Bullous systemic lupus erythematosus

INTRODUCTION — Bullous systemic lupus erythematosus (BSLE) is a rare autoimmune blistering disorder that typically manifests as an acute vesiculobullous eruption in a patient with known systemic lupus erythematosus (SLE). Rarely, BSLE is the initial clinical manifestation of SLE.

The differential diagnosis of blistering in patients with SLE is broad; therefore, careful assessment is necessary to confirm the diagnosis. The classic histologic and immunofluorescence findings of BSLE are separation within the dermal-epidermal junction, a neutrophilic infiltrate in the superficial dermis, immunoglobulin G (IgG) deposition at the dermal-epidermal junction, and antibody deposition on the dermal side of basement membrane zone-split skin. Anti-collagen VII autoantibodies are the serologic marker of BSLE. A rapid response to dapsone therapy is characteristic.

The clinical manifestations, diagnosis, and management of BSLE will be reviewed here. An overview of blistering skin disorders and a summary of the cutaneous manifestations of lupus erythematosus are provided separately. (See "Approach to the patient with cutaneous blisters" and "Overview of cutaneous lupus erythematosus".)

EPIDEMIOLOGY — BSLE is a rare disorder for which epidemiologic data are limited [1,2]. In accordance with the epidemiology of systemic lupus erythematosus, BSLE is more frequent in females than in males. BSLE usually occurs in adults between the ages of 20 and 40 years; however, children and older adults also may be affected [3].  

PATHOGENESIS — The clinical manifestations of BSLE result from the disruption of epidermal-dermal adhesion secondary to antibody formation against type VII collagen, the major component of the anchoring fibrils in the cutaneous basement membrane zone (figure 1). Anchoring fibrils play a critical role in the attachment of the epidermis to the dermis. (See "Epidermolysis bullosa acquisita", section on 'Type VII collagen'.)

Antibodies against type VII collagen are detectable in sera from patients with BSLE and are directed against the noncollagenous type 1 and type 2 (NC1 and NC2) domains of type VII collagen. In particular, the NC1 domain plays an important role in maintaining the structure of the dermal-epidermal junction through its interaction with other basement membrane zone components important for adhesion, including type IV collagen, laminin 332, and fibronectin. Additional seroreactivity against laminin 332, laminin 311, and/or bullous pemphigoid antigen 1 has been reported in patients with BSLE, possibly as a result of epitope spreading [4].

The finding that in vitro exposure of human skin to autoantibodies from patients with BSLE can induce both separation within the dermal-epidermal junction and leukocyte recruitment supports a pathogenic role for autoantibodies in BSLE [5]. A neutrophilic infiltrate in the superficial dermis is a characteristic finding in BSLE, and a pathogenic role for recruited neutrophils may explain the efficacy of dapsone, a drug that inhibits neutrophil chemotaxis, for BSLE (see 'First-line treatment' below). In addition, complement activation might play a role in formation of bullae [6].

Other potential contributors to the development of BSLE include drug exposure and genetic factors. The development of BSLE after administration of methimazole and exacerbation during nivolumab treatment have been reported [7,8], and there appears to be a genetic predisposition for BSLE with overrepresentation of HLA-DR2 alleles [9].

ASSOCIATION WITH SYSTEMIC LUPUS ERYTHEMATOSUS — BSLE is considered a manifestation of underlying systemic lupus erythematosus (SLE), and most patients with BSLE have a preceding diagnosis of SLE. However, there are multiple reports, particularly in children and adolescents, in which BSLE was the first clinical presentation of SLE [10-15].

In most patients, the development of BSLE is not related to SLE activity. However, an association with active lupus nephritis has been proposed based upon reports of patients with lupus nephritis and BSLE [16-18]. In a review of 118 patients with BSLE from published reports and 10 additional patients with BSLE, 50 percent of patients had lupus nephritis (mainly class III or IV), 19 percent had neuropsychiatric involvement, and 45 percent had hematologic involvement [18].

CLINICAL MANIFESTATIONS — BSLE usually has an acute onset. Tense vesicles and blisters appear on normal-appearing or erythematous skin (picture 1A-B). In addition, rose-colored or red macules without overlying vesicles or bullae are often present. Approximately one-quarter of patients may develop urticarial plaques [18]. Centrifugal extension of erythematous, vesicular plaques, mimicking erythema gyratum repens, has rarely been reported [19,20].

Lesions predominate on the trunk and the extensor surfaces of the limbs. A photodistribution or history of photoexacerbation is suggestive of BSLE if present but is not obligate. Mucosa can be involved, especially the mouth. Blisters along the vermilion border of the lip are characteristic [21]. Esophagitis dissecans superficialis (sloughing of the esophageal mucosa) has been reported as a rare complication [22].

Pruritus is absent or mild. Pigmentary changes (ie, hyper- or hypopigmentation) are common, may remain after lesion resolution, and may take months to years to resolve. Although it is often reported that lesions of BSLE heal with neither milia formation nor scarring, in a review of 128 patients with BSLE, milia and scarring occurred in 21 and 16 percent of patients, respectively [18].

DIAGNOSIS — Most patients with BSLE have an existing diagnosis of systemic lupus erythematosus (SLE), therefore, a blistering eruption in patients with SLE should prompt consideration of this diagnosis. However, an evaluation is necessary to distinguish BSLE from the multiple other blistering disorders that occur in patients with SLE. Occasionally, BSLE is the initial presentation of SLE. (See 'Differential diagnosis' below.)

Diagnostic criteria — The diagnostic process for BSLE involves a careful review of clinical, histologic, immunofluorescence, and serologic findings. Although some proposed diagnostic criteria stipulate that a diagnosis of BSLE requires a diagnosis of SLE [23,24], we challenge this assertion given that in rare cases, BSLE is the first clinical manifestation of SLE.

The following criteria seem adequate to diagnose BSLE:

●Mandatory features:

•An acute eruption of vesicles and/or bullae on normal-appearing or erythematous skin

•Histopathologic finding of subepidermal blistering and a neutrophil-predominant infiltrate in the superficial dermis

•Direct immunofluorescence (DIF) finding of linear or granular immunoglobulin (Ig)G, IgM, or IgA deposition at the basement membrane zone

•Elevated antinuclear antibody titer

•Exclusion of other blistering diseases (table 1A-B)

●Supportive features (usually present):

•Preexisting or new diagnosis of SLE (rarely, BSLE is the initial sign of SLE)

•Indirect immunofluorescence (IIF) results demonstrating binding of antibodies to the dermal side of basement membrane zone-split skin or immunoelectron microscopic (IEM) study demonstrating antibody deposition beneath the lamina densa

•Anti-collagen VII antibodies detectable in serum via enzyme-linked immunosorbent assay (ELISA) or immunoblotting

•Clinical features that are less consistent with epidermolysis bullosa acquisita than BSLE:

-Lesion resolution occurring without scarring or formation of milia

-Rapid response to dapsone therapy

Our approach — Our initial evaluation of patients with suspected BSLE consists of:

●A lesional skin biopsy for routine histologic examination

●A perilesional skin biopsy for DIF

If these findings are consistent with BSLE (subepidermal blister with neutrophil-predominant superficial dermal infiltrate and linear or granular deposition of IgG, IgA, IgM, and/or C3 at the basement membrane zone), we proceed with:

●IIF on basement membrane zone-split human skin (IEM is an alternative study)

If IIF demonstrates antibody binding to the dermal side of basement membrane zone-split skin, we proceed with antigen-specific testing (ELISA or immunoblotting) to assess for antibodies to type VII collagen in the patients' serum. If antibodies against type VII collagen are detected, the differential diagnosis includes BSLE and epidermolysis bullosa acquisita. Of note, the classic IIF findings and serum anti-collagen VII antibodies are not detected in a minority of patients with BSLE. (See 'Diagnostic criteria' above and 'Differential diagnosis' below and 'Diagnostic tests' below.)

Careful review of the clinical presentation is useful for distinguishing between BSLE and epidermolysis bullosa acquisita and can aid in distinguishing BSLE from other blistering diseases in challenging cases. The clinical, histologic, and immunofluorescence findings that suggest other blistering diseases are reviewed in the tables (table 1A-B).

Patients with clinical and laboratory findings consistent with BSLE who do not have a preexisting diagnosis of SLE should be evaluated for underlying SLE. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults" and "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis".)

Diagnostic tests — The diagnostic tests for BSLE are reviewed below.

Histopathology — A 4 mm punch biopsy from lesional skin usually provides a sufficient specimen for histopathologic examination. A biopsy of a fresh vesicle is preferred.

Microscopic examination will reveal a bulla at the dermal-epidermal junction with an intact overlying epidermis (picture 2). A neutrophil-predominant inflammatory infiltrate is present beneath the bulla and within the superficial dermis adjacent to the bulla. Alignment of neutrophils along the epidermal-dermal junction with leukocytoclasis is common [18]. Papillary "microabscesses" similar to those observed in dermatitis herpetiformis can be present (picture 3). When present, mucin deposits in the dermis are suggestive of BSLE [25-27]. Interface dermatitis, a common feature of other types of cutaneous lupus erythematosus, is absent.

Direct immunofluorescence — The skin biopsy for DIF should be taken from perilesional skin. A 4 mm punch biopsy is usually sufficient.

DIF testing is positive in essentially all patients with BSLE. Linear continuous deposition of IgG at the dermal-epidermal junction is the most frequent finding (present in 70 to 80 percent of patients), but fluorescence can also be granular (present in approximately 30 percent of patients) and can occur with other immunoreactants, including IgA, IgM, and C3 (each present in approximately 70 percent of patients) based upon review of the literature. A "u-serrated" staining pattern is classic in diseases such as BSLE where staining localizes to the sublamina densa [28].

Indirect immunofluorescence — IIF is a technique that can be used to detect circulating antibodies. In particular, IIF performed with basement membrane zone-split skin allows for more precise localization of cutaneous antibody deposition and is helpful for narrowing the differential diagnosis of autoimmune subepidermal blistering diseases. The technique involves incubation of a skin substrate in a 1 M sodium chloride or ethylenediaminetetraacetic acid (EDTA) solution to induce separation at the level of lamina lucida. The technique is reviewed in greater detail separately. (See "Approach to the patient with cutaneous blisters", section on 'Indirect immunofluorescence'.)

Antibody deposition localized to the dermal side of human basement membrane zone-split skin usually occurs in BSLE, epidermolysis bullosa acquisita, and a few rare subepidermal blistering diseases (anti-p200 pemphigoid and anti-laminin 332 pemphigoid). In contrast, antibody deposition in bullous pemphigoid is found on the epidermal side of salt-split skin.

Antigen-specific serologic testing — Either ELISA or immunoblotting can be used to detect circulating antibodies against type VII collagen. An ELISA test that detects the noncollagenous type 1 (NC1) and type 2 (NC2) domains of type VII collagen is commercially available. Immunoblotting on dermal skin extract will show reactivity against 290 kD or 145 kD proteins of type VII collagen [3,6,9,25,29-31]. Our review of the literature suggests that approximately 70 percent of patients with BSLE will have a positive antigen-specific serologic test.

Immunoelectron microscopy — IEM can be used to determine the presence and location of antibody deposits within skin. In BSLE, IEM typically identifies antibody deposits below the lamina densa [32]. Rarely, antibodies are found in the epidermis or on and beneath the lamina densa [3,30]; some authors suggest that these alternative findings indicate different subtypes of BSLE.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of BSLE includes other subepidermal autoimmune blistering diseases and other blistering disorders that can occur more frequently in patients with systemic lupus erythematosus (SLE).

Autoimmune blistering diseases — Autoimmune blistering diseases that share clinical, histologic, and/or immunofluorescence features with BSLE include epidermolysis bullosa acquisita (EBA), linear IgA bullous dermatosis (LABD), dermatitis herpetiformis, and anti-p200 pemphigoid:

●Epidermolysis bullosa acquisita – Like BSLE, EBA is an autoimmune subepidermal blistering disorder that can exhibit antibody binding on the dermal side of basement membrane zone-split skin and antibody formation against type VII collagen. (See "Epidermolysis bullosa acquisita".)

The cutaneous manifestations of the classical subtype of EBA (skin fragility, noninflammatory tense bullae, and lesion resolution with scarring and milia formation) help to distinguish this subtype from BSLE (picture 4A-B). Distinguishing BSLE from inflammatory BSLE is more challenging because scarring and milia formation are less prominent features. Examples of findings that make EBA less likely include concurrent SLE, the histologic finding of mucin in the dermis, and a rapid response to dapsone. A minority of patients with EBA respond to dapsone but usually not as rapidly and completely as BSLE patients [33]. In addition, BSLE usually resolves within a year, while EBA has a more chronic course. (See 'Prognosis' below.)

●Linear IgA bullous dermatosis – LABD is an uncommon autoimmune blistering disease that shares the histologic findings of subepidermal blistering and a neutrophil-predominant dermal infiltrate with BSLE. Annular plaques with peripheral vesiculation are a common presentation of LABD, particularly in children (picture 5). Unlike BSLE, indirect immunofluorescence studies on basement membrane zone-split skin will exhibit deposits of IgA on the epidermal side of split skin. (See "Linear IgA bullous dermatosis".)

●Dermatitis herpetiformis – Dermatitis herpetiformis classically presents as clusters of intensely pruritic blisters or erosions with a predilection for the elbows, forearms, knees, buttocks, and scalp (picture 6). Histopathology can be indistinguishable from BSLE; however, the direct immunofluorescence finding of IgA deposition in the dermal papilla is a distinguishing feature of dermatitis herpetiformis. (See "Dermatitis herpetiformis".)

●Anti-p200 pemphigoid – Like BSLE and EBA, anti-p200 pemphigoid is a subepidermal blistering disease that exhibits antibody binding on the dermal side of basement membrane zone-split skin. Anti-p200 pemphigoid is rare and can have varying clinical presentations; most often the clinical features are reminiscent of bullous pemphigoid. Distinguishing features of anti-p200 pemphigoid include immunoelectron microscopy findings of labeling in the lower part of the lamina lucida and enzyme-linked immunosorbent assay testing showing reactivity against laminin gamma-1. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Anti-p200 (laminin gamma-1) pemphigoid'.)

Other disorders — Other subtypes of cutaneous lupus erythematosus may present with blistering. Blistering can occur at the periphery of plaques of subacute cutaneous lupus erythematosus and as a rare feature of discoid lupus erythematosus (picture 7) [34]. Toxic epidermal necrolysis-like acute cutaneous lupus erythematosus is a rare presentation of acute cutaneous lupus erythematosus that manifests as widespread, often photoaggravated erythema with secondary skin detachment (picture 8). (See "Overview of cutaneous lupus erythematosus".)

In addition, immunosuppressive therapy for SLE can increase risk for blistering infections, such as bullous impetigo, disseminated herpes simplex virus infections, and disseminated herpes zoster infections. Antiphospholipid antibody syndrome, which can occur in association with SLE, can result in cutaneous thrombosis and secondary necrosis and skin detachment. (See "Clinical manifestations of antiphospholipid syndrome".)

Neutrophilic lupus erythematosus is a relatively new concept that includes BSLE and other neutrophilic dermatoses that may occur in association with lupus erythematosus [35]. The author has seen bullous lesions in two patients with nonbullous neutrophilic eruption of lupus erythematosus, a type of neutrophilic lupus erythematosus characterized by pruritic papules and plaques with a neutrophilic infiltrate [36]. Unlike BSLE, antibodies against type VII collagen are not a feature of neutrophilic eruption of lupus erythematosus.

TREATMENT — Data on therapeutic options for BSLE are limited. Treatment recommendations are primarily derived from case reports and expert opinion.

First-line treatment — Dapsone is considered the treatment of choice for BSLE based upon clinical experience [3,10-12,25,37]. The response to treatment is typically rapid [38]. New blister formation usually stops within the first few days of treatment.

Of note, patients requiring the initiation or augmentation of immunosuppressive therapy for systemic manifestations of systemic lupus erythematosus (SLE) may experience concurrent improvement in BSLE [37]. For these patients, dapsone can be added to immunosuppressive therapy if the improvement in BSLE is insufficient. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults".)

Dapsone therapy for BSLE in adults is usually started at a dose of 50 mg per day and may be increased to 100 mg per day if needed to achieve disease control. Once a complete response has been achieved, the dose of dapsone should be reduced to the lowest dose necessary to control the disease. In our experience, most adults initially require between 25 mg per day (or 100 mg twice a week) and 100 mg per day to maintain improvement. Dose reductions should be attempted periodically. Treatment usually can be stopped completely within one year. When patients do not respond to 100 mg per day of dapsone within one month, the diagnosis of BSLE should be confirmed and other therapies initiated. (See 'Refractory disease' below.)

Dapsone is generally well-tolerated. Hemolysis is an expected side effect that can become severe in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Thus, testing for G6PD deficiency is indicated prior to dapsone therapy. Examples of other side effects include methemoglobinemia, peripheral neuropathy, hepatitis, and pancreatitis. Agranulocytosis and pancytopenia and dapsone hypersensitivity syndrome are rare, potentially life-threatening side effects. Laboratory monitoring for hematologic and hepatic side effects is indicated during therapy.

Refractory disease — Although dapsone is well-accepted as first-line therapy, the management of patients who fail to respond to dapsone or who cannot tolerate dapsone is less clear. Because dapsone is usually highly effective for BSLE, the diagnosis should be reassessed in patients who fail to respond to dapsone prior to the initiation of alternative treatments. (See 'Diagnosis' above.)

Second-line therapies include a variety of immunomodulatory agents. Because of a paucity of efficacy data, selection of a second-line agent is based upon factors such as patient comorbidities, tolerance for side effects, and the treatment regimen required for underlying SLE.

Therapies that have been reported beneficial for BSLE in small numbers of patients include methotrexate [17], mycophenolate mofetil [16,39], colchicine, antimalarials, and rituximab [40-42], with these agents often given in conjunction with systemic glucocorticoids. Although systemic glucocorticoids are often effective in the treatment of SLE, the response of BSLE to systemic glucocorticoids varies [12,37]. Anakinra, an interleukin-1 receptor antagonist, appeared effective in a patient with BSLE refractory to hydroxychloroquine, colchicine, mycophenolate mofetil, and rituximab [18].

Our preferred initial interventions for BSLE in adults that fails to respond adequately to dapsone is the addition of either colchicine (1 mg per day) or hydroxychloroquine (400 mg per day) to dapsone (100 mg per day) given that these are well-tolerated and widely available agents. If the response remains poor after one month, we transition to other therapies, typically methotrexate, mycophenolate mofetil, or rituximab. Selection among these agents is dependent upon patient comorbidities. If widespread BSLE remains after one month of monotherapy with one of these agents, an oral glucocorticoid (eg, prednisone 0.5 to 1 mg/kg per day) can be added. Once remission is achieved, the glucocorticoid is slowly tapered as tolerated.  

Children — The approach to the treatment of BSLE is similar in adults and children with the exception of adjusted drug dosing. The author typically starts dapsone at a dose of 1.5 mg/kg per day and titrates the dose upward as needed. The dose of dapsone should not exceed 2 mg/kg per day.

PROGNOSIS — The prognosis of BSLE is usually excellent. Most patients will be controlled with dapsone. Treatment can usually be stopped within one year. A few patients will have recurrences.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cutaneous lupus erythematosus".)

SUMMARY AND RECOMMENDATIONS

●Bullous systemic lupus erythematosus (BSLE) is a rare autoimmune blistering disorder that can occur in patients with systemic lupus erythematosus (SLE). In rare cases, BSLE is the initial clinical manifestation of SLE. (See 'Introduction' above and 'Association with systemic lupus erythematosus' above.)

●BSLE usually occurs in young adults but also can occur in children and older adults. (See 'Epidemiology' above.)

●The pathogenesis of BSLE involves antibody formation against type VII collagen, the major component of anchoring fibrils in the epidermal basement membrane zone. (See 'Pathogenesis' above.)

●BSLE usually manifests an acute eruption of tense vesicles and blisters with or without underlying erythema. The trunk and extensor surfaces of the extremities are the most common sites of involvement. A photodistribution may be evident. (See 'Clinical manifestations' above.)

●The diagnosis of BSLE involves review of clinical, histologic, immunofluorescence, and serologic findings. Findings that support a diagnosis of BSLE include (see 'Diagnosis' above):

•Histopathologic finding of subepidermal blistering and a neutrophil-predominant inflammatory infiltrate in the superficial dermis

•Direct immunofluorescence study demonstrating linear or granular deposition of immunoglobulin (Ig)G, IgM, IgA, or C3 at the basement membrane zone

•Localization of antibody deposition to the dermal side of basement membrane zone-split skin (via indirect immunofluorescence) or lamina densa (via immunoelectron microscopy)

•Detection of antibodies against type VII collagen in serum (via enzyme-linked immunosorbent assay or immunoblotting)

●We suggest dapsone for the initial treatment of BSLE (Grade 2C). Most patients with BSLE have rapid responses to dapsone. The diagnosis should be confirmed in patients who fail to respond to dapsone. Patients with BSLE who cannot be treated successfully with dapsone may respond to other immunomodulatory therapies. (See 'Treatment' above.)