discoid eczema.

23.6  Dermatitis/eczema 5635 of patients. Also, if the patch-​test challenge sites are inspected at the appropriate time, immediate (15 min) weal and flare responses are seen, and sometimes late phase (6 h) responses. The practical difficulty is in determining whether these positive skin tests correlate with clinically significant allergic provocation. Most patients have current or previous mucosal allergies of asthma or rhinitis, and immediate reactions in prick tests generally correlate well with the allergic provocation of those symptoms, rather than the eczema. However, very strongly positive prick-​test responses to a given allergen often indicate that the allergen will aggravate the ec- zema. Positive patch tests with atopic allergens are reported to occur only in individuals with current or past eczema, and not in people with mucosal allergies and no eczema. Again, a strong patch-​test re- sponse to a given allergen often indicates that the allergen has a sig- nificant role in provoking the eczema. Historical enquiry into which agents clearly exacerbate the eczema is usually unrewarding. One approach to establishing clinical relevance is allergen avoidance. Allergen avoidance This is only seriously practicable for house-​dust mites, and foods. There is controversy in the literature as to the value of allergen avoidance measures. Tan et al. showed highly significant beneficial effects, whereas two other studies failed to show any benefit. The difference between the studies was the rigour of the dust-​mite ex- clusion measures. Tan encased all the bedding components (duvet, pillows, and mattress) in sealed encasements, treated the carpets with a spray combining acaricidal and allergen-​denaturing activity, and used a high-​power high-​filtration vacuum cleaner. Gutgesell used bedding encasements and a vacuum cleaner, and Oosting et al. only used bedding encasements. In fact in Tan’s study, the combin- ation of allergen-​denaturing spray and vacuum cleaning resulted in a great reduction in the allergen load in the carpets, but the overall effect was not significantly better than that from the simple vacuum cleaner alone. So it is hard to explain why there are such differences in the results of the three studies. Dietary allergen exclusion has been explored in many studies, with the best effects being reported for infants and small children. Microbes Atopic eczema is highly susceptible to colonization and infection by coagulase-​positive staphylococci. This was thought to result from the high relative humidity at the skin surface; even though the skin is dry to the touch the permeability barrier is defective, and there is a high transepidermal water loss. It is now known that an additional factor in the poor resistance to staphylococci is deficient production of the antimicrobial peptides β-​defensins. Colonization by staphylococci that produce superantigens may lead to a general exacerbation of the eczematous inflammation. Infection by staphylococci results in folliculitis and/​or acute exacer- bations of eczema with weeping and crusting. Also, the development of fissures of the eyelids and/​or ear lobes is usually a sign of staphylo- coccal infection. Eczema is also susceptible to infection with herpes viruses, either herpes simplex or varicella–​zoster. Eczema herpeticum is a poten- tially very serious condition that may lead to ocular damage, herpes encephalitis, or pneumonitis. The head and neck pattern of eczema is thought to be pro- voked by the ubiquitous skin-​surface yeast Malassezia. Evidence is circumstantial, but is derived from the therapeutic response fol- lowing treatment with imidazole antifungal agents. Treatment of atopic eczema The general approach is to: (1), avoid any provoking factors (i.e. ir- ritants, contact sensitizers, or atopic allergens); (2), suppress inflam- mation with topical steroids (Box 23.6.2); and (3), give supporting symptomatic treatment. Allergen avoidance If clear allergic provoking factors can be identified then avoid- ance measures can make a significant contribution to the control of atopic eczema. Dust-​mite avoidance must be done properly; ideally, all three elements of the bedding (mattress, top covers, and pillows) should be encased in bags of the appropriate dust-​ proof material. However, these are often hot and intolerable, and replacing duvet/​quilts with cotton cellular blankets that can be washed frequently is an alternative. Similarly, acrylic pillows, and duvets can be subjected to hot washing and tumble drying every three months. The avoidance of dietary provocations is often practised, particu- larly in babies and children, on an empirical basis. This should only be continued if good evidence that it is contributing can be obtained by provocation challenge. Infection Staphylococcal infection requires antibiotics; it is better to use sys- temic antibiotics for 7–​10 days than topical forms, to reduce bac- terial resistance. In patients with recurrent skin infection, the use of moisturizers containing antiseptic agents in the bath or applied directly to the skin is helpful. Itch The mediators of itch in atopic eczema are not known, but the con- tribution of histamine is minimal. Although antihistamines are often given, it is more likely that the sedating effects of older anti- histamines such as chlorpheniramine or trimeprazine make them better at symptom relief than non​sedating modern forms. Skin inflammation A crucial part of topical therapy is the use of emollient moistur- izers (Box 23.6.2). These are available as liquid oils, thin creams, Box 23.6.2  Treatment of eczema Moisturizers/​emollients • Liquid oils or creams • Greasy ointments Topical steroids • See Box 23.6.3 Topical calcineurin antagonists • Tacrolimus • Pimecrolimus Systemic drugs • Azathioprine • Ciclosporin Additional treatments • Antibiotics if infected • If wet/​oozing, potassium permanganate soaks (1/​10 000)

section 23  Disorders of the skin 5636 and thick ointments, with varying degrees of water miscibility. The application of moisturizers that the patient finds agreeable can have excellent anti-​itch and soothing effects, thus reducing scratching and hence contributing to controlling the eczema. The technique of wet wrapping can be very helpful, particularly in ba- bies and small children. This involves the initial application of a moisturizer to the limbs and torso, followed by the application of a double layer of tubular bandages, the inner layer being wetted with tepid water. Topical steroids are the mainstay of treatment of the skin in- flammation (see Box 23.6.3). In many patients, the chronic use of topical steroids may be ineffective or can result in steroid-​induced side effects of striae, skin atrophy, and telangiectasia. In this case, the topical calcineurin antagonists tacrolimus or pimecrolimus are indicated. If these are ineffective, a range of systemic drugs may be used. These include azathioprine, ciclosporin, methotrexate, and mycophenolate mofetil. Systemic steroids are reserved for acute rescue therapy of acute flares, but should not be used for long-​term therapy. Other forms of dermatitis/​eczema Seborrhoeic eczema Seborrhoeic eczema is a response to the ubiquitous saprophytic skin yeast Malassezia. The rash comprises erythematous dry areas, most classically affecting the nasolabial folds, scalp, and ears. The most minimal form of seborrhoeic eczema is dandruff; if it is more active the scalp becomes itchy and finally inflamed, with red scaly areas most typically around the hair margin. There may be circular co- alescing areas on the central chest and/​or upper back. Seborrhoeic eczema can mimic psoriasis, and indeed there is an entity termed sebopsoriasis, which behaves like psoriasis, but is in the distri- bution of seborrhoeic eczema. Most people experience minimal seborrhoeic eczema at some time. It is not known what causes the relationship with the fungus to change so that it induces an inflam- matory reaction. People infected with HIV are prone to developing florid seborrhoeic eczema. Treatment The main treatment is with antifungal agents such as imidazoles in shampoo and topical forms; for severe cases, systemic agents such as fluconazole may be used. For very symptomatic cases, low-​potency topical steroids in combination with antifungal agents can be used to gain control, after which imidazole antifungals are usually sufficient for long-​term control. Dyshidrotic (pompholyx) eczema This is an intensely itchy eruption affecting the palms and/​or soles. It is characterized by tiny vesicles and blisters (pompholyx), which initially appear as small grey dots. The affected areas then become reddened, with hyperkeratotic scale that can fissure leading to painful splits. This is often a very chronic eczematous condition. It is thought that there is an associated disturbance of the structure or function of the sweat glands in the affected areas, hence the term dyshidrotic. Differential diagnosis It is important to exclude the presence of allergic contact dermatitis by careful history taking and diagnostic patch tests. It is also im- portant to avoid irritants such as soaps; greasy moisturizers should be used as substitutes. Potent topical steroids are normally required, but often the condition is only poorly controlled. Systemic agents such as azathioprine may be required for the long-​term control of severe cases. Asteatotic eczema Asteatosis indicates lack of oil/​grease, a condition that develops gradually with increasing age, and that preferentially affects the lower legs. The epidermal surface becomes dry, and cracks develop in the scale. These cracks can become red and itchy, a characteristic appearance called eczema craquelé, one pattern of asteatotic eczema (Fig. 23.6.5). The other main pattern is a more typical eczematous inflammation, usually distributed on the lower legs in association with a generalized dryness and hyperkeratosis. Treatment The main component of treatment is replacement of the epidermal oils by the application of greasy moisturizers. In the acute phase, moderate-​potency topical steroids in an ointment base may be re- quired to bring the symptoms under control. Varicose eczema Following deep venous thrombosis in the leg veins, the valves in the veins are damaged, causing a rise in the venous pressure gradient down the legs. Any cause of venous hypertension may Box 23.6.3  Topical steroids Category 1: mild • Hydrocortisone Category 2: moderate • Clobetasone butyrate Category 3: potent • Betamethasone valerate Category 4: super potent • Clobetasol propionate Fig. 23.6.5  Asteatotic eczema.

23.6  Dermatitis/eczema 5637 reverse the direction of flow, channelling returning blood into the superficial veins. The raised pressure transmitted to the small veins and postcapillary venules results in plasma transudation, deposition of fibrin (which produces sclerosis and skin teth- ering), and leakage of erythrocytes, generating haemosiderin. The haemodynamic changes alter the nutritional provision to the skin. As part of this, perhaps by analogy with the processes underlying asteatotic eczema, there may develop a rather diffuse eczematous process. If the skin’s nutritive blood supply is sufficiently com- promised the tissue may break down, resulting in venous ulcer disease (Chapter 23.12). Differential diagnosis It is common for allergic contact dermatitis to develop on the lower legs affected by venous ulcers. The contact allergy is in response to ingredients of the many medicaments and impregnated bandages that are applied as part of the treatment. Treatment The most important component of therapy is external compression with stockings or bandages. This can improve the haemodynamics and restore the direction of venous return, with associated improve- ment in nutritive skin blood flow. The eczema is treated with mois- turizers and a range of topical corticosteroids. Ultraviolet-​induced eczema or photodermatitis Some people develop eczema in areas exposed to sunlight, mainly the face, neck, and dorsa of hands. There are two types of this photodermatitis; an apparently spontaneous reactivity to light, and chemically sensitized photoallergy. Many drugs can act as photoallergens, becoming converted to allergens by the combined effect of ultraviolet (UV) radiation and as yet undefined metabolic factors in the individual. Well-​known examples are thiazide diur- etics and quinine. The causal role is demonstrated by photopatch tests, in which the suspect chemical is applied to the back in du- plicate; one test site is irradiated with long-​wavelength ultraviolet (UVA), and the other is simply occluded. The role of photoallergy is shown by a positive response only at the UV-​irradiated test site. Even in people who develop apparently spontaneous photo­ dermatitis, there is often the suspicion that plant-​derived substances such as sesquiterpene lactones from the chrysanthemum family may be involved. Treatment This involves minimizing exposure to sunlight by wearing thick clothing and hats. Sunblock creams are only helpful if they are very thick and opaque. Potent topical steroids and even systemic agents such as azathioprine may be required. FURTHER READING Calnan CD, Fregert S, Magnusson B (1976). The International Contact Dermatitis Research Group. Cutis, 18, 708–​10. Cavani A, et al. (2003). Human CD25+ regulatory T cells maintain immune tolerance to nickel in healthy, nonallergic individuals. J Immunol, 171, 5760–​8. Coenraads PJ, Smit J (1995). Epidemiology. In: Rycroft RJG, et al. (eds) Textbook of contact dermatitis, 3rd edition, pp. 133–​50. Springer-​ Verlag, Berlin. David TJ, et al. (2000). Dietary factors in established atopic dermatitis. In: Williams HC (ed) Atopic dermatitis: the epidemiology, causes and prevention of atopic dermatitis, pp. 193–​201. Cambridge University Press, Cambridge. de Jongh GJ, et al. (2005). High expression levels of keratinocyte anti- microbial proteins in psoriasis compared with atopic dermatitis. J Invest Dermatol, 125, 1163–​73. Dickel H, et al. (2002). Importance of irritant contact dermatitis in oc- cupational skin disease. Am J Clin Dermatol, 3, 283–​9. Diepgen T (2000). Is the prevalence of atopic dermatitis increasing? In: Williams HC (ed) Atopic dermatitis: the epidemiology, causes and prevention of atopic dermatitis, pp. 96–​109. Cambridge University Press, Cambridge. Diepgen TL, Coenraads PJ (1999). The epidemiology of occupational contact dermatitis. Int Arch Occup Environ Health, 72, 496–​506. Friedmann PS (1991). Graded continuity, or all or none—​studies of the human immune response. Clin Exp Dermatol, 16, 79–​84. Friedmann PS (2006). Contact sensitisation and allergic contact dermatitis: immunobiological mechanisms. Toxicol Lett, 162, 49–​54. Friedmann PS, et al. (1993). Early time course of recruitment of im- mune surveillance in human skin after chemical provocation. Clin Exp Immunol, 91, 351–​6. Gerberick GF, et al. (2000). Local lymph node assay: validation assess- ment for regulatory purposes. Am J Contact Dermatitis, 11, 3–​18. Gutgesell C, et al. (2001). Double-​blind placebo-​controlled house dust mite control measures in adult patients with atopic dermatitis. Br J Dermatol, 145, 70–​4. Kusel MM, et al. (2005). Support for 2 variants of eczema. J Allergy Clin Immunol, 116, 1067–​72. Lachapelle JM (1995). Histopathological and immunohistopathological features of irritant and allergic contact dermatitis. In: Rycroft RJG, Menne T, Frosch PJ (eds) Textbook of contact dermatitis, 3rd edition, pp. 91–​102. Springer-​Verlag, Berlin. Lintu P, et al. (2001). Systemic ketoconazole is an effective treatment of atopic dermatitis with IgE-​mediated hypersensitivity to yeasts. Allergy, 56, 512–​17. Meding B (1990). Epidemiology of hand eczema in an industrial city. Acta Derm Venereol Suppl (Stockh), 153, 1–​43. Miles EA, et al. (1996). Peripheral blood mononuclear cell proliferative responses in the first year of life in babies born to allergic parents. Clin Exp Allergy, 26, 780–​8. Mudde GC, Bheekha R, Bruijnzeel-​Koomen CA (1995). Consequences of IgE/​CD23-​mediated antigen presentation in allergy. Immunol Today, 16, 380–​3. Newell L, et al. (2013). Sensitization via healthy skin programs Th2 responses in individuals with atopic dermatitis. J Invest Dermatol, 133, 2372–​80. Ohmen JD, et al. (1995). Overexpression of IL-​l0 in atopic derma- titis:  contrasting cytokine patterns with delayed-​type hypersensi- tivity reactions. J Immunol, 154, 1956–​63. Oosting AJ, et al. (2002). Effect of mattress encasings on atopic derma- titis outcome measures in a double-​blind, placebo-​controlled study:  the Dutch mite avoidance study. J Allergy Clin Immunol, 110, 500–​6. Palmer CN, et al. (2006). Common loss-​of-​function variants of the epi- dermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet, 38, 441–​6.

section 23  Disorders of the skin 5638 Patrick E, Maibach HI (1995). Predictive assays:  animal and man, and in vitro and in vivo. In: Rycroft RJG, Menne T, Frosch P (eds) Textbook of contact dermatitis, 3rd edition, pp. 705–​47. Springer-​ Verlag, Berlin. Raghupathy R (2001). Pregnancy: success and failure within the Th1/​ Th2/​Th3 paradigm. Semin Immunol, 13, 219–​27. Schultz Larsen FV (1993). The epidemiology of atopic dermatitis. Monogr Allergy, 31, 9–​28. Strachan DP (1989). Hay fever, hygiene, and household size. BMJ, 299, 1259–​60. Tan BB, et  al. (1996). Double-​blind controlled trial of effect of housedust-​mite allergen avoidance on atopic dermatitis. Lancet, 347, 15–​18. Warner JA, et  al. (1996). Prenatal sensitisation. Pediatr Allergy Immunol, 7, 98–​101. Willis CM, Stephens CJM, Wilkinson JD (1993). Differential pat- terns of epidermal leukocyte infiltration in patch test reactions to structurally unrelated chemical irritants. J Invest Dermatol, 101, 364–​70.

23.7 Cutaneous vasculitis, connective tissue disea

23.7 Cutaneous vasculitis, connective tissue diseases, and urticaria 5639 Volha Shpadaruk and Karen E. Harman

ESSENTIALS Vasculitis (angiitis) denotes necrotizing inflammation of the blood vessels; occlusive vasculopathy implies vascular occlusion without significant vascular inflammation (Box 23.7.1). A small-​vessel cuta- neous vasculitis is the most common vasculitis affecting the skin, and may be the first sign of a systemic vasculitis, but 50% of patients have no systemic disease. The clinical findings must be integrated with the results of serological, pathological, and imaging studies to reach a diagnosis. Systemic lupus erythematosus is diagnosed if four or more of the American College of Rheumatology revised criteria for the clas- sification of the disease are present, either sequentially or simul- taneously. These include four mucocutaneous signs:  malar rash, discoid rash, photosensitivity, and oral ulcers. Skin lesions are the first manifestation of systemic lupus erythematosus in 23–​28% of patients; about 73% of patients report photosensitivity, and up to 91% develop cutaneous symptoms at some stage in the evolution of their disease. Dermatomyositis is an uncommon multisystem autoimmune disease in which inflammatory skin changes are associated with polymyositis of skeletal muscle. The clinical spectrum ranges from pure cutaneous disease, through coexisting patterns of cutaneous/​ systemic disease, to isolated inflammatory polymyositis. Cutaneous involvement may precede the onset of myositis by several years, but some patients never have muscle involvement (amyopathic dermatomyositis). Scleroderma means thickened, fibrotic, bound-​down skin. It might develop in association with a systemic connective tissue disease (systemic sclerosis) or present as a localized cutaneous problem. Localized scleroderma, unlike systemic sclerosis, is a self-​limiting condition confined to the skin and subcutaneous tissue; it does not transform into systemic sclerosis. Dermatologists tend to use the term ‘morphoea’ for localized disease, while paediatricians and rheumatologists refer to the same condition as ‘scleroderma’. Panniculitis is inflammation of the subcutaneous fat, sometimes associated with vasculitis. It presents with erythematous subcuta- neous nodules, most often on the lower leg. Historical perspective The systemic vasculitides are characterized by inflammation of blood vessels leading to tissue or end organ injury, depending on the size of the vessels affected. The initial descriptions of vasculitis were isolated case reports by William Heberden in the 1760s. Kussamul and Meier described a case of polyarteritis nodosa in 1866. In the twentieth century, the first description of granulomatosis with polyangiitis (Wegener’s granulomatosis), eosinophilic granulomatosis with polyangiitis (Churg–​Strauss syndrome), Takayasu arteritis and giant cell arteritis, and Kawasaki disease were published. Wegener’s granulomatosis, Churg–​Strauss syndrome, and Henoch–​Schönlein purpura were known by their eponyms until the present decade (see Box 23.7.2). The initial classification of vasculitis was proposed by Zeek in 1952, who recognized five types of vasculitis based on vessel size. The classification of vasculitis has subsequently evolved with the 23.7 Cutaneous vasculitis, connective tissue diseases, and urticaria Volha Shpadaruk and Karen E. Harman Box 23.7.2  New nomenclature adopted in the 2012 CHCC definitions • Wegener’s granulomatosis = granulomatosis with polyangiitis (GPA) • Churg–​Strauss syndrome  =  eosinophilic granulomatosis with poly­ angiitis (EGPA) • Henoch–​Schönlein purpura = IgA vasculitis CHCC, Chapel Hill Consensus Conference. Box 23.7.1  Definitions • Vasculitis (angiitis)—​necrotizing inflammation of the blood vessels • Occlusive vasculopathy—​vascular occlusion without significant vascular inflammation (i.e. occlusion without vasculitis)

section 23  Disorders of the skin 5640 recognition of new vasculitis syndromes, an improved under- standing of pathogenesis and the discovery of antineutrophil cyto- plasmic antibody (ANCA). While our understanding of vasculitis remains incomplete, classification systems are imperfect but key cri- teria include vessel size, clinical, and immunopathological findings. Important classifications historically include the 1990 American College of Rheumatology criteria (pre-​ANCA) and the 1994 Chapel Hill Consensus Conference (CHCC) criteria. In 2011 another Chapel Hill Consensus Conference was convened to review the 1994 system. Key updates, published in 2012 (2012 CHCC) include a move away from eponyms to names reflecting aetiopathogenesis (Box 23.7.3), and the classification of ANCA-​associated and im- mune complex-​associated vasculitis as specific types of small-​vessel vasculitis. Pathogenesis Vasculitis can be primary (idiopathic), or secondary, associated with diseases such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, infections, or malignancy. The exact pathological mechanisms causing vasculitis are unknown and are likely to vary in different types of vasculitis. In vasculitis associated with infection, direct invasion of vessels walls can occur, probably as a result of antigens on the surface of infectious agents binding to complementary endothelial ligands. In others, binding or trapping of immune complexes are likely to be a key factor in the pathogen- esis. In primary vasculitis, the pathogenesis is believed to be auto- immune and a good model for this comes from antiglomerular basement membrane (GBM) disease in which type IV collagen has been recognized as the antigen and target of the immune response. The additional role of genetic susceptibility is illustrated in this ex- ample by the association with HLA-​DRB1*15:01. ANCA antibodies are detected in many patients with the ANCA-​associated vasculit- ides and although ANCA have been shown to activate and degranu- late neutrophils in vitro, it is unclear exactly what role it plays in these diseases. In addition to genetic predisposition, environmental fac- tors such as tobacco smoke, organic solvents, and infections might influence individual susceptibility to the development of vasculitis. An interesting observation to explain is the variability in dis- ease expression in terms of site, both size of blood vessels involved (e.g. small, medium, large), and organ (e.g. generalized or organ-​ specific). These differences might be due to physical factors, such as temperature, hydrostatic pressure and turbulence (e.g. turbulence may favour the deposition of immune complexes). In addition, blood ves- sels vary throughout the body, designed to meet the needs of their host organ. Endothelial antigen expression is likely to vary and this might explain the different patterns of disease according to the where the target antigen is expressed. Another factor to consider is the embry- ology of blood vessels: most vessels are derived from mesoderm with the exception of the aortic root and arch which are derived from the neural crest, and this might be part of the explanation for certain vas- culitides favouring the aortic arch, such as syphilitic aortitis, which along with neurosyphilis is a manifestation of tertiary syphilis. In many of the vasculitides, a common final pathway is the re- lease of proteolytic enzymes, and oxygen free radicals from activated neutrophils, and these damage the vessel walls and the surrounding tissues. Inflammation and necrosis of blood vessel walls leads to the extravasation of red blood cells, vascular obstruction, and tissue is- chaemia or infarction. The clinical features depend on the size of the affected vessels, the sites involved (frequently the earliest signs are in the skin), and the intensity of the inflammation (see Table 23.7.1). Assessment of patients with suspected vasculitis A description of individual vasculitides follows but when assessing a patient with suspected vasculitis, there are several general issues to consider. Firstly, is there involvement of small, medium, or large ves- sels? The clinical signs reflect the vessels involved (see Table 23.7.1) and will help narrow down the potential diagnoses. Is it localized or systemic? What is the cause and is it primary or secondary? Could it be a vasculitis mimic? The section dealing with cutaneous Box 23.7.3  Nomenclature of the vasculitides adopted by the 2012 International Chapel Hill Consensus Conference (CHCC 2012) Large-​vessel vasculitis Takayasu arteritis Giant Cell Arteritis Medium-​vessel vasculitis Polyarteritis nodosa Kawasaki disease Small-​vessel vasculitis • ANCA-​associated vasculitis Microscopic polyangiitis (MPA) Granulomatosis with polyangiitis (GPA) Eosinophilic granulomatosis with polyangiitis (EGPA) • Immune complex small-​vessel vasculitis Antiglomerular basement membrane (GBM) disease Cryoglobulinaemic vasculitis IgA vasculitis (Henoch–​Schönlein) Hypocomplementaemic urticarial vasculitis (anti-​C1q vasculitis) Variable-​vessel vasculitis Behçet’s disease Cogan’s syndrome Single-​organ vasculitis Cutaneous leucocytoclastic angiitis Cutaneous arteritis Primary central nervous system vasculitis Isolated aortitis Others Vasculitis associated with systemic disease Lupus vasculitis Rheumatoid vasculitis Sarcoid vasculitis Others Vasculitis associated with a probable aetiology Hepatitis C virus-​associated cryoglobulinaemic vasculitis Hepatitis B virus-​associated vasculitis Syphilis-​associated aortitis Drug-​associated immune complex vasculitis (e.g. sulphonamides, peni- cillins, thiazide diuretics) Drug-​associated ANCA-​associated vasculitis (e.g. Propylthiouracil, hydralazine and allopurinol with induction of MPO-​ANCA). Cancer-​associated vasculitis Others

23.7  Cutaneous vasculitis, connective tissue diseases, and urticaria 5641 Table 23.7.1  The cutaneous manifestations of vasculitis according to vessel size. Note that there is overlap and mixed signs may be seen due to involvement of vessels of variable size. Note that medium-​sized vessels are sited deep in the skin so require a deep skin biopsy, including subcutaneous fat, in order to obtain a histological diagnosis. Vessel size Small Medium Large Clinical signs in the skin Palpable purpura • Papules and plaques • Often in crops • Dependent sites, typically lower legs • May be necrotic & ulcerate • May be pustular See Fig. 23.7.1 Dermal and subcutaneous nodules May necrose & ulcerate See Fig. 23.7.2 Mainly affects internal organs & cutaneous involvement less common (no large vessels in the skin) Haemorrhagic vesicles & bullae See Fig. 23.7.1 Livedo reticularis Patchy or broken rather than a continuous network (livedo racemosa) See Fig. 23.7.3 May cause necrosis & ulceration of skin/​mucosa in the territory of an affected large vessel e.g. scalp or tongue in GCA Urticarial papules & plaques • Last >24 hrs • Leave bruise-​like marks Digital infarcts and gangrene Limb ischaemia Splinter haemorrhages Deep ulcers May be PG-​like Nail-​fold infarcts PG, pyoderma gangrenosum; GCA, giant cell arteritis. Fig. 23.7.1  Palpable purpura on the legs. Many lesions are bullous. These are signs of a small-​vessel vasculitis, regardless of cause, which classically produces crops of palpable purpura on the lower legs. Fig. 23.7.2  Necrotic papules and ulcers on the leg in a patient with granulomatosis with polyangiitis (Wegener’s granulomatosis). Note the appearances are quite different to the crops of palpable purpura seen on the lower legs as a typical sign of a small-​vessel vasculitis (Fig. 23.7.1).

section 23  Disorders of the skin 5642 small-​vessel vasculitis describes the general approach to a patient with suspected vasculitis and discusses differential diagnoses. Large-​vessel vasculitis Giant cell arteritis (GCA) Giant cell arteritis, also known as temporal arteritis, affects the larger and medium-​sized arteries, particularly those of the head and neck (Box 23.7.4). Patients, usually women aged over 50 years, can present with fever, headache, a tender temporal artery/​scalp, jaw claudication, vision changes, including blindness, anaemia, and an elevated erythrocyte sedimentation rate. Cutaneous in- volvement is not common but might present as a tender scalp nodule that can ulcerate and might be misdiagnosed as a basal cell skin carcinoma (see Chapter 23.14). Scalp ulceration can be bilat- eral and occasionally, there might be ulceration or infarction of the tongue. Useful investigations include an erythrocyte sedimenta- tion rate (ESR), an ophthalmologic examination, and a temporal artery biopsy. If there is acute visual loss, therapy with systemic corticosteroids should be commenced while awaiting the results of investigations. Takayasu arteritis (TAK) Both giant cell arteritis and takayasu arteritis (TAK) are granu- lomatous vasculitides affecting the aorta and its major branches such that there is debate as to whether they are the same disease. TAK tends to affect younger patients, less than 50 (Box 23.7.5). The granulomatous arteritis of TAK is followed by fibrosis and stenosis. It might present with claudication or cold peripheries, limb ischaemia, unequal or absent pulses, bruits, and renovascular hypertension. Cutaneous manifestations are not common but in- clude inflamed and ulcerated nodules, or pyoderma gangrenosum-​ like ulcers. Useful diagnostic studies include arteriography, doppler ultrasonography, and MRI/​MRA. (a) (b) Fig. 23.7.3  Patchy livedo (livedo racemosa) seen on the thigh (a) and knee (b). Physiological livedo reticularis is a continuous network and typically disappears in warm temperatures. In contrast, livedo racemosa is patchy and persistent. Box 23.7.4  Giant cell arteritis CHCC 2012 definition • An arteritis, often granulomatous, usually affecting the aorta and/​or its major branches, with a predilection for the branches of the carotid and vertebral arteries. Often involves the temporal artery. Onset usu- ally in patients older than 50 and often associated with polymyalgia rheumatica. CHCC, Chapel Hill Consensus Conference. Box 23.7.5  Takayasu arteritis CHCC 2012 definition • An arteritis, often granulomatous, predominantly affecting the aorta and/​or its major branches. Onset usually in patients younger than 50. CHCC, Chapel Hill Consensus Conference.

23.7  Cutaneous vasculitis, connective tissue diseases, and urticaria 5643 Medium-​vessel vasculitis Polyarteritis nodosa (PAN) Polyarteritis nodosa is a life-​threatening necrotizing vasculitis, which results in aneurysms that can be demonstrated by arteri- ography of renal or mesenteric arteries (Box 23.7.6). Historically, some cases have been associated with hepatitis B infection, but in the CHCC 2012 nomenclature, these cases should now be classified as hepatitis B virus-​associated vasculitis. Polyarteritis nodosa is more common in men, with an average age of onset of approximately 50 years of age. It might present with non-​ specific constitutional symptoms, abdominal or testicular pain, periph- eral neuropathy, renal insufficiency with active sediment, and vascular hypertension. Cutaneous manifestations include livedo reticularis, cu- taneous nodules, ulcers, peripheral gangrene, and palpable purpura. There is a localized, cutaneous form of polyarteritis nodosa that behaves in a more benign fashion. Cutaneous polyarteritis nodosa Pathogenesis and pathology A benign cutaneous form of polyarteritis nodosa has been de- scribed, but the relationship of this condition to the systemic disease is uncertain, and the cause is unknown. A necrotizing vasculitis af- fects small and medium-​sized muscular-​walled arteries in the deep dermis and subcutis. Clinical features Painful cutaneous nodules, purpura, ulceration, and livedo reticularis (see ‘Thrombo-​occlusive vasculopathies’) occur on the lower limbs (Fig. 23.7.4). The livedo is typically patchy or broken, rather than a continuous network as seen in physiological livedo (see Fig. 23.7.3). Cutaneous polyarteritis nodosa can be associated with fever, malaise, arthralgia, myalgia, and peripheral neuropathy, but major organs are not involved. Patients with hepatitis B might have features of chronic hepatitis. The disease is chronic and recurrent. Investigation Patients should be screened for systemic involvement, but labora- tory findings are generally unremarkable, except for leukocytosis and an elevated erythrocyte sedimentation rate. Deep incisional bi- opsies are necessary to demonstrate the primary vascular pathology. Treatment Treatment of patients who do not have hepatitis B include high-​dose oral corticosteroids 1 mg/​kg/​day tapered down slowly (over a year). In patients with severe disease three daily IV pulses of methylprednisolone 500–​1000 mg might be considered. Cyclophosphamide and other immunosuppressants and immunomodulators might be needed to achieve remission. Patients with hepatitis B-​associated polyarteritis nodosa might benefit from a combination of antivirals and immuno- suppression. Pain control is important in such patients (some patients require opiates). Compression bandaging can promote healing, but might not be tolerated because of pain. Kawasaki disease Kawasaki disease (mucocutaneous lymph node syndrome) is a multisystem vasculitis of infants and small children (Box 23.7.7). It is most common in Japan with an increased incidence in later winter or spring. The disease follows an acute course over 4–​6 weeks, with high fever, oedema, and erythema of the palms and soles, and/​or oedema of the hands and feet, an erythematous rash, bilateral conjunctival injec- tion, dry red fissured lips, a ‘strawberry’ tongue, and cervical lymph- adenopathy. Coronary aneurysms develop in about 20% of patients, and ischaemic heart disease causes myocardial infarction and sudden death. Useful investigations include an ESR, coronary angiogram, or echocardiogram. Intravenous γ-globulin plus aspirin controls fever and reduces the formation of aneurysms. Box 23.7.6  Polyarteritis nodosa CHCC 2012 definition • A necrotizing arteritis of medium-​sized or small arteries without glom- erulonephritis or vasculitis in arterioles, capillaries, or venules; and not associated with ANCA. CHCC, Chapel Hill Consensus Conference. Fig. 23.7.4  Painful ulcers on a background of livedo on the lower legs. The ulceration was preceded by palpable purpura and nodules. A biopsy showed a medium-​vessel vasculitis and there was no evidence of systemic involvement. The findings were consistent with the benign cutaneous form of polyarteritis nodosa. Box 23.7.7  Kawasaki disease CHCC 2012 definition • An arteritis associated with mucocutaneous lymph node syndrome and predominantly affecting medium-​sized and small arteries. Coronary arteries are often involved. Aorta and large arteries may be involved. Usually occurs in infants and young children. CHCC, Chapel Hill Consensus Conference.

section 23  Disorders of the skin 5644 Small-​vessel vasculitis ANCA-​associated vasculitis (AAV) ANCA-​associated vasculitis (Box 23.7.8) affects people of all ages, but is most common in adults in their 50s and 60s, and is the most common primary systemic vasculitis affecting adults. The three major subtypes have overlapping features, including the cutaneous features which are listed next. Although in the latest Chapel Hill Consensus Conference classification, AAV is included in small-​ vessel vasculitis, these disorders can also affect medium-​sized ves- sels and the cutaneous clinical signs reflect this. Granulomatosis with polyangiitis
(GPA, Wegener’s granulomatosis) Granulomatosis with polyangiitis presents wiith necrotizing granulomatous inflammation usually involving the upper and lower respiratory tract, and necrotizing vasculitis affecting pre- dominantly small-​ to medium-​sized vessels (e.g. capillaries, venules, arterioles, arteries, and veins). Necrotizing glomerulo- nephritis is common. The condition can occur at any age, but increased incidence in young and middle-​aged adults. Can cause sinusitis, pulmonary infiltrates, haemoptysis, haematuria, pauci-​immune rapidly pro- gressing glomerulonephritis. Useful diagnostic studies include urin- alysis and microscopy, c-​ANCA (90%), sinus/​chest imaging, biopsy. Treatments include steroids and cyclophosphamide for induction of remission, methotrexate or azathioprine for maintenance; tri- methoprim/​sulphamethoxazole might prevent upper airway relapse caused by infection. Microscopic polyangiitis (MPA) Microscopic polyangiitis is a necrotizing vasculitis, with few or no immune deposits, predominantly affecting small vessels (i.e. ca- pillaries, venules, or arterioles). A  necrotizing arteritis involving small-​ and medium-​sized arteries may also be present. Necrotizing glomerulonephritis is very common. A  pulmonary capillaritis without asthma often occurs. Granulomatous inflammation is absent. Compared with granulomatosis with polyangiitis, microscopic polyangiitis is not granulomatous and there is more renal and less pulmonary involvement. It can cause a pauci-​immune rapidly progressing glomerulonephritis, sinusitis, pulmonary infiltrates, haemoptysis, and neuropathy. Useful diagnostic studies include urinalysis and microscopy, p-​ANCA (70%), sinus/​chest imaging, bi- opsy. Treatment approach is similar to that for granulomatosis with polyangiitis. Eosinophilic granulomatosis with polyangiitis (EGPA, Churg–​Strauss syndrome) Eosinophilic granulomatosis with polyangiitis presents with eosinophil-​rich and necrotizing granulomatous inflammation often involving the respiratory tract, and necrotizing vasculitis predomin- antly affecting small-​ to medium-​sized vessels, and associated with asthma and eosinophilia. ANCA is most frequent when glomerulo- nephritis is present. In addition to the lungs, the eosinophil-​rich granulomatous in- flammation can affect peripheral nerves, kidneys, and skin. It can occur at any age, but is typically found in patients 30–​40 years old. It can cause asthma, allergic rhinitis, pulmonary infiltrates, neur- opathy, and glomerulonephritis. Useful diagnostic studies include eosinophilia, ANCA (50%, perinuclear > cytoplasmic), sinus/​chest imaging, biopsy. Chest radiograph might show shifting pulmonary infiltrates. The vasculitic phase does not develop until about three years after the onset of asthma in Churg–​Strauss syndrome. Clinical features Cutaneous lesions have been described during the course of disease in around 70% of patients, but signs of a cutaneous vasculitis are present at disease onset in more than 40% of patients with micro- scopic polyangiitis and 8–​10% of those with granulomatosis with polyangiitis (Wegener’s granulomatosis). The cutaneous findings vary, and reflect involvement of small and medium-​sized vessels (see Table 23.7.1) but the most common (and least specific) finding in all three conditions are: • Palpable purpuric rash on the lower extremities (Fig. 23.7.1). • Progressive ulceration in granulomatosis with polyangiitis (Wegener’s granulomatosis) may resemble pyoderma gangrenosum, and can affect unusual sites such as the face, neck, or perianal skin (pyoderma gangrenosum usually affects the lower legs). • Livedo reticularis. • Patients with granulomatosis with polyangiitis (Wegener’s granulomatosis) or eosinophilic granulomatosis with polyangiitis (Churg–​Strauss syndrome) can develop lesions associated with a large-​vessel vasculitis, such as cutaneous ulcers or subcutaneous nodules. • In both GPA and EGPA (Wegener’s granulomatosis and Churg–​ Strauss syndrome), ulcerated papules (papulonecrotic lesions, see Fig. 23.7.2) resembling rheumatoid nodules are found on the limbs, particularly the elbows, but can occur on the face and scalp. These diseases are discussed in further detail in other organ-​ specific chapters (in particular Sections 15, 18, 19, and 21). Immune complex small-​vessel vasculitis See Box 23.7.9. Box 23.7.8  ANCA-​associated vasculitis CHCC 2012 definition • Necrotizing vasculitis, with few or no immune deposits, predomin- antly affecting small vessels (i.e. capillaries, venules, arterioles, and small arteries), associated with MPO-​ANCA or PR3-​ANCA. Not all pa- tients have ANCA. Add a prefix indicating ANCA reactivity (e.g. PR3-​ ANCA, MPO-​ANCA, and ANCA negative). CHCC, Chapel Hill Consensus Conference. Box 23.7.9  Immune complex vasculitis CHCC definitions as revised in 2012 • Vasculitis with moderate to marked vessel wall deposits of immuno- globulin and/​or complement components predominantly affecting small vessels (i.e. capillaries, venules, arterioles, and small arteries). Glomerulonephritis is frequent.

23.7  Cutaneous vasculitis, connective tissue diseases, and urticaria 5645 IgA vasculitis (Henoch–​Schönlein purpura) Pathogenesis Henoch–​Schönlein purpura is triggered by infection, often in the upper respiratory tract, and is associated with IgA immune com- plexes in the circulation and vessel walls (Box 23.7.10). It is the most common small-​vessel systemic vasculitis in children, but it may also affect adults. Clinical features The cutaneous signs are similar to those of other cutaneous small-​ vessel vasculitides, but in children the urticarial component might be more prominent than in adults. A symmetrical macular erythema develops on the extensor surfaces of the limbs, the buttocks, and back. Lesions become raised, palpable, and purpuric, but regress over 10 to 14 days. In addition, children can have any combination of arth- ritis, gastrointestinal tract involvement, and nephritis. Infantile acute haemorrhagic oedema of the skin is a benign condition that is prob- ably a variant of Henoch–​Schönlein purpura in which the oedema- tous component is particularly marked. If needed, useful diagnostic studies include skin biopsy or renal biopsy showing IgA deposition. Treatment In the absence of severe systemic disease, treatment is supportive. Corticosteroids or dapsone might be prescribed in severe disease, although it is not known if these drugs affect the duration of illness or the frequency of relapse. Rapidly progressive renal failure is rare, and the prognosis is excellent. Relapses are usually mild and do not require treatment. Cryoglobulinaemic vasculitis (and occlusive vasculopathy) Aetiology, pathogenesis, and pathology Vasculitis arising from presence of cryoglobulins (Box 23.7.11). Cryoglobulins are immunoglobulins that precipitate at low temper- atures and are classified according to their immunochemical com- position. More common in the middle-​aged, women, and those with autoimmune or lymphoproliferative diseases. It is strongly associ- ated with hepatitis C virus infection. It can cause purpura, livedo reticularis, ulcers, neuropathy, arthralgias, and glomerulonephritis. • Type I  cryoglobulins (monoclonal immunoglobulins IgG and IgM) are present in 25% of cases. Note that in this type, the cryo- globulin causes vascular occlusion rather than a vasculitis. • Type II mixed cryoglobulins (a mixture of monoclonal and poly- clonal immunoglobulins) are present in 25% of cases. • Type III mixed cryoglobulins (polyclonal immunoglobulins only) are present in 50% of cases. Most patients are women aged 30–​50 years. Type I cryoglobulinaemia is always associated with a malignant haematological disorder such as chronic lymphatic leukaemia, mul- tiple myeloma, or Waldenström’s macroglobulinemia. The cryo- globulins obstruct the vessels rather than trigger an inflammatory vasculitis, and are associated with cold sensitivity (Fig. 23.7.5). A skin biopsy, best taken from affected but not ulcerated skin, re- veals an occlusive vascular disease (vasculopathy). The small cu- taneous blood vessels are plugged by homogenous eosinophilic material, and there is red blood cell extravasation with a perivascular mononuclear cell infiltrate, but no vasculitis. In most patients, hepatitis C virus (HCV) infection underlies type II mixed cryoglobulinaemia. This would now be termed HCV-​ associated cryoglobulinaemic vasculitis. Hepatitis C virus infection triggers B-​cell clonal expansions with production of IgM, primarily in the liver. These expansions are associated with high serum levels of polyclonal rheumatoid factor and cryoglobulins, as well as mono- clonal gammopathy of undetermined significance and, rarely, non-​Hodgkin’s B-​cell lymphoma. The pathogenesis of malignant Box 23.7.10  IgA vasculitis CHCC 2012 definition • Vasculitis, with IgA1-​dominant immune deposits, affecting small ves- sels (predominantly capillaries, venules, or arterioles). Often involves skin and gut, and frequently causes arthritis. Glomerulonephritis indis- tinguishable from IgA nephropathy may occur. CHCC, Chapel Hill Consensus Conference. Box 23.7.11  Cryoglobulinaemic vasculitis 2012 CHCC definition • Vasculitis with cryoglobulin immune deposits affecting small vessels (predominantly capillaries, venules, or arterioles) and associated with serum cryoglobulins. Skin, glomeruli, and peripheral nerves are often involved. CHCC, Chapel Hill Consensus Conference. Fig. 23.7.5  Purpura on the lower leg and foot which has blistered in areas. Note that these are large patches rather than crops of palpable purpura as seen in a small-​vessel vasculitis. A skin biopsy revealed an occlusive vasculopathy rather than a vasculitis. Investigations revealed a cryoprotein, which in this case was cryofibrinogenaemia but type I cryoglobulinaemia would give a similar picture.

section 23  Disorders of the skin 5646 B-​cell transformation is uncertain. HCV causes both cytotoxic and autoimmune hepatitis, and clonal B-​cell expansion occus in blood and liver. HCV virions bind to IgG and form immune complexes that are precipitated in the vessel walls of many organs. The com- plexes then activate the complement cascade, producing a small-​ vessel vasculitis affecting venules, capillaries, and arterioles. Mixed cryoglobulinaemia can also be associated with connective tissue dis- eases such as rheumatoid arthritis or systemic lupus erythematosus, as well as other infections. Clinical features Patients with type I cryoglobulinaemia, an occlusive vasculopathy, complain of Raynaud’s phenomenon, mottling of the skin, or blotchy cyanosis on exposure to cold. Acrocyanosis affects the helices of the ears as well as the fingers and toes (Fig. 23.7.6). Cold-​induced le- sions might be urticarial and then become purpuric. Cold triggers the formation of large haemorrhagic bullae that break down to pro- duce ulcers. More than 90% of patients with type II mixed cryoglobulinaemia develop palpable purpura, and in most this is the first sign of the disease. Fifteen per cent (15%) of patients have chronic leg ulcers, usually above the malleoli. These are surrounded by purpura, but patients have no other evidence of stasis (Fig. 23.7.7). Patients may also have Raynaud’s phenomenon (30%), cold urticaria (10%), arth- ralgia (70%), renal involvement (20–​30%), and/​or sensorimotor neuropathy (60%). Clinical investigation Useful diagnostic studies include cryoglobulins, rheumatoid factor, complement (C4), hepatitis C RNA, and a skin biopsy. Measuring complement C4 is a useful screening test because C4 is very low in mixed cryoglobulinaemia. Cryoglobulins are present in serum, but the blood specimen taken for cryoglobulins must be kept warm (37°C) and it can be easier to send the patient rather than the sample to the immunology laboratory. Rheumatoid factor can sometimes be detected. A skin biopsy might show obstructive vasculopathy (Type I cryoglobulinaemia) or vasculitis (mixed cryoglobulinaemia). Treatment Underlying lymphoproliferative disorders or connective tissue diseases should be treated, and patients should keep warm. Compression bandaging might reduce venous stasis and improve leg ulceration. In hepatitis C virus infection, interferon-​α reduces viral load and cryoglobulinaemia, but about 80% of responders relapse within 6 months. Few data are available on the response of neur- opathy, renal disease, or cutaneous ulceration to this treatment. The treatment for patients without hepatitis C virus infection, or those with progressive disease, can involve corticosteroids in combination with cytotoxic agents, although the new directly acting antiviral drugs might offer the best approach. Plasmapheresis has been used to treat rapidly progressive cryoglobulinaemic vasculitis. Hypocomplementaemic urticarial vasculitis Pathogenesis and pathology Urticarial vasculitis (Box 23.7.12) occurs in association with con- nective tissue diseases, serum sickness (approximately 10  days after the administration of drugs or vaccines), infection (including HCV), IgM or IgG gammopathy, and haematological malignan- cies. Skin biopsies show prominent dermal oedema with evidence Fig. 23.7.6  Acrocyanosis of the fingers in a young girl with an urticarial vasculitis, but no systemic disease. She also had chilblain-​like lesions on the ears and nose. Although cold appeared to trigger cutaneous disease, no cryoglobulins were found. Fig. 23.7.7  Ulceration surrounded by palpable purpura in a patient with mixed cryoglobulinaemic vasculitis. Box 23.7.12  Hypocomplementaemic urticarial vasculitis CHCC 2012 definition • Vasculitis accompanied by urticaria and hypocomplementaemia affecting small vessels (i.e. capillaries, venules, or arterioles), and as- sociated with anti-​C1q antibodies. Glomerulonephritis, arthritis, ob- structive pulmonary disease, and ocular inflammation are common. CHCC, Chapel Hill Consensus Conference.

23.7  Cutaneous vasculitis, connective tissue diseases, and urticaria 5647 of a leukocytoclastic vasculitis, but changes of vasculitis might be quite subtle. Clinical features Urticaria is characterized by the presence of a recurring itchy rash consisting of smooth, pale papules and plaques with an erythema- tous halo (weals) that fade in about 24 h to leave normal skin. By contrast, the weals of urticarial vasculitis are tender or they burn, they last up to 72 h, and may resolve leaving bruising (Fig. 23.7.8). Urticarial vasculitis is associated with low complement levels in 18% of patients—​these patients have hypocomplementaemic urticarial vasculitis and are included in the Chapel Hill Consensus Conference 2012 definition of vasculitis. This subtype is more likely to be associated with systemic disease, and patients have a higher incidence of arthritis, obstructive pulmonary disease, and gastro- intestinal symptoms than those with normal complement levels. Some patients with low complement levels have anti-​C1q anti- bodies and overlapping features with systemic lupus erythematosus, including pleuritis, glomerulonephritis, eye symptoms, and posi- tive antinuclear antibodies. Treatment Antihistamines or non​steroidal anti-​inflammatory drugs (NSAIDs) can be effective. Prednisolone is helpful, but alternatives such as dap- sone, colchicine, or hydroxychloroquine should be considered to avoid the side effects of prolonged treatment with systemic corticosteroids. Single-​organ vasculitis See Box 23.7.13. Small-​vessel cutaneous vasculitis This is also known as leukocytoclastic angiitis/​vasculitis, cutaneous ​ small-​vessel necrotizing vasculitis, allergic vasculitis, and hypersen- sitivity angiitis. Aetiology and pathology The aetiology of small-​vessel cutaneous vasculitis is uncertain (idio- pathic) in at least 50% of patients, but has been ascribed to infections in 15–​20% of patients, inflammatory diseases such as connective tissue diseases in 15–​20% of patients, drugs in 10–​15% of patients (usually 7–​21 days after commencing the drug), and malignancies, especially lymphoproliferative disorders, in 5% of patients. Small-​vessel cutaneous vasculitis involves dermal small vessels, predominantly postcapillary venules. The histological findings include perivascular neutrophilic inflammation extending into vessel walls, with swelling and injury of endothelial cells; necrosis of vessel walls; fibrinoid deposition around vessels (fibrinoid ne- crosis); and extravasation of red blood cells. The presence of nu- clear dust is indicative of leukocytoclasis (fragmentation of the nuclei of neutrophils). Clinical features Palpable purpura, usually on the lower leg, is the hallmark of small-​ vessel cutaneous vasculitis (Fig. 23.7.9, Box 23.7.14) The purpuric lesions are palpable because the purpura is accompanied by inflam- mation and increased vascular permeability. This contrasts with the flat petechiae and purpura seen in non​inflammatory condi- tions such as thrombocytopenic purpura. Radial diffusion of red blood cells that have leaked from small vessels in the upper dermis produces small oval or round purpuric papules. Thrombosis with Box 23.7.13  Single Organ Vasculitis CHCC 2012 definition • Vasculitis in arteries or veins of any size in a single organ that has no features that indicate that it is a limited expression of a systemic vas- culitis. The involved organ and vessel type should be included in the name (e.g. cutaneous small-​vessel vasculitis (SVV), testicular arter- itis, central nervous system vasculitis). Vasculitis distribution may be unifocal or multifocal (diffuse) within an organ. Some patients originally diagnosed with single-​organ vasculitis (SOV) will develop additional disease manifestations that warrant re-​defining the case as one of the systemic vasculitides (e.g. cutaneous arteritis later becoming systemic polyarteritis nodosa, and so on). CHCC, Chapel Hill Consensus Conference. Fig. 23.7.8  Urticarial vasculitis: tender urticated papules and plaques that are associated with purpura and resolve with bruising. Fig. 23.7.9  Palpable purpura is the hallmark of small-​vessel cutaneous vasculitis. Small oval or round purpuric papules are found in areas of stasis (below the knee), at pressure sites (elbows, sacrum, waist band), or at sites of cooling.

section 23  Disorders of the skin 5648 infarction is unusual in a small-​vessel cutaneous vasculitis, but ir- regularly outlined indurated areas of haemorrhagic infarct are produced when deeper dermal or subcutaneous vessels become thrombosed in other conditions. Patients present with a symmetrical purpuric rash in dependent areas such as the leg, at sites of trauma (Koebner phenomenon), pressure sites (elbows, sacrum, waist band), or sites of cooling. Oval or circular erythematous lesions rapidly become raised (palpable) and purpuric, sometimes coalescing into larger polycyclic lesions (Figs. 23.7.10). Some patients develop annular purpuric lesions with haemorrhagic or vesicular centres, or superficial ulceration. Intense inflammation produces haemorrhagic bullae or pustules. Lesions fade gradually over three or four weeks leaving macular pigmenta- tion (haemosiderin) or atrophic scars. Differential diagnosis Purpura does not blanch with light pressure, unlike erythema. Purpuric lesions can be divided into those that are associated with inflammatory pathology (vasculitis) and are palpable, and those that are non​inflammatory and flat (i.e. macular). Scattered flat purpuric spots can be a non​specific finding on the legs in association with inflammatory dermatoses such as psoriasis or stasis eczema. The frail sun-​damaged skin on the forearms of older patients, or skin that has been thinned after prolonged ex- posure to corticosteroids, is prone to developing large flat bruises (ecchymoses) after minor trauma. Scurvy causes perifollicular purpura with corkscrew hairs in the centre. Disorders associ- ated with thrombocytopenia produce flat purpuric lesions and petechiae. Cholesterol emboli might produce asymmetrical acral petechiae and subcutaneous nodules, often in association with livedo reticularis (see ‘Thrombo-​occlusive vasculopathies’). Livedo reticularis is also associated with vasculitis affecting deeper cutaneous vessels. Disseminated intravascular coagula- tion (see ‘Septic vasculitis’) produces extensive irregularly out- lined haemorrhagic areas. The vasculitic lesions in idiopathic small-​vessel cutaneous vasculitis are clinically and histologically identical to the cu- taneous lesions in small-​vessel cutaneous vasculitis occurring as a component of a systemic disease. The clinician must rule out systemic disease and also search for other cutaneous signs of vasculitis, such as livedo reticularis or nodules. Patients with systemic vasculitis may give a history of prodromal symptoms such as rather non​specific flu-​like symptoms, myalgia, migra- tory arthralgia, or synovitis. Clinical investigation The history, physical examination, and investigations must de- termine the extent of any systemic disease and identify causative agents: drugs; infections including hepatitis B or C; or conditions associated with circulating immune complexes, such as con- nective tissue diseases, inflammatory bowel disease, lymphoma, multiple myeloma, leukaemia, and solid tumours (Box 23.7.15). If these laboratory studies are normal, further testing to rule out a systemic vasculitis is probably not warranted unless the history and physical examination are not consistent with limited cutaneous disease. A streptococcal sore throat is a common pre- cursor of vasculitis in children, and otitis media, dental caries, cystitis, and sinusitis occasionally play a role. In many countries tuberculosis or leprosy is the most common cause; bacterial endocarditis and meningococcal septicaemia are often missed. Other treatable infections occasionally causing vasculitis are syphilis and those caused by neisseria, rickettsiae, and myco- plasma. Although viral causes cannot usually be eliminated, any history of a recent flu-​like illness or vaccination might be relevant. A skin biopsy to confirm a small-​vessel cutaneous vasculitis should be taken from a palpable purpuric lesion about 12–​24 hr old. A  biopsy taken too late might not show the initial injury. However, the histology is unlikely to reveal the cause of the vascu- litis, exclude systemic disease, or distinguish one form of systemic vasculitis from another. In patients with evidence of medium vessel involvement (e.g. if there is patchy livedo reticularis or ulcerated nodules), an in- cisional biopsy down to fat is necessary to detect pathology in arterioles or small arteries, but if a large-​vessel vasculitis is Box 23.7.14  Clinical features of small-​vessel cutaneous vasculitis • Symmetric palpable purpura of the lower extremities and other de- pendent areas of the body. • Lesions typically develop in crops and may be associated with pruritus, pain, and burning. • Round, port wine-​coloured papules, and plaques with inflammation may be seen. • Diascopy of purpuric lesions (application of direct pressure to the le- sion with a glass slide) demonstrates partial blanching; the blanchable component indicates underlying inflammation (erythema), whereas the non​blanchable component represents haemorrhage (purpura). • Other clinical presentations include urticarial lesions, ulcerative, or infarcted lesions, vesicles, pustules, nodules, livedo, and targetoid lesions. Ulcers or nodules may indicate deeper or medium vessel involvement. CHCC, Chapel Hill Consensus Conference. Fig. 23.7.10  Vasculitic papules have coalesced into plaques in this patient with chronic vasculitis. Stasis localizes disease and aggravates the clinical findings.

23.7  Cutaneous vasculitis, connective tissue diseases, and urticaria 5649 suspected, a biopsy from involved tissue in muscle, nerve, or lung will be more informative than a skin biopsy. The investigation of the systemic vasculitides is discussed in more detail in Sections 19 and 21. Treatment Precipitating agents (drugs or infection) must be identified and removed, but it might still take several weeks for vasculitis to settle. Local factors that might exacerbate or localize vascu- litis (cooling, stasis, trauma) should be minimized by simple measures such as warmth, leg elevation, support stockings, and exercise. Dapsone (50–​200 mg/​day) is effective in controlling limited cu- taneous vasculitis. Colchicine (0.5 mg twice daily) and low-​dose methotrexate (10–​25 mg/​week) have also been recommended. Most patients with small-​vessel vasculitis limited to the skin do not re- quire systemic corticosteroids or more aggressive treatment with immunosuppressive agents. Prognosis Idiopathic small-​vessel vasculitis confined to the skin resolves within a few weeks or months. Most patients have a single episode, but about 10% have recurrent disease that may last months or years. Exercise-​induced vasculitis fades in a few days. Increased understanding of the pathogenesis of vasculitis is likely to lead to the development of targeted immunotherapy with monoclonal antibodies to cell adhesion molecules or cyto- kines that will control the autoimmune response and reduce inflammation. Vasculitis associated with systemic disease Connective tissue diseases Patients with diseases such as systemic sclerosis, rheumatoid arth- ritis, or systemic lupus erythematosus can develop signs of small-​ vessel cutaneous vasculitis, including palpable purpuric lesions on the legs, palms, or digits, haemorrhagic bullae, papulonecrotic purpuric lesions, urticarial vasculitis, or punched-​out necrotic ulcers (Box 23.7.16). Vasculitis can also involve larger vessels, particularly in rheumatoid arthritis (Chapter  19.5) and systemic lupus erythematosus, with livedo reticularis (see ‘Thrombo-​ occlusive vasculopathies’), ulcers, nodules, digital gangrene, or pyo- derma gangrenosum-​like lesions. Vasculitis associated with a probable aetiology Septic vasculitis Pathogenesis Organisms can damage blood vessels by direct invasion, by the release of endotoxins that provoke a thrombotic response (dis- seminated intravascular coagulation), or by inducing an immune-​ mediated vasculitis. Purpuric lesions are most often seen in infective endocarditis, meningococcaemia, gonococcaemia, Gram-​negative septicaemia, and certain rickettsial infections. A septic vasculitis can follow any intravascular procedure. Clinical features The cutaneous signs in infective endocarditis include mucosal pe- techiae, Osler’s nodes (tender erythematous spots on the pulps of the fingers and toes), and Janeway’s lesions (non​tender red or haemorrhagic macules or nodules on the palms and soles). In sub- acute disease, circulating immune complexes probably trigger a leukocytoclastic vasculitis in small vessels that is responsible for mucocutaneous lesions, but septic emboli may play a direct role in the pathogenesis of vasculitic lesions in acute disease. Unilateral emboli following a percutaneous arterial puncture may indicate a septic endarteritis. Disseminated intravascular coagulation (DIC) is a devastating disease characterized by extensive purpura, haematomas, haemorrhagic infarcts, and gangrene. Persistent cyanosis of the extremities is an early sign. DIC is not a vasculitis, but an occlusive vasculopathy in which fibrin thrombi occlude ca- pillaries, venules, and vessels in the deeper dermis and subcutis, leading to ischaemia and infarction. DIC is discussed in detail Chapter 22.7.5. The purpuric lesions of acute meningococcaemia are present on the limbs or trunk in 80–​90% of patients within 12–​36  h of dis- ease onset, but can be small and few in number (Chapter 8.6.5). These lesions are followed by disseminated intravascular coagu- lation, with large irregular indurated ecchymoses with central necrosis that may progress to extensive gangrene. Septic em- boli in Gram-​negative septicaemia caused by Escherichia coli, Pseudomonas, or Klebsiella produce vasculitic lesions that pre- sent as erythematous weals and papules that become irregularly purpuric and necrotic. Box 23.7.15  Preliminary laboratory screening should include: Full blood count, Inflammatory markers (erythrocyte sedimentation rate, C-​reactive protein), Urinalysis, renal function tests, Liver function tests, Hepatitis B and C serology, Complement levels (C3, C4), Immunoglobulins, Rheumatoid factor Antinuclear antibody ASO titre +/​-​ throat swab if appropriate Cryoglobulins should be measured if C4 is low ANCA CHCC, Chapel Hill Consensus Conference. Box 23.7.16  Vasculitis associated with systemic disease CHCC 2012 definition • Vasculitis that is associated with and may be secondary to (caused by) a systemic disease. The name (diagnosis) should have a prefix term specifying the systemic disease (e.g. rheumatoid vasculitis, lupus vas- culitis, and so on). CHCC, Chapel Hill Consensus Conference.

section 23  Disorders of the skin 5650 The immune complex-​mediated febrile illnesses in pa- tients with chronic meningococcaemia or chronic disseminated gonococcaemia are associated with arthralgia, arthritis, and cuta- neous vasculitis. Scattered purpuric papules and vesicopustules ap- pear on the trunk and extremities in chronic meningococcaemia, but have a predilection for the palms, fingers, and soles in dissem- inated gonococcaemia. The histology is a leukocytoclastic vasculitis with thrombosis in small vessels. The maculopapular rash of Rocky Mountain spotted fever is ini- tially erythematous, but becomes petechial and purpuric within 24–​ 48 h. Rickettsia rickettsii invades the walls of small cutaneous vessels, inducing a focal lymphocytic vasculitis with extravasation of red blood cells, and occasional thrombosis. Infections are dealt with in detail in Section 8. Cutaneous vasculitis and malignancy Small-​vessel cutaneous vasculitis, and urticarial vasculitis have been described in association with lymphoproliferative disorders such as Hodgkin’s disease, mycosis fungoides, lymphosarcoma, adult T-​cell leu- kaemia, multiple myeloma, and less often with solid tumours (e.g. cancer of the colon, kidney, prostate, head and neck, or breast). Vasculitis might present two to four years before the manifestation of the tumour. Thrombo-​occlusive vasculopathies Livedo reticularis and livedo racemosa Clinical features Livedo reticularis is seen most often on the legs. The skin develops a mottled reddish-​purple reticulated discoloration that reflects sluggish vascular flow in the superficial dermis (Fig. 23.7.11). Some venous stasis is common. A  continuous livedo network is likely to be physiological, and disappears when the skin is warmed. Broken, discontinuous, or patchy and persistent livedo reticularis, that does not disappear with warming and sometimes in associ- ation with painful cutaneous ulceration and nodules (evidence of a vasculitis) (Figs 23.7.3 and 23.7.12), occurs with hyperviscosity states (polycythaemia rubra vera, antiphospholipid antibodies, cryoglobulinaemia), medium-​vessel vasculitis (connective tissue diseases, polyarteritis nodosa, and granulomatosis with polyangiitis (Wegener’s granulomatosis)), and emboli, including cholesterol em- boli. Patchy and persistent livedo is also termed livedo racemosa (Fig. 27.7.3), rather than reticularis. Differential diagnosis and investigation Erythema ab igne is a reticulated hyperpigmented staining that can develop on any skin surface after chronic exposure to heat from a radiator, open fire, or hot-​water bottle. Deep biopsies from subcuta- neous nodules are required to demonstrate diagnostic pathology such as cholesterol emboli or a medium-​vessel vasculitis. Livedoid vasculopathy This is also known as segmental hyalinizing vasculitis, livedo reticularis with summer/​winter ulceration, and livedoid vasculitis. Pathogenesis and pathology This idiopathic disorder predominantly affects young to middle-​ aged women. The condition is primarily an occlusive vasculopathy rather than a necrotizing vasculitis. Hyaline thrombi occlude small vessels in the upper and mid dermis. Occlusion may be associated with endothelial swelling, extravasation of red blood cells, fibrinoid material in vessel walls, infarction of the superficial dermis, and scat- tered perivascular lymphocytes. Endothelial, platelet, or lymphocyte activation with the release of proinflammatory cytokines may play some part in the pathogenesis of hypercoagulation. Clinical features Focal purpuric lesions on the lower legs and dorsum of the feet break down to form small excruciatingly painful ulcers that are sur- rounded by a purpuric rim (Fig. 23.7.13). Ulcers heal slowly, leaving Fig. 23.7.11  Extensive livedo reticularis. Fig. 23.7.12  Painful cutaneous ulceration, necrotizing vasculitis, and livedo reticularis in a patient with antiphospholipid antibodies.

23.7  Cutaneous vasculitis, connective tissue diseases, and urticaria 5651 atrophie blanche (porcelain-​white stellate scars with a rim of telangi- ectasia) and net-​like hyperpigmentation. The condition pursues a chronic course, sometimes with seasonal exacerbations. Investigation and treatment Livedoid vasculopathy can be a manifestation of an underlying coagulopathy, such as antiphospholipid syndrome or protein C defi- ciency, but in general, investigations reveal no evidence of abnormal- ities in fibrinolytic or coagulation systems. Pain must be controlled. Antiplatelet therapy, antithrombotic regimens, fibrinolytic agents, and intravenous immunoglobulin have all been recommended, but there is no consensus over management, and treatment is difficult. Treatment for vasculitis with drugs such as systemic corticosteroids is generally ineffective. Hypertensive ulcer (Martorell’s ulcer) Hypertensive ulcers were described in 1945. The pathogenesis might be linked to a thrombo-​occlusive vasculopathy of cutaneous arteri- oles in long-​standing hypertension, but the existence of this entity is controversial. A purpuric lesion appears on the anterolateral aspect of the shin between the mid and lower third of the leg. It becomes necrotic and forms a superficial ulcer with an erythematous or purpuric rim. Patients have no signs of venous or arterial insufficiency. The ulcers, which can be bilateral, are extremely painful. Management involves the control of hypertension, pain relief, and compression bandaging. Neutrophilic dermatoses Neutrophilic dermatoses This heterogeneous group is linked by the histopathological finding of a heavy dermal infiltrate of neutrophils with leukocytoclasis, but limited evidence of vasculitis. Sweet’s syndrome (acute febrile
neutrophilic dermatosis) Sweet’s syndrome was described in 1964. The condition usually af- fects women in their sixth decade. Pathogenesis and pathology The cause is unknown and 50–​70% of cases are idiopathic, but in up to 50% of cases Sweet’s syndrome may be associated with malig- nancy (haematological or solid tumours) or immunological disease (rheumatoid arthritis, dermatomyositis, relapsing polychondritis, inflammatory bowel disease). Less frequently, a variety of infections or certain drugs such as granulocyte colony stimulating factor ap- pear to have precipitated the disease. A skin biopsy shows a dense neutrophilic infiltrate in the upper dermis, with leukocytoclasis and nuclear dust. The dermis is oedematous. Vessels show endothelial swelling without a true vasculitis. Clinical features The syndrome is characterized by the sudden onset of fever, neutrophilia, and tender erythematous nodules and plaques, most frequently on the face and upper trunk (Fig. 23.7.14). The plaques appear oedematous, but blisters are unusual; occasionally they may be pustular. Other features include conjunctivitis or episcleritis, oral ulcers, arthralgia, and arthritis. Investigations and treatment Infection should be excluded by blood culture. The erythrocyte sedi- mentation rate is elevated, and patients have a marked neutrophilia. Underlying malignancy should be excluded by the history, physical examination, and appropriate investigations. A skin biopsy is essential to confirm the diagnosis. Most patients respond rapidly to systemic corticosteroids (0.5–​1.0 mg/​kg) used in association with potent top- ical corticosteroids, but the disease might relapse as corticosteroids are reduced. A minority of patients have chronic relapsing disease. Bowel-​associated dermatosis–​arthritis syndrome Pathogenesis This syndrome is seen in 10–​20% of patients who have had bowel bypass surgery to treat morbid obesity, or after extensive resection Fig. 23.7.13  Livedoid vasculopathy with small painful ulcers that eventually healed to leave porcelain-​white stellate scars (atrophie blanche). This patient has no evidence of systemic disease or abnormalities in coagulation. A skin biopsy revealed an occlusive vasculopathy without vasculitis. Fig. 23.7.14  Sweet’s syndrome: oedematous plaques in a woman with myeloid leukaemia.

section 23  Disorders of the skin 5652 of the small bowel. It occurs less frequently in patients with an ab- normal segment of bowel in other diseases, such as diverticulitis or inflammatory bowel disease. The overgrowth of bacteria in a blind loop, with the deposition of immune complexes, is thought to trigger disease. The histopathological changes resemble those of Sweet’s syndrome. Clinical features The syndrome is characterized by purpuric papules and small vesiculopustular lesions on the trunk and extremities. These might be associated with polyarthritis, malaise, and fever. Some patients have cryoglobulinaemia. Management should be directed at cor- recting the underlying cause. Cutaneous lupus erythematosus Cutaneous lupus erythematosus (CLE) is an autoimmune disease, which has a broad range of cutaneous pathology. It is two to three times more common than systemic lupus erythematosus (SLE). Aetiology and pathogenesis The pathogenesis of cutaneous lupus erythematosus (CLE) is un- certain, but in genetically predisposed individuals ultraviolet (UV) light might play some part in triggering and perpetuating disease through apoptosis and the release of proinflammatory cytokines. UV exposure can also lead to increased synthesis and expression of the Ro/​SS-​A antigen on keratinocytes. It has been hypothesized that autoantigens on the surface of apoptotic cells might stimulate the immune system, and antibodies to Ro are very common in sub- acute cutaneous lupus erythematosus (SCLE) and may be detected in other types of cutaneous lupus erythematosus. Drugs that cause photosensitive SCLE skin lesions also trigger the production of Ro (SS-​A) autoantibodies. However, the role of these autoantibodies in the pathogenesis is not proven. Certain genes (e.g. HLA, TNF​α gene promoter) increase susceptibility to subacute cutaneous lupus erythematosus. Pathology Skin biopsies show a lichenoid (interface) dermatitis with apoptotic basal keratinocytes, a T-​cell inflammatory infiltrate at the dermo–​ epidermal junction, periadnexal inflammation, and perivascular in- flammation without vasculitis. Inflammation and basal cell damage are most marked in chronic cutaneous lesions. The prevalence of cutaneous lupus ranges from 14.6 to 68 per 100 000 people. All races are affected. Most forms of cutaneous lupus erythematosus affect women more than men. Classification Cutaneous lupus erythematosus is classified into acute, subacute, and chronic subtypes (Box 23.7.17), but patients often have more than one type of lesion. The terms discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus (SCLE) are used in two ways: either to describe a subtype of lupus skin lesion, or to refer to subsets of patients who share certain clinical and laboratory features. At present, dermatologists use the only universally accepted criteria for the classification of systemic lupus erythematosus, which was proposed by the American College of Rheumatology (ACR). Box 23.7.17  Subtypes of cutaneous lupus erythematosus (LE) Acute cutaneous lupus erythematosus (ACLE) • Presents in third decade of life • Occurs in active systemic lupus erythematosus Localized form Oedematous malar erythema (‘butterfly rash’) Photosensitivity Non​scarring lesions, however depigmentation may occur Generalized form Occurs below and above the neck and described as ‘maculopapular rash of lupus’ May resemble a drug rash Subacute cutaneous lupus erythematosus (SCLE) • Affects young to middle-​age females • May have systemic lupus erythematosus, but low risk of severe disease • Photosensitivity • Anti-​Ro antibodies • Superficial scaly annular lesions (common) involve the V-​area of the neck, the upper trunk, upper limbs, and hands (sparing the knuckles cf. dermatomyositis) • Papulosquamous lesions (less common) may resemble psoriasis or eczema • Face is affected less often than in other forms of cutaneous lupus erythematosus • Non​scarring, but postinflammatory hypopigmentation is common • Affected mothers may have infants with neonatal lupus erythematosus Chronic cutaneous lupus erythematosus—​four types: Discoid lupus erythematosus (DLE) • Most common form of chronic cutaneous lupus erythematosus • Frequently occurs without evidence of systemic lupus erythematosus • Usually localized to the head and neck, but may be widespread • Erythematous telangiectatic plaques or hyperkeratotic plaques with adherent keratotic scale • Plaques on the face tend to spare the nasolabial fold • Acne-​like plugged follicles involve the concha of the ears • Plaques may involve the vermillion border of the lips or eyelids • Lichen planus-​like lesions develop on the buccal mucosa • Chronic plaques cause scarring and deformity • Perifollicular inflammation leads to irreversible hair loss (scarring alopecia) • Dyspigmentation (increased or decreased) is common in dark skins Lupus erythematosus profundus (LEP) • Subcutaneous nodules-​ painful and firm • Tends to involve the shoulders, upper arms, face, and buttocks • Overlying skin may be affected by discoid lupus erythematosus • Fat loss is a disfiguring complication • Subcutaneous nodules may calcify and ulcerate Chilblain lupus • Less common form of chronic cutaneous lupus erythematosus • Resembling frostbite • Painful, violaceous plaques, and nodules in cold-​exposed area • Ulceration or erosion occurs on acral surfaces (fingers, toes), nose, ears Lupus erythematosus tumidus • Occurring mainly in males • Extreme photosensitivity • Lesions on the face and trunk • Erythematous, oedematous, urticaria-​like with sharp border and smooth surface

23.7  Cutaneous vasculitis, connective tissue diseases, and urticaria 5653 Acute cutaneous lupus erythematosus (ACLE) This condition occurs in third decade of life and it is frequently as- sociated with active systemic lupus erythematosus. There are two forms, localized and generalized. In the localized form, oedematous malar erythema develops in photosensitive patients with active systemic lupus erythematosus. The rash is commonly described as a ‘butterfly’ rash: erythema on the cheeks, over the nasal bridge, and sparing the nasolabial folds. The rash can be confused with acne rosacea and seborrhoeic dermatitis. The lesions are usually transient, resolving rapidly without scarring once the patient is protected from UV light. Subepidermal bullae are an uncommon manifestation associated with antibodies to basement membrane zone antigens, including type VII collagen. The rarer generalized form presents with a pruritic, widespread eruption of symmetrical macules and papules that are photosensi- tive and may look like a drug rash. It may resemble dermatomyo- sitis as both diseases involve the dorsum of the hand. However, dermatomyositis involves the distal and proximal interphalangeal and metacarpophalangeal joints, while they are spared in acute cutaneous lupus erythematosus (Fig. 23.7.16). Immunologically, antinuclear antibody (ANA), dsDNA, and anti-​Sm antibodies are found in most cases. Subacute cutaneous lupus erythematosus (SCLE) Subacute cutaneous lupus erythematosus was first recognized in 1979 as a distinct subtype of lupus erythematosus with a low risk of severe systemic lupus erythematosus. This pattern of disease is associated with photosensitivity and anti-​Ro (SS-​A) antibodies. Subacute cutaneous lupus erythematosus may be induced by a variety of drugs, including hydrochlorothiazide, calcium-​channel blockers, angiotensin-​converting enzyme inhibitors, proton pump inhibitors, and terbinafine. The scaly, erythematous lesions develop in a photosensitive distri- bution (Figs. 23.7.15 and 23.7.16), and can be annular (Fig. 23.7.17) or, less frequently, papulosquamous (resembling psoriasis). Lesions do not scar but they might leave behind pigmentation change, usu- ally hypopigmentation. Women with subacute cutaneous lupus erythematosus might have infants affected by neonatal lupus erythematosus, because anti-​Ro antibodies cross the placenta. These infants present with photosensitive cutaneous disease (usually subacute cutaneous lupus erythematosus) or congenital heart block, but rarely both. Infants can also develop transient haemolytic anaemia, thrombocytopenia, leukopenia, and elevated liver function tests. Skin signs resolve over four to six months, but heart block is permanent. Rarely, infants af- fected by neonatal lupus erythematosus develop a connective tissue disease later in life. Fig. 23.7.15  Subacute cutaneous lupus erythematosus: nonscarring scaly erythematous papules are distributed in a photosensitive distribution on the chest and arms. Fig. 23.7.16  Cutaneous lupus erythematosus involves the skin between the knuckles, by contrast with the scaly papules of dermatomyositis (Gottron’s papules), which occur over the knuckles. Fig. 23.7.17  Subacute cutaneous lupus erythematosus (SCLE) may adopt a striking annular configuration, when it can be confused with tinea corporis (ringworm), but typically the scale of SCLE is on the inner border of the rings, and the rash is in a photosensitive distribution.

section 23  Disorders of the skin 5654 Chronic cutaneous lupus erythematosus (CCLE) Discoid lupus erythematosus is the most common form of chronic cutaneous lupus erythematosus (Box 23.7.17). It occurs more often in females in their fourth and fifth decades of life. It has a more benign course compared with other chronic cutaneous lupus erythematosus subtypes. Most discoid lesions are localized to the head and neck, but it may be widespread and affects the extensor forearms and hands. (Figs. 23.7.18–​23.7.23). Discoid lupus erythematosus le- sions appear as a well-​demarcated, scaly, erythematous macule or papule, which gradually transforms into a coin-​shaped (discoid) plaque with scale (which is painful to remove). Plaques tend to affect hair follicles and cause scarring alopecia. Sun exposure and trauma (Koebner phenomenon) tend to exacerbate the disease. Squamous cell carcinomas may rarely occur within chronic lesions of discoid lupus erythematosus. Lupus erythematosus profundus (LEP) is a lobular panniculitis that occurs in 1–​3% of patients with cutaneous lupus erythematosus (Fig. 23.7.24). LEP tends to affect the upper arms, legs, face, and breasts. It has a chronic course, with relapses and remissions, and due to fat loss, leaves disfiguring, atrophic scars. Cold-​induced chilblain lupus is characterized by purple plaques on the fingers or toes (Fig. 23.7.25) which may ulcerate (Fig. 23.7.26); chronic lesions develop a warty surface (Fig. 23.7.27). The histology is not specific, but this pattern of disease may be associated with sys- temic lupus erythematosus. Lupus erythematosus tumidus is an uncommon variant that does not scar, but is associated with photosensitivity. Smooth, erythema- tous, urticated nodules appear on sun-​exposed skin, and may per- sist for weeks. The diagnosis is clinical, as most patients do not have lupus antibodies, and the histology may not be diagnostic. Non​specific cutaneous signs in systemic
lupus erythematosus Forty to seventy per cent (40–​70%) of patients with systemic lupus erythematosus develop non​scarring alopecia. Causes include lupus hairs (hairs break off at the front of the scalp), telogen effluvium Fig. 23.7.18  Chronic erythematous telangiectatic plaques in a photosensitive distribution on the face of a woman who has systemic lupus erythematosus. Fig. 23.7.19  Discoid lupus erythematosus. This man has well-​defined, scaly plaques on the face. Note the pale areas of atrophic scarring. From R Graham-​Brown, K Harman, G Johnston (2016) Lecture Notes: Dermatology, 11th Edition. Copyright © 2016, John Wiley and Sons. Fig. 23.7.20  Chronic discoid lupus erythematosus causes scarring and deformity, seen here on the bridge of the nose.

23.7  Cutaneous vasculitis, connective tissue diseases, and urticaria 5655 (shedding after severe illness), and alopecia areata. In contrast, dis- coid lupus erythematosus can cause scarring alopecia (Box 23.7.17 and Fig. 23.7.21). Patients with systemic lupus erythematosus might have periungual erythema and discrete papular telangiectasia on the palms or finger tips. Some have Raynaud’s phenomenon. About 10–​20% of patients with systemic lupus erythematosus have some form of vasculitis. Linear telangiectasia is present on the posterior nail fold (a sign of a connective tissue disease also found in dermatomyositis, systemic sclerosis, and 5% of cases of rheumatoid arthritis). Thrombosed vessels might be carried forward into a ragged cuticle. Painless red-​black lesions of the nail fold or finger pulp (Bywater’s lesions) reflect micro-​infarcts of superficial dermal vessels, and are most common in rheumatoid arthritis, but can be seen in systemic lupus erythematosus (Fig. 23.7.28). Urticaria is common in systemic lupus erythematosus, but long-​ lasting tender urticarial lesions that fade to leave bruises are a sign of urticarial vasculitis, sometimes an indication of an underlying com- plement deficiency. A  small-​vessel cutaneous vasculitis (palpable purpura) might be associated with cryoglobulinaemia (see ‘Small-​ vessel cutaneous vasculitis’ earlier on in this chapter). Fixed livedo reticularis in a broken rather than a continuous physiological pattern might be linked to the antiphospholipid syn- drome, a medium-​vessel vasculitis, recurrent thromboses, and neurological complications. Atrophie blanche, a sign of vasculitis or Fig. 23.7.21  Discoid lupus erythematosus in the scalp causes a scarring alopecia that may be extensive and disfiguring. Fig. 23.7.22  The plugged lesions of discoid lupus erythematosus in the concha of the ears were misdiagnosed as acne, and in this patient with dark skin have caused hyperpigmentation. Fig. 23.7.23  Discoid plaques on the vermillion border of the lips are triggered by ultraviolet light. Fig. 23.7.24  Lupus panniculitis on the upper arm presented as a deep tender nodule. The overlying skin is affected by discoid lupus erythematosus. Chronic ulceration is a troublesome complication that may be precipitated by a biopsy.

section 23  Disorders of the skin 5656 obstructive vasculopathy, can be present on the plantar surface of the toes (Fig. 23.7.29) or fingers. Differential diagnosis Red faces are common, but the distribution and morphology of the rash will provide important clues to the underlying diagnosis. Patients with a malar (butterfly) rash that spares the sun-​protected skin on the eyelids, behind the ears, and under the chin can be photosensitive, but drugs cause photosensitivity more often than lupus erythematosus. Pustules are not found in cutaneous lupus erythematosus; in- stead consider rosacea or steroid-​induced acne (a complication in patients treating cutaneous lupus erythematosus with potent topical steroids). Seborrhoeic dermatitis produces a superficial scaly facial erythema involving the nasolabial folds (unlike lupus erythematosus), mid-​forehead, and scalp (dandruff). Seborrhoeic dermatitis is not photosensitive, does not scar, and is not usually associated with hair loss (Chapter 23.6). The cutaneous signs in dermatomyositis (see ‘Cutaneous fea- tures of dermatomyositis’ next) are similar to those of lupus erythematosus; however, the intense itching that plagues patients with cutaneous dermatomyositis is not a feature of cutaneous lupus erythematosus. Both conditions are photosensitive, but the facial rash in dermatomyositis is more oedematous than in cutaneous lupus erythematosus, and tends to involve the nasolabial folds, un- like cutaneous lupus erythematosus. The rash of dermatomyositis targets the skin over the joints on the hands, whereas cutaneous lupus erythematosus tends to involve the skin between the joints (Fig. 23.7.16). In patients with subacute cutaneous lupus erythematosus, a drug-​ induced aetiology must be considered. The annular lesions might be mistaken for dermatophyte infection (ringworm), but the trailing edge of scale is on the inner edge of the ring and follows the erythema (Fig. 23.7.17), whereas in dermatophyte infection, scale on the outer Fig. 23.7.25  Purple plaques on the toes or fingers are characteristic of chilblain-​like cutaneous lupus erythematosus. Fig. 23.7.26  Ulceration of the fingertips in a patient with chilblain lupus erythematosus. Fig. 23.7.27  Chronic hyperkeratotic chilblain lesions may fissure. Fig. 23.7.28  Vascular involvement in systemic lupus erythematosus may present with infarcts of the nail fold (Bywater’s lesions). This patient also has extensive atrophie blanche (hypopigmented atrophic skin with telangiectasia) on the dorsa of the fingers, indicative of vascular damage.

23.7  Cutaneous vasculitis, connective tissue diseases, and urticaria 5657 edge of the expanding ring is followed by erythema. Subacute cu- taneous lupus erythematosus must also be differentiated from ery- thema multiforme (Chapter  23.16) and psoriasis (Chapter  23.5). Psoriasis might coexist with cutaneous lupus erythematosus and can be exacerbated by the antimalarials used to treat cutaneous lupus erythematosus; check for psoriatic nail pitting or onycholysis. Hypertrophic discoid lupus erythematosus may simulate a squa- mous cell skin cancer. Clinical investigation Systemic disease should be excluded by the history, physical examination, and laboratory studies including examination of the urine, a full blood count, routine biochemistry, and immun- ology (antinuclear antibodies, antibodies to extractable nuclear antigens, antihistone antibodies in suspected drug-​induced lupus erythematosus, and complement levels). The diagnosis should be confirmed by the histological examination of a skin biopsy. Immunofluorescence testing is not required unless the lesions are bullous. In annular subacute cutaneous lupus erythematosus, dermatophyte infection should be excluded by mycological culture of a skin scrape. Treatment Treatment aims to minimize scarring and pigment change by controlling cutaneous disease. Patients should be advised to stop smoking (smokers have disease that is more severe and which is less responsive to antimalarials, possibly due to altered drug metabolism). Patient education on heat, sun, and drug avoid- ance is important. Also patients should be advised to avoid ma- nipulation of the lesions as it may trigger new lesions (Koebner phenomenon). Photoprotection is essential (Box 23.7.18). Some patients are sen- sitive to both UVA (penetrates glass) and UVB, while others are sen- sitive to UVA alone or UVB alone. Occasionally, visible light triggers disease. Adequate sun protection will reduce the need for topical corticosteroids or systemic treatment. Physical sunscreens with ti- tanium dioxide or zinc oxide provide good broad-​spectrum pro- tection. Sunblocking films can be applied to glass to prevent UVA penetration. In such patients vitamin D levels should be monitored and addressed as necessary. Very potent topical corticosteroids or calcineurin inhibitors are required to control inflammation and prevent scarring. Initially, a very potent topical corticosteroid (such as clobetasol propionate 0.05% ointment) should be thinly applied twice daily to all lesions, including those on the face. Clobetasol propionate scalp application can be used for discoid lesions in the scalp. It might take several weeks of treatment before the inflammation settles, particularly in thick discoid lesions. Atrophy is unlikely if treatment is supervised, but the strength of corticosteroid should be reduced gradually to less potent preparations as soon as the inflammation is controlled and the lesions have flattened. Calcineurin inhibitors have emerged in recent years and are an alternative to topical corticosteroids, especially for use on the face. Tacrolimus 0.1% ointment is usually effective and prevents develop- ment of telangiectasia (a side effect of topical steroids). Patients should be shown how to apply the treatment (steroid phobia causes undertreatment), and be advised that treatment aims to control inflammation and further damage, but will not alter scars or pigmentation. Patients with disfiguring scars or pigment change need advice on the use of cosmetic camouflage creams. Patients with widespread cutaneous lupus erythematosus or lo- calized disease that does not respond to topical treatment need systemic treatment with an antimalarial in addition to topical treat- ment. Hydroxychloroquine 200 mg twice daily (<6.5 mg/​kg per day) is effective after about 8–​12 weeks in most patients, and is well-​ tolerated, but is less effective in smokers. Ocular toxicity has been re- ported with the related drug chloroquine, but hydroxychloroquine may be safer, provided the maximum dose is not exceeded. Visual acuity should be checked, and patients should see an optician an- nually. Mepacrine (quinacrine) can be used in combination with hydroxychloroquine. Other options include dapsone, thalidomide, and gold. Systemic corticosteroids can be used (e.g. prednisolone 0.5–​1 mg/​ kg/​day) and tapered over 2–​4 weeks. Immunosuppressants such as methotrexate can be used, with recommended dose 7.5–​25 mg or- ally or subcutaneously once a week. Immunomodulators, such as dapsone (25–​150 mg/​day), have been shown to be effective in some cases of lupus panniculitis, subacute cutaneous lupus erythematosus, and discoid lupus Fig. 23.7.29  This woman with systemic lupus erythematosus had no signs of active disease apart from atrophie blanche on the plantar surface of her toes. Atrophie blanche indicates either obstructive vasculopathy or vasculitis. The skin may ulcerate after minor trauma or in cold weather. It is important to examine the toes of any patient with
a connective tissue disease. Box 23.7.18  Strategies for photoprotection • Limit sun exposure, particularly between 11.00 a.m. and 2.00 p.m. • Wear clothing with a tight weave • Wear wide-​brimmed hats (a brim of 7 cm) • Use high-​factor broad-​spectrum sunscreens containing the physical blocker titanium dioxide or zinc oxide to block the entire UV and vis- ible light spectrum. • Apply sunscreen liberally in the morning to all exposed sites • Reapply sunscreen four hourly during the hours of sunlight • Consider vitamin D supplements in patients who need to photoprotect

section 23  Disorders of the skin 5658 erythematosus. Dapsone can cause agranulocytosis, haemolysis, methaemoglobineamia, or hypersensitivity reactions. Patients who have glucose-​6-​phosphate dehydrogenase (G6PD) deficiency should not take this drug. Rituximab, a chimeric monoclonal antibody that targets CD20, can be effective in cases of refractory subacute cutaneous lupus erythematosus and systemic lupus erythematosus with cutaneous lesions. Prognosis Systemic lupus erythematosus is most frequent in patients with acute cutaneous lupus erythematosus or lupus erythematosus-​ non​specific skin lesions. One-​half of patients with subacute cuta- neous lupus erythematosus fulfil the criteria for systemic lupus erythematosus, but only 10–​15% of patients presenting with sub- acute cutaneous lupus erythematosus develop severe manifestations of systemic lupus erythematosus. Drug-​induced subacute cutaneous lupus erythematosus does not always reverse on withdrawal of the triggering drug. Discoid lupus erythematosus eventually remits in 50% of those with localized disease (confined to the head and neck). Most pa- tients with localized chronic cutaneous disease, including lupus panniculitis and lupus erythematosus tumidus, do not develop sig- nificant systemic disease. Discoid lupus erythematosus occurs with systemic lupus erythematosus in 5–​10% of patients, but those with widespread discoid lupus erythematosus are most at risk. The course is benign and renal disease, if it occurs, is usually mild. Dermatomyositis Dermatomyositis is a multisystem autoimmune disorder affecting skin, muscle, and blood vessels. It has characteristic cutaneous changes and can be associated with muscle weakness and inflam- mation. In adults, the disease is often associated with an underlying malignancy (carcinoma or lymphoma). Aetiology, genetics, pathogenesis, and pathology The cause of the disease is unknown. However, T lymphocytes, pre- dominantly of the CD4 + phenotype, appear to play a pathogenic role in mediating microvascular injury and the apoptosis of basal kera- tinocytes. Cytokines and chemokines released by activated T cells and keratinocytes can induce and perpetuate inflammation. UV-​induced apoptosis might also play a part in the pathogenesis of skin lesions. A range of factors might be important in the aetiology of the disease: genetics (HLA-​B* in children and HLA-​DR3 and B14 in adults); infections (toxoplasmosis, parvovirus B19, coxsackie B virus, staphylococcal osteomyelitis and arthritis); malignancy (lung, breast, female genital tract, gastrointestinal tract, kidney or testes and lymphoma); autoantibodies (Jo-​1, PL-​12, PM-​1). The cutaneous histological features include an interface derma- titis (vacuolar degeneration of basal keratinocytes and apoptosis), mild perivascular inflammation, oedema, and deposition of dermal mucin. The histological features are usually similar to those of cu- taneous lupus erythematosus, but the acute vesiculobullous variant might resemble graft-​versus-​host disease. Dermatomyositis affects adults and children of all races. Females are affected more often than males. Clinical features Skin and muscle involvement usually present within a short time of each other, but the extent of skin involvement does not correlate with severity of muscle disease. Skin and muscle problems present concurrently in 60% of patients, whereas in 10% muscle involve- ment precedes inflammatory cutaneous disease, and in 30% the skin involvement presents weeks or a few months before the onset of myositis (Box 23.7.19). The term amyopathic dermatomyo- sitis (dermatomyositis sine myositis) describes a subset of patients, usually female, in whom muscle involvement does not develop until up to 20 years after the onset of cutaneous dermatomyositis. These patients are still at risk of interstitial lung disease or internal malignancy. Cutaneous dermatomyositis, unlike cutaneous lupus erythema­ tosus, can cause pruritus, burning, and pain. Ultraviolet light exacerbates or triggers the rash in up to 50% of patients, but pa- tients might not realize that the rash is photosensitive. A symmet- rical violaceous or heliotrope (violet-​red) erythema of the eyelids or periorbital skin is associated with fine scale and periorbital oedema or facial swelling (Figs. 23.7.30 and 23.7.31). Intense oe- dema can lead to blisters. Erythema also affects the cheeks, the V-​area of the upper chest and neck, the posterior neck, upper back, and shoulders (shawl sign), the extensor aspects of the shoulders, Box 23.7.19  Clinical features of dermatomyositis Dermatomyositis is an idiopathic inflammatory myopathy associated with a characteristic skin rash. Key features are a proximal myopathy and cutaneous findings which typically include erythema on sun-​exposed sites, a heliotrope rash, and oedema on the eyelids, Gottron’s papules (over the joints), periungual erythema with ragged cuticles and dilated nailfold capillaries. Fig. 23.7.30  Periorbital oedema and facial swelling was misdiagnosed as angioedema in this woman with dermatomyositis.

23.7  Cutaneous vasculitis, connective tissue diseases, and urticaria 5659 arms, forearms, and fingers, and bony prominences of the el- bows, knees, knuckles, and greater trochanter of the hip (holster sign). Scalp involvement can be associated with diffuse alopecia (Fig. 23.7.32). The hands should be examined using magnification (an ophthal- moscope or dermatoscope) to assess the nail fold. Signs in the hands or nails can be diagnostic, and are listed in Box 23.7.20 (Figs. 23.7.33 to 23.7.36). Chronic inflammation results in poikiloderma (hypo-​ and hyperpigmentation, atrophy, and telangiectasia). Vasculopathy, with necrosis and ulceration, and cutaneous calcinosis (Fig. 23.7.37) are less common in adults than children. Other clinical features include interstitial lung disease, which can be fatal, Raynaud’s phenomenon, and constitutional symptoms such as fever, fatigue, and weight loss. In severe cases, the myopathy can affect the oesophageal and respiratory musculature. A subset of patients might present with ‘mechanic’s hands’ (Box 23.7.20 and Fig. 23.7.36), skin changes on the digits that simulate Fig. 23.7.31  The characteristic heliotrope (violet-​red) erythema of the eyelids is revealed more clearly when the patient closes her eyes. From Harris A et al. (1995). Dermatomyositis presenting in pregnancy. Br J Dermatol, 133, 783–​5, with permission. Copyright © 2006, John Wiley and Sons. Fig. 23.7.32  Scalp erythema with hair loss may be difficult to manage in dermatomyositis, and simulates the scarring alopecia in chronic cutaneous lupus erythematosus. Box 23.7.20  Dermatomyositis: signs in the hands • Periungual erythema • Tortuous nailfold capillaries and capillary dropout (avascular areas) • Thickened irregular cuticles with capillary haemorrhage • Gottron’s papules (flat-​topped violaceous scaly papules over the dorsal interphalangeal joints) are present in about one-​third of patients, and are pathognomonic of dermatomyositis. Gottron’s papules evolve into hypopigmented atrophic areas with irregular telangiectasia. • Linear streaks of erythema over the extensor tendons of the fingers. • Mechanic’s hands: hyperkeratosis, scaling, and fissuring on the tips and lateral aspects of the digits simulates a contact dermatitis Fig. 23.7.33  Periungual erythema, tortuous nailfold capillaries, capillary dropout (avascular areas), and/​or thickened irregular cuticles with capillary haemorrhage are more common in dermatomyositis than in lupus erythematosus. Fig. 23.7.34  Flat-​topped violaceous scaly papules over the dorsal interphalangeal joints (Gottron’s papules) are pathognomonic of dermatomyositis. Chronic papules develop depressed porcelain-​white centres, with prominent telangiectasia (see Fig. 23.7.35).

section 23  Disorders of the skin 5660 those of a contact dermatitis seen in a manual worker. These changes can be a manifestation of the antisynthetase syndrome, a subset of dermatomyositis characterized by these skin changes plus Raynaud’s phenomenon, interstitial lung disease, arthritis, and fevers. It is associated with antibodies to aminoacyl-​tRNA synthetases, most commonly anti-​Jo1. Dermatomyositis is associated with internal malignancy in 20–​30% of adult patients, most commonly ovary, lung, gastrointestinal tract, breast, and lymphomas. The increased risk can persist for five years after diagnosis, but is greatest in the first year, and in women. Signs linked to malignancy include corticosteroid resistance, an intense erythematous flush on the shoulders, neck, face, and scalp (malig- nant suffusion) and cutaneous ulceration. Differential diagnosis Cutaneous lupus erythematosus can resemble dermatomyositis clinically and histologically, but intense pruritus is not a feature Fig. 23.7.35  Chronic changes in dermatomyositis. Note the Gottren’s papules over the joints have been replaced with porcelain-​white atrophic scars with telangiectasia. Fig. 23.7.36  Hyperkeratosis, scaling, and fissuring on the lateral aspects of the fingers (mechanic’s hands) simulates contact dermatitis. Fig. 23.7.37  Cutaneous calcinosis, necrosis, and ulceration in a
12-​year-​old child with chronic dermatomyositis.

23.7  Cutaneous vasculitis, connective tissue diseases, and urticaria 5661 of lupus erythematosus. When cutaneous lupus erythematosus involves the hands, the rash tends to spare the joints, whereas Gottron’s papules occur over the joints. Lesions tend to be oe- dematous in dermatomyositis, but hyperkeratotic in lupus erythematosus. Scalp erythema and scale might be confused with seborrhoeic dermatitis, but the purplish colour, periorbital oedema, and predi- lection of lesions for light-​exposed skin suggest dermatomyositis. Alopecia is not a feature of dermatitis. Mechanic’s hands might be misdiagnosed as contact dermatitis. Facial oedema might be mis- diagnosed as angioedema. Dermatomyositis can also simulate psor- iasis. Dermatomyositis or a dermatomyositis-​like rash has been induced by several drugs. Clinical investigation Investigations are aimed at establishing a diagnosis and screening for underlying malignancy or internal organ involvement. A bi- opsy of involved skin is helpful and should reveal an interface dermatitis, but the changes are not specific and will not distinguish dermatomyositis from cutaneous lupus erythematosus. Muscle involvement should be investigated with serum muscle enzymes, electromyography, and muscle biopsy or muscle MRI. Patients with pulmonary symptoms should have chest radiography and pulmonary function tests, and high-​resolution computed tomog- raphy (CT) is the investigation of choice for associated interstitial lung disease. Autoantibodies are found in approximately 80% of patients with dermatomyositis. About a third have antinuclear antibodies. There are several myositis-​specific antibodies associated with dermato- myositis of which the commonest are anti-​Jo1 (15–​20%), anti-​Mi2 (<10%), anti-​SRP (5–​10%), anti-​p155 (15–​20%), and anti-​MDA5 (50–​75% Asian patients). Other autoantibodies which might be detected include anti-​Ro/​SS-​A, anti-​La/​SS-​B, and anti-​PM/​Scl; these can indicate the existence of an overlapping connective tissue disease. A thorough history and physical examination are important in screening for underlying malignancy or disease-​associated organ involvement. Investigations other than routine blood tests, urin- alysis, and faecal occult bloods should be guided by clinical find- ings but might include chest radiography, CT/​MRI of the chest, abdomen, and pelvis and endoscopy. Women should be offered mammography and bimanual examination of the pelvis, with a cervical smear, CA125 blood levels, and transvaginal ultrasonog- raphy. Reinvestigation for internal malignancy should be considered periodically. Criteria for diagnosis The diagnosis of cutaneous dermatomyositis is based on the pres- ence of the typical cutaneous signs, with or without muscle in- volvement, combined with the cutaneous histology of an interface dermatitis. Treatment Treatment options for dermatomyositis are summarized in Box 23.7.21. Pruritus, skin pain, and burning can be difficult to manage, but may be helped by sedating antihistamines such as hydroxyzine, cooling baths, aqueous cream with 1% menthol, and moisturizers or soap substitutes to prevent dry skin (common in older people). Cutaneous dermatomyositis is less responsive to treatment than cutaneous lupus erythematosus, but the approach is similar. Optimal topical therapy will minimize the dose of systemic im- munosuppressive drugs. Protective clothing, wide-​brimmed hats, and high-​factor sun blocks are essential. Potent or highly potent top- ical corticosteroid ointments applied twice daily can control limited cutaneous disease, as may 0.1% tacrolimus ointment. Steroid lotions may relieve scalp irritation. Cosmetic camouflage can reduce dis- figurement, particularly in patients with long-​standing disease and poikiloderma. Most patients require oral therapy, but randomized controlled trials are required to evaluate treatments. Hydroxychloroquine (200–​400 mg/​day) can be beneficial, but takes 8–​12 weeks to have an effect, and up to six months for maximal benefit. Smoking might diminish its effectiveness so patients should be advised to stop smoking. Hydroxychloroquine is less effective in cutaneous dermatomyositis than in cutaneous lupus erythematosus. Ocular toxicity has been reported with the related drug chloroquine, but hydroxychloroquine might be safer provided the maximum dose is not exceeded. Visual acuity should be checked, and patients should see an optician annually. Oral prednisolone (0.5–​1 mg/​kg per day) in reducing doses over two to three months might control symptomatic cutaneous disease while hydroxychloroquine is taking effect. Bolus infusions of methylprednisolone (500 mg/​day IV for three days) can be tried and often a good alternative to high dose of oral steroids. Dapsone may be helpful (50–​300 mg/​day). Immunosuppressives such as methotrexate (7.5–​15 mg once a week), azathioprine (1.5–​3 mg/​kg/​day), ciclosporin (100 mg/​day), mycophenolate mofetil (2–​ 3 g/​day in divided doses), and chlorambucil have been used with Box 23.7.21  Therapeutic ladder for treatment of cutaneous Dermatomyositis First line • Topical: corticosteroids and /​or calcineurin inhibitors (pimecrolimus 1% cream, tacrolimus 0.03%, or 0.1% ointment); sunscreen • Antimalarials—​Hydroxychloroquine usually given first and may be combined with others • Strict photo protection (see Box 23.7.18) • Antipruritics—​antihistamines (hydroxyzine), tricyclic antidepressants (doxepin, amitriptyline, nortriptyline) Second line • Methotrexate​ • Mycophenolate mofetil • Azathioprine • Dapsone • Systemic corticosteroids Third line • Intravenous immunoglobulin • Tumour necrosis factor (TNF)-α inhibitors • Rituximab • Cyclophosphamide • Ciclosporin A • Other systemic agents: thalidomide, rapamycin • Other therapies:  stem-​cell transplant, plasmapheresis, total body irradiation

section 23  Disorders of the skin 5662 varying success in refractory skin disease. Several studies indicated a successful role of intravenous immunoglobulin, 1 g/​kg for two days per month for 4–​6 months. TNF​α might play a part in the patho- genesis of dermatomyositis and TNF​α inhibitors, such as infliximab, have been tried, as has the anti CD20 biologic therapy rituximab, with some success. In severe cases plasma exchange and extracor- poreal chemotherapy might be useful. Prognosis The prognosis is variable and unpredictable. Some patients have acute and fulminant disease, whereas in others it runs a chronic course punctuated by remissions and relapses. Skin and muscle disease tend to respond in parallel with treatment, but as immunosuppressants are gradually withdrawn, cutaneous disease may relapse without recurrence of muscle weakness. Interstitial lung disease and underlying, internal malignancy can be fatal. Scleroderma The sclerodermatous disorders are characterized by tight, stiff, fi- brotic skin which feels hard (sclero). It may be localized or general- ized and may be purely cutaneous or part of a multisystem disease. The different subtypes are outlined in Fig. 23.7.38. Systemic sclerosis Systemic sclerosis is reviewed in detail in Chapter 19.11.3, but the cutaneous features are discussed next. Aetiology, genetics, pathogenesis, and pathology Systemic sclerosis is a connective tissue disease that is character- ized by collagen accumulation (fibrosis) associated with vascular injury and autoantibodies. The small arteries and microvasular beds of target organs appear to be damaged before the onset of fi- brosis. Mesenchymal cells (fibroblasts, smooth muscle cells, and endothelial cells), activated by unknown stimuli, produce in- creased amounts of collagen, proteoglycan, and fibronectin, while lymphocyte activation produces autoantibodies and cytokines. The generation of autoantibodies is influenced by hereditary factors, including the presence of certain major histocompatibility com- plex genes. It has been suggested that autoantibodies to basement membrane antigens might be involved in vascular injury, and that chronic activation of B cells, with release of cytokines, might play some part in the stimulation of fibroblasts and the development of skin fibrosis, but it is still not clear if autoantibodies have a direct role in the pathogenesis. Skin biopsies show thickened dermis, with broad collagen bun- dles extending into subcutaneous fat. The walls of small vessels are thickened, with intimal fibrosis and thrombosis. Epidemiology The distribution of clinical subtypes and antibody prevalence varies among populations and geographic regions. The prevalence of sys- temic sclerosis is reported to be between 13 and 105–​140 per mil- lion, and it has an annual incidence of between 2.6 and 20–​28 per million. Genetic, ethnic, and environmental factors may explain these variations. Systemic sclerosis is more common in women, and black women are most at risk. The average age of onset is between 40 and 50 years, with limited cutaneous systemic sclerosis occurring in older women more than often diffuse cutaneous disease. Raynaud’s phenomenon occurs in 3–​15% of the population. Clinical features Systemic sclerosis is divided into two major subtypes, depending primarily on the extent of cutaneous involvement (Fig. 23.7.38). The clinical features are given in Box 23.7. 22. Limited cutaneous systemic sclerosis This is also known as CREST; C:  calcinosis cutis, R:  Raynaud’s phenomenon, E:oesophageal dysmotility:  S:  sclerodactyly, T: telangiectasia. Raynaud’s phenomenon is the first sign of disease, and can pre- cede other features by 10–​15  years. Symmetrical thickening and tightening of the skin distal to the metacarpophalangeal joints (sclerodactyly) restricts opposition of the palms when the wrists are extended. This prayer sign indicates joint or skin pathology, or short- ening of the finger flexor muscles. Well-​defined telangiectatic mac- ules (mats) appear on the hands, tongue, lips, and face (Fig. 23.7.39). Raynaud’s phenomenon is associated with linear periungual nailfold telangiectasia (usually without capillary dropout) (Figs. 23.7.40 and 23.7.41), atrophy of the finger pulps with breaking of the finger nails, resorption of bone in the terminal phalanges, and painful ischaemic ulceration that heals leaving pitted scarring of the finger tips (Fig. 23.7.42). Nodules of cutaneous calcinosis can become inflamed and ulcerate, discharging chalky material (Fig. 23.7.43). Cellulitis might complicate ulceration. Systemic problems, such as oesophageal dysmotility causing dys- phagia, interstitial lung disease with pulmonary hypertension, or biliary cirrhosis, might not develop for decades, if at all. Diffuse cutaneous systemic sclerosis The disease starts abruptly with the sudden onset of non-​ pitting oedema of the hands, feet, and face, often associated Limited Cutaneous Diffuse Cutaneous Plaque Localized Scleroderma (Morphoea) Systemic Sclerosis Linear Eosinophilic Fasciitis Fig. 23.7.38  Scleroderma subsets.

23.7  Cutaneous vasculitis, connective tissue diseases, and urticaria 5663 with constitutional symptoms and a rheumatoid-​like arthritis. Raynaud’s phenomenon usually develops within one year of the skin changes. Patients might complain of pruritus. The nailfold capillaries are distorted and irregular; fingers and toes become dusky and cyanotic. Sclerodactyly and flexion contractures produce a claw-​like deformity with painful ulcer- ations of the finger tips and knuckles (rat-​bite necroses). Sclerosis spreads to the proximal extremities, chest, face, scalp, and trunk over 3–​12 months, or might be present at disease onset. Facial sclerosis gives the face a mask-​like stiffness with a reduced mouth aperture (Fig. 23.7.44), radial furrowing around the lips, and a pinched nose. The skin of the neck is ridged and tightened when the head is extended. This neck sign is positive in more than 90% of patients. Pigment change is common, with either generalized hyperpigmentation or focal hypo-​ or hyperpigmentation in areas of sclerosis. Signs of systemic involvement include hypertension and abnor- malities in gastrointestinal, pulmonary, renal, or cardiac function (Chapter 19.11.3). Box 23.7.22  Clinical features of systemic sclerosis Limited cutaneous systemic sclerosis • Raynaud’s phenomenon for years or decades • Dilated nailfold capillary loops, usually without capillary destruction • Skin sclerosis limited to the hands, face, neck, feet, and forearms, or absent • May have cutaneous calcinosis, telangiectasia, or oesophageal hypomotility • Late incidence of pulmonary hypertension, with or without interstitial lung disease • Anticentromere antibodies in 70–​80% • Also known as CREST Diffuse cutaneous systemic sclerosis • Onset of Raynaud’s phenomenon within one year of onset of skin changes • Nailfold capillary dilatation and capillary destruction (also seen in dermatomyositis and overlap syndromes) • Skin sclerosis (tightness, thickening, non​pitting induration) affecting the arms, chest, abdomen, back, or thighs, in addition to acral sclerosis (face, feet, hands) • Sclerodactyly (fingers and/​or toes), digital pitting scars, or loss of substance of the digital finger pads (pulp loss) • Tendon friction rubs • Early interstitial lung disease (bibasilar pulmonary fibrosis), oli- guric renal failure, diffuse gastrointestinal disease, and myocardial involvement • Anti-​DNA topoisomerase I (anti-​Scl-​70) antibodies in 30% • Absence of anticentromere antibodies Fig. 23.7.39  Well-​defined telangiectatic macules (mats) on the face of a man with long-​standing limited cutaneous systemic sclerosis. This patient also has cutaneous calcinosis, Raynaud’s phenomenon, oesophageal hypomotility, and anticentromere antibodies. Fig. 23.7.40  Linear periungual nailfold telangiectasia in a young female patient with limited cutaneous systemic sclerosis and Raynaud’s phenomenon. Fig. 23.7.41  Linear periungual telangiectasia in the nail fold of the patient illustrated in Fig. 23.7.40, viewed through a dermatoscope.

section 23  Disorders of the skin 5664 Differential diagnosis Raynaud’s phenomenon with normal nailfold capillaries and no autoantibodies might be idiopathic or linked to β-​blocker therapy, hyperviscosity syndromes, emboli, or atherosclerosis. Systemic scler- osis must be distinguished from localized forms of scleroderma (see ‘Localized scleroderma’), but these patients do not have Raynaud’s phenomenon, and the nailfold capillaries are normal. Some features of systemic sclerosis, including Raynaud’s phenomenon, might be present in patients with rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis/​polymyositis, and Sjögren’s syndrome. Environmental agents and some drugs can induce a scleroderma-​ like disease (Box 23.7.23). Cutaneous thickening and induration is seen in conditions such as lipodermatosclerosis (the lower leg in venous stasis), sclerodema adultorum (triggered by infection—​ firm non​pitting oedema of the face, neck, trunk; increased dermal acid mucopolysaccharides), scleromyxoedema (increased dermal acid mucopolysaccharides), chronic graft-​versus-​host disease, and porphyria cutanea tarda (sun-​exposed skin, blistering, skin fragility). Clinical investigation Evaluation should include the assessment of systemic involve- ment (lung, heart, kidney, gastrointestinal tract), functional im- pairment and impact on quality of life. Skin thickening is assessed by palpating and pinching the skin. Generally, a skin biopsy is not required. Autoantibodies specific for different subtypes of systemic scler- osis, or for overlap syndromes with other connective tissue dis- eases, are present in 95% of patients, usually at the onset of disease (Table 23.7.2). These persist throughout the course of the disease. Less than 1% of patients have more than one systemic sclerosis-​ specific antibody. Criteria for diagnosis Raynaud’s phenomenon is defined as episodic bilateral di-​ or triphasic vascular reactions (pallor, cyanosis, and erythema) of the fingers, toes, ears, or nose that are provoked by cold or emo- tion. The diagnostic criteria for systemic sclerosis are discussed in Chapter 19.11.3. Treatment Moisturizers and sedating antihistamines might reduce prur- itus. Patients should avoid nicotine and keep peripheries warm Fig. 23.7.42  Raynaud’s phenomenon, atrophy of finger pulps with breaking of fingernails, calcinosis, and painful ulceration heals leaving pitted scarring of the finger tips in limited cutaneous systemic sclerosis. Fig. 23.7.43  Nodules of cutaneous calcinosis may become inflamed and ulcerate, discharging chalky material. Telangiectatic mats are visible on the palm and finger pulps. Fig. 23.7.44  Reduced mouth aperture in a patient with diffuse cutaneous systemic sclerosis. Box 23.7.23  Agents that cause a scleroderma-​like disease • Chemicals (polyvinyl chloride, solvents, pesticides) • Drugs (bleomycin, pentazocine, ethosuximide, penicillamine) • Paraffin • Contaminated rapeseed oil (toxic oil syndrome) • L-tryptophan • Gadolinium based MRI contrast media (nephrogenic systemic fibrosis)

23.7  Cutaneous vasculitis, connective tissue diseases, and urticaria 5665 (Box 23.7.24). Fingertip ulceration in Raynaud’s phenomenon might be complicated by secondary infection. Moisturizers (ointments) relieve dryness and cracking of the fingers. Topical antibiotics or antibiotic–​steroid combinations can be helpful in superficial ulcers. Hydrocolloid dressings can relieve pain and promote healing. Systemic treatments to improve peripheral circulation, prevent the synthesis and release of harmful cytokines, and inhibit or reduce fibrosis are discussed in Chapter  19.11.3, but placebo-​controlled trials are needed to evaluate these treatments. Prognosis Patients with systemic sclerosis have a fourfold risk of death com- pared with the general population, but the risk of death varies be- tween subgroups. Renal, pulmonary, and cardiac involvement are independent adverse predictors, but as the severity of the cardiovas- cular, pulmonary, and renal disease correlates with the extent of cu- taneous involvement, the extent of skin sclerosis is a useful marker of severity and prognosis. Ten-​year survival in patients with limited cutaneous systemic sclerosis is 65–​88%, whereas that in patients with diffuse cutaneous disease ranges from 61 to 75%. An erythrocyte sedimentation rate greater than 15–​25 mm/​h, or a haemoglobin level lower than 12.5–​11 g/​dl, is associated with a 2.5–​3-​fold increase in mortality. Specific autoantibodies provide additional prognostic information (Table 23.7.2). Localized scleroderma Localized scleroderma (morphoea) refers to a group of conditions in which increased collagen deposition causes localized skin thickening (Fig. 23.7.45). Some patients have more than one type of lesion. Aetiology, genetics, pathogenesis, and pathology The pathogenesis of localized scleroderma is unknown, but auto- antibodies might play a role. The activation of T lymphocytes and cytokine release can stimulate dermal fibroblast proliferation and collagen production. Endothelial cells also appear to be activated. Infection with agents such as Borrelia burgdorferi has been impli- cated in the pathogenesis of some cases of morphoea, but these find- ings have not been substantiated. The histological features are similar to those in the involved skin in systemic sclerosis. The histological features of eosinophilic fasci- itis, a deep variant, include marked inflammation including eosino- phils, and fibrous thickening of the deep fascia and subcutis. Epidemiology The prevalence of localized scleroderma has been estimated to be 27 cases per million. Females are affected more often than males. Linear scleroderma is more common in children, whereas plaque-​ type morphoea (the most common form of localized scleroderma) is more common in adults. Clinical features Plaque morphoea Patients have one or more lesions, usually on the trunk. These start as erythematous patches that progress to indurated smooth shiny white or yellow plaques with violet borders (the lilac ring) (Fig. 23.7.45). This form of morphoea is self-​limiting. Inactive Table 23.7.2  Autoantibodies in systemic sclerosis Antibody Type of sclerosis Clinical associations Anticentromere antibodies Limited cutaneous sclerosis High risk: calcinosis, ischaemic digital loss, pulmonary hypertension Low risk: pulmonary fibrosis Low mortality Anti-​Scl-​70 (topoisomerase) antibodies Diffuse cutaneous sclerosis Pulmonary fibrosis High mortality from ventricular failure secondary to pulmonary disease Anti-​Th/​To antibodies Mild skin involvement Severe pulmonary fibrosis Poor prognosis Anti-​RNA polymerase family antibodies Diffuse cutaneous sclerosis Systemic sclerosis-​related renal crisis High mortality Antifibrillarin antibodies/​anti-​U3 RNP antibodies Diffuse cutaneous sclerosis Some populations: myositis, pulmonary hypertension, renal disease Box 23.7.24  Improving peripheral circulation and treating Raynaud’s phenomenon • Avoid nicotine and β-​blockers • Thermal underwear to raise core temperature • Thermal gloves and/​or socks • Thick-​soled padded footwear • Warm hands for 5 min every 4 h in warm water • Warm hands in warm water before going outdoors • Heat pads (purchased in outdoor activity shops) • Hand or foot warmers (battery powered) • Glyceryl trinitrate (nitroglycerin) patches • Oral calcium antagonists (e.g. nifedipine) • Angiotensin receptor inhibitors (e.g. losartan), or phosphodiesterase inhibitors (e.g. sildenafil) • Iloprost is used in critical ischaemia Fig. 23.7.45  Plaque morphoea is the most common form of localized scleroderma. Note the hyperpigmented bands beneath the breasts and on the lower abdomen. On palpation, these areas felt firm and thickened, typical of morphoea.

section 23  Disorders of the skin 5666 lesions hyperpigment (Fig. 23.7.46). Generalized morphoea is a rare variant, usually seen in adults, in which much of the skin becomes sclerotic. Internal organs are not involved, but involvement of the chest wall causes disabling restrictive lung defects. Linear scleroderma A unilateral sclerotic band extends along a limb. Deep atrophy might affect underlying subcutaneous tissues, including muscle and bone, so that the limb becomes shortened and wasted. The face is affected in the rare en coup de sabre linear variant in children (Fig. 23.7.47). Disfiguring hemifacial atrophy might be the end result if deeper tis- sues are affected. These children can also develop neurological com- plications (seizures, headache, and hemiparesis), eye problems, and misalignment of the jaws. Eosinophilic fasciitis (Shulman’s syndrome) This scleroderma-​like disorder involves the deep fascia, and might be triggered by vigorous exercise. Patients develop symmetrical in- duration of the skin and subcutaneous tissues, usually of the distal limbs. The reddish-​brown subcutaneous plaques are initially oe- dematous, but become indurated and brawny. Peripheral eosino- philia is common. Differential diagnosis Early plaque morphoea can simulate both granuloma annulare and erythema chronicum migrans (see ‘Annular erythemas’, next). Extragenital lichen sclerosus resembles plaque morphoea, but in li- chen sclerosus the surface is slightly hyperkeratotic with follicular plugs. Patients might also have genital lichen sclerosus. Some pa- tients have both lichen sclerosus and morphoea. Eosinophilic fasciitis must be differentiated from conditions such as cellulitis, deep venous thrombosis, postirradiation injury, toxic oil syndromes, and l-​tryptophan-​induced eosinophilia–​myalgia syndrome. Clinical investigation A deep elliptical skin biopsy that extends from normal into abnormal skin can be helpful in diagnosing plaque morphoea, but sometimes the changes are subtle. A full-​thickness biopsy that includes fascia and muscle is required in deep variants such as eosinophilic fasciitis. Patients might have autoantibodies, including antinuclear anti- bodies, anti-​Scl-​70, anticentromere antibody, anti-​double-​stranded DNA, anticardiolipin antibody, and rheumatoid factor, but their sig- nificance is unclear. Bone and joints should be evaluated in patients with linear sclero- derma, and limb length discrepancy should be excluded. In linear scleroderma affecting the face, a periodic eye examination should be performed, and MRI considered to detect central nervous system involvement. Treatment Treatments have not been evaluated in controlled trials. Plaque morphoea remits spontaneously, and no treatment is required, but a potent topical corticosteroid ointment can be used until the inflammatory ring has settled. Psoralen UVA bath and oral phototherapy (PUVA) and low-​dose UVA1 (340–​400 nm) have been reported to be effective in widespread morphoea and linear scleroderma. Linear scleroderma is difficult to manage, and a multidiscip- linary approach is essential. Complications such as joint contrac- tures or malocclusion should be addressed. Monthly intralesional triamcinolone might halt the progression of disease affecting the scalp and forehead. Intravenous methylprednisolone, oral prednis- olone, and/​or methotrexate have been recommended for progressive linear disease. Once the disease is inactive, reconstructive surgery can reduce deformity. Eosinophilic fasciitis eventually remits spon- taneously in many patients, but oral corticosteroids, methotrexate, and azathioprine have been prescribed. Fig. 23.7.46  The sclerotic plaque on the hip of this child is pigmenting as it softens. Fig. 23.7.47  En coup de sabre morphoea, now inactive, has left a linear groove on the forehead of this young woman.

23.7  Cutaneous vasculitis, connective tissue diseases, and urticaria 5667 Prognosis Plaque morphoea is a self-​limiting disease that usually slowly re- solves over three to five years. Eosinophilic fasciitis also remits spon- taneously in about one-​third of patients. Rheumatoid arthritis Rheumatoid arthritis (RA) is a chronic inflammatory arthritis in which extra-​articular manifestations are common. It is discussed in detail in Chapter  19.5, but the cutaneous manifestations are outlined next. Cutaneous features The common cutaneous features of rheumatoid arthritis are listed in Box 23.7.25; these signs are most obvious in the hands. Rheumatoid nodules (RN) are found in 20–​30% of patients. They are firm, subcutaneous, painless papules or nodules located at the periarticular regions mainly on the extensor surfaces of the fingers and elbows. Nodules are linked to both seropositivity for rheuma- toid factor, and severe systemic manifestations. Rarely, nodules may ulcerate or become infected. The nodules are composed of fibrin-​ like material surrounded by palisading histiocytes with an outer zone of chronic inflammatory cells. Similar nodules may be found in 5–​7% of patients with systemic lupus erythematosus. Rheumatoid vasculitis is most common in seropositive pa- tients with long-​standing nodular disease and is regarded as a late complication of rheumatoid arthritis. Vasculitis can involve small or medium-​sized vessels and the clinical signs vary accordingly. Medium vessel involvement presents with broken livedo, nodules, and painful punched-​out ulcers, often along the lateral malleoli or pretibial region. Twenty per cent (20%) of patients with severe vasculitis have digital gangrene. It can involve internal organs and therefore can be potentially life-​threatening. Small-​vessel cutaneous vasculitis manifests as palpable purpura, which might become nec- rotic and ulcerate, or urticarial vasculitis. Vasculitic lesions are common on the fingers, even in patients without systemic vasculitis. They include splinter haemorrhages, linear telangiectasia in the nail fold, and petechiae and brownish purpuric lesions of the nail fold or finger pulp (Bywater’s lesions) that might infarct and heal leaving small scars. Ten per cent (10%) of patients with rheumatoid arthritis have leg ulcers, but the pathogenesis is multifactorial (Fig. 23.7.48). Trauma, skin fragility, and immobility with venous stasis cause leg ulcers more often than vasculitis. Painful rapidly enlarging ulcers with undermined bluish-​red borders can be caused by pyoderma gangrenosum (Fig. 23.7.49) (Chapter 23.15). Patients with Felty’s syndrome (rheumatoid arthritis, leukopenia, and splenomegaly) might develop chronic leg ulcers that are refractory to treatment. Interstitial granulomatous dermatitis with arthritis is an un- common condition of unknown cause that can be associated with severe rheumatoid arthritis and other systemic autoimmune dis- eases. Tender linear indurated bands arise symmetrically on the axilla, trunk, and inner portions of the thighs. Rheumatoid neutro- philic dermatitis, another condition of unknown cause, is associated with severe rheumatoid arthritis, and is characterized by papules, plaques, nodules, and urticarial weals. Blistering diseases, including mucous membrane pemphigoid, pemphigus, epidermolysis bullosa acquisita, and subcorneal pustular dermatoses, have been reported in association with rheumatoid arthritis. Panniculitis Introduction Panniculitis is a group of diseases characterized by the inflamma- tion of subcutaneous fat. There are many causes, as detailed in Box 23.7.26, and the most common types are described next. Aetiology, genetics, pathogenesis, and pathology The panniculitides are classified histologically according to whether they predominantly affect the fibrous septa, that separate lobules of fat, or affect the fat lobules themselves, and whether there is an asso- ciated vasculitis. Panniculitis might commence in subcutaneous fat, Box 23.7.25  Cutaneous features of rheumatoid arthritis (RA) Rheumatoid arthritis specific skin changes: • Rheumatoid nodules or nodulosis • Rheumatoid neutrophilic dermatosis • Rheumatoid vasculitis (signs of small or medium vessel involvement) Rheumatoid arthritis: • Related non​specific skin manifestations • Pale, shiny, and atrophic skin in long-​standing disease • Skin fragility and easy bruising • Palmar erythema • Erythema nodosum • Livid (Raynaud-​like) fingertips • Onycholysis • Periungual erythema and dilated nailfold capillaries • Pyoderma gangrenosum • Urticaria • Leg ulcers (often multifactorial: vasculitis, stasis, pyoderma gangrenosum, Felty’s syndrome) • Pressure ulcers Fig. 23.7.48  Leg ulcers are common in rheumatoid arthritis, and difficult to manage. Biopsy may not be diagnostic. Stasis, trauma, and vasculitis have contributed to ulceration in this man with long-​standing rheumatoid arthritis.

section 23  Disorders of the skin 5668 or be caused by dermal inflammation extending into subcutaneous fat. The common subtypes of panniculitis are listed in Box 23.7.26. Some of the panniculitides likely to be encountered by the general physician are considered next, but many are covered elsewhere in organ-​specific chapters. Septal panniculitis Erythema nodosum Aetiology The pathogenesis is unknown, but erythema nodosum may be a hypersensitivity response to an infection or an underlying inflammatory disease. Inflammation might be triggered by immune complexes deposited in the venules of the septa in sub- cutaneous fat. A type IV delayed hypersensitivity reaction might be involved. Erythema nodosum is frequently linked to streptococcal infec- tions in children. The most common associations in adults include infections (bacterial, including TB, viral, fungal), drugs, sarcoidosis (erythema nodosum and bilateral hilar adeno­pathy), lymphoma, and inflammatory bowel disease, as well as miscellaneous condi- tions ranging from Sweet’s syndrome to pregnancy. In about one-​ third of cases no precipitating factor is identified. Erythema nodosum is a septal panniculitis. The septa are in- flamed and thickened, neutrophils are present in early lesions, Fig. 23.7.49  Pyoderma gangrenosum presents as painful, rapidly enlarging ulcers with undermined bluish-​red borders. In the early stages, this may respond to topical treatment with a very potent corticosteroid or tacrolimus. Box 23.7.26  Subtypes of panniculitis Septal panniculitis With large-​vessel vasculitis: • Superficial thrombophlebitis (see Chapter 23.12) • Cutaneous polyarteritis nodosa Without vasculitis: • Erythema nodosum • Rheumatoid nodule • Necrobiosis lipoidica (see Chapter 23.15) • Scleroderma and eosinophilic fasciitis Lobular panniculitis With large-​vessel vasculitis: • Nodular vasculitis Without vasculitis: • α1-​Antitrypsin deficiency • Cold panniculitis • Sclerosing panniculitis (lipodermatosclerosis) (Fig. 23.7.50) • Calciphylaxis • Lupus panniculitis (lupus profundus) • Pancreatic panniculitis • Infective panniculitis (infection of subcutaneous fat in immunosup- pressed patients) • Traumatic or factitial panniculitis • Cytophagic histiocytic panniculitis and subcutaneous T-​cell lymphoma • (Weber–​Christian disease is no longer considered to be a distinct entity) Fig. 23.7.50  Sclerosing panniculitis (lipodermatosclerosis) is a lobular panniculitis found in association with venous stasis.

23.7  Cutaneous vasculitis, connective tissue diseases, and urticaria 5669 a perivascular lymphocytic infiltrate is present in the overlying dermis, and variable numbers of giant cells and histiocytes form granulomas. Vasculitis is not a feature of typical erythema nodosum, but the erythema nodosum-​like lesions that develop in Behçet’s and Crohn’s disease have a vasculitic histology. Epidemiology Erythema nodosum is the most common type of panniculitis. Most cases appear between the second and fourth decades, with a peak incidence between the ages of 20 and 30 years. It occurs more fre- quently in women. Both the incidence and prevalence of associated aetiological fac- tors vary geographically. Most cases occur in the first half of the year, possibly linked to an increase in streptococcal infections; one of the most common causes in the United Kingdom is a strepto- coccal sore throat. Sarcoidosis and tuberculosis are common causes where the incidence of these diseases is high. Ulcerative colitis and Crohn’s disease are common associations seen in secondary care in the United Kingdom. Worldwide, erythema nodosum is com- monly caused by lepromatous leprosy. This is a widespread and often very persistent reaction to local antigen, and is not typical of erythema nodosum in general. It can become pustular and necrotic. Other associations of erythema nodosum include blastomycosis, coccidioidomycosis, Trichophyton verrucosum, lymphogranuloma venereum, cat-​scratch disease, ornithosis, leukaemia, Epstein–​ Barr virus, Hodgkin’s disease, tularaemia, histoplasmosis, yersinia, pregnancy, and drugs such as the contraceptive pill and sulphonamides. Clinical features Tender, erythematous, warm nodules measuring 1–​5 cm or more in diameter are distributed symmetrically on the shins, ankles, and knees (Fig. 23.7.51). Less often, nodules appear on the arms or trunk. The nodules fade over two to six weeks (more quickly in children), taking on the appearance of a deep bruise. They do not ulcerate, and resolve without loss of fat or scarring. Erythema nodosum can be associated with fever, malaise, arthralgia, and headache, or problems such as abdominal pain, vomiting, or diar- rhoea. A  chronic migratory variant (subacute nodular migra- tory panniculitis; erythema nodosum migrans) is less common (Fig. 23.7.52). Differential diagnosis Lesions are subcutaneous and erythematous rather than purpuric. The symmetrical distribution suggests an endogenous reaction rather than an exogenous cause such as trauma, cellulitis, or in- sect bite. Erythema nodosum can be differentiated clinically from nodular vasculitis (erythema induratum of Bazin; see ‘Nodular vas- culitis’ next) by the distribution of the lesions (shins rather than calves) and the absence of ulceration, atrophy, or scarring. The cord-​like lesions of superficial thrombophlebitis are usually on the sides of the leg. Investigation Underlying causes must be excluded by history taking and exam- ination. Investigations should be guided by the local prevalence of aetiological factors such as bacterial, viral, fungal, or protozoal infections. Preliminary investigations might include a full blood count, erythrocyte sedimentation rate, urinalysis, and chest radiog- raphy. A skin biopsy is seldom required. Treatment Underlying causes should be identified and treated. Pain relief with NSAIDs is generally all that is required for erythema nodosum. Elevation or bed rest can be helpful in acutely painful disease, and patients might benefit from support stockings to control swelling. Potassium iodide has been recommended in persistent disease. Fig. 23.7.51  Erythema nodosum presenting with tender erythematous nodules on the shins in a patient with sarcoidosis. Fig. 23.7.52  The chronic migratory form of erythema nodosum presented as a tender expanding indurated lesion on the leg that persisted for several months. Panniculitis was demonstrated on biopsy. No trigger was identified.

section 23  Disorders of the skin 5670 Rarely, oral corticosteroids are needed, but infection must be excluded first. The prognosis will depend on that of the underlying disease. Idiopathic erythema nodosum is a self-​limiting condition with an excellent prognosis. Relapses are uncommon. Lobular panniculitis Nodular vasculitis (erythema induratum of Bazin) Aetiology Nodular vasculitis is the most common form of lobular panniculitis with vasculitis. It is considered to be a reactive disorder. Bazin de- scribed this form of vasculitis in 1861, and a link with tuberculosis was recognized in the early 1900s. Mycobacterium tuberculosis
DNA has been demonstrated in cutaneous biopsy specimens; how- ever, in many patients no underlying factor is identified. Stasis and cooling play some part in the localization of disease. The path- ology is a lobular panniculitis with fat necrosis and vasculitis, pri- marily affecting the venules and veins of the fibrous septa. This disease affects obese middle-​aged women. Clinical features Tender indurated erythematous nodules and plaques develop slowly on the calves of fat legs, where the skin is cyanotic and cold. The subcutaneous nodules might ulcerate and heal slowly, leaving atrophic scars. Recurrences are frequent. Patients tend to have evidence of venous insufficiency of the lower legs, but are otherwise healthy. Nodular vasculitis runs a protracted course over many years. Tuberculosis should be excluded by chest radiography and a Mantoux test. A deep incisional biopsy is required to demonstrate the pathology. The indolent presentation, distribution of lesions, ulceration, and scarring differentiate nodular vasculitis from ery- thema nodosum. Treatment Tuberculosis must be treated. Venous stasis should be controlled by weight loss, compression bandages, elevation, and exercise. NSAIDs might relieve pain. α1-​Antitrypsin deficiency Lung and liver disease associated with deficiency in α1-​antitrypsin are discussed elsewhere (Chapter 12.13). Pathogenesis, genetics, and pathology α1-​Antitrypsin (AAT) is a circulating inhibitor of serine protease. Subnormal levels of AAT can result in panniculitis, as well as pul- monary or liver disease. The genetic variants are classified into four primary categories (Z,S,M,F). The 90 or more allelic variants of the AAT gene can be divided into three major categories of muta- tion, which result in enzyme deficiency, null mutations, or altered enzyme function. Enzyme function can be significantly impaired, despite normal serum levels of AAT, but most cases associated with panniculitis have the ZZ genotype, with AAT levels below normal. The most common histological findings are an acute lobular panniculitis accompanied by neutrophils, fat necrosis, and foamy macrophages. α1-​Antitrypsin allele studies have estimated a frequency of 116 million carriers globally, and 3.4 million individuals with the known deficiency allele combinations. Approximately 70 000 to 100 000 individuals in the United States of America and Europe have α1-​antitrypsin deficiency. The sexes are affected equally. Adults are affected by panniculitis more often than children. Clinical features Recurrent erythematous plaques and nodules develop on the hips, thighs, and buttocks. Nodules may suppurate, with the release of oily material (Fig. 23.7.53). Panniculitis is characteristically induced or exacerbated by trauma. α1-​Antitrypsin deficiency is also associated with emphysema, hepatitis, cirrhosis, vasculitis, and angioedema. The proximal distribution combined with nodules that ulcerate and suppurate, helps distinguish this from other panniculitides. Investigation and treatment A deep biopsy of a fresh nodule will reveal a suppurative panniculitis. The serum level of α1-​antitrypsin and its phenotype are only useful if the clinical and histological findings are compatible with panniculitis associated with α1-​antitrypsin deficiency. This panniculitis might respond to drugs that inhibit neutro- phil function, such as dapsone or colchicine. Tetracycline anti- biotics can have a direct effect on serine proteases released from neutrophils, and can be helpful in some patients. NSAIDs and Fig. 23.7.53  This patient presented with recurrent painful, erythematous nodules, and plaques. The involvement of the torso and proximal limbs, and the tendency to break down and leak fluid, was in keeping with a diagnosis of α-​1-​antitrypsin deficiency. The diagnosis was confirmed by demonstrating low serum levels and a ZZ genotype. This image shows a plaque on the upper arm from which fluid is beginning to leak.

23.7  Cutaneous vasculitis, connective tissue diseases, and urticaria 5671 hydroxychloroquine have also been recommended. Severe, unre- sponsive disease can be treated with pooled human α-​1-​antitrypsin (there is no recombinant form available yet). Cold panniculitis This form of panniculitis is seen most often in the winter in plump young female horse riders wearing tight clothing that provides insufficient insulation and restricts the blood supply to the subcutaneous fat. The rider develops chilblains affecting the thighs (Chiltern chaps) (Fig. 23.7.54) and buttocks (Berkshire buttocks). The ill-​defined mottled bluish-​red plaques resolve without scarring. Riders should be advised to wear loose-​fitting warm clothing. Weber–​Christian disease More than 70 years ago Weber used this term to describe a nodular relapsing panniculitis with fever and lipoatrophy (Fig. 23.7.55). Many cases considered to be examples of Weber–​Christian disease have subsequently been given more specific clinicopathological diagnoses, and most authors no longer consider it to be a distinct entity. Annular erythemas This group of disorders, also known as gyrate or figurate erythemas, is characterized by lesions that begin as red papules or macules and spread centrifugally to produce rings or arcuate shapes. Erythema annulare centrifugum Erythema annulare centrifugum is thought to be a hypersensitivity reaction, and has been linked to a variety of aetiological factors ran- ging from infection to drugs and malignancy, but in most cases the cause is unknown. Lymphocytes cluster tightly around the small blood vessels in the superficial and mid dermis. Epidermal changes (spongiosis, parakeratosis) might be present in superficial lesions. It is more common in adults than children. Clinical Patients have one or more lesions, most often on the trunk or prox- imal limbs (Fig. 23.7.56). The lesions start as erythematous papules or macules, and slowly expand by 2–​3 mm/​day into well-​defined annular or arcuate shapes (maximum 10 cm diameter) with central clearing, and then fade over days to weeks to leave normal skin. The trailing inner edge of the erythematous ring can be finely scaly in Fig. 23.7.54  Cold panniculitis causes mottled bluish-​red chilblains on the thigh of a young female horse rider, so-​called ‘Chiltern chaps’. Fig. 23.7.55  Multiple areas of lipoatrophy on the arm. Lipoatrophy, appearing as indented areas, may be a consequence of some forms of panniculitis.

section 23  Disorders of the skin 5672 superficial lesions. Sometimes lesions are oedematous and vesicular; they can be itchy. Most cases pursue a chronic course over several years, but eventu- ally regress spontaneously. Differential diagnosis The scale of tinea corporis (ringworm) is more pronounced, and typically is on the outer margin of the ring. Sometimes psoriasis can be annular but there would usually be other features including more typical plaques. Cutaneous lupus and sarcoidosis can also be annular occasionally, but would have distinct histological fea- tures. Granuloma annulare tends be less erythematous, the ring is composed of coalescing papules that give the lesion a beaded edge if the skin is stretched, lesions are smooth not scaly, and the evolution is less rapid than erythema annulare centrifugum. The cutaneous lesions of subacute cutaneous lupus erythematosus are widespread and are linked to photosensitivity. Neonatal cutaneous lupus should be considered in infants. Smooth annular lesions can also be a manifestation of urticaria, but these fade over 24 h. Erythema annulare centrifugum should also be differentiated from the other annular erythemas: erythema migrans and gyrate ery- thema (see next). Investigation and treatment Fungal infection should be excluded by taking a skin scrape for mycological culture. Topical corticosteroids can relieve irritation, but have no effect on the course of the disease. Erythema gyratum repens Waves of rapidly expanding (1 cm/​day) erythematous concentric bands give the skin the appearance of wood grain. This is a rare manifestation of internal malignancy. Erythema migrans Pathogenesis Erythema migrans is the first sign of Lyme borreliosis, an infection caused by spirochaetes of the group Borrelia burgdorferi sensu lato, which is transmitted by the bite of Ixodes scapularis and related ticks (see Chapter 8.6.33). B. burgdorferi sensu stricto transmits the dis- ease in the United States of America, whereas Borrelia garinii and Borrelia afzelii cause most of the illness in Europe. The skin is in- filtrated by T lymphocytes, with a predominance of CD4+ helper/​ inducer cells, as well as numerous plasma cells and CD68+ macro- phages. Epidermal Langerhans’ cells are invaded by B. burgdorferi in early Lyme borreliosis. Epidemiology Lyme borreliosis occurs with similar frequency in men and women, and affects people of all ages. The disease is found in forested areas throughout most of Europe, but particularly in Germany (Black Forest), Austria, Slovenia, and Sweden. It has been reported in Russia, Mexico, Asia, Australia, and South Africa. Lyme disease also occurs in the coastal areas of the north-​east United States of America, the upper Midwest, and the West Coast. Birds, mice, deer, voles, and lizards are the major reservoirs of borrelia. Clinical features The disease is divided into three stages: early localized disease, early disseminated disease, and persisting late disease. Erythema migrans occurs around 7–​10 days after the tick bite in patients with early localized disease. A small erythematous macule or papule appears at the site of the bite, usually the knee, groin, or ax- illa. As spirochaetes spread through the skin, the erythema extends over days to weeks to produce either an annular lesion with central clearing, or a roundish erythematous patch (Fig. 23.7.57). Lesions Fig. 23.7.57  Erythema migrans occurs around 7–​10 days after the tick bite, and continues for days to weeks. Doxycycline is the treatment of choice for early localized disease. Fig. 23.7.56  Erythema annulare centrifugum is the most common of the annular erythemas. Scale is visible on the inner edge of the erythematous ring.

23.7  Cutaneous vasculitis, connective tissue diseases, and urticaria 5673 range in size from 10 cm to more than 50 cm diameter. A papule with a punctum might be visible in the centre of the primary le- sion. Erythema migrans is not scaly and the signs can be subtle, but are more obvious if the skin is warmed. The lesion might be slightly pruritic. Flu-​like symptoms are common in the early localized stage. The haematogenous spread of spirochaetes might induce additional lesions. The rash clears spontaneously, usually in three days to eight weeks, but persistence for more than one year has been recorded. Late cutaneous manifestations are seen more frequently in Europe than in the United States of America. Acrodermatitis chronica atrophicans is a chronic progressive skin condition characterized by bluish-​red discoloration of the skin on acral surfaces (dorsa of hands and feet, lower leg). Initially the skin is swollen, but this is followed by atrophy, when the skin appears thin and wrinkled. These changes might be associated with arthritis or polyneuropathy. Lymphadenosis benigna cutis is another chronic manifestation of borrelia infection, in which painless erythematous nodules develop on the ear lobe, nipple, or scrotum. Systemic manifestations (cardiac, rheumatological, ophthalmo- logical, neurological) are discussed elsewhere (see Chapters 16.7.1, 24.16). Treatment If the tick is attached for less than 48 h, infection is less likely. A single 200 mg dose of doxycycline prevents Lyme borreliosis when given within 72 h of a tick bite. A 14–​21-​day course of doxycycline is re- commended for early localized or disseminated infection. The prognosis is excellent in patients with erythema migrans treated for Lyme borreliosis; persistent infection and relapses are rare. The natural course of disease in European borreliosis is not as well defined as in the United States of America. Urticaria and angioedema Introduction Urticaria (‘hives’ or ‘nettle rash’) is characterized by a red (ery- thematous), raised, itchy (pruritic) eruption of papules and plaques resulting from vasodilatation, increased blood flow and vascular permeability in the superficial (papillary) dermis. Chronic urticaria/​ angioedema presents with weals, angioedema, or both occurring most days and lasting more than six weeks. Acute urticaria is characterized by an episode of spontaneous weals lasting for less than six weeks. Angioedema consists of transient swellings of the deep (reticular) dermis, subcutaneous and submucosal tissues, and may coexist with urticaria. The swelling is usually painful rather than itchy. Anaphylactic/​anaphylactoid episodes involve multiple organ sys- tems and can also be associated with urticaria and angioedema. The latter are discussed in detail in Chapters 4.3 and 17.3. Chronic urticaria or angioedema is defined as disease on most days for longer than six weeks. Aetiology and pathology The principal underlying disease mechanism is mast cell acti- vation, which results in mast cell degranulation, releasing hista- mine, cytokines, chemokines, and other inflammatory mediators such as prostaglandins and leukotrienes. Together the effects in- clude vasodilatation and increased vascular permeability. The mast cell component of urticaria (weals and pruritus) responds well to antihistamines. However, antihistamines are less effective in con- trolling the angioedema, probably due to their inability to affect nonhistamine-​related tissue oedema which might be involved in the pathogenesis of angioedema. Histologically, the appearance is variable, but there can be evi- dence of dermal oedema and an infiltrate, possibly including CD4

section 23  Disorders of the skin 5674 As the typical lesions are frequently not present at examination, a detailed history is the cornerstone of diagnosis and should include the nature of the lesions, their frequency, timing, and any putative triggers, as well as other symptoms, drug history, and family his- tory. Although delayed reactions are well described (e.g. wheat and carbohydrate antigens associated with meat), potential allergic food triggers are most frequently relevant in the 60 min before the onset of the episode. The clinical features of allergic disease are discussed in Chapter 4.3. It can be helpful to test for dermographism by gentle rubbing of the skin and examining for an urticarial response within a few minutes. A diagnosis of C1 esterase inhibitor deficiency is suggested by a history of recurrent episodes of angioedema and abdominal pain. The swellings are not typically pruritic. Although urticaria is not as- sociated, there can be prodromal erythema in up to 25%. Classically, the oedema develops over 12–​36 h and takes 2–​5 days to subside. Episodes can arise spontaneously or following minor trauma, such as dental work. Other triggers include oestrogens, angiotensin-​ converting enzyme inhibitors, or infection. Clinical investigation and treatment Table 23.7.3 shows a possible investigation strategy based on the known aetiologies. The approach to the investigation of allergic dis- ease is discussed in Chapter 4.3. In practice, it is not uncommon for all investigations to be normal in spontaneous chronic urti- caria/​angioedema, which are then, rather unsatisfactorily, currently grouped as idiopathic. C4 is a useful screening test for untreated C1 esterase inhibitor deficiency, and if low, then C1 esterase inhibitor levels and/​or function can be measured. Management of chronic spontaneous urticaria Start with a regular long-​acting non​sedating H1 antihistamines, unless the episode frequency is low, in which case the antihistamine can be taken as required. It might be necessary to increase the dose Table 23.7.3  Classification and investigation of urticaria/​angioedema Aetiology Mechanism Investigations Spontaneous Cause unknown Can be triggered by stress, infection, drugs
(e.g. NSAIDs) Typically negative FBC: eosinophil count can be raised in parasitic infection and in drug-​induced urticaria Urinalysis: haematuria and proteinuria,-​ to screen for infection and renal tract involvement in vasculitis Acute phase response: elevated ESR or CRP, indicates infection, vasculitis or paraproteinaemia (high ESR and normal CRP) Thyroid function and autoantibodies Skin biopsy: if unusual clinical features or suspected vasculitis Autoimmune IgG auto-​antibody to mast cell IgE receptor or to IgE bound to mast cells Associated with autoimmune thyroiditis Thyroid antibodies, thyroid function, ANA Specialist centres may undertake a basophil histamine release test and an autologous serum skin test Inducible Physical induction of mast cell degranulation Aquagenic: contact with hot or cold water Cholinergic: exercise, heat, or emotion Cold-​induced: cold wind, cold water Delayed pressure: sitting, lying, tight clothing Dermographism: minor trauma Solar: sunshine Heat induced: hot shower/​bath Challenge testing with appropriate stimuli, e.g. dermographism, ice cube, exercise, pressure Cryoglobulins (cold urticaria) Allergic contact urticarial (IgE-​mediated) IgE specific to food, airborne allergens, drugs (e.g. penicillin, latex, pollens, grass) Skin prick testing or specific IgE to allergen Drug-​induced Increased availability of bradykinin (ACE inhibitors, ARBs), NSAIDS, opiates Response to avoidance C1 esterase inhibitor deficiency Genetic: enhanced kinin producation, activation of complement, fibrinolysis, and coagulation system Acquired: binding of C1 by paraprotein C4 and C1 esterase inhibitor level/​function, autoimmune screen, lymphoproliferative screen Vasculitis Vessel wall inflammation Deposition of immunoglobulin and complement Triggered by infection, e.g. hepatitis B/​C or streptococcus, drugs (penicillin, allopurinol, quinolones, carbamazepine), autoimmune disease, malignancy, paraproteinaemia. FBC, liver, and renal function tests, ESR, urinalysis, ASOT, hepatitis
B/​C, Ig electrophoresis, autoimmune screen, ANCA, C3, and C4,
skin biopsy Lymphoproliferative Paraproteinaemia Paraprotein in blood and urine Food constituent (non-​IgE),
e.g. salicylates (rare) Unknown Response to exclusion Infection Complement activation due to immune complex formation Parasites, viral exanthems, EBV, hepatitis B and C Relevant serology, stool microscopy ACE, angiotensin-​converting enzyme; ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; ARB angiotensin receptor blocker; ASOT, antistreptolysin O titre; CRP, C-​reactive protein; EBV, Epstein–​Barr virus; ESR, erythrocyte sedimentation rate; FBC, full blood count; NSAID, non​steroidal anti-​inflammatory drug.

23.7  Cutaneous vasculitis, connective tissue diseases, and urticaria 5675 (up to four times recommended dose) or add a second antihista- mine to gain satisfactory control, as long as the benefits outweigh the risks. If these measures fail it might be necessary to consider using other approaches, such as the use of a leukotriene-​receptor antag- onist. Tranexamic acid can be a helpful adjunct to the therapy of angioedema. Other agents such as ciclosporin, omalizumab, mycophenolate mofetil, methotrexate, and tacrolimus can be used for very severe disease. It is advisable to avoid ACE inhibitors. The carrying of adrenaline autoinjectors should be considered if there is a history of angioedema affecting the upper airway, or if there are other anaphylactoid features, subject to the ab- sence of contraindications. Clearly, if there is an allergic cause for the urticaria/​angioedema, or if there is a defined trigger, then the patient should be counselled on avoidance. It is also wise to avoid potential exacerbating factors such as aspirin and NSAIDs. Acute treatment for a severe episode associated with hereditary C1 esterase inhibitor deficiency can be with C1 inhibitor concen- trate or fresh frozen plasma. Prophylactic treatment of hereditary angioedema is often by attenuated androgens and/​or tranexamic acid; there are several new developments, including genetically en- gineered C1 esterase inhibitor, kallikrein inhibitor, and bradykinin B2 receptor antagonist. Prognosis Up to 20% of patients with chronic urticaria attending hospital departments will be symptomatic 10 years after first presentation. More prolonged duration associates with more severe disease, the presence of angioedema, and positive antithyroid antibodies. FURTHER READING Cutaneous vasculitis Calabrese LH (2014). Vasculitis: determinants of disease patterns. Nat Rev Rheumatol, 10, 454–​62. Cardy CM, Carruthers D (2010). Large vessel vasculitides. Medicine, 38, 97–​100. Forbess L, Bannykh S (2015). Polyarteritis nodosa. Rheum Dis Clin North Am, 41, 33. Goeser R, Laniosz V, Wetter A (2014). A practical approach to the diagnosis, evaluation, and management of cutaneous small-​vessel vasculitis. Am J Clin Dermatol, 15, 299. Hewins P, Jayne D (2010). Medium vessel vasculitis. Medicine, 38, 93–​6. Houchens N, Parekh V (2014). An approach to the evaluation and management of vasculitis. Hospital Medicine Clinics, 3, e362–​e77. Kallenberg CGM (2014). Key advances in the clinical approach to ANCA-​associated vasculitis. Nat Rev Rheumatol, 10, 484–​93. Mahr A, De M (2015). Classification and classification criteria for vasculitis:  achievements, limitations and prospects. Curr Opin Rheumatol, 27, 1–​9. Ntatsaki E, et al. (2014). BSR and BHPR guidelines for the manage- ment of adult with ANCA-​associated vasculitis. Rheumatology (Oxford), 53, 2306–​9. Watts RA (2014). Classification of vasculitis: from historical contro- versies to present day pragmatic consensus. Indian J Rheumatol, 9, 120–​6. Watts RA, et  al. (2015). Classification, epidemiology and clinical subgrouping of antineutrophil cytoplasmic antibody (ANCA)-​ associated vasculitis. Nephrol Dial Transplant, 30, i14–​i22. Cutaneous lupus erythematosus Albrecht J, et al. (2004). Dermatology position paper on the revision of the 1982 ACR criteria for systemic lupus erythematosus. Lupus, 13, 839–​49. Okon LG, Werth VP (2013). Cutaneous lupus erythematosus: diag- nosis and treatment. Best Pract Res Clin Rheumatol, 27, 391. Sontheimer RD (2004). Skin manifestations of systemic autoimmune connective tissue disease: diagnostics and therapeutics. Best Pract Res Clin Rheumatol, 18, 429–​62. Cutaneous features of dermatomyositis Auriemma M, et al. (2014). Cutaneous signs of classical dermatomyo- sitis. Giornale Italiano di dermatologia e venereologia: organo uffi- ciale, Societã Italiana Di Dermatologia e Sifilografia, 149, 505. Femia N, et al. (2013). Cutaneous dermatomyositis: an updated review of treatment options and internal associations. Am J Clin Dermatol, 14, 291. Lam C, Vleugels R (2012). Management of cutaneous dermatomyo- sitis. Dermatol Ther, 25, 112. Scleroderma Asano Y, Sato S (2015). Vasculopathy in scleroderma. Semin Immunopathol, 37, 489–​500. Cepeda EJ, Reveille JD (2004). Autoantibodies in systemic sclerosis and fibrosing syndromes: clinical indications and relevance. Curr Opin Rheumatol, 16, 723–​32. LeRoy EC, Medsger TA Jr (2001). Criteria for the classification of early systemic sclerosis. J Rheumatol, 28, 1573–​6. LeRoy EC, et al. (1988). Scleroderma (systemic sclerosis): classifica- tion, subsets and pathogenesis. J Rheumatol, 15, 202–​5. Nadashkevich O, Davis P, Fritzler MJ (2004). A proposal of criteria for the classification of systemic sclerosis. Med Sci Monit, 10, CR615–​21. Nagaraja, V., Denton, C., & Khanna, D. (2015). Old medications and new targeted therapies in systemic sclerosis. Rheumatology (Oxford, England), 54, 1944–​53. Stern EP, Denton C (2015). The pathogenesis of systemic sclerosis. Rheum Dis Clin North Am, 41, 367–​82. Rheumatoid arthritis Douglas, KMJ, et al. (2006). Cutaneous abnormalities in rheumatoid arthritis compared with non-​inflammatory rheumatic conditions. Ann Rheum Dis, 65, 1341. Gkogkolou P, Luger T, Böhm M (2014). Skin involvement in con- nective tissue diseases. G Ital Dermatol Venereol, 147, 481. Gkogkolou P, Luger TA, Böhm M (2014). Cutaneous manifestations of rheumatic diseases: clinical presentation and underlying patho- physiology. G Ital Dermatol Venereol, 149, 483–​503. Jorizzo JL, et al. (1983). Dermatologic conditions reported in patients with rheumatoid arthritis. J Am Acad Dermatol, 8, 439–​57. Sayah A, et al. (2005). Rheumatoid arthritis: a review of the cutaneous manifestations. J Am Acad Dermatol, 53, 191–​209; quiz 10–​2. Panniculitis Requena L, et al. (2001). Panniculitis: part I. Mostly septal panniculitis. J Am Acad Dermatol, 45, 163–​83; quiz 84–​6.

section 23  Disorders of the skin 5676 Requena L, et  al. (2001). Panniculitis:  part II. Mostly lobular panniculitis. J Am Acad Dermatol, 45, 325–​61; quiz 62–​4. White JW Jr, et al. (1998). Weber–​Christian panniculitis: a review of 30 cases with this diagnosis. J Am Acad Dermatol, 39, 56–​62. Annular erythemas Dinser R, et al. (2005). Antibiotic treatment of Lyme borreliosis: what is the evidence? Ann Rheum Dis, 64, 519–​23. Hengge UR, et al. (2003). Lyme borreliosis. Lancet Infect Dis, 3, 489–​500. Hsu S, Le E, Khoshevis M (2001). Differential diagnosis of annular le- sions. Am Family Physician, 64, 290. Mullegger RR (2004). Dermatological manifestations of Lyme borreliosis. Eur J Dermatol, 14, 296–​309. Urticaria and angioedema Deacock SJ (2008). An approach to the patient with urticaria. Clin Exp Immunol, 153, 151. Gompels MM, et al. (2005). C1 inhibitor deficiency: consensus docu- ment. Clin Exp Allergy, 139, 379–​94. Grattan CEH, Humphreys F (2007). Guidelines for evaluation and management of urticaria in adults and children. Br J Dermatol, 157, 1116–​23. Greaves MW (2014). Pathology and classification of urticaria. Immunol Allergy Clin North Am, 34, 1–​9. Powell RJ, et  al. (2015). BSACI guidelines for the management of chronic urticaria and angioedema. Clin Exp Allergy, 45, 547–​65.

23.8 Disorders of pigmentation 5677 Eugene Healy

23.8 Disorders of pigmentation 5677 Eugene Healy

ESSENTIALS Normal human skin colour results from the reflection of light from haemoglobin in blood, and carotenoids and melanin pigmenta- tion in skin. Melanin pigmentation is the major component for determining differences in skin colour between races. Increases and decreases in skin pigmentation (hyperpigmentation and hypopigmentation, respectively) can be localized or generalized, can result from a wide variety of physiological or pathological pro- cesses, including both genetic and acquired factors, and may reflect underlying systemic disease. Addison’s disease (primary adrenocortical hypofunction) can re- sult in diffuse hyperpigmentation, more pronounced in sun-​exposed areas, sites exposed to trauma (such as the elbows and knees), the creases of the palms and soles, surgical scars, the buccal and gingival mucosa, as well as the nipples and genital region. Numerous drugs can cause changes in pigmentation (e.g. amiodarone can cause a blue-​grey discolouration of the skin, whereas bleomycin can cause a flagellate pattern of hyperpigmentation). Vitiligo is characterized by white patches of variable size, but in some darker-​skinned people the margin or entire patch may be an inter- mediate colour of light brown (trichrome vitiligo). Patches may be gen- eralized or segmental in distribution, and the borders are often irregular. In the generalized form lesions are usually symmetrical, and the more frequently involved sites are around the orifices (eyes, nose, mouth), flexures (axillae, groins, genitals), and extensor surfaces (elbows, knees, digits). The isomorphic or Koebner phenomenon can occur, in which trauma to the skin can produce lesions at that site. The skin is usually normal otherwise, with no evidence of scaling or atrophy. Microbial diseases such as pityriasis versicolor, leprosy, and syph- ilis are important infectious causes of hypopigmentation. Irrespective of cause and associations with underlying systemic disease, disorders of pigmentation can cause considerable distress to sufferers due to the visible nature of this condition. Introduction Melanin is synthesized in intracellular organelles called melanosomes by the melanocyte, a dendritic cell situated in the basal layer of the epidermis and in the hair follicle. Melanocytes develop from melanoblasts which arise from the neural crest and migrate to the skin during embryogenesis where they differen- tiate into melanin-​producing cells. The amount of melanin in the epidermis relates to constitutive skin colour (i.e. genetically de- termined white, brown, or black skin) and facultative skin pigmen- tation (e.g. resulting from ultraviolet radiation-​induced tanning). There are two types of melanin, brown-​black eumelanin and red-​ yellow phaeomelanin, and the combination of these in different proportions results in a wide variety of skin and hair colours worldwide. The biochemical pathways responsible for the syn- thesis of the two melanin types involve the sequential manufacture of several melanin intermediates from the precursor amino acid tyrosine, and require certain melanogenic enzymes, including tyro- sinase, tyrosinase-​related protein 1, and dopachrome tautomerase (tyrosinase-​related protein 2) (Fig. 23.8.1). Melanin-​laden melanosomes are passed along the dendrites of the melanocyte, and into adjacent keratinocytes; approximately 36–​40 keratinocytes receive melanin from a single melanocyte, thus forming the epidermal melanin unit. In keratinocytes, especially in the basal layer of the epidermis, the melanin becomes packaged over the nucleus to protect the DNA against incident ultraviolet (UV) radiation. It is widely accepted that eumelanin is photoprotective, with greater quantities of eumelanin in darker-​skinned races. Although there has been some debate about the photoprotective versus phototoxic effects of phaeomelanin, the evidence suggests that phaeomelanin in the physiological situation also protects against DNA damage caused by repeated exposure to UV. Some variation in pigmentation exists within and between dif- ferent skin sites in most individuals, for example, the freckling (ephelides) of fair Celtic skin, and the lighter pigmentation on the palms and soles of black skin. Increases and decreases in skin pigmentation (hyperpigmentation and hypopigmentation, re- spectively) can result from a wide variety of physiological and patho- logical processes. The degree to which alterations in pigmentation are obvious to an independent observer, and the amount of con- cern that they cause affected individuals, is often influenced by the patient’s natural (constitutive) skin colour and the extent to which the altered pigmentation contrasts with this. However, even minor alterations in pigment can cause significant distress to patients, pos- sibly related to the fact that mild pigmentary changes can often be 23.8 Disorders of pigmentation Eugene Healy

section 23  Disorders of the skin 5678 detected relatively easily by individuals from the same racial group as the affected person. Normal skin pigmentation Skin and hair colour varies within and across populations, with vari- ations in hair colour greater in light-​skinned than more pigmented races. Despite the large differences in constitutive skin colour be- tween races, and despite the number of melanocytes varying at dif- ferent body sites (with greater numbers on the face and genitals), similar numbers of melanocytes are present at comparable sites in white, brown, and black skin, but the melanosomes are signifi- cantly larger in black skin. Greater amounts of total melanin, es- pecially eumelanin, are present in darker coloured skin but, in general, all normal human skin contains a mixture of eumelanin and phaeomelanin, with the overall ratio and amount of these two mel- anin types determining skin colour. A combination of genome-​wide association studies and research on biological processes in skin/​melanocytes has identified multiple genes which influence variation in normal human skin, hair, and eye colour. A single evolutionary alteration in the SLC24A5 gene (OMIM 609802)  (substitution of threonine for alanine at codon 111) is responsible for lighter skin pigmentation, and has become fixed in European populations. In addition, certain heterozygous variants of the melanocortin 1 receptor (MC1R) gene cause fair skin type in white populations, whereas compound heterozygous and homozygous MC1R variants lead to red hair. Other genes relevant to variation in skin, hair, and/​or eye pigmentation within and across populations include the agouti signalling protein (ASIP)(OMIM 600201), tyrosinase (TYR) (OMIM 606933), tyrosinase-​related pro- tein 1 (TYRP1) (OMIM 115501), solute carrier family 45, member 2 (SLC45A2, also known as membrane associated transporter protein, MATP) (OMIM 606202), KIT ligand (KITLG) (OMIM 184745), solute carrier family 24 (sodium/​potassium/​calcium exchanger), member 4 (SLC24A4) (OMIM 609840), interferon regulatory factor 4 (IRF4) (OMIM 601900), pink-​eyed dilution (OCA2) (OMIM 611409), and HECT domain and RCC1-​like domain 2 (HERC2) (OMIM 605837) genes. In general, cutaneous melanocytes are restricted to the hair follicles in non​human primates and mammals, and it is thought that the development of melanocytes in human skin evolved in Africa as a means of photoprotection, possibly to prevent the photodegradation of folate and/​or to avoid blistering sunburn leading to infection and death in childhood and early adulthood. As human populations moved out of Africa, the subsequent light- ening of skin secondary to genetic changes might have occurred to enable the UVB-​induced synthesis of vitamin D in skin, or resulted from the loss of selective pressure from UV radiation (i.e. the lack of a requirement for high-​level photoprotection in places with lower UV radiation exposure), or possibly because of other non​pigment related evolutionary advantages (e.g. MC1R is expressed in many somatic tissues, including musculoskeletal and nervous systems, during embryogenesis). UV radiation-​induced pigmentation/​tanning UV radiation is a frequent cause of increased skin pigmentation, with UVB and UVA both able to stimulate tanning (Fig. 23.8.2). In general, the history of sun exposure is obvious, and there is a sharp cut-​off in pigmentation between exposed and unexposed sites. The speed of development, colour, and intensity of the tan differs be- tween individuals, with people having a Celtic skin phenotype less likely to tan, or more likely to tan poorly following UV radiation exposure. Several molecular mechanisms have been proposed to underlie the tanning response, and signalling via the melanocortin 1 re- ceptor secondary to increased α-​melanocyte-​stimulating hormone (αMSH) is thought to be one important mechanism. Although 5,6-dihydroxy- indole-2- carboxylic acid Tyrosine DOPAquinone Eumelanin CysteinylDOPA 1,4-Benzothiazine intermediates Phaeomelanin Tyrosinase Tyrosinase or Tyrosinase-related protein 1 DOPAchrome tautomerase Glutathione or Cysteine CysteinylDOPA- quinones Ortho-quinonimine LeukoDOPAchrome (cycloDOPA) DOPA DOPAchrome 5,6-dihydroxy -indole Indole-5,6- quinone Indole-5,6-quinone- carboxylic acid Fig. 23.8.1  Melanin synthesis pathways in the melanosome. DOPA, 3,4-​dihydroxyphenylalanine.

23.8  Disorders of pigmentation 5679 repeated exposure to UV radiation causes melanin synthesis and an increase in the total amount of melanin in skin, the initial changes in skin colour during tanning may result from a redistribution of some melanin to a higher level in the epidermis. In a single individual, the degree of melanin synthesis and thus the degree of tanning is dependent on the dose of UV radiation (including UV radiation in- tensity and duration of exposure). Whereas the increased amount of melanin in tanned skin is considered to offer greater protection against UV radiation, photoprotection by other mechanisms (e.g. thickening of the stratum corneum) is also physiologically im- portant. It should be noted that there are indications that tanning might be a response to DNA damage, which alongside the other ef- fects of UV radiation in skin (including photoaging and skin cancer) has led to the viewpoint that ‘there is no such thing as a healthy tan’. Hyperpigmentation The causes of hyperpigmentation are given in Table 23.8.1. Endocrine causes of hyperpigmentation Several hormones can stimulate melanin synthesis in melano- cytes. These include proopiomelanocortin (POMC), a peptide synthesized in the pituitary (a precursor of adrenocorticotropic hormone, ACTH), αMSH (the first 13 amino acids of ACTH), and β-​melanocyte-​stimulating hormone (βMSH). In Addison’s disease (primary adrenocortical hypofunction) the lowered serum cortisol level means that there is a lack of negative feedback on the pituitary synthesis of ACTH and related POMC peptides. This results in dif- fuse hyperpigmentation that is more pronounced in sun-​exposed sites, and is similar to that observed following the exogenous admin- istration of ACTH, αMSH, and βMSH. Pigmentation is also more evident at sites exposed to trauma, such as the elbows and knees, as well as at the creases of the palms and soles, surgical scars, the buccal and gingival mucosa, the nipples, and genital region; however, the absence of hyperpigmentation does not exclude the diagnosis of Addison’s disease (see Chapter 13.5.1). Hyperpigmentation in an Addisonian pattern can occur in Cushing’s syndrome (raised serum cortisol), where it arises from excess adrenocorticotropic hormone secretion from a pituitary ad- enoma (termed Cushing’s disease), or ectopic adrenocorticotropic hormone secretion from a malignancy (e.g. bronchial small cell car- cinoma, pulmonary carcinoid tumours). Similarly, diffuse marked hyperpigmentation is seen in Nelson’s syndrome following bilateral adrenalectomy for pre-​existing Cushing’s disease, where high cir- culating adrenocorticotropic hormone levels from a pituitary ad- enoma are increased further as a result of the absence of negative feedback by cortisol from the adrenals. Generalized pigmentation of the skin can also be observed in patients with thyrotoxicosis caused by Graves’ disease. Hyperpigmentation is also common in pregnancy, with darkening of the linea alba to form the linea nigra, and pigmentation of the nipples, genital skin, and face; the hypermelanosis of the cheeks, chin, and forehead is termed melasma (see next) and is also seen in women taking oral contraceptives. Melasma Melasma, also known as chloasma, is a hyperpigmentary disorder affecting the face. It generally develops symmetrically as darker brown areas on the cheeks, upper lip, forehead, and chin, and is seen more frequently in women, but also affects men. It is more common in darker-​skinned white individuals who tan well and in people with brown skin colour, and is more apparent following sun exposure, sometimes fading during the winter months and relapsing during the summer. In some cases histology shows increased melanin in the epi- dermis, whereas in others the melanin is in dermal melanophages. The exact pathogenesis of melasma is unclear, but several factors seem important in aggravating the condition (e.g. pregnancy, oral contraceptives, and exposure to UV radiation). Theories that have been postulated to explain its aetiology include the melanogenic effects of oestrogens, locally produced αMSH, aberrant Wingless-​ related integration site (Wnt) pathway signalling, and altered se- creted frizzled-​related protein 2 (sFRP2) expression in lesional skin. Some authors have suggested that the disorder might arise as a re- sult of a photosensitivity reaction to some ingredient in cosmetic products. In addition, certain drugs (e.g. phenytoin) can induce a melasma-​like condition. Melasma might resolve after parturition or when contraceptives are discontinued, but in a proportion of cases it can last for several years. Adherence to adequate sun protection measures is impera- tive as part of any treatment strategy. Topical bleaching agents, such as those containing hydroquinone, can be helpful, but it is important that the concentration of hydroquinone is not greater than 2–​4%, as higher concentrations seem more likely to cause hyperpigmentation (ochronosis), or in some cases be toxic to melanocytes and cause per- manent depigmentation. Hydroquinone can also be combined with topical corticosteroids to reduce the occurrence of contact dermatitis and post-​inflammatory hyperpigmentation. Other therapeutic agents include tretinoin, azelaic acid, and 4% N-​acetyl-​4-​S-​cysteaminylphenol, and a triple combination approach of topical hydroquinone, tretinoin, and a corticosteroid can have beneficial effects. Fig. 23.8.2  Ultraviolet radiation-​induced tanning in a white individual.

section 23  Disorders of the skin 5680 Chemical and drug-​induced hyperpigmentation Increased skin pigmentation at localized skin sites can occur fol- lowing contact with certain chemicals in plants and perfumes when combined with UV radiation exposure. Phytophotodermatitis is an inflammatory and hyperpigmentary reaction at a skin site that has been in contact with a plant containing furocoumarins or psoralens, and subsequently been exposed to UV radiation. The inflamma- tion (consisting of erythema and sometimes blistering) and later pigmentation is often streaked, because of the accidental nature of the contact between the plant juices and the skin. Although less fre- quent, berloque dermatitis is a similar entity in which the offending agent is bergapten (5-​methoxypsoralen), found in bergamot oil, which is present in some perfumes. The hands can be affected by phytophotodematitis after squeezing or slicing fruit, as this allows exposure to psoralens present in the peel. Topical treatment with nitrogen mustards can cause localized hyperpigmentation through an unknown mechanism. Another cause of linear streaks of pigmentation secondary to exogenous agents is that of following systemic therapy with the anticancer drug bleomycin, which induces a flagellate derma- tosis. The site of the reaction and the streaky nature of the initial inflammation and later pigmentation might be caused partially by scratching of the skin by the patient during the bleomycin therapy. Generalized pigmentation or more localized pigmentation of the mucosae and/​or nails can be seen during treatment with a wide variety of drugs and therapeutic agents. In some situations the cause is generally obvious to the patient, for example, during photochemotherapy for psoriasis with psoralen and UVA (PUVA). In cases of generalized pigmentation secondary to systemic medi- cations the discolouration of the skin can vary from brown to slate grey, depending on the causative drug (Fig. 23.8.3). Medications re- sponsible for this type of pigmentation are listed in Table 23.8.1. For example, amiodarone can cause a generalized blue-​grey discolour- ation of the skin. Fixed drug eruptions are localized inflammatory reactions in skin, caused by various agents including antimicrobials, analgesics/​ non​steroidal anti-​inflammatories, sedatives, mucolytics, metals, and halides. The inflammatory reaction recurs at the same skin site on each occasion the offending agent is ingested, and seems to result from ‘drug-​reactive’ intraepidermal CD8 + T cells in the skin at the affected location. Multiple lesions can occur, but in most cases soli- tary lesions are observed. Upon resolution of the inflammation there remains, in many cases, a brownish discolouration caused by pig- mentary incontinence resulting from damage to the basal layer of the epidermis; deposition of the melanin in dermal macrophages causes persistence of the pigmentation for weeks to months. The skin site often becomes progressively darker as more melanin accumulates Table 23.8.1  Causes of skin hyperpigmentation Type Cause Localized Lentigo type Lentigo simplex, lentigo senilis, lentigo maligna, Peutz–​Jeghers syndrome, xeroderma pigmentosum, LEOPARD syndrome, Carney complex, PUVA lentigines Café-​au-​lait type Normal skin (fewer than six), neurofibromatosisa type 1 (von Recklinghausen’s disease), McCune–​Albright syndrome, Fanconi’s anaemia Naevoid type Junctional naevus, congenital melanocytic naevus, Becker’s naevus, naevus spilus, naevus of Ota, naevus of Ito, Mongolian blue spot, seborrhoeic keratosis (early stage) Drugs Fixed drug eruption (caused by various drugs, e.g. nonsteroidal anti-​inflammatories), minocycline, bleomycin-​induced flagellate dermatosis Melasma Pregnancy, oral contraceptives, idiopathic Infections Erythrasma, tinea (pityriasis) versicolor Inflammatory/​ postinflammatory Lichen planus, psoriasis, eczema, trauma (e.g. burns), acne vulgaris Miscellaneous Incontinentia pigmenti, urticaria pigmentosa, acanthosis nigricans, morphoea, erythema ab igne, poikiloderma, tattoo ink, primary localized cutaneous amyloidosis (macular amyloidosis, lichen amyloidosis) Generalized Endocrine Addison’s disease, Cushing’s disease, Nelson’s syndrome, ACTH-​ and αMSH-​secreting tumours, thyrotoxicosis Drugs Phenothiazines/​chlorpromazine, antimalarials (chloroquine, hydroxychloroquine, quinine), anticancer drugs (busulfan, cyclophosphamide, dactinomycin, doxorubicin, fluorouracil, hydroxycarbamide, methotrexate), miscellaneous (amiodarone, minocycline, phenytoin) Ultraviolet radiation Natural sunshine, artificial sources (broadband UVB, narrowband UVB, UVA, PUVA) Postinflammatory Lichen planus, psoriasis, eczema, and so on Nutritional deficiency Malabsorption, malnutrition Miscellaneous Haemochromatosis, scleroderma, porphyria cutanea tarda, liver disease, dyskeratosis congenita, Fanconi’s anaemia, confluent and reticulated papillomatosis ACTH, adrenocorticotropic hormone; αMSH, α-​melanocyte-​stimulating hormone; PUVA, psoralen and UVA; UV, ultraviolet. Note that the distinction between localized and generalized is not absolute, and that generalized pigmentation can be diffuse (e.g. on the trunk) or consist of localized pigmentation on several body sites. a Neurofibromatosis is described in Chapter 24.17.

23.8  Disorders of pigmentation 5681 with each subsequent exposure to the drug. Discontinuation of the offending agent and its future avoidance is the treatment of choice. Urticaria pigmentosa Urticaria pigmentosa is the most common manifestation of a group of cutaneous mastocytosis disorders in which excess mast cells are present in the skin (Fig. 23.8.4). In the adult-​onset disease, which is usually lifelong, lesions often first appear in the 20–​40 year age group, and affect internal organs (e.g. bone marrow, liver) as well as the skin. By contrast, childhood-​onset disease typically arises in the first year of life, but can appear at any time in the first decade, and tends to clear spontaneously. The skin exhibits multiple brown or red-​brown macules and pap- ules on the trunk and limbs, which urticate on rubbing (Darier’s sign), causing oedema and redness typical of a weal and flare re- sponse. In one variant of the adult disease, known as telangiectasia macularis eruptiva perstans, the disorder is characterized by mul- tiple telangiectatic lesions on the skin. The lesions can be pruritic, and generalized flushing can occur as a result of mast cell degranula- tion. The cause of urticaria pigmentosa is unclear in most cases, but mutations in the KIT gene (OMIM 164920) have been identified in some affected individuals. Despite the lifelong aspect of the adult disease, the prognosis is generally good, although patients with mastocytosis are at increased risk of osteoporosis. The mainstay of treatment for mastocytosis is to avoid substances that trigger mast cell degranulation, and to sup- press the itch with antihistamines. Phototherapy (narrowband UVB or PUVA) can temporarily clear or improve the skin, but long-​term phototherapy can lead to skin cancer, and the skin lesions of urti- caria pigmentosa relapse when phototherapy is discontinued. Potent topical steroids can also clear the skin lesions, but the risk of steroid atrophy and systemic adrenocortical suppression limits their use. Assessment of bone mineral density, for example, by dual-​energy X-​ ray (DEXA) scan, is helpful for detecting concomitant osteoporosis. Incontinentia pigmenti Incontinentia pigmenti is a disorder with four recognized stages (vesiculobullous, verrucous, pigmented, and atrophic), although the lesions from the first three phases may overlap. The lesions, which are linear or grouped, tend to arise on the extremities (often on the flexor surface) and on the lateral parts of the trunk. The blistering phase, with erythematous areas and vesicles/​bullae, is seen at birth or usually within the first couple of months of life; it is thought that the disease can also begin and progress in utero. The warty lesions develop between two and six weeks of life, often on an erythema- tous base, in whorls or patches. Later, streaks and whorls of pig- mentation with an appearance suggestive of marble cake appear, and usually last for years. The pigmentation, which can appear re- ticulate and range from blue-​grey to brown, slowly resolves leaving atrophic hypopigmented reticulate areas, especially on the calves. Abnormalities of the teeth, nails, hair, eyes, and central nervous system can also occur. The X-​linked condition mainly affects females (more than 95% of cases), generally being prenatally lethal in males, although some cases have been reported in boys. The genetic alterations responsible for the disorder reside in the IKBKG (also known as NF-​κB essential modulator; NEMO) gene (OMIM 300248) on chromosome Xq28; most cases are accounted for by genomic rearrangement resulting in deletion of part of the IKBKG gene, rather than a single base muta- tion at this locus. IKBKG plays a role in the activation of NF-​κB, which functions as a transcription factor controlling inflammation, immunity, and apoptosis. In affected females, due to the random inactivation of an X chromosome (lyonization), cells expressing the abnormal IKBKG allele undergo apoptosis, and are replaced by cells with the active Fig. 23.8.3  Slate-​grey pigmentation, diffuse on the scalp and more pronounced at the nape of the neck, secondary to oral minocycline treatment for rosacea. Fig. 23.8.4  Multiple pigmented macules and papules on the trunk and upper limbs in a patient with urticaria pigmentosa.

section 23  Disorders of the skin 5682 IKBKG on the normal X chromosome. In affected males, this re- placement by cells with a normal IKBKG gene is not possible, re- sulting in intrauterine mortality, or death from infection during childhood. In females, treatment for the skin lesions is usually not required, but monitoring and treatment for other related problems is usually recommended, including ophthalmological monitoring for the first 3–​5 years of life. McCune–​Albright syndrome Also known as Albright’s syndrome, this condition consists of hyperpigmented (café-​au-​lait) patches, fibrous dysplasia of bones, and precocious puberty (the latter is more common in affected fe- males, but can also occur in males with McCune–​Albright syn- drome) (Fig. 23.8.5). The hyperpigmented patches vary in size, but are usually large with irregular/​jagged borders, and develop either at birth or more commonly during the first two years of life. The bone lesions, which often affect the long bones, tend to de- velop during the first decade of life and manifest as bone pains and fractures, and sometimes deformities. Cystic spaces are seen in the cortex of affected bones on radiography. Overgrowth of the skull can lead to problems with vision and hearing. Puberty begins be- fore 10 years of age in most females, and in the first 5 years of life in about half of all cases. Other endocrine problems are also en- countered, including hyperthyroidism, hyperparathyroidism, and Cushing’s syndrome. McCune–​Albright syndrome is caused by postzygotic somatic activating mutations in the stimulatory G protein gene (GNAS, also known as GNAS1; OMIM 139320), with the mutation frequently observed at codon 211, which normally codes for arginine in the wild-​type protein. Lifespan is usually normal, and therapies are dir- ected towards the treatment of complications. Fractures generally heal without sequelae. Localized pigmentation caused by dermal melanocytosis Localized dark pigmentation of the skin can arise from the for- mation of collections of melanocytes in the dermis during embry- onic development, possibly as a result of impaired migration of melanoblasts from the neural crest. The lesions are seen more fre- quently in oriental races, and have a blue or slate-​brown colour. The hyperpigmentation in naevus of Ota affects the skin on one side of the face in an area innervated by the ophthalmic and maxillary division of the trigeminal nerve, and can involve the eye (sclera, iris, retina). In naevus of Ito, the skin over the shoulder (innervated by the posterior supraclavicular and lateral brachial cutaneous nerves) is af- fected. The Mongolian blue spot, frequent on the lower back, occurs in most East Asian babies and is also common in black children. It usually fades during childhood; however, it might persist throughout life, whereas naevus of Ota and naevus of Ito are generally lifelong. Treatment with laser to destroy the dermal melanocytosis can im- prove cosmetic appearances in naevus of Ota and naevus of Ito but lesions can recur. Ophthalmological review is recommended for naevus of Ota because of the risk of glaucoma in cases affecting the eye. Ocular melanoma has also been reported in some cases. Post-​inflammatory hyperpigmentation/​ hypopigmentation Inflammation resulting from a wide variety of causes can frequently lead to the development of dyspigmentation at that site. The con- dition is more common and more problematic in darker-​skinned subjects. The degree of dyspigmentation varies, and can follow in- flammation from exogenous stimuli (trauma, burns) as well as from inflammatory skin disorders (e.g. acne vulgaris, atopic eczema, li- chen planus, lupus erythematosus, morphoea/​systemic sclerosis, macular amyloid) (Fig. 23.8.6). In cases where the hyperpigmentation arises secondarily to damage to the epidermal basal cell layer (e.g. lichen planus and lupus erythematosus), there is pigmentary incontinence by the basal epidermal cells, and subsequent phagocytosis of the melanin by macrophages (in this situation also known as melanophages) in the dermis. The tendency is for these melanophages to remain in the dermis for a long period, thus the hyperpigmentation can take many months to resolve. Hyperpigmentation resulting from excess melanin in the epi- dermis can also occur as a result of inflammation, although hypo- pigmentation (possibly resulting from reduced melanin transfer to keratinocytes) is more frequent. Hypopigmentation frequently follows psoriasis, atopic eczema, discoid lupus erythematosus, sys- temic lupus erythematosus, and pityriasis versicolor. Fig. 23.8.5  Café-​au-​lait patches with jagged borders in a child with McCune–​Albright syndrome. Fig. 23.8.6  Post-​inflammatory hyperpigmentation on the trunk and upper limbs in a patient with psoriasis; the psoriasis has cleared in some areas (as a result of systemic antipsoriatic therapy) leaving the post-​ inflammatory hyperpigmentation.

23.8  Disorders of pigmentation 5683 Hypopigmentation The causes of hypopigmentation are given in Table 23.8.2. Vitiligo Vitiligo is a disorder with reduced pigmentation resulting from the death of melanocytes in the epidermis, with or without the concomi- tant death of melanocytes in the hair bulb. There are various theories as to the mechanism of melanocyte death, including damage to the cell from a variety of factors (e.g. reactive oxygen species), and/​or activation of the immune system (antibody and cell mediated) to recognize melanocyte-​specific antigens. The prevalence of vitiligo varies from about 0.38 to 1.78% in dif- ferent populations, and the disease can begin at any age, with ap- proximately 50% of cases affected before the age of 20 years. The condition is usually more problematic in darker-​skinned individ- uals, who may view it as a social stigma because of the combination of significant cosmetic impairment and the incorrect suspicion by others that the hypopigmentation may be a manifestation of leprosy. Males and females are equally affected. A family history is noted in up to one-​third of cases, and genetic factors are important in its sus- ceptibility/​pathogenesis, with many of the genetic loci associated with the disorder encoding immunoregulatory or melanocytic pro- teins. In general there is no obvious precipitating cause for most pa- tients presenting with vitiligo, but certain chemicals (hydroquinone derivatives, monobenzone, para-​tert-​butylcatechol) are toxic to melanocytes, and can cause vitiligo-​like depigmentation. The areas of hypopigmentation manifest as white patches of vari- able size (Fig. 23.8.7), but in some darker-​skinned individuals the margin or entire patch may be an intermediate colour of light brown (trichrome vitiligo). Patches may be generalized or segmental in dis- tribution, and the borders are irregular, similar to those of countries on a map. In the generalized form lesions are usually symmetrical, and the more frequently involved sites are around the orifices (eyes, nose, mouth), flexures (axillae, groins, genitals), and extensor sur- faces (elbows, knees, digits). The isomorphic or Koebner phenom- enon can occur, in which trauma to the skin can produce lesions at that site. The skin is usually normal otherwise, with no evidence of scaling or atrophy, but occasionally the lesions undergo an ini- tial inflammatory stage with raised erythematous (and sometimes hyperpigmented) borders. Although usually distinct clinically, microbial diseases such as pityriasis versicolor (Chapter 23.10), leprosy (Chapter 8.6.28), and syphilis (Chapter 8.6.37) are important infectious causes of hypo- pigmentation. For example, in leprosy, hypomelanosis is a feature of the tuberculoid and borderline tuberculoid types; in tuberculoid leprosy, light touch and, later, pinprick sensations are also impaired in the hypopigmented patch, there is often a lack of sweating, there might be loss of hair and an adjacent enlarged peripheral nerve might be palpable, which can be mistaken for an enlarged lymph node. There is an association between vitiligo and several autoimmune diseases, including hyperthyroidism and hypothyroidism, per- nicious anaemia, diabetes mellitus, and adrenal insufficiency (Addison’s disease). Vitiligo has also been reported in patients with several other disorders (psoriasis, alopecia areata, lichen planus, my- asthenia gravis, rheumatoid arthritis, and morphoea/​scleroderma), but the relevance of these diseases in a condition that is relatively common is unclear. Halo naevi can occur in patients with vitiligo, presumably as a result of an immunological response to melano- cytes cross-​reacting with the melanocytic naevus cells. Similarly, vitiligo can occur in individuals with melanoma, secondary to the antitumour immune response reacting against melanocytes at other skin sites. Although squamous cell carcinoma and basal cell car- cinoma of the skin have been reported occasionally in people with vitiligo, there is some evidence to suggest that the incidence of skin cancer may be lower in individuals with vitiligo; this may be because the skin is generally covered by clothing for cosmetic reasons, but Table 23.8.2  Causes of skin hypopigmentation Type Cause Localized Vitiligo Includes vitiligo vulgaris, vitiligo in patients with melanoma, and in Vogt–​Koyanagi–​Harada syndrome Naevus-​related Halo naevus, naevus depigmentosus, depigmentation within/​around a melanoma Postinflammatory Eczema (pityriasis alba), psoriasis (frequently post-​UV therapy), and so on Chemical/​drugs Hydroquinones, topical corticosteroids Congenital Piebaldism, Waardenburg’s syndrome, tuberous sclerosisa Infective Pityriasis (tinea) versicolor, leprosy, onchocerciasis, syphilis, yaws, pinta Scarring Trauma, surgical, discoid lupus erythematosus Miscellaneous Morphoea, lichen sclerosus, idiopathic guttate hypomelanosis, hypomelanosis of Ito Generalized Congenital Oculocutaneous albinism type I, oculocutaneous albinism type II, Prader–​Willi syndrome, Angelman syndrome, Chédiak–​Higashi syndrome, Hermansky–​ Pudlak syndrome, Griscelli syndrome Endocrine Hypopituitarism, hypogonadism (males) Vitiligo a Tuberous sclerosis is described in Chapter 24.17. Fig. 23.8.7  Loss of skin pigmentation on the dorsa of the hands in a subject with vitiligo.

section 23  Disorders of the skin 5684 may also be due to elevated p53 expression in depigmented and normal skin in subjects with vitiligo. Vitiligo per se does not increase the risk of melanoma because the melanocytes necessary to give rise to melanoma are missing from the epidermis at the affected skin site. Furthermore, germline TYR polymorphisms which increase vitiligo susceptibility might promote immune responses against neoplastic as well as normal melanocytes, thus protecting against this tumour. Nevertheless, patients with vitiligo are advised to use good sun pro- tection measures (see Chapter 23.9) and there is evidence that treat- ment of vitiligo with UV radiation increases the risk of developing skin cancer in subjects with vitiligo. Vitiligo might last for many years, or it can repigment spontan- eously. When it does repigment, the pigment initially appears around hair follicles, and is thought to represent proliferation and migration of new melanocytes from precursors in the bulge region of the follicle. In general, therapies for vitiligo are limited, and the choice of treat- ment often depends on the constitutive skin colour of the patient. In people with lighter skin colour, advice on the use of sunscreens might be sufficient. Potent topical steroids and/​or UV radiation or topical calcineurin inhibitors can be employed with varying success, but UV radiation, if unsuccessful, can exaggerate the difference in colour be- tween normal and vitiliginous skin in darker-​skinned patients. In cases where there is stabilization of the vitiligo (i.e. lack of progres- sion of depigmentation) some authors consider surgical intervention with minigrafting of pigmented skin onto the affected sites. Cosmetic camouflage can be helpful in those cases that do not repigment spon- taneously, or those failing to respond to therapy. In addition, counsel- ling is important for those distressed by the condition. Endocrine causes of hypopigmentation Lighter pigmentation of skin can occur in endocrine disorders. Hypopituitarism often leads to a generalized skin pallor that is thought to result from a lack of proopiomelanocortin peptides, including αMSH and adrenocorticotropic hormone. Similarly, men who have hypogonadism (e.g. as a result of castration) have been reported to exhibit generalized skin pallor. The tanning response is impaired in these men, as it is in people with hypopituitarism. The administration of testosterone re-​establishes UV radiation-​induced tanning in hypogonadic men, whereas the administration of αMSH does likewise in cases of hypopituitarism. Depigmentation/​greying of hair The reduction and loss of pigment in hair, resulting in its greying (canities), is a normal ageing response in adults. The initial greying seems to result from a dilution of the pigment, secondary to a pro- gressive decline in the number and activity of melanocytes in some hairs, with the overall grey effect being the consequence of a mixture of hypopigmented/​white and normal-​coloured (blond, brown, and so on) hairs. Eventually the hair might appear white, as a result of most of the hairs lacking melanocytes. Canities affects most indi- viduals, frequently beginning in the fourth and fifth decades of life (senile canities), but can occur earlier in some people (premature canities). Rapid greying or whitening of the hair has been observed in some people as a result of diffuse alopecia areata causing generalized hair thinning on the scalp, with loss of pigmented hairs and retention of grey/​white depigmented hairs. In circumscribed alopecia areata, the hair loss might similarly be confined to pigmented hairs, with depigmented hairs surviving, or alternatively, during hair regrowth there may be earlier or selective regrowth of white hairs in the af- fected area. The presence of a localized patch of white hair, termed poliosis, can arise from a congenital or acquired defect; examples of the former include piebaldism and Waardenburg’s syndrome, whereas examples of the latter include alopecia areata and vitiligo. Piebaldism In this autosomal dominant condition, non​pigmented patches of skin are seen on the central forehead (often in a diamond or tri- angular shape and in association with a white forelock), as well as on the chest, abdomen, arms, and legs. The hypopigmented areas are present at birth, and do not vary throughout life, being caused by an absence of melanocytes in the affected skin. Islands of nor- mally pigmented skin are often seen in the hypomelanotic areas, and the hands, feet, and back are usually pigmented normally. Mutations in the KIT proto-​oncogene (OMIM 164920), and deletions within this locus on chromosome 4q are responsible. The consequently re- duced ability of the KIT ligand (stem cell factor) to signal via the KIT receptor on developing melanoblasts results in reduced survival of these cells during embryogenesis, thus causing the lack of mel- anocytes in affected skin sites. Deletion and mutation of SNAI2 (OMIM 602150), a zinc-​finger transcription factor gene that influ- ences SCF/​c-​kit signalling, can also result in piebaldism. Treatment for piebaldism is, in general, restricted to cosmetic camouflage, photoprotection with clothing and sunscreens, and in some cases skin grafting. Waardenburg’s syndrome Waardenburg’s syndrome, the severity of which varies widely, fea- tures the following abnormalities from birth: a white forelock, white eyebrows, premature greying of the hair, heterochromatic irides, and hypomelanotic macules on the skin, in combination with lateral dis- placement of the inner canthi/​dystopia canthorum, hypertrophy of the nasal bridge, and congenital neurosensory deafness in a propor- tion of cases. There are four subgroups, types I  to IV, with type II differing from type I by the absence of the lateral displacement of the inner canthi/​dystopia canthorum; type III (Klein–​Waardenburg syn- drome) being similar to type I, but with limb abnormalities; and type IV (Waardenburg–​Shah syndrome) being a combin- ation of Waardenburg’s syndrome and aganglionic megacolon (Hirschsprung’s disease). Types I  and III result from defects in the PAX3 gene (OMIM 606597), type II is caused by mutations in the microphthalmia-​ associated transcription factor (MITF; OMIM 156845), SOX10 (OMIM 602229), SLUG (SNAI2; OMIM 602150)  and KITLG (OMIM 184745) genes, whereas type IV is caused by alterations in the endothelin-​B receptor (EDNRB; OMIM 131244), endothelin 3 (EDB3; OMIM 131242), and SOX10 genes. In general, the pigmen- tation defects seem to occur as a result of effects on MITF signalling (caused by mutations in MITF or in genes that control MITF activity) or KIT ligand/​KIT signalling, which are important for neural crest and melanocyte development. However, in cases of Waardenburg’s syndrome type IV caused by EDNRB and EDB3 alterations, the megacolon and pigmentation abnormalities are caused by defective

23.8  Disorders of pigmentation 5685 EDB3/​EDNRB signalling, which is necessary for the migration of neuron precursor cells to the gastrointestinal tract, and melanoblasts into skin. Similar to piebaldism, there is no simple effective treat- ment for the pigmentary defects in Waardenburg’s syndrome. Oculocutaneous albinism type I In this type of albinism (OCA1) there is a lifelong absence of mel- anin pigment in the skin, hair, and eyes such that, irrespective of race, the skin is pink, the hair white, the irides light-​coloured, and the red-​eye reflex prominent. There is an absence of pigmented naevi and freckling. Photophobia, visual impairment, and nystagmus are common. The condition is autosomal recessive, and the genetic defect re- sponsible for the condition lies in the tyrosinase (TYR; OMIM 606933)  gene. The tyrosinase enzyme is essential for normal melanogenesis, catalysing the production of DOPAquinone in the melanin synthetic pathway (Fig. 23.8.1). Although mutations in the coding region of the TYR gene can inhibit the enzymatic activity of tyrosinase, there is evidence that mutant tyrosinase might fail to traffic adequately to the melanosome, where it is required for mel- anin synthesis. There is no specific treatment for the lack of skin pigmentation in OCA1 (or OCA2), but advice at an early age on appropriate photoprotective clothing and sunscreens, and limiting sun exposure, are important to reduce the risk of skin cancer devel- opment in later life. Oculocutaneous albinism type II Oculocutaneous albinism type II (tyrosinase-​positive albinism; OCA2) is more common in black populations, whereas OCA1 is more frequent in whites. In OCA2 in whites there is absence of pig- ment in the skin, hair, and eyes, but pigmented naevi might be seen. In darker populations, the presence of some melanin pigmentation is seen, and blacks with this type of albinism tend to have yellow hair and pigmented freckles on their skin. Affected individuals might also have nystagmus and photophobia. The condition is autosomal recessive, and results from muta- tions in the pink-​eyed dilution gene (OCA2; OMIM 611409) and/​ or deletions of this locus on chromosome 15q. The exact function of the protein encoded by the OCA2 gene has been debated, but it is thought that OCA2 results from a failure of the gene product to control melanosomal pH, thus reducing tyrosinase activity, or from effects on posttranslational processing of tyrosinase or on transport of tyrosine into the melanosome. The fact that people with OCA2 in darker populations have yellow hair suggests that the net effect is an absence of eumelanin production, whereas some phaeomelanin can still be synthesized. In hotter climates, appropriate sun protection is necessary to limit the development of skin cancers, and regular monitoring of affected individuals is recommended to identify skin cancers at an early stage. Praeder–​Willi and Angelman syndromes Both these syndromes exhibit lighter pigmentation of the skin, hair, and retina, in association with developmental delay and behavioural abnormalities. In Prader–​Willi syndrome there is concomitant obesity, hypotonia, hypogonadism, and short stature. In Angelman syndrome there is hypotonia, ataxia, motor retardation, epilepsy, ab- sence of speech, and a characteristic facies. Cytogenetic and molecular investigations of Prader–​Willi syn- drome have demonstrated deletions in the paternal copy of chromo- some 15q (or maternal uniparental disomy, which gives rise to two copies of chromosome 15q, both of which are maternal in origin), whereas deletions of the maternal copy of this region (or paternal uniparental disomy) are observed in Angelman syndrome, suggesting that both disorders are caused by loss of function of imprinted genes on chromosome 15q as a result of epigenetic modi- fication. Alterations in the gene for the E6-​associated protein ubi- quitin-​protein ligase (UBE3A; OMIM 601623) have been detected in Angelman syndrome, whereas the deletions in Prader–​Willi syndrome affect the SNRPN (OMIM 182279)  and NDN (OMIM 602117) genes. Depigmentation in Prader–​Willi syndrome occurs predomin- antly in those cases with 15q deletions, rather than in patients with maternal uniparental disomy. Similarly, hypopigmentation is infre- quent in cases of Angelman syndrome with very small deletions, indicating that the affected gene in cases with hypopigmentation may be located further along the same chromosome. These observa- tions, coupled with the fact that the human OCA2 gene, mutations of which cause OCA2, is also located on chromosome 15q has led to the hypothesis that reduced expression of the OCA2 gene through haploinsufficiency is responsible for the hypopigmentation pheno- type in Prader–​Willi and Angelman syndromes. However, UBE3A can regulate transcription of the melanocortin 1 receptor (MC1R) gene, thus alterations in UBE3A may reduce signalling via MC1R leading to fairer skin in Angelman syndrome. Hermansky–​Pudlak syndrome The features of this rare autosomal recessive syndrome are oculocutaneous albinism, which can vary in the degree of hypo- pigmentation, in association with a bleeding diathesis caused by a platelet abnormality, and deposits of pigment in cells of the reticu- loendothelial system. Pulmonary fibrosis and granulomatous colitis can also occur. It is more common in Puerto Ricans, but has been reported worldwide. The underlying problem is a defect in lysosomal ceroid-​ lipofuscin storage affecting several organelles within cells, including melanosomes, lysosomes, and platelet dense granules, resulting in abnormal synthesis/​development of these organelles; platelet num- bers are normal, and the diagnosis is confirmed by a lack of platelet dense bodies on electron microscopy or examination of the numbers of CD69-​positive structures in platelets by super-​resolution micros- copy. Based on genetic heterogeneity there are at least ten subtypes of Hermansky–​Pudlak syndrome (HPS1, HPS2, and so on), which are caused by mutations in different genes; HPS1 on chromosome 10q (OMIM 604982), AP3B1 on 5q (causing HPS2; OMIM 603401), HPS3 on 3q (OMIM 606118), HPS4 on 22q (OMIM 606682), HPS5 on 11p (OMIM 607521), HPS6 on 10q (OMIM 607522), DTNBP1 on 6p (resulting in HPS7; OMIM 607145), and BLOC1S3 on 19q (causing HPS8; OMIM 609762), BLOC1S6 on 15q (resulting in HPS9; OMIM 604310) and recently AP3D1 on 19p (resulting in HSP10). Avoidance of aspirin-​containing products is warranted and platelet transfusion is the suggested treatment of choice for bleeding episodes. Treatment with desmopressin (1-​desamino-​8-​d-​arginine vasopressin; dDAVP) has been suggested to reduce the bleeding

section 23  Disorders of the skin 5686 tendency in some cases, but was not shown to reduce the bleeding time in most cases in an open-​label trial, hence it has been suggested that responses to dDAVP should be determined on an individual basis. Avoidance of exposure to cigarette smoke, early treatment of lung infections, and pneumococcal/​influenza vaccination are advo- cated to limit additional lung pathology. Lung transplantation has been employed in some cases for treatment of pulmonary fibrosis, and infliximab has been reported as a useful treatment for the granulomatous colitis. Chédiak–​Higashi syndrome This uncommon disorder consists of reduced pigmentation of the skin, hair, and eyes, with atypical inclusions in several cell types, including leucocytes, bone marrow, spleen, liver, kidney, some endo- crine glands, and the mucosa of the gastrointestinal tract. Decreased retinal pigmentation, photophobia, and nystagmus may also occur. Abnormally large melanosomes are present in melanocytes, and are retained in the melanocyte rather than being transported to the asso- ciated keratinocytes in the skin, accounting for the reduced pigmen- tation. The giant granules in leucocytes similarly affect their function, and markedly increase susceptibility to bacterial (staphylococcal and streptococcal) and viral infections, often resulting in death during the first decade of life. In those who survive for longer, lymphadenop- athy and hepatosplenomegaly develop (called the accelerated phase), with the patient ultimately dying from lymphoma. Some of these pa- tients may develop neurological problems. The disorder is autosomal recessive, resulting from mutations in the lysosomal trafficking regulator gene on chromosome 1q (LYST; OMIM 606897). It is thought that the genetic abnormality causes fu- sion of the secretory lysosomes in neutrophils, cytotoxic T lympho- cytes, and natural killer cells, inhibiting the secretion of proteases by these cells. This is also thought to be the case with melanosomes, where a failure to fuse to the plasma membrane of the dendrites in- hibits melanosome transfer to surrounding keratinocytes. In add- ition, some of the clinical problems in Chédiak–​Higashi syndrome may be caused by an inability to repair lesions in the plasma mem- brane (which seem to occur in all eukaryotic cells), because of the reduced ability of lysosomes to fuse with and therefore repair the cell membrane. There is limited effective therapy for the underlying problem, and treatment is based on the complications that arise (e.g. antibiotics for infections); however, haematopoietic stem cell trans- plantation has been reported as helpful in restoring haematological and immunological function in this condition. FURTHER READING Ammann S, et al. (2016). Mutations in AP3D1 associated with im- munodeficiency and seizures define a new type of Hermansky–​ Pudlak syndrome. Blood, 127, 997–​1006. Ezzedine K, et al. (2015). Vitiligo. Lancet, 386, 74–​84. Frisoli ML, Harris JE (2017). Vitiligo: mechanistic insights lead to novel treatments. J Allergy Clin Immunol, 140, 654–62. Gianfrancesco F, et  al. (2000). Genomic rearrangement in NEMO impairs NF-​kappaB activation and is a cause of incontinentia pigmenti: the International Incontinentia Pigmenti (IP) Consortium. Nature, 405, 466–​72. Giebel LB, Spritz RA (1991). Mutation of the KIT (mast/​stem cell growth factor receptor) protooncogene in human piebaldism. Proc Natl Acad Sci USA, 88, 8696–​9. Halaban R, et al. (2000). Endoplasmic reticulum retention is a common defect associated with tyrosinase-​negative albinism. Proc Natl Acad Sci USA, 97, 5889–​94. Healy E, et al. (2000). Melanocortin-​1-​receptor gene and sun sensi- tivity in individuals without red hair. Lancet, 355, 1072–​3. Hermansky F, Pudlak P (1959). Albinism associated with hemor- rhagic diathesis and unusual pigmented reticular cells in the bone marrow:  report of two cases with histochemical studies. Blood, 14, 162–​9. Huynh C, et al. (2004). Defective lysosomal exocytosis and plasma membrane repair in Chédiak-​Higashi/​beige cells. Proc Natl Acad Sci USA, 101, 16795–​800. Jin Y, et al. (2010). Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo. N Engl J Med, 362, 1686–​97. Jin Y, et al. (2012). Genome-​wide association analyses identify 13 new susceptibility loci for generalized vitiligo. Nat Genet, 44, 676–​80. Kantor B, et al. (2004). Establishing the epigenetic status of the Prader–​ Willi/​Angelman imprinting center in the gametes and embryo. Hum Mol Genet, 13, 2767–​79. Kemp EH, et al. (2002). The melanin-​concentrating hormone receptor 1, a novel target of autoantibody responses in vitiligo. J Clin Invest, 109, 923–​30. Lamason RL, et al. (2005). SLC24A5, a putative cation exchanger, af- fects pigmentation in zebrafish and humans. Science, 310, 1782–​6. Lee HO, Levorse JM, Shin MK (2003). The endothelin receptor-​B is required for the migration of neural crest-​derived melanocyte and enteric neuron precursors. Dev Biol, 259, 162–​75. Lerner AB, McGuire JS (1961). Effects of alpha-​ and beta-​melano- cyte stimulating hormones on the skin colour of man. Nature, 189, 176–​9. Longley BJ, et al. (1996). Somatic c-​KIT activating mutation in urti- caria pigmentosa and aggressive mastocytosis:  establishment of clonality in a human mast cell neoplasm. Nat Genet, 12, 312–​14. Miller R, Ashkar FS, Jacobi J (1970). Hyperpigmentation in thyrotoxi- cosis. J Am Med Assoc, 213, 299. Nelson DH, Meakin JW, Thorn GW (1960). ACTH-​producing pitu- itary tumors following adrenalectomy for Cushing’s syndrome. Ann Intern Med, 52, 560–​9. Nishimura EK, et al. (2002). Dominant role of the niche in melanocyte stem-​cell fate determination. Nature, 416, 854–​60. Ogg GS, et al. (1998). High frequency of skin-​homing melanocyte-​spe- cific cytotoxic T lymphocytes in autoimmune vitiligo. J Exp Med, 188, 1203–​8. Paradisi A, et al. (2014). Markedly reduced incidence of melanoma and nonmelanoma skin cancer in a nonconcurrent cohort of 10,040 pa- tients with vitiligo. J Am Acad Dermatol, 71, 1110–​6. Rinchik EM, et al. (1993). A gene for the mouse pink-​eyed dilution locus and for human type II oculocutaneous albinism. Nature, 361, 72–​6. Robinson S, et al. (2010). Protection against UVR involves MC1R-​me- diated non-​pigmentary and pigmentary mechanisms in vivo. J Invest Dermatol, 130, 1904–​13. Sánchez-​Martín M, et al. (2003). Deletion of the SLUG (SNAI2) gene results in human piebaldism. Am J Med Genet A, 122A, 125–​32. Sepulveda FE, et  al. (2015). LYST controls the biogenesis of the endosomal compartment required for secretory lysosome function. Traffic, 16, 191–​203.

23.8  Disorders of pigmentation 5687 Smahi A, et  al. (1991). Activating mutations of the stimulatory G protein in the McCune–​Albright syndrome. N Engl J Med, 325, 1688–​95. Sulem P, et al. (2007). Genetic determinants of hair, eye and skin pig- mentation in Europeans. Nat Genet, 40, 835–​7. Sulem P, et al. (2008). Two newly identified genetic determinants of pigmentation in Europeans. Nat Genet, 40, 835–​7. Szabo G, et al. (1969). Racial differences in the fate of melanosomes in human epidermis. Nature, 222, 1081–​2. Tadokoro T, et al. (2005). Mechanisms of skin tanning in different racial/​ethnic groups in response to ultraviolet radiation. J Invest Dermatol, 124, 1326–​32. Tomita, Y, et al. (1989). Human oculocutaneous albinism caused by single base insertion in the tyrosinase gene. Biochem Biophys Res Commun, 164, 990–​6. Valverde P, et al. (1995). Variants of the melanocyte-​stimulating hor- mone receptor gene are associated with red hair and fair skin in hu- mans. Nat Genet, 11, 328–​30. Wei AH, Li W (2013). Hermansky–​Pudlak syndrome:  pigmentary and non-​pigmentary defects and their pathogenesis. Pigment Cell Melanoma Res, 26, 176–​92. Zazo Seco C, et al. (2015). Allelic mutations of kitlg, encoding kit ligand, cause asymmetric and unilateral hearing loss and waardenburg syn- drome type 2. Am J Hum Genet, 97, 647–​60.

23.9 Photosensitivity 5688 Hiva Fassihi and Jane M

23.9 Photosensitivity 5688 Hiva Fassihi and Jane McGregor

ESSENTIALS Normal human skin is photosensitive in that it reddens following acute sunlight exposure and tans and thickens following chronic sun- light exposure. Skin cancer, particularly non​melanoma skin cancer, is also a consequence of high cumulative sun exposure in genetically predisposed normal individuals (predominantly those with fair skin). Outside the range of normal photosensitivity, there are several conditions in which patients exhibit diverse abnormal cutaneous reactions to sunlight. These are broadly described together as the photosensitivity disorders, but in fact they comprise a very heteroge- neous group of skin conditions. Abnormal cutaneous photosensitive responses range from easy sunburn (as in drug phototoxicity and the DNA repair photodermatoses) and pain (erythropoietic protoporphyria), through to complex inflammatory responses such as urticaria, ec- zema, or epidermal necrosis induced by specific wavelengths of sun- light, the so-​called idiopathic photodermatoses. Introduction The sun emits a spectrum of electromagnetic radiation from high frequency γ rays to low frequency radio waves. Terrestrial solar radiation, or sunlight, is a portion of this electromagnetic radiation, not absorbed or scattered by the atmosphere, which reaches the Earth’s surface and is essential for life. It is made up of ultraviolet radiation (UVR) (290–​400 nm) which is responsible for vitamin D synthesis, visible light (400–​800 nm) required for photosynthesis, and infrared (800  nm–​1  mm) which provides warmth. Ultraviolet radiation is divided into UVC (which does not reach the Earth’s surface), UVB (290–​320  nm), and UVA (320–​400 nm). Apart from vitamin D synthesis, it is broadly held that exposure of the skin to UVR is otherwise deleterious, causing sunburn and skin cancer. UVR and visible light also play a role in several photosensitivity disorders, a very heterogenous group of skin conditions (Table 23.9.1). Acute effects of sunlight on normal skin The main acute effects of UVR on normal human skin are erythema (sunburn), pigmentation (tanning), and immunosuppression. Sensitivity of the skin to sunlight is genetically determined and used to define the Fitzpatrick skin type classification for white-​skinned individuals ranging from Celtic to Mediterranean: • Skin type I/​II—​sunburns, tans with difficulty • Skin type III/​IV—​sometimes sunburns, usually tans Sunburn Sunburn is acute inflammation following sun exposure with ery- thema, heat, pain, and swelling of the skin, associated with systemic upset when severe. The erythema begins 3–​6 hours after exposure, peaks by 12–​24 hours, and resolves after 48 hours or so. UVB is 1000 times more effective at inducing sunburn than UVA. The standard photobiological measure of photosensitivity is the minimal ery- thema dose (MED), which is generally defined as that dose of UVB required to produce ‘just perceptible erythema 12 hours following skin irradiation’. The pathophysiological changes that induce erythema have not been fully established. Many cytokines are released after UVR ex- posure of which TNFα is an important mediator of inflammation. Histologically keratinocytes appear to undergo apoptosis (sunburn cells), probably triggered by UVR-​induced DNA damage. Pigmentation Pigmentation of the skin following UVR occurs in two distinct phases: immediate pigment darkening and delayed tanning. Immediate pigmentation occurs during irradiation with UVA, and is transient. It is maximal immediately after exposure and lasts only a few hours. This results from oxidation and redistribution of melanin within the epidermis. Delayed tanning occurs predominantly with UVB and is maximal 72 hours after irradiation. It is the result of new melanin production by melanocytes in the epidermis. UVR triggers melanocytes to become 23.9 Photosensitivity Hiva Fassihi and Jane McGregor

23.9  Photosensitivity 5689 more metabolically active with increased dendritic branching, tyro- sinase activity, and transfer of melanosomes to keratinocytes. Immune suppression There is evidence in animals and humans that T-​lymphocyte-​mediated immune responses are suppressed from about 24 hours after exposure of the skin to UVR, lasting a few days. Experimentally this can be demonstrated by reduction in both the sensitization and elicitation phase of contact hypersensitivity following UVR irradiation at the site of application on the skin. It is because of immunosuppression that UVR can be used as phototherapy to treat some inflammatory skin diseases, such as eczema an psoriasis. Clinically, it is evidenced by the reactivation of herpes simplex infection on acutely sun-​exposed sites. UVB is a more potent immunosuppressor, but there is a syner- gistic effect between UVA and UVB in solar radiation. Low doses of UVR only immunosuppress the skin at the site of irradiation, but higher doses at one site lead to immune suppression of distant non-​ irradiated parts of the skin. The physiological function of UVR-​induced immune suppression is unknown. The major clinical significance is probably in detection and elimination of skin cancer cells, as evidenced by the high in- cidence of skin cancer in people on immunosuppressive drugs fol- lowing transplantation. Chronic effects of sunlight exposure Photoageing Ultraviolet radiation causes the long-​term skin changes known as ‘photoageing’. Chronically exposed skin, particularly in skin types I/​II, becomes wrinkled, furrowed, fragile, inelastic (solar elastosis), dry, and rough, with irregular pigmentation (lentigines) and broken blood vessels (telangiectasia). These changes are different and often superimposed on changes in the skin that occur as a result of chronological ageing. At the molecular level, photoageing reflects ultraviolet radiation-​ generated reactive oxygen species causing damage. The action spec- trum for photoageing has not been fully determined in humans and the relative contribution of UVB vs. UVA in this process is unknown. However, UVA penetrates deeper into the dermis than UVB, so UVB damage predominates in the epidermis and UVA in the dermis. Photo-​carcinogenesis UVB irradiation and UVA, to a lesser degree, result in DNA damage through the formation of DNA photoproducts in skin cells. This damage, if not repaired, can result in UV ‘signature mutations’ re- ported in tumour suppressor genes (such as p53) of skin cancer cells. Epidemiological evidence indicates two patterns of risk for ma- lignant change; acute intense sunburn (for basal cell carcinoma and melanoma), and chronic exposure (for actinic keratoses, squamous cell, and basal cell carcinoma). Both melanoma and non​melanoma skin cancers are more common in sun-​sensitive skin types I/​II (see Chapter 23.14). Idiopathic photodermatoses The idiopathic photosensitivity disorders comprise a heterogeneous group of skin conditions in which patients exhibit abnormal im- munological responses to UVR. They include polymorphic light eruption (PLE), chronic actinic dermatitis (CAD), actinic prurigo (AP), hydroa vacciniforme (HV), and solar urticaria (SU). Diagnosis relies on an accurate and detailed history, particularly of the onset and offset time of the eruption in relation to sun exposure, as well as a description of the eruption, since the transient nature of the acute photodermatoses means there may be nothing to see on the skin at the time of consultation. Routine investigations include lupus serology (antinuclear anti- body (ANA) and extractable nuclear antigen (ENA)), porphyrin analysis where relevant, HLA class II typing (if a diagnosis of ac- tinic prurigo is considered), and biochemistry and haematinics if systemic medication is to be employed. Skin biopsy is not routinely undertaken but might help in selected cases where the diagnosis is in doubt, or if lupus needs to be excluded. Monochromatic phototesting is useful in some instances to confirm a diagnosis of photosensitivity and to define the provoca- tion spectrum, particularly for solar urticaria and chronic actinic dermatitis. Polymorphic light eruption (PLE) This is the most common of the photosensitivity disorders, with approximately 12% of the UK population affected. The prevalence increases with increasing latitude. Severity varies greatly between patients; some develop the rash only occasionally on sunny for- eign holidays, others repeatedly throughout summer in the United Kingdom. All skin types and all ages are susceptible, but it is more common in skin types I–​II and the median age of onset is 25 years. Table 23.9.1  Photosensitivity disorders Idiopathic Polymorphic light eruptiona Chronic actinic dermatitisa Actinic prurigo Hydroa vacciniforme Solar urticaria Exogenous Drugs (oral ingestion or topical sensitization) Metabolic Congenital erythropoietic porphyria or Gunther’s disease Porphyria cutanea tarda Variegate porphyria Erythropoietic protoporphyria Genetic Xeroderma pigmentosum Cockayne syndrome Trichothiodystrophy Bloom syndrome Photo-​aggravated skin conditions Lupus erythematosus Dermatomyositits Darier’s disease Bullous pemphigoid and pemphigus Atopic/​seborrhoeic dermatitisa Psoriasisa Rosaceaa Actinic lichen planus Melasmaa a Most common conditions

section 23  Disorders of the skin 5690 The female:male ratio is 4:1 and there is a possible association with lupus erythematosus. Evidence suggests a genetic basis for polymorphic light eruption, but the pathogenesis of this condition is not otherwise established. A type IV hypersensitivity reaction to autologous photo-​induced antigens in individuals who are defective in UVR-​induced immuno- suppression has been suggested. Both UVB and UVA (and occasion- ally visible light) can trigger the eruption, but UVA appears to be more common. Polymorphic light eruption typically presents during the spring and summer months in susceptible individuals. A few days of ex- posure might be required in spring before the eruption develops and thereafter it appears between 30 minutes and several hours after sun exposure as an itchy erythematous papular rash, which resolves within a few days without scarring. The ‘V’ of the chest and the arms are the most frequently affected sites (Fig. 23.9.1). Sparing of some areas (such as the face and backs of the hands) despite exposure to sunlight is common and occurs as a result of the ‘hardening’ phe- nomenon. As a result of this, many patients describe gradual im- provement as summer progresses. Diagnosis is usually made from the history, sometimes in asso- ciation with examination findings or photographs. Serum tests for antinuclear antibody and extractable nuclear antigen are required to exclude lupus erythematosus. For milder cases, sun avoidance and judicious use of sunblock is all that is required to suppress the condition but, for others, short courses of oral prednisolone and/​or prophylactic phototherapy are used. Chronic actinic dermatitis (CAD) Chronic actinic dermatitis is a relatively common condition in the context of the photosensitivity disorders. It occurs almost exclu- sively in older patients (usually more than 60 years) with a male pre- dominance. Patients are typically chronically sun exposed and many are keen gardeners. A variant of chronic actinic dermatitis has been described in younger patients with human immunodeficiency virus (HIV) disease and also, very rarely, in young atopics. Chronic actinic dermatitis presents as a chronic eczema on sun-​ exposed sites, notably on the face, dorsum of the hands and the neck (Fig. 23.9.2). Although it can worsen over the summer months, it persists throughout the year and patients might not notice its re- lationship to sun exposure. Patch testing often reveals multiple contact allergens, many to airborne antigens, such as colophony and compositae oleoresins (sesquiterpene lactone). Contact allergy to sunscreens is also common in this population. Confirmation of the diagnosis is by monochromatic phototesting, which typically demonstrates extreme photosensitivity (markedly reduced minimal erythema dose responses) to UVB in particular, sometimes extending into the UVA range. Skin biopsy might occa- sionally be required to distinguish chronic actinic dermatitis from photosensitive mycosis fungoides or Sézary’s syndrome (cutaneous lymphoma), which it can mimic. Treatment includes general sun avoidance measures, topical ster- oids, and sunblock, but systemic therapy is usually also required to control the symptoms. Prednisolone, azathioprine, ciclosporin, and mycophenolate mofetil have all been used. Actinic prurigo (AP) This is a rare condition which typically presents for the first time in childhood (3–​10 years), with a female bias, often improving with age. It is more common in North American Indians and in the Mestizo populations of Central and South America. A diagnosis of actinic prurigo is made on clinical grounds, sup- ported by HLA-​DR4 Class II typing which is found in 90% of indi- viduals (compared with 30% of the general population). The subtype DRB1*0407 is frequently present. Patients with the condition present with itchy excoriated papules and nodules, predominantly on sun-​exposed sites (Fig. 23.9.3) but also covered areas, typically the buttocks and backs of legs, during the summer months. Occasionally there is also cheilitis and con- junctivitis, more common in American Indians. Actinic prurigo leaves hypopigmented and atrophic scars at affected sites. There is an association with atopy, especially eczema, and it has a significant impact on quality of life, at least in children. Treatment includes sun protection and avoidance. For milder cases desensitization phototherapy, as for polymorphic light eruption, can Fig. 23.9.1  Polymorphic light eruption. Fig. 23.9.2  Chronic actinic dermatitis.

23.9  Photosensitivity 5691 help reduce the severity of the eruption during the summer, but for most individuals systemic therapy is required. Oral prednisolone will clear the acute eruption but is not an option for maintenance. Thalidomide is routinely used for actinic prurigo and is highly effective. Hydroa vacciniforme (HV) Hydroa vacciniforme is a very rare but severe photodermatosis which presents in childhood as a papulovesicular eruption on sun-​ exposed sites. The lesions classically resolve over several weeks to leave varioliform scarring, hence the name (Fig. 23.9.4). Recent studies have shown that hydroa vacciniforme and the Epstein–​Barr virus (EBV) are strongly associated. EBV levels in the blood are very high and correlate with disease severity. Histology from hydroa vacciniforme skin lesions shows a dermal infiltrate made up of a significant number of lymphocytes (γ- δ- T cells) containing EBV encoded small nuclear RNA (EBER). In addition, there is notable intraepidermal vesicle formation and focal epidermal keratinocyte necrosis which, in the appropriate clinical setting, is diagnostic. Managements is by vigilant sun avoidance. Antiviral therapy for hydroa vacciniforme has been tried, but objective trials of re- sponse to therapy have not been carried out. There is no systemic treatment that is of proven value. The literature suggests that most cases show spontaneous remission during adolescence. However, patients should be monitored long-​term because of the risk of EBV-​ associated lymphoma, particularly in those with severe hydroa vacciniforme-​like eruptions. Solar urticaria (SU) Solar urticaria is a rare and sometimes disabling condition in which urticaria (erythema and weals) occurs on exposed sites, often fol- lowing just a few minutes of sunlight. The wealing characteristically resolves within hours, although solar urticarial vasculitis has been described in which lesions persist for more than 24 hours, and re- solves with bruising. It can occur at any age, but is unusual in children. Like other physical urticarias, it appears to be a transient problem occurring over several years and then spontaneously resolving. There are no studies describing the demographics of this condition. Monochromatic phototesting shows that urtication can occur in susceptible individuals across various wavelengths, including UVR and visible light. Porphyrins should be checked since erythropoietic protoporphyria can, albeit rarely, present with solar urticaria. Treatment in milder cases involves general measures of sun avoid- ance and antihistamines, often in supranormal doses. Desensitization phototherapy can be helpful in selected patients, but is not suitable when the condition is severe. There are published small case series showing the potential benefits of ciclosporin, omalizumab (anti-​IgE), intravenous immunoglobulin, and plasmapheresis in severe cases. Drug-​induced photosensitivity (oral and topical) Many drugs can cause photosensitization in predisposed individ- uals, meaning that the presence of the drug in the skin of some patients alters their cutaneous response to sunlight. Table 23.9.2 demonstrates some of the important and common drug photosensi- tivity reactions. Other exogenous photosensitizers include topical agents, such as sunscreens and plants which contain psoralens. Fig. 23.9.3  Actinic prurigo. Fig. 23.9.4  Hydroa vacciniforma.

section 23  Disorders of the skin 5692 The most common mechanism of photosensitivity caused by drugs is phototoxicity. Clinically this may present in a variety of ways, including immediate erythema or pain, but more com- monly it presents as an increased tendency to sunburn. A  small number of phototoxic drugs cause pseudoporphyria in which the photosensitizing effect is of skin fragility and blistering. Photoallergy is an uncommon cutaneous reaction to sunlight in which, often following an acute phototoxic (erythemal) response, dermatitis occurs on the sun-​exposed skin some days or weeks later. This has been reported with the use of phenothiazines and also with musk ambrette, once widely used in fragrances, but which has now been withdrawn in most countries. Para-​aminobenzoic acid (PABA) and benzophenones (both used in sunscreens) have also been re- ported as causing photoallergy, although the incidence of this re- action is low. Calcium channel antagonists can cause progressive exposed site telangiectasia. Evidence suggests that some phototoxic drugs can also be photocarcinogenic, although this work has been done in vitro and with animal models and might not be clinically relevant to humans. Azathioprine and the fluoroquinolone antibiotics are two examples. Cutaneous porphyrias A detailed discussion of all aspects of porphyrias is presented in Chapter 12.5.  Here we focus on the cutaneous manifestations. The cutaneous porphyrias are a group of inherited disorders of haem biosynthesis and include congenital erythropoietic por- phyria (CEP or Gunther’s disease), sporadic and familial porphyria cutanea tarda (PCT), variegate porphyria (VP), and erythropoietic protoporphyria (EPP) (Table 23.9.3). Identical skin signs can be seen where there is an acquired alteration of porphyrins (e.g. associ- ated with porphyrin-​producing hepatic tumours, or in patients with sideroblastic or myeloproliferative anaemia). Photosensitivity, which includes pain, skin fragility, blistering (Fig. 23.9.5) and scarring, derives from the interaction of porphy- rins at various levels within the skin and penetrating wavelengths of visible light at around 400 nm. Excess hair growth and pigmentation are also seen. The genes for all the enzymes in the human haem biosynthetic pathway have now been characterized, affording a better under- standing of the genetic basis of the porphyrias. Decreased enzyme activity is compensated by an increase in substrate in an attempt to maintain haem synthesis. Such accumulation of substrate character- izes each of the porphyrias, but the clinical presentation, even within families, is very variable. Diagnosis is by analysis of urine, blood, and faeces for porphyrins. Associated pathologies should be sought, including iron overload, haemochromatosis, liver pathology (hepatitis, cirrhosis, and hepa- toma), and HIV in selected patients. Treatment, where possible, includes sun avoidance (particularly for erythropoietic protoporphyria where the pain following sun exposure may be excruciating), venesection (to reduce iron load) and low dose chloroquine (both for porphyria cutanea tarda, but Table 23.9.2  Common photosensitizing drug reactions Skin reactions following exposure to sunlight Exogenous photosensitizers Easy sunburn (phototoxicity) Fluoroquinolone antibiotics, tetracyclines, chlorpromazine, thiazide diuretics, quinine, amiodarone Immediate pain or burning sensation (phototoxicity) amiodarone, chlorpromazine, coal tar Skin fragility and blistering (pseudoporphyria) Nalidixic acid, tetracycline, naproxen, amiodarone, furosemide Dermatitis (photoallergy) Chlorpromazine, PABA (para-​ aminobenzoic acid), benzophenones Progressive exposed site telangectasia Calcium channel antagonists (amlodipine, diltiazem) Delayed redness, blistering, and hyperpigmentation Psoralens, phytophotodermatitis (plant psoralens, e.g. in cow parseley) Photocarcinogenic (not established in humans) Fluoroquinolone antibiotics, azathioprine Table 23.9.3  Characterization and clinical features in the cutaneous porphyrias Defective enzyme in haeme biosynthetic pathway Disorder Cutaneous features Other features Uroporphrinogen III synthasw Congenital erythropoietic porphyria (CEP or Gunther’s disease) Blistering and skin fragility, with mutilating scarring of eyelids, earlobes, and scalp. Keratoconjunctivitis may lead to blindness. Rare condition of variable severity. Many present in infancy with red staining of nappy due to urinary porphyrins. Haemolytic anaemia and splenomegaly. Erythrodontia and pathological fractures. Uroporphyrinogen decarboxylase Porphyria cutanea tarda (PCT)—​familial and sporadic Blistering, skin fragility, and milia. Skin thickening, hyperpigmentation, and hypertrichosis. Usually presents in adulthood. Investigate for underlying liver pathology, hepatitis, and HIV where indicated. Look for haemochromatosis. Increased risk of hepatocellular carcinoma. Protoporphyrinogen oxidase Variegate porphyria (VP) Skin fragility, blistering, and scarring with milia as for PCT. May be associated with neurovisceral attacks: –​  acute abdominal pain –​  confusion –​  convulsions –​  hyponatraemia Increased risk of hepatocellular carcinoma. Ferrochelatase Erythropoietic protoporphyria (EPP) Painful skin (and oedema when severe) following sun exposure. Hepatic necrosis and liver failure reported.

23.9  Photosensitivity 5693 with monitoring for ocular toxicity), and bone marrow transplant- ation in selected cases (for congenital erythropoietic porphyria). The DNA repair photodermatoses Cellular organisms have evolved a complex set of DNA damage repair enzymes, many of which, as a consequence of life on Earth and chronic sun exposure, are directed towards the repair of UVR-​ induced DNA damage. The best characterized of these are the seven nucleotide excision repair (NER) enzymes, one of which is defective in each of the complementation groups A–​G of the rare autosomal recessive disorder known as xeroderma pigmentosum (XP). This is characterized by severe and exaggerated sunburn on minimal ex- posure and early onset of skin cancer. There is also a variant form of XP, with a later onset of phenotypic features of pigmentary change and skin cancers. In the XP variant, there is defective postreplicative translesional DNA synthesis as a result of a mutation in the human polymerase eta gene. The genetics of inherited cancers are further discussed in Chapter 5.3. Other related DNA repair-​defective disorders include Cockayne’s syndrome, trichothiodystrophy, and Bloom syndrome which exhibit a variable degree of acute photosensitivity to UVR, but skin cancer is not a feature (Table 23.9.4). Fig. 23.9.5  Skin fragility and blistering seen in porphyria cutanea
tarda. Table 23.9.4  DNA repair photodermatoses DNA repair disorder Molecular defect Diagnostic test Clinical features Comments Xeroderma pigmentosum (XP) complementation group A to G (XP-​A
to XP-​G) Mutations in any one of seven of genes (XPA through to XPG) involved in the repair of UVR-​ induced photoproducts in DNA by the process of nucleotide excision repair (NER). Reduction in post UVR DNA repair in cultured skin fibroblasts through measurement of unscheduled DNA synthesis (UDS). Analysis of DNA for the defective gene confirming complementation groups and causative mutation(s). Progressive pigmentary changes at exposed sites, significant increased risk of UVR-​induced skin and mucous membrane cancers, ocular disease, severe and exaggerated sunburn in about 60% of cases, neurodegeneration in approximately 30% of affected cases. Rigorous sun avoidance to prevent skin cancer. No effective treatment for neurological disorder. XP variant (XP-​V) Mutations in the POLH (XPV) gene encoding DNA polymerase eta, required for replication past UVR damaged sites. UDS is normal. Specific sensitivity to UVR in the presence of caffeine. Analysis of DNA for causative mutation(s). Multiple skin cancers from 30s onward. No neurological manifestations, severe sunburn, or ocular disease are observed. Rigorous sun avoidance to prevent skin cancers. Cockayne syndrome (CS) Mutations in one of two genes, ERCC8 (CSA) and ERCC6 (CSB). involved in NER. Defective post UVR recovery of RNA synthesis in cultured skin fibroblasts. Analysis of DNA for causative mutation(s). Progressive postnatal growth failure, short stature, microcephaly, cachexia, abnormal development, photosensitivity, premature ageing, retinal degeneration, and sensorineural deafness. No specific treatment available. Trichothiodystrophy (TTD) Mutations ERCC2 (XPD), ERCC3 (XPB) or GTF2H5 in photosensitive cases. These three genes encode the XPD, XPB and p8/​TTDA subunits of the TFIIH in NER pathway respectively. Mutations in a gene of unknown function, MPLKIP (TTDN1), have been found in a few cases of non​photosensitive TTD. Amino acid hair analysis shows reduction in cysteine concentration. Reduction in post UVR DNA repair in cultured skin fibroblasts through measurement UDS. Analysis of DNA for causative mutation(s). Short, brittle, sulphur-​deficient hair with a pattern of alternating light and dark ‘tiger-​tail’ bands under polarized light microscopy, photosensitivity, ichthyosis, developmental delay, short stature, haematological abnormalities, skeletal abnormalities, and maternal pregnancy complications. No specific treatment available. Bloom syndrome Mutation in BS gene which encodes a DNA helicase. High frequency sister chromatid exchange and high spontaneous mutation rate in cultured cells. Easy sunburn, growth retardation, internal malignancies prevail at young age (e.g. gastro-​intestinal and breast). No specific treatment available.

section 23  Disorders of the skin 5694 Photo-​aggravated dermatoses These comprise a heterogeneous group of skin disorders which are aggravated by exposure to sunlight, although the mechanism by which they occur is not known (Table  23.9.1). These photo-​ aggravated dermatoses differ from true photodermatoses in that they can occur without UVR and visible light exposure. Those conditions characteristically worsened by sun exposure in- clude lupus erythematosus, dermatomyositis, bullous pemphigoid and pemphigus, and Darier’s disease. For others, exacerbation oc- curs in only a few patients, for example: • Photoaggravation is described in about 10% of people with atopic dermatitis. Photoaggravation has also been noted in seborrhoeic dermatitis. It is important to differentiate this from chronic actinic dermatitis, a photodermatosis caused by UVR exposure. • In psoriasis, photosensitivity is thought to be secondary to poly- morphic light eruption or sunburn in an individual with pre-​ existing psoriasis who exhibits Kobner phenomenon. • Rosacea is often exacerbated by sunlight exposure with increasing erythema, papules, and pustules on the cheeks, chin, nose, and forehead. • Actinic lichen planus has been reported mainly in people from the Middle East, East Africa, and India. Non​pruritic grey mac- ules appear on the face, neck, and dorsum of hands. • Melasma is a common in women and presents with sharply de- marcated, hypermelanosis of forehead, upper lip, cheeks, and chin. It becomes more apparent after sunlight exposure. FURTHER READING Beattie PE, et al. (2003). Characteristics and prognosis of idiopathic solar urticaria: a cohort of 87 cases. Arch Dermatol, 139, 1149–​54. Chew AL, et al. (2010). Contact and photocontact sensitization in chronic actinic dermatitis: a changing picture. Contact Dermatitis, 62, 42–​6. Cleaver JE, Lam ET, Revet I (2009). Disorders of nucleotide excision repair: the genetic and molecular basis of heterogeneity. Nat Rev Genet, 10, 756–​68. Dawe RS, Crombie IK, Ferguson J (2000). The natural history of chronic actinic dermatitis. Arch Dermatol, 136, 1215–​20. Dawe RS, Ibbotson SH (2014). Drug-​induced photosensitivity. Dermatol Clin, 32, 363–​8. Faghri S, et al. (2008). Trichothiodystrophy: a systematic review of 112 published cases characterises a wide spectrum of clinical manifest- ations. J Med Genet, 45, 609–​21. Fassihi H, et al. (2016). Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect. Proc Natl Acad Sci U S A, 113, E1236–​45. Ferguson J, Dover JS (eds) (2010). Photodermatology. Manson Publishing Ltd, London. Grabczynska SA, et al. (1999). Actinic prurigo and polymorphic light eruption: common pathogenesis and the importance of HLA-​DR4/​ DRB1*0407. Br J Dermatol, 140, 232–​6. Gupta G, Man I, Kemmett D (2000). Hydroa vacciniforme: a clinical and follow-​up study of 17 cases. J Acad Dermatol, 42 part 2, 208–​13. Murphy GM (2004). Investigation of photosensitive disorders. Photodermatol Photoimmunol Photomed, 20, 305–​11. Murphy GM (2009). Ultraviolet radiation and immunosuppression. Br J Dermatol, 161 Suppl 3, 90–​5. Nance MA, Berry SA (1992). Cockayne syndrome: review of 140 cases. Am J Med Genet, 42, 68–​84. O’Donovan P, et al. (2005). Azathioprine and UVA light generate mu- tagenic oxidative DNA damage. Science, 309, 1871–​74. O’Gorman SM, Murphy GM (2014). Photoaggravated disorders. Dermatol Clin, 32, 385–​98. Pleasance ED, et al. (2010). A comprehensive catalogue of somatic mu- tations from a human cancer genome. Nature, 463, 191–​6. Sarkany RPE (2016). The cutaneous porphyrias. In: Griffiths CEM, et al. (eds) Rook’s textbook of dermatology, 9th edition, Chapter 60, pp. 60.1–60.20. Blackwell, Oxford.

Bullous pemphigoid

Bullous pemphigoid

ESSENTIALS Autoimmune bullous diseases of the skin are a heterogenous group of blistering diseases that affect the skin and/​or mucosal membranes. They are associated with significant morbidity and mortality and may present to several different specialists. They are broadly divided into two groups depending on the location of the blisters formed in the skin, which may be subepidermal (pemphigoids, linear IgA disease, dermatitis herpetiformis, epidermolysis bullosa acquisita) or intraepidermal (pemphigus group). Pathogenic autoantibodies (IgG, IgA) target either the proteins that provide keratinocyte adhe- sion (intraepidermal disease) or the proteins of hemidesmosomes that attach the basal cell layer to the basement membrane zone (subepidermal disease). Blisters are often firm in subepidermal dis- ease but burst easily in intraepidermal disease, leading to erosions. Systemic steroids are the mainstay of treatment and may be required at high doses (e.g. 0.5–​1 mg/​kg), with the pemphigus group often requiring higher doses. Topical steroids and oral tetracyclines are especially beneficial in the pemphigoid group. Over the past years rituximab (monoclonal anti-​CD20 antibody) has shown promising results in the treatment of pemphigus. Other immunosuppressant drugs are often needed as steroid sparing agents to control the disease. Introduction Autoimmune bullous diseases are caused by IgG and/​or IgA auto- antibodies to the components of the epidermal structures that pro- vide cell-​to-​cell (desmosome) or cell to basement membrane zone adhesion (hemidesmosome). Antibodies to desmosomes lead to intraepidermal disease and to hemidesmosomes, subepidermal dis- ease. Table 23.4.1 shows the immunopathological characteristics of these diseases including the targeted structures. Clinically, they af- fect a wide age range and can present as tense blisters (subepidermal) or erosions/​flaccid blisters (intraepidermal) with or without mu- cosal involvement and scarring. Clinical characteristics and differ- ential diagnoses are summarized in Table 23.4.2 and Table 23.4.3, respectively. Subepidermal diseases Firm blisters are often seen when antibodies target components of hemidesmosomes (Fig. 23.4.1) leading to separation of basal cells from the basement membrane zone and dermis. There might be mu- cosal involvement or scarring. Antibodies can be visualized in the form of a line along the basement membrane zone with immuno- fluorescence studies. Subepidermal diseases include bullous pem- phigoid, mucous membrane pemphigoid, pemphigoid gestationis, linear IgA disease, epidermolysis bullosa acquisita, and dermatitis herpetiformis. Bullous pemphigoid Aetiology and epidemiology This is the most common autoimmune blistering disease in the West, affecting 7–​40 people per million per year, with a female predilection. The exact cause is unknown but trigger factors such as trauma, radiation, and drugs have been suggested. There is evidence of asso- ciation with loop diuretics and bullous pemphigoid is more preva- lent in patients with neurological diseases such as cerebrovascular disease, dementia, Parkinson’s disease, motor neuron disease, and multiple sclerosis. The incidence is on the rise with increase in the ageing population. Pathogenesis There are two main target antigens, a transmembrane protein known as BP180 (collagen XVII, BPAg2) and an intracellular protein, BP230 (BPAg1). Animal models have shown antibodies to these struc- tures to be pathogenic. Blisters are caused by IgG antibody–​antigen binding, complement activation, recruitment of inflammatory cells, and secretion of proteolytic enzymes that separate the basal cells from the underlying dermis. Clinical features Erythematous plaques and tense blisters on trunk and limbs often present with intense itch (Fig. 23.4.2). In some cases blisters might not be apparent and only an inflammatory, excoriated, and eczema-​ like rash can be seen. Involvement of mucosal membranes is rare 23.4 Autoimmune bullous diseases Kathy Taghipour and Fenella Wojnarowska

ESSENTIALS

ESSENTIALS

Introduction

Introduction

Subepidermal diseases

Subepidermal diseases

Table 23.4.1 Immunopathological characteristics of

Table 23.4.1 Immunopathological characteristics of main autoimmune bullous diseases

23.4  Autoimmune bullous diseases 5613 and, in cases of extensive involvement, other differentials such as mucous membrane pemphigoid should be considered. Pemphigoid blisters often burst leaving eroded and weeping areas that are prone to infection. Patients are in significant discomfort with itch and sore- ness during the active stage of the disease. Diagnosis Clinical diagnosis should be followed with histological and im- munofluorescence studies. A skin biopsy from a fresh, intact blister is analysed with light microscopy and a perilesional biopsy is taken from the skin adjacent to a blister with intact epidermis for direct immunofluorescense. Histology with haematoxylin and eosin staining shows a subepidermal cleft with dermal inflammatory cells consisting of eosinophils and neurtorphils. Direct and indirect im- munofluorescence (using serum or blister fluid if no venous access) show linear deposition of IgG and C3 localized along the basement membrane zone (Fig. 23.4.3). Indirect immunofluorescence can be performed on skin that has been artificially split with normal saline, and bullous pemphigoid serum stains the roof of the split. Serum antibodies to BP180 and BP230 can be measured with enzyme linked immunosorbent assay (ELISA) and antibody titre to BP180 might be related to disease activity. Table 23.4.1  Immunopathological characteristics of main autoimmune bullous diseases Autoimmune bullous dermatosis Target structure Target antigen Immunofluorescence picture Subepidermal diseases Bullous pemphigoid Hemidesmosome BP180, BP230, rarely P200 Linear IgG along the basement membrane zone Mucous membrane pemphigoid Hemidesmosome, anchoring fillament BP180, BP230, laminin 332, α6β4 integrin, collagen VII Linear IgG/​IgA along the basement membrane zone Linear IgA disease Hemidesmosome BP180 and its shed ectodomain Linear IgA along the basement membrane zone Epidermolysis bullosa acquisita Anchoring fibrils Collagen VII Linear IgG along the basement membrane zone Dermatitis herpetiformis Microfibrils Likely epidermal tissue transglutaminase Granular deposition in dermal papillae Intraepidermal diseases Pemphigus vulgaris Desmosome Desmoglein1 and 3 Intercellular IgG deposition on epitherlium and mucosa Pemphigus foliaceus Desmosome Desmoglein 1 Intercellular IgG deposition on epithelium Paraneoplastic pemphigus Desmosome Plakins Intercellular and basement membrane zone IgG on epithelium and rat bladder Table 23.4.2  Clinical characteristics and treatment of main autoimmune bullous diseases Autoimmune bullous dermatosis Age group Frequency Clinical features First-​line treatment Subepidermal diseases Bullous pemphigoid Elderly with average age of 80 years 7–​40 per million population per year Itch, urticated plaques and tense blisters on limbs, trunk, and flexures Topical or systemic steroids, Mucous membrane pemphigoid Middle age and elderly Rare, 1–​2 per million population per year Blisters and scarring of oropharynx, oesophagus, ocular, genital, and airway mucosae with or without skin involvement Systemic steroids; dapsone, cyclophosphamide Linear IgA disease Children, young adults and >60 years of age Rare, 0.5 per million population per year Blisters, often at the edge of red plaques (string of pearls) on trunk and limbs (face and genitals in children) with frequent mucosal involvement Dapsone, erythromycin in children Epidermolysis bullosa acquisita All ages 0.25 cases per million population per year Tense blisters and erosions on friction (mechanobullous involvement) with scarring Systemic steroids Dermatitis herpetiformis Young adults, mostly males 4–​35 per million population per year Itchy vesicles on extensor areas (e.g. elbows, knees, buttocks) Gluten-​free diet, dapsone Intraepidermal diseases Pemphigus vulgaris Middle age but with a peak at 70 years 7 per million population per year in the UK Superficial blisters and erosion on skin and mucosa Systemic steroids Pemphigus foliaceus As pemphigus vulgaris As pemphigus vulgaris. There is an endemic form Superficial blisters and erosions on scalp, chest, and upper limbs without mucosal involvement Systemic steroids Paraneoplastic pemphigus All ages Rare Severe mucosal lesions, erosions, and blistering of the skin mainly on upper body and palmoplantar regions. It is often associated with haematological malignancies Unresponsive to treatment but may improve if the underlying malignancy is treated

section 23  Disorders of the skin 5614 Treatment and prognosis Patients with bullous pemphigoid are often frail with multiple co-​ morbidities. The aim of treatment is to control the disease with the least toxic agents. Potent topical steroids applied generously on af- fected areas are effective as sole agents (in mild to moderate dis- ease) or in combination with systemic agents. Oral corticosteroids provide rapid improvement at doses of 0.3–​1 mg/​kg/​day depending on the severity of disease, but high doses are poorly tolerated in older people. The patient should be weaned off corticosteroids slowly to avoid relapse. Anti-​inflammatory antibiotics such as tetracyclines and erythromycin are effective in moderate disease and are a good treatment option with low toxicity. In persistent disease other im- munosuppressants may be needed, most commonly azathioprine and mycophenolate mofetil, and rarely immune therapy such as intravenous immunoglobulins, plasmapheresis, and rituximab. Bullous pemphigoid is self-​limiting but can last from months to years. Mortality is highest in the first year and is often related to adverse effects of systemic steroids and immunosuppressants. The early use of anti-​inflammatory antibiotics might increase in future and trials are underway to compare the efficacy of these agents with systemic steroids. Mucous membrane pemphigoid Aetiology and epidemiology Mucous membrane pemphigoid is a rare blistering disease with an incidence of 1–​2 per million population per year in Western Europe. It affects middle-​aged and older individuals with a female preponder- ance. Multiple systems can be involved and patients might present to several specialists including dermatology, ophthalmology, oral medi- cine, respiratory, and gastroenterology. The cause is unknown. Pathogenesis IgG and/​or IgA antibodies target components of the basement mem- brane zone. In addition to bullous pemphigoid antigens (mainly BP180 and less commonly BP230), several other antigens have been identified which include laminin 332, collagen VII, and α6β4 in- tegrin. Animal models have shown pathogenicity of the antibodies. Clinical features The predominant feature is mucosal involvement with subse- quent scarring, and skin lesions might also be present. The oral mucosa is the most commonly affected site with blisters, erosions, and desquamative gingivitis (Fig. 23.4.4). There is significant pain Table 23.4.3  Differential diagnoses of autoimmune bullous disease Differential diagnosis Diagnostic clues Inflammatory diseases Eczema Lichen planus Vasculitis Lupus Erythema multiforme Histology confirms the diagnosis. Immunofluorescence tests are negative Infectious diseases Herpes simplex Herpes zoster Impetigo Staphylococcus scalded skin syndrome Skin swabs for virus and bacteria Physical causes of blistering Trauma Burn Ultraviolet light Insect bite History of exposure and spontaneous resolution Genetic diseases Epidermolysis bullosa group Hailey-​Hailey disease Family history Drug-​induced blistering Fixed drug eruption Pseudoporphyria cutanea tarda Bullous drug reactions Toxic epidermal necrolysis Drug history (e.g. paracetamol, frusemide, antiepileptic drugs) Metabolic causes of blistering Porphyria cutanea tarda Relevant metabolic tests, negative immunofluorescence, and possible history of exacerbation on exposure to sunlight Oedema-​induced blisters Oedema is apparent (e.g. in cellulitis) Fig 23.4.1  The basement membrane zone of the skin and mucosa.

23.4  Autoimmune bullous diseases 5615 which might lead to reduced oral intake and malnutrition. Ocular involvement is a significant feature and can be subtle initially, but can progress rapidly. Subsequent scarring and symblepharon can lead to blindness (Fig. 23.4.5). Hoarseness, coughing, and stridor are signs of respiratory tract involvement and tracheos- tomy might be required to keep the airways patent. Oesophageal stenosis causes dysphagia and genital tract scarring can lead to structural abnormalities, sexual dysfunction, and micturition problems. Involvement of the skin is often localized and associated with scarring. Diagnosis Clinical signs of mucosal erosions and scarring should prompt the diagnosis. Biopsies should be taken for haematoxylin and eosin staining (from a fresh blister) as well as direct immunofluores- cence (perilesional with intact epidermis). Histology shows a pic- ture similar to that of bullous pemphigoid with a subepidermal cleft, and direct immunofluorescence shows deposition of IgG and or IgA along the basement membrane zone. Indirect immunofluorescence might show low titres of antibodies or be negative. When salt-​split skin is used in indirect immunofluorescence, the staining with IgG, and/​or IgA can be on the roof or the floor of the split, depending on the targeted antigen. Antibodies to BP180 and BP230 deposit on the roof and those to laminin 332, collagen VII and α6β4 integrin stain the floor. ELISA can further characterize the antibody types. Commercial ELISA is currently available for BP180, BP230, and collagen VII. Treatment and prognosis Treatment of mucous membrane pemphigoid is challenging. The aim is to control the disease to prevent scarring, although this might be inevitable despite treatment. The evidence for various treatments is poor due to lack of large trials and the rarity of the disease. Topical steroids are useful for both skin and oral surfaces. In mild disease, anti-​inflammatory antibiotics (tetracyclines, erythromycin) and dapsone are effective. In moderate to severe disease, systemic steroids, and other immunuosuppressants such as azathioprine are often used, but for oesophageal and ocular Fig 23.4.2  Tense and haemorrhagic blisters on background of erythematous skin in bullous pemphigoid. Courtesy of Whittington Health. Fig 23.4.3  IgG autoantibodies binding to the basement membrane zone in bullous and mucous membrane pemphigoid. Fig 23.4.4  Desquamative gingivitis of the gums. Fig 23.4.5  End-​stage ocular disease, showing scarring and symblepharon.

section 23  Disorders of the skin 5616 disease the best evidence is for cyclophosphamide. For more re- fractory disease, intravenous immunoglobulins and rituximab may be needed. The disease runs a chronic course and can last for years. The prog- nosis is best for patients with only skin and oral mucosal disease and less favourable for those with ocular, nasopharyngeal, and genital involvement. The presence of antibodies to laminin 332 is thought to be associated with more severe disease. Linear IgA disease Aetiology and epidemiology Linear IgA disease is a rare subepidermal bullous disease that affects both adults and children. There are two peaks of onset; one in child- hood and young adults, and the other after the age of 60 years. The incidence in Western Europe is reported to be 0.5 per million popu- lation per year. Drug-​induced linear IgA disease is well-​recognized with the most commonly reported drugs being vancomycin and non​steroidal anti-​inflammatory drugs. An association with ulcera- tive colitis has been described and, in some cases, skin symptoms resolve after colectomy. The incidence of lymphoproliferative dis- orders in these patients is also higher. There is a strong association with HLA-​B8, HLA-​CW7, and HLA-​DR3. Pathogenesis Autoantibodies of IgA type react to various antigens of the hemi­ desmosomes mainly BP180 and its physiologically shed ectodomains but also BP230 and LAD285, and cause a subepidermal split. Clinical features The disease presents with sudden onset of pruritic, urticated plaques, with blisters located around the edge of the plaques in an annular fashion known as ‘string of pearls’ (Fig. 23.4.6). Blisters are often located on trunk, limbs, and oral mucosa; face and genital areas are commonly affected in children along with the nasopharyngeal mucosa. A new consensus suggests that severe mucosal involvement should be classed as mucous membrane pemphigoid instead. Diagnosis Histology is not diagnostic and shows a subepidermal blister with variable infiltration by inflammatory cells. Immunofluorescence studies are essential for diagnosis and are performed on a perilesional skin biopsy and serum, showing deposition of IgA antibodies along the basement membrane zone. In salt-​split skin, the antibodies usu- ally stain the roof and rarely the floor or both. Treatment and prognosis Most patients respond well to dapsone and sulphonamide drugs (sulphapyridine, sulphamethoxypyridazine) and some respond to anti-​inflammatory antibiotics (tetracyclines, erythromycin). Other immunosuppressants are rarely required. The disease usually re- mits within 3–​6 years but can take a chronic course. The prognosis is often good in children and symptoms tend to resolve by puberty. Epidermolysis bullosa acquisita Aetiology, epidemiology, and pathogenesis This is a very rare disease affecting less than 0.25 cases per mil- lion population per year in Western Europe affecting all ages and ethnic groups. It is characterized by IgG autoantibodies against collagen VII, which is a component of the anchoring fibrils in the dermoepidermal junction. An association with Crohn’s disease has been reported. Clinical features Similar to its genetic counterpart, dystrophic epidermolysis bullosa, epidermolysis bullosa acquisita causes mechanobullous fragility in patients. This means that blisters and erosions develop at the site of minor trauma and are often seen on knees, elbows, hands, and feet. There is also an inflammatory subtype that resembles bullous pemphigoid. Mucosal involvement and nail dystrophy are common. Milia (small keratin cysts) and atrophic scarring are often seen at the site of healed blisters. Diagnosis Mechanobullous fragility in adults is an important clinical sign for diagnosis which should be followed by immunopathology studies. A linear deposition of IgG antibodies on the basement membrane zone is seen with immunofluorescence studies. Antibodies are lo- cated to the dermal side of salt-​split skin in indirect immunofluores- cence. Antibodies to collagen VII can be confirmed by ELISA. Treatment and prognosis The disease is often refractory. Wound management and avoidance of trauma are important aspects of the treatment; however, systemic agents such as systemic steroids, dapsone, sulphonamide drugs (sulphapyridine and sulphamethoxypyridazine), and immunosup- pressive treatments are often necessary. Refractory disease might respond to intravenous immunoglobulins, immunoadsorption, or rituximab. Although the course of the disease is often chronic, long-​ term prognosis for patients who respond to immunosuppressants is excellent. Dermatitis herpetiformis Aetiology and epidemiology This is a subepidermal blistering disease that is the cutaneous mani- festation of gluten sensitive enteropathy, or coeliac disease. It affects young adults with a predilection for white males. There is a strong association with HLA DQ-​2 and HLA DQ-​8 and the incidence is Fig 23.4.6  Annular blistering lesions in linear IgA disease.

23.4  Autoimmune bullous diseases 5617 higher among first-​degree relatives, with 18% having a family his- tory. The incidence in northern Europe and the United States ranges from 4 to 35 per million population per year with the disease being more common in Scandinavia, western Ireland, and Hungary, and rare in Asia and Africa. Pathogenesis Tissue transglutaminase is the antigen target for coeliac disease and has a homologous structure to epidermal transglutaminase, which is thought to be the antigen for dermatitis herpetiformis. IgA antibodies are deposited in the dermal papillae in dermatitis herpetiformis, which triggers an inflammatory response, neutrophilic infiltrate, and blistering. It is not yet clear whether IgA epidermal transglutaminase antibodies are directly pathogenic. An animal model using genetic- ally primed DQ8 mice has shown that in a minority gluten can induce blisters with the characteristic histology and granular IgA deposition. However this was not associated with circulating antibodies to skin, endomysium, gluten, gliadin, or tissue transglutaminases, nor with enteropathy (see Chapter 15.10.3 Coeliac disease). Clinical features An intensely itchy eruption typically presents on extensor surfaces such as knees, elbows, buttocks, and can also involve the scalp and neck. The rash consists of small vesicles and papules which might not be detected clinically due to intense itch and excoriation. Mucosae are not usually affected. Diagnosis Histology from an intact lesion shows a subepidermal cleft with neutrophils and possibly eosinophils at the dermal papillae. Direct immunofluorescence of uninvolved skin is required to confirm the diagnosis and shows a granular deposition of IgA in the dermal pa- pillae along the basement membrane zone (Fig. 23.4.7). These de- posits might resolve with a gluten-​free diet. The presence of antitissue transglataminase and antiendomysial antibodies should be checked to investigate for underlying coeliac disease. Screening for autoimmune thyroid disease and diabetes is also recommended, as are serology tests for other autoimmune dis- eases, if relevant. A commercial ELISA is available in some centres for epidermal transglutaminase antibodies. Treatment and prognosis The main element of the treatment is a gluten-​free diet; how- ever, it could take over a year for the skin symptoms to improve with diet alone. Dapsone and sulphonamides (sulphapyridne and sulphamethoxypyridazine) provide fast relief of symptoms while a gluten-​free diet, which should be lifelong, takes effect. Symptoms noticeably recur on ingestion of gluten and dietician reviews may be needed to motivate the patient. Titres of epidermal and tissue transglutaminase antibodies can be used to monitor adherence to gluten-​free diet and might reduce the need for duodenal biopsies. The prognosis is good in patients who adhere to a gluten-​free diet and the majority will be able to reduce or discontinue dapsone. Intraepidermal diseases Intraepidermal diseases encompass the pemphigus group (pem- phigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus), characterized by flaccid and superficial blisters and erosions on the skin and/​or mucosae. Autoantibodies target the intercellular adhe- sion complex (desmosomes, Fig. 23.4.8) between the keratinocytes, which leads to separation of the cells and blister formation within the epidermis. Pemphigus vulgaris Epidemiology and genetics This is the commonest type of pemphigus which affects the mucosal membranes, with or without skin involvement. It is rare in Western Europe (7 per million population per year in the United Kingdom) but is more common in the Middle East, India, North Africa, and among the Jewish population. Middle-​aged and young individuals of both sexes can be affected, with a further peak of incidence in the seventh decade. There is a strong association with certain HLA types in different populations and a gene polymorphism in the target antigen (desmoglein 3). Pemphigus can be induced by drugs such as angiotensin-​converting enzyme inhibitors and penicillamine. Pathogenesis Autoantibodies target desmogleins which are components of desmo- somes. The main target antigen in pemphigus vulgaris is desmoglein 3 which is found in the lower parts of the epidermis and in mucosal surfaces. Desmoglein 1, which is present in the upper layer of the epidermis, but not in mucosae, might also be targeted. As a result of this antigen-​antibody interaction the keratinocyts separate from each other and float within the blister that is formed (acantholysis). Antibodies to desmoglein 3 and desmoglein 1 are usually of the IgG type and are directly pathogenic as proven by several animal studies. The titres of antibodies correlate with disease activity. Clinical features Pemphigus vulgaris often presents with oral blisters and erosions involving the palate, gum, tongue, and buccal mucosa (Fig. 23.4.9). This can lead to dysphagia, dehydration, and malnutrition. Involvement of the skin might be simultaneous or follow the oral manifestations after months. Fragile and superficial blisters on the skin burst easily and are rarely seen intact (Fig. 23.4.10). Scalp, face, and trunk are commonly affected and other mucosal surfaces such as the pharynx and genitalia Fig 23.4.7  IgG antibodies binding to the dermal side of the basement membrane zone of split skin.

section 23  Disorders of the skin 5618 might also be involved. The skin is sore and the denuded blisters are prone to infection, which in extensive disease can lead to sepsis. As the erosions heal they can leave small scabbed plaques. Diagnosis Histopathology of an intact blister shows acantholysis and an intraepidermal blister with mixed inflammatory cell infiltrate. The basal cell layer, above which the blister is formed, remains intact and forms a single row of cells in a pattern that is known as ‘tombstoning’. The diagnosis is made with immunofluorescence studies which show labelling of the intercellular space where the IgG antibodies are de- posited (Fig. 23.4.11). Direct immunofluorescence is performed on a biopsy from intact skin or mucosa adjacent to a blister/​erosion, and in- direct immunofluorescence utilizes serum added to various substrates rich in desmogleins (e.g. normal human skin and monkey oesophagus). Indirect immunofluorescence and ELISA (for both desmoglein 1 and 3) provide the titre of circulating antibodies and are useful in moni- toring of disease activity and characterizing subtypes of pemphigus. Treatment and prognosis In localized or limited disease, potent topical steroids might be useful; however, systemic steroids at high doses (usually 1 mg/​kg) are often needed in the initial stages of the disease to achieve rapid control. The addition of gastric and bone protective measures are essential at this stage. Adjuvant treatment should be introduced to allow reduction of systemic steroids; these include agents such as azathioprine, mycophenolate mofetil, and cyclophosphamide. Rituximab (a monoclonal chimeric anti-​CD20 antibody) has shown promising results in the treatment of pemphigus. It selectively tar- gets the CD20 molecule that is expressed by B cells, which in turn reduces the IgG production by plasma cells. It is thought that early treatment with rituximab is associated with a better outcome as it reshapes the repertoire of B cells, leading to a reduction in the quan- tity of memory B cells after treatment. The downside is the risk of life-​threatening infections and thus it should be used for selected pa- tients only. Other treatment options for refractory disease are intra- venous immunoglobulins and immunoadsorption/​plasmapheresis. Future treatments might include more targeted therapy such as desmoglein peptides to block the binding sites for autoantibodies. KEY Dsg desmoglein 1 PF + PV DP Desmoplakins PNP PG Plakoglobin PNP intercellular contact layer plasma membrane Dsg desmoglein 3 PV Pemphigus vulgaris PV Pemphigus foliaceus PF Paraneoplastic pemphigus PNP Fig 23.4.8  The desmosome and its target antigens. Fig 23.4.9  Oral erosions on tongue, palate, and labial mucosa in pemphigus vulgaris. Courtesy of Whittington Health.

23.4  Autoimmune bullous diseases 5619 Pemphigus foliaceus Epidemiology and genetics This is a rare subtype of pemphigus with a sporadic and an endemic form. The endemic form (fogo selvagem) is seen in Brazil, Colombia, and Tunisia, and is thought to be related to insect exposure as it af- fects individuals living in rural areas near rivers, and resolves when they move away. A slight preponderance for young females has been found in North Africa. Both sporadic and endemic forms share similar HLA II alleles. Pathogenesis Autoantibodies to desmoglein 1 target this component of the ad- hesion complex that is located in the upper layer of epidermis, below the stratum corneum (subcorneal). Blisters are more super- ficial than pemphigus vulgaris. Animal studies have confirmed the pathogenicity of the antibodies. A similar clinical picture is seen with staphylococcal scalded skin syndrome where the toxin cleaves desmoglein 1, leading to superficial blisters. Clinical features Erosions and crusting are seen in a seborrhoeic distribution af- fecting scalp, face, torso, and upper limbs. In contrast to pemphigus vulgaris, mucosal surfaces are not involved. Diagnosis Histology shows a subcorneal split and immunofluorescence shows antibody deposition in the intercellular space. Indirect immuno- fluorescence (positive on substrates rich in desmoglein 1 and nega- tive for desmoglein 3) and ELISA (positive for desmoglein 1 and negative for desmoglein 3)  can differentiate pemphigus foliaceus from pemphigus vulgaris. Treatment and prognosis The treatment is similar to that of pemphigus vulgaris with topical treatment and systemic steroids to achieve remission. Steroid sparing agents should be used as per treatment of pemphigus vulgaris. The disease can take a chronic course but eventually remits. Elucidating environmental factors that trigger the endemic dis- ease might lead to better understanding of the disease pathogenesis in future. Paraneoplastic pemphigus Epidemiology and genetics This is a rare subtype of pemphigus that was first recognized as an entity in 1990. It is associated with an underlying malignancy, which is often haematological, such as non-​Hodgkin’s lymphoma, chronic lymphocytic leukaemia, and Castleman’s disease. Its genetic basis is not well characterized and seems to be different to other subtypes of pemphigus. Fig 23.4.10  Erosions and excoriations in pemphigus. Courtesy of Whittington Health. Fig 23.4.11  Immunofluorescence demonstrating antibody binding in the epidermis in pemphigus.

section 23  Disorders of the skin 5620 Pathogenesis There are antibodies against various antigens of the adhesion complex, mainly plakins, which are also found in transitional and other types of epithelia, but also desmogleins and bullous pemphigoid antigens. Clinical features Patients present with severe mucosal erosion and skin eruption involving a large area of the body. There can be involvement of the palms and soles with blisters mimicking erythema multiforme, as well as nasopharynx, genital, and respiratory mucosal erosions. A  lichenoid type of eruption might also be seen. There is often multiorgan involvement and the patients are unwell with respiratory failure as the usual cause of death. Diagnosis Histology shows intraepidermal cleavage and possibly basal cell ne- crosis and is not diagnostic. Direct immunofluorescence of uninvolved skin shows both intercellular and intraepidermal desposition of antibodies. A sub- strate with transitional epithelia such as rodent bladder (devoid of desmogleins) is used in indirect immunofluorescence to confirm the presence of antibodies to plakins. The patients should be investi- gated for underlying malignancy if not known. Treatment and prognosis The disease is resistant to treatment but might improve if the underlying malignancy is treated. Immunosuppression is needed to improve the skin symptoms. Prognosis is poor and most patients die. FURTHER READING Bolotin D, Petronic-​rosic V (2011). Dermatitis herpetiformis. Part I: epidemiology, pathogenesis, and clinical presentation. J Am Acad Dermatol, 64, 1017–​24. Bolotin D, Petronic-​rosic V (2011). Dermatitis herpetiformis. Part II: diagnosis, management, and prognosis. J Am Acad Dermatol, 64, 1027–​33. Chan LS, et al. (2002). The first international consensus on mucous membrane pemphigoid:  definition, diagnostic criteria, patho- genic factors, medical treatment, and prognostic indicators. Arch Dermatol, 138, 370–​9. Colliou N, et al. (2013). Long-​term remissions of severe pemphigus after rituximab therapy are associated with prolonged failure of desmoglein B cell response. Sci Transl Med, 5, 175ra30. Harman KE, Albert S, Black MM (2003). Guidelines for the manage- ment of pemphigus vulgaris. Br J Dermatol, 149, 926–​37. Lloyd-​lavery A, et al. (2013). The associations between bullous pem- phigoid and drug use: a UK case-​control study. JAMA Dermatol, 149, 58–​62. Taghipour K, et al. (2010). The association of bullous pemphigoid with cerebrovascular disease and dementia:  a case-​control study. Arch Dermatol, 146, 1251–​4. Venning VA, et  al. (2012). British Association of Dermatologists’ guidelines for the management of bullous pemphigoid 2012. Br J Dermatol, 167, 1200–​14. Wojnarowska F, et al. (1988). Chronic bullous disease of childhood, childhood cicatricial pemphigoid, and linear IgA disease of adults: a comparative study demonstrating clinical and immunopathologic overlap. J Am Acad Dermatol, 19(5 Pt 1), 792–​805.

Thiviyani Maruthappu and David P. Kelsell 23.4 Aut

Thiviyani Maruthappu and David P. Kelsell 23.4 Autoimmune bullous diseases 5612 Kathy Taghipour and Fenella Wojnarowska