Am J Clin Dermatol DOI 10.1007/s40257-014-0098-0

REVIEW ARTICLE

Bullous Systemic Lupus Erythematosus: A Review and Update to Diagnosis and Treatment James J. Contestable • Kim D. Edhegard Jon H. Meyerle

•

Ó Springer International Publishing Switzerland 2014

Abstract Bullous systemic lupus erythematosus (BSLE) is a rare cutaneous complication of systemic lupus erythematosus (SLE). It is a heterogeneous disease that is caused by autoantibodies to the dermoepidermal junction, mainly type VII collagen. Similarities in histology and immunopathology exist between BSLE and other primary bullous dermatoses, namely dermatitis herpetiformis (DH) and epidermolysis bullosa acquisita (EBA), respectively. EBA and BSLE commonly share the same autoantibody to type VII collagen and heterogeneous clinical presentations, creating a diagnostic challenge. However, clinical presentation combined with histology, immunological testing, and concomitant diagnosis of SLE distinguish this entity from other similar dermatoses. Diagnosis of this disease is important given its coexistence with SLE and its many complications. New developments in IgG subtyping have shown subtle variations in IgG subtypes between EBA and BSLE. In addition, rituximab was recently found to be efficacious in recalcitrant cases of BSLE that do not respond to dapsone and immunosuppressants. We review the topic of BSLE with emphasis on clinical, histologic, and immunopathologic features, as well as new methods of diagnosis and treatment.

Key Points Immunobullous diseases share many similarities in their clinical and pathological presentations. Determining the specific diagnosis for these diseases is important as it may change treatment options and prognosis. Differentiation of bullous systemic lupus erythematosus (BSLE) from epidermolysis bullosa acquisita (EBA) presents a diagnostic challenge. Recently, IgG subtyping has shown a subtle immunological variance between BSLE and EBA. Dapsone should be trialed in a patient with BSLE as it can have a dramatic response; however, steroids are commonly needed for systemic symptoms of SLE and refractory BSLE. Additionally, rituximab has been successfully used in recalcitrant cases of BSLE, which may target the pathogenesis of the disease.

1 Introduction J. J. Contestable (&)
K. D. Edhegard Department of Dermatology, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889-5600, USA e-mail: [email protected] K. D. Edhegard e-mail: [email protected] J. H. Meyerle Department of Dermatology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA e-mail: [email protected]

Bullous systemic lupus erythematosus (BSLE) is an uncommon blistering eruption that can occur in patients with systemic lupus erythematosus (SLE). Between 59 and 85 % of SLE patients will have skin manifestations of their disease, but less than 5 % will develop bullous disease [1–3]. BSLE is typically a subepidermal, transient, tense, vesiculobullous eruption, which normally heals without scarring or milia. The bullae can affect any area of the body to include the mucosa, but have a predilection for the trunk,

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2 Diagnosis

in patients with SLE [4, 6, 8, 13, 15]; however, it is also seen in other races, ages, and in males [2, 3, 13, 14, 16, 17]. Presentation is often acute with onset of tense vesicles and bullae over inflamed and/or normal skin, which generally has clear or, less often, hemorrhagic contents (Fig. 1a, b). Blisters mostly appear on sun-exposed areas, but patients commonly have blisters on non-sun-exposed skin and mucosa [13]. There is a predilection for the trunk, upper extremities, supraclavicular region, face, vermillion border, and oral mucosa [2, 4–8, 10, 17–20]. Extensor surface involvement, in contrast to DH, is much less common, but cases involving the knees, feet, and hands have been reported [3, 9, 10]. In contrast to EBA, blisters almost always heal without scarring or milia; however, hypopigmented, more often than hyperpigmented, macules may remain after erosions heal [20]. In comparison to DH, pruritus may be present but is usually mild [3]. It is important to remember that all cases of BSLE require a diagnosis of SLE. The 1997 American College of Rheumatology (ACR) revised criteria for SLE [21] were recently validated by the Systemic Lupus International Collaborating Clinic (SLICC) group in 2012 [22]. A new classification system was also proposed by this group [22] which is more sensitive, leading to less misdiagnosis of SLE [22]. Therefore, two possible systems exist for the diagnosis of SLE. Concurrent systemic symptoms or flare of the patient’s SLE may be present in addition to bullae in patients with BSLE. When an SLE flare is present, nephritis most commonly occurs in conjunction with BSLE [2, 3, 10, 11]. However, some case-series would suggest limited correlation between systemic SLE flare and BSLE [14, 23]. The clinical presentation of BSLE is distinct from classic autoimmune EBA. Classic EBA is considered a non-inflammatory bullous disease that heals with scarring and milia; however, an inflammatory type is also described [24, 25]. In contrast to BSLE, EBA is more common in the fourth and fifth decades of life [20, 25]. Although an immunobullous disease, the appearance of acquired EBA may resemble dystrophic epidermolysis bullosa, with fragile blisters appearing over hands, knuckles, elbows, knees, and sacrum [25]. Oral mucosal involvement may also be extensive in some cases. Bullae appear over non-inflamed or previously scarred skin in classic EBA [25]. Additionally, EBA is a chronic autoimmune disease that can be difficult to treat, while BSLE is more likely to regress completely with successful treatment [25]. Inflammatory EBA does present with tense bullae over inflamed skin and therefore further complicates the clinical diagnosis.

2.1 Clinical Features

2.2 Histopathology

BSLE mainly affects young women, frequently of African descent, usually in their second to fourth decades, as observed

As previously mentioned, the histopathology of BSLE has many similarities to DH. In almost all cases of BSLE, there

upper extremities, neck, face, and vermillion border [4–8]. Bullae may appear on erythematous or normal skin. Clinically similar to bullous pemphigoid (BP), linear IgA bullous dermatosis, epidermolysis bullosa acquisita (EBA), and dermatitis herpetiformis (DH), it is important for physicians to consider BSLE when confronted with a bullous skin eruption. Multiple case reports show that BSLE can be the initial presentation of SLE [5, 6, 8, 9]. Some cases of BSLE are associated with increased activity of SLE, particularly lupus nephritis [2, 3, 10, 11]. Therefore, timely diagnosis of BSLE is important to prevent further complications of SLE that may coexist. While BSLE is considered a variant of SLE, the presentation, histology, and immunopathology of BSLE differ from other manifestations of cutaneous lupus erythematosus (CLE), such as acute CLE (ACLE), subacute CLE (SCLE), and chronic CLE (CCLE). While each form of CLE has its own associated genetic loci [12], histological and immunological patterns are similar in ACLE, SCLE, and CCLE. This is not the case in BSLE, which has distinctive histological and immunological patterns, as summarized in Table 1. However, it should be mentioned that bullous lesions can present in ACLE and SCLE due to intense inflammation and necrosis of keratinocytes or vacuolization [1]. In contrast to bullae of BSLE, ACLE and SCLE bullae will always occur over an erythematous base. Diagnosis of this disease can be difficult due to histologic similarities to DH and EBA and immunologic similarities to EBA. Most BSLE patients will have autoantibodies present in their serum to the NC1 domain of type VII collagen, a shared antigen with EBA; however, the other clinical, histological, and immunological features of BSLE are more heterogeneous [13, 14]. Despite the clinical similarity of BSLE to other immunobullous dermatoses, the combination of its histology, immunological features, and the presence of criteria for SLE often help to establish the correct diagnosis. This literature review focuses on the diagnosis of BSLE, similarities with other immunobullous diseases, and proposed treatments. In addition, new data regarding diagnosis and novel treatments will be discussed. A literature search was performed using MEDLINE using the specific search term ‘bullous systemic lupus erythematosus [text word]’ (no exclusions were utilized); thereafter, a manual search of each article’s references was undertaken to ensure a more complete sample of existing case reports/series and review articles.

Bullous Systemic Lupus Erythematosus Table 1 Differential diagnosis of bullous disorders that may mimic BSLE Disease

Clinical presentation

Histology

DIF

IIF/split skin substrate

Cutaneous lupus erythematous (CLE)

Acute: malar or diffuse rash, macular, erythematous

Lichenoid tissue pattern with epidermal atrophy, hydropic changes, apoptotic keratinocytes, and dermal mononuclear infiltrate at the DEJ, mucin deposits in dermis

Positive lupus band test, granular IgG, IgM and C3 at BMZ

May show ANA or dsDNA antibodies in granular pattern

Subacute: annular, psoriasis-like lesion, scaly Chronic: (mostly discoid lupus) scaly, round or annular plaques that scar

Bullous systemic lupus erythematosus (BSLE)

Patient meets ACR or SLICC criteria for SLE, tense blisters on inflamed or normal skin, typically trunk, upper extremities, face, lips, and oral mucosal involvement; nonscarring, classically without milia

Subepidermal blisters, neutrophilic microabcesses in papillary dermis, abundant mucin deposits in dermis, absence of eosinophils

Linear or granular of IgG, IgA, IgM, and C3 at the BMZ

Circulating IgG antiBMZ antibodies— dermal pattern or negative (some with epidermal)

Bullous pemphigoid (BP)

Tense blisters on inflamed or normal skin, and urticarial plaques, typically on the flexor surfaces of the arms and legs, lateral trunk; no mucosal involvement; more common in elderly patients

Subepidermal bulla with inflammatory eosinophilpredominant infiltrate, also containing lymphocytes and neutrophils

Linear deposits of IgG and/or C3 at the BMZ

Circulating IgG antiBMZ antibodies— epidermal pattern and within lamina lucida

Epidermolysis bullosa acquisita (EBA)

Skin fragility, trauma-induced blisters healing with scarring and milia, typically on extensor surfaces, mucous membranes commonly involved; middle-aged patients

Classical: subepidermal bulla with sparse mononuclear cell infiltrate Inflammatory: subepidermal bulla with mixed, neutrophilic infiltrate

Linear deposits of IgG and C3 at the BMZ, rarely IgA and IgM

Circulating IgG antiBMZ antibodies— dermal pattern

Linear IgA bullous dermatosis

Tense blisters on erythematous skin, pruritic plaques with blisters at the border of healing lesions, most common on flexor surfaces, trunk, perineum, face, oral mucosa

Subepidermal bulla with inflammatory, neutrophil- or eosinophil-predominant infiltrate

Linear deposits of IgA and C3 at the BMZ

Circulating IgA antiBMZ antibodies— epidermal, dermal, or mixed pattern

Dermatitis herpetiformis (DH)

Intensely pruritic erythematous papules and small vesicles in herpetiform arrangement, typically on elbows, knees, buttocks, back, shoulders, face, and scalp; associated GSE; young adults and children affected

Subepidermal bulla with neutrophil microabscesses in dermal papillae

Granular deposits of IgA and C3 at the tips of the dermal papillae only

Negative

DIF direct immunofluorescence, IIF indirect immunofluorescence, ACR American College of Rheumatology, SLICC Systemic Lupus International Collaborating Clinic, SLE systemic lupus erythematosus, GSE gluten-sensitive enteropathy, DEJ dermoepidermal junction, C3 complement component 3, BMZ basement membrane zone, ANA anti-nuclear antibody, ds-DNA double-stranded DNA

is a predominance of neutrophils in the upper dermis with microabcesses concentrated within dermal papillae (Fig. 2a, b). Subepidermal blistering is present with dermal edema and perivascular inflammatory infiltrate in the superficial and middle dermis. Importantly, large deposits of mucin are common in the reticular dermis [20]. This latter finding is a distinguishing feature of BSLE histopathology. Mucin is also present in other forms of CLE but neutrophilic infiltration is much more suggestive of BSLE (Table 1) [26]. In comparison, the histopathology of EBA is much more heterogeneous but has much less dermal inflammatory infiltrate in its classic form [25].

2.3 Immunopathology The pathogenesis of BSLE is likely related to autoantibodies to type VII collagen. It is known that these antibodies are directed against non-collagenous domain type 1 and 2 (NC1 and NC2) of type VII collagen, found in the basement membrane zone (BMZ) [19, 27]. Type VII collagen is a major component of anchoring fibrils that attach the dermis to the epidermis. More specifically, NC1 domains interact with type IV collagen, laminin-5, and fibronectin, which all play roles in adhesion between the lamina densa, lamina lucida, and keratinocytes [20]. In addition to autoantibodies to type VII collagen, Chan et al.

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[28] found that autoantibodies to laminin-5, laminin-6, and BP antigen 1 were also present in a BSLE patient. It is theorized that epitope spreading causes autoimmunity to these antigens, with antibodies to type VII collagen being the inciting factor [28]. All major classes of immunoglobulin are found to be present in deposits around the dermoepidermal junction (DEJ) of BSLE patients but IgG is found most frequently, followed by IgA and IgM [19]. Deposits of these antibodies are found in biopsies of lesional as well as uninvolved skin. Complement is found almost exclusively in perilesional tissue. Therefore, it is theorized that antibody-mediated activation of complement is the cause of bulla formation [29]. In vitro studies do not mimic the in vivo milieu, and have not shown a direct requirement for complement

binding to induce subepidermal splitting [30]. In support of the pathogenicity of antibodies to type VII collagen, a study by Herrero-Gonzalez et al. [30] found that antibodies to type VII collagen from a patient with BSLE serum in the presence of leukocytes caused in vitro subepidermal splits of human skin. This was previously proven in a similar model for EBA [31], and solidified by passive transfer of antibodies to type VII collagen from a human patient with EBA to mice with development of disease [32]. This underscores the immunopathological similarities and diagnostic challenge that exists between BSLE and EBA. However, IgG subclass concentration appears to differ between EBA and BSLE, suggesting a distinct immunological divergence. Recent studies have shown that IgG2 and IgG3 deposits are more closely related to BSLE

Fig. 1 a Example of clinical picture of a BSLE patient with disease over shoulders, trunk, and neck. Note that tense bullae appear over mildly inflamed skin in this patient b Note tense bullae with excoriations and healing lesions leading to erythematous, hyperpigmented and hypopigmented macules. No scaring or milia is present. BSLE bullous systemic lupus erythematosus

Fig. 2 a Note blister formation with cellular infiltrate concentrated in the upper dermis (9100). b Note the cellular infiltrate is neutrophilic with subepidermal blistering and dermal edema (9200)

Bullous Systemic Lupus Erythematosus

patients, while IgG1 and IgG4 may be more indicative of EBA [29, 30, 33, 34].

2.5 Enzyme-Linked Immunosorbent Assay (ELISA) and Western Immunoblot

2.4 Immunofluorescence and Immunoelectron Microscopy

Like many aspects of BSLE, heterogeneity exists between BSLE patients and the autoantibodies that they possess [14, 19, 27, 28]. However, the majority of sera from both BSLE and EBA patients have similar autoantibody profiles to the 290 and 145-kD proteins of type VII collagen via immunoblotting [19, 20, 25, 34]. New assays are being developed that should make the diagnosis of BSLE faster and more accurate [27, 33, 34]. These ELISA assays utilize NC1 and NC2 domain epitopes to detect the presence of circulating antibodies to type VII collagen in patient serum. Subclass analysis of IgG autoantibodies with ELISA assays shows variance between BSLE and EBA. The assay developed by Komorowski et al. [34] showed that only 37.7 % of EBA patients had a presence of IgG3 in their serum. This is consistent with previous research that showed higher levels of IgG1 and IgG4 in EBA patients [33, 36, 37]. In contrast, BSLE patients have higher levels of IgG2 and IgG3 [29, 30, 33].

Classic immunopathologic features of BSLE show deposition of immunoreactants along the DEJ under direct immunofluorescence (DIF) staining and direct immunoelectron microscopy (IEM). As mentioned previously, IgG, IgA, IgM, and complement components are commonly present at the DEJ in BSLE patients. Both granular and/or linear patterns can be seen. The deposits are continuous along the DEJ and have been found to extend into the dermis as well as perivascular regions [20]. DIF studies of BSLE patients can be similar to that of CLE patients but most closely resemble that of EBA (Table 1) [26, 35]. However, this differs from DH, wherein IgA deposits are largely contained within the dermal papillae. DIF studies on salt-split skin samples from BSLE patients show immune reactant deposition along the dermal side of the blister cavity, below the lamina densa in the BMZ, where type VII collagen is found (Fig. 3a, b). After indirect immunofluorescence (IIF) is positive on intact skin, use of salt-split skin using 1.0 mol/L NaCl is the preferred method to carry out confirmatory IIF studies. Normal human skin substrate is used with patient serum to detect the presence of circulating antibodies. Based on the presence of antibodies to type VII collagen and location of the immunoreactant deposits, BSLE is subtyped into one of three categories (Table 2) [13, 14]. However, based on the current case-study data, no clinical differences exist between each subtype. The diagnostic differences between each subtype demonstrate the heterogeneity of BSLE, while still maintaining its autoimmune nature that targets the DEJ. Fig. 3 a Direct immunofluorescence: IgA; subepidermal split with prominent broad staining along the dermoepidermal junction at the base of the blister (type VII collagen). b Direct immunofluorescence: IgG; subepidermal split with prominent broad staining along the dermoepidermal junction at the base of the blister (type VII collagen). Staining of the keratinocyte nuclei reflects a positive in vivo anti-nuclear antibody

2.6 Diagnostic Criteria and Subtypes The diagnostic criteria of BSLE was first described by Camisa and Sharma in 1983 [2] and were revised in 1988 [3]. These criteria were (1) diagnosis of SLE based on ACR criteria; (2) vesicles and/or bullae; (3) histopathologic features similar to DH; (4) DIF with IgG and/or IgM and often IgA at the BMZ; and (5) IIF testing that can be negative or positive for circulating autoantibodies against the BMZ via the salt-split skin technique. The diagnosis of BSLE was later divided into three groups based on the presence of antibodies to type VII collagen and location of the antibodies against the BMZ [13, 14]. Type I, the most common type, requires evidence

J. J. Contestable et al. Table 2 Subtypes of BSLE IIF

ELISA/Immunoblot

Direct IEM

Presence of antibodies to type VII collagen

BSLE type 1

Positive or negative for dermal staining of salt-split skin

Positive or negative reaction to 290 and 145 kD proteins from human skin basement membrane extracts

Ig deposits in upper dermis and beneath and on the lamina densa

? (Positive)

BSLE type 2

Negative for staining of split skin Positive for epidermal staining of salt-split skin

Scattered granular deposits in the upper dermis, but none on or beneath the lamina densa Ig deposits in the epidermis. May also have deposits present in the upper dermis and lamina densa

- (Negative)

BSLE type 3

Negative reaction to the 290 and 145 kD proteins from basement membrane extracts Positive or negative reaction to 290 and 145 kD proteins from basement membrane extracts

?/- (Either positive or negative)

BSLE bullous systemic lupus erythematosus, IIF indirect immunofluorescence, ELISA enzyme-linked immunosorbent assay, IEM immunoelectron microscopy, kD kilodalton, Ig immunoglobulin

of autoantibodies to type VII collagen, either circulating as determined by IIF or deposited via direct IEM. Type II is characterized by the lack of autoantibodies to type VII collagen entirely. Type III, the most recently proposed subgroup, is based on the presence of autoantibodies that bind either epidermal or both dermal and epidermal epitopes. As this subgroup identification demonstrates, there is diagnostic heterogeneity within BSLE (Table 2). The criteria suggested by Camisa and Sharma were made before IEM, ELISA, and immunoblot technology were more broadly available in the diagnosis of BSLE and EBA. IIF, immunoblot, IEM, and ELISA can detect circulating antibodies to the BMZ in a patient’s serum. However, recent studies suggest that ELISA testing is faster and likely more sensitive and specific for detecting antibodies against NC1 and NC2 of type VII collagen [27, 34]. In addition, ELISA does not lead to as much protein denaturing as is seen in immunoblotting, and may utilize antigenic epitopes that more closely resemble in vivo binding sites [34].

3 Treatment Proper diagnosis of BSLE is important given treatment options and disease prognosis in comparison to other immunobullous diseases that mimic BSLE, such as DH and EBA. For example, rapid response to dapsone in concert with immunosuppressants has been reported in BSLE [3, 5, 8, 15, 23, 24, 38]. However, DH also responds very well to dapsone alone and cases of EBA respond to combined therapy of dapsone and corticosteroids [24, 38]. Hall et al. [23] reported cases resistant to steroids and hydroxychloroquine, which responded dramatically to the addition of dapsone (50–100 mg/day initially). An initial dose of 50 mg/day is most common [3, 5, 23, 39–41] but ranges between 25 and 200 mg/day [15, 42]. Cessation of dapsone therapy resulted

in the reappearance of new lesions in some cases but re-administration was again effective [3, 23]. Dapsone can be stopped within 1 year without recurrence of bullae in BSLE [40, 43]. Side effects of dapsone are most commonly hematological; therefore, dosages higher than 100 mg/day should be used cautiously in patients who are at risk for anemia and/ or symptoms from mild methemoglobinemia. While dapsone is reported to be helpful in BSLE, it is not uncommon for patients to be unresponsive or resistant to dapsone [2, 16, 44]. In these cases, corticosteroids and/or immunosuppressants have been efficacious. Many patients who present with BSLE are on current maintenance doses of immunosuppressive therapy for SLE [18]. Increasing the dosage of their current regimen has shown to be effective for bullous lesions [18]. Patients may present with concomitant systemic symptoms of SLE, namely lupus nephritis, and require systemic corticosteroids and/or immunosuppressant medications. Many cases of BSLE have been shown to respond to these treatments, with or without dapsone. Case reports have shown efficacy of a number of treatment regimens, some of which are shown in Fig. 4. Recently, rituximab (an anti-CD20 monoclonal antibody) has been shown to be effective in cases refractory to dapsone, corticosteroids, or immunosuppressants [4, 45]. The dosage of rituximab is similar to the effective dose in EBA, specifically two treatments of 1,000 mg dosed 2 weeks apart [4, 24, 45]. In both BSLE and EBA, there is evidence that antibodies to type VII collagen are responsible for bullae formation [30, 31]. Rituximab depletes mature B-cells that are CD20? and therefore likely reduces the quantity of circulating anti-type VII collagen antibodies.

4 Conclusions BSLE is a heterogeneous disease that must be considered in any patient presenting with bullae, especially with a

Bullous Systemic Lupus Erythematosus Fig. 4 Treatment algorithm and flowchart with suggested treatments steps. BSLE bullous systemic lupus erythematosus, SLE systemic lupus erythematosus, MMF mycophenolate mofetil, AZA azathioprine

history of SLE or other symptoms suggestive of SLE. It differs in presentation, histology, and immunopathology from more common dermatological manifestations of lupus erythematosus. However, some similarities do exist. When considering patients presenting with bullous lesions there are clear similarities in presentation to BSLE, DH, EBA, BP, and linear IgA bullous dermatosis. However, clinical presentation, histology, and immunopathology (including DIF, IIF, IEM, and/or ELISA and immunoblot) can delineate between these conditions. ACR or SLICC criteria must also be met in order to consider this diagnosis. Therefore, it is important to evaluate patients for systemic symptoms and immune markers of SLE when the diagnosis of BSLE is considered. Dapsone is a possible treatment for BSLE, but its efficacy is variable. Recently, rituximab has shown promise in those resistant or unresponsive to immunosuppressants. Acknowledgments No sources of funding were used to prepare this review. James J. Contestable, Jon H. Meyerle, and Kim D. Edhegard have no conflicts of interest that are directly relevant to the content of this review.

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