# 57 - 62 Immunologically Mediated Skin Diseases

### 62 Immunologically Mediated Skin Diseases

slow to heal, but when they do, irregularly shaped white scars form. 
The majority of cases are secondary to venous hypertension, but pos­
sible underlying illnesses include disorders of hypercoagulability, for 
example, antiphospholipid syndrome and factor V Leiden (Chaps. 
122 and 369).
In pyoderma gangrenosum, the border of untreated active ulcers 
has a characteristic appearance consisting of an undermined necrotic 
violaceous edge and a peripheral erythematous halo. The ulcers often 
begin as pustules that then expand rather rapidly to a size as large 
as 20 cm. Although these lesions are most commonly found on the 
lower extremities, they can arise anywhere on the surface of the body, 
including at sites of trauma (pathergy). An estimated 30–50% of cases 
are idiopathic, and the most common associated disorder is inflamma­
tory bowel disease. Less commonly, pyoderma gangrenosum is asso­
ciated with seropositive rheumatoid arthritis, myelodysplasia, acute 
myelogenous leukemia, a monoclonal gammopathy (usually IgA), or 
an autoinflammatory disorder. Because the histology of pyoderma gan­
grenosum may be nonspecific (dermal infiltrate of neutrophils when in 
untreated state), the diagnosis requires clinicopathologic correlation, in 
particular, the exclusion of similar-appearing ulcers such as vasculitis, 
Meleney’s ulcer (synergistic infection at a site of trauma or surgery), 
dimorphic fungi, cutaneous amebiasis, spider bites, and factitial. In 
the hematologic disorders, the ulcers may be more superficial with a 
pustulobullous border, and these lesions provide a connection between 
classic pyoderma gangrenosum and acute febrile neutrophilic derma­
tosis (Sweet syndrome).
FEVER AND RASH
The major considerations in a patient with a fever and a rash are 
inflammatory diseases versus infectious diseases. In the hospital set­
ting, the most common scenario is a patient who has a drug rash plus 
a fever secondary to an underlying infection. However, it should be 
emphasized that a drug reaction can lead to both a cutaneous eruption 
and a fever (“drug fever”), especially in the setting of DRESS, AGEP, or 
serum sickness–like reaction. Additional inflammatory diseases that 
are often associated with a fever include pustular psoriasis, erythro­
derma, and Sweet syndrome. Lyme disease, secondary syphilis, and 
viral and bacterial exanthems (see “Exanthems,” above) are examples of 
infectious diseases that produce a rash and a fever. Lastly, it is impor­
tant to determine whether or not the cutaneous lesions represent septic 
emboli (see “Purpura,” above). Such lesions usually have evidence 
of ischemia in the form of purpura, necrosis, or impending necrosis 
(gunmetal-gray color). In the patient with thrombocytopenia, however, 
purpura can be seen in inflammatory reactions such as morbilliform 
drug eruptions and infectious lesions. In addition, because of venous 
hypertension, lesions of a morbilliform drug eruption that are below 
the knee can be purpuric.
■
■FURTHER READING
Bolognia JL, Schaffer JV, Cerroni L (eds): Dermatology, 5th ed. 
Philadelphia, Elsevier, 2024.
Callen JP et al (eds): Dermatological Signs of Systemic Disease, 5th ed. 
Edinburgh, Elsevier, 2017.
Fazel N (ed): Oral Signs of Systemic Disease. Switzerland, Springer, 
2019.
Kurtzman D: Rheumatologic dermatology. Clin Dermatol 36:439, 
2018.
Taylor SC et al (eds): Taylor and Kelly’s Dermatology for Skin of Color, 
2nd ed. New York, McGraw-Hill, 2016.

Kim B. Yancey, Benjamin F. Chong, 

Thomas J. Lawley

Immunologically 

Mediated Skin Diseases
A number of immunologically mediated skin diseases and immuno­
logically mediated systemic disorders with cutaneous manifestations 
are now recognized as distinct entities with consistent clinical, his­
tologic, and immunopathologic findings. Clinically, these disorders 
are characterized by morbidity (pain, pruritus, disfigurement) and, 
in some instances, risk of mortality (largely due to loss of epidermal 
barrier function and/or secondary infection). The major features of 
the more common immunologically mediated skin diseases are sum­
marized in this chapter (Table 62-1), as are autoimmune systemic 
disorders with cutaneous manifestations.
Immunologically Mediated Skin Diseases 
CHAPTER 62
AUTOIMMUNE CUTANEOUS DISEASES
■
■PEMPHIGUS VULGARIS
Pemphigus refers to a group of autoantibody-mediated intraepidermal 
blistering diseases characterized by loss of cohesion between epidermal 
cells (a process termed acantholysis). Manual pressure to the skin of 
these patients may elicit the separation of the epidermis (Nikolsky’s 
sign). This finding, while characteristic of pemphigus, is not specific to 
this group of disorders and is also seen in toxic epidermal necrolysis, 
Stevens-Johnson syndrome, and a few other skin diseases.
Pemphigus vulgaris (PV) is a mucocutaneous blistering disease that 
predominantly occurs in patients >40 years of age. PV typically begins 
on mucosal surfaces and often progresses to involve the skin. This dis­
ease is characterized by fragile, flaccid blisters that rupture to produce 
extensive denudation of mucous membranes and skin (Fig. 62-1). The 
mouth, scalp, face, neck, axilla, groin, and trunk are typically involved. 
PV may be associated with severe skin pain; some patients experience 
pruritus as well. Lesions usually heal without scarring except at sites 
complicated by secondary infection or mechanically induced dermal 
wounds. Postinflammatory hyperpigmentation is usually present for 
some time at sites of healed lesions.
Biopsies of early lesions demonstrate intraepidermal vesicle 
formation secondary to loss of cohesion between epidermal cells 
(i.e., acantholytic blisters). Blister cavities contain acantholytic epi­
dermal cells, which appear as round homogeneous cells containing 
hyperchromatic nuclei. Basal keratinocytes remain attached to the 
epidermal basement membrane; hence, blister formation takes place 
within the suprabasal portion of the epidermis. Lesional skin may 
contain focal collections of intraepidermal eosinophils within blister 
cavities; dermal alterations are slight, often limited to an eosino­
phil-predominant leukocytic infiltrate. Direct immunofluorescence 
microscopy of lesional or intact patient skin shows deposits of IgG 
on the surface of keratinocytes; deposits of complement components 
are typically found in lesional but not in uninvolved skin. Deposits 
of IgG on keratinocytes are derived from circulating autoantibodies 
to cell-surface autoantigens. Such circulating autoantibodies can be 
demonstrated in 80–90% of PV patients by indirect immunofluores­
cence microscopy; monkey esophagus is the optimal substrate for 
these studies. Patients with PV have IgG autoantibodies to desmo­
gleins (Dsgs), transmembrane desmosomal glycoproteins that belong 
to the cadherin family of calcium-dependent adhesion molecules. 
Such autoantibodies can be precisely quantitated by enzyme-linked 
immunosorbent assay (ELISA). Patients with early PV (i.e., mucosal 
disease) have IgG autoantibodies to Dsg3; patients with advanced 
PV (i.e., mucocutaneous disease) have IgG autoantibodies to both 
Dsg3 and Dsg1. Experimental studies have shown that autoanti­
bodies from patients with PV are pathogenic (i.e., responsible for 
blister formation) and that their titer correlates with disease activity.

TABLE 62-1  Immunologically Mediated Blistering Diseases
DISEASE
CLINICAL MANIFESTATIONS
HISTOLOGY
IMMUNOPATHOLOGY
AUTOANTIGENSa
Pemphigus vulgaris
Oromucosal lesions, flaccid blisters, 
denuded skin
Acantholytic blister formed in 
suprabasal layer of epidermis
Pemphigus foliaceus
Crusts and shallow erosions on 
scalp, central face, upper chest, 
and back
Acantholytic blister formed in 
superficial layer of epidermis
Paraneoplastic pemphigus
Painful stomatitis with 
papulosquamous or lichenoid 
eruptions that may progress to 
blisters
Acantholysis, keratinocyte 
necrosis, and vacuolar 
interface dermatitis
PART 2
Cardinal Manifestations and Presentation of Diseases
Bullous pemphigoid
Large tense blisters on flexor 
surfaces and trunk
Subepidermal blister with 
eosinophil-rich infiltrate
Pemphigoid gestationis
Pruritic, urticarial plaques rimmed 
by vesicles and bullae on the trunk 
and extremities
Teardrop-shaped, subepidermal 
blisters in dermal papillae; 
eosinophil-rich infiltrate
Dermatitis herpetiformis
Extremely pruritic small papules and 
vesicles on elbows, knees, buttocks, 
and posterior neck
Subepidermal blister with 
neutrophils in dermal papillae
Linear IgA disease
Pruritic papulovesicles on extensor 
surfaces; occasionally larger, 
arciform blisters
Subepidermal blister with 
neutrophil-rich infiltrate
Epidermolysis bullosa acquisita
Blisters, erosions, scars, and 
milia on sites exposed to trauma; 
widespread, inflammatory, tense 
blisters may be seen initially
Subepidermal blister that may 
or may not include a leukocytic 
infiltrate
Mucous membrane pemphigoid
Erosive and/or blistering lesions of 
mucous membranes and possibly 
the skin; scarring of some sites
Subepidermal blister that may 
or may not include a leukocytic 
infiltrate
aAutoantigens bound by these patients’ autoantibodies are defined as follows: Dsg1, desmoglein 1; Dsg3, desmoglein 3; BPAG1, bullous pemphigoid antigen 1; BPAG2, 
bullous pemphigoid antigen 2.
Abbreviation: BMZ, basement membrane zone.
Recent studies have shown that the anti-Dsg autoantibody profile 
in these patients’ sera as well as the tissue distribution of Dsg3 and 
Dsg1 determine the site of blister formation in patients with PV. 
Coexpression of Dsg3 and Dsg1 by epidermal cells protects against 
pathogenic IgG antibodies to either of these cadherins but not 
against pathogenic autoantibodies to both.
PV can be life-threatening. Prior to the availability of glucocor­
ticoids, mortality rates ranged from 60% to 90%; the current figure 
is ~5%. Common causes of morbidity and death are infection and 
complications of treatment. Bad prognostic factors include advanced 
age, widespread involvement, and the requirement for high doses of 
glucocorticoids (with or without other immunosuppressive agents) 
for control of disease. The course of PV in individual patients is 
variable and difficult to predict. Some patients experience remis­
sion, while others may require long-term treatment or succumb 
to complications of their disease or its treatment. The mainstay of 
treatment is systemic glucocorticoids alone or in combination with 
other immunosuppressive agents. Patients with moderate to severe 
PV are usually started on prednisone at doses ≤1 mg/kg per day (single 
morning dose). If new lesions continue to appear after 1–2 weeks 
of treatment, the dose of prednisone may need to be increased and/
or combined with another immunosuppressive agent. Among these, 
rituximab in combination with prednisone often achieves remission 
(though maintenance therapy may be required to prevent relapse). 
Other immunosuppressive agents sometimes combined with pred­
nisone to treat PV include azathioprine, mycophenolate mofetil, or 
cyclophosphamide. Patients with severe, treatment-resistant disease 
may derive benefit from plasmapheresis (six high-volume exchanges 
[i.e., 2–3 L per exchange] over ~2 weeks) and/or IV immunoglobulin 
(IVIg). It is important to bring severe or progressive disease under 
control quickly in order to lessen the severity and/or duration of this 
disorder. Increasingly, rituximab and daily glucocorticoids are used 
early in PV patients to avert the development of advanced and/or 
treatment-resistant disease.

Cell surface deposits of IgG on 
keratinocytes
Dsg3 (plus Dsg1 in patients 
with skin involvement)
Cell surface deposits of IgG on 
keratinocytes
Dsg1
Cell surface deposits of IgG 
and C3 on keratinocytes 
and (variably) similar 
immunoreactants in epidermal 
BMZ
Plakin protein family 
members and desmosomal 
cadherins (see text for 
details)
Linear band of IgG and/or C3 in 
epidermal BMZ
BPAG1, BPAG2
Linear band of C3 in epidermal 
BMZ
BPAG2 (plus BPAG1 in 
some patients)
Granular deposits of IgA in 
dermal papillae
Epidermal 
transglutaminase
Linear band of IgA in epidermal 
BMZ
BPAG2 (see text for 
specific details)
Linear band of IgG and/or C3 in 
epidermal BMZ
Type VII collagen
Linear band of IgG, IgA, and/or 
C3 in epidermal BMZ
BPAG2, laminin-332, or 
others
■
■PEMPHIGUS FOLIACEUS
Pemphigus foliaceus (PF) is distinguished from PV by several features. 
In PF, acantholytic blisters are located high within the epidermis, usu­
ally just beneath the stratum corneum. Hence, PF is a more superfi­
cial blistering disease than PV. The distribution of lesions in the two 
disorders is much the same, except that in PF mucous membranes 
are almost always spared. Patients with PF rarely have intact blisters 
but rather exhibit shallow erosions associated with erythema, scale, 
and crust formation. Mild cases of PF can resemble severe seborrheic 
dermatitis; severe PF may cause extensive exfoliation. Sun exposure 
(ultraviolet irradiation) may be an aggravating factor.
PF has immunopathologic features in common with PV. Specifically, 
direct immunofluorescence microscopy of perilesional skin demon­
strates IgG on the surface of keratinocytes. Similarly, patients with PF 
have circulating IgG autoantibodies directed against the surface of 
keratinocytes. In PF, autoantibodies are directed against Dsg1, a 160kDa desmosomal cadherin. These autoantibodies can be quantitated 
by ELISA. As noted for PV, the autoantibody profile in patients with PF 
(i.e., anti-Dsg1 IgG) and the tissue distribution of this autoantigen (i.e., 
expression in oral mucosa that is compensated by coexpression of Dsg3) 
are thought to account for the distribution of lesions in this disease.
Endemic forms of PF are found in south-central rural Brazil, where 
the disease is known as fogo salvagem (FS), as well as in selected sites 
in Latin America and Tunisia. Endemic PF, like other forms of this 
disease, is mediated by IgG autoantibodies to Dsg1. Clusters of FS 
overlap with those of leishmaniasis, a disease transmitted by bites of the 
sand fly Lutzomyia longipalis. Studies have shown that sand fly salivary 
antigens (specifically, the LJM11 salivary protein) are recognized by 
IgG autoantibodies from FS patients (as well as by monoclonal anti­
bodies to Dsg1 derived from these patients). The demonstration that 
mice immunized with LJM11 produce antibodies to Dsg1 suggests 
that insect bites may deliver salivary antigens, initiate a cross-reactive 
humoral immune response, and lead to FS in genetically susceptible 
individuals.

A
B
FIGURE 62-1  Pemphigus vulgaris. A. Flaccid bullae are easily ruptured, resulting in 
multiple erosions and crusted plaques. B. Involvement of the oral mucosa, which is 
almost invariable, may present with erosions on the gingiva, buccal mucosa, palate, 
posterior pharynx, or tongue. (Courtesy of Robert Swerlick, MD; with permission.)
Although pemphigus has been associated with several autoimmune 
diseases, its association with thymoma and/or myasthenia gravis is 
particularly notable. To date, >30 cases of thymoma and/or myasthenia 
gravis have been reported in association with pemphigus, usually with 
PF. Patients may also develop pemphigus as a consequence of drug 
exposure; drug-induced pemphigus usually resembles PF rather than 
PV. Drugs containing a thiol group in their chemical structure (e.g., 
penicillamine, captopril, enalapril) are most commonly associated with 
drug-induced pemphigus. Nonthiol drugs linked to pemphigus include 
penicillins, cephalosporins, and piroxicam. Some cases of drug-induced 
pemphigus are durable and require treatment with systemic glucocor­
ticoids and/or immunosuppressive agents.
PF is generally a less severe disease than PV and usually carries 
a better prognosis. Localized disease can sometimes be treated with 
topical or intralesional glucocorticoids; more active cases can usually 
be controlled with systemic glucocorticoids either alone or in com­
bination with other immunosuppressive agents. Patients with severe, 
treatment-resistant disease may require more aggressive interventions, 
as described above for patients with PV.

■
■PARANEOPLASTIC PEMPHIGUS
Paraneoplastic pemphigus (PNP) is an autoimmune acantholytic 
mucocutaneous disease associated with an occult or confirmed 
neoplasm. Patients with PNP typically have painful stomatitis in 
association with papulosquamous and/or lichenoid eruptions that 
often progress to blisters. Palm and sole involvement are common in 
these patients and raise the possibility that prior reports of neoplasia-

associated erythema multiforme may have represented unrecognized 
cases of PNP. Biopsies of lesional skin from these patients show 
varying combinations of acantholysis, keratinocyte necrosis, and 
vacuolar-interface dermatitis. Direct immunofluorescence microscopy 
of a patient’s skin shows deposits of IgG and complement on the 
surface of keratinocytes and (variably) similar immunoreactants in 
the epidermal basement membrane zone. Patients with PNP have IgG 
autoantibodies to cytoplasmic proteins that are members of the pla­
kin family (e.g., desmoplakins I and II, bullous pemphigoid antigen 
[BPAG] 1, envoplakin, periplakin, and plectin) and to other proteins 
(e.g., Dsg1, Dsg3, and α2-macroglobulin like-1). Passive transfer 
studies have shown that autoantibodies from patients with PNP are 
pathogenic in animal models.

Immunologically Mediated Skin Diseases 
CHAPTER 62
The predominant neoplasms associated with PNP are non-Hodgkin’s 
lymphoma, chronic lymphocytic leukemia, thymoma, spindle cell 
tumors, Waldenström’s macroglobulinemia, and Castleman’s disease; 
the last-mentioned neoplasm is particularly common among children 
with PNP. Rare cases of seronegative PNP have been reported in 
patients with B-cell malignancies previously treated with rituximab. 
In addition to severe skin lesions, many patients with PNP develop 
life-threatening bronchiolitis obliterans. PNP is generally resistant to 
conventional therapies (i.e., those used to treat PV); rarely, a patient’s 
disease may ameliorate or even remit following ablation or removal of 
underlying neoplasms.
■
■BULLOUS PEMPHIGOID
Bullous pemphigoid (BP) is a polymorphic autoimmune subepidermal 
blistering disease usually seen in the elderly. Initial lesions may consist 
of urticarial plaques; most patients eventually display tense vesicles or 
blisters on either normal-appearing or erythematous skin (Fig. 62-2). 
The lesions are usually distributed over the lower abdomen, groin, 
and flexor surface of the extremities; oral mucosal lesions are found in 
some patients. Pruritus may be nonexistent or severe. As lesions evolve, 
tense blisters tend to rupture and be replaced by erosions with or with­
out surmounting crust. Nontraumatized blisters heal without scarring. 
FIGURE 62-2  Bullous pemphigoid with tense vesicles and bullae on erythematous, 
urticarial bases. (Courtesy of the Yale Resident’s Slide Collection; with permission.)

The major histocompatibility complex class II allele HLA-DQβ1∗0301 
is prevalent in patients with BP. Though most cases occur sporadically, 
BP can be triggered by medications (e.g., furosemide, dipeptidyl 
peptidase-4 inhibitors, immune checkpoint inhibitors), ultraviolet 
light, or ionizing radiation. Several studies have shown that BP is 
associated with neurologic diseases (e.g., stroke, dementia, Parkinson’s 
disease, and multiple sclerosis).

Biopsies of early lesional skin demonstrate subepidermal blisters 
and histologic features that roughly correlate with the clinical character 
of the lesion under study. Lesions on normal-appearing skin generally 
contain a sparse perivascular leukocytic infiltrate with some eosino­
phils; conversely, biopsies of inflammatory lesions typically show an 
eosinophil-rich infiltrate at sites of vesicle formation and in perivas­
cular areas. In addition to eosinophils, cell-rich lesions also contain 
mononuclear cells and neutrophils. It is not possible to distinguish 
BP from other subepidermal blistering diseases by routine histologic 
studies alone.
PART 2
Cardinal Manifestations and Presentation of Diseases
Direct immunofluorescence microscopy of normal-appearing per­
ilesional skin from patients with BP shows linear deposits of IgG and/
or C3 in the epidermal basement membrane. The sera of ~70% of these 
patients contain circulating IgG autoantibodies that bind the epidermal 
basement membrane of normal human skin in indirect immunofluo­
rescence microscopy. IgG from an even higher percentage of patients 
reacts with the epidermal side of 1 M NaCl split skin (an alternative 
immunofluorescence microscopy test substrate used to distinguish 
circulating IgG autoantibodies to the basement membrane in patients 
with BP from those in patients with similar, yet different, subepidermal 
blistering diseases; see below). In BP, circulating autoantibodies recog­
nize 230- and 180-kDa hemidesmosome-associated proteins in basal 
keratinocytes (i.e., BPAG1 and BPAG2, respectively). Autoantibodies 
to BPAG2 are thought to deposit in situ, activate complement, produce 
dermal mast-cell degranulation, and generate granulocyte-rich infil­
trates that cause tissue damage and blister formation.
BP may persist for months to years, with exacerbations or remis­
sions. Extensive involvement may result in widespread erosions and 
compromise cutaneous integrity; elderly and/or debilitated patients 
may die. Local or minimal disease can sometimes be controlled with 
potent topical glucocorticoids alone; more extensive lesions generally 
respond to systemic glucocorticoids either alone or in combination 
with other agents. Adjuncts to systemic glucocorticoids include doxy­
cycline, azathioprine, mycophenolate mofetil, and rituximab.
■
■PEMPHIGOID GESTATIONIS
Pemphigoid gestationis (PG), also known as herpes gestationis, is a 
rare, nonviral, subepidermal blistering disease of pregnancy and the 
puerperium. PG may begin during any trimester of pregnancy or 
present shortly after delivery. Lesions are usually distributed over the 
abdomen, trunk, and extremities; mucous membrane lesions are rare. 
Skin lesions in these patients may be quite polymorphic and consist 
of erythematous urticarial papules and plaques, vesiculopapules, and/
or frank bullae. Lesions are almost always extremely pruritic. Severe 
exacerbations of PG frequently follow delivery, typically within 24–48 h. 
PG tends to recur in subsequent pregnancies, often beginning earlier 
during such gestations. Brief flare-ups of disease may occur with 
resumption of menses and may develop in patients later exposed to 
oral contraceptives. Occasionally, infants of affected mothers have 
transient skin lesions.
Biopsies of early lesional skin show teardrop-shaped subepidermal 
vesicles forming in dermal papillae in association with an eosinophil-rich 
leukocytic infiltrate. Differentiation of PG from other subepidermal 
bullous diseases by light microscopy is difficult. However, direct 
immunofluorescence microscopy of perilesional skin from PG patients 
reveals the immunopathologic hallmark of this disorder: linear depos­
its of C3 in the epidermal basement membrane. These deposits develop 
as a consequence of complement activation produced by low-titer IgG 
anti–basement membrane autoantibodies directed against BPAG2, 
the same hemidesmosome-associated protein that is targeted by auto­
antibodies in patients with BP—a subepidermal bullous disease that 
resembles PG clinically, histologically, and immunopathologically.

The goals of therapy in patients with PG are to prevent the devel­
opment of new lesions, relieve intense pruritus, and care for erosions 
at sites of blister formation. Many patients require treatment with 
moderate doses of daily glucocorticoids (i.e., 20–40 mg of prednisone) 
at some point in their course. Mild cases (or brief flare-ups) may be 
controlled by vigorous use of potent topical glucocorticoids. Infants 
born of mothers with PG appear to be at increased risk of being born 
slightly premature or “small for dates.” Current evidence suggests that 
there is no difference in the incidence of uncomplicated live births 
between PG patients treated with systemic glucocorticoids and those 
managed more conservatively. If systemic glucocorticoids are admin­
istered, newborns are at risk for development of reversible adrenal 
insufficiency.
■
■DERMATITIS HERPETIFORMIS
Dermatitis herpetiformis (DH) is an intensely pruritic, papulovesicular 
skin disease characterized by lesions symmetrically distributed over 
extensor surfaces (i.e., elbows, knees, buttocks, back, scalp, and pos­
terior neck) (see Fig. 59-8). Primary lesions in this disorder consist 
of papules, papulovesicles, or urticarial plaques. Because pruritus is 
prominent, patients may present with excoriations and crusted papules 
but no observable primary lesions. Patients sometimes report that their 
pruritus has a distinctive burning or stinging component; the onset 
of such local symptoms reliably heralds the development of distinct 
clinical lesions 12–24 h later. Almost all DH patients have associated, 
usually subclinical, gluten-sensitive enteropathy (Chap. 336), and 
>90% express the HLA-B8/DRw3 and HLA-DQw2 haplotypes. DH 
may present at any age, including in childhood; onset in the second to 
fourth decades is most common. The disease is typically chronic.
Biopsy of early lesional skin reveals neutrophil-rich infiltrates within 
dermal papillae. Neutrophils, fibrin, edema, and microvesicle forma­
tion at these sites are characteristic of early disease. Older lesions may 
demonstrate nonspecific features of a subepidermal bulla or an excori­
ated papule. Because the clinical and histologic features of this disease 
can be variable and resemble those of other subepidermal blistering 
disorders, the diagnosis is confirmed by direct immunofluorescence 
microscopy of normal-appearing perilesional skin. Such studies dem­
onstrate granular deposits of IgA (with or without complement com­
ponents) in the papillary dermis and along the epidermal basement 
membrane zone. IgA deposits in the skin are unaffected by control of 
disease with medication; however, these immunoreactants diminish 
in intensity or disappear in patients maintained for long periods on 
a strict gluten-free diet (see below). Patients with DH have granular 
deposits of IgA in their epidermal basement membrane zone and 
should be distinguished from individuals with linear IgA deposits at 
this site (see below).
Although most DH patients do not report overt gastrointestinal 
symptoms or have laboratory evidence of malabsorption, biopsies of 
the small bowel usually reveal blunting of intestinal villi and a lympho­
cytic infiltrate in the lamina propria. As is true for patients with celiac 
disease, this gastrointestinal abnormality can be reversed by a glutenfree diet. Moreover, if maintained, this diet alone may control the skin 
disease and eventuate in clearance of IgA deposits from these patients’ 
epidermal basement membrane zones. Subsequent gluten exposure 
in such patients alters the morphology of their small bowel, elicits a 
flare-up of their skin disease, and is associated with the reappearance 
of IgA in their epidermal basement membrane zones. As in patients 
with celiac disease, dietary gluten sensitivity in patients with DH is 
associated with IgA anti-endomysial autoantibodies that target tissue 
transglutaminase. Studies indicate that patients with DH also have 
high-avidity IgA autoantibodies to epidermal transglutaminase and 
that the latter is co-localized with granular deposits of IgA in the papil­
lary dermis of DH patients. Patients with DH also have an increased 
incidence of thyroid abnormalities, achlorhydria, atrophic gastritis, 
and autoantibodies to gastric parietal cells. These associations likely 
relate to the high frequency of the HLA-B8/DRw3 haplotype in these 
patients, since this marker is commonly linked to autoimmune disor­
ders. The mainstay of treatment of DH is dapsone, a sulfone. Patients 
respond rapidly (24–48 h) to dapsone but require careful pretreatment

evaluation (e.g., screening for glucose-6-phosphate dehydrogenase 
deficiency) and close follow-up to ensure that complications are 
avoided or controlled. All patients taking dapsone at ≥100 mg/d will 
have some hemolysis and methemoglobinemia, which are expected 
pharmacologic side effects of this agent. Gluten restriction can control 
DH and lessen dapsone requirements; this diet must rigidly exclude 
gluten to be of maximal benefit. Many months of dietary restriction 
may be necessary before a beneficial result is achieved. Good dietary 
counseling by a trained dietitian is essential.
■
■LINEAR IGA DISEASE
Linear IgA disease, once considered a variant form of DH, is actually a 
separate and distinct entity. Clinically, patients with linear IgA disease 
may resemble individuals with DH, BP, or other subepidermal blister­
ing diseases. Lesions typically consist of papulovesicles, bullae, and/or 
urticarial plaques that develop predominantly on central or flexural 
sites. Oral mucosal involvement occurs in some patients. Severe pru­
ritus resembles that seen in patients with DH. Patients with linear IgA 
disease do not have an increased frequency of the HLA-B8/DRw3 hap­
lotype or an associated enteropathy and therefore are not candidates for 
treatment with a gluten-free diet.
Histologic alterations in early lesions may be virtually indistinguish­
able from those in DH. However, direct immunofluorescence micros­
copy of normal-appearing perilesional skin reveals a linear band of 
IgA (and often C3) in the epidermal basement membrane zone. Most 
patients with linear IgA disease have circulating IgA anti-basement 
membrane autoantibodies directed against neoepitopes in the pro­
teolytically processed extracellular domain of BPAG2. These patients 
generally respond to treatment with dapsone (50–200 mg/d) alone or 
in combination with low daily doses of prednisone.
■
■EPIDERMOLYSIS BULLOSA ACQUISITA
Epidermolysis bullosa acquisita (EBA) is a rare, noninherited, poly­
morphic, chronic, subepidermal blistering disease. (The inherited 
form is discussed in Chap. 425.) Patients with classic or noninflam­
matory EBA have blisters on noninflamed skin, atrophic scars, milia, 
nail dystrophy, hair loss, and oral lesions. Because lesions generally 
occur at sites exposed to minor trauma, classic EBA is considered a 
mechanobullous disease. Other patients with EBA have widespread 
inflammatory scarring and bullous lesions that resemble severe BP. 
Inflammatory EBA may evolve into the classic, noninflammatory 
form of this disease. Rarely, patients present with lesions that pre­
dominate on mucous membranes. The HLA-DR2 haplotype is found 
with increased frequency in EBA patients. Studies suggest that EBA 
is sometimes associated with inflammatory bowel disease (especially 
Crohn’s disease).
The histology of lesional skin varies with the character of the 
lesion being studied. Noninflammatory bullae are subepidermal, 
feature a sparse leukocytic infiltrate, and resemble the lesions in 
patients with porphyria cutanea tarda. Inflammatory lesions consist of 

neutrophil-rich subepidermal blisters. EBA patients have continu­
ous deposits of IgG (and frequently C3) in a linear pattern within 
the epidermal basement membrane zone. Ultrastructurally, these 
immunoreactants are found in the sublamina densa region in associa­
tion with anchoring fibrils. Approximately 50% of EBA patients have 
demonstrable circulating IgG anti-basement membrane autoantibodies 
directed against type VII collagen—the collagen species that makes 
up anchoring fibrils. Such IgG autoantibodies bind the dermal side 
of 1 M NaCl split skin (in contrast to IgG autoantibodies in patients 
with BP). Studies have shown that passive transfer of experimental or 
patient IgG against type VII collagen can produce lesions in mice that 
clinically, histologically, and immunopathologically resemble those in 
patients with EBA.
Treatment of EBA is generally unsatisfactory. Some patients with 
inflammatory EBA may respond to systemic glucocorticoids, either 
alone or in combination with immunosuppressive agents. Other 
patients (especially those with neutrophil-rich inflammatory lesions) 
may respond to dapsone. The chronic, noninflammatory form of EBA 
is largely resistant to treatment, although some patients may respond 

to prednisone in combination with rituximab, cyclosporine, mycophe­
nolate mofetil, azathioprine, or IVIg.

■
■MUCOUS MEMBRANE PEMPHIGOID
Mucous membrane pemphigoid (MMP) is a rare, acquired, subepithe­
lial immunobullous disease characterized by erosive lesions of mucous 
membranes and skin that result in scarring of at least some sites of 
involvement. Common sites include the oral mucosa (especially the 
gingiva) and conjunctiva; other sites that may be affected include the 
nasopharyngeal, laryngeal, esophageal, and anogenital mucosa. Skin 
lesions (present in about one-third of patients) tend to predominate 
on the scalp, face, and upper trunk and generally consist of a few scat­
tered erosions or tense blisters on an erythematous or urticarial base. 
MMP is typically a chronic and progressive disorder. Serious compli­
cations may arise as a consequence of ocular, laryngeal, esophageal, 
or anogenital lesions. Erosive conjunctivitis may result in shortened 
fornices, symblepharon, ankyloblepharon, entropion, corneal opaci­
ties, and (in severe cases) blindness. Similarly, erosive lesions of the 
larynx may cause hoarseness, pain, and tissue loss that, if unrecognized 
and untreated, may eventuate in complete destruction of the airway. 
Esophageal lesions may result in stenosis and/or strictures that could 
place patients at risk for aspiration. Strictures may also complicate 
anogenital involvement.
Immunologically Mediated Skin Diseases 
CHAPTER 62
Biopsies of lesional tissue generally show subepithelial vesicu­
lobullae and a mononuclear leukocytic infiltrate. Neutrophils and 
eosinophils may be seen in biopsies of early lesions; older lesions may 
demonstrate a scant leukocytic infiltrate and fibrosis. Direct immu­
nofluorescence microscopy of perilesional tissue typically reveals 
deposits of IgG, IgA, and/or C3 in the epidermal basement membrane. 
Because many patients with MMP exhibit no evidence of circulating 
anti-basement membrane autoantibodies, testing of perilesional skin 
is important diagnostically. Although MMP was once thought to be a 
single nosologic entity, it is now largely regarded as a disease pheno­
type that may develop as a consequence of an autoimmune reaction 
to a variety of molecules in the epidermal basement membrane (e.g., 
BPAG2, laminin-332, type VII collagen, α6β4 integrin) and other anti­
gens yet to be completely defined. Studies suggest that MMP patients 
with autoantibodies to laminin-332 have an increased relative risk 
for cancer. Treatment of MMP is largely dependent upon the sites of 
involvement. Due to potentially severe complications, patients with 
ocular, laryngeal, esophageal, and/or anogenital involvement require 
aggressive systemic treatment with dapsone, prednisone, or the latter 
in combination with other immunosuppressive agents (e.g., rituximab, 
azathioprine, mycophenolate mofetil, or cyclophosphamide), or IVIg. 
Less threatening forms of the disease may be managed with topical or 
intralesional glucocorticoids.
AUTOIMMUNE SYSTEMIC DISEASES WITH 
PROMINENT CUTANEOUS FEATURES
■
■DERMATOMYOSITIS
The cutaneous manifestations of dermatomyositis (Chap. 377) are 
often distinctive but at times may resemble those of systemic lupus 
erythematosus (SLE) (Chap. 368), scleroderma (Chap. 372), or other 
overlapping connective tissue diseases (Chap. 372). The extent and 
severity of cutaneous disease may or may not correlate with the extent 
and severity of the myositis. The cutaneous manifestations of dermato­
myositis are similar, whether the disease appears in children or in the 
elderly, except that calcification of subcutaneous tissue is a common 
late sequela in childhood dermatomyositis. Dermatomyositis may be 
associated with interstitial lung disease or cancer.
The cutaneous signs of dermatomyositis may precede or follow 
the development of myositis by weeks to years. Cases lacking muscle 
involvement (i.e., dermatomyositis sine myositis or amyopathic derma­
tomyositis) have been reported. The most common manifestation is a 
purple-red discoloration of the upper eyelids, sometimes associated 
with scaling (“heliotrope” erythema; Fig. 62-3) and periorbital edema. 
Erythema on the cheeks and nose in a “butterfly” distribution may 
resemble the malar eruption of SLE. Erythematous or violaceous thin,

PART 2
Cardinal Manifestations and Presentation of Diseases
FIGURE 62-3  Dermatomyositis. Periorbital violaceous erythema characterizes the 
classic heliotrope rash. (Courtesy of James Krell, MD; with permission.)
scaly plaques are common on the upper trunk and neck (shawl sign), 
the scalp, lateral aspects of the thighs (holster sign), and the extensor 
surfaces of the forearms and hands (tendon streaking). Approximately 
one-third of patients have violaceous, flat-topped papules over the dor­
sal interphalangeal joints that are pathognomonic of dermatomyositis 
(Gottron’s papules) (Fig. 62-4). Thin violaceous papules and plaques 
on the elbows and knees of patients with dermatomyositis are referred 
to as Gottron’s sign. These lesions can be contrasted with the erythema 
and scaling on the dorsum of the fingers that spares the skin over the 
interphalangeal joints of some SLE patients. Periungual telangiectasias 
and edema may be prominent in patients with dermatomyositis. Other 
patients, particularly those with long-standing disease, develop areas 
of hypopigmentation, hyperpigmentation, mild atrophy, and telangi­
ectasia known as poikiloderma. Poikiloderma is rare in both SLE and 
FIGURE 62-4  Dermatomyositis showing involvement of the hands with erythematous 
flat-topped papules over the joints (i.e., Gottron’s papules) as well as periungual 
erythema and telangiectasias. (Courtesy of Justin Cheeley, MD; with permission.)

scleroderma and thus can serve as a clinical sign that distinguishes 
dermatomyositis from these two diseases. Cutaneous changes may 
be similar in dermatomyositis and various overlap syndromes where 
thickening and binding down of the skin of the hands (sclerodactyly) 
as well as Raynaud’s phenomenon can be seen. However, the presence 
of severe muscle disease, Gottron’s papules, heliotrope erythema, and 
poikiloderma serves to distinguish patients with dermatomyositis. Skin 
biopsy of the erythematous, scaling lesions of dermatomyositis may 
reveal only mild nonspecific inflammation, but sometimes may show 
changes indistinguishable from those found in cutaneous lupus erythe­
matosus (LE), including epidermal atrophy, hydropic degeneration of 
basal keratinocytes, and dermal changes consisting of interstitial mucin 
deposition and a mild mononuclear cell perivascular infiltrate. Direct 
immunofluorescence microscopy of lesional skin is usually negative, 
although granular deposits of immunoglobulin(s) and complement in 
the epidermal basement membrane zone have been described in some 
patients. Treatment should be stratified based on the relative severity 
of disease. Topical treatments include glucocorticoids, sunscreens, and 
aggressive photoprotective measures. Treatment of systemic disease 
includes antimalarials (though some patients may develop a drug 
eruption upon initiation of therapy) or systemic glucocorticoids in 
conjunction with methotrexate, mycophenolate mofetil, azathioprine, 
rituximab, or IVIg.
■
■LUPUS ERYTHEMATOSUS
The cutaneous manifestations of LE (Chap. 368) can be divided into 
acute, subacute, and chronic types. Acute cutaneous LE is characterized 
by erythema of the nose and malar eminences in a “butterfly” distribu­
tion (Fig. 62-5A). The erythema is often sudden in onset, accompanied 
by edema and fine scale, and correlated with systemic involvement. 
Patients may have widespread involvement of the face as well as ery­
thema and scaling of the extensor surfaces of the extremities and upper 
chest (Fig. 62-5B). These acute lesions, while sometimes evanescent, 
usually last for days and are often associated with exacerbations of 
systemic disease. Skin biopsy of acute lesions typically shows hydropic 
degeneration of basal keratinocytes, dermal edema, and (in some 
cases) a sparse perivascular infiltrate of mononuclear cells in the upper 
dermis as well as dermal mucin. Direct immunofluorescence micros­
copy of lesional skin frequently reveals deposits of immunoglobulin(s) 
and complement in the epidermal basement membrane zone. Treat­
ment of cutaneous disease includes topical glucocorticoids, aggressive 
photoprotection, antimalarials, and control of systemic disease. Treat­
ment of systemic disease associated with acute cutaneous LE includes 
systemic glucocorticoids in conjunction with antimalarials and other 
immunosuppressive agents.
Subacute cutaneous lupus erythematosus (SCLE) is characterized by 
a widespread photosensitive, nonscarring eruption. In most patients, 
renal and central nervous system involvement is mild or absent. SCLE 
may present as a papulosquamous eruption that resembles psoriasis or 
as annular polycyclic lesions. In the papulosquamous form, discrete 
erythematous papules arise on the upper back, upper chest, shoulders, 
extensor surfaces of the arms, and dorsum of the hands; lesions are 
uncommon on the central face and the flexor surfaces of the arms as 
well as below the waist. These slightly scaling papules tend to merge 
into plaques. The annular form involves the same areas and presents 
with erythematous papules that evolve into oval, circular, or poly­
cyclic lesions. The lesions of SCLE are more widespread than those 
in patients with discoid LE and have less tendency for scarring. In 
many patients with SCLE, drugs (e.g., hydrochlorothiazide, calcium 
channel blockers, antifungals, proton pump inhibitors) may induce 
or exacerbate disease. Skin biopsy typically reveals epidermal changes 
that include atrophy, hydropic degeneration of basal keratinocytes, 
and apoptosis accompanied by an infiltrate of mononuclear cells in 
the upper dermis. Direct immunofluorescence microscopy of lesional 
skin reveals deposits of immunoglobulin(s) in the epidermal basement 
membrane zone in about one-half of these cases. A particulate pattern 
of IgG deposition throughout the epidermis has been associated with 
SCLE. Most SCLE patients have anti-Ro autoantibodies. Local therapy 
alone is usually unsuccessful. Most patients require treatment with

A
B
FIGURE 62-5  Acute cutaneous lupus erythematosus (LE). A. Acute cutaneous 
LE on the face, showing prominent, scaly, malar erythema. Involvement of other 
sun-exposed sites is also common. B. Acute cutaneous LE on the upper chest, 
demonstrating brightly erythematous and slightly edematous papules and plaques. 
(Courtesy of Robert Swerlick, MD; with permission.)
aminoquinoline antimalarial drugs. Low-dose therapy with oral glu­
cocorticoids is sometimes necessary. Photoprotective measures against 
both ultraviolet B and ultraviolet A wavelengths are very important.
Chronic cutaneous LE has multiple subtypes; discoid LE (DLE) is the 
most common. DLE is characterized by discrete lesions, most often 
found on the face, scalp, and/or external ears. It is unusual to see DLE 
lesions below the neck without lesions above the neck. The lesions 
are erythematous papules or plaques with a thick, adherent scale that 
occludes hair follicles (follicular plugging). When the scale is removed, 
its underside shows small excrescences that correlate with the openings 
of hair follicles (so-called “carpet tacking”), a finding relatively specific 
for DLE. Long-standing lesions develop central atrophy, scarring, 
and hypopigmentation but frequently have erythematous, sometimes 
raised borders (Fig. 62-6). These lesions persist for years and tend 
to expand slowly. Up to 20% of patients with DLE eventually meet 
the American College of Rheumatology criteria for SLE, but lower 
percentages of DLE patients develop SLE under the Systemic Lupus 
International Collaborating Clinics classification criteria and European 
League Against Rheumatism and American College of Rheumatology 
classification criteria. Typical discoid lesions are frequently seen in 
patients with SLE. Biopsy of DLE lesions shows hyperkeratosis, follicular 
plugging, atrophy of the epidermis, hydropic degeneration of basal 
keratinocytes, thickening of the epidermal basement membrane zone, 

Immunologically Mediated Skin Diseases 
CHAPTER 62
FIGURE 62-6  Discoid lupus erythematosus (DLE). Erythematous to violaceous, 
dyspigmented, atrophic plaques with scarring of the face and scalp. (Courtesy of 
Robert Swerlick, MD; with permission.)
dermal mucin, and a mononuclear cell infiltrate adjacent to epidermal, 
adnexal, and microvascular basement membranes. Direct immuno­
fluorescence microscopy demonstrates immunoglobulin(s) and com­
plement deposits at the basement membrane zone in ~90% of cases. 
Treatment is focused on control of local cutaneous disease and consists 
mainly of photoprotection and topical or intralesional glucocorticoids. 
If local therapy is ineffective, use of aminoquinoline antimalarial agents 
may be indicated.
■
■SCLERODERMA AND MORPHEA
The skin changes of scleroderma (Chap. 372) may be limited or dif­
fuse. In both instances, disease usually begins on the fingers, hands, 
toes, feet, and face, with episodes of recurrent nonpitting edema. 
Sclerosis of the skin commences distally on the fingers (sclerodac­
tyly) and spreads proximally, usually accompanied by resorption of 
bone of the fingertips, which may have punched out ulcers, stellate 
scars, or areas of hemorrhage (Fig. 62-7). The fingers may shrink 
and become sausage-shaped, and, because the fingernails are usually 
unaffected, they may curve over the end of the fingertips. Periungual 
telangiectasias are usually present, but periungual erythema is rare. In 
diffuse disease, the extremities show contractures and calcinosis cutis; 
facial involvement includes a smooth, unwrinkled brow, taut skin over 
the nose, shrinkage of tissue around the mouth, and perioral radial 
FIGURE 62-7  Scleroderma showing acral sclerosis, matlike telangiectasias, and 
focal digital ulcers.  (Courtesy of Justin Cheeley, MD; with permission.)