Immunologically Mediated Skin Diseases
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Immunologically Mediated Skin Diseases
Kim B. Yancey
Thomas J. Lawley
A number of immunologically mediated skin diseases and immunologically mediated systemic disorders with cutaneous manifestations are now recognized as distinct entities with consistent clinical, histologic, and immunopathologic findings. Many of these disorders are due to autoimmune mechanisms. Clinically, they are characterized by morbidity (pain, pruritus, disfigurement) and in some instances by 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 summarized in this chapter (Table1).
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TABLE 1 Immunologically Mediated Blistering Diseases |
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PEMPHIGUS VULGARIS
Pemphigus vulgaris (PV) is a blistering skin disease seen predominantly in elderly patients. Patients with PV have an increased incidence of the HLA-DR4 and -DRw6 serologically defined haplotypes. This disorder is characterized by the loss of cohesion between epidermal cells (a process termed acantholysis) with the resultant formation of intraepidermal blisters. Clinical lesions of PV typically consist of flaccid blisters on either normal-appearing or erythematous skin. These blisters rupture easily, leaving denuded areas that may crust and enlarge peripherally. Substantial portions of the body surface may be denuded in severe cases. Manual pressure to the skin of these patients may elicit the separation of the epidermis (Nikolsky's sign). This finding, while characteristic of PV, is not specific to this disorder and is also seen in toxic epidermal necrolysis, Stevens-Johnson syndrome, and a few other skin diseases. Lesions in PV typically present on the oral mucosa, scalp, face, neck, axilla, and trunk. In most patients, lesions begin in the mouth; involvement of other mucosal surfaces (e.g., pharyngeal, laryngeal, esophageal, conjunctival, vulval, or rectal) can occur in severe disease. Pruritus may be a feature of early pemphigus lesions; extensive denudation may be associated with severe pain. Lesions usually heal without scarring, except at sites complicated by secondary infection or mechanically induced dermal wounds. Nonetheless, postinflammatory hyperpigmentation is usually present at sites of healed lesions for some time.
Biopsies of early lesions demonstrate intraepidermal vesicle formation secondary to loss of cohesion between epidermal cells (i.e., acantholytic blisters). Blister cavities contain acantholytic epidermal cells, which appear as round homogeneous cells containing hyperchromatic nuclei. Basal keratinocytes remain attached to the epidermal basement membrane, hence blister formation is 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 eosinophil-predominant leukocytic infiltrate. Direct immunofluorescence microscopy of lesional or intact patient skin shows deposits of IgG on the surface of keratinocytes; in contrast, deposits of complement components are typically found in lesional but not uninvolved skin. Deposits of IgG on keratinocytes are derived from circulating autoantibodies directed against cell-surface antigens. Circulating autoantibodies can be demonstrated in 80 to 90% of PV patients by indirect immunofluorescence microscopy; monkey esophagus is the optimal substrate for these studies. Patients with PV have IgG autoantibodies directed against desmogleins (Dsgs), transmembrane desmosomal glycoproteins that belong to the cadherin supergene family of calcium-dependent adhesion molecules. Such autoantibodies can now be precisely quantitated by enzyme-linked immunosorbent assay (ELISA). Most patients with early PV (i.e., only mucosal involvement) have only anti-Dsg3 autoantibodies; most patients with advanced disease (i.e., involvement of skin and mucosa) have both anti-Dsg3 and anti-Dsg1 autoantibodies. 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 pemphigus. Experimental studies have also shown that these autoantibodies are pathogenic (i.e., responsible for blister formation) and that their titer correlates with disease activity.
PV can be life-threatening. Prior to the availability of glucocorticoids, the mortality ranged from 60 to 90%; the current mortality is approximately 5%. Common causes of morbidity and mortality are infection and complications of treatment with glucocorticoids. 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 achieve remission (40% of patients in some series), but others may require long-term treatment or succumb to complications of their disease or its treatment. The mainstay of treatment is systemic glucocorticoids. Patients with moderate to severe disease are usually started on prednisone, 60 to 80 mg/d. If new lesions continue to appear after 1 to 2 weeks of treatment, the dose may need to be increased. Many regimens combine an immunosuppressive agent with systemic glucocorticoids for control of PV. The most frequently used are either azathioprine (1 to 2 mg/kg per day), or mycophenolate mofetil (20 to 35 mg/kg per day), cyclophosphamide (1 to 2 mg/kg per day). It is important to bring severe or progressive disease under control quickly to lessen the severity and/or duration of this disorder.
PEMPHIGUS FOLIACEUS
Pemphigus foliaceus (PF) is distinguished from PV by several features. In PF, acantholytic blisters are located high within the epidermis, usually just beneath the stratum corneum. Hence PF is a more superficial 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 demonstrate intact blisters but rather exhibit shallow erosions associated with erythema, scale, and crust formation. Mild cases of PF resemble severe seborrheic dermatitis; severe PF may cause extensive exfoliation. Sun exposure (ultraviolet irradiation) may be an aggravating factor. A blistering skin disease endemic to south central Brazil known as fogo selvagem, or Brazilian pemphigus, is clinically, histologically, and immunopathologically indistinguishable from PF.
Patients with PF have immunopathologic features in common with PV. Specifically, direct immunofluorescence microscopy of perilesional skin demonstrates IgG on the surface of keratinocytes. As in PV, patients with PF frequently have circulating IgG autoantibodies against keratinocyte cell surface antigens. Guinea pig esophagus is the optimal substrate for indirect immunofluorescence microscopy studies of sera from patients with PF. In PF, autoantibodies are directed against Dsg1, a 160-kDa desmosomal cadherin. As noted for PV, the autoantibody profile in patients with PF (i.e., anti-Dsg1) and the normal tissue distribution of this autoantigen (i.e., low expression in oral mucosa) is thought to account for the distribution of lesions in this disease.
Although pemphigus has been associated with several autoimmune diseases, its association with thymoma and/or myasthenia gravis is particularly notable. To date, more than 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. The most frequently implicated agent is penicillamine; other offenders include captopril, rifampin, piroxicam, penicillin, and phenobarbital. Drug-induced pemphigus usually resembles PF rather than PV; autoantibodies in these patients have the same antigenic specificity as they do in other pemphigus patients. In most patients, lesions resolve following discontinuation of the drug; however, some patients require treatment with systemic glucocorticoids and/or immunosuppressive agents.
PF is generally a far less severe disease than PV and carries a better prognosis. Localized disease can be treated conservatively with topical or intralesional glucocorticoids; more active cases can usually be controlled with systemic glucocorticoids.
PARANEOPLASTIC PEMPHIGUS
Paraneoplastic pemphigus (PNP) is an autoimmune acantholytic mucocutaneous disease associated with an occult or confirmed neoplasm. Patients with PNP typically show painful mucosal erosive lesions in association with papulosquamous eruptions that often progress to blisters. Palm and sole involvement is common in these patients and raises the possibility that prior reports of neoplasia-associated erythema multiforme actually 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 patient 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 against cytoplasmic proteins that are members of the plakin family (e.g., desmoplakins I and II, bullous pemphigoid antigen 1, envoplakin, periplakin, and plectin) and cell-surface proteins that are members of the cadherin family (e.g., Dsg3). Because immunoadsorption of anti-Dsg3 IgG is sufficient to eliminate the ability of PNP sera to induce blisters in an experimental passive transfer animal model, these particular autoantibodies are thought to play the key pathogenic role in blister formation in these patients.
Although PNP is generally resistant to conventional therapies (i.e., those used to treat PV), patients may improve (or even remit) following resection of underlying neoplasms. The predominant neoplasms associated with this disorder are non-Hodgkin's lymphoma, chronic lymphocytic leukemia, Castleman's disease, thymoma, and spindle cell tumors.
BULLOUS PEMPHIGOID
Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease usually seen in the elderly. Lesions typically consist of tense blisters on either normal-appearing or erythematous skin. The lesions are usually distributed over the lower abdomen, groin, and flexor surface of the extremities; oral mucosal lesions are found in 10 to 40% of patients. Pruritus may be nonexistent or severe. As lesions evolve, tense blisters tend to rupture and be replaced by flaccid lesions or erosions with or without surmounting crust. Nontraumatized blisters heal without scarring. The major histocompatibility complex class II allele HLA-DQβ1*0301 is prevalent in patients with BP. Despite isolated reports, several studies have shown that patients with BP do not have an increased incidence of malignancy in comparison with appropriately age- and gender-matched controls.
While biopsies of early lesional skin demonstrate subepidermal blisters, the histologic features depend on the character of the particular lesion. Lesions on normal-appearing skin generally show a sparse perivascular leukocytic infiltrate with some eosinophils; conversely, biopsies of inflammatory lesions typically show an eosinophil-rich infiltrate within the papillary dermis at sites of vesicle formation and in perivascular areas. In addition to eosinophils, cell-rich lesions also contain mononuclear cells and neutrophils. It is not always possible to distinguish BP from other subepidermal blistering diseases by routine histologic techniques.
Immunopathologic studies have broadened our understanding of this disease and aided its diagnosis. Direct immunofluorescence microscopy of normal-appearing perilesional skin shows linear deposits of IgG and/or C3 in the epidermal basement membrane. The sera of approximately 70% of these patients contain circulating IgG autoantibodies that bind the epidermal basement membrane of normal human skin in indirect immunofluorescence microscopy. An even higher percentage of patients shows reactivity to the epidermal side of 1 M NaCl split skin [an alternative immunofluorescence microscopy test substrate that is commonly used to distinguish circulating IgG anti-basement membrane autoantibodies in patients with BP from those in patients with similar, yet different, subepidermal blistering diseases (e.g., epidermolysis bullosa acquisita, see below)]. No correlation exists between the titer of these autoantibodies and disease activity. In BP, circulating autoantibodies recognize 230- and 180-kDa hemidesmosome-associated proteins in basal keratinocytes [i.e., bullous pemphigoid antigen (BPAG)1 and BPAG2, respectively]. Autoantibodies are thought to develop against these antigens (more specifically, initially against BPAG2), deposit in situ, and activate complement that subsequently produces dermal mast cell degranulation and granulocyte-rich infiltrates that cause tissue damage and blister formation.
BP may persist for months to years, with exacerbations or remissions. Although extensive involvement may result in widespread erosions and compromise cutaneous integrity, the mortality rate is relatively low. Nonetheless, deaths may occur in elderly and/or debilitated patients. The mainstay of treatment is systemic glucocorticoids. Patients with local or minimal disease can sometimes be controlled with topical glucocorticoids alone; patients with more extensive lesions generally respond to systemic glucocorticoids either alone or in combination with immunosuppressive agents. Patients will usually respond to prednisone, 40 to 60 mg/d. In some instances, azathioprine (1 to 2 mg/kg per day), mycophenolate mofetil (20 to 35 mg/kg per day), or cyclophosphamide (1 to 2 mg/kg per day) are necessary adjuncts.
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 very pruritic. Severe exacerbations of PG frequently occur after delivery, typically within 24 to 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 demonstrate 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 often difficult. However, direct immunofluorescence microscopy of perilesional skin from PG patients reveals the immunopathologic hallmark of this disorder—linear deposits of C3 in the epidermal basement membrane zone. These deposits develop as a consequence of complement activation produced by low titer IgG anti-basement membrane zone autoantibodies. Recent studies have shown that the majority of PG sera contain autoantibodies that recognize BPAG2, the same 180-kDa hemidesmosome-associated protein that is targeted by autoantibodies in patients with BP—a subepidermal bullous disease that resembles PG morphologically, histologically, and immunopathologically.
The goals of therapy in patients with PG are to prevent the development of new lesions, relieve intense pruritus, and care for erosions at sites of blister formation. Most patients require treatment with moderate doses of daily glucocorticoids (i.e., 20 to 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. Although PG was once thought to be associated with an increased risk of fetal morbidity and mortality, the best evidence now suggests that these infants are only at increased risk of being slightly premature or “small for dates.” Current evidence suggests that there is no difference in the incidence of uncomplicated live births in PG patients treated with systemic glucocorticoids and in those managed more conservatively. If systemic glucocorticoids are administered, 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 posterior neck. The primary lesion in this disorder is a papule, papulovesicle, or urticarial plaque. 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 to 24 h later. Almost all DH patients have an associated, usually subclinical, gluten-sensitive enteropathy, and more than 90% express the HLA-B8/DRw3 and HLA-DQw2 haplotypes. DH may present at any age, including 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 formation at these sites are characteristic of early disease. Older lesions may demonstrate nonspecific features of a subepidermal bulla or an excoriated papule. Because the clinical and histologic features of this disease can be variable and resemble other subepidermal blistering disorders, the diagnosis is confirmed by direct immunofluorescence microscopy of normal-appearing perilesional skin. Such studies demonstrate granular deposits of IgA (with or without complement components) 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 may 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 .
Although most DH patients do not report overt gastrointestinal symptoms or have laboratory evidence of malabsorption, biopsies of small bowel usually reveal blunting of intestinal villi and a lymphocytic infiltrate in the lamina propria. As is true for patients with celiac disease, this gastrointestinal abnormality can be reversed by a gluten-free 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 zone. 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 zone. As in patients with celiac disease, dietary gluten sensitivity in patients with DH is associated with IgA anti-endomysial autoantibodies that target tissue transglutaminase. Recent studies suggest that patients with DH also have high-avidity IgA autoantibodies against epidermal transglutaminase and that the latter is co-localized with granular deposits of IgA in the papillary dermis of DH patients. Patients with DH also have an increased incidence of thyroid abnormalities, achlorhydria, atrophic gastritis, and antigastric parietal cell antibodies. 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 disorders. The mainstay of treatment of DH is dapsone, a sulfone. Patients respond rapidly (24 to 48 h) to dapsone (50 to 200 mg/d) but require careful pretreatment evaluation and close follow-up to ensure that complications are avoided or controlled. All patients on more than 100 mg/d dapsone will have some hemolysis and methemoglobinemia. These 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 counselling by a trained dietitian is essential.
LINEAR IGA DISEASE
Linear IgA disease, once considered a variant form of dermatitis herpetiformis, is actually a separate and distinct entity. Clinically, these patients may resemble patients with typical cases of DH, BP, or other subepidermal blistering diseases. Lesions typically consist of papulovesicles, bullae, and/or urticarial plaques, predominantly on extensor (as seen in “classic” DH), central, or flexural sites. Oral mucosal involvement occurs in some patients. Severe pruritus resembles that in patients with DH. Patients with linear IgA disease do not have an increased frequency of the HLA-B8/DRw3 haplotype or an associated enteropathy and hence are not candidates for a gluten-free diet.
The histologic alterations in early lesions may be virtually indistinguishable from those in DH. However, direct immunofluorescence microscopy of normal-appearing perilesional skin reveals linear deposits of IgA (and often C3) in the epidermal basement membrane zone. Most patients with linear IgA disease demonstrate circulating IgA anti-basement membrane autoantibodies against epitopes in the extracellular domain of BPAG2, a transmembrane protein found in hemidesmosomes of basal keratinocytes. These patients generally respond to treatment with dapsone, 50 to 200 mg/d.
EPIDERMOLYSIS BULLOSA ACQUISITA
EBA is a rare, noninherited, polymorphic, chronic, subepidermal blistering disease. Patients with classic or noninflammatory EBA have blisters on noninflamed skin, atrophic scars, milia, nail dystrophy, and oral lesions. Because lesions generally occur at sites exposed to minor trauma, classic EBA is considered to be 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. Rare patients present with lesions that predominate on mucous membranes. The HLA-DR2 haplotype is found with increased frequency in EBA patients. Recent studies suggest that EBA is often associated with inflammatory bowel disease (especially Crohn's disease).
The histology of lesional skin varies depending on the character of the lesion being studied. Noninflammatory bullae show subepidermal blisters with a sparse leukocytic infiltrate and resemble those in patients with porphyria cutanea tarda. Inflammatory lesions consist of a subepidermal blister and neutrophil-rich leukocytic infiltrates in the superficial dermis. EBA patients have continuous deposits of IgG (and frequently C3 as well as other complement components) in a linear pattern within the epidermal basement membrane zone. Ultrastructurally, these immunoreactants are found in the sublamina densa region in association with anchoring fibrils, wheat stack–like structures that extend from the lamina densa into the underlying papillary dermis. Approximately 50% of EBA patients have circulating IgG anti-basement membrane autoantibodies directed against type VII collagen—the collagen species that comprises anchoring fibrils. Such IgG autoantibodies bind the dermal side of 1 M NaCl split skin (in contrast to IgG autoantibodies in patients with BP that bind either epidermal or both sides of this indirect immunofluorescence microscopy test substrate).
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 this disease is largely resistant to treatment, although some patients may respond to cyclosporine or intravenous immunoglobulin.
CICATRICIAL PEMPHIGOID
Cicatricial pemphigoid (CP) is a rare, acquired, subepithelial blistering disease characterized by erosive lesions of mucous membranes and skin that result in scarring of at least some sites of involvement. Immunopathologically, perilesional mucosa and skin of patients with CP demonstrate in situ deposits of immunoreactants in epithelial basement membranes. Common sites of involvement include the oral mucosa (especially the gingiva) and conjunctiva; other sites that may be affected include the nasopharyngeal, laryngeal, esophageal, urogenital, and rectal 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 scattered erosions or tense blisters on an erythematous or urticarial base. CP is typically a chronic and progressive disorder. Serious complications may arise as a consequence of ocular, laryngeal, esophageal, or urogenital lesions. Erosive conjunctivitis may result in shortened fornices, symblephara, ankyloblepharon, entropion, corneal opacities, 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 may place patients at risk for aspiration. Strictures may also complicate urogenital involvement.
Biopsies of lesional tissue generally demonstrate subepithelial vesiculobullae 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 immunofluorescence microscopy of perilesional tissue typically demonstrates deposits of IgG, IgA, and/or C3 in these patients' epithelial basement membranes. Because many of these patients show no evidence of circulating anti-basement membrane autoantibodies, testing of perilesional skin is important diagnostically. Although CP was once thought to be a single nosologic entity, it is now largely regarded as a disease phenotype that may develop as a consequence of an autoimmune reaction against a variety of different molecules in epithelial basement membranes (e.g., BPAG2, laminin 5, type VII collagen, and other antigens yet to be completely defined). Treatment of CP is largely dependent upon sites of involvement. Due to potentially severe complications, ocular, laryngeal, esophageal, and/or urogenital involvement require aggressive systemic treatment with dapsone, prednisone, or the latter in combination with another immunosuppressive agent (e.g., azathioprine, mycophenolate mofetil, or cyclophosphamide) or intravenous immunoglobulin. 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 are often distinctive but at times may resemble those of systemic lupus erythematosus (SLE) scleroderma, or other overlapping connective tissue diseases. The extent and severity of cutaneous disease may or may not correlate with the extent and severity of the myositis. The cutaneous manifestations of dermatomyositis are similar whether the disease appears in childhood or old age, except that calcification of subcutaneous tissue is a common late sequela in childhood dermatomyositis.
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) have also been reported. The most common manifestation is a purple-red discoloration of the upper eyelids, sometimes associated with scaling and periorbital edema. Erythema on the cheeks and nose in a “butterfly” distribution may resemble the eruption in SLE. Erythematous or violaceous scaling patches are common on the upper anterior chest, posterior neck, scalp, and the extensor surfaces of the arms, legs, and hands. Erythema and scaling may be particularly prominent over the elbows, knees, and the dorsal interphalangeal joints. Approximately one-third of patients have violaceous, flat-topped papules over the dorsal interphalangeal joints that are pathognomonic of dermatomyositis (Gottron's sign or Gottron's papules; ). These lesions can be contrasted with the erythema and scaling on the dorsum of the fingers in some patients with SLE, which spares the skin over the interphalangeal joints. Periungual telangiectasia may be prominent, and a lacy or reticulated erythema may be associated with fine scaling on the extensor surfaces of the thighs and upper arms. Other patients, particularly those with long-standing disease, develop areas of hypopigmentation, hyperpigmentation, mild atrophy, and telangiectasia known as poikiloderma. Poikiloderma is rare in both SLE and scleroderma and thus can serve as a clinical sign that distinguishes dermatomyositis from these two diseases. Cutaneous changes may be similar in scleroderma and dermatomyositis and may include thickening and binding down of the skin of the hands (sclerodactyly) as well as Raynaud's phenomenon. However, the presence of severe muscle disease, Gottron's papules, heliotrope erythema, and poikiloderma serve to distinguish patients with dermatomyositis. Skin biopsy of erythematous, scaling lesions of dermatomyositis may reveal only mild nonspecific inflammation but sometimes may show changes indistinguishable from those found in SLE, including epidermal atrophy, hydropic degeneration of basal keratinocytes, edema of the upper dermis, and a mild mononuclear cell 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 directed at the systemic disease. In the few instances where adjunctive cutaneous therapy is desirable, topical glucocorticoids are sometimes useful. These patients should avoid exposure to ultraviolet irradiation and use photoprotective measures such as sunscreens.
LUPUS ERYTHEMATOSUS
The cutaneous manifestations of lupus erythematosus (LE) 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” distribution. 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 erythema and scaling of the extensor surfaces of the extremities and upper chest. These acute lesions, while sometimes evanescent, usually last for days and are often associated with exacerbations of systemic disease. Skin biopsy of acute lesions may show only a sparse dermal infiltrate of mononuclear cells and dermal edema. In some instances, cellular infiltrates around blood vessels and hair follicles are notable, as is hydropic degeneration of basal cells of the epidermis. Direct immunofluorescence microscopy of lesional skin frequently reveals deposits of immunoglobulin(s) and complement in the epidermal basement membrane zone. Treatment is aimed at control of systemic disease; photoprotection in this, as well as in other forms of LE, is very important.
Subacute cutaneous lupus erythematosus (SCLE) is characterized by a widespread photosensitive, nonscarring eruption. About half of these patients have SLE in which severe renal and central nervous system involvement is uncommon. SCLE may present as a papulosquamous eruption that resembles psoriasis or annular lesions that resemble those seen in erythema multiforme. In the papulosquamous form, discrete erythematous papules arise on the back, chest, shoulders, extensor surfaces of the arms, and the dorsum of the hands; lesions are uncommon on the face, flexor surfaces of the arms, and below the waist. The slightly scaling papules tend to merge into large plaques, some with a reticulate appearance. The annular form involves the same areas and presents with erythematous papules that evolve into oval, circular, or polycyclic lesions. The lesions of SCLE are more widespread but have less tendency for scarring than do lesions of discoid LE. Skin biopsy reveals a dense mononuclear cell infiltrate around hair follicles and blood vessels in the superficial dermis, combined with hydropic degeneration of basal cells in the epidermis. Direct immunofluorescence microscopy of lesional skin reveals deposits of immunoglobulin(s) in the epidermal basement membrane zone in about half these cases. A particulate pattern of IgG deposition around basal keratinocytes has recently been associated with SCLE. Most SCLE patients have anti-Ro antibodies. Local therapy is usually unsuccessful, and most patients require treatment with aminoquinoline antimalarials. Low-dose therapy with oral glucocorticoids is sometimes necessary; photoprotective measures against both ultraviolet B and A wavelengths are very important.
Discoid lupus erythematosus (DLE) is characterized by discrete lesions, most often on the face, scalp, or external ears. 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 will show small excrescences that correlate with the openings of hair follicles and is termed a “carpet tack” appearance. This finding is relatively specific for DLE. Long-standing lesions develop central atrophy, scarring, and hypopigmentation but frequently have erythematous, sometimes raised borders at the periphery. These lesions persist for years and tend to expand slowly. Only 5 to 10% of patients with DLE meet the American Rheumatism Association criteria for SLE. However, typical discoid lesions are frequently seen in patients with SLE. Biopsy of DLE lesions shows hyperkeratosis, follicular plugging, and atrophy of the epidermis; hydropic degeneration of basal keratinocytes; and a mononuclear cell infiltrate adjacent to epidermal, adnexal, and microvascular basement membranes. Direct immunofluorescence microscopy demonstrates immunoglobulin(s) and complement deposits at the basement membrane zone in about 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 antimalarials may be indicated.
SCLERODERMA AND MORPHEA
The skin changes of scleroderma usually begin on the hands, feet, and face, with episodes of recurrent nonpitting edema. Sclerosis of the skin begins distally on the fingers (sclerodactyly) and spreads proximally, usually accompanied by resorption of bone of the fingertips, which may have punched out ulcers, stellate scars, or areas of hemorrhage . The fingers may actually shrink in size and become sausage-shaped, and since the fingernails are usually unaffected, the nails may curve over the end of the fingertips. Periungual telangiectasias are usually present, but periungual erythema is rare. In advanced cases, 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 furrowing. Matlike telangiectasias are often present, particularly on the face and hands. Involved skin feels indurated, smooth, and bound to underlying structures; hyperpigmentation and hypopigmentation are also often present. Raynaud's phenomenon, i.e., cold-induced blanching, cyanosis, and reactive hyperemia, is present in almost all patients and can precede development of scleroderma by many years. The combination of calcinosis cutis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia has been termed the CREST syndrome. Anticentromere antibodies have been reported in a very high percentage of patients with the CREST syndrome but in only a small minority of patients with scleroderma. Skin biopsy reveals thickening of the dermis and homogenization of collagen bundles. Direct immunofluorescence microscopy of lesional skin is usually negative.
Morphea, which has been called localized scleroderma, is characterized by localized thickening and sclerosis of skin, usually affecting young adults or children. Morphea begins as erythematous or flesh-colored plaques that become sclerotic, develop central hypopigmentation, and demonstrate an erythematous border. In most cases, patients have one or a few lesions, and the disease is termed localized morphea. In some patients, widespread cutaneous lesions may occur, without systemic involvement. This form is called generalized morphea. Most patients with morphea do not have autoantibodies. Skin biopsy of morphea is indistinguishable from that of scleroderma. Linear scleroderma is a limited form of disease that presents in a linear, bandlike distribution and tends to involve deep as well as superficial layers of skin. Scleroderma and morphea are usually quite resistant to therapy. For this reason, physical therapy to prevent joint contractures and to maintain function is employed and is often helpful.
Diffuse fasciitis with eosinophilia is a clinical entity that can sometimes be confused with scleroderma. There is usually the sudden onset of swelling, induration, and erythema of the extremities frequently following significant physical exertion. The proximal portions of extremities (arms, forearms, thighs, legs) are more often involved than are the hands and feet. While the skin is indurated, it is usually not bound down as in scleroderma; contractures may occur early secondary to fascial involvement. The latter may also cause muscle groups to be separated (i.e., the “groove sign”) and veins to appear depressed (i.e., sunken veins). These skin findings are accompanied by peripheral blood eosinophilia, increased erythrocyte sedimentation rate, and sometimes hypergammaglobulinemia. Deep biopsy of affected areas of skin reveals inflammation and thickening of the deep fascia overlying muscle. An inflammatory infiltrate composed of eosinophils and mononuclear cells is usually found. Patients with eosinophilic fasciitis appear to be at increased risk to develop bone marrow failure or other hematologic abnormalities. While the ultimate course of eosinophilic fasciitis is uncertain, many patients respond favorably to treatment with prednisone in doses ranging from 40 to 60 mg/d.
The eosinophilia-myalgia syndrome, a disorder reported in epidemic numbers in 1989 and linked to ingestion of L-tryptophan manufactured by a single company in Japan, is a multisystem disorder characterized by debilitating myalgias and absolute eosinophilia in association with varying combinations of arthralgias, pulmonary symptoms, and peripheral edema. In a later phase (i.e., 3 to 6 months after initial symptoms), these patients often develop localized sclerodermatous skin changes, weight loss, and/or neuropathy. The precise cause of this syndrome, which may resemble other sclerotic skin conditions, is unknown. However, the implicated lots of L-tryptophan contained the contaminant 1,1-ethylidene bis[tryptophan]. This contaminant may be pathogenic or a marker for another substance that provokes the disorder.