19-29 Dermatology

29 Dermatology

Dermatology SH Ibbotson Clinical examination in skin disease 1210 Functional anatomy and physiology 1212 Investigation of skin disease 1214 Presenting problems in skin disease 1216 Lumps and lesions 1216 Rash 1216 Blisters 1218 Itch 1219 Photosensitivity 1220 Leg ulcers 1223 Abnormal pigmentation 1224 Hair and nail abnormalities 1224 Acute skin failure 1224 Principles of management of skin disease 1225 General measures 1225 Topical treatments 1225 Phototherapy and photochemotherapy 1227 Systemic therapies 1227 Dermatological surgery 1228 Non-surgical treatments 1228 Skin tumours 1229 Malignant tumours 1229 Benign skin lesions 1234 Common skin infections and infestations 1235 Bacterial infections 1235 Viral infections 1238 Fungal infections 1239 Infestations 1241 Acne and rosacea 1241 Eczemas 1244 Psoriasis and other erythematous scaly eruptions 1247 Lichenoid eruptions 1252 Urticaria 1252 Bullous diseases 1254 Toxic epidermal necrolysis 1254 Immunobullous diseases 1255 Pigmentation disorders 1257 Decreased pigmentation 1257 Increased pigmentation 1258 Hair disorders 1258 Nail disorders 1260 Skin disease in general medicine 1261 Conditions involving cutaneous vasculature 1261 Connective tissue disease 1262 Granulomatous disease 1263 Porphyrias 1263 Abnormal deposition disorders 1264 Genetic disorders 1264 Reactive disorders 1264 Drug eruptions 1265

1210 • DERMATOLOGY Involvement of face Central Hairline Cheeks and nasal bridge: ‘butterfly’ distribution Sparing of light-protected sites, e.g. behind ears, under chin Overall description of individual lesions Discrete, grouped, confluent, reticulate (lace-like), linear Observation If symmetrical Extensor, e.g. psoriasis Flexor, e.g. eczema Involvement of hands, including nail folds and finger webs The patient must be undressed, with make-up and dressings removed, and examined in good lighting. Consider the following: • Age • General health • Distress • Scratching Distribution of rash Symmetrical vs asymmetrical Proximal vs distal vs facial Localised vs widespread Eye involvement e.g. Conjunctivitis/blepharitis in rosacea or eyelash loss in alopecia areata General medical examination Including lymph nodes and other systems as indicated Involvement of axillae/groins e.g. hidradenitis suppurativa Oral and genital involvement Nail involvement Psoriatic changes in nails and peri-ungual involvement Palmoplantar pustulosis Magnifying lens image of benign naevus Morphology of rash Monomorphic or polymorphic Detailed morphology of individual lesions Use a magnifying lens in good lighting to assist Use correct terminology (see definitions throughout text) Reticulate (lacy) network on buccal mucosa in lichen planus. May also be genital involvement Joint involvement e.g. Psoriatic arthritis Examination of scalp Hair loss Scalp changes Alopecia areata Arthritis, plaque psoriasis and psoriatic nail dystrophy

Clinical examination in skin disease

Clinical examination in skin disease • 1211

B A C To find the PASI score, add together: (A) Sum for each part × (B) % of that part involved × (C) % weighting of that body part Minimum = 0; maximum = 72 Four body parts are each scored individually Each of the four body parts is scored: Redness (erythema) 0–4 Thickness (induration) 0–4 Scaling (desquamation) 0–4 The area of each involved body part is scored: 10% 20% 30% 40% 0 0% 1 < 10% 2 10–29% 3 30–49% 4 50–69% 5 70–89% 6 90–100% Plaque Blisters/bullae Pustule Macule/patch Papule Nodule • Onset and course • Exacerbating/relieving factors • Past history of skin disease, atopy or autoimmune disease • Social history, occupation, recreation • Psychological impact, gauged by health- related life quality indices • Always take a detailed drug and allergy history • Include all systemic and topical drugs, and over-the-counter preparations It is tempting to examine the skin first. This is a mistake; take a history, then examine the skin and the rest of the patient.

History-taking
Drug/allergy history • General examination, incl. peripheral lymph nodes, may be indicated/important • Skin diseases may have systemic features (e.g. cardiovascular disease in psoriasis); many systemic diseases have dermatological features (e.g. diabetes)
General examination
Examination of skin • Examine skin, hair, nails and mucous membranes • Is it a rash or a lesion? • Distribution and morphology important for rash • Use of a magnifying lens and/or dermatoscope may be invaluable • Site, size and detailed morphology of a lesion are essential factors to elicit
Closer inspection
Define type of lesion using correct terminology Helps in differential diagnosis and allows colleagues to visualise the process. Other definitions are provided in the chapter. Macule: circumscribed flat area of colour change ≤ 1 cm diameter; patch: > 1 cm Discrete elevation ≤ 1 cm diameter Like papule but deeper (into dermis or subcutaneous layer),

1 cm diameter Raised area > 1 cm diameter with flat top Large (> 1 cm diameter) fluidfilled blister Vesicle Small (≤ 1 cm diameter) fluidfilled blister Visible accumulation of pus in blister Petechiae/purpura Petechiae: tiny macules due to extravascular blood in dermis; purpura: larger, may be palpable

Score activity Tools for objective assessment of disease severity (e.g. Psoriasis Area and Severity Index, PASI) are important in assessing severity and treatment responses. Include:

1212 • DERMATOLOGY The remaining 10% of epidermal cells are: • Langerhans’ cells: these are dendritic, bone marrowderived cells that circulate between the epidermis and local lymph nodes. Their prime function is antigen presentation to lymphocytes. Other dermal antigenpresenting dendritic cells are also present. • Melanocytes: these occur predominantly in the basal layer and are of neural crest origin. They synthesise the pigment melanin from tyrosine, package it in melanosomes and transfer it to surrounding keratinocytes via their dendritic processes. • Merkel cells: these occur in the basal layer and are thought to play a role in signal transduction of ﬁne touch. Their embryological derivation is unclear. Basement membrane The basement membrane (Fig. 29.1) is an anchor for the epidermis and allows movement of cells and nutrients between dermis and epidermis. The cell membrane of the epidermal basal cell is attached to the basement membrane via hemi-desmosomes. The lamina lucida lies immediately below the basal cell membrane and is composed predominantly of laminin. Anchoring ﬁlaments extend through the lamina lucida to attach to the lamina densa. This electron-dense layer consists mostly of type IV collagen; from it extend loops of type VII collagen, forming anchoring ﬁbrils that fasten the basement membrane to the dermis. Dermis The dermis is vascular and supports the epidermis structurally and nutritionally. It varies in thickness from just over 1 mm on the inner forearm to 4 mm on the back. Fibroblasts are the predominant cells but others include mast cells, mononuclear phagocytes, T lymphocytes, dendritic cells, neurons and endothelial cells. The acellular part of the dermis consists mainly of collagen I and III, elastin and reticulin, synthesised by ﬁbroblasts. Support is provided by an amorphous ground substance (mostly glycosaminoglycans, hyaluronic acid and dermatan sulphate), whose production and catabolism are altered by hormonal changes and ultraviolet radiation (UVR). Based on the pattern of collagen ﬁbrils, the superﬁcial dermis is termed the ‘papillary dermis’, and the deeper, coarser part is the ‘reticular dermis’. Epidermal appendages Hair follicles There are 3–5 million hair follicles, epidermal invaginations that develop during the second trimester. They occur throughout the skin, with the exception of palms, soles and parts of the genitalia (glabrous skin). The highest density of hair follicles is on the scalp (500–1000/cm2). Newborns are covered with ﬁne ‘lanugo’ hairs, which are usually non-pigmented and lack a central medulla; these are subsequently replaced by vellus hair, which is similar but more likely to be pigmented. By contrast, scalp hair becomes terminal hair, which is thicker with a central medulla, is usually pigmented and grows longer. At puberty, vellus hairs in hormonally sensitive regions, such as the axillary and genital areas, become terminal hairs. Human hairs grow in a cycle with three phases: anagen (active hair growth), catagen (transitional phase) and telogen (resting phase). The duration of each phase varies by site. On the scalp, anagen lasts several years, catagen a few days and Diseases affecting the skin are common, and important because the absence of normal skin function, as well as sometimes being life-threatening, can severely impair quality of life. This may be exacerbated by the fact that people with skin disease can suffer the effects of stigma, often brought about by the ill-informed understanding of others with respect to skin diseases, particularly as regards visually disﬁguring skin changes or the belief that they are contagious. Skin diseases affect all ages and there are more than 2000 different types and presentations. Assessment of the skin is valuable in the management of anyone presenting with a medical problem and, conversely, assessment of the other body systems is important when managing primary skin diseases. This chapter concentrates on common skin diseases and those that are important components of general medical conditions. Skin infections, including those related to the human immunodeﬁciency virus (HIV), tuberculosis, leprosy (Hansen’s disease) and syphilis are also discussed in Chapters 12, 17, 11 and 13, respectively. Functional anatomy and physiology The skin covers just under 2 m2 in the average adult. The outer layer is the epidermis, a stratiﬁed squamous epithelium consisting mainly of keratinocytes. The epidermis is attached to, but separated from, the underlying dermis by the basement membrane. The dermis is less cellular and supports blood vessels, nerves and epidermal-derived appendages (hair follicles and sweat glands). Below it is the subcutis, consisting of adipose tissue. Epidermis In most sites, the epidermis is only 0.1–0.2 mm thick, except on the palms or soles, where it can extend to several millimetres. Keratinocytes make up approximately 90% of epidermal cells (Fig. 29.1). The main proliferative compartment is the basal layer. Keratinocytes synthesise a range of structural proteins, such as keratins, loricrin and ﬁlaggrin (ﬁlament aggregating protein), which play key roles in maintaining the skin’s barrier function. Keratinocytes are also responsible for synthesis of vitamin D under the inﬂuence of ultraviolet B (UVB) light (p. 1049). There are more than 50 types of keratin and their expression varies by body site, site within the epidermis and disease state. Mutations of certain keratin genes can result in blistering disorders (p. 1254) and ichthyosis (characterised by scale without major inﬂammation). As keratinocytes migrate from the basal layer, they differentiate, producing a variety of protein and lipid products. Keratinocytes undergo apoptosis in the granular layer before losing their nuclei and becoming the ﬂattened corneocytes of the stratum corneum (keratin layer). The epidermis is a site of lipid production, and the ability of the stratum corneum to act as a hydrophobic barrier is the result of its ‘bricks and mortar’ design; dead corneocytes with highly cross-linked protein membranes (‘bricks’) lie within a metabolically active lipid layer synthesised by keratinocytes (‘mortar’). Terminal differentiation of keratinocytes relies on the keratin ﬁlaments being aggregated and this is, in part, mediated by ﬁlaggrin. Mutations of the ﬁlaggrin gene are found in icthyosis vulgaris and in some patients with atopic eczema (p. 1245). The skin is a barrier against physical stresses. Cell-to-cell attachments must be able to transmit and dissipate stress, a function performed by desmosomes. Diseases that affect desmosomes, such as pemphigus (p. 1256), result in blistering due to keratinocyte separation.

Functional anatomy and physiology • 1213

oestrogens reducing it. In animals, sebum is important for hair waterprooﬁng but its role in humans is unclear. Sweat glands Eccrine sweat glands develop in the second trimester and are also epidermal invaginations found all over the body. Their coiled ducts open directly on to the skin surface. They play a major role in thermoregulation and, unusually, are innervated by cholinergic ﬁbres of the sympathetic nervous system. Eccrine glands of the palms and soles are innervated differently and are activated in the telogen around 3 months. The length of hair at different sites reﬂects the differing lengths of anagen. Sebaceous glands Sebaceous glands are epidermal downgrowths, usually associated with hair follicles and composed of modiﬁed keratinocytes. The cells of the sebaceous gland (sebocytes) produce a range of lipids, discharging the contents into the duct around the hair follicle. Sebum excretion is under hormonal control, with androgens increasing it (as do progesterones, to a lesser degree) and Fig. 29.1 Structure of normal skin. Anchoring filament (laminin 332) Basement membrane Epidermis Desmosome (desmoglein-1 and 3, desmoplakin) Tonofilaments (keratins 5 and 14) Hemi-desmosome (BP230, type XVII collagen, α6β4 integrin, plectin) Anchoring fibrils (collagen VII) Basal keratinocyte Basal cell membrane Lamina lucida (laminin-1) Lamina densa (type IV collagen) Sublamina densa Epidermis Dermis Stratum corneum (keratin layer) Granular layer Prickle cell layer Basal layer Hair shaft Langerhans' cell Melanocyte Keratinocytes containing keratins 1 and 10 Keratinocytes containing keratins 5 and 14 Epidermis Dermis Subcutis Eccrine sweat duct Superficial vascular plexus Sebaceous gland Hair sheath Eccrine sweat gland Deep vascular plexus Hair matrix Dermal papilla Subcutaneous vessel

1214 • DERMATOLOGY of the lesion clearer. Granulomatous skin diseases may have a characteristic appearance under diascopy, such as in lupus vulgaris (cutaneous tuberculosis), in which ‘apple jelly nodules’ are typically seen on diascopy. Skin biopsy Skin biopsy is a mainstay investigation in dermatology and can be used in a range of dermatological presentations. In the most common scenario, a skin biopsy is undertaken in order to obtain tissue on which to perform standard histopathology. However, tissue may also be subjected to a variety of staining and culture techniques, including immunostaining. Histopathological examination of skin biopsies is especially ‘ﬁght or ﬂight’ response. Apocrine sweat glands are restricted to the axillae and the mammary and genital areas, are connected to hair follicles and are not involved in thermoregulation. Nails Fingernail growth commences at approximately 8 weeks of gestation and is complete by 32 weeks. Toenails develop slightly later. The anatomy of the nail apparatus is covered later in the chapter (p. 1260). Blood vessels and nerves Human skin has a plentiful blood supply, arranged in superﬁcial and deep plexuses consisting of arterioles, arterial and venous capillaries, and venules. The upper plexus in the papillary dermis communicates with the lower plexus at the junction between the dermis and the subcutis. Capillary loops arise from terminal arterioles in the horizontal papillary plexus. Blood vessels are supplied by sympathetic and parasympathetic nerves, with the relative contributions of the pathways differing by site. Sympathetic signals are important in mediating autonomic-induced vasoconstriction. The blood supply of skin is far greater than that required for normal skin physiology and reﬂects the importance of skin in thermoregulation. Functions of the skin The skin has many functions, all of which can be affected by disease (Box 29.1). Skin changes associated with ageing are shown in Box 29.2. Investigation of skin disease Magnifying glass A hand-held or freestanding magnifying lens used under good lighting conditions (ideally daylight) is valuable for examination of the skin. Wood’s light Wood’s light is a long-wavelength UVA/short-wavelength visible (violet) light source that can be used in various ways. In hypopigmentation, such as in vitiligo, it can help in appreciating the extent of disease. In pigmented conditions, such as melasma, it can determine whether pigmentation is mainly epidermal (sharp cut-off under Wood’s lamp) or mixed epidermal and dermal (ill-deﬁned cut-off). Wood’s lamp can also be used to help with the diagnosis of some fungal infections because of their characteristic ﬂuorescence. Dermatoscopy and diascopy Dermatoscopy (also known as dermoscopy and epiluminescence microscopy) is increasingly performed with hand-held dermatoscopes. What makes dermatoscopy unique is the fact that it allows visualisation through contact of a glass plate on the instrument with a liquid ﬁlm applied to the skin, or through special optics to allow non-contact dermatoscopy, enabling deeper structures to be seen without interference from reﬂection and refraction of light in the epidermis. Diascopy is simply pressing on the lesion with a glass slide. This provides some of the effect of dermatoscopy, but is mainly used to remove blood from vascular lesions to make the appearance 29.1 Functions of the skin Function Structure/cell involved Protection against: Chemicals, particles, desiccation Stratum corneum Ultraviolet radiation Melanin produced by melanocytes and transferred to keratinocytes Stratum corneum hyperproliferation Antigens, haptens Langerhans’ cells, lymphocytes, mononuclear phagocytes, mast cells, dermal dendritic cells Microorganisms Stratum corneum, Langerhans’ cells, mononuclear phagocytes, mast cells, dermal dendritic cells Maintenance of ﬂuid balance Prevents loss of water, electrolytes and macromolecules Stratum corneum Shock absorber Strong, elastic and compliant covering Dermis and subcutaneous fat Sensation Specialised nerve endings mediating pain and withdrawal Itch leading to scratch and removal of a parasite Metabolism Detoxiﬁcation of xenobiotics, retinoid metabolism, isomerisation of urocanic acid Predominantly keratinocytes Temperature regulation Eccrine sweat glands and blood vessels Protection, and ﬁne manipulation of small objects Nails Hormonal Steroidogenesis, testosterone synthesis and conversion to other androgenic steroids Hair follicles, sebaceous glands Conversion of thyroxine (T4) to triiodothyronine (T3) Keratinocytes Conversion of 7-dehydrocholesterol to vitamin D Keratinocytes Pheromonal Importance unknown in humans Apocrine sweat glands, possibly sebaceous glands Psychosocial, grooming and sexual behaviour Appearance, tactile quality of skin, hair, nails

Investigation of skin disease • 1215

point being at 96 hours. When interpreting patch test readings, it is important to determine the clinical relevance of any allergic reactions before giving avoidance advice. Photopatch testing is similar to patch testing but investigates delayed hypersensitivity to an agent (usually a sunscreen or a non-steroidal anti-inﬂammatory drug (NSAID)) after the absorption of UVR. It involves applying substances in duplicate and irradiating one set with UVR (typically UVA, 5 J/cm2), readings then being conducted in a similar manner to patch testing. Prick tests and speciﬁc immunoglobulin E testing Prick tests are used to investigate cutaneous type I (immediate) hypersensitivity to various antigens such as pollen, house dust mite or dander. The skin is pricked with commercially available stylets through a dilution of the appropriate antigen solution (p. 86). Alternatively, specific immunoglobulin E (IgE) levels to antigens can be measured in serum. If challenge tests are undertaken for patients with suspected allergy, these must be performed under controlled conditions due to the potential risk of triggering a severe reaction (p. 86). Phototesting Phototesting is extremely valuable in the assessment of suspected photosensitivity. The mainstay investigation is monochromator phototesting, which involves exposing the patient’s back to increasing doses of irradiation using narrow wavebands across the solar spectrum and then assessing responses, using the minimal erythema dose (MED) at each waveband. This is the dose required to cause just perceptible skin reddening and is compared with values for the normal population. If a patient has reduced MED (develops erythema at lower doses than healthy subjects), this indicates abnormal photosensitivity. Thus, monochromator phototesting can be used to determine whether a patient is abnormally photosensitive, which wavebands are involved and how sensitive the patient is (p. 1220). Provocation testing can be performed with a broadband (usually UVA) source to induce rash at a test site (most useful for polymorphic light eruption) and can be helpful for diagnosis. Provocation testing to a variety of light sources, including artiﬁcial compact ﬂuorescent lamps, may also be indicated, the latter being most relevant in patients with severe photosensitivity. Patients who are referred for phototherapy will also commonly undergo an MED test, in which they are exposed to a series of test doses of the light source that will be used therapeutically (often narrowband UVB); the MED is determined 24 hours later (or 72–96 hours for the psoralen–ultraviolet A (PUVA) minimal phototoxic dose; p. 1227). This allows treatment regimens to be individualised, based on a patient’s erythemal responses, and may detect abnormal photosensitivity. Blood tests Although most patients presenting with a skin problem do not need blood tests as part of their investigations, there are many systemic diseases that can present with skin features and, indeed, blood tests may also be indicated in the investigation of primary skin disease. A wide range of possible investigations may be required and some examples include haemoglobin, iron studies and thyroid function tests in pruritus or hair loss; autoantibody screening if lupus is suspected; porphyrin plasma scan for skin fragility and hypertrichosis; and hepatitis screening in lichen useful for tumour diagnosis. When a dermatologist or pathologist with dermatopathology expertise is involved, it can also assist in the diagnosis of inﬂammatory skin diseases. It is rare for histopathology of a previously undiagnosed inﬂammatory skin disease to provide a diagnosis on its own; clinico-pathological correlation is critical. Most biopsies are stained with haematoxylin and eosin but other stains may be useful in special situations, such as for fungal hyphae, iron or mucin. Direct immunoﬂuorescence can also be undertaken on a fresh skin biopsy, allowing antigen visualisation using ﬂuorescein-labelled antibodies; this is especially important in the diagnosis of autoimmune bullous disorders or connective tissue disease, such as cutaneous lupus. Microbiology Bacteriology Bacterial swabs may identify a causative infective agent. However, organisms identiﬁed from the skin surface may not be the cause of the skin disease but instead may simply reﬂect colonisation of skin that has already been damaged by a primary skin disease. Virology A number of techniques, including immunoﬂuorescence and polymerase chain reaction (PCR), are available to diagnose herpes simplex or herpes zoster viruses from vesicle ﬂuid (p. 106). Mycology Scale, nail clippings (or scrapings of crumbly subungual hyperkeratosis) and plucked hairs can be examined by light microscopy. If potassium hydroxide and a simple light microscope are available, this can be performed in any outpatient clinic. Microbiology laboratories will also routinely undertake microscopy and culture for fungi and yeasts. Patch testing Patch testing is the investigation of choice for delayed, cellmediated, type IV hypersensitivity, which clinically manifests as dermatitis. Potential allergens (see Box 29.22, p. 1247) are applied as patches to the back under occlusion for 48 hours, in vehicles and at concentrations that minimise false-positive and false-negative reactions. After 48 hours the patches are removed and patch-test readings are undertaken at time points of up to 7 days after patch-test application, with the most typical time 29.2 Skin changes in old age • Chronological ageing: due to the intrinsic ageing process. • Photo-ageing: due to cumulative ultraviolet radiation (UVR) exposure and superimposed on intrinsic ageing. • Typical changes: include atrophy, laxity, yellow discoloration, wrinkling, dryness, irregular pigmentation, and thinning and greying of hair. • Causes: age-related alterations in structure and function of the skin, cumulative effects of environmental insults, especially UVR and smoking, cutaneous consequences of disease in other organ systems. • Consequences: reduction in immune and inﬂammatory responses, reduction in absorption and clearance of topical medications, reduced healing, increased susceptibility to irritants, dermatitis, adverse drug effects (including topical glucocorticoid-induced atrophy and purpura) and diseases such as skin cancer.

1216 • DERMATOLOGY Is it a melanocytic naevus or a malignant melanoma? This is a common clinical scenario and one that it is critical to resolve correctly. • The precise nature of the change should be determined (as above). Listen to the patient and pay attention to subtle changes, as people know their skin well. • If the patient has other pigmented lesions, then these should be examined too, as they may be informative. For example, if the presenting lesion looks different from the others, then suspicion of melanoma is increased; conversely, if the patient has multiple basal cell papillomas, this may be reassuring – although do not be falsely reassured. • Is there a positive family history of melanoma? A suspicious naevus in a patient with a ﬁrst-degree relative with melanoma probably warrants excision. The ABCDE ‘rule’ is a guide to the characteristic features of melanoma (Box 29.3 and see Figs 29.2 and 29.15), although melanomas should ideally be diagnosed before the diameter is greater than 0.5 cm. Loss of normal skin markings in a pigmented lesion may be suggestive of melanoma. Conversely, normal skin markings and ﬁne hairs dispersed evenly over a lesion are reassuring but do not exclude melanoma. The Glasgow seven-point checklist is another useful guide: • major features: change in size, shape and colour • minor features: diameter > 0.5 cm, inﬂammation, oozing, bleeding, itch or altered sensation. Patients with one major or one minor feature should be referred for further evaluation. Investigations and management If a benign diagnosis, such as basal cell papilloma, is made on clinical grounds, then the patient can be reassured and the lesion either left or treated: for example, with cryotherapy. If there are concerns about the diagnosis or malignancy is suspected on clinical grounds, then skin biopsy in order to obtain a tissue diagnosis is the usual approach. An incisional biopsy may be indicated, although if the lesion is small, excision may be most appropriate. If signiﬁcant concern exists about the possibility of malignant melanoma, initial excision with a 2 mm margin would usually be undertaken prior to more deﬁnitive management once histology was conﬁrmed. Further management of a changed lesion would, of course, depend on the histology of the diagnostic biopsy. Rash A rash is the other common presentation in dermatology. The main categories of scaly rashes are listed in Box 29.4. The most common type of rash presentation is maculopapular. Diagnosis can often be made on clinical grounds, although a biopsy may be required. planus. These diverse examples emphasise the importance of considering an underlying systemic disease when assessing a patient with a dermatological presentation. Imaging Imaging techniques are not typically required but X-rays, ultrasound, magnetic resonance imaging (MRI) or computed tomography (CT) may occasionally be indicated in specific situations, such as in metastatic melanoma or in a patient presenting with a diagnosis of cutaneous sarcoid. Presenting problems in skin disease The major presentations in dermatology are outlined below. Detail of the underlying disorders is mostly provided in the disease-speciﬁc sections further on in the chapter. Lumps and lesions The term lump or lesion is typically used to describe a papule or nodule, although sometimes may refer to a macule or plaque (p. 1211). A new or changing lump is one of the key dermatology presentations. Clinical assessment Detailed history-taking and examination are essential: • Change: Is the lump new or has there been a change in a pre-existing lesion? What is the nature of the change – size, colour, shape or surface change? Has change been rapid or slow? Are there other features – pain, itch, inﬂammation, bleeding or ulceration (deﬁnition of ‘ulcer’: an area from which the epidermis and at least the upper part of the dermis have been lost – see Fig. 29.9, p. 1223)? • Patient: What is the patient’s age? Are they fair-skinned and freckled? Has there been much sun exposure? Have they used sunbeds or lived in sunny climates? Have they used photoprotection? • Site: Is it on a sun-exposed or covered site? The scalp, face, upper limbs and back in men, and face, hands and lower legs in women, are the most chronically sunexposed sites. • Are there other similar lesions? These might include actinic keratoses (see Fig. 29.13, p. 1231) or basal cell papillomas (see Fig. 29.17, p. 1234). • Morphology: Tenderness, size, symmetry, regularity of border, colour, surface characteristics and the presence of features such as crust (deﬁnition: dried exudate of blood or serous ﬂuid – see Fig. 29.19, p. 1235), scale (deﬁnition: a ﬂake arising from the stratum corneum; any condition with a thickened stratum corneum can cause scaling – see Fig. 29.13, p. 1231) and ulceration must be assessed. Stretching the skin and using a magnifying lens can be helpful, such as for detecting the raised, pearled edge of a basal cell carcinoma (see Fig. 29.11, p. 1229). • Dermatoscopy: This can be used to detect the presence of abnormal vessels, such as in basal cell carcinoma or the characteristic keratin cysts in basal cell papillomas. It is invaluable for assessing pigmented and vascular lesions (Fig. 29.2). 29.3 ABCDE features of malignant melanoma • Asymmetry • Border irregular • Colour irregular • Diameter > 0.5 cm • Elevation irregular (+ Loss of skin markings)

Presenting problems in skin disease • 1217

Fig. 29.2 Dermatoscopy. A A changing lesion. B Dermatoscopy highlights the abnormal pigment network and other features suggestive of melanoma. Excision biopsy conﬁrmed the diagnosis of superﬁcial spreading malignant melanoma (Breslow thickness 0.8 mm). C Another changing lesion. D Dermatoscopy highlights the vascular lacunae of this benign angioma and the patient was reassured. A D C B 29.4 Causes and clinical features of common scaly rashes Diagnosis Distribution Morphology Associated signs Atopic eczema (p. 1245) Face and ﬂexures Poorly deﬁned erythema, scaling Vesicles Licheniﬁcation if chronic Shiny nails Infra-orbital crease ‘Dirty neck’ (grey–brown discoloration) Psoriasis (p. 1247) Extensor surfaces Lower back Well-deﬁned Erythematous plaques Silvery scale Nail pitting, onycholysis Scalp involvement Axillae and genital areas often affected Joint involvement Köbner phenomenon (p. 1252) Pityriasis rosea (p. 1251) ‘Fir tree’ pattern on trunk Well-deﬁned Small, erythematous plaques Collarette of scale Herald patch Drug eruption (p. 1265) Widespread Macules and papules Erythema and scale Exfoliation Possible mucosal involvement or erythroderma Pityriasis versicolor (p. 1240) Upper trunk and shoulders Hypo- and hyper-pigmented scaly patches Lichen planus (p. 1252) Distal limbs Flexural aspect of wrists Lower back Shiny, ﬂat-topped, violaceous papules Wickham’s striae White, lacy network on buccal mucosa Nail changes Scarring alopecia Köbner phenomenon Tinea corporis (p. 1240) Asymmetrical Often isolated lesions Erythematous, often annular plaques Peripheral scale (sometimes pustules) Expansion with central clearing Possible nail, scalp, groin involvement Secondary syphilis (p. 337) Trunk and proximal limbs Palms and soles Red macules and papules, which become ‘gun-metal’ grey History of chancre Systemic symptoms, e.g. malaise and fever

1218 • DERMATOLOGY Blisters A blister is a ﬂuid-ﬁlled collection in the skin. The term vesicle is used for small lesions and bulla for larger lesions (p. 1211). Blistering occurs due to loss of cell adhesion within the epidermis or subepidermal region (see Fig. 29.1). The clinical presentation depends on the site or level of blistering within the skin, which in turn reﬂects the underlying cause (p. 1254). There are a limited number of conditions that present with blisters (Box 29.5): • Intact blisters are not often seen if the split is high in the epidermis (below the stratum corneum), as the blister roof is so fragile that it ruptures easily, leaving erosions (deﬁnition: an area of skin denuded by complete or partial loss of the epidermis). This occurs in pemphigus foliaceus, staphylococcal scalded skin syndrome (see Fig. 29.20, p. 1236) and bullous impetigo. • If the split is lower in the epidermis, then intact ﬂaccid blisters and erosions may be seen, as occurs in pemphigus vulgaris and toxic epidermal necrolysis (see Fig. 29.41, p. 1254). • If the split is subepidermal, then tense-roofed blisters are seen. This occurs in bullous pemphigoid (see Fig. 29.42, p. 1256), epidermolysis bullosa acquisita and porphyria cutanea tarda (see Fig. 29.52, p. 1264). • If there are foci of separation at different levels of the epidermis, as in dermatitis (p. 1244), then multilocular bullae made up of coalescing vesicles can occur. Clinical assessment Important aspects of the history include: • Age at onset and duration of rash. Atopic eczema often starts in early childhood and psoriasis between 15 and 40 years, and both may be chronic. Infective or druginduced rashes are more likely to be of short duration and the latter to occur in relation to drug ingestion. Duration of individual lesions is also important, as in urticaria, for example. • Body site at onset and distribution. Flexural sites are more typically involved in atopic eczema, and extensor surfaces and scalp in psoriasis. Symmetry is often indicative of an endogenous disease, such as psoriasis, whereas asymmetry is more common with exogenous causes, such as contact dermatitis or infections like herpes zoster. • Itch. Eczema is usually extremely itchy and psoriasis may be less so. • Preceding illness and systemic symptoms. Guttate psoriasis may be precipitated by a β-haemolytic streptococcal throat infection; almost all patients with infectious mononucleosis (p. 241) treated with amoxicillin will develop an erythematous maculopapular eruption; a history of chancre at the site of inoculation may be elicited in a presentation of secondary syphilis; malaise and arthralgia are common in drug eruptions and vasculitis. The morphology of the rash and the characteristics of individual lesions are important (Box 29.4). Investigations and management It is important to have a short differential diagnosis based on clinical assessment in order to direct investigations. For example, in psoriasis, no investigations may be needed and initial management with patient counselling and topical therapies may sufﬁce. If the diagnosis is unclear, then a diagnostic skin biopsy and other targeted investigations based on the clinical picture may be required. An initial management plan should also be implemented. For example, in a child presenting with a rash that has features suggestive of impetigo, skin and nasal swabs should be performed and, once these have been taken, topical or systemic antibiotics should be introduced, depending on clinical extent of disease, and management should be adjusted accordingly, dependent on investigation ﬁndings and clinical course. In contrast, if a patient presents with a maculopapular rash shortly after introduction of a new drug, then drug withdrawal, diagnostic biopsy, full blood count, including eosinophil count, and liver and renal function tests, in parallel with topical emollients and glucocorticoids, may be indicated. Fig. 29.3 A systematic approach to the diagnosis of blistering diseases. (TEN = toxic epidermal necrolysis) Think of immunobullous causes Bullous pemphigoid, pemphigus, linear IgA disease, bullous lupus Systematic approach to the diagnosis of blistering diseases Exclude infection Herpes simplex, varicella zoster, Staphylococcus aureus Consider common diseases in which blisters are uncommon Peripheral oedema, cellulitis, allergic contact dermatitis, other eczemas Remember blisters in drug eruptions Fixed drug eruptions, erythema multiforme, vasculitis, TEN 29.5 Causes of acquired blisters Localised Generalised Vesicular Herpes simplex Herpes zoster Impetigo Pompholyx Eczema herpeticum* Dermatitis herpetiformis Acute eczema Bullous Impetigo Cellulitis Stasis oedema Acute eczema Insect bites Fixed drug eruption Toxic epidermal necrolysis* Erythema multiforme Stevens–Johnson syndrome* Bullous pemphigoid Pemphigus* Epidermolysis bullosa acquisita Lupus erythematosus Porphyria cutanea tarda Pseudoporphyria Drug eruptions *Usually with mucosal involvement too.

Presenting problems in skin disease • 1219

Medical condition Cause of pruritus Treatment* Liver disease Central opioid effect Elevation in bile salts may contribute Naltrexone Colestyramine Rifampicin Sedative antihistamines UVB Renal failure Unknown; uraemia contributes UVB Oral activated charcoal Haematological disease Anaemia Polycythaemia rubra vera Lymphoma Laukaemia Myeloma Iron deﬁciency Unknown (often aquagenic pruritus) Unknown Iron replacement Endocrine disease Diabetes mellitus Increased infection risk, e.g. candidiasis, tinea Treatment of infection Medical condition Cause of pruritus Treatment* Thyrotoxicosis Hypothyroidism Carcinoid syndrome (p. 678) Unknown Unknown 5-HT-mediated HIV infection Infection, infestation Treatment of infection Eosinophilic folliculitis Local corticosteroids, UVB Seborrhoeic dermatitis Anti-pityrosporal treatment Unknown UVB Malignancy Unknown Psychogenic Unknown Psychotherapy, anxiolytics, antidepressants *In addition to speciﬁc treatment of the primary condition and symptomatic treatments, such as emollients. (5-HT = 5-hydroxytryptamine, serotonin; UVB = ultraviolet B) 29.7 Secondary causes of pruritus synonymous; however, ‘pruritus’ is often used when itch is generalised. Itch can arise from primary cutaneous disease or be secondary to systemic disease, which may cause itch by central or peripheral mechanisms. Even when the mechanism is peripheral, there are not always signs of primary skin disease. The nerve endings that signal itch are in the epidermis or near the dermo-epidermal junction. The underlying mechanisms of itch are not fully understood. Transmission is by unmyelinated slow-conducting C ﬁbres through the spinothalamic tract to the thalamus and then the cortex. Aδ ﬁbres also seem to be involved in transmitting signals to the spinal cord, and the heat-sensitive transient receptor potential (TRP) channels 1–4 are important. There is an inhibitory relationship between pain and itch. Scratching may relieve the symptom of itch after the sensation has ceased and this is either by stimulation of ascending sensory pathways that inhibit itch-transmitting neurons at the spinal cord (Wall’s ‘gate’ mechanism), or by direct damage to cutaneous sensory nerves. The mechanisms of itch in most systemic diseases remain unclear. The itch of kidney disease, for example, may be mediated by circulating endogenous opioids. The clinical observation that peritoneal dialysis helps reduce itch more frequently than haemodialysis is consistent with this, with smaller molecules generally being dialysed more readily if the peritoneal membrane is used rather than a dialysis machine membrane. Clinical assessment It is important to determine whether skin changes are primary (a process in the skin causing itch) or secondary (skin changes caused by rubbing and scratching because of itch). This requires a thorough history and examination, sometimes with investigations, to exclude systemic disease. Many common primary skin disorders are associated with itch (Box 29.6). If itch is not connected with primary skin disease, other causes should be considered (Box 29.7). These include liver diseases (mainly cholestatic diseases, such as primary biliary cirrhosis), malignancies (generalised itch may be the presenting feature Clinical assessment Detailed history-taking and examination are critical. A history of onset, progression, mucosal involvement, drugs and systemic symptoms should be sought. Clinical assessment of the distribution, extent and morphology of the rash should be made. The Nikolsky sign is useful: sliding lateral pressure from a ﬁnger on normal-looking epidermis can dislodge and detach the epidermis in conditions with intra-epidermal defects, such as pemphigus and toxic epidermal necrolysis. A systematic approach to diagnosis is required (Fig. 29.3). Investigations and management Investigations and initial management will be guided by the clinical presentation and differential diagnosis, and are described in more detail under the speciﬁc diseases. For example, an initial approach may include directed investigations, such as incisional diagnostic skin biopsy for histology and direct immunoﬂuorescence, indirect immunoﬂuorescence and other targeted blood tests or skin swabs. Management should be based on the likely diagnosis and begin in parallel with investigations, until the diagnosis is conﬁrmed. Itch Itch describes the unpleasant sensation that leads to scratching or rubbing. The terms ‘itch’ and ‘pruritus’ are 29.6 Primary skin diseases causing pruritus Generalised pruritus • Scabies • Eczemas • Pre-bullous pemphigoid • Urticarias • Xeroderma of old age • Psoriasis Localised pruritus • Eczemas • Lichen planus • Dermatitis herpetiformis • Pediculosis • Tinea infections

1220 • DERMATOLOGY Photosensitivity Cutaneous photosensitivity is an abnormal response of the skin to UVR or visible radiation. The sun is the natural source but patients may also be exposed to artiﬁcial sources of UVR through the use of sunbeds and/or phototherapy (p. 1227). Chronic UVR exposure increases skin cancer risk and photo-ageing (p. 1215). Acute exposure can induce erythema (redness) as a normal response (Fig. 29.5). However, abnormal photosensitivity occurs when a patient reacts to lower doses than would normally cause a response, either with a heightened erythemal reaction or the development of a rash. Photo-aggravated skin diseases are exacerbated by sunlight but not caused by it. The main photosensitive and photo-aggravated diseases are listed in Box 29.9. Fig. 29.4 An overall approach to the investigation and management of itch (pruritus). Investigate for underlying causes of itch (Box 29.7) Itch (pruritus) Itch plus rash Primary skin disease Diagnose and manage underlying skin disease (Box 29.6) Only secondary changes of excoriation due to itch Itch, no rash of lymphoma), haematological conditions (generalised itch in chronic iron deﬁciency or water contact-provoked (aquagenic) intense itch in polycythaemia), endocrine diseases (including hypo- and hyperthyroidism), chronic kidney disease (in which severity of itch is not always clearly associated with plasma creatinine concentration) and psychogenic causes (such as in ‘delusions of infestation’). Itch is common in pregnancy and may be due to one of the pregnancy-speciﬁc dermatoses. Making a correct diagnosis is particularly important in pregnancy, as some disorders can be associated with increased fetal risk (Box 29.8). Investigations and management Investigations should be directed towards ﬁnding an underlying cause and there will be a different approach for itch with rash, as opposed to itch with no signs of primary skin disease (Fig. 29.4). If there are no signs of primary skin disease, investigations should be undertaken to exclude systemic disease or iatrogenic causes. Psychogenic itch should be considered only if organic disease has been ruled out. There are no consistently effective therapies to suppress itch, and so establishing the underlying cause is critical. If a clear-cut diagnosis cannot be made, non-speciﬁc approaches can be used for symptom relief. These include sedation, often with H1 receptor antihistamines, along with emollients and counter-irritants (such as topical menthol-containing preparations). UVB phototherapy is useful for generalised itch due to a variety of causes but the only randomised controlled study of efﬁcacy is in chronic kidney disease. Other treatments include low-dose tricyclic antidepressants (probably through similar mechanisms to those involved when these drugs are used for chronic pain) and opiate antagonists. If a psychogenic itch is considered likely, antidepressants and/or cognitive behavioural therapy may be effective. Itch of any cause can be severe and its potentially major adverse effects on quality of life are not always fully appreciated. Assessments of impact on quality of life, such as Dermatology Life Quality Index (DLQI) scores, are essential. 29.8 Causes of pruritus in pregnancy Diagnosis Pregnancy, gestation and features Treatment Polymorphic eruption of pregnancy (pruritic urticarial papules and plaques, PUPP) Typically ﬁrst pregnancy and uncommonly recurs 3rd trimester, after delivery Polymorphic urticated papules and plaques, start in striae Chlorphenamine, emollients Topical glucocorticoids Acute cholestasis of pregnancy (p. 1284) 3rd trimester and commonly recurs in subsequent pregnancies Abnormal liver function tests Increased fetal and maternal risk Emollients Chlorphenamine Colestyramine UVB Early delivery Pemphigoid gestationis Any stage, often 2nd trimester and commonly recurs in subsequent pregnancies Urticated erythema, blistering initially periumbilical Characteristic histology and immunoﬂuorescence Topical or oral glucocorticoids Prurigo gestationis 2nd trimester Excoriated papules Emollients Topical glucocorticoids Chlorphenamine UVB Pruritic folliculitis 3rd trimester Sterile pustules on trunk Topical glucocorticoids UVB (UVB = ultraviolet B)

Presenting problems in skin disease • 1221

and UVA1 (340–400 nm). UVA2 behaves biologically more like UVB, and UVA1 can be used therapeutically for several skin conditions, such as morphoea and eczema. Patients with photosensitivity diseases can be abnormally sensitive to UVB, UVA, visible light (over 400 nm) or, commonly, a combination of wavebands. UVB is absorbed by window glass, whereas UVA and visible light are transmitted through glass. Clinical assessment Taking a careful history is essential, as the patient may not have the rash when assessed. Seasonal pattern and distribution of rash are important. Key sites are the face (particularly nose, cheeks and forehead), top of ears, neck (Fig. 29.7), bald scalp, back of hands and forearms. Sparing is often seen under the chin and nose, behind the ears, on the upper eyelids and the distal digits – as we normally walk about with our eyes open and ﬁngers ﬂexed! It can be misleading if there is covered site involvement. Patients who are sensitive to UVA and visible light may be affected through clothing. These patients commonly experience perennial symptoms and may not be aware of the association with daylight exposure. Other photosensitive conditions, such as actinic prurigo or chronic actinic dermatitis, may also involve covered sites. Sparing of habitually exposed sites, such as the face and back of hands, occurs most commonly in polymorphic light eruption (PLE) and is called the ‘hardening phenomenon’. Importantly, some conditions, such as solar urticaria, develop rapidly after sunlight exposure, whereas others, such as cutaneous lupus, can take several days to evolve. Investigations and management If photosensitivity is suspected, the patient should be referred to a specialist centre for monochromator phototesting (p. 1215), if feasible. Other investigations will often include provocation, Sunlight consists mainly of visible light, and the UVR component is divided into three wavebands (Fig. 29.6), according to the Commission Internationale de l’Eclairage (CIE): • UVC (200–280 nm), which is absorbed by ozone and does not reach the Earth’s surface. • UVB (280–315 nm), which constitutes less than 10% of UVR exposure but is around 1000-fold more potent than UVA and so accounts for the erythemal ‘sunburning’ effects of sunlight. • UVA (315–400 nm), which is the most abundant UVR component reaching the Earth’s surface. The arbitrary division between UVB and UVA regions is more often considered to be at 320 nm by photobiologists, and the UVA region can be further subdivided into UVA2 (320–340 nm) Fig. 29.5 Sunburn. Acute exposure to ultraviolet radiation results in an erythemal response that peaks 12–24 hours later. Sensitivity depends on the individual’s constitutive skin phototype. 29.9 The photosensitivity and photo-aggravated diseases Cause Condition Clinical features Immunological (previously known as idiopathic) Polymorphic light eruption (PLE) Seasonal, itchy, papulovesicular rash on photo-exposed sites; face and back of hands often spared. Often hours of UVR exposure needed to provoke; lasts a few days; affects about 20% in Northern Europe, more common in young women Chronic actinic dermatitis (CAD) Chronic dermatitis on sun-exposed sites. Most common in elderly males. Predominantly UVB, but also often UVA and visible light photosensitivity. Most also have contact allergies Solar urticaria Immediate-onset urticaria on photo-exposed sites. Usually UVA and visible light photosensitivity. Can occur at any age Actinic prurigo Uncommon, presents in childhood. Often familial, with strong HLA association. Some similarities to PLE, although scarring occurs Hydroa vacciniforme Rare childhood photodermatosis. Varioliform scarring Drugs (variety of mechanisms) Phototoxicity Usually UVA (and visible light) photosensitivity Most common. Exaggerated sunburn and exfoliation. Many drugs such as thiazides, tetracyclines, ﬂuoroquinolones, quinine, NSAIDs Pseudoporphyria NSAIDs, retinoids, tetracyclines, furosemide are examples Photoallergy Usually to topical agents, particularly sunscreens and NSAIDs Metabolic Porphyrias Pellagra Mainly porphyria cutanea tarda and erythropoietic protoporphyria (p. 378). Photo-exposed site dermatitis due to tryptophan deﬁciency (see Fig. 14.15, p. 378) Photogenodermatoses Xeroderma pigmentosum Rare. Defect in DNA excision repair, abnormal photosensitivity, photo-ageing and skin cancer. There may be neurological features Photo-aggravation of pre-existing conditions Lupus erythematosus Can also be drug-induced (see Box 29.35, p. 1266) Erythema multiforme p. 1264 Rosacea p. 1243 (HLA = human leucocyte antigen; NSAID = non-steroidal anti-inﬂammatory drug; UVA/UVB = ultraviolet A/B; UVR = ultraviolet radiation)

1222 • DERMATOLOGY mechanism of desensitisation is uncertain. Other approaches may be necessary, depending on disease and severity, and may include antihistamines (useful in two-thirds of patients with solar urticaria) and systemic immunosuppression (sometimes required in the immunological photodermatoses). Patients with photosensitivity are at risk of vitamin D deﬁciency because of reduced synthesis in the skin and should be advised to optimise dietary vitamin D intake or take supplements (p. 1052). Sunscreens Sunscreens can be divided into two categories: chemical sunscreens, which absorb specific wavelengths of UVR, and physical sunscreens, which reﬂect UVR and the shorter visible wavelengths (see Fig. 29.6). Sunscreens are now highly sophisticated and most offer protection against UVB and most UVA wavelengths. If a patient is abnormally photosensitive to the longer wavelengths of UVA and the visible part of the spectrum (for example, in cutaneous porphyrias and solar urticaria), then conventional sunscreens are not beneﬁcial and speciﬁc reﬂectant sunscreens are required. Historically, these agents were less cosmetically acceptable due to visible light reﬂection, but current formulations, some of which are tinted, have reduced this problem. Sunscreen protection levels are described by sun protection factor (SPF). This is the ratio of the dose of UVR required to produce skin erythema in the presence and absence of the sunscreen. A sunscreen of SPF20 means that it would take 20 times as long for a person to develop sunburn in the presence of the sunscreen, as compared to not using it. Therefore, SPF is really a sunburn protection factor and is not a good guide to how well a sunscreen will perform in protecting against other reactions (such as skin pain in erythropoietic protoporphyria or UVR-induced immunosuppression). SPF values are determined under experimental conditions whereas, in practice, people tend to use 25–33% of the amount of sunscreen required to achieve patch or photopatch testing and screening for lupus and the porphyrias (p. 1263). Rarely, investigations such as human leucocyte antigen (HLA) typing in suspected actinic prurigo, or DNA excision repair functional activity or genotyping in suspected xeroderma pigmentosum, may be required. Management depends on the cause. If there is a phototoxic drug or chemical cause, this must be addressed: for instance, by stopping the drug or treating the porphyria. Counselling in regard to sun avoidance is essential: keeping out of direct sun in the middle of the day, covering up with clothing, wearing hats with a wide brim and careful use of high-factor sunscreens. Paradoxically, in some conditions, particularly PLE and solar urticaria, phototherapy can be used to induce ‘hardening’; the Fig. 29.7 Chronic actinic dermatitis. Note the sharp cut-off and sparing behind the ear in the shadow cast by the earlobe (Wilkinson’s triangle). Fig. 29.6 The electromagnetic spectrum. The action spectrum is not well deﬁned for many conditions and, for some, is approximate and may vary between patients. The action spectrum for non-melanoma skin cancer mirrors that for erythema. The action spectrum for melanoma is not known but includes ultraviolet (UV) B. Photoprotection measures vary, depending on condition, although the mainstay always includes behavioural modiﬁcation, clothing cover and appropriate sunscreen choices. (UVR = ultraviolet radiation) 200 nm 290 nm 320 nm 400 nm Atmospheric ozone Window glass Behavioural avoidance, shelter, clothing Sunscreens γ-rays X-rays UVC UVB UVA Visible Infrared Sunburn (erythema) Pigmentation Skin cancer Skin ageing Porphyria Most photodermatoses Most drug photosensitivity Skin disorders and the main wavelengths involved UVR absorbers or reflectors Wavelength 760 nm UVA2 Grenz rays UVA1

Presenting problems in skin disease • 1223

and subcutis, which may produce the well-known ‘inverted champagne bottle’ appearance. Ulceration, often precipitated by trauma or infection, follows. Venous ulcers typically occur on the medial lower leg (Fig. 29.9). Complications of venous leg ulceration include bacterial colonisation and infection, and contact allergic dermatitis to topical medicaments, dressings and bandages. Lipodermatosclerosis may cause lymphoedema and hyperkeratosis; rarely, a squamous cell carcinoma (SCC) may develop in a long-standing venous ulcer (Marjolin’s ulcer). Leg ulceration due to arterial disease Deep, painful, punched-out ulcers on the lower leg, especially the shin and foot and in the context of intermittent claudication, are the stated SPF. Patient counselling is therefore important with regard to adequate application of sunscreen. All sunscreens offer, at best, partial protection only and are no substitute for modifying behaviour and covering up. Leg ulcers Leg ulcer is not a diagnosis, but a symptom of an underlying disease in which there is complete loss of the epidermis, leaving dermal layers exposed. Ulcers on the lower leg are frequently caused by vascular disease but there are other causes, as summarised in Box 29.10. Clinical assessment A detailed history of the onset and course of leg ulceration and predisposing conditions should be elicited. The site and surrounding skin should be assessed. Varicose veins are often present, although not inevitably. Assessment of the venous and arterial vasculature and neurological examination are critical. The site of ulceration may also help to indicate the underlying primary cause (Fig. 29.8). Full clinical examination is essential as the ulcer may be arising in the context of systemic disease, such as vasculitis. Leg ulceration due to venous disease Varicose veins, a history of deep venous thrombosis and obesity are predisposing factors. Incompetent valves in the deep and perforating veins of the lower leg result in retrograde ﬂow of blood to the superﬁcial system, and a rise in capillary pressure (‘venous hypertension’). Pericapillary ﬁbrin cufﬁng occurs, leading to impairment of local tissue oxygenation and homeostasis. The ﬁrst symptom in venous ulceration is often heaviness of the legs, followed by oedema. Haemosiderin pigmentation, pallor and ﬁrmness of surrounding skin, and sometimes venous/gravitational eczema (p. 1247) subsequently develop. This progresses to lipodermatosclerosis – ﬁrm induration due to ﬁbrosis of the dermis Fig. 29.8 Causes of lower limb ulceration. The main types of leg ulcer tend to affect particular sites. Anterior Posterior Venous Vasculitis Arterial Neuropathic Fig. 29.9 A chronic venous ulcer on the medial lower leg, with surrounding lipodermatosclerosis. 29.10 Causes of leg ulceration Venous hypertension • Sometimes following deep vein thrombosis Arterial disease • Atherosclerosis • Vasculitis • Buerger’s disease Small-vessel disease • Diabetes mellitus • Vasculitis Haematological disorders • Sickle-cell disease • Cryoglobulinaemia • Spherocytosis • Polycythaemia • Myeloma • Waldenström’s macroglobulinaemia • Immune complex disease Neuropathy • Diabetes mellitus • Leprosy (Hansen’s disease) • Syphilis Tumour • Squamous cell carcinoma • Basal cell carcinoma • Malignant melanoma • Kaposi’s sarcoma Trauma • Injury • Factitious

1224 • DERMATOLOGY grafting (such as pinch and mince grafts) may hasten healing of clean ulcers but do not reduce recurrence risk. Leg ulcers can be very persistent. Symptomatic relief, including oral analgesics and sometimes chronic pain management, is important. Once the ulcer has healed, ongoing use of compression hosiery may limit the risk of recurrence. Abnormal pigmentation Loss of skin pigmentation (depigmentation), reduction in pigmentation (hypopigmentation) and increased pigment (hyperpigmentation) are features of a variety of disorders. A detailed history and examination, including use of a Wood’s light, are required to establish the diagnosis. Investigations will depend on the presentation. For example, microscopy of skin scrapings should be undertaken if hypopigmentation is associated with inﬂammation and scaling; screening for autoimmune disease may be required if vitiligo is suspected; and investigation for endocrine disease or the porphyrias may be appropriate in hyperpigmentation. Further details of the speciﬁc conditions are included on page 1257. Hair and nail abnormalities Many conditions affect the skin appendages, particularly hair and nails. Conditions causing hair loss (alopecia) are listed in Box 29.30 (p. 1259). Nail changes may be a marker for systemic disease (e.g. iron deﬁciency) or be a feature of certain skin conditions (e.g. psoriasis). Acute skin failure Acute skin failure is a medical emergency. Several conditions can cause widespread and acute failure of many skin functions (see Box 29.1, p. 1214), including thermoregulation, ﬂuid balance control and barrier to infection. Many of these conditions involve widespread dilatation of the dermal vasculature and can provoke high-output cardiac failure; they are also associated with increased protein loss from the skin and often from the gut. Many lead to acute skin failure by causing erythroderma (erythema affecting at least 90% of the body surface area), although severe autoimmune blistering diseases and the spectrum of Stevens–Johnson syndrome/toxic epidermal necrolysis (TEN) disease can produce acute skin failure without erythroderma (p. 1254). Clinical assessment Detailed history-taking and full examination are required. Particular attention should be paid to drug history, chronology and history of any preceding skin disease. Eczema, psoriasis, drug eruptions and cutaneous T-cell lymphoma (Sézary’s syndrome, p. 1232) are among the diseases that can either present with, or progress to, erythroderma. Other causes include the psoriasis-like condition, pityriasis rubra pilaris, and rare types of ichthyosis. Erythroderma may occur at any age and is associated with severe morbidity and signiﬁcant mortality (see Fig. 29.35D, p. 1249). Older people are at greatest risk, especially if they have comorbidities. Erythroderma may appear suddenly or evolve slowly. In dark skin, the presence of pigmentation may mask erythema, giving a purplish hue. Erythrodermic patients are usually systemically unwell with shivering and hypothermia, secondary to excess heat loss. They may also be pyrexial, however, and unable to lose heat due to damage to sweat gland function and sweat duct occlusion. likely to be due to arterial disease. Risk factors include smoking, hypertension, diabetes and hyperlipidaemia. The foot is cold and dusky, and the skin atrophic and hairless. Peripheral pulses are absent or reduced. A vascular surgical assessment should be sought urgently (p. 502). Leg ulceration due to vasculitis Vasculitis can cause leg ulceration either directly through epidermal necrosis due to damage to the underlying vasculature, or indirectly due to neuropathy. Leg ulceration due to neuropathy The most common causes of neuropathic ulcers are diabetes and leprosy. Microangiopathy also contributes to ulceration in diabetes (p. 758). The ulcers occur over weight-bearing areas, such as the heel. In the presence of neuropathy, protection of skin from trauma is essential to prevent ulceration. Investigations Appropriate investigations include: • Full blood count to detect anaemia and blood dyscrasias. • Urea and electrolytes to assess renal function. • Urinalysis for glycosuria. • Bacterial swab if there is a purulent discharge, rapid extension, cellulitis, lymphangitis or sepsis. This can guide antibiotic therapy for secondary infection but pathogenic bacteria are not always the same as those identiﬁed from the ulcer surface. • Doppler ultrasound to assess arterial circulation. An ankle systolic pressure to brachial systolic pressure index (ABPI) of below 0.8 suggests signiﬁcant arterial disease and a vascular surgery opinion should be sought. However, arterial calciﬁcation, such as in diabetes, can produce a spuriously high ABPI. Pulse oximetry may also be useful, although ABPI is the preferred investigation if feasible. Management General advice on exercise, weight loss and smoking cessation is important in all cases. Speciﬁc management depends on making the correct diagnosis to identify the cause(s) of ulceration. Underlying factors, such as diabetes or anaemia, must be treated. Oedema must be reduced by leg elevation and, if there is no arterial compromise, graduated compression bandaging from toes to knees to enhance venous return and improve healing. Compression bandaging is effective for individuals with an ABPI of more than 0.8 but should be avoided if the ABPI is less than 0.8. If the ulcer is purulent, weak potassium permanganate soaks may help, and exudate and slough can be removed with normal saline or clean water. Dressings do not themselves heal leg ulcers, but can reduce discomfort and odour and, by reducing colonisation by potential pathogens, may reduce the frequency of secondary infection. A variety of dressings may be used, including non-adherent and absorbent (alginates, hydrogels, hydrocolloids) types. The frequency of dressing changes varies; heavily exudative ulcers may need daily dressings, whereas changes once weekly may sufﬁce for drier ulcers. Occasionally, leeches may be used topically for ulcers with heavy adherent exudate. Surrounding eczema should be suppressed with a topical glucocorticoid. Commonly, this is venous eczema, but there should be a low threshold for referral for patch testing, as contact allergy to topical applications is common (p. 1215). Systemic antibiotics are indicated only if there is evidence of infection, as opposed to colonisation. Various techniques of split-thickness

Principles of management of skin disease • 1225

impact of the disease on quality of life and the person’s support network. The psychological impact of chronic skin diseases should not be under-estimated and it is important to remember that psychiatric illness can also manifest as a skin disease, such as in delusions of infestation or trichotillomania. Careful clinical assessment, taking psychological factors into account, is essential and any management strategy must include approaches to address the psychological well-being of the patient. Topical treatments Topical treatments are ﬁrst-line therapy for most skin diseases and many can be treated effectively by topical therapies alone. Selection of the appropriate active drug/ingredient and vehicle is essential. Ointments are preferred to creams for dry skin conditions, such as chronic eczemas, as they are more hydrating and contain fewer preservatives than creams, and so allergy risk is reduced. However, patients ﬁnd creams easier to apply and so adherence may be better. Gels and lotions can be easier to use on hair-bearing sites. The molecular weight and lipid–water coefﬁcient of a drug determine its skin penetration, with larger, water-soluble, polar molecules penetrating poorly. In skin disease, if the stratum corneum is impaired – as in eczema – increased drug absorption occurs. Occlusion under dressings also increases absorption. Drugs can be used in different potencies or concentrations, or in combination with other active ingredients, and many are available in more than one formulation. The properties of different vehicles are listed in Box 29.11. Overall, adherence to topical treatments can be problematic, so it is essential for patients to know exactly what is required of them and for regimens to be kept as simple as possible. Emollients, topical glucocorticoids and other selected key topical therapies that are widely used in a diverse range of skin conditions are detailed below. For the more diseasespeciﬁc therapies, detailed descriptions are included in the disease sections. Tachycardia and hypotension may be present because of volume depletion. Peripheral oedema is common in erythroderma, owing to low albumin and high-output cardiac failure. Lymph nodes may be enlarged, either as a reaction to skin inﬂammation or, rarely, due to lymphomatous inﬁltration. Investigations and management Investigations are required to establish the underlying cause and to identify any systemic impact, such as hypoalbuminaemia and electrolyte disturbances. Skin biopsy may be necessary if the cause is unclear. Regardless of the cause, important aspects of the management of erythroderma include supportive measures to ensure adequate hydration, maintenance of core temperature and adequate nutrition. Insensible ﬂuid loss can be many litres above normal losses. Protein may be lost directly from the skin and through the gut because of the protein-losing enteropathy that often accompanies conditions such as erythrodermic psoriasis. To reduce the risks of infection, any intravenous cannulae should be sited in peripheral veins, if possible. In the initial management of acute erythroderma, urinary catheterisation is often required (for patient comfort and accurate ﬂuid balance monitoring) but catheters should be removed as soon as possible. Frequent application of a simple ointment emollient (such as white soft parafﬁn/liquid parafﬁn mix) is usually appropriate. Principles of management of skin disease General measures General measures that apply in all skin diseases include establishment of the correct diagnosis, removal of precipitating or aggravating factors, use of safe, effective treatments and consideration of the patient holistically, taking into account the 29.11 Characteristics of vehicles used in topical treatments Vehicle Deﬁnition Use Site Cosmetic acceptability Risk of contact sensitisation Creams Emulsions of oil and water (aqueous cream) Acute presentations Cooling, soothing Well absorbed Mild emollients All sites, including mucous membranes and ﬂexures, but not hair-bearing areas Very good Helps adherence Signiﬁcant, due to preservatives, antimicrobials and often lanolin Ointments Greasy preparations Insoluble in water (white soft parafﬁn) Soluble (emulsifying ointment) Chronic dry skin conditions Occlusive and emollient Hydrating Mildly anti-inﬂammatory Avoid hair-bearing areas and ﬂexures Moderate Low Lotions Water-based Liquid formulations Often antiseptic and astringent (potassium permanganate) Cooling effect Cleans the skin and removes exudates Large areas of the skin and the scalp Good, but can sting if in an alcoholic base Rare Gels Thickened lotions Hydrophilic and hydrophobic bases For speciﬁc sites Hair-bearing areas and the face Good Low Pastes Semi-solid preparations consisting of ﬁnely powdered solids suspended in an ointment Occlusive, protective Hydrating Circumscribed skin lesions, (psoriasis, lichen simplex chronicus) Any area of skin Often used in medicated bandages Moderate Moderate

1226 • DERMATOLOGY cessation of use. Nevertheless, glucocorticoids are invaluable for many sites, particularly the ﬂexures. Topical glucocorticoids are often formulated in combination with antiseptics, antibiotics or antifungals, and their controlled use may be appropriate in infected eczema or ﬂexural psoriasis. Intralesional injections of glucocorticoids can be used in a variety of indications, including nodular prurigo, keloid scar (deﬁnition of ‘scar’: replacement of normal structures by ﬁbrous tissue at the site of an injury, although keloid scar describes a pathological process extending beyond the site of injury), acne cysts and alopecia areata. Anti-infective agents Antiseptics should be considered before antibiotics, as they cover a wide range of organisms and help to reduce the risk of antibiotic resistance. Antibiotics can be used either for their anti-infective properties (p. 1236) or for their anti-inﬂammatory properties (pp. 1242 and 1244). Topical antiviral and antifungal agents are also widely used for a range of mild skin infections (p. 1239). Calcineurin inhibitors The topical calcineurin inhibitors, tacrolimus and pimecrolimus, can be used to treat eczema and a variety of other conditions, through local cutaneous immunosuppression (p. 1244). Immune response modiﬁers Topical imiquimod was introduced for the treatment of anogenital warts but can be used for a diverse range of other skin diseases, including actinic keratosis, Bowen’s disease, basal cell carcinoma, lentigo maligna, cutaneous lupus and common and planar warts. Its mechanism of action is via stimulation of endogenous Th2 immune responses and release of cytokines, including interferon-gamma (IFN-γ). It can cause signiﬁcant inﬂammation, requiring dose adjustments, but subclinical disease may respond to treatment. Dressings A ‘wound’ covering is called a dressing. Box 29.13 shows the indications for their use. The active agent, vehicle and ‘wound’ type should be considered. Wet lesions should be treated with Emollients These are mainstays in the treatment of eczema, psoriasis and many other conditions, and are used to moisturise, lubricate, protect and ‘soften’ skin. They are essentially vehicles without active drug and are available in many formulations: creams, ointments, gels and bath, shower and soap substitutes. White soft parafﬁn is the most effective and is widely used. Topical glucocorticoids Glucocorticoids are available in a variety of formulations, potencies and strengths, most commonly as creams and ointments (Box 29.12). Selection of the correct product depends on the condition being treated, body site and duration of expected use. Mild topical glucocorticoids are used in delicate areas, such as the face or genitals, and close supervision of glucocorticoid use at these sites is required. In contrast, very potent glucocorticoids may be required under occlusion for chronic resistant disease such as nodular prurigo. Adverse cutaneous effects of chronic glucocorticoid use include atrophy (deﬁnition: an area of thin, translucent skin caused by loss of epidermis, dermis or subcutaneous fat – Fig. 29.10), striae (deﬁnition: linear, atrophic, pink, purple or white bands caused by connective tissue changes – Fig. 29.10), petechiae and purpura (deﬁnition: haemorrhagic macules or papules caused by extravasated blood – see p. 1211) and telangiectasiae (definition: visible dilatations of small cutaneous blood vessels – see Fig. 29.11A), increased risk of infection and systemic absorption, causing Cushingoid features and suppression of the hypothalamic–pituitary–adrenal axis. However, under-treatment with glucocorticoids is more common than over-treatment in routine clinical practice. In general, the lowest potency of glucocorticoid should be used for the shortest period to gain control of the disease; this can be achieved by initial use of a more potent glucocorticoid, with reduction in potency or frequency of application as control is gained. Tolerance or tachyphylaxis can develop with chronic use, so intermittent courses of treatment are advised. Caution is required with glucocorticoids in psoriasis, as rebound, unstable or pustular psoriasis can occur with sudden Fig. 29.10 Striae and atrophy induced by excess prolonged potent topical glucocorticoid use. UK trade names are given in brackets. 29.12 Potencies and strengths of commonly used topical glucocorticoid preparations Mild • Hydrocortisone 0.5%, 1%, 2.5% • Hydrocortisone 1% and fusidic acid 2% (Fucidin H) Moderate • Clobetasone butyrate 0.05% (Eumovate) • Betamethasone valerate 0.025% (Betnovate-RD) • Fluocinolone acetonide 0.00625% (Synalar 1 : 4) Potent • Betamethasone valerate 0.1% (Betnovate) • Betamethasone valerate 0.1% and clioquinol 3% (Betnovate-C) • Fluocinolone acetonide 0.025% (Synalar) • Hydrocortisone butyrate 0.1% (Locoid) • Mometasone furoate 0.1% (Elocon) Very potent • Clobetasol propionate 0.05% (Dermovate)

Principles of management of skin disease • 1227

on local antimicrobial prescribing guidelines. Several antibiotics, such as tetracyclines, erythromycin and co-trimoxazole are used predominantly for their anti-inﬂammatory effects in indications such as acne vulgaris, bullous pemphigoid and pyoderma gangrenosum. Antihistamines A range of H1 and H2 receptor antagonists are used in dermatology. For diseases in which histamine in the skin is relevant (such as urticaria), non-sedating antihistamines should be given: for example, fexofenadine or cetirizine. For pruritic conditions such as eczema, the sedating effect of antihistamines like hydroxyzine or chlorphenamine is important. However, antihistamines are widely used in older patients for the symptom of pruritus due to a variety of causes such as xeroderma, metabolic impairment, malignancy or concomitant drugs. Sedating antihistamines should be used with caution in older patients, as they may increase the risk of falls and accidents in the home, with disastrous consequences. Careful choice of drug and dose is therefore essential. Leukotriene receptor antagonists, such as montelukast, may be added to antihistamine regimes. Retinoids Oral retinoids are used in a range of conditions, including acne, psoriasis and other keratinisation disorders. They promote differentiation of skin cells and have anti-inﬂammatory effects. Isotretinoin (13-cis-retinoic acid) is widely used for moderate to severe acne (p. 1243). Acitretin can be effective in psoriasis and other keratinisation disorders, such as ichthyosis, as can alitretinoin (9-cis-retinoic acid) in hand and foot eczema and bexarotene in cutaneous T-cell lymphoma. Adverse effects of retinoids include dryness of the skin and mucous membranes, abnormalities in liver function or hepatitis, increase in serum triglycerides (levels should be checked before and during therapy) and mood disturbances. Alitretinoin and bexarotene can cause hypothyroidism. Systemic retinoids are teratogenic and must be prescribed along with a robust form of contraception. Females must have a negative pregnancy test before, during and after therapy, and pregnancy must be avoided for 2 months after stopping isotretinoin and 2 years after stopping acitretin. Immunosuppressants Systemic glucocorticoids, particularly prednisolone, are widely used in inﬂammatory skin diseases, such as eczema, immunobullous disease and connective tissue disorders. Methotrexate, azathioprine and mycophenolate mofetil are effective in eczema and psoriasis either alone or as glucocorticoid-sparing agents. Further details on the mechanism of action, adverse effects and monitoring requirements for these agents are provided on page 1004, although it is important to be aware that there may be different approaches to treatment regimens and doses between specialties for some drugs. For example, in dermatology, methotrexate is used in a once-weekly regimen, with doses of up to 25 mg per week, depending on the response (p. 1004). Hydroxycarbamide is an alternative immunosuppressant to methotrexate in psoriasis, but appears to be less effective and the risk of myelosuppression is greater. Ciclosporin (p. 1005) has a rapid onset of action and is effective in inducing clearance of psoriasis and eczema. Monitoring of blood pressure and renal function is required. Ciclosporin should be used only with caution after phototherapy, particularly PUVA, because of the wet dressings. Paste bandages can be used in conjunction with topical emollients and glucocorticoids to soothe and cool, ease pruritus and scratching, and reduce inﬂammation. Dressings for venous leg ulcers are described on page 1224. Phototherapy and photochemotherapy Ultraviolet radiation (UVR) treatments (most commonly, narrowband ultraviolet B and psoralen–ultraviolet A (PUVA)) are used in the management of many different diseases. The best evidence for their efﬁcacy is in psoriasis, atopic eczema, vitiligo and chronic urticaria, although there is also evidence that UVB is helpful in treating generalised itch associated with chronic kidney disease and a range of other diverse skin conditions. Psoralens are natural photosensitisers found in a number of plants. They intercalate between the strands of DNA and, on excitation with UVA, cross-link the DNA strands. Psoralens are therefore prodrugs that are activated only in skin that is exposed to UVA. Psoralens can also be applied topically in a bath before irradiation with UVA (bath PUVA) or can be applied in creams or gels for localised topical PUVA. PUVA is a more complex treatment than UVB and has more adverse effects; in particular, cumulative exposure to PUVA increases the risk of skin cancer, particularly squamous cell carcinoma. Therefore, PUVA is generally used for poor responders to UVB, or in diseases such as plaque-stage cutaneous T-cell lymphoma or pityriasis rubra pilaris, where it is the phototherapy of ﬁrst choice. Phototherapy or PUVA may be offered as a whole-body or localised treatment. Longer-wavelength UVA1 (340–400 nm) is also used for several conditions, particularly the ﬁbrosing skin diseases such as morphoea, where efﬁcacy has been shown and there is a lack of other well-proven therapies. The evidence base for its place in the management of several diseases, such as eczema, is not fully proven and availability of UVA1 is mainly through centres of specialist expertise. Systemic therapies General information is provided here for drugs used in a range of skin diseases; details of other drugs are provided in diseasespeciﬁc sections. Antibiotics Antibiotics are generally used for their anti-infective properties, particularly for staphylococcal and streptococcal skin infections. In these indications, the correct antibiotic should be selected, based on bacterial sensitivity and patient factors. As examples, oral ﬂucloxacillin may be indicated for clinically infected eczema, intravenous ﬂucloxacillin for cellulitis, and clarithromycin for a patient with a staphylococcal carbuncle who is penicillin-allergic. Optimal therapeutic doses and courses must be chosen, based 29.13 Indications for dressings • Protection • Symptomatic relief from pain or itch • Maintenance of direct application of topical treatment • Possible improvement in healing time • Reduction of exudate • Reduction of odour

1228 • DERMATOLOGY affecting epidermis and upper dermis, such as benign naevi and skin tags. Mohs’ micrographic surgery Mohs’ micrographic surgery is employed to ensure adequate tumour excision margins, while conserving unaffected tissue. It is most commonly used for basal cell carcinoma (p. 1229). Non-surgical treatments Cryotherapy Cryotherapy is a destructive treatment using liquid nitrogen to cause cell-wall and membrane destruction and cell death. Liquid nitrogen can be applied either with a cotton bud or, more effectively, with a spray gun. A wide variety of conditions can be treated but it is essential for the correct diagnosis to be made ﬁrst, if necessary by diagnostic biopsy. Cryotherapy should not be used to treat melanocytic naevi. Benign lesions, such as viral warts and basal cell papillomas, respond well, and cryotherapy can also be effective for actinic keratoses, Bowen’s disease or superﬁcial non-melanoma skin cancer. Malignant indications require more vigorous treatment, usually with two cycles, and this is normally carried out in secondary care. Considerable inflammation, blistering and pigmentary change, particularly hypopigmentation, can occur. Caution is required to avoid damage to tendons and nerves, especially when using cryotherapy on digits. Laser therapy Laser therapy involves treatment with monochromatic light. Skin components (chromophores), such as haemoglobin and melanin, absorb speciﬁc wavelengths of electromagnetic radiation, and these wavelengths can therefore be used to destroy these targets selectively and to treat certain skin disorders. Lasers targeting haemoglobin are employed for vascular abnormalities, such as spider naevi, telangiectasiae and port-wine stains, and lasers targeting melanin can treat benign pigmentary disorders or pigment in tattoos or drug-induced hyperpigmentation (for example, secondary to minocycline). Melanin lasers can also be used for hair removal if the hair is pigmented. Light delivery in short pulses restricts damage to the treated site. The carbon dioxide laser emits infrared light that is absorbed by water in tissues and can therefore be used for destructive purposes. The depth of effect can be controlled, such that the carbon dioxide laser is widely employed for resurfacing in photorejuvenation or acne scarring. Signiﬁcant morbidity is associated with this destructive laser, although this may be minimised with fractionated regimens, and general anaesthesia is usually required. Photodynamic therapy Photodynamic therapy (PDT) is widely used in dermatology, predominantly for actinic keratoses, Bowen’s disease and superﬁcial basal cell carcinoma (p. 1229). Radiotherapy and grenz (Bucky) ray therapy Radiotherapy can be employed for several skin conditions, including non-melanoma skin cancer or lentigo maligna that is not suitable for surgical treatment, but its use in dermatology has declined. Scarring and poikiloderma can occur at treated increased risk of skin cancer. Long-term use of ciclosporin is not advised. Dapsone is an immunomodulator and may be used in diseases in which neutrophils are implicated, such as dermatitis herpetiformis (p. 1256). Haemolysis, methaemoglobinaemia and hypersensitivity can occur, and monitoring is required (pp. 123 and 269). Hydroxychloroquine is of particular value in cutaneous lupus. More details on the mechanism of action, adverse effects and monitoring requirements are provided on page 1005. Biological therapies Biological inhibitors of pro-inﬂammatory cytokines, including tumour necrosis factor alpha (TNF-α) inhibitors, ustekinumab (an antibody to the p40 component of interleukin (IL)-12 and IL-23), guselkumab (an antibody to IL-23), secukinumab and ixekizumab (antibodies to IL-17A) and brodalumab (an antibody to the IL-17 receptor) are effective treatments for psoriasis. Rituximab, which causes depletion of B cells, may be used in pemphigus vulgaris. More details on the dosages, mechanism of action and adverse effects of these agents are provided on page 1006. Omalizumab, a monoclonal antibody directed against immunoglobulin E (IgE), was introduced for allergic asthma but may also have a role in non-allergic diseases, such as treatment-resistant urticaria (pp. 86 and 572). Intravenous immunoglobulin, pooled from donor plasma, may be used in the treatment of dermatomyositis (p. 1039) and occasionally may be indicated in other dermatological diseases. Dermatological surgery Most dermatological surgical procedures are performed under local anaesthetic. Knowledge of local anatomy is essential, particularly the locations of vessels and nerves. In certain sites, such as the ﬁngers, soles of the feet and nose, local cutaneous nerve blocks are useful. Some sites are associated with particular risks, such as keloidal scarring on the upper trunk of young patients, unsightly scars over the scapulae, and poor healing and risk of ulceration following procedures on the lower legs. Excision biopsy This involves surgical removal of the lesion followed by histological examination. The most common indication is suspicion of malignancy. The lesion and line of excision should be marked out and the margin of excision decided before the procedure. It is important to excise down to the appropriate anatomical plane. Depending on body site, a range of procedures can minimise the resulting defect. Healing by secondary intention may also achieve good cosmetic results. Curettage Curettage involves using a small, spoon-shaped implement (curette), not only as a deﬁnitive treatment but also to obtain histology. Curettage does not preserve tissue architecture very well, however, and it may be difﬁcult to distinguish between dysplasia and invasive malignancy. It can be an effective treatment for basal cell papillomas, actinic keratoses, intra-epidermal carcinoma and superﬁcial basal cell carcinoma. Shave excision Shave excision using local anaesthetic may be used for simple and effective treatment of raised superﬁcial benign skin lesions

Skin tumours • 1229

(more than 150), which is immunosuppressive, are also at increased risk of skin cancer, particularly SCC. Despite UVB being a complete carcinogen, there is no evidence at present that UVB phototherapy signiﬁcantly increases skin cancer risk, although ongoing vigilance is required. Ionising radiation, notably radiotherapy, thermal radiation and chemical carcinogens, such as arsenic or coal tar, can increase NMSC risk, particularly SCC. A role for oncogenic human papillomaviruses in SCC development is also implicated, particularly in immunosuppressed patients, where viral DNA is detected in more than 80% of tumours. Chronic inflammation is a risk factor for SCC, which may arise in chronic skin ulcers (p. 1223), discoid lupus erythematosus or vulgaris, and the scarring genetic skin disease dystrophic epidermolysis bullosa (see Box 29.25, p. 1254), in which up to 50% of patients develop SCC. Malignant tumours Basal cell carcinoma The incidence of NMSC has increased dramatically in recent decades and basal cell carcinoma (BCC) accounts for more than 70% of cases. In Europe, the ratio of BCC to SCC is 4–5 : 1 in immunocompetent patients. It is a malignant tumour that rarely metastasises; it is thought to derive from immature pluripotent epidermal cells and is composed of cells with similarities to basal layer epidermis and appendages. Lesions typically occur at sites of moderate sun exposure, particularly the face, and are slow-growing. The incidence increases with age and males are more commonly affected. Lesions may ulcerate and invade locally; hence the term ‘rodent ulcer’. Clinical features Early BCCs usually present as pale, translucent papules or nodules, with overlying superﬁcial telangiectatic vessels (nodular BCC). If untreated, they increase in size and ulcerate, to form a crater with a rolled, pearled edge and ectatic vessels (Fig. 29.11). There may be some pigmentation or a cystic component. A superﬁcial multifocal type can occur, frequently on the trunk, and may be large (up to 10 cm in diameter); often there are multiple lesions. Superﬁcial BCC usually presents as a red/ brown plaque or patch with a raised, thread-like edge, which is sites, although these are minimised if fractionated regimens are chosen. Superﬁcial radiotherapy is now rarely employed to treat benign dermatoses. Even more superﬁcial ionising radiation (grenz, or Bucky, rays) can be useful for localised dermatoses that are having severe effects on quality of life, if conventional treatments have been inadequate; for example, it may avoid the need for systemic immunosuppression in a patient with severe recalcitrant localised scalp psoriasis. Skin tumours Pathogenesis Skin cancer is the most common malignancy in fair-skinned populations. It is subdivided into non-melanoma skin cancer (NMSC) and melanoma. NMSC is further subdivided into the most common skin cancer, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). The latter has precursor noninvasive states of intra-epithelial carcinoma (Bowen’s disease, BD) and dysplasia (actinic keratosis, AK). Melanoma is much less common than NMSC, but because of its metastatic risk it is the cause of most skin cancer deaths. UVR is a complete carcinogen and is the main environmental risk factor for skin cancer, which is much more common in countries with high ambient sun exposure, such as Australia. Skin cancer risk also increases if an individual migrates to such a country when young, particularly if less than 10 years of age. Epidemiological evidence supports a close link between chronic UVR exposure and risk of SCC and AK, and a modest link between sun exposure and BCC risk. Melanoma usually arises on sites that are intermittently exposed to UVR, and episodes of sunburn have been implicated as a risk factor for melanoma. There is good evidence to show that sunbed exposure is also a risk for both melanoma and NMSC, particularly when exposure starts in adolescence and early adult life. Strategies to reduce sun exposure are therefore important for skin cancer prevention, with reliance mainly on behavioural modiﬁcation, covering up and judicious sunscreen use. Indeed, there is evidence to show that sunscreen use reduces naevi development in children, and in adults regular sunscreen use reduces the risk of AK and SCC and is likely also to have preventative roles in melanoma and BCC development. There are identiﬁable genetic predispositions for some skin cancers, such as in xeroderma pigmentosum, an autosomal recessive condition caused by an inherited defect in DNA excision repair (pp. 1221 and 1321), or basal cell naevus (Gorlin’s) syndrome, an autosomal dominant disorder caused by lossof-function mutations affecting the PTCH1 tumour suppressor genes, with consequent activation of the Hedgehog pathway (p. 1321). Interestingly, the Hedgehog pathway is also almost invariably activated in sporadic BCC, which usually contain somatic mutations in PTCH1 and less commonly in the SMO gene, which lies in the same signalling pathway. The genetics of SCC are heterogeneous and less clearly deﬁned, with several mutations and pathways implicated, including TP53, CDKN2A/p16, NOTCH, EGFR and the MAPK signalling pathways. Interestingly, many of the mutations seen in SCC also occur in the pre-cancers AK and BD. The genetics of melanoma are discussed on page 1232. Cutaneous immune surveillance is also critical and immunosuppressed organ transplant recipients have a greatly increased risk of skin cancer, particularly SCC. Interestingly, patients who have received high treatment numbers of PUVA Fig. 29.11 Basal cell carcinoma. A A nodular BCC showing the translucent nature of the tumour and the abnormal arborising vessels. B An ulcerated BCC showing the raised, rolled edge. A B

1230 • DERMATOLOGY be required, although follow-up may be appropriate as not all tumours that are incompletely excised recur. However, this is not recommended for tumours at high-risk sites or for inﬁltrative morphoeic BCC, where complete excision is advisable. Cryotherapy may be effective for BCC but can cause blistering and scarring, so is best suited to small, superﬁcial lesions at low-risk sites. Radiotherapy can be invaluable for large BCC lesions in frail patients but is less commonly used because of the risk of scarring. Medical therapies can be used to treat low-risk BCC, particularly when surgery is not appropriate for a patient. Topical immunomodulators, such as imiquimod, are effective for low-risk BCC and may be particularly useful for patients who are not able to attend a hospital clinic setting but are able to apply a topical preparation at home over a 6-week period. Imiquimod usually induces a prominent inﬂammatory reaction and patients should be advised that dose adjustments may be required. Topical 5-ﬂuorouracil can also be effective for low-risk small lesions of superﬁcial BCC, but is rarely used since it usually provokes an intense inﬂammatory reaction. Intralesional interferon-alpha2b has been used for BCC but multiple treatments and high cost preclude its regular use. PDT is an effective treatment for low-risk, predominantly superﬁcial BCC, as well as AK and BD. Usually, topical porphyrin PDT is employed, which involves application of a porphyrin prodrug to the lesion to be treated. The prodrug is taken up and converted by the cell’s haem cycle to protoporphyrin IX, a photosensitiser. This is photochemically activated by visible (normally red) light, usually delivered by a light-emitting diode (LED), in the presence of oxygen, causing the production of reactive oxygen species, which cause destruction of treated tissue. The photosensitiser is taken up preferentially by diseased skin, and adverse effects in normal skin are minimised. PDT is at least as effective as cryotherapy and surgery for superﬁcial BCC and may be preferred at sites of poor healing, such as the lower leg, or where cosmetic outcome is important. PDT is not as effective as surgery for long-term clearance of nodular BCC but can be considered if surgery is not appropriate. Pain during irradiation may occur during PDT, although adjustments to the irradiation regime can reduce discomfort. PDT is usually undertaken in the outpatient clinic setting and is well suited to frail elderly patients who are not able to undertake treatment with topical agents at home. Rarely, advanced BCC may be locally invasive or even metastasise. Major advances have been made in targeted drug development, and Hedgehog pathway inhibitors, such as vismodegib and sonidegib, can be used effectively for disease control and palliation in this setting, although there may be signiﬁcant associated drug-induced toxicity. Squamous cell carcinoma Squamous cell carcinoma (SCC) is a malignancy that arises from epidermal keratinocytes and is the second most common skin cancer, occurring most frequently in elderly males and smokers. There is a close association between cumulative UVR exposure and SCC risk, with most SCC lesions occurring on chronically sun-exposed sites in white populations and often arising at sites of ﬁeld-change carcinogenesis, with coexistent precursors of AK and BD commonly evident. In the immunosuppressed patient population, such as organ transplant recipients, SCC is the most common skin cancer and its incidence is dramatically increased, particularly in association with the duration of immunosuppression often best seen by stretching the skin; this helps to distinguish it from Bowen’s disease. Less commonly, a morphoeic, inﬁltrative BCC presents as a poorly deﬁned, slowly enlarging, sclerotic yellow/grey plaque. Diagnosis and management The diagnosis is often obvious clinically, based on the features mentioned above, although a diagnostic conﬁrmatory biopsy may be required prior to definitive treatment. Management depends on the characteristics of the tumour and on patient factors, including comorbidities and patient wishes. Essentially, treatment will be either surgical or, in some cases, medical (Box 29.14). Surgical excision, ideally with a 4–5 mm margin, is the treatment of choice, with a cure rate of approximately 95%. Curettage and cautery may also be effective for selected lesions. Management of inﬁltrative morphoeic BCC and/or lesions at difﬁcult sites, such as around the eye, may require more complex techniques such as Mohs’ micrographic surgery to ensure adequate tumour excision margins, while conserving unaffected tissue. This involves processing of frozen sections of all margins in stages (usually on the same day) until all the tumour is removed. The procedure is time-consuming (so can be difﬁcult for elderly, frail patients) and requires particular surgical and pathology skills, but is associated with the highest long-term cure rates, with 98–99% clear at 5-year follow-up. If a surgical approach is used for management of BCC and the primary tumour is not completely excised, re-excision may 29.14 Management of non-melanoma skin cancer and pre-cancer Basal cell carcinoma • Excision results in the lowest recurrence rates • Mohs’ micrographic surgery is effective for high-risk BCC • Medical treatments are often appropriate for low-risk superﬁcial tumours in patients with comorbidities • Cryotherapy and topical 5-ﬂuorouracil can be used for superﬁcial BCC • Topical photodynamic therapy and topical imiquimod are both effective in superﬁcial BCC • BCC in patients with Gorlin’s syndrome should not be treated with radiotherapy • Hedgehog pathway inhibitors can induce clinical response in patients with advanced inoperable BCC Squamous cell carcinoma • Excision is the treatment of choice for invasive SCC • Most recurrences or metastases occur within 5 years • Medical management is not usually considered for invasive SCC Carcinoma in situ (Bowen’s disease) • For single/few lesions on good healing sites, cryotherapy, curettage, photodynamic therapy, topical imiquimod and 5-ﬂuorouracil are options • For multiple lesions and/or poor healing sites such as the lower leg, photodynamic therapy, where feasible, is the treatment of choice, although topical 5-ﬂuorouracil or imiquimod is an alternative Actinic keratosis • For single/few lesions on good healing sites, cryotherapy, curettage, 5-ﬂuorouracil/salicylic acid and ingenol mebutate are options. especially if hyperkeratotic • For multiple lesions/ﬁeld change, conventional or daylight photodynamic therapy, topical 5-ﬂuorouracil, imiquimod or diclofenac in hyaluronic acid gel may be effective

Skin tumours • 1231

Actinic keratosis Actinic keratoses (AK) are scaly, erythematous lesions arising on chronically sun-exposed sites. Histology shows dysplasia, although the diagnosis of typical AK is usually made on clinical grounds (Fig. 29.13). They are common in fair-skinned people who have had signiﬁcant sun exposure, are often multiple and increase with age. The prevalence is much higher in Australia than in the UK and some surveys have shown a prevalence of more than 50% in those over 40 years old. The rate of progression to SCC is less than 0.1% and spontaneous resolution is possible. However, SCC can also arise de novo and without progression from AK. Increase in size, ulceration, bleeding, pain or tenderness can be indicative of transformation into SCC. Management Several treatments are available for AK (see Box 29.14). Emollients and photoprotection, including high-factor sunscreens, may sufﬁce for mild disease. Single or low numbers of lesions of AK can be effectively treated with cryotherapy. Hyperkeratotic lesions may be treated with the antimetabolite 5-ﬂuorouracil, combined with salicylic acid, or may require curettage and cautery. Multiple lesions require ﬁeld-directed therapy; 5-ﬂuorouracil is widely used in this setting and is effective but topical imiquimod is an alternative. Diclofenac in a hyaluronic acid gel base can also be used topically for low-grade maintenance control of AK, the rationale for its use being the over-expression of cyclooxygenase (COX)-2 in AK lesions. Topical ingenol mebutate can also be used and has the advantage of a short treatment regime, although severe inﬂammation may be induced. PDT is widely used for ﬁeld-change multiple AK, with high efﬁcacy rates; it is at least as effective as cryotherapy or 5-ﬂuorouracil. The relative selectivity of treatment allows subclinical disease to be treated, while sparing normal skin. A regimen using daylight to activate the photosensitiser is increasingly used worldwide for extensive mild AK, with high efﬁcacy rates, comparable to hospital-based PDT but without the need for specialised equipment and allowing patients to be treated at home. and the degree of sun exposure and damage accrued pretransplant. The risk of SCC is also increased in HIV infection. Furthermore, SCC arising in the immunosuppressed is more likely to behave aggressively or to metastasise. Clinical features The tumours usually occur on chronically sun-exposed sites, such as bald scalp, tops of ears, face and back of hands. The clinical presentation may be diverse, ranging from rapid development of a painful keratotic nodule in a pre-existing area of dysplasia (Fig. 29.12) to the de novo presentation of an erythematous, inﬁltrated, often-warty nodule or plaque that may ulcerate. The clinical appearance depends on histological grading; well-differentiated tumours more often present as deﬁned keratotic nodules (Fig. 29.12), whereas poorly differentiated tumours tend to be ill deﬁned and inﬁltrative, and may ulcerate. SCC has metastatic potential; some tumours, such as those on lips and ears and in immunosuppressed patients, behave more aggressively and are more likely to metastasise to draining lymph nodes. Management Early diagnosis is important and complete surgical excision is the usual treatment of choice (see Box 29.14). Standard excision with a 4–6 mm margin is advised and the cure rate is approximately 90–95%. Mohs’ surgery is an option but is used less frequently for SCC than for BCC. High-risk SCC should be treated aggressively, with a wider margin of excision of at least 6 mm where feasible. This may include larger, thicker lesions, tumours at sites where metastases are more likely, such as the ear, lip or non-sun-exposed sites, and those occurring in the immunosuppressed and/or with histology showing the tumour to be poorly differentiated, with evidence of lymphatic, vascular or perineural involvement or a high mitotic index. Such patients and those with metastatic disease require management via a multidisciplinary team. In patients who are at high risk for further SCC, systemic retinoids may have a role in reducing the rate of SCC development, but rapid appearance of tumours occurs on drug cessation. Occasionally, curettage and cautery may be appropriate if the tumour is small and low-risk and either surgical excision is contraindicated or the patient is unwilling to proceed. Radiotherapy may be indicated if surgical excision is not feasible. Cryotherapy and topical non-surgical therapies are not usually used in invasive SCC because of risk of recurrence and metastasis. Fig. 29.12 Squamous cell carcinoma. A A centrally keratinous, symmetrical, well-differentiated SCC. Clinically, this could be confused with keratoacanthoma. B An SCC arising from an area of epidermal dysplasia. A B Fig. 29.13 Actinic keratosis. Close-up of a hyperkeratotic AK on the ear.

1232 • DERMATOLOGY radiation, the synthetic retinoid bexarotene, interferon-alpha, extracorporeal photopheresis and systemic anti-lymphoma chemotherapy regimens may be needed. Management of advanced disease invariably requires a multidisciplinary team approach, with collaboration between dermatologists, pathologists and haematological oncologists. Melanoma Melanoma is a malignant tumour of epidermal melanocytes. While only 4% of skin cancers are melanomas, they account for 80% of skin cancer deaths. There has been a steady rise in the incidence of melanoma in fair-skinned populations over recent decades, with the highest ﬁgures in Australasia. Primary prevention and early detection are essential, as therapy for advanced and metastatic disease remains unsatisfactory. Pathophysiology Risk factors for melanoma include fair skin, freckles, red hair, number of naevi and sunlight exposure. The type of sunlight exposure is under debate but intermittent exposure, such as recreational time in the sun, sunburn and sunbed use, is implicated. Patients with multiple atypical naevi (dysplastic naevus syndrome) and fair-skinned people, often with variant alleles in the melanocortin-1 gene, are at increased risk of melanoma. A family history of melanoma increases the risk but a strong family history is unusual. Rarely, autosomal dominant inheritance of melanoma with incomplete penetrance can occur due to mutations in CDKN2A, which encodes the p16 tumour suppressor protein. In these patients, the lifetime risk of melanoma is more than 50%. Several other susceptibility genes and potential genetic targets for therapeutic intervention in advanced disease have also been identiﬁed. Clinical features Melanoma can occur at any age and site and in either sex, but typically affects the leg in females and back in males. It is rare before puberty. The classiﬁcation of invasive malignant melanoma is shown in Box 29.15. Early lesions may be in situ and pre-invasive before becoming invasive melanoma with metastatic potential. Any change in naevi or development of new lesions should be assessed to exclude malignancy and, for this, the dermatoscope is invaluable (see Fig. 29.2, p. 1217). Real-time non-invasive imaging techniques are being investigated as tools to assist in diagnosis but are largely experimental. If there is any doubt, excision is advised. Superﬁcial spreading melanoma Superﬁcial spreading melanoma (SSM) is the most common type in Caucasians. It usually presents as a slowly enlarging, macular, pigmented lesion, with increasing irregularity in shape and pigment; this superﬁcial, radial growth phase can last for Bowen’s disease Clinical features Bowen’s disease (BD) is the name given to an intra-epidermal carcinoma that usually presents as a slowly enlarging, erythematous, scaly plaque on the lower legs of fair-skinned elderly women (Fig. 29.14) but other sites can also be involved. It can be confused with eczema or psoriasis, but is usually asymptomatic and does not respond to topical glucocorticoids. It may also be hard to distinguish from superﬁcial BCC. Transformation into SCC occurs in 3% or less. Diagnosis Incisional biopsy is usually undertaken to conﬁrm the diagnosis. This shows an intra-epidermal carcinoma with no invasion through the basement membrane. Histology may also be obtained by curettage but this does not allow distinction from invasive SCC to be made, due to loss of tissue orientation and architecture. Management While curettage or excision may be appropriate in some settings, non-surgical therapies are generally preferred (see Box 29.14), especially on the lower legs. PDT, in particular, may be advantageous for BD on the lower leg because of relative selectivity of treatment and sparing of normal tissue, thus reducing the risk of poor healing and ulceration at this vulnerable site. Given the low risk of malignant transformation, the option of no active treatment may also be appropriate for some elderly frail patients. Cutaneous lymphomas The most common form of cutaneous T-cell lymphoma is mycosis fungoides (MF). This can persist for years in patch and plaque stages, often resembling eczema or psoriasis. Only sometimes does it progress through to nodules and ﬁnally a systemic stage, Sézary’s syndrome. B-cell lymphomas, on the other hand, usually present as nodules or plaque-like tumours. The diagnosis of cutaneous T-cell lymphoma requires a high index of suspicion, particularly in patients thought to have unusual recalcitrant forms of eczema or psoriasis. Treatment is symptomatic and there is no evidence that it alters prognosis. In the early stages of cutaneous T-cell lymphoma, systemic or local glucocorticoids may be indicated; alternatively, narrowband UVB phototherapy (for patch-stage MF) or PUVA (for plaque-stage MF) may be used. Once lesions have moved beyond plaque stage, localised radiotherapy, electron beam Fig. 29.14 Intra-epidermal carcinoma (Bowen’s disease). The lower leg is a common site and lesions are often treated non-surgically. 29.15 Classiﬁcation of cutaneous malignant melanoma Melanoma without metastatic potential • Melanoma in situ • Lentigo maligna Melanoma with metastatic potential • Superﬁcial spreading melanoma • Nodular melanoma • Acral lentiginous melanoma • Subungual melanoma • Lentigo maligna melanoma

Skin tumours • 1233

tumour (the maximal depth from epidermal granular cell layer to deepest tumour cells) is critical for management and prognosis. The presence of ulceration may lead to under-estimation of the Breslow thickness. The mitotic rate and the presence or absence of any evidence of lymphovascular or perineural involvement should also be ascertained. The clinical staging of melanoma extent is essential, in order to establish whether disease is primary and localised, or if there is nodal or metastatic spread. Wide excision of melanoma with a low risk of metastasis (stage 1 disease, Breslow thickness < 1 mm) with a 1 cm clear margin is accepted practice. The margin of excision for more advanced disease is controversial, although a 2–3 cm margin for thicker tumours is generally advised as an attempt to reduce risk of local recurrence. There is no evidence that more radical surgery with 4–6 cm margins is beneﬁcial. The majority of tumours can be excised without the need for grafting. For tumours with a Breslow thickness of 1 mm or more, a sentinel lymph node biopsy should be considered. This is usually performed at the time of wider excision and involves injection of radiolabelled blue dye at the site of the primary melanoma, allowing identiﬁcation of the draining ‘sentinel’ node by radioscintigraphy; this sentinel node is then removed and examined in detail by histology, immunohistochemistry and/or PCR of melanocyte gene products to look for tumour deposits. If the biopsy is positive, local lymphadenectomy is usually offered. This procedure provides additional prognostic information but there is no evidence that it improves survival. Local recurrence of disease and palpable local node involvement should be treated surgically. Localised cutaneous metastases or in transit disease may be amenable to palliation with electrochemotherapy if there is no evidence of widespread metastatic disease. Despite the major advances in treatment options for advanced melanoma, the prognosis for metastatic disease remains poor and treatment options are palliative. Genetic developments have facilitated the introduction of tumour-targeted treatments for advanced, unresectable and/or metastatic disease, such as the B-Raf and c-Kit kinase inhibitors for patients expressing these gene mutations, notably dabrafenib and vemurafenib, with demonstrable clinical responses. Immunotherapy with ipilimumab, which blocks T-cell activation by inhibiting CTLA-4, alone or in combination with the programmed cell death (PD1) pathway blockers nivolumab or pembrolizumab, provides clinically meaningful improvements in quality of life and survival to patients with advanced disease. Standard chemotherapy may also be used in some cases of metastatic disease, although outcomes are poor. Other biological and gene therapies and vaccines are also being investigated. It is important for patients with advanced melanoma to be managed through a multidisciplinary team in order to optimise care and facilitate their inclusion in clinical trials. All patients should be advised regarding ongoing photoprotection, with sensible behaviour in the sun, covering up, wearing hats and high-factor sunscreen use. However, evidence has shown that despite patients with melanoma being advised to photoprotect, many follow this advice only for the ﬁrst year following diagnosis, thus emphasising the need for ongoing reinforcement of guidance with regard to photoprotection. It is also prudent to advise patients who are photoprotecting to optimise oral vitamin D through diet and/or supplements. Prognosis Patients with a primary tumour of less than 1 mm Breslow thickness have more than a 95% chance of disease-free survival approximately 2 years. Subsequently, the lesion may become palpable and this is indicative of a vertical growth phase, with dermal invasion; when this occurs, the tumour has the potential to invade lymphatics and vessels and to become metastatic (Fig. 29.15A). Approximately 50% of melanomas arise from a pre-existing naevus. Nodular melanoma Nodular melanoma is most common in the ﬁfth and sixth decades, particularly in men and on the trunk (Fig. 29.15B). This may account in part for the increased mortality rates from melanoma in men, as these are tumours with greater metastatic risk. They often present as a rapidly growing nodule that may bleed and ulcerate. Nodular melanomas may be heavily pigmented, or relatively amelanotic and erythematous, and be confused with benign vascular lesions. A rim of pigmentation may, however, be seen under the dermatoscope. Lesions may develop de novo or from a pre-existing naevus or SSM. Lentigo maligna melanoma This arises from a prolonged pre-invasive phase termed lentigo maligna. It occurs as a very slowly expanding, pigmented, macular lesion, usually on photo-exposed head and neck sites of elderly patients; histology shows in situ changes only. This phase may last for several years before a nodule of invasive melanoma develops in a proportion of cases (lentigo maligna melanoma). Acral lentiginous or palmoplantar melanoma This accounts for only approximately 10% of melanomas in fair-skinned races and is more common in dark-skinned people, in whom it is responsible for 50% of cases. This indicates that UVR exposure may not be implicated in acral melanoma risk. Subungual melanoma This form of melanoma is rare. It may present as a painless, proximally expanding streak of pigmentation arising from the nail matrix, and progresses to nail dystrophy and involvement of the adjacent nail fold (Hutchinson’s sign). Diagnosis and management The diagnosis is made by excision biopsy of a suspicious lesion. The initial biopsy should include a 2 mm margin, followed up where possible by wider excision if the diagnosis is conﬁrmed. Occasionally, radiotherapy or imiquimod may be used for lentigo maligna, if surgery is not feasible. The Breslow thickness of the Fig. 29.15 Superﬁcial spreading melanoma. A A superﬁcial spreading malignant melanoma with a palpable area indicative of vertical growth phase (Breslow thickness 1.3 mm). B A nodular malignant melanoma arising de novo and with Breslow thickness of 3.5 mm. B A

1234 • DERMATOLOGY background skin changes in Fig. 29.12A), become more common with age, and are often referred to as ‘liver spots’ or ‘age spots’. They can vary in colour from light to very dark brown. Distinction from melanoma is essential and histology may be required. Haemangiomas Benign vascular tumours or hamartomas are common and include Campbell de Morgan spots (Fig. 29.17), which present as pink/ red papules on the upper half of the body. They can sometimes be difﬁcult to distinguish from melanocytic lesions, particularly if they are thrombosed or occur on particular sites, such as the lip or genitalia. The dermatoscope is helpful for this (see Fig. 29.2, p. 1217). Basal cell papilloma Basal cell papillomas (also known as seborrhoeic warts or keratoses) are common, benign epidermal tumours (Fig. 29.17). They may be ﬂat, raised, pedunculated or warty-surfaced, and can appear to be ‘stuck on’. They occur in both sexes and with increasing age, and are most common on the face and trunk. The colour may vary from yellow to almost black and the surface may seem ‘greasy’, with pinpoint keratin plugs visible, particularly with a magnifying lens. If there is no doubt about the diagnosis, they can be left alone or treated by cryotherapy or curettage if they are cosmetically troublesome. If there is a suspicion of melanoma, excision or diagnostic biopsy should be undertaken. Melanocytic naevi Melanocytic naevi (moles) are localised benign clonal proliferations of melanocytes. It is thought that they may arise as the result of abnormalities in the normal migration of melanocytes during development. It is quite normal to have 20–50, although, interestingly, individuals with red hair have fewer. Genetic and environmental factors are implicated. Monozygotic twins have higher concordance in naevi numbers than dizygotic twins. Individuals who have had greater sun exposure have higher numbers of naevi. Most melanocytic naevi appear in childhood and early adult life, or during pregnancy or oestrogen therapy. The onset of a new mole is less common after the age of 25 years. Congenital melanocytic naevi occur at or shortly after birth. at 10 years, but this ﬁgure drops to approximately 50% for a tumour of greater than 3.5 mm thickness. Survival rates fall to less than 10% for those with advanced nodal or metastatic disease. Benign skin lesions In practice, it is often difﬁcult to distinguish between skin cancer and a benign lesion on clinical grounds; if there is any doubt, biopsy and histology are required. Benign melanocytic naevi and basal cell papillomas, in particular, can often be mistaken for melanoma, even by dermatologists. Keratoacanthoma, while benign, is also commonly considered to be invasive SCC on clinical grounds. Keratoacanthoma This benign tumour has a striking clinical presentation of rapid growth over weeks to months and subsequent spontaneous resolution. It is thought to be associated with chronic sun exposure and most commonly occurs on the central face. The classical appearance is of an isolated dome-shaped nodule often of 5 cm or more in diameter, with a central keratin plug (Fig. 29.16). Clinically and histologically, the lesion often resembles SCC (see Fig. 29.12A). Most are treated surgically, either by curettage and cautery or by excision, to rule out SCC and to avoid the unsightly scar after spontaneous resolution. Freckle Histologically, a freckle (ephelis) consists of normal numbers of melanocytes, but with focal increases in melanin in keratinocytes. They are most common on sun-exposed sites in fair-skinned individuals, particularly children and those with red hair, and on the face. There is a familial tendency. Clinically, freckles are brown macules that darken following UVR exposure. Lentigo A lentigo (plural lentigines) consists of increased numbers of melanocytes along the basement membrane, but without formation of the nests that occur in melanocytic naevi. These lesions usually occur at sites of chronic sun exposure (see the Fig. 29.16 Keratoacanthoma. Fig. 29.17 A typical basal cell papilloma. Note the neighbouring basal cell papillomas and the coincidental benign angiomas (Campbell de Morgan spots).

Common skin infections and infestations • 1235

Acrochordon Acrochordons, or skin tags, are benign pedunculated lesions; they are most common in skin flexures and usually have a very characteristic clinical appearance. However, they may sometimes be confused with melanocytic naevi. Treatment is not required unless there is diagnostic doubt or they are causing symptoms, such as irritation, or for cosmetic reasons. Cryotherapy or snip or shave excision may be appropriate in that situation. Lipoma Lipomas are benign tumours of adipocytes that are characteristically soft and lie more deeply in the skin than epidermal tumours; they are usually diagnosed easily on clinical grounds. A variant, angiolipoma, is typically painful. Treatment is not required unless there is diagnostic doubt or they are symptomatic or cosmetically troublesome, in which case a diagnostic biopsy or surgical excision may be required. Common skin infections and infestations Bacterial infections Impetigo Impetigo is a common and highly contagious superficial bacterial skin infection. There are two main presentations: bullous impetigo, caused by a staphylococcal epidermolytic toxin, and non-bullous impetigo (Fig. 29.19), which can be caused by either Staphylococcus aureus or streptococci, or both together. Staphylococcus spp. are the most common agents in temperate climates, whereas streptococcal impetigo is more often seen in hot, humid areas. All ages can be affected but non-bullous disease particularly affects young children, often in late summer. Outbreaks can arise in conditions of overcrowding Clinical features Acquired melanocytic naevi are classified according to the microscopic location of the melanocyte nests (Fig. 29.18). Junctional naevi are usually macular, circular or oval, and mid- to dark brown. Compound and intradermal naevi are nodules because of the dermal component, and may be hair-bearing. Intradermal naevi are usually less pigmented than compound naevi. Their surface may be smooth, cerebriform, hyperkeratotic or papillomatous. Some individuals have large numbers of naevi, often at unusual sites, such as the scalp, palms or soles, and these may frequently appear ‘atypical’ in terms of variability in pigmentation, size and shape. Some may be very dark or pink and may show a depigmented or inﬂamed halo. If these naevi are removed, then ‘dysplastic changes’ are often seen. Such naevi are known to occur in some rare families with an inherited melanoma predisposition. However, the signiﬁcance of such changes in non-familial cases is unclear and there is no consensus on management and follow-up. Although approximately 50% of melanomas arise in pre-existing naevi, most naevi do not become malignant; although a changing naevus must be taken seriously, most will not be melanomas. Malignant change is most likely in large congenital melanocytic naevi (risk may correlate with the size of the lesion) and possibly in families who have been diagnosed as showing large numbers of atypical naevi with a history of melanoma. Diagnosis and management Melanocytic naevi are normal and do not require excision, unless malignancy is suspected or they become repeatedly inﬂamed or traumatised. Advice on photoprotection is important for fair-skinned individuals with multiple naevi. Blue naevi These are melanocytic naevi in which there is a proliferation of spindled melanocytes relatively deep within the dermis. Light scattering means that the pigment appears blue rather than brown. They may be difﬁcult to distinguish from nodular melanoma and are therefore often excised. Dermatoﬁbroma A dermatoﬁbroma is a characteristically ﬁrm, often pigmented, raised lesion, most commonly found on the lower legs. Its aetiology is unclear, although a reactive process secondary to insect bites or trauma is one hypothesis. There is frequently a ring of pigment around the lesion and dimpling when the skin is pinched, reﬂecting epidermal tethering. Fig. 29.18 Classiﬁcation of melanocytic naevi. Classiﬁcation is based on microscopic location of the nests of naevus cells. Junctional Compound Intradermal Fig. 29.19 Non-bullous impetigo.

1236 • DERMATOLOGY Ecthyma Ecthyma is caused by either staphylococci or streptococci, or both together, and is characterised by adherent crusts overlying ulceration. It occurs worldwide but is more common in the tropics. In Europe, it occurs more frequently in children. Predisposing factors include poor hygiene, malnutrition and underlying skin disease, such as scabies. It is commonly seen in drug abusers, and minor trauma can predispose to lesion development. Folliculitis, furuncles and carbuncles Hair follicle inﬂammation can be superﬁcial, involving just the ostium of the follicle (folliculitis), or deep (furuncles and carbuncles). Superﬁcial folliculitis The primary lesions are follicular pustules and erythema. Superﬁcial folliculitis is often infective, caused by Staph. aureus, but can also be sterile and caused by physical (for example, traumatic epilation) or chemical (for example, mineral oil) injury. Staphylococcal folliculitis is most common in children and often occurs on the scalp or limbs. Pustules usually resolve without scarring in 7–10 days but can become chronic. In older children and adults, they may progress to a deeper form of folliculitis. The condition and poor hygiene or in institutions. A widespread form can occur in neonates. Predisposing factors are minor skin abrasions and the existence of other skin conditions, such as infestations or eczema. In non-bullous impetigo, a thin-walled vesicle develops; it rapidly ruptures and is rarely seen intact. Dried exudate, forming golden crusting, arises on an erythematous base. In bullous disease, the toxins cleave desmoglein-1, causing a superﬁcial epidermal split and the occurrence of intact blisters with clear to cloudy ﬂuid, which last for 2–3 days. The face, scalp and limbs are commonly affected but other sites can also be involved, particularly if there are predisposing factors such as eczema. Lesions may be single or multiple and coalesce. Constitutional symptoms are uncommon. A bacterial swab should be taken from blister ﬂuid or an active lesion before treatment commences. Around one-third of the population is a nasal carrier of Staphylococcus, so swabs from the nostrils should also be obtained. In mild, localised disease, topical treatment with mupirocin or fusidic acid is usually effective and limits the spread of infection. The use of topical antiseptics and soap and water to remove infected crusts is also helpful. Staphylococcal carriage should be treated, with mupirocin topically to the nostrils, if swabs are positive. In severe cases, an oral antibiotic, such as ﬂucloxacillin or clarithromycin, is indicated. If nephritogenic streptococci are isolated then systemic antibiotics should be considered to reduce the risk of streptococcal glomerulonephritis (p. 401). Underlying disease, such as infestations, must be treated and cross-infection minimised. Scarring does not occur but there may be temporary dyspigmentation. Staphylococcal scalded skin syndrome Staphylococcal scalded skin syndrome (SSSS) is a potentially serious exfoliating condition occurring predominantly in children, particularly neonates (Fig. 29.20). It is caused by systemic circulation of epidermolytic toxins from a Staph. aureus infection. The same toxins are implicated in bullous impetigo, which is a localised form of SSSS. The focus of infection may be minor skin trauma, the umbilicus, urinary tract or nasopharynx. The child presents with fever, irritability and skin tenderness. Erythema usually begins in the groin and axillae, and around the mouth. Blisters and superﬁcial erosions develop over 1–2 days and can rapidly involve large areas, with severe systemic upset. Bacterial swabs should be obtained from possible primary sites of infection. A skin snip should also be taken for urgent histology. This is a sample of the superﬁcial peeling skin removed by ‘snipping with scissors’, without the need for local anaesthetic. It shows a split beneath the stratum corneum, and differentiates SSSS from toxic epidermal necrolysis, in which the whole epidermis is affected (see Fig. 29.41, p. 1254). Systemic antibiotics and intensive supportive measures should be commenced immediately. Bacterial swabs from nostrils, axillae and groins should be taken from family members to exclude staphylococcal carriage. Although the acute presentation of SSSS is often severe, rapid recovery and absence of scarring are usual, as the epidermal split is superﬁcial. Toxic shock syndrome This condition is characterised by fever, desquamating rash, circulatory collapse and multi-organ involvement (p. 252). It is caused by staphylococcal toxins and early cases were thought to arise with tampon use. Intensive supportive care and systemic antibiotics are required. Fig. 29.20 Staphylococcal scalded skin syndrome. A Extensive erythema and superﬁcial peeling of the skin. B The condition was rapidly diagnosed by examination of a frozen section of skin snip. A, From Savin JA, Dahl M, Hunter JAA. Clinical dermatology, 3rd edn. Oxford: Blackwell; 2002. A B

Common skin infections and infestations • 1237

has malaise, fever and leucocytosis, and streptococcal serology will often be positive. The face (erysipelas) and legs (cellulitis) are most often affected and the site is hot, painful, erythematous and oedematous. Blistering often occurs and may be haemorrhagic. Regional lymphadenopathy is common. Erysipelas typically has a well-deﬁned edge due to its more superﬁcial level of involvement, whereas cellulitis is typically ill deﬁned. Treatment is usually with intravenous ﬂucloxacillin, with clarithromycin, clindomycin and vancomycin as alternatives for penicillin-allergic patients. Milder cases may be treated with oral antibiotics. If cases are untreated, sequelae include lymphoedema, cavernous sinus thrombosis, sepsis and glomerulonephritis. Mycobacterial infections Mycobacterium leprae infection may involve the skin and its manifestations will be inﬂuenced by host immunity, patients with high levels of immunity presenting with paucibacillary Fig. 29.21 Staphylococcal carbuncle. Fig. 29.22 Acute cellulitis of the leg. Note the chronic lymphoedema and the haemorrhagic blistering. Blister ﬂuid was positive for group G streptococci. Fig. 29.23 Erysipelas. Note the blistering and the crusted rash with raised, erythematous edge. The yellow discoloration is due to topical iodine treatment. is often self-limiting and may respond to irritant removal and antiseptics. More severe cases may require topical or systemic antibiotics and treatment of Staph. aureus carrier sites. Deep folliculitis (furuncles and carbuncles) A furuncle (boil) is an acute Staph. aureus infection of the hair follicle, usually with necrosis. It is most common in young adults and males. It is usually sporadic but epidemics occasionally occur. Malnutrition, diabetes and HIV predispose, although most cases arise in otherwise healthy people. Any body site can be involved but neck, buttocks and anogenital areas are common. Infection is often associated with chronic Staph. aureus carriage in the nostrils and perineum, and may be due to resistant strains, such as meticillin-resistant organisms (MRSA). Friction caused by tight clothing may be contributory. Initially, an inﬂammatory follicular nodule develops and becomes pustular, ﬂuctuant and tender. Crops of lesions sometimes occur. There may be fever and mild constitutional upset. Lesions rupture over days to weeks, discharge pus, become necrotic and leave a scar. If a deep Staph. aureus infection of a group of contiguous hair follicles occurs, this is termed a carbuncle and is associated with intense deep inﬂammation (Fig. 29.21). This usually occurs in middle-aged men, often with predisposing conditions such as diabetes or immunosuppression. A carbuncle is an exquisitely tender nodule, usually on the neck, shoulders or hips, associated with severe constitutional symptoms. Discharge, necrosis and scarring are usual. Bacterial swabs must be taken and treatment is with anti-staphylococcal antibiotics, e.g. ﬂucloxacillin, and sometimes incision and drainage. Other staphylococcal toxins may also be pathogenic. For example, Panton–Valentine leukocidin-producing Staph. aureus can cause recurrent abscesses (deﬁnition: localised collections of pus in cavities) and may be difﬁcult to eradicate. Cellulitis and erysipelas Cellulitis is inﬂammation of subcutaneous tissue, due to bacterial infection (Fig. 29.22). In contrast, erysipelas is bacterial infection of the dermis and upper subcutaneous tissue (Fig. 29.23), although in practice it may be difﬁcult to distinguish between them. These conditions are most commonly caused by group A streptococci but culture of swabs from affected sites is often negative. There is frequently a source of organism entry, such as an ear infection, varicose eczema/ulcer or tinea pedis, and swabs should also be taken from these sites. Diabetes and immunosuppression are predisposing factors. The patient usually

1238 • DERMATOLOGY characteristic circular erosions (‘pits’) on the soles. It is usually asymptomatic. The bacterium can be identiﬁed in skin scrapings and typically occurs in association with hyperhidrosis, which must be treated to prevent recurrence. Treatment is as for erythrasma. Other bacterial skin infections Syphilis and the non-venereal treponematoses are described on pages 337 and 253. There has been a marked increase in incidence of syphilis. Skin signs may be subtle; for example, secondary syphilis may be misdiagnosed as pityriasis rosea. Lesions on palms, soles and mucosae should raise suspicion. Microscopic identiﬁcation of the spirochaete may be possible and syphilitic serology should be undertaken using enzyme immunoassay or PCR-based techniques, depending on availability. Lyme disease is described on page 255. Viral infections Herpesvirus infections The cutaneous manifestations of the human herpesviruses are described on page 247. Topical antivirals may sufﬁce for prophylaxis or treatment of mild viral disease, such as herpes simplex cold sore virus infection. Systemic antivirals are indicated for signiﬁcant viral skin disease. For example, systemic aciclovir should be prescribed for eczema herpeticum (see Fig. 11.14, p. 247). Papillomaviruses and viral warts Viral warts are extremely common and are caused by the DNA human papillomavirus (HPV). There are over 90 subtypes, based on DNA sequence analysis, causing different clinical presentations. Transmission is by direct virus contact, in living or shed skin, and is encouraged by trauma and moisture such as in swimming pools. Genital warts are spread by sexual activity and show a clear relationship with cervical and intra-epithelial cancers of the genital area. HPV-16 and 18 appear to inactivate tumour suppressor gene pathways and lead to squamous cell carcinoma of the cervix or intra-epithelial carcinoma of the genital skin (p. 242). Vaccinations are available against HPV-16 and 18 and are recommended for adolescent females before they become sexually active. The relationship between skin HPV and skin cancer is unclear. Individuals who are systemically immunosuppressed – after organ transplantation, for example – have greatly increased risks of skin cancer and HPV infection but a causal link is not certain. Clinical features Common warts are initially smooth, skin-coloured papules, which become hyperkeratotic and ‘warty’. They are most common on the hands (Fig. 29.24) but can occur on the face, genitalia and limbs, and are often multiple. Plantar warts (verrucae) have a slightly protruding rough surface and horny rim, and are often painful on walking. Paring reveals capillary loops that distinguish plantar warts from corns. Other varieties of wart include: • mosaic warts: mosaic-like sheets of warts • plane warts: smooth, ﬂat-topped papules, usually on the face and backs of hands, which may be pigmented and therefore misdiagnosed • facial warts: often ﬁliform • genital warts: may be papillomatous and exuberant. tuberculoid leprosy and those with low immune resistance developing multibacillary lepromatous leprosy. Hypopigmented or erythematous patches, with associated altered or lost sensation, or skin thickening, nodules and inﬁltration should raise suspicion of a diagnosis of leprosy (p. 267). The skin may also be an extrapulmonary site of involvement in tuberculosis, usually due to infection with Mycobacterium tuberculosis. Skin manifestations depend on the route of infection, previous sensitisation and host immunity. There may be a variety of cutaneous features, including the red–brown scarring inﬂammatory plaques seen in lupus vulgaris due to direct skin inoculation; scrofuloderma, which describes the skin changes overlying lymph nodes or joints infected with tuberculosis; and the reactive nodular and ulcerated changes seen in patients with high levels of immune response, notably the tuberculids and erythema induratum (Bazin’s disease). On diascopy, an ‘apple jelly’ appearance is typically seen, indicating the granulomatous nature of skin involvement. Granulomas evident on skin biopsy should certainly raise suspicion of a diagnosis of mycobacterial infection. Culture of organisms may be tricky but PCR can assist with diagnosis. Patients should be thoroughly investigated for signs of tuberculosis at pulmonary or other extrapulmonary sites (p. 588). Reactivation of latent tuberculosis is a particular concern for patients receiving treatment with immunosuppressants and biological agents, particularly TNF-α antagonists for conditions such as psoriasis. Vigilance is required in screening and workup of such patients prior to consideration of these therapeutic agents. Other mycobacterial skin infections may occur, such as Mycobacterium marinum, typically seen in those who clean tropical ﬁsh tanks. Sporotrichoid spread of granulomatous nodules from the site of inoculation along lymphatics is typical; granulomatous changes are seen on histology and resolution usually occurs with a prolonged course of antibiotics such as doxycycline or minocycline. Resolution may also take place spontaneously or after destructive therapies, such as cryotherapy. Leishmaniasis This protozoan infection may be restricted to the skin or there may be may be systemic features depending on the species, which occur in different geographical areas (p. 281). Necrotising soft tissue infections and anthrax See pages 226 and 266, respectively. Erythrasma Erythrasma is a mild, chronic, localised, superﬁcial skin infection caused by Corynebacterium minutissimum, which is part of the normal skin ﬂora. Warmth and humidity predispose to this infection, which usually occurs in ﬂexures and toe clefts. It is asymptomatic or mildly itchy and lesions are well deﬁned, red–brown and scaly. C. minutissimum has characteristic coralpink ﬂuorescence under Wood’s light. Microscopy and culture of skin scrapings can conﬁrm the diagnosis but are not usually needed if Wood’s light examination is positive. A topical azole (clotrimazole or miconazole) or fusidic acid is usually effective. Oral erythromycin can be used for extensive or resistant disease. Antiseptics can be used to prevent disease recurrence. Pitted keratolysis This is another superﬁcial skin infection caused by Corynebacterium and Streptomyces spp., and possibly other organisms, producing

Common skin infections and infestations • 1239

Orf Orf is a parapoxvirus skin infection and is an occupational risk for those who work with sheep and goats. Inoculation of virus, usually into ﬁnger skin, causes signiﬁcant inﬂammation and necrosis, which typically resolves within 2–6 weeks. No speciﬁc treatment is required, unless there is secondary infection. Erythema multiforme (p. 1264) can be provoked by orf. Other viral exanthems See page 236. Fungal infections Fungal skin infections can be superﬁcial (dermatophytes and yeasts) or, less commonly, deep (chromomycosis or sporotrichosis); the latter are seen more often in tropical climates or in the immunocompromised. Dermatophyte infections (ringworm) are extremely common and usually caused by fungi of the Microsporum, Trichophyton and Epidermophyton species. The fungi can originate from soil (geophilic) or animals (zoophilic), or be conﬁned to human skin (anthropophilic). Dermatophyte infections usually present with skin (tinea corporis), scalp (tinea capitis), groin (tinea cruris), foot (tinea pedis) and/or nail (onychomycosis) involvement (Fig. 29.26). Diagnosis Skin scrapings, hair pluckings or nail clippings must be taken from areas of disease activity – typically, the advancing lesion edge for skin involvement, the crumbling dystrophic nail and subungual hyperkeratosis for nail involvement, and plucked hair from scalp or other affected hair-bearing sites – in order to conﬁrm the diagnosis by microscopy and culture (p. 1215). Management The azoles (ketoconazole, miconazole), triazoles (itraconazole, ﬂuconazole) and triallylamines (terbinaﬁne) are used most widely in fungal skin disease. Topical antifungals such as terbinaﬁne or miconazole may sufﬁce, although systemic treatment (terbinaﬁne, itraconazole or griseofulvin) may be required for stubborn or extensive disease and scalp or nail involvement. Indeed, prolonged courses of systemic treatment may be needed for nail involvement. The fungistatic agent griseofulvin, given orally, is usually used for fungal infection of scalp or nails in children in the UK, as it is the only drug licensed in children for this indication; outside the UK, and in adults, terbinaﬁne is usually the treatment of Management Most viral warts resolve spontaneously, although this may take years and active treatment is therefore often sought. However, asymptomatic warts generally should not be treated. Viral warts are particularly problematic and more recalcitrant to treatment in immunosuppressed patients following organ transplantation. Treatments are destructive. Salicylic acid or salicylic/lactic acid combinations and regular wart paring for several months are the most consistently effective treatments. For certain types of warts, such as ﬁliform facial warts, cryotherapy is generally the treatment of choice, but for common hand and foot warts salicylic acid wart paint should be used ﬁrst. Cryotherapy is usually the next step and is repeated 2–4-weekly. However, caution is required, particularly on the hands, as over-vigorous cryotherapy can lead to scarring, nail dystrophy and even tendon rupture. Periungual and subungual warts can be problematic and nail cutting and subsequent electrodessication may help. Several other therapies have been used for recalcitrant warts, including topical formaldehyde, podophyllotoxin, trichloroacetic acid, cantharidin, topical or systemic retinoids, intralesional bleomycin or interferon injections, and contact sensitisation with, for example, diphencyprone. Imiquimod and PDT may also be beneﬁcial, particularly for multiple warts in immunosuppressed patients, and laser therapy can have a role in some cases. Molluscum contagiosum Molluscum contagiosum is caused by a DNA poxvirus skin infection. It is most common in children over the age of 1 year, particularly those with atopic dermatitis. It also occurs frequently in immunosuppressed patients, including those with HIV (p. 306). Lesions are dome-shaped, ‘umbilicated’, skin-coloured papules with central punctum (Fig. 29.25). They are often multiple and found at sites of apposition, such as the side of the chest and the inner arm. Spontaneous resolution occurs but can take months. Prior to resolution, they often become inﬂamed and may leave small, atrophic scars. Destructive therapies may be painful and risk scarring, and the decision not to treat is often sensible. Gentle squeezing with forceps after bathing can hasten resolution. Topical salicylic acid, podophyllin, cantharidin, trichloroacetic acid, cryotherapy and curettage are alternatives. Efﬁcacy with imiquimod has also been reported. Fig. 29.24 Viral wart on the ﬁnger. The capillary loops are evident within the warty hyperkeratosis. Periungual sites are common and more difﬁcult to treat. Fig. 29.25 Molluscum contagiosum. Note the central umbilication.

1240 • DERMATOLOGY audouinii (anthropophilic)) shows minimal inﬂammation; M. canis (from dogs and cats) infections are more inﬂammatory and can be identiﬁed by green ﬂuorescence with Wood’s light. Kerion is a boggy, inﬂammatory area of tinea capitis, usually caused by zoophilic fungi such as cattle ringworm (T. verrucosum). Onychomycosis This is a fungal infection of the nail plate and the species involved are generally those that cause tinea capitis or tinea pedis. Onychomycosis usually presents with yellow/brown nail discoloration, crumbling, thickening and subungual hyperkeratosis. Usually, some nails are spared, there is asymmetry and toenails are more commonly involved. Candidiasis This is a superﬁcial skin or mucosal infection caused by a yeast-like fungus, Candida albicans (p. 300). Infections are usually not serious, unless the patient is immunocompromised, in which case deeper tissues can be involved (p. 316). The organism has a predilection for warm, moist environments and typical presentations are napkin candidiasis in babies, genital and perineal candidiasis, intertrigo and oral candidiasis. The diagnosis can be conﬁrmed by microscopy and culture of skin swabs, and treatment is with topical or systemic antifungals, such as azoles. Pityriasis versicolor Pityriasis versicolor is a persistent, superﬁcial skin condition caused by various species of the commensal yeast Malassezia, most commonly Malassezia globosa, but sometimes M. sympadialis or M. furfur, It occurs in men and women and in different races. It is found more frequently in warmer, humid climates, and is usually more severe and persistent in the immunocompromised. It is characterised by scaly, oval macules on the upper trunk, usually hypopigmented but occasionally hyperpigmented. Hypopigmentation is more obvious after sun exposure and tanning. The diagnosis can be conﬁrmed by microscopy of skin scrapings, showing ‘spaghetti and meatballs’ hyphae. Treatment with selenium sulphide or ketoconazole shampoos and topical or systemic azole antifungal agents is usually effective, although recurrence is common because these yeasts are skin commensals, and maintenance topical therapy may be required. Altered pigmentation can persist for months after treatment. choice. In addition to systemic antifungals, short courses of systemic or topical glucocorticoid are often used in kerion on the basis of reducing inﬂammation and possible hair loss. However, glucocorticoid use is controversial, with no good evidence of beneﬁt. Tinea corporis Tinea corporis should feature in the differential diagnosis of a red, scaly rash (p. 1217). Typically, lesions are erythematous, annular and scaly, with a well-deﬁned edge and central clearing. There may also be pustules at the active edge. Lesions are usually asymmetrical and may be single or multiple. The degree of inﬂammation is dependent on the organism involved and the host immune response. Microsporum canis (from dogs) and Trichophyton verrucosum (from cats) are common culprits. Ill-advised use of topical glucocorticoids can modify the clinical presentation and increase disease extension (tinea incognito). Tinea cruris This is extremely common worldwide and is usually caused by Trichophyton rubrum. Itchy, erythematous plaques develop in the groins and extend on to the thighs, with a raised active edge (Fig. 29.26A). Tinea pedis Tinea pedis or ‘athlete’s foot’ is the most common fungal infection in the UK and USA, and is usually caused by anthropophilic fungi, such as T. rubrum, T. interdigitale and Epidermophyton ﬂoccosum. It typically presents as an itchy rash between the toes, with peeling, ﬁssuring and maceration. Involvement of one sole or palm (tinea manuum) with ﬁne scaling is characteristic of T. rubrum infection. Vesiculation or blistering is more often seen with T. mentagrophytes. Tinea capitis This is a dermatophyte infection of scalp hair shafts and is most common in children. It typically presents as an area of scalp inﬂammation and scaling, often with pustules and partial hair loss (Fig. 29.26B). Infection may be within the shaft (endothrix, most commonly caused by T. tonsurans), causing patchy hair loss with broken hairs at the surface (‘black dot’), little inﬂammation and no ﬂuorescence with Wood’s light. Infection outside the hair shaft (ectothrix, most commonly caused by Microsporum Fig. 29.26 Dermatophyte infections. A Trichophyton rubrum infection of the groin (tinea cruris). B Microsporum canis infection of the scalp (tinea capitis). A B

Acne and rosacea • 1241

and cervical lymphadenopathy. The diagnosis is conﬁrmed by identifying the living louse or nymph on the scalp or on a black sheet of paper after careful ﬁne-toothed combing of wet hair following conditioner application. The empty egg cases (‘nits’) are easily seen on the hair shaft (p. 1210) and are hard to dislodge. Treatment is recommended for the affected individual and any infected household/school contacts. Eradication in school populations is difﬁcult because of poor adherence and treatment resistance. Topical treatment with dimeticone, permethrin, carbaryl or, less often, malathion in lotion or aqueous formulations may be effective and should be applied twice at an interval of 7–10 days. Rotational treatments within a community may avoid resistance. ‘Wet-combing’ (physical removal of live lice by regular combing of conditioned wet hair – ‘bug busting’) can sufﬁce but may be less effective than pharmacological treatments. Vaseline should be applied to eyelashes/brows twice daily for at least a fortnight. High-temperature washing of clothing and bedding is required. Treatment resistance and recurrence can be problematic. Body lice These are similar to head lice but live on clothing, particularly in seams, and feed on the skin. Poor hygiene and overcrowded conditions predispose. Itch, excoriation (deﬁnition: a linear ulcer or erosion resulting from scratching) and secondary infection occur. Dry-cleaning and high-temperature washing or insecticide treatment of clothes are required. Treatment options are as for head lice. For heavy infestation, oral ivermectin may be indicated. Pubic (crab) lice Usually, these are sexually acquired and very itchy. Management is as for head and body lice and whole-body treatment should be undertaken. Pubic hair may need to be shaved. Sexual and other close contacts should also be treated and patients should also be screened for sexually transmitted diseases. Acne and rosacea Acne vulgaris Acne is chronic inﬂammation of the pilosebaceous units. It is extremely common, generally starts during puberty and has been estimated to affect over 90% of adolescents. It is usually most severe in the late teenage years but can persist into the thirties and forties, particularly in females (Box 29.16). Infestations Scabies Scabies is caused by the mite Sarcoptes scabiei. It spreads in households and environments where there is intimate personal contact. The diagnosis is made by identifying the scabietic burrow (deﬁnition: a linear or curvilinear papule, caused by a burrowing scabies mite; p. 234 and Fig. 29.27) and visualising the mite (by extracting with a needle or using a dermatoscope). In small children, the palms and soles can be involved, with pustules. Pruritus is prominent. The clinical features include secondary eczematisation elsewhere on the body; the face and scalp are rarely affected, except in infants. Involvement of the genitals in males and of the nipples commonly occurs. Even after successful treatment, itch can continue and occasionally nodular lesions persist. Topical treatment of the affected individual and all asymptomatic family members/physical contacts is required to ensure eradication. Two applications 1 week apart of an aqueous solution of permethrin or malathion to the whole body, excluding the head, are usually successful. If there is poor adherence, immunosuppression or heavy infestation (crusted ‘Norwegian’ scabies), systemic treatment with a single oral dose of ivermectin is sometimes appropriate. Head lice Infestation with the head louse, Pediculus humanus capitis, is common. It is highly contagious and spread by direct head-tohead contact. Scalp itch leads to scratching, secondary infection Fig. 29.27 Scabies. A Burrows evident on the palm of the hand. B A mite still in its egg, seen on light microscopy of scrapings over a burrow. Note that the mite has only six legs, unlike adult mites, which have eight. A B 29.16 Acne in adolescence • Epidemiology: acne vulgaris is most common between the ages of 12 and 20. It often begins around 10–13 years of age, lasts 5–10 years and usually resolves by age 20–25. • Emotional effects: at all ages acne can have negative effects on self-esteem, but it is especially important to assess how it affects an adolescent. Depression and suicideal ideation may occur. The consequences (whether acne is objectively severe or not) can be devastating, leading to embarrassment, school avoidance, and life-long effects on ability to form friendships, attract partners, and acquire and keep employment. • Treatment: effective treatments aim to improve the condition, prevent worsening (including later scarring) and restore emotional well-being and self-esteem.

1242 • DERMATOLOGY • Acne excoriée: self-inﬂicted excoriations due to compulsive picking of pre-existing or imagined acne lesions. It usually affects teenage girls, and underlying psychological problems are common. • Secondary acne: comedonal acne can be caused by greasy cosmetics or occupational exposure to oils, tars or chlorinated aromatic hydrocarbons. Predominantly pustular acne can occur in patients using systemic or topical glucocorticoids, oral contraceptives, anticonvulsants, lithium or antineoplastic drugs, such as the epidermal growth factor receptor (EGFR) inhibitors. Most patients with acne do not have an underlying endocrine disorder but acne is a common feature of polycystic ovary syndrome (p. 658), which should be suspected if acne is moderate to severe and associated with hirsutism and menstrual irregularities. Virilisation should also raise suspicion of an androgen-secreting tumour. Investigations Investigations are not required in typical acne vulgaris. Secondary causes and suspected underlying endocrine disease or virilisation should be investigated (p. 657). Management Mild to moderate disease Mild disease is usually managed with topical therapy (p. 1225). If comedones predominate, then topical benzoyl peroxide or retinoids should be used. Benzoyl peroxide has both anticomedogenic and antiseptic effects. It is an irritant, which may contribute to the therapeutic response, but this can be minimised by adjusting treatment regimes. Azelaic acid may Pathogenesis The key components are increased sebum production; colonisation of pilosebaceous ducts by Propionibacterium acnes, which in turn causes inﬂammation; and hypercorniﬁcation and occlusion of pilosebaceous ducts (Fig. 29.28). Severity of acne is associated with sebum excretion rate, which increases at puberty. Both androgens and progestogens increase sebum excretion and oestrogens reduce it, but most patients with acne have normal hormone proﬁles. There may be a positive family history and there is high concordance in monozygotic twins, indicating that genetic factors are important, but the candidate genes are poorly deﬁned. Clinical features Acne usually affects the face and often the trunk. Greasiness of the skin may be obvious (seborrhoea). The hallmark is the comedone (deﬁnition: open comedones (blackheads) are dilated keratin-ﬁlled follicles, which appear as black papules due to the keratin debris; closed comedones (whiteheads) usually have no visible follicular opening and are caused by accumulation of sebum and keratin deeper in the pilosebaceous ducts – Fig. 29.28). Inﬂammatory papules, nodules and cysts occur and may arise from comedones (Fig. 29.29). Scarring may follow deep-seated or superﬁcial acne and may be keloidal. There are also distinct clinical variants: • Acne conglobata: characterised by comedones, nodules, abscesses, sinuses (deﬁnition: cavities or channels that permit the escape of pus or ﬂuid) and cysts, usually with marked scarring. It is rare, usually affecting adult males, and most commonly occurs on trunk and upper limbs. It may be associated with hidradenitis suppurativa (a chronic, inﬂammatory disorder of apocrine glands, predominantly affecting axillae and groins), scalp folliculitis and pilonidal sinus. • Acne fulminans: a rare but severe presentation of acne, associated with fever, arthralgias and systemic inﬂammation, with raised neutrophil count and plasma viscosity. It is usually found on the trunk in adolescent males. Costochondritis can occur. Fig. 29.28 Pathogenesis of acne. Rupture of obstructed sebaceous gland, with release of contents into dermis Increased sebum secretion rate Bacterial colonisation of duct and release of inflammatory mediators Occlusion of pilosebaceous duct Epidermis Sebaceous gland Hair follicle Fig. 29.29 Cystic acne in a teenager. A Before treatment. B After prolonged systemic antibiotic treatment. A B

Acne and rosacea • 1243

be prevented by adequate treatment of active acne. Keloid scars may respond to intralesional glucocorticoid and/or silicone dressings. Carbon dioxide laser, microdermabrasion, chemical peeling or localised excision can also be considered for scarring. UVB phototherapy or PDT can occasionally be used in patients with inﬂammatory acne who are unable to use conventional therapy, such as isotretinoin. There is no convincing evidence to support a causal association between diet and acne. The psychological impact of acne must not be under-estimated and should be considered in management decisions (Box 29.16). Rosacea This chronic inﬂammatory condition affects the central face and consists of flushing, erythema, papules, pustules and telangiectasiae. The cause is unknown. Rosacea is distinct from acne vulgaris; sebum excretion is normal and comedones are absent. The relative contribution of Demodex mite and cutaneous vasomotor instability to the pathogenesis of rosacea remains poorly deﬁned. Clinical features Rosacea most commonly affects fair-skinned, middle-aged females and can be exacerbated by heat, sunlight and alcohol. The convexities of nose, forehead, cheeks and chin are typically involved (Fig. 29.30). The condition is heterogeneous and intermittent flushing, followed by fixed erythema and telangiectasiae, predominates in some; in others, papules and pustules are prominent. Sebaceous gland hyperplasia and soft tissue overgrowth of the nose (rhinophyma) can occur, particularly in males. Conjunctivitis and blepharitis may also occur. Facial lymphoedema can be an added complication. Investigations Usually, no investigations are required and the diagnosis is obvious clinically. However, rosacea must be distinguished from acne vulgaris, systemic lupus erythematosus, photosensitivity disorders and seborrhoeic dermatitis (the latter may coexist with rosacea). also be used for mild acne and has both antimicrobial and anti-comedogenic action. Topical retinoids, in particular all-trans retinoic acid and adapalene, are widely employed for mild to moderate comedonal acne vulgaris. Treatment should be initially applied at low concentrations for short duration and increased as tolerated. Patients with mild inﬂammatory acne should respond to topical antibiotics, such as erythromycin or clindamycin, which can be used in combination with other treatments. For moderate inﬂammatory acne, a systemic tetracycline should be used at adequate dose for 3–6 months in the ﬁrst instance (p. 1227; Fig. 29.29B). Oxytetracycline must be taken on an empty stomach, in a dose of up to 1.5 g a day. It has a good safety proﬁle, even with long-term use, but adherence may be a challenge. Lymecycline is an alternative and is taken once daily, with or without food, thereby improving adherence. Doxycycline is another option but commonly causes photosensitivity. Minocycline is used less frequently, as it can cause hyperpigmentation, autoimmune hepatitis and drug-induced lupus, and monitoring is required. If the patient fails to respond, then alternatives include erythromycin or trimethoprim. In women with acne, oestrogen-containing oral contraceptives can be a useful adjunct, as they are associated with a small reduction in sebum production. Combined oestrogen and antiandrogen (such as cyproterone acetate) contraceptives may provide additional efﬁcacy, particularly in women with acne and hirsutism, as seen in polycystic ovary syndrome (p. 658). Patients should be referred for consideration of isotretinoin (13-cis-retinoic acid) if there is a failure to respond adequately to 6 months of therapy with these combined systemic and topical approaches (p. 1227). Moderate to severe disease Isotretinoin (13-cis-retinoic acid) has revolutionised the treatment of moderate to severe acne that has not responded adequately to other therapies. It has multifactorial mechanisms of action, with reduction in sebum excretion by over 90%, follicular hypercornification, P. acnes colonisation and inflammation. Oral isotretinoin is usually used at a dose of 0.5–1 mg/kg over 4 months. Sebum excretion typically returns to baseline within a year after treatment cessation, although clinical beneﬁt is usually longer-lasting. Many patients will not require further treatment, although a second or third course of isotretinoin may be needed. A low-dose continuous or intermittent-dose regimen may occasionally be considered for a longer duration in patients who relapse after a higher-dose regimen, and may also be beneﬁcial for older females with persistent acne. Combination with systemic glucocorticoid may be required in the short term for severe acne, in order to minimise the risk of disease ﬂare early in the treatment course. Thorough screening and monitoring are required, given the side-effect proﬁle of isotretinoin, particularly with respect to teratogenicity and possible mood disturbance (p. 1227). Pregnancy must be avoided during treatment and for a minimum of 2 months after drug cessation, and a strict pregnancy prevention programme and regular pregnancy testing are required. Depression and suicide have been reported in association with isotretinoin, although a causal role has not been established. However, pre-drug screening for depressive symptoms should be undertaken and mood monitored during therapy. Other treatments and physical measures Intralesional injections of triamcinolone acetonide may be required for inﬂamed acne nodules or cysts, which can also be incised and drained, or excised under local anaesthetic. Scarring may Fig. 29.30 Rosacea. Typical erythematous papulopustular rosacea affecting the mid-face.

1244 • DERMATOLOGY are commonly positive, particularly for staphylococci, although clinical assessment is required in order to ascertain whether swab results are of clinical signiﬁcance and whether antibiotic treatment is required. Individuals with atopic eczema have an increased susceptibility to herpes simplex virus (HSV) and are at risk of developing a widespread infection, eczema herpeticum. The presence of small, punched-out lesions on a background of worsening eczema suggests the possibility of secondary HSV infection. Skin scrapings to rule out secondary fungal infection should also be considered. Total IgE and speciﬁc IgE tests and skin prick tests are not routinely undertaken in atopic eczema as they are not usually helpful, although they may occasionally be indicated in some cases as directed by the history. Patch tests should be performed if contact allergic dermatitis is suspected (see Box 29.22 below). Skin biopsy is not usually required unless there is diagnostic doubt. Management A general approach to the management of eczema includes advice, education and support, required for patients with eczema of any type (Fig. 29.31). Input from patient support groups, such as the National Eczema Society in the UK, can be very helpful. Intensive and prolonged treatments are often required and chronic eczema can have a major and devastating adverse impact on personal and family lives. Emollients and topical glucocorticoids are mainstays of treatment for all eczema types, in order to improve skin barrier function, limit transepidermal water loss and reduce inﬂammation. Emollients can be used as bath additives and soap substitutes, and applied directly to the skin, often combined with antiseptics. Sedative antihistamines are useful if sleep is interrupted but non-sedating antihistamines are ineffective, as the itch of eczema is not primarily mediated by histamine. Ointments are preferred for chronic eczema, whereas cream- or lotion-based treatment may be more appropriate for acute eczema (see Box 29.11). Treatment is once to twice daily (p. 1225). Hydrocortisone (1%) or clobetasone butyrate is generally used on the face, with more potent glucocorticoids restricted to trunk and limbs (see Box 29.12). A good strategy is to employ an intensive regimen with more potent glucocorticoids initially and then taper use according to response. A key principle is to use the least potent glucocorticoid that is effective for the shortest possible time. The patient should be given instructions on how much to apply, using the ﬁngertip unit for guidance (a strip of glucocorticoid cream on distal phalanx pulp should cover two palm-size areas). It is also important to monitor glucocorticoid use and the easiest way to do this is ask how long it takes to use a speciﬁc size of glucocorticoid tube. The side-effects of topical glucocorticoid therapy need to be considered but glucocorticoid phobia and under-treatment of eczema are often more of a problem than over-treatment. Particular care should be taken on certain sites, such as the face and ﬂexures, and in children and the elderly (see Box 29.2 and Fig. 29.10, p. 1226). The clinical features of eczema inﬂuence the choice of topical treatment. For example, appropriate treatment of acute exudative eczema could be with potassium permanganate soaks, emollients and topical glucocorticoids under wet wraps. Chronic eczema may be best treated with a potent topical glucocorticoid in an ointment formulation and occlusion with a paste bandage to ease itching and scratching. The topical calcineurin inhibitors tacrolimus and pimecrolimus may be useful glucocorticoid-sparing agents for eczema, particularly on the face; they cause local cutaneous immunosuppression. 29.18 The clinical morphology of eczema Acute • Erythema, oedema, usually typically ill deﬁned • Papules, vesicles and occasionally bullae • Exudation, ﬁssuring • Scaling Chronic • May be as above but less oedema, vesiculation and exudate • Licheniﬁcation: skin thickening with pronounced skin markings, secondary to chronic rubbing and scratching • Fissures (deﬁnition: slit-shaped deep ulcers), excoriations • Dyspigmentation: hyper- and hypopigmentation can occur 29.17 Classiﬁcation of eczema Endogenous • Atopic, seborrhoeic Exogenous • Irritant, allergic, photo-allergic, chronic actinic dermatitis Characteristic patterns and morphology • Asteatotic, discoid, gravitational, lichen simplex, pompholyx Management Mild disease may respond to topical antimicrobials, such as metronidazole or azelaic acid. Topical ivermectin may be beneﬁcial in some cases, supporting a contributory role of Demodex in pathogenesis. Tetracycline or erythromycin for 3–6 months is usually effective in inﬂammatory pustular disease resistant to topical therapy (p. 1227). Relapse may require intermittent or chronic antibiotic use. Erythema and telangiectasiae do not usually respond well to antibiotics but vascular laser therapy may be effective. Topical vasoconstrictors, such as the α2-adrenoceptor agonist brimonidine, may be of beneﬁt in some cases where erythema and telangiectasiae predominate. Systemic isotretinoin may be helpful in severe resistant disease and rhinophyma may require laser therapy or surgery. Eczemas The term ‘eczema’ derives from the Greek word ‘to boil’ and is synonymous with the other descriptive term, ‘dermatitis’. Eczema describes a clinical and histological pattern, which can be acute or chronic and has several causes. Acutely, epidermal oedema (spongiosis) and intra-epidermal vesiculation (producing multilocular blisters) predominate, whereas with chronicity there is more epidermal thickening (acanthosis). Vasodilatation and T-cell lymphocytic inﬁltration of the upper dermis also occur. Clinical features There are several patterns of eczema (Box 29.17) but the clinical features are similar, irrespective of the cause (Box 29.18). Some subtypes of eczema have speciﬁc distinguishing features and these are discussed in more detail below. Investigations Bacterial and viral swabs for microscopy and culture are important in suspected secondary infection. Bacterial swabs

Eczemas • 1245

Fig. 29.31 General management approaches: atopic eczema. (PDE = phosphodiesterase; PUVA = psoralen-ultraviolet A; UVA1 = ultraviolet A1; UVB = narrowband ultraviolet B) Next steps Narrowband UVB, PUVA/UVA1 (depending on availability, patient age etc.) Initial steps Accurate diagnosis Establishing severity and impact Removal of triggers and treatable causes, such as infection, and allergens Education and support of patient and family Psychological support General treatment approach Emollients, topical glucocorticoids, topical calcineurin inhibitors, sedating antihistamines Consider bandages, wet wraps Inpatient admission If feasible, for intensive inpatient care ± Phototherapy ± Systemic treatment Immunosuppression Prednisolone, azathioprine, ciclosporin, methotrexate Systemic retinoids Acitretin or alitretinoin for hand eczema For severe resistant disease Dupilumab (Trials in progress with other biologics and PDE inhibitors) Consider Initial burning and stinging may limit use but are usually transient side-effects. Bacterial and viral skin infection risk may be increased due to immunosuppression. Caution should be employed with sun exposure and these agents should not be used in combination with phototherapy because of their immunosuppressive effects. Atopic eczema This is the most common subtype of eczema. The prevalence has increased dramatically since the early 1980s, and the disease now affects at least 20% of schoolchildren and 5–10% of adults in the UK. Pathogenesis Generalised prolonged hypersensitivity to common environmental antigens, such as pollen and house-dust mite, is the hallmark of atopy, in which there is a genetic predisposition to produce excess IgE. Atopic individuals manifest one or more of a group of diseases that includes asthma, hay fever, food and other allergies, and atopic eczema. Genetic factors play an important role in all of these conditions, supported by higher concordance of atopic disease in monozygotic twins compared with dizygotic twins. Filaggrin gene mutations increase the risk of developing atopic eczema by more than threefold, emphasising the importance of epidermal barrier impairment in this disease. Other genes are also likely to be implicated, with many other susceptibility loci identiﬁed, although these studies require further replication. Decreased skin barrier function may also allow greater penetration of allergens through the epidermis, and thus cause immune stimulation and subsequent inﬂammation. The interaction between genes and environment is important; it has been estimated that 60–80% of individuals are genetically susceptible to the induction of IgE-mediated sensitisation to environmental allergens such as food and animal hair. Eczema is characterised by inﬁltration of Th2 cells, which are known to play a role in activating mast cells and eosinophils, as well as stimulating IgE production by IgE-producing B cells. The contributing roles of the microbiome are also being explored. Thus, the pathogenesis of atopic eczema is complex and multifactorial, involving an interplay of contributing factors. Clinical features Atopic eczema is extremely itchy and scratching accounts for many of the signs (Fig. 29.32). Widespread cutaneous dryness (also known as xeroderma or xerosis) is another feature. The distribution and character of the rash vary with age (Box 29.19). Complications are listed in Box 29.20. Investigations The diagnosis of atopic eczema is made using clinical criteria (Box 29.21). Interestingly, while most patients with atopic eczema have raised total IgE levels and IgE-speciﬁc antibodies, this is not a prerequisite for the diagnosis, as a signiﬁcant minority have normal levels of IgE.

1246 • DERMATOLOGY Management The general principles of management are as described in Figure 29.31. Emollients and topical glucocorticoids, tar and ichthammol paste bandages, or wet wraps in children, are often required. Topical calcineurin inhibitors may be used as glucocorticoid-sparing agents but should not be used in infected eczema. Secondary infection should be treated but positive skin swabs in isolation, without clinical evidence of infection, do not necessarily require treatment with antibiotics, although antiseptics would be appropriate. Sedating antihistamines may help to break the itch/scratch cycle. Identiﬁcation and avoidance of allergens are important. Phototherapy is generally the next step, if topical therapies are insufﬁcient (see Fig. 29.31). Narrowband UVB is usually the initial phototherapy of choice and can also be used in children. PUVA or UVA1 can also be chosen if UVB is ineffective, although mainly in adults as PUVA is generally avoided in children. Localised phototherapy may be used for eczema on hands and feet and PUVA may be more effective in that situation. Systemic immunosuppression with, for example, oral glucocorticoids, intermittent ciclosporin, azathioprine or methotrexate may be needed if the response to topical therapies and phototherapy is inadequate. Systemic retinoids, such as acitretin or alitretinoin, may be indicated: for example, in hand and foot eczema. Encouraging early trial data are emerging to support the use of dupilumab, which blocks IL-4Rα, and the anti-IL-13 agents lebrikizumab and tralokinumab in atopic eczema. Phosphodiesterase 4 inhibitors are also being investigated. Seborrhoeic eczema This is an erythematous scaly rash affecting the scalp (dandruff), central face, nasolabial folds, eyebrows, central chest and upper back. It is associated with, and may be due to, overgrowth of Malassezia yeasts. When severe, it may resemble psoriasis. Severe or recalcitrant seborrhoeic eczema can be a marker of immunodeﬁciency, including HIV infection (p. 314). Topical azoles, such as ketoconazole shampoo and cream, often combined with mild glucocorticoid, are mainstays. Treatment often needs to be repeated due to disease recurrence. Discoid eczema Discoid eczema, which is also known as nummular eczema, is common and characteristically consists of discrete, coin-shaped eczematous lesions, which are often impetiginised and most commonly occur on the limbs of men. It is an eczema type that can be due to any chronic itchy condition, whether primarily of the skin or secondary to an underlying disease. Initial management should include topical antiseptics, in addition to emollients and topical glucocorticoids. Judicious antibiotic use may also be required for acute ﬂares. 29.21 Diagnostic criteria for atopic eczema Itchy skin rash (or history of itch or rubbing from parent) and at least three of the following: • History of involvement of skin creases (or cheeks if < 4 years) • History of atopic disease (asthma, hay fever) (or in a ﬁrst-degree relative if < 4 years) • Dry skin (xeroderma) • Visible ﬂexural eczema (cheeks, forehead, outer limbs if < 4 years) • Onset in ﬁrst 2 years of life 29.20 Complications of atopic eczema Secondary infection Bacterial • Staphylococcus aureus most common Viral • Herpes simplex virus can cause a widespread severe eruption – eczema herpeticum • Papillomavirus and molluscum contagiosum are more common in atopic eczema, especially if treated with topical glucocorticoids Increased susceptibility to irritants • Defective barrier function Increased susceptibility to allergy • Food allergy – mainly relevant in infants; eggs, cow’s milk protein, nuts, ﬁsh, wheat and soya may cause an immediate reaction with angioedema and/or urticaria rather than exacerbation of eczema • Anaphylaxis in severe allergy • Increased risk of sensitisation to type IV allergens because of impaired barrier function Impact on life and health • Poor sleep, loss of schooling, behavioural difﬁculties, failure to thrive in children • Impact on sleep, work, relationships, hobbies, psychology and quality of life in adults 29.19 Atopic eczema: distribution and character of rash Babies and infants • Often acute and facial involvement prominent • Trunk involved but nappy area usually spared Children • Flexures: behind knees, antecubital fossae, wrists and ankles Adults • Face and trunk usually involved, limb involvement not restricted to ﬂexures • Licheniﬁcation common Fig. 29.32 Atopic eczema. A This patient had life-long chronic atopic eczema and experienced a generalised ﬂare of disease triggered by infection. B Licheniﬁcation of chronic ﬂexural eczema secondary to rubbing and scratching. B A

Psoriasis and other erythematous scaly eruptions • 1247

in combination with topical glucocorticoids. Patients must be advised to use caution with ﬂammable emollients and to avoid bathroom slippages related to emollients on ﬂoor and feet, and this is particularly relevant for the elderly. Gravitational eczema Gravitational or stasis eczema occurs on the lower legs and is often associated with signs of venous insufﬁciency: oedema, loss of hair, induration, lipodermatosclerosis and ulceration. Emollients should be used and topical glucocorticoids should be applied to eczematous areas but not to ulcers. There is a high risk of sensitisation to topical preservatives (such as chlorocresol), antibiotics (such as neomycin) and bandages (such as rubber additives). Oedema and ulceration are treated by leg elevation and compression bandages (p. 1224). Lichen simplex Licheniﬁcation of eczema occurs secondary to chronic rubbing and scratching, and lichen simplex is a localised form. Common sites include the neck, lower legs and anogenital region. Treatment with emollients and very potent topical glucocorticoids may be required, often impregnated in tape or with occlusion. Pompholyx Intensely itchy vesicles and bullae occur on the palms, palmar surface and sides of the ﬁngers and soles. Pompholyx may have several causes, which include atopic eczema, irritant and contact allergic dermatitis and fungal infection. The underlying cause must be treated or removed. Psoriasis and other erythematous scaly eruptions Psoriasis Psoriasis is a chronic inﬂammatory, hyperproliferative skin disease. It is characterised by well-deﬁned, erythematous scaly plaques, Irritant eczema Detergents, alkalis, acids, solvents and abrasives are common irritants. Strong irritants have acute effects, whereas weaker irritants commonly cause chronic eczema, especially of the hands, after prolonged exposure. Individual susceptibility varies and the elderly, atopic and fair-skinned are predisposed. Irritant eczema accounts for most occupational cases of eczema and is a signiﬁcant cause of time off work. Irritant avoidance, including protective clothing (such as gloves), is essential. Emollients and topical glucocorticoids are indicated. Allergic contact eczema This occurs due to a delayed hypersensitivity reaction following contact with antigens or haptens. Previous allergen exposure is required for sensitisation and the reaction is speciﬁc to the allergen or closely related chemicals. Common allergens are listed in Box 29.22. Allergy persists indeﬁnitely and eczema occurs at sites of allergen contact and can secondarily spread beyond this. The distribution of eczema can be very informative with regard to possible culprits. There are many recognisable patterns of sites of eczema involvement, such as earlobes, wrists and umbilicus due to contact with nickel in earrings, watches and jeans studs; hands and wrists due to rubber gloves; and upper eyelids due to colophony from rubbing of the eyes in nail varnish wearers. Oedema may also be a feature (Fig. 29.33). Allergen avoidance is key and may involve a change of occupation, recreational activities or hobbies. It is important to ensure that patients are fully informed as to the nature and likely occurrence of allergens and good detective work is required to scrutinise lifestyle and daily activities. Treatment with emollients and topical glucocorticoids helps but will not sufﬁce if there is continued allergen exposure. Asteatotic eczema This occurs in dry skin and is common in the elderly. Low humidity caused by central heating, over-washing, diuretics and cholesterol-lowering drugs predispose. The most common site is the lower legs, and a ‘crazy paving’ pattern of ﬁne ﬁssuring on an erythematous background is seen. Emollients are a mainstay, Fig. 29.33 Allergic contact eczema. This was caused by the application of an antihistamine cream. The acute eczematous reaction and bilateral periorbital oedema are typical. 29.22 Common type IV delayed hypersensitivity allergens Allergen Source Nickel Jewellery, jean studs, bra clips, watches Dichromate Cement, leather, matches Rubber chemicals Clothing, shoes, rubber gloves, tyres Colophony Sticking plaster, collodion, nail varnish Paraphenylenediamine Hair dye, clothing, tattoos Balsam of Peru Perfumes, citrus fruits, shower/bath products Neomycin, benzocaine Topical medications Parabens Preservative in cosmetics and creams Wool alcohols Lanolin, cosmetics, creams Epoxy resin Resin adhesives, glues Methyl- and chloromethylisothiazolinone Preservatives, with increasing numbers of cases of allergy reported

1248 • DERMATOLOGY and IL-23), TNF-α, IFN-γ and intercellular adhesion molecule (ICAM)-1 • vascular changes, with tortuosity of dermal capillary loop vessels and release of mediators, such as vascular endothelial growth factor (VEGF). The initiating event for psoriasis is unknown. Disordered cell proliferation is a key feature; this was previously thought to be the primary event but is now considered to be secondary to inﬂammatory change. The transit time for keratinocyte migration, from basal layer to shedding from stratum corneum, is shortened from approximately 28 to 5 days, so that immature cells reach the stratum corneum prematurely. Proliferation rate is also increased in non-lesional skin but to a lesser extent. Similarly, even the clinically unaffected nails of patients with psoriasis grow more quickly than those of controls. While immunological factors clearly play a key role in psoriasis, the precise mechanisms of disease initiation and the sequence of events that lead to psoriasis are not fully deﬁned. particularly affecting extensor surfaces, scalp and nails, and usually follows a relapsing and remitting course. Psoriasis affects approximately 1.5–3% of Caucasians but is less common in Asian, South American and African populations. It occurs equally in both sexes and at any age; although it is uncommon under the age of 5 years, more than 50% of patients present before the age of 30 years. The age of onset follows a bimodal distribution, with an early-onset type in the teenage or early adult years, often with a family history of psoriasis, a more severe disease course and strong HLA association. The later-onset type is typically seen between 50 and 60 years, usually without a family history and with a less severe disease course. Pathogenesis Both genetic and environmental factors are important. Twin studies show concordance rates of 60–75% and 15–20% for psoriasis arising in monozygotic and dizygotic twins, respectively. The age at onset and severity of disease are often similar in familial cases. If one parent has psoriasis, the chance of a child being affected is about 15–20%; if both parents have the disease, this rises to 50% and the risk is increased further if a sibling also has the disease. Variants of the HLA-C region within the major histocompatibility complex (MHC) on chromosome 6 account for almost half of the heritability of psoriasis. However, at least 70 other loci are implicated, with susceptibility variants that lie within or close to genes involved in regulating epidermal barrier function, antigen presentation, cytokine production, notably IL-13 and IL-23, T-cell differentiation (especially Th-1 and Th-17 subsets) and nuclear factor kappa B (NFκB) signalling. Some of the loci that predispose to psoriasis overlap with those implicated in Crohn’s disease, ankylosing spondylitis and psoriatic arthritis. Environmental triggers for psoriasis are shown in (Box 29.23). Although the theory is controversial, stress may exacerbate psoriasis in susceptible individuals and psoriasis is itself a cause of psychological stress. Likewise, there is a higher incidence of smoking and heavy alcohol consumption in patients with psoriasis but it is unclear whether this is cause or effect. There is also an association between psoriasis and metabolic syndrome (p. 730). The histological changes of psoriasis are shown in Figure 29.34. The main features are: • keratinocyte hyperproliferation and abnormal differentiation, leading to retention of nuclei in the stratum corneum • inﬂammation, with a T-cell (mainly activated Th-1 and Th-17) lymphocytic inﬁltrate and release of cytokines and adhesion molecules, such as interleukins (including IL-17 Fig. 29.34 The histology of psoriasis. Upper dermal T-lymphocyte infiltrate Irregular thickening of epidermis Dilated and tortuous capillary loops Micro-abscess Supra-papillary plate thinning Hyperkeratosis Parakeratosis Keratin layer Epidermis Dermis Psoriasis Normal 29.23 Exacerbating factors in psoriasis Trauma • Lesions can appear at sites of skin trauma, such as scratches or surgical wounds (Köbner isomorphic phenomenon) Infection • β-haemolytic streptococcal throat infections often precede guttate psoriasis (see Fig. 29.35C) • Severe psoriasis may be the initial presentation of HIV infection Sunlight • Psoriasis may occur or worsen after sun exposure, mainly due to Köbnerisation at sites of sunburn or polymorphic light eruption Drugs • Antimalarials, β-adrenoceptor antagonists (β-blockers), lithium, NSAIDs and TNF-α inhibitors can exacerbate psoriasis • ‘Rebound’ ﬂare of psoriasis may occur after withdrawal of systemic glucocorticoids or potent topical glucocorticoids. Rebound psoriasis is often unstable and may be pustular Psychological factors • Anxiety and stress may exacerbate psoriasis in predisposed individuals (NSAID = non-steroidal anti-inﬂammatory drug; TNF-α = tumour necrosis factor alpha)

Psoriasis and other erythematous scaly eruptions • 1249

a streptococcal throat infection and evolves rapidly. Individual lesions are droplet-shaped, small (usually less than 1 cm in diameter), erythematous, scaly and numerous. An episode of guttate psoriasis may clear spontaneously or with topical treatment within a few months, but UVB phototherapy is often required and is highly effective. Guttate psoriasis often heralds the onset of plaque psoriasis in adulthood. Erythrodermic psoriasis Generalised erythrodermic psoriasis is a medical emergency (Fig. 29.35D). Pustular psoriasis Pustular psoriasis may be generalised or localised. Generalised pustular psoriasis is uncommon, unstable and life-threatening. It will often emerge in the context of plaque disease and the onset is usually sudden, with large numbers of small, sterile pustules on an erythematous background, often merging into sheets, with waves of new pustules in subsequent days. The patient is usually febrile and systemically unwell, and this must be dealt with as a medical emergency (p. 1224). Unstable pustular psoriasis may be precipitated as a rebound phenomenon following either topical or systemic glucocorticoid use in a patient with psoriasis. Localised pustular psoriasis of the palms and soles (palmoplantar pustulosis) is more common, chronic and closely associated with smoking; small, sterile pustules and erythema develop and resolve with pigmentation and scaling (p. 1210). A localised form of sterile pustulosis of a few digits (acropustulosis) can also occur. It is unclear whether these localised forms of pustulosis are truly psoriatic. Arthropathy Between 5% and 10% of individuals with psoriasis develop an inﬂammatory arthropathy, which can take on a number of patterns (p. 1035). Joint involvement is more likely in patients with psoriatic nail disease. Clinical features Psoriasis has several different presentations (Fig. 29.35). Plaque psoriasis This is the most common presentation and usually represents more stable disease. The typical lesion is a raised, well-demarcated erythematous plaque of variable size (Fig. 29.35A). In untreated disease, silver/white scale is evident and more obvious on scraping the surface, which reveals bleeding points (Auspitz sign). The most common sites are the extensor surfaces, notably elbows and knees, and the lower back. Others include: • Scalp: involvement is seen in approximately 60% of patients. Typically, easily palpable, erythematous scaly plaques are evident within hair-bearing scalp and there is clear demarcation at or beyond the hair margin. Occipital involvement is common and difﬁcult to treat. Less often, ﬁne diffuse scaling may be present and difﬁcult to distinguish from seborrhoeic dermatitis. Involvement of other ‘seborrhoeic sites’, such as eyebrows, nasolabial folds and the pre-sternal area, is not uncommon and again may be confused with seborrhoeic dermatitis. Temporary hair loss can occur but permanent loss is unusual. • Nails: involvement is common, with ‘thimble pitting’, onycholysis (separation of the nail from the nail bed, Fig. 29.35B), subungual hyperkeratosis and periungual involvement (p. 1210). • Flexures: psoriasis of the natal cleft and submammary and axillary folds is usually symmetrical, erythematous and smooth, without scale. • Palms: psoriasis of the palms can be difﬁcult to distinguish from eczema. Guttate psoriasis This is most common in children and adolescents and is often the initial presentation (Fig. 29.35C). It may present shortly after Fig. 29.35 Psoriasis. A Chronic plaque psoriasis, most prominent on extensor surfaces. B Nail involvement, with coarse pitting and separation from the nail plate (onycholysis). C Guttate psoriasis following a streptococcal throat infection. D Erythrodermic psoriasis. A C D B

1250 • DERMATOLOGY If topical treatment is insufﬁcient, then UVB phototherapy or PUVA should usually be the next step. If the patient continues to have active disease or early recurrence, then the addition of systemic retinoid such as acitretin to UVB or PUVA can be effective. Alternatively, immunosuppressants, such as methotrexate or ciclosporin, may be required. For difﬁcult treatment-resistant disease, fumaric acid esters, apremilast and biologics should be considered (p. 1005 and Fig. 29.37). The active component of fumaric acid ester therapy is dimethyl fumarate and efﬁcacy in psoriasis has been conﬁrmed. Common adverse effects are ﬂushing and diarrhoea. Lymphopenia is also expected at effective doses. Apremilast is indicated for moderate to severe psoriasis resistant to standard measures. Of the biological agents, the anti-TNF-α agents (etanercept, inﬂiximab, adalimumab or golimumab), ustekinumab (an inhibitor Investigations Skin biopsy is not usually required but may be performed if there is diagnostic doubt. An infection screen, particularly throat swab and/or serology for recent streptococcal infection, may be informative in guttate psoriasis. Assessment of impact on life using the DLQI and disease extent using PASI (Psoriasis Area and Severity Index, p. 1211) is essential. Due to the association of psoriasis with metabolic syndrome, comorbidities and cardiovascular risk factors should be assessed and managed (p. 730). HIV testing should be considered in severe or recalcitrant psoriasis. Management Counselling about diagnosis and management of skin involvement and other comorbidities is paramount. Information and services must be available for patients. Psoriasis can have a major impact on all aspects of life and this must not be under-estimated. Reassurance is also needed, as the condition is generally not life-threatening. Advice regarding reduction in risk factors for cardiovascular disease should be given (smoking cessation, reduction of alcohol intake, adequate exercise and a normal body mass index). Associated diseases, such as hypertension and diabetes, should be treated. Patients need to be involved in their own management, as the disease is usually chronic and the beneﬁt/risk proﬁle of treatments must be discussed and tailored to individuals. The endpoint for treatment also needs to be discussed because complete disease clearance may not be practical or appropriate and patients vary considerably in their treatment requirements. Extent of disease and impact on quality of life must be taken into account. Patient adherence to topical and systemic therapies is essential and dependent on the treatment practicalities. The treatment approach generally follows a stepwise progression, with treatment categories broadly summarised (Fig. 29.36). Topical treatments, including emollients, are the first-line approach. Vitamin D receptor agonists, such as calcipotriol, calcitriol and tacalcitol, are often used as ﬁrst-line topical treatment. The mechanism of action includes increased differentiation and reduction of proliferation, reducing plaque scale and thickness. Calcipotriol is most widely used and can be applied once to twice daily; if less than 100 g of ointment is used each week, there is no risk of hypercalcaemia. Vitamin D analogues can cause irritation but this is often temporary. Topical glucocorticoids may be required in the management of psoriasis, particularly at ﬂexural or facial sites, and may be alternated or combined with vitamin D analogues. However, safe, appropriately supervised and judicious use is necessary, with awareness of the potential risk of rebound unstable or pustular psoriasis with glucocorticoid over-use or sudden cessation. Dithranol and coal tar are effective and, like vitamin D analogues, work by increasing differentiation and inhibiting proliferation. Although often effective, they are messy and time-consuming. Modiﬁed versions of Goeckerman’s regimen (the combination of coal tar and UVB) are still used, but coal tar has a characteristic odour and can be irritant. Short-contact dithranol therapy at relatively high concentrations applied for 15–30 minutes can be used but causes brown staining of skin and purple discoloration of light hair. In recent years, efforts have been made to improve the tolerance of tar and dithranol preparations, but at reduced efﬁcacy. Overall, the use of tar and dithranol has reduced in recent years but they can be highly effective in selected patients. Fig. 29.36 General management approaches: psoriasis. (IL = interleukin; PUVA = psoralen–ultraviolet A; TNF-α = tumour necrosis factor alpha; UVB = ultraviolet B) Consider Anti-IL-17 Secukinumab Ixekizumab Brodalumab Initial steps Accurate diagnosis Establishing severity and impact Removal or treatment of triggers Identification of comorbidities (especially in severe disease) Education, support, psychological input General treatment approach Emollients, topical vitamin D analogues, tars, dithranol, retinoids ± Topical glucocorticoids, e.g. flexural sites Next steps Narrow-band UVB (or excimer laser, if available, for localised disease), PUVA Inpatient admission If feasible, for intensive inpatient care ± Phototherapy/PUVA ± Systemic treatment Systemic agents Methotrexate, ciclosporin, acitretin (can add to phototherapy or PUVA) May consider Fumaric acid esters/apremilast For resistant disease Biologics Anti-TNF-α Infliximab Etanercept Adalimumab Anti-IL-12/23 Ustekinumab Anti-IL-23 Guselkumab

Psoriasis and other erythematous scaly eruptions • 1251

Mucosal involvement is rare. There is a small risk of recurrence. Symptomatic relief can be achieved with emollients and mild topical glucocorticoids. Post-inﬂammatory hyperpigmentation can supervene, particularly in darker skin types. Pityriasis lichenoides chronica This is rare but typically presents within the ﬁrst three decades of life. The aetiology is unclear but the condition is part of a spectrum and remits spontaneously. The more acute variety (pityriasis lichenoides et varioliformis acuta, PLEVA) presents as crops of papules that rapidly evolve with central necrosis, each attack lasting up to 3 months. The more chronic variety presents as a persistent, widespread, scaly eruption. Characteristically, lesions are brown papules with a mica-like scale (‘cornﬂake’). The condition ﬂuctuates but can persist for months or years. Emollients, topical glucocorticoids and long-term oral erythromycin can occasionally be helpful. UVB phototherapy or PUVA is usually effective, although recurrences are high. Drug eruptions It is essential to consider a drug cause in anyone presenting with an erythematous maculopapular or papulosquamous eruption, and a careful drug history is critical (p. 1265). Exfoliation (‘peeling’) and post-inﬂammatory hyper- or, less commonly, hypopigmentation can occur. Other causes Secondary syphilis (p. 337), pityriasis versicolor (p. 1240) and fungal infection with Tinea corporis (p. 1240) can all cause an of IL-12 and IL-23), guselkumab (an IL-23 inhibitor) and secukinumab or ixekizumab (an IL-17 inhibitor) may all be effective and this is a rapidly evolving ﬁeld. More details of the mechanisms of action and adverse effects of these agents are provided on page 1006. Individualised management is essential. For example, a patient with localised plaque psoriasis on elbows, knees and sacrum should respond to topical treatment only, whereas someone with guttate psoriasis is likely to need phototherapy as a ﬁrst-line approach because of difficulties in topical drug application in extensive disease. A patient with extensive chronic plaque psoriasis and signiﬁcant arthropathy would be better suited to a systemic drug, such as methotrexate, than phototherapy, which would be unlikely to improve joint symptoms. Thus, whilst a stepwise general approach to management (see Fig. 29.36) may offer guidance, the correct choice for any given patient must be determined on an individual basis. Pityriasis rosea This is an acute, self-limiting exanthem that particularly affects young adults and occurs worldwide, with a slight female predominance. It usually presents in spring and summer, although no infective agent has been identiﬁed and its aetiology is unknown. It is characterised by the appearance of a ‘herald patch’, an oval lesion (1–2 cm) with a central pinkish (salmon-coloured) centre, a darker periphery and a characteristic collarette of scale. It is followed 1–2 weeks later by a widespread papulosquamous eruption, which is typically arranged in a symmetrical ‘ﬁr tree’ pattern on the trunk. Individual lesions also have a collarette of scale. An inverse variant with ﬂexural involvement can occur. Fig. 29.37 Developments in understanding of key pathways and drug targets in psoriasis. Other drug targets are also under development, such as Janus kinase (JAK) inhibitors (tofacitinib and baricitinib) and sphingosine-1-phosphate receptor (S1PR1) antagonists (ponesimod). This diagrammatic image is illustrative of key pathways and drug targets but is not comprehensive. (AMP = adenosine monophosphate; cAMP = cyclic adenosine monophosphate; GM-CSF = granulocyte macrophage colony-stimulating factor; IL = interleukin; TNF-α = tumour necrosis factor alpha) Infliximab Etanercept Adalimumab Golimumab Dendritic cell Neutrophil GM-CSF T cell IL-12 IL-23 IL-23 Secukinumab Ixekizumab Infliximab Etanercept Adalimumab Golimumab Ustekinumab Guselkumab Brodalumab Phosphodiesterase 4 Adenylyl cyclase Keratinocyte ↑Inflammatory cytokines TNF-α IFN-γ IL-17A IL-17R IL-17A TNF-α Apremilast cAMP AMP Gene activation AC AC

1252 • DERMATOLOGY presents as an inﬂammatory scarring alopecia, often with tufting of residual hairs. The classical presentation of lichen planus is unmistakable, but less common atypical variants, which include annular, atrophic, actinic, linear, bullous, follicular, pigmented and ulcerative types, can be a diagnostic challenge. Investigations A skin biopsy should be performed if there is diagnostic doubt. A careful drug history must be taken, as, although the classical presentation of lichen planus is usually ‘idiopathic’, the main differential is a drug-induced lichenoid reaction (see below). Other differential diagnoses include psoriasis, pityriasis rosea, pityriasis lichenoides chronica and secondary syphilis. Screening for underlying disease, such as hepatitis, must be considered. Management The condition is usually self-limiting, although rarely it may persist for years, particularly oral lichen planus. Treatment is symptomatic and potent local glucocorticoids (topical, with occlusion or by injection for hypertrophic disease, or as oral rinse for oral involvement) may help the intense itch; short courses of systemic glucocorticoids are sometimes required for extensive disease. UVB, PUVA or UVA1 can be beneﬁcial and, for recalcitrant disease, retinoids or immunosuppressants, such as ciclosporin or methotrexate, may be needed. A low but signiﬁcant risk of malignant transformation exists with persistent oral and genital disease, so active treatment, surveillance and smoking cessation are important. Drug-induced lichenoid eruptions Drug-induced lichenoid reactions that are clinically and histologically difﬁcult to distinguish from idiopathic lichen planus are important to identify. The likely culprits are gold, quinine, proton pump inhibitors, sulphonamides, penicillamine, antimalarials, antituberculous drugs, thiazide diuretics, β-blockers, angiotensinconverting enzyme (ACE) inhibitors, NSAIDs, sulphonylureas, lithium and dyes in colour developers (see Box 29.35, p. 1266). Graft-versus-host disease In the acute stage of graft-versus-host disease (GVHD, p. 937), there is a distinctive dermatitis associated with hepatitis. After about 3 months, chronic GVHD can present with a lichenoid eruption on the palms, soles, face and upper trunk. Progressive sclerodermatous skin thickening, associated with pigmentary changes, may lead to contractures and limited mobility. Urticaria Urticaria (‘hives’) is caused by localised dermal oedema secondary to a temporary increase in capillary permeability. If oedema involves subcutaneous or submucosal layers, the term angioedema is used. Clinical features Acute urticaria may be associated with angioedema of the lips, face, tongue, throat and, rarely, wheezing, abdominal pain, headaches and even anaphylaxis (p. 75). Urticaria present for less than 6 weeks is considered to be acute, and chronic if it continues for more than 6 weeks. Individual weals (deﬁnition: evanescent discrete areas of dermal oedema, often centrally white due to masking of local blood supply by ﬂuid; weals can erythematous papulosquamous rash and must be considered in the differential diagnosis of erythematous papulosquamous rashes. Lichenoid eruptions Lichen planus Lichen planus occurs worldwide. It typically presents as a pruritic rash; the mucosae, hair and nails may also be involved. Pathogenesis The disease probably has an autoimmune basis since there is an association with inﬂammatory bowel disease, primary biliary cirrhosis, autoimmune hepatitis, hepatitis B and C, alopecia areata, myasthenia gravis (p. 1141) and thymoma. There are also similarities with graft-versus-host disease (GVHD, p. 937). Lichen planus can occasionally occur in families and possible HLA associations have been reported but there is no clear inheritance pattern. On skin biopsy, characteristic histological changes include hyperkeratosis, basal cell degeneration and a heavy, band-like T-lymphocyte inﬁltrate in the papillary dermis, with afﬁnity for the epidermis (epidermotropism). The dermo-epidermal junction has a ‘sawtooth’ appearance. Clinical features Lichen planus occurs in both sexes and at any age, although usually between 30 and 60 years. It generally presents on the distal limbs, most commonly on the ﬂexural aspects of the wrists and forearms (Fig. 29.38), and on the lower back. It is intensely itchy and lesions are violaceous, shiny, ﬂat-topped, polygonal papules, with a characteristic ﬁne lacy, white network on the surface (Wickham’s striae). New lesions may appear at sites of skin trauma (Köbner phenomenon) and the rash may become generalised. Individual lesions may last for many months and can become hypertrophic and modiﬁed by scratching, particularly on the lower legs. The eruption usually remits over months but can become chronic, particularly with hypertrophic disease. Post-inﬂammatory pigmentary change is common, particularly in darker skin types. Mucous membrane involvement occurs in 30–70% of patients, usually as a network of white, lacy striae on the buccal mucosae (p. 1210) and tongue. These oral changes are often asymptomatic and should be sought on examination. Genital and other mucosal surfaces can also be affected (pp. 334 and 336). Nail involvement occurs in about 10% and can range from longitudinal ridging to a destructive nail dystrophy, scarring (pterygium) and nail loss (p. 1261). Scalp involvement usually Fig. 29.38 Lichen planus. Violaceous papules on the ﬂexural aspect of forearm, arising at a site of minor linear trauma (Köbner phenomenon).

Urticaria • 1253

Investigations Investigations should be guided by the history and possible causes but are often negative, particularly in acute urticaria. Some or all of the following may be appropriate: • Full blood count: eosinophilia in parasitic infection or drug cause. • Erythrocyte sedimentation rate (ESR) or plasma viscosity: elevated in vasculitis. • Urea and electrolytes, thyroid and liver function tests, iron studies: may reveal an underlying systemic disorder. • Total IgE and speciﬁc IgE to possible allergens: shellﬁsh, peanut, house-dust mite. Particularly relevant if there is angioedema. • Autoantibodies, particularly antinuclear factor: positive in systemic lupus erythematosus (SLE) and often positive in urticarial vasculitis. Other autoimmune diseases, such as Fig. 29.39 Urticaria. Erythema, reﬂecting dilated dermal vessels, and oedema (with upper dermal oedema obscuring the erythema centrally) are evident. Note the absence of epidermal changes. Fig. 29.40 Pathogenesis of urticaria. Mast cell degranulation occurs in a variety of ways. (1) Type I hypersensitivity causes degranulation. (2) Spontaneous mast cell degranulation in chronic urticaria. (3) Chemical mast cell degranulation. (4) Autoimmunity, with IgE antibodies directed against IgE receptors or IgE itself. Histamine and the leukotrienes are especially relevant mediators in urticaria. Heparin release is probably not a major factor in urticaria but plays a role in the osteoporosis that can occur in systemic mastocytosis. (IgE = immunoglobulin E; NSAID = non-steroidal anti-inﬂammatory drug) Histamine Inflammatory mediators

• prostaglandins

• leukotrienes

• chemotactic cytokines

for eosinophils and

neutrophils Heparin 5-hydroxytryptamine Proteases Aspirin NSAIDs Morphine Codeine Benzoic acid Mast cell Granules High-affinity IgE receptor (FcεRI) Antigen Autoantibody to FcεRI and IgE Increased capillary permeability Key IgE

29.24 Causes of urticaria Acute and chronic urticaria • Autoimmune: due to antibodies that cross-link the IgE receptor on mast cells • Allergens in foods and inhalants • Contact allergens: latex, animal saliva • Drugs: see Box 29.35 (p. 1266) • Physical stimuli: heat, cold, pressure, sun, sweat, water • Infections: intestinal parasites, hepatitis • Others: SLE, pregnancy, thyroid disease • Idiopathic: chronic spontaneous urticaria and angioedema Urticarial vasculitis • Hepatitis B, SLE, idiopathic (IgE = immunoglobulin E; SLE = systemic lupus erythematosus) be papules, macules, patches and plaques – Fig. 29.39) last for less than 24 hours; if they persist, urticarial vasculitis needs to be considered. Clariﬁcation of the duration of urticaria can be achieved by drawing around the weal and re-assessing 24 hours later. History-taking should probe for possible causes, including medications (Box 29.24). Physical triggers can also be assessed in challenge testing, such as eliciting dermographism or pressure testing. Enquiry about family history and medication, particularly ACE inhibitors, is important in angioedema. Examination may be unremarkable or weals may be evident (Fig. 29.39). The skin should be stroked ﬁrmly with an orange stick in order to ascertain whether dermographism is present or not. Mast cell degranulation and release of histamine and other vasoactive mediators is the basis of urticaria (Fig. 29.40). Chronic spontaneous urticaria (previously called ‘chronic idiopathic’ or ‘chronic ordinary’ urticaria) is the most common chronic urticaria and has an autoimmune pathogenesis in some cases.

1254 • DERMATOLOGY Toxic epidermal necrolysis Toxic epidermal necrolysis (TEN) is a medical emergency, as the extensive mucocutaneous blistering is associated with a high mortality rate. It is usually drug-induced (see Box 29.35, p. 1266), with anticonvulsants, sulphonamides, sulphonylureas, NSAIDs, allopurinol and antiretroviral therapy often implicated. Usually 1–4 weeks after drug commencement, the patient becomes systemically unwell and often pyrexial. Erythema and blistering develop, initially on the trunk but rapidly involving all skin; an early warning sign is cutaneous pain. Sheets of blisters coalesce and denude, and the underlying skin is painful and erythematous (Fig. 29.41). Gentle lateral pressure on stroking the skin results in epidermal detachment (Nikolsky sign), demonstrating the severity of skin fragility. Mucous membrane involvement and blistering are usual. Blistering of skin and mucosae may be haemorrhagic. A disease severity score (Box 29.26) is used to predict outcome. The main differential diagnosis is staphylococcal scalded skin syndrome (p. 1236), although the diagnosis is usually obvious in an adult patient with a culprit drug. There is often overlap with Stevens–Johnson syndrome and targetoid lesions, especially on palms and soles, may be evident. Skin rheumatoid arthritis and autoimmune hepatitis or thyroid disease, may be associated. • Complement C3 and C4 levels: if these are low due to complement consumption, C1 esterase inhibitor activity should be measured. • Infection screen: hepatitis screen and HIV may be indicated. • Skin biopsy: if urticarial vasculitis is suspected. • Challenge tests: to conﬁrm physical urticarias, such as dermographism, pressure, heat, cold. Management Removal or treatment of any trigger is essential, although this may not be identiﬁed in the majority of cases. Urticaria may be precipitated by aspirin, NSAIDs, codeine and opioids, and it is advisable to suggest alternatives such as paracetamol. In chronic urticaria, non-sedating antihistamines, such as fexofenadine, loratadine or cetirizine, are usually beneﬁcial. If there is lack of response after 2 weeks, an alternative non-sedating antihistamine should be used and an H2-blocker, such as cimetidine or ranitidine, can be added. Mast cell stabilisers or leukotriene receptor antagonists, such as montelukast, can be used for more recalcitrant disease. For chronic urticaria, narrowband UVB phototherapy is valuable and has proven efﬁcacy. Systemic glucocorticoids are widely prescribed for urticaria but are not indicated in the majority of cases. If systemic glucocorticoids are used, efﬁcacy may be seen only at relatively high doses and they are appropriate only for occasional short courses in the acute setting, usually in association with angioedema. Patients with a history of life-threatening anaphylaxis, as in peanut or wasp sting allergy, should carry a self-administered adrenaline (epinephrine) injection kit. The management of anaphylaxis and hereditary angioedema is discussed on pages 76 and 87. The IgE monoclonal antibody omalizumab may be effective in patients with severe recalcitrant urticaria. Bullous diseases Blistering can occur at any level in the skin and there are a variety of different presentations, depending on the underlying defect and level of involvement. Knowledge of the molecular basis of many blistering disorders has advanced considerably through understanding of the basic processes of cell adhesion and studies of rare genetic blistering disorders, particularly epidermolysis bullosa (Box 29.25). This section concentrates on primary blistering skin diseases. Fig. 29.41 Toxic epidermal necrolysis. Note the extensive erythema, oedema and epidermal loss secondary to carbamazepine. 29.25 Classiﬁcation of epidermolysis bullosa Type Mode of inheritance Level of blister* Abnormality Simple Autosomal dominant Epidermal basal cell Keratins 5 and 14 Junctional Autosomal recessive Lamina lucida Laminin-5 and α6β4 integrin Dystrophic Autosomal dominant and recessive Dermis below lamina densa Collagen VII *See Figure 29.1 (p. 1213). 29.26 Disease severity score for toxic epidermal necrolysis: SCORTEN Factor • Age > 40 years • Heart rate > 120 beats/min • Cancer or haematological malignancy • Involved body surface area > 10% • Blood urea > 10 mmol/L (28 mg/dL) • Serum bicarbonate < 20 mmol/L • Blood glucose ≥ 14 mmol/L (252 mg/dL) Mortality rates • 0–1 factor present = 3% • 2 factors = 12% • 3 factors = 35% • 4 factors = 58% • ≥ 5 factors = 90% From Bastuji-Garin S, Fouchard N, Bertocchi M, et al. SCORTEN: a severity-ofillness score for toxic epidermal necrolysis. J Invest Dermatol 2000; 115:149–153.

Bullous diseases • 1255

Pathogenesis The disease is caused by autoantibodies (BP-230 and BP-180) directed against the hemi-desmosomal BP antigens, BPAg-1 (intracellular) and BPAg-2 (transmembranous type XVII collagen), respectively. Antibody–antigen binding initiates complement activation and inﬂammation, with hemi-desmosomal damage and subepidermal blistering. Clinical features There is often a lengthy prodrome of an itchy, urticated, erythematous rash prior to the development of tense bullae (Fig. 29.42A). Milia (deﬁnition: small epidermal keratin cysts) may develop due to basement membrane disruption. Mucosal involvement is uncommon. 29.27 Age of onset in immunobullous skin disorders Disease Age Pemphigus vulgaris 40–60 years Pemphigus foliaceus Any age (endemic form in parts of Brazil and South Africa, from teenage years on) Bullous pemphigoid Sixties and over Dermatitis herpetiformis Young, associated with coeliac disease Linear IgA disease Any age Pemphigoid gestationis Pregnant females Epidermolysis bullosa acquisita Any age Bullous lupus erythematosus Young black females 29.28 Clinical and investigation ﬁndings in the immunobullous disorders Disease Site of blisters Nature of blisters Mucous membrane involvement Antigen Circulating antibody (indirect IF) Fixed antibody (direct IF) Pemphigus vulgaris Trunk, head Flaccid, fragile, many erosions 100% Desmoglein-1 and 3 (120 kD) IgG IgG, C3 intercellular (epidermal) Pemphigus foliaceus Trunk Often not present, multiple erosions, may mimic dermatitis No Desmoglein-1 IgG IgG, C3 intercellular (epidermal) Bullous pemphigoid Trunk, ﬂexures and limbs Tense, milia as blisters resolve Occasional BP-230 and 180 IgG (70%) IgG, C3 at BMZ Dermatitis herpetiformis Elbows, lower back, buttocks Excoriated and often not present No Unknown Anti-endomysial and tissue transglutaminase Granular IgA in papillary dermis Linear IgA disease Widespread Tense, often annular conﬁguration, ‘string of beads’ Frequent Unknown 50% have low titres of circulating antibody Linear IgA at BMZ Pemphigoid gestationis Periumbilical and limbs Tense, milia as blisters resolve Rare Collagen XVII (part of hemi-desmosome, BP-180) Circulating antibodies to BP-180 (type XVII collagen) (and BP-230) C3 at BMZ Epidermolysis bullosa acquisita Widespread Tense, scarring, milia Common (50%) Type VII collagen IgG (anti-type VII collagen) IgG at BMZ Bullous lupus erythematosus Widespread Tense Rare Type VII collagen Anti-type VII collagen IgG, IgA, IgM at BMZ (BMZ = basement membrane zone; IF = immunoﬂuorescence; Ig = immunoglobulin) snip may allow early diagnosis. If there is diagnostic doubt, then full-thickness skin biopsy should be undertaken for histology and direct immunoﬂuorescence in order to exclude immunobullous or other diagnoses. Identiﬁcation and discontinuation of the causative drug are essential. Sepsis and multi-organ failure are major risks. Intensive care in a dedicated dermatology ward or intensive care or burns unit is of paramount importance. Treatment is supportive, with regular sterile dressings and emollients, careful attention to ﬂuid balance and treatment of infection if it develops. Urethral and ocular involvement is common and must be looked for and treated symptomatically. Ocular and urethral scarring can be problematic in survivors. There is no conclusive evidence that intravenous immunoglobulins, systemic glucocorticoids or ciclosporin improve outcomes and survival. Immunobullous diseases There are various subtypes of immunobullous disease that affect patients of different ages and have clinical characteristics (Box 29.27). The key investigation is an elliptical biopsy taken from the edge of a recent blister (Box 29.28). The sample is halved: one half is put in formalin for subsequent histology, while the other is sent fresh for direct immunoﬂuorescence. Serum should also be sent for indirect immunofluorescence in suspected immunobullous disease (p. 1215). Bullous pemphigoid Bullous pemphigoid (BP) is the most common immunobullous disease and occurs worldwide. It is a disease of the elderly, with an average age of onset of 65 years; males and females are equally affected.

1256 • DERMATOLOGY Pathogenesis The cause is IgG1 and IgG4 autoantibodies, directed against desmogleins-1 and 3, resulting in intra-epidermal blistering. The syndrome may occur spontaneously or be secondary to drugs such as penicillamine or captopril and underlying malignancy (paraneoplastic pemphigus). Pemphigus foliaceus is a very superficial form, in which antibodies are directed against desmoglein-1 only and affect just the most superﬁcial epidermis. Clinical features Skin and mucosae are usually involved, although disease may be restricted to mucosae only, which may be severely affected. Due to the higher level of split within the epidermis, the blisters are ﬂaccid, easily ruptured and often not seen intact. Erosions are common and the Nikolsky sign is positive. The trunk is usually affected. The condition is associated with signiﬁcant morbidity and mortality. Investigations The diagnosis can be made by skin biopsy, which shows intra-epidermal blistering and acantholysis, with positive direct immunoﬂuorescence for IgG (usually IgG1 or IgG4) and C3 at the periphery of keratinocytes, giving a ‘chicken wire’ appearance within the epidermis. The titres of circulating epidermal autoantibodies can also be used to monitor disease activity. Investigations should screen for associated autoimmune disease or malignancy if paraneoplastic pemphigus is suspected. Management Pemphigus is more difﬁcult to treat than BP and high-dose systemic glucocorticoids such as prednisolone (0.5–1.0 mg/kg/ day) are usually required. Azathioprine and cyclophosphamide are most often used as glucocorticoid-sparing agents but a range of other immunosuppressants may be considered for severe recalcitrant disease, including methotrexate, ciclosporin, mycophenolate mofetil, intravenous immunoglobulins, plasma exchange, extracorporeal photopheresis and rituximab. Often, long-term treatment is required to prevent relapse. Dermatitis herpetiformis Dermatitis herpetiformis (DH) is an autoimmune blistering disorder that is strongly associated with coeliac disease (CD). While fewer than 10% of individuals with CD develop DH, almost all patients with DH have evidence of partial villous atrophy on intestinal biopsy, even if they have no gastrointestinal symptoms (p. 806). It is unclear why some CD patients develop DH and others do not. Although DH is a bullous disease, intact vesicles and blisters are seldom seen, as the condition is so pruritic that excoriations on extensor surfaces of arms, knees, buttocks, shoulders and scalp may be the only signs. The diagnosis can be made by skin biopsy, which shows subepidermal vesiculation in the dermal papillae and a neutrophil- and eosinophil-rich inﬁltrate. Direct immunoﬂuorescence shows granular IgA in the papillary dermis. Anti-endomysial antibodies and tissue transglutaminase should be assessed and jejunal biopsy undertaken if indicated. The condition usually responds to a gluten-free diet but, if not, dapsone can also be used. Linear IgA disease This occurs in children (chronic bullous disease of childhood) and adults, and is usually self-limiting, although it can be active for a few years. Drugs, notably vancomycin, can be a secondary cause. Blisters Investigations The diagnosis can be made by skin biopsy, which shows subepidermal blistering with an eosinophil-rich inﬂammatory infiltrate. Direct immunofluorescence demonstrates the presence of IgG and C3 at the basement membrane (Fig. 29.42B). Indirect immunofluorescence may show positive titres of circulating anti-epidermal antibodies. Distinction from epidermolysis bullosa acquisita requires immunoﬂuorescence studies using the patient’s serum on salt-split skin. In BP, the immunoreactants localise to the epidermal side (hemi-desmosome) of split skin, whereas in epidermolysis bullosa acquisita they localise to the base of the split (type VII collagen/anchoring ﬁbrils). Management Very potent topical glucocorticoids are effective and may be sufﬁcient in frail elderly patients; they need to be applied to all sites, however, and not just lesional skin. Tetracyclines, such as doxycycline, have an important role and may limit the use of systemic glucocorticoids. However, most patients with extensive disease require systemic glucocorticoids (0.75 mg/ kg/day or less), often combined with immunosuppressants as glucocorticoid-sparing agents. In severe refractory disease, other therapies, such as intravenous immunoglobulin or rituximab, are sometimes used but are of unproven efﬁcacy. The condition often burns out over a few years. Pemphigus Pemphigus is less common than BP and patients tend to be younger. Fig. 29.42 Bullous pemphigoid. A Large, tense, unilocular blisters. B Immunoﬂuorescence on salt-split skin, showing a subepidermal blister and linear IgG and C3 deposition at the basement membrane zone. A B Epidermis Split Dermis

Pigmentation disorders • 1257

of patches of hypopigmentation. A positive family history of vitiligo is relatively common in those with extensive disease, and this type is also associated with other autoimmune diseases. Trauma and sunburn may (through the Köbner phenomenon) precipitate the appearance of vitiligo. It is thought to be the result of cell-mediated autoimmune destruction of melanocytes but why some areas are targeted and others are spared is unclear. Clinical features Generalised vitiligo is often symmetrical and involves hands, wrists, feet, knees and neck, as well as areas around body oriﬁces (Fig. 29.43). The hair of the scalp, beard, eyebrows and lashes may also depigment. Segmental vitiligo is restricted to one part of the body but not necessarily a dermatome. The patches of depigmentation are sharply deﬁned, and in Caucasians may be surrounded by hyperpigmentation. Spotty perifollicular pigment may be seen within the depigmentation and is often the ﬁrst sign of repigmentation. There is no history or evidence of inﬂammation within the patches, which may be helpful in distinguishing vitiligo from post-inﬂammatory hypopigmentation. Sensation in the depigmented patches is normal (unlike in tuberculoid leprosy, p. 267). Wood’s light examination enhances the contrast between pigmented and non-pigmented skin. The course is unpredictable but most patches remain static or enlarge; a few repigment spontaneously. Management Protecting the patches from excessive sun exposure with clothing or sunscreen may be helpful to avoid sunburn. Camouﬂage cosmetics may be beneﬁcial, particularly in those with dark skin. In fair skin, photoprotection and cosmetic cover may be all that is required. Very potent or potent topical glucocorticoids have limited efﬁcacy with respect to repigmentation. Topical pimecrolimus or tacrolimus may also have a role as a glucocorticoid-sparing agent. Phototherapy with narrowband UVB or PUVA can also be used. Narrowband UVB is the most effective repigmentary treatment available for generalised vitiligo, but even very prolonged courses often do not produce a satisfactory outcome. The absence of leucotrichia (white hairs in the area of vitiligo) and the presence of a trichrome pattern (three colours – normal skin colour, hypopigmentation and depigmentation) are good prognostic features. Vitiligo on the face, trunk and proximal limbs is more likely to respond than that on hands and feet. can arise on erythematous, urticated or otherwise normal-looking skin and often form an annular conﬁguration at the edge of the lesion: ‘clusters of jewels’ (herpetiform) and ‘string of beads’ (annular/ polycyclic). Mucosal involvement is common and ophthalmology input important, as corneal scarring is a risk with longstanding disease. Linear IgA is seen at the basement membrane on direct immunoﬂuorescence and localises to either roof or ﬂoor of salt-split skin. Dapsone, sulfapyridine, prednisolone, colchicine or intravenous immunoglobulin may be effective. Epidermolysis bullosa acquisita This chronic blistering disease affects skin and mucosae, and scarring, hair loss and nail dystrophy may be problematic. Blisters often follow trauma and milia develop. It can be very difﬁcult to distinguish from other immunobullous diseases, such as bullous pemphigoid. It is caused by an IgG antibody to type VII collagen, which provokes subepidermal blistering and a mixed inﬂammatory inﬁltrate, although the latter may not be prominent. Direct immunofluorescence on perilesional skin shows IgG and C3 at the dermo-epidermal junction and pattern analysis may be helpful in distinction from bullous pemphigoid. Indirect immunoﬂuorescence microscopy on salt-split normal human skin typically shows IgG and IgA in the ﬂoor of the artiﬁcially induced blister, whereas in BP antibody localisation would be to the roof of the blister. Epidermolysis bullosa acquisita is very difﬁcult to treat, as it often does not respond well to immunosuppressants. Mainstays of treatment include systemic glucocorticoids in combination with dapsone or colchicine. Other immunosuppressive approaches may be required and include ciclosporin, azathioprine, immunoglobulins, plasmapheresis and rituximab. The condition may be associated with inﬂammatory bowel disease, rheumatoid arthritis, multiple myeloma and lymphoma, and thus associated comorbidities should be sought. Porphyria cutanea tarda and pseudoporphyria These conditions may also cause blistering (see Boxes 29.9 and 29.35, pp. 1221 and 1266). Porphyria is discussed in more detail on page 378. Pigmentation disorders Decreased pigmentation Disorders causing hypopigmentation and/or depigmentation include: • vitiligo • albinism • pityriasis alba: depigmented areas on the face, particularly in children, with or without scale and usually considered to be eczematous • pityriasis versicolor (p. 1240): hypopigmentation or, less commonly, hyperpigmentation can occur • idiopathic guttate hypomelanosis: multiple small areas of depigmentation arising in chronically sun-exposed skin • rarely, phenylketonuria (p. 369) and hypopituitarism. Vitiligo Vitiligo is an acquired condition affecting 1% of the population worldwide. Focal loss of melanocytes results in the development Fig. 29.43 Vitiligo. Symmetrical localised patches of depigmented skin.

1258 • DERMATOLOGY • Photo-exposed site hyperpigmentation: occurs in some of the porphyrias but can also be drug-induced. • Drug-induced pigmentation (Box 29.29): may be diffuse or localised. It is not always due to hypermelanosis but sometimes is caused by deposition of the drug or a metabolite. • Focal hypermelanosis: seen in lesions such as freckles and lentigines, characterised by focal areas of increased pigmentation. Establishing the cause is important. Photoprotection may minimise the risk of increasing pigmentation. Topical hydroquinone preparations can be used for skin lightening in some types of hyperpigmentation, although caution is required, particularly in darker skin types. Hair disorders These can be subdivided into disorders that cause loss of hair (alopecia) or excessive hair growth (hypertrichosis and hirsutism). Alopecia Alopecia is characterised by loss of hair. It can be further subdivided into localised and diffuse, and into scarring and non-scarring subtypes (Box 29.30). Pathogenesis Alopecia can be observed in association with inﬂammatory disorders that cause scarring (lichen planus, discoid lupus) and others that do not cause scarring (tinea capitis, psoriasis, seborrhoeic eczema). These conditions are discussed elsewhere. Alopecia areata has an autoimmune basis and there is a strong genetic component, with a family history in approximately 20% of cases. In addition to atopy, it is associated with other autoimmune diseases, particularly thyroid disease, and with Down’s syndrome. The cause of androgenetic alopecia is unclear but likely to be multifactorial, with genetic, hormonal and end-organ receptor sensitivity to the factors implicated. Clinical features Alopecia areata This usually presents with well-defined, localised, noninﬂammatory, non-scarring patches of alopecia, usually on the Exceptionally, depigmentation of normal non-lesional skin or a surgical approach with autologous melanocyte transfer, using a range of techniques including split-skin grafts and blister roof grafts, is sometimes used on dermabraded recipient skin in speciﬁc severe cases. The impact of vitiligo differs markedly between populations. In the Indian subcontinent, the effects are more readily discernible than in pale-skinned individuals in northern Europe. Depigmentation is also seen in leprosy, which means that individuals with vitiligo are often stigmatised. The emotional impact of vitiligo may be immense; psychological support is essential and is important in conveying realistic expectations of possible treatment approaches. Oculocutaneous albinism Albinism results from a range of genetic abnormalities that lead to reduced melanin biosynthesis in the skin and eyes; the number of melanocytes is normal (in contrast to vitiligo). Albinism is usually inherited as an autosomal recessive trait and there are several different types and presentations. Type 1 albinism is due to a defect in the tyrosinase gene, whose product is rate-limiting in the production of melanin. Affected individuals have an almost complete absence of pigment in the skin and hair at birth, with consequent pale skin and white hair, and failure of melanin production in the iris and retina. Patients have photophobia, poor vision not correctable with refraction, rotatory nystagmus, and an alternating strabismus associated with abnormalities in the decussation of nerve ﬁbres in the optic tract. A second form of albinism is due to a defect in the P gene, which encodes an ion channel protein in the melanosome. Patients may have gross reduction of melanin in the skin and in the eyes, but may be more mildly affected than type 1 albinos. Establishing the subtype of albinism requires genetic analysis, as there is considerable phenotypic heterogeneity. Oculocutaneous albinos are at grossly increased risk of sunburn and skin cancer. In equatorial regions, many die from squamous cell carcinoma or, more rarely, melanoma in early adult life. Interestingly, they may develop pigmented melanocytic naevi and freckle in response to sun exposure. Management Strict photoprotection (p. 1221), with sun avoidance (including occupational exposure), clothing, hats and sunscreens, is important. Early diagnosis and treatment of skin tumours is essential. Increased pigmentation • Diffuse hyperpigmentation: most commonly due to hypermelanosis but other pigments may be deposited in the skin, such as orange discoloration with carotenaemia and bronze with haemochromatosis (p. 895). • Endocrine pigmentation: may occur in several conditions. Melasma (chloasma) describes discrete patches of facial pigmentation that occur in pregnancy and in some women taking oral contraceptives. The mechanism for this localised increased hormonal sensitivity is unknown. Diffuse pigmentation, sometimes worse in the skin creases and mucosae, may be a feature of Addison’s disease (p. 671), Cushing’s syndrome (p. 666), Nelson’s syndrome (p. 669) and chronic renal failure due to increased levels of pituitary melanotrophic peptides, including adrenocorticotrophic hormone (ACTH; p. 669). 29.29 Drug-induced pigmentation Drug Appearance Amiodarone Photo-exposed sites, slate-grey Arsenic Diffuse bronze pigmentation Raindrop depigmentation Bleomycin Usually ﬂexural, brown Busulfan Diffuse brown Chloroquine Photo-exposed sites, blue-grey Clofazimine Red Mepacrine Yellow Minocycline Temples, shins, gingiva, sclera, scar sites, slate-grey Phenothiazines Photo-exposed sites, slate-grey Psoralens Photo-exposed sites, brown

Hair disorders • 1259

Androgenetic alopecia Male-pattern baldness is physiological in men over 20 years old, although it can also occur in teenagers. It is also found in women, particularly post-menopausal ones. Characteristically, this involves bitemporal recession initially and subsequent involvement of the crown (‘male pattern’), although it is often diffuse in women. Investigations Important investigations include full blood count, renal and liver function tests, iron studies, thyroid function, autoantibody screen and syphilis serology, as several systemic diseases, particularly iron deﬁciency and hypothyroidism, can cause diffuse non-scarring alopecia. Hair pull tests may help to establish the ratio of anagen to telogen hairs but require expertise for interpretation. Scrapings and pluckings should be sent for mycology if there is localised inﬂammation. Scalp biopsy and direct immunoﬂuorescence of scarring alopecia may conﬁrm a diagnosis of lichen planus or discoid lupus erythematosus but expert interpretation is needed. Management Any underlying condition, such as iron deﬁciency, should be treated and may result in clinical improvement. Alopecia can have a major impact on quality of life and psychological support is usually required. It is particularly important to establish realistic expectations. Hair may spontaneously regrow in alopecia areata and it may be appropriate to offer no active intervention as, while some treatments may induce some hair regrowth, there is no evidence that any treatment fundamentally alters the course of the disease. There may be some response to topical or intralesional glucocorticoids. PUVA or immunotherapy with diphencyprone may be effective, with evidence of hair regrowth, but there is a risk of relapse on discontinuation of treatment. Short courses of systemic glucocorticoids are occasionally used in an attempt to limit acutely progressive extensive alopecia areata but should not be used in the long term; the risk of relapse on discontinuation is high. Ongoing trials of Janus kinase (JAK) inhibitors may provide future hope for patients with this difﬁcult disease. Some males with androgenetic alopecia may be helped by systemic ﬁnasteride. Topical minoxidil can be used in males and females with androgenetic alopecia but, if an effect is obtained, treatment must be continued and is expensive. In females, anti-androgen therapy, such as cyproterone acetate, can be used. Wigs are often appropriate for extensive alopecia. Scalp surgery and autologous hair transplants are expensive but can be used for androgenetic alopecia. Hypertrichosis Hypertrichosis is a generalised or localised increase in hair and may be congenital or acquired. It can be primary or secondary: for example, to drugs such as ciclosporin, minoxidil or diazoxide, malignancy or eating disorders. Laser therapy or eﬂornithine, which inhibits ornithine decarboxylase and arrests hair growth while it is being used, may be helpful. When the hypertrichosis follows a male pattern, it is called hirsutism. Hirsutism Hirsutism is the growth of terminal hair in a male pattern in a female (p. 657). The cause of most cases is unknown and, while it may occur in hyperandrogenism, Cushing’s syndrome and polycystic ovary syndrome, only a small minority of patients have scalp (Fig. 29.44). Pathognomonic ‘exclamation mark’ hairs are seen (broken hairs, tapering towards the scalp) during active hair loss. A diffuse pattern can uncommonly occur on the scalp. Eyebrows, eyelashes, beard and body hair can be affected. Alopecia totalis describes complete loss of scalp hair, and alopecia universalis is complete loss of all hair. Nail pitting may occur (p. 1261). Spontaneous regrowth is usual for small patches of alopecia but the prognosis is less good for larger patches, more extensive involvement, early onset and an association with atopy. Fig. 29.44 Alopecia areata. The relatively extensive involvement and encroachment on posterior hairline are poor prognostic features. 29.30 Classiﬁcation and causes of alopecia Localised Diffuse Non-scarring Tinea capitis Alopecia areata Androgenetic alopecia Traumatic (trichotillomania, traction, cosmetic) Syphilis Androgenetic alopecia Telogen efﬂuvium Hypothyroidism Hyperthyroidism Hypopituitarism Diabetes mellitus HIV disease Nutritional (especially iron) deﬁciency Liver disease Post-partum Alopecia areata Syphilis Drug-induced: chemotherapy, retinoids Scarring Discoid lupus erythematosus Lichen planopilaris Herpes zoster Pseudopelade Tinea capitis/kerion Morphoea (en coup de sabre) Idiopathic Developmental defects Discoid lupus erythematosus Radiotherapy Folliculitis decalvans Lichen planopilaris

1260 • DERMATOLOGY differential is subungual melanoma, although rapid onset, lack of nail-fold involvement and proximal clearing as the nail grows are clues to the diagnosis of haematoma. If there is diagnostic doubt, a biopsy may be needed. Nail involvement in skin diseases • Dermatophyte infection/onychomycosis: this is described on page 1240. • Psoriasis: nail involvement is common (see Fig. 29.35B, p. 1249). a demonstrable hormonal abnormality. Psychological distress is often signiﬁcant and oral contraceptives containing an antiandrogen such as cyproterone acetate, laser therapy or topical eﬂornithine may be beneﬁcial. Nail disorders The nails can be affected by both local and systemic disease. The nail apparatus consists of the nail matrix and the nail plate, which arises from the matrix and lies on the nail bed (Fig. 29.45). The cells of the matrix and, to a lesser extent the bed, produce the keratinous plate. Important information may be obtained from nail-fold examination, including dilated capillaries and ragged cuticles in connective tissue disease (Fig. 29.46) and the boggy inﬂammation of paronychia. The latter commonly occurs chronically in individuals undertaking wet work, in those with diabetes or poor peripheral circulation, and subsequent to increased cosmetic nail procedures and vigorous manicuring. Normal variants Longitudinal ridging and beading of the nail plate occur with age. White transverse patches (striate leuconychia) are often caused by airspaces within the plate. Nail trauma • Nail biting/picking is a very common habit. Repetitive proximal nail-fold trauma (often involving the thumb nail) results in transverse ridging and central furrowing of the nail. • Chronic trauma from poorly-ﬁtting shoes and sport can cause thickening and disordered growth of the nail (onychogryphosis) and subsequent ingrowing toenails. • Splinter haemorrhages are ﬁne, linear, dark brown longitudinal streaks in the plate (see Fig. 16.89, p. 529). They are usually caused by trauma, especially if distal. Uncommonly, they can occur in nail psoriasis and are also a hallmark of infective endocarditis. • Subungual haematoma is red, purple or grey–brown discoloration of the nail plate, usually of the big toe (Fig. 29.47). These haematomas are usually due to trauma, although a history of this may not be clear. The main Fig. 29.45 The nail plate and bed. Arrows indicate the direction of nail growth. Fig. 29.46 Dermatomyositis. A Photo-aggravation. B Note the prominent periungual involvement. Erythema, dilated and tortuous capillaries in the proximal nail fold, and ragged cuticles are features of connective tissue disease. A B Fig. 29.47 Subungual haematoma. Hyponychium Nail bed Nail plate Matrix Proximal nail fold Cuticle Distal phalanx

Skin disease in general medicine • 1261

Skin disease in general medicine Many skin conditions present to other medical specialties. These are listed in Box 29.31 and the most common ones that are not discussed elsewhere are detailed below. Conditions involving cutaneous vasculature Vasculitis Vasculitic involvement of the skin usually presents as palpable purpura (see Fig. 24.53, p. 1042). The diagnosis is conﬁrmed by skin biopsy, along with histology and immunoﬂuorescence examination. Underlying causes and their treatment are discussed on page 1040. Pyoderma gangrenosum The initial lesion of pyoderma gangrenosum (PG) is usually a painful, tender, inﬂamed nodule or pustule, which breaks down centrally and rapidly progresses to an ulcer with an indurated, undermined purplish or pustular edge (Fig. 29.49). Lesions may be single or multiple and are classiﬁed as ulcerative, pustular, bullous or vegetative. PG usually occurs in adults and, although it may occur in isolation, is usually associated with underlying disease, particularly inﬂammatory bowel disease, inﬂammatory arthritis, blood dyscrasias, immunodeﬁciencies and HIV infection. Investigation should be made with these associations in mind. The diagnosis is largely clinical, as histology is not speciﬁc. Analgesia, treatment of secondary bacterial infection and supportive • Eczema: nails may be shiny due to rubbing skin. Fine pitting can occur. If there is periungual eczema, the nail may become dystrophic, with thickening and transverse ridging. Paronychia is common. • Lichen planus: there may be longitudinal ridging and thinning of the nail, giving a sandpaper texture (trachyonychia), erythematous streaks (erythronychia), subungual hyperkeratosis, pigmentation and, in severe cases, pterygium (splitting of nail due to central ﬁbrosis and scarring, giving a winged appearance) and a destructive nail dystrophy. • Alopecia areata: nail-plate pitting and trachyonychia can occur. Nail involvement in systemic disease The nails may be affected in many systemic diseases and important examples are detailed below: • Beau’s lines: horizontal ridges/indentations in nail plate occur simultaneously in all nails (Fig. 29.48B). They typically follow a systemic illness and are thought to be due to temporary growth arrest of cells in the nail matrix; they subsequently migrate out as the nail grows. Normal nail growth is approximately 0.1 mm/day for ﬁngers and 0.05 mm/day for toes, so the timing of the systemic upset can usually be estimated by the position of the Beau’s lines. • Koilonychia: this concave or spoon-shaped nail-plate deformity is caused by iron deﬁciency (Fig. 29.48C). • Clubbing: in the early stages, the angle between the proximal nail and nail fold is lost. In its more established form, there may be swelling of the distal digits (Figs 29.48D and E) or toes. Causes include bronchogenic carcinoma, asbestosis (especially with mesothelioma), suppurative or ﬁbrosing lung disease, cyanotic congenital heart disease, infective endocarditis, inﬂammatory bowel disease, biliary cirrhosis and thyrotoxicosis; rarely, clubbing can be familial or idiopathic. • Nail discoloration: whitening may occur in hypoalbuminaemia. ‘Half-and-half’ nails (white proximally and red/brown distally) may be found in renal failure. Antimalarials and some other drugs occasionally discolour nails. Nail involvement in congenital disease Nails can be affected in congenital diseases, such as pachyonychia congenita, a rare, usually autosomal dominant, condition caused by mutations in differentiation-speciﬁc keratin genes 6A, 6B, 16 and 17. This results in palmoplantar keratoderma and gross nail discoloration and thickening, due to subungual hyperkeratosis, from birth. Fig. 29.48 The nail in systemic disease. A Normal nail. B Beau’s line. C Koilonychia. D and E Digital clubbing. A B C D E 29.31 Skin problems in general medicine Primary skin problems • Cellulitis • Vasculitis • Leg ulcers • Pressure sores Skin involvement in multisystem disease • Genetic: neuroﬁbromatosis, tuberous sclerosis • Xanthomas • Amyloidosis • Porphyria • Sarcoidosis • Systemic lupus erythematosus • Systemic sclerosis Non-speciﬁc and variable skin reactions to systemic disease • Urticaria • Erythema multiforme • Annular erythemas • Erythema nodosum • Pyoderma gangrenosum • Sweet’s syndrome • Generalised pruritus Skin conditions associated with malignancy • Dermatomyositis • Generalised pruritus • Acanthosis nigricans • Superﬁcial thrombophlebitis Skin problems associated with speciﬁc medical disorders • Liver: generalised pruritus, pigmentation, spider naevi, palmar erythema, nail clubbing • Kidney: generalised pruritus, uraemic frost, pigmentation • Diabetes mellitus: necrobiosis lipoidica, diabetic dermopathy • Cutaneous Crohn’s disease Skin problems secondary to treatment of systemic disease • Drug eruptions Miscellaneous • Granuloma annulare • Morphoea

1262 • DERMATOLOGY Connective tissue disease Lupus erythematosus This autoimmune disorder can be subdivided into systemic lupus erythematosus (SLE) and cutaneous lupus, which includes discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus (SCLE). The features of SLE are discussed on page 1035. Drug-induced DLE and SCLE should always be considered (see Box 24.78, p. 1057, and Boxes 29.34 and 29.35 below). DLE typically presents as scaly red plaques with follicular plugging, usually on photo-exposed sites of the face, head and neck, which resolve with scarring and pigmentary change. If the scalp is involved, scarring alopecia usually occurs (Fig. 29.50). Most patients with DLE do not develop SLE. Patients with SCLE may have extensive cutaneous involvement, usually aggravated by sun exposure, with an annular, polycyclic or papulosquamous eruption. Systemic involvement is uncommon and the prognosis usually good. There is a strong association with antibodies to Ro/SS-A antigen. A diagnosis of cutaneous lupus is conﬁrmed by histopathology and direct immunoﬂuorescence. Cutaneous lupus may respond to topical glucocorticoids, antimalarials or immunosuppressants. Antimalarials and photoprotection are important mainstays in the management of cutaneous lupus, and systemic immunosuppression may be required for resistant disease. Paradoxically, low-dose UVA1 phototherapy can be effective for lupus. Systemic sclerosis This autoimmune multisystem disease presents with severe Raynaud’s syndrome, digital ulcers and skin ﬁbrosis. Dilated nail-fold capillaries and ragged cuticles are frequent. The clinical features and management are described on page 1037. Morphoea Morphoea is a localised cutaneous form of scleroderma that can affect any site at any age. It usually presents as a thickened dressings are important. Systemic treatment with glucocorticoids, dapsone, ciclosporin or other immunosuppressants is often required. Tetracyclines may be added for their anti-inﬂammatory effects. Treatment with TNF-α inhibitors and ustekinumab may be effective in severe recalcitrant PG. Once healing has taken place, recurrences are typically only intermittent. Other neutrophilic dermatoses These include Sweet’s acute febrile neutrophilic dermatosis and the neutrophilic dermatosis of rheumatoid disease, which are characterised by intense inﬂammation, mainly consisting of neutrophils, around dermal blood vessels. There can be damage to vessels (‘vasculopathy’) but usually no frank vasculitis. Pressure sores Localised, prolonged, pressure-induced ischaemia can lead to the development of pressure sores, which can occur in up to 30% of the hospitalised elderly. They are associated with considerable morbidity, mortality and expense to health services. The main risk factors are immobility, poor nutrition, local tissue hypoxia – for example, with anaemia, peripheral vascular disease, diabetes, sepsis and skin atrophy – or barrier impairment, such as in eczema. A localised area of erythema develops at sites of bony prominences (particularly sacrum, greater trochanter, ischial and calcaneal tuberosities, and lateral malleolus). This progresses to a blister and then erosion, which will develop into a deep necrotic ulcer, usually colonised by Pseudomonas aeruginosa if pressure is not alleviated. Prevention is key and involves identiﬁcation of at-risk patients and regular repositioning and use of pressure-relieving mattresses. Predisposing factors, such as anaemia and poor nutrition, should be corrected. Once established, signiﬁcant infection must be treated and necrotic tissue debrided. Dressings encourage granulation, although surgical intervention may sometimes be needed. Fig. 29.50 Scarring inﬂammatory alopecia. This patient had systemic lupus erythematosus and additional cutaneous features of scarring inﬂammatory discoid lupus erythematosus. Fig. 29.49 Pyoderma gangrenosum. This young patient had Crohn’s disease. Note the cribriform pattern of re-epithelialisation, which is characteristic of this condition.

Skin disease in general medicine • 1263

and plaques, infiltrative changes in scars and erythema nodosum (see Fig. 17.59, p. 609). It has been reported more commonly and may be more severe in those of African, African American or Indian ancestry. Investigation is described on page 609. Cutaneous disease may respond to topical or intralesional glucocorticoids, cryotherapy, UVA1, laser or PDT (pp. 1226–1228). Clinical features and management of systemic disease are discussed on pages 608 and 610. Cutaneous Crohn’s disease Cutaneous Crohn’s disease (p. 813) is rare but may present as perianal and peristomal inﬁltrative plaques, lymphoedema, sinuses or ﬁstulae, and oral granulomatous disease. These changes are termed ‘metastatic’ Crohn’s and histology shows non-caseating granulomas. Reactive skin changes can also occur in the form of erythema nodosum and pyoderma gangrenosum (pp. 1265 and 1261). Treatment is of the underlying disease (p. 820). Porphyrias The porphyrias (described on p. 378) are a diverse group of diseases, caused by reduced or absent activity of specific enzymes in the porphyrin–haem biosynthetic pathway. Due to this loss of enzyme activity, porphyrin precursors proximal to the implicated enzyme step accumulate. If the accumulated porphyrins absorb visible light, then there will be skin features and photosensitivity, which explains why some porphyrias have skin features (porphyria cutanea tarda) and others do not (acute intermittent porphyria; p. 379). The most common skin presentations are photo-exposed site blistering, skin fragility and pain on daylight exposure. Cutaneous porphyrias: fragility and blisters Although porphyria cutanea tarda (PCT) may be genetically inherited, this is uncommon and acquired PCT is the most common porphyria worldwide. It is caused by an underlying chronic liver disease, in association with hepatic iron overload. The liver disease is often only diagnosed through investigation of the violaceous plaque, which may become hyper- or hypopigmented. Plaques can become generalised. Linear forms exist and, if in the scalp, are associated with scarring hair loss (en coup de sabre). There is usually no systemic involvement. Topical glucocorticoids or immunosuppressants or phototherapy, particularly PUVA or UVA1, can be effective, and systemic immunosuppression may be used for resistant extensive disease. Dermatomyositis Dermatomyositis is a multisystem disease, predominantly affecting skin, muscles and blood vessels. Typical cutaneous features include a violaceous ‘heliotrope’ erythema periorbitally and involving the upper eyelids, but this can sometimes affect the upper trunk, shoulders (‘shawl sign’) and limbs. Linear erythematous streaks may also be observed on the back of hands and ﬁngers, and papules over the knuckles (Gottron’s papules). Tortuous dilated nail-fold capillaries, often best seen with a dermatoscope, and ragged cuticles are usually evident. Photo-aggravation of the cutaneous features is often prominent (see Fig. 29.46A, p. 1260). The clinical features and management are described on page 1039. Granulomatous disease Granuloma annulare This is common and may be reactive, although a trigger is usually not apparent. The hallmark is the presence of dermal granulomas, which are usually palisading and associated with alteration of dermal collagen (necrobiosis). The condition is generally asymptomatic and may present as an isolated dermal lesion with a raised papular annular edge, or may be more generalised. An association between generalised disease and diabetes has been proposed but not conﬁrmed. Lesions often resolve spontaneously. Intralesional glucocorticoids or cryotherapy can be used for localised disease, and UVB or UVA1 phototherapy or PUVA for generalised disease. Necrobiosis lipoidica This condition has some histological features in common with granuloma annulare, although necrobiosis predominates. The lesion has a characteristic yellow, waxy, atrophic appearance, often with violaceous edge (Fig. 29.51). Underlying blood vessels are easily seen because of tissue atrophy. Necrobiosis lipoidica typically appears on the shins and is prone to ulceration after trauma. There is a strong association with diabetes: most patients with necrobiosis lipoidica have or develop diabetes, although less than 1% of diabetic patients develop necrobiosis lipoidica. Treatment is difﬁcult and includes very potent topical or intralesional glucocorticoids, topical calcineurin inhibitors, PUVA or UVA1 phototherapy and systemic immunosuppression. Sarcoidosis This condition is characterised by the presence of non-caseating granulomas. The cause is unknown, although infectious and genetic factors have been proposed. It is usually a multisystem disease (p. 608), with skin lesions in about one-third of patients. Cutaneous features can occur in isolation and include violaceous inﬁltrated dermal plaques and nodules, which can affect any site but particularly digits and nose (lupus pernio), more generalised hyper- or hypopigmented or annular papules Fig. 29.51 Necrobiosis lipoidica. Atrophic yellow plaques with violaceous edges, on the shins of a patient with diabetes mellitus.

1264 • DERMATOLOGY Amyloidosis Cutaneous amyloid may present as periocular plaques in primary systemic amyloidosis (p. 81) and amyloid associated with multiple myeloma, but is uncommon in systemic amyloidosis secondary to rheumatoid arthritis or other chronic inﬂammatory diseases. Amyloid inﬁltration of blood vessels may manifest as ‘pinch purpura’ following skin trauma. Macular amyloid is more common in darker skin types and appears as pruritic grey/brown macules or patches, usually on the back. Potent topical glucocorticoids can be beneﬁcial, although it is often treatment-resistant. Genetic disorders Neuroﬁbromatosis This is described in detail on page 1131. Tuberous sclerosis This is an autosomal dominant condition and two genetic loci have been identiﬁed: TSC-1 (chromosome 9) encoding hamartin, and TSC-2 (chromosome 16) encoding tuberin. The hallmark is hamartomas in many systems. The classic triad of clinical features comprises learning disability, epilepsy and skin lesions but there is marked heterogeneity in clinical features. Skin changes include pale oval (ash leaf) macules that occur in early childhood; yellowish/pink papules in the mid-face (angioﬁbromas, ‘adenoma sebaceum’), occurring in adolescence; periungual and subungual ﬁbromas; and connective tissue naevi (shagreen patches, often on lower back). Gum hyperplasia, retinal phakomas (ﬁbrous overgrowths), renal, lung and heart tumours, cerebral gliomas and calciﬁed basal ganglia may also occur. Reactive disorders Erythema multiforme Erythema multiforme has characteristic clinical and histological features and can be triggered by a variety of factors (Box 29.32) but a cause is not always identiﬁed. The disease is likely to have an immunological basis. Lesions are multiple, erythematous, annular, targetoid ‘bull’s eyes’ (Fig. 29.53) and may blister. Stevens–Johnson syndrome (pp. 1224 and 1254) is a severe form of erythema multiforme with marked blistering, mucosal involvement (mouth, eyes and genitals) and systemic upset. Identiﬁcation and removal/treatment of any trigger are essential. Analgesia and topical glucocorticoids may provide symptomatic relief. Supportive care is required in Stevens–Johnson syndrome, including ophthalmology input. skin presentation and it is thus an important diagnosis not to miss. Typical features are increased skin fragility, blistering, erosions, hypertrichosis, scarring and milia occurring on light-exposed areas, particularly the backs of the hands (Fig. 29.52). Less common features include facial hypertrichosis, hyperpigmentation and morphoea-like changes. Variegate porphyria (VP) and hereditary coproporphyria (HCP) may be indistinguishable on skin features and it is important to make the correct diagnosis, as acute neurovisceral attacks, which may be drug-induced (p. 1265), can occur in VP and HCP but not in PCT. Pseudoporphyria may also be impossible to distinguish from PCT on clinical grounds but is most frequently caused by a drug (commonly naproxen; see Box 29.35) or by sunbed use; on investigation, porphyrins are normal. A PCT-like presentation may also be seen in uraemia due to renal failure, but is caused by raised porphyrins due to impaired elimination rather than an enzyme defect. Management of PCT requires removal or treatment of any underlying cause, which may involve venesection, iron chelation, very low-dose hydroxychloroquine once or twice per week and photoprotection. Cutaneous porphyria: pain on sun exposure Erythropoietic protoporphyria is caused by a genetic defect in the ferrochelatase gene that leads to ferrochelatase enzyme deﬁciency. It is an important diagnosis to consider. The presentation is usually in early childhood, although the diagnosis is often delayed. In part this is because, although the baby or child cries due to immediate pain on sunlight exposure, physical signs are often absent or minimal and thus a link with sunlight may not always be considered. The deﬁcient ferrochelatase activity leads to accumulation of lipid-soluble protoporphyrins in the skin, explaining the photosensitivity manifest as pain on daylight exposure. Multiple pigment gallstones, anaemia (usually only problematic if considered to be due to iron deﬁciency) and, rarely, severe liver disease can occur, which may be fatal and requires liver transplantation. In addition to photoprotection, UVB phototherapy may be effective for the symptoms of photosensitivity and, more recently, the use of alpha-melanocyte-stimulating hormone (α-MSH) analogues has been explored. Abnormal deposition disorders Xanthomas Deposits of fatty material in the skin, subcutaneous fat and tendons may be the ﬁrst clue to primary or secondary hyperlipidaemia (pp. 346 and p. 373). Fig. 29.52 Porphyria cutanea tarda. Skin fragility, blistering, scarring, milia and hypertrichosis on the back of hands and ﬁngers in hepatitis C. 29.32 Provoking factors in erythema multiforme Infections • Viral: herpes simplex, orf, infectious mononucleosis, hepatitis B, HIV • Mycoplasma and other bacterial infections Drugs • Sulphonamides, penicillins, barbiturates and carbamazepine Systemic disease • Sarcoidosis, malignancy, systemic lupus erythematosus Other • Radiotherapy, pregnancy

Skin disease in general medicine • 1265

Annular erythemas This group of chronic, poorly deﬁned, annular, erythematous and often scaly eruptions can be further subdivided and may be secondary to an identiﬁable cause. Erythema chronicum migrans can be associated with Lyme disease (Borrelia burgdorferi, p. 255). Erythema marginatum can occur in rheumatic fever (p. 515) or Still’s disease (p. 1040). Erythema gyratum repens typically presents as concentric circles of erythema and scale with an advancing edge and is usually associated with underlying malignancy. Erythema annulare centrifugum presents with expanding, scaly, erythematous rings, with central fading. A trigger may not be apparent but possible associations include fungal infection, drugs, autoimmune or endocrine diseases, such as lupus or thyroid disease, and malignancy, particularly haematological. An underlying trigger must be sought and removed or treated. Topical glucocorticoids or phototherapy may be helpful for chronic disease. Acanthosis nigricans Hyperkeratosis and pigmentation are typical and affected sites have a velvety texture. The ﬂexures, especially axillae and, in dark-skinned people, sides of neck, are involved (pp. 1325, 1326 and 720). There are several types, mainly associated with insulin resistance. Most often, acanthosis nigricans is found in conjunction with obesity and regresses with weight loss. It can be associated with malignancy, usually adenocarcinoma (particularly gastric), when it is usually more extensive and pruritic, and can involve mucous membranes. Drug eruptions Virtually all drugs may have cutaneous adverse effects (Fig. 29.54) and this should be considered in the differential diagnosis of most presentations of skin disease. Drugs can exert their adverse effects via several mechanisms, which can be broadly subdivided into non-immunological and immunological (Box 29.34). Fig. 29.53 Erythema multiforme in a young woman. Herpes simplex virus infection was the trigger. 29.33 Provoking factors in erythema nodosum Infections • Bacteria: streptococci, mycobacteria, Brucella, Mycoplasma, Rickettsia, Chlamydia • Viruses: hepatitis B and infectious mononucleosis • Fungi Drugs • Sulphonamides, sulphonylureas, oral contraceptives Systemic disease • Sarcoidosis, inﬂammatory bowel disease, malignancy Other • Pregnancy 29.34 Types of drug eruption Non-immunological Predictable • Striae due to glucocorticoids (see Fig. 29.10, p. 1226) • Asteatosis with statins • Candidal infections with antibiotics • Worsening of psoriasis with lithium, β-blockers, antimalarials, NSAIDs • Urticaria with aspirin due to mast cell degranulation • Bradykinin-mediated angioedema due to ACE inhibitors • Doxycycline photosensitivity • Dapsone haemolysis Immunological Unpredictable • Immediate IgE-mediated hypersensitivity (type I): penicillin-induced urticaria and anaphylaxis • Antibody-mediated (type II): penicillin-induced haemolysis • Immune complex-mediated (type III): drug-induced serum sickness or vasculitis • Delayed hypersensitivity (type IV): drug-induced erythema multiforme, lichenoid or pemphigus-like reaction; drug-induced lupus (ACE = angiotensin-converting enzyme; IgE = immunoglobulin E; NSAIDs = non-steroidal anti-inﬂammatory drugs) Erythema nodosum This is characterised histologically by a septal panniculitis of subcutaneous fat (see Fig. 17.59, p. 609). An identiﬁed trigger is often present (Box 29.33). Lesions are typically painful, indurated violaceous nodules on the shins and lower legs. Systemic upset, arthralgias and fever are common. Spontaneous resolution occurs over a month or so, leaving bruise-like marks. Any underlying cause should be identiﬁed and removed or treated. Bed rest, leg elevation and an oral NSAID frequently offer symptomatic relief. Systemic glucocorticoids are effective but seldom required, and must be avoided when there is a possibility of infection. Potassium iodide, dapsone or hydroxychloroquine may be effective for resistant disease but these are rarely required. Acquired reactive perforating dermatosis The hallmark of this condition is transepidermal elimination of dermal material, particularly collagen and elastic tissue. It presents as keratotic papules, particularly in patients with diabetes and chronic renal disease. Treatment with topical glucocorticoids, retinoids, PUVA or UVA1 therapy may help. There are other related perforating dermopathies, with characteristic histology.

1266 • DERMATOLOGY 29.35 Clinical patterns of drug eruptions Reaction pattern Clinical features Examples of causative drugs Exanthematous Erythema, maculopapular Antibiotics (especially ampicillin), anticonvulsants, gold, penicillamine, NSAIDs, carbimazole, anti-TNF drugs and other biological therapies Urticaria and angioedema Sometimes accompanied by angioedema Salicylates, opiates, NSAIDs, antibiotics, dextran, ACE inhibitors Angioedema alone Lichenoid Violaceous, lichen planus-like, dyspigmentation Gold, penicillamine, antimalarials, thiazides, NSAIDs, β-blockers, ACE inhibitors, sulphonamides, lithium, sulphonylureas, proton pump inhibitors, quinine, antituberculous, dyes in colour developers Purpura and vasculitis Palpable purpura and necrosis Allopurinol, antibiotics, ACE inhibitors, NSAIDs, aspirin, anticonvulsants, diuretics, oral contraceptives Erythema multiforme Target-like lesions and bullae on extensor aspects of limbs See Box 29.32, p. 1264 Erythema nodosum Tender, painful, dusky, erythematous nodules on shins See Box 29.33, p. 1265 Exfoliative dermatitis There may be erythroderma Allopurinol, carbamazepine, barbiturates, penicillins, PAS, isoniazid, gold, lithium, penicillamine, ACE inhibitors Toxic epidermal necrolysis Rapid evolution, extensive blistering, erythema, necrolysis, mucosal involvement Anticonvulsants, antibiotics, especially sulphonamides, NSAIDs, terbinaﬁne, sulphonylureas, antiretrovirals, allopurinol Photosensitivity (p. 1220) Photo-exposed site rash, may be sunburn-like, exfoliation, lichenoid Thiazides, amiodarone, quinine, NSAIDs, tetracyclines, ﬂuoroquinolones, phenothiazines, sulphonamides, retinoids, psoralens Drug-induced lupus Photosensitivity, discoid lesions, urticarial or erythema multiforme-like. May have positive lupus serology and anti-histone antibodies Allopurinol, thiazides, ACE inhibitors, PAS, anticonvulsants, β-blockers, gold, hydralazine, minocycline, penicillamine, lithium, proton pump inhibitors Psoriasiform rash Rash resembles psoriasis See Box 29.23 (p. 1248) DRESS Facial oedema, fever, extensive rash, lymphadenopathy, eosinophilia and systemic involvement Anticonvulsants, trimethoprim, minocycline, allopurinol, dapsone, terbinaﬁne AGEP/toxic pustuloderma Rapid onset of sterile, non-follicular pustules on erythematous base Ampicillin/amoxicillin, erythromycin, quinolones, sulphonamides, terbinaﬁne, diltiazem, hydroxychloroquine Acneiform eruptions Rash resembles acne Lithium, anticonvulsants, oral contraceptives, androgens, glucocorticoids, antituberculous drugs, EGFR antagonists (cetuximab and erlotinib) Pigmentation See Box 29.29 (p. 1258) Bullous eruptions Often at pressure sites and there may be other features, such as purpura, milia Barbiturates, penicillamine, furosemide Pseudoporphyria May be indistinguishable from porphyria cutanea tarda clinically NSAIDs, tetracyclines, retinoids, furosemide, nalidixic acid Exacerbation of acute hepatic porphyrias See page 1263 Always check all drugs for safety of use in porphyrias against standard guidelines Drug-induced immunobullous disease May resemble pemphigoid, pemphigus, dermatomyositis, scleroderma, epidermolysis bullosa acquisita Penicillamine, ACE inhibitors, vancomycin Fixed drug eruptions Round/oval, erythema, oedema ± bullae Same site every time drug is given Pigmentation on resolution Tetracyclines, sulphonamides, penicillins, quinine, NSAIDs, barbiturates, anticonvulsants Hair loss Diffuse Cytotoxic agents, oral retinoids, anticoagulants, anticonvulsants, antithyroid drugs, lithium, oral contraceptives, inﬂiximab Hypertrichosis Excessive hair growth in non-androgenic distribution Diazoxide, minoxidil, ciclosporin (ACE = angiotensin-converting enzyme; AGEP = acute generalised exanthematous pustulosis; DRESS = drug rash with eosinophilia and systemic symptoms; EGFR = epidermal growth factor receptor; NSAIDs = non-steroidal anti-inﬂammatory drugs; PAS = para-aminosalicylic acid; TNF = tumour necrosis factor)

Further information • 1267

Clinical features Cutaneous drug reactions typically present in speciﬁc patterns (Box 29.35). Non-immunologically mediated reactions can theoretically occur in anyone, given sufﬁcient exposure to the drug, although idiosyncratic factors, such as genetic predisposition, may render some more susceptible. There is limited information on genetic determinants of drug responses and adverse effects, although advances have been made, e.g. with azathioprine (p. 1227), and provide exciting opportunities for therapeutic personalised medicine. Immunologically mediated cutaneous drug eruptions typically commence within days to weeks of starting the drug. Detailed history-taking relating to prescribed and non-prescribed medications is essential and there may be other clues (Box 29.36). Investigations and management The suspected drug must be stopped. If drug-induced photosensitivity is considered, the patient should be phototested while on the drug to conﬁrm the diagnosis, and again after drug withdrawal to conﬁrm resolution of photosensitivity (p. 1215). An eosinophilia and abnormalities in liver function tests may occur in adverse drug reactions and, for example, speciﬁc IgE to penicillin may be raised in penicillin-induced rash but, otherwise, speciﬁc investigations are not available. Rechallenge with drug is not usually undertaken unless the reaction is mild, as this can be risky. Drug withdrawal may not be straightforward and substitute drugs may be required. Antihistamines and/or topical or systemic glucocorticoids may provide supportive management, depending on the type of cutaneous reaction. The management of anaphylaxis is described on page 76. 29.36 Diagnostic clues to drug eruptions • Past history of reaction to suspected drug • Introduction of suspected drug a few days to weeks before onset of rash • Recent prescription of a drug commonly associated with rashes (penicillin, sulphonamide, thiazide, allopurinol) • Symmetrical eruption that ﬁts with a well-recognised pattern, caused by a current drug • Resolution of rash following drug cessation Further information Websites bad.org.uk British Association of Dermatologists: guidelines and patient information for many skin diseases. cochrane.org/cochrane-reviews Many relevant skin reviews, including sun protection (CD011161), psoriasis (CD001976, CD007633, CD005028, CD001213, CD009481, CD010497, CD010017, CD009687, CD001433), eczema (CD009864, CD005205, CD004054, CD005500, CD005203, CD008642, CD008426, CD003871, CD004416, CD006135, CD007770), skin cancer (CD005413, CD008955, CD007281, CD003412, CD004415, CD007041, CD005414, CD007869, CD004835, CD010308, CD010307, CD011161), leg ulcers (CD010182, CD002303, CD003557, CD001737, CD008599, CD001733, CD000265, CD008394, CD001177, CD009432, CD001273, CD011354, CD001836), acne (CD004425, CD011946, CD002086, CD000194, CD007917), rosacea (CD003262), urticaria (CD007770, CD006137, CD008596), alopecia (CD007628, CD004413), skin infections (CD009992, CD003584, CD004685, CD004767, CD010095, CD003261), bullous pemphigoid (CD002292). nice.org.uk National Institute for Health and Care Excellence: guidance for skin cancer (NG14, NG34, PH32, CSG8, TA172, TA321, TA268, TA319, TA384, TA400, TA366, TA357, TA396, TA269, IPG446, IPG478, DG19), atopic eczema (QS44, CG57, TA81, TA82, TA177), psoriasis (CG153, TA146, TA372, TA368, TA103, TA134, TA350, TA180), sun exposure (NG34, PH32), vitamin D (PH56), urticaria (TA339, ESUOM31), rosacea (ESNM43, ESNM68), scabies (ESUOM29), photodynamic therapy (IPG155, MTG6) and Grenz rays (IPG236). sign.ac.uk Scottish Intercollegiate Guidelines Network: no. 120 – Management of chronic venous leg ulcers; 121 – Diagnosis and management of psoriasis and psoriatic arthritis in adults; 125 – Management of atopic eczema in primary care; 140 – Management of primary cutaneous squamous cell carcinoma. Fig. 29.54 Drug eruption. Possible drug causes of rash should always be considered. This was doxycycline-induced photosensitivity in a farmer.

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01-1 Clinical decision-making

02-2 Clinical therapeutics and good prescribing

03-3 Clinical genetics

04-4 Clinical immunology

05-5 Population health and epidemiology

06-6 Principles of infectious disease

01-7 Poisoning

02-8 Envenomation

03-9 Environmental medicine

04-10 Acute medicine and critical illness

01-11 Infectious disease

02-12 HIV infection and AIDS

03-13 Sexually transmitted infections

04-14 Clinical biochemistry and metabolic medicine

05-15 Nephrology and urology

06-16 Cardiology

07-17 Respiratory medicine

08-18 Endocrinology

09-19 Nutritional factors in disease

10-20 Diabetes mellitus

11-21 Gastroenterology

12-22 Hepatology

13-23 Haematology and transfusion medicine

14-24 Rheumatology and bone disease

15-25 Neurology

16-26 Stroke medicine

17-27 Medical ophthalmology

18-28 Medical psychiatry

19-29 Dermatology

20-30 Maternal medicine

21-31 Adolescent and transition medicine

22-32 Ageing and disease

23-33 Oncology

24-34 Pain and palliative care

25-35 Laboratory reference ranges

19-29 Dermatology

29 Dermatology