eMedicine Specialties > Dermatology > Connective Tissue Diseases

Lupus Erythematosus, Bullous

Author: Hillary D Johnson-Jahangir, MD, PhD, Staff Physician, Department of Dermatology, Columbia University Medical Center
Coauthor(s): Julie V Schaffer, MD, Assistant Professor of Dermatology and Pediatrics, Director of Dermatology Resident Education, Director of Pediatric Dermatology Unit, New York University School of Medicine
Contributor Information and Disclosures

Updated: Jun 18, 2009

Introduction

Background

Bullous systemic lupus erythematosus (BSLE) is an autoantibody-mediated subepidermal blistering disease that occurs in patients with systemic lupus erythematosus (SLE).¹ The diagnosis of bullous systemic lupus erythematosus requires the following elements:

• Fulfillment of the American College of Rheumatology criteria for systemic lupus erythematosus (see Systemic Lupus Erythematosus)
• An acquired vesiculobullous eruption
• Histologic evidence of a subepidermal blister and a predominantly neutrophilic dermal infiltrate
• Direct immunofluorescence (DIF) microscopy demonstrating immunoglobulin G (with or without immunoglobulin A [IgA] and immunoglobulin M) deposits at the basement membrane zone (BMZ)
• Evidence of antibodies to type VII collagen via DIF or indirect immunofluorescence (IIF) on salt-split skin, immunoblotting, immunoprecipitation, enzyme-linked immunosorbent assay (ELISA), or immunoelectron microscopy

All 5 criteria are needed for a diagnosis of type 1 bullous systemic lupus erythematosus, whereas only the first 4 criteria are needed to diagnose type 2 (undetermined location of antigen or dermal antigen other than type VII collagen) and type 3 (epidermal antigen) bullous systemic lupus erythematosus. Type VII collagen, a component of anchoring fibrils, is also targeted in epidermolysis bullosa acquisita (EBA). However, unlike epidermolysis bullosa acquisita, bullous systemic lupus erythematosus tends to respond dramatically to treatment with dapsone.

Not all blistering eruptions that occur in patients with lupus erythematosus represent bullous systemic lupus erythematosus as defined above. Vesiculobullous skin lesions can also develop as a result of extensive damage to the epidermal basal layer (and even suprabasal keratinocytes) due to an intense interface dermatitis in the setting of lupus erythematosus–specific skin disease. Such patients may present with a severe form of acute or subacute cutaneous lupus erythematosus (SCLE) that resembles erythema multiforme (Rowell syndrome)² or toxic epidermal necrolysis (TEN).^3,4,5 Because epidermolysis bullosa acquisita and bullous systemic lupus erythematosus share the same target antigen, distinguishing between the 2 may be difficult.

The Finnish Medical Society Duodecim has updated guidelines for systemic lupus erythematosus. For a summary, see Systemic Lupus Erythematosus (SLE).⁶

Pathophysiology

The production of autoantibodies represents a central feature of systemic lupus erythematosus. For example, antinuclear antibodies (ANAs) are detected in almost all affected individuals. In addition to this general tendency, injury to the dermoepidermal junction by the interface dermatitis of cutaneous lupus erythematosus might expose new epitopes and precipitate the development of antibodies that specifically target the BMZ.

The autoantibody repertoire of systemic lupus erythematosus can include nonpathogenic and pathogenic anti-BMZ antibodies. Patients with nonbullous systemic lupus erythematosus often have circulating antibodies to various components of the BMZ (including bullous pemphigoid antigens 1 and 2), which may have a role in formation of the lesional lupus band (ie, granular antibody deposition at the BMZ in normal-appearing skin). Although the lupus band appears to co-localize with type VII collagen, the noncollagenous (NC1) 1 domain of this protein does not represent the target antigen for circulating antibodies in systemic lupus erythematosus patients without clinical blistering.

In patients with bullous systemic lupus erythematosus, antibodies directed at the BMZ likely mediate the blistering phenotype by directly interfering with adhesive connections at the dermoepidermal junction and through induction of complement-dependent inflammation that leads to tissue injury and dermoepidermal separation. Proteolytic damage caused by recruited neutrophils contributes to the latter process.

In type 1 bullous systemic lupus erythematosus (which accounts for most cases), antibodies against type VII collagen may weaken or block anchoring fibril-mediated connections between the lamina densa of the basement membrane and the papillary dermis. In both epidermolysis bullosa acquisita and bullous systemic lupus erythematosus, antigenic epitopes reside within the NC1 and NC2 domains of type VII collagen, which are localized to the lamina densa and the underlying dermis, respectively.⁷ The cartilage matrix protein (CMP) subdomain the NC1 domain has been shown to bind to antibodies from patients with epidermolysis bullosa acquisita and systemic lupus erythematosus, suggesting this subdomain serves as an immunodominant antigenic epitope.⁸

Subepidermal blisters can be induced in mice by the passive transfer of such autoantibodies from epidermolysis bullosa acquisita patients, but not the Fab fragments alone.^9,10 This demonstrates that human epidermolysis bullosa acquisita autoantibodies are pathogenic and that complement-mediated inflammation (which requires the Fc fragment) has an important role in the blistering process. Antibodies recognizing bullous pemphigoid antigen 1, laminin-5, and laminin-6 have also been described in patients with bullous systemic lupus erythematosus.¹¹ While autoreactive helper T cells and dysregulation of regulatory T cells may play a role in other autoimmune blistering disorders such as pemphigus and bullous pemphigoid, autoimmunity to type VII collagen has not been shown to involve aberrant regulatory T cell function.^12,13,14

The term acute syndrome of apoptotic pan-epidermolysis (ASAP) has been proposed for the toxic epidermal necrolysis–like cutaneous injury pattern that can occur in settings of lupus erythematosus, acute graft versus host disease, pseudoporphyria, and the classic drug-hypersensitivity syndrome.¹⁵ Fas-Fas ligand interactions have been implicated in the massive keratinocyte apoptosis that characterizes ASAP. Toxic epidermal necrolysis–like cutaneous lupus erythematosus must be differentiated from drug-induced toxic epidermal necrolysis occurring in a patient with lupus erythematosus.

Frequency

International

Bullous systemic lupus erythematosus accounts for 2-3% of cases of autoimmune subepidermal blistering disease, with an estimated incidence of fewer than 0.5 cases per million population per year.

Mortality/Morbidity

• The development of bullous systemic lupus erythematosus in patients with systemic lupus erythematosus does not typically lead to increased mortality. Morbidity depends on the extent of the eruption and the response to therapy. Fortunately, unlike epidermolysis bullosa acquisita, treatment with dapsone is successful in most cases of bullous systemic lupus erythematosus.
• Toxic epidermal necrolysis–like lupus erythematosus can result in considerable morbidity and even mortality if extensive areas of skin are denuded, especially in the context of severe systemic manifestations of lupus erythematosus.

Race

Persons of any race can develop bullous systemic lupus erythematosus, but it occurs most frequently in African Americans.

Sex

Bullous systemic lupus erythematosus affects women more often than men, reflecting the female preponderance in systemic lupus erythematosus.

Age

Bullous systemic lupus erythematosus most often manifests in the second through fourth decades of life, but it has been reported in children and older adults.

Clinical

History

• Bullous systemic lupus erythematosus is characterized by the rapid development of a widespread vesiculobullous eruption. The blistering activity does not necessarily correlate with that of the patient's lupus erythematosus–specific skin or systemic disease, but parallel exacerbations (often involving lupus nephritis) have been described. Bullous systemic lupus erythematosus occasionally represents the initial clinical manifestation of systemic lupus erythematosus.
  • Bullous systemic lupus erythematosus may be accompanied by pruritus of variable intensity. Mucosal lesions are often painful.
  • Patients can exhibit any of the symptoms associated with systemic lupus erythematosus. These can include fever; weight loss; fatigue; photosensitivity; arthralgias; arthritis; and manifestations of renal, pulmonary, cardiac, and/or central nervous system disease. See eMedicine's articles in the Internal Medicine section (Systemic Lupus Erythematosus) and Neurology section (Systemic Lupus Erythematosus) for details on the clinical manifestations of systemic lupus erythematosus.
• Patients with toxic epidermal necrolysis–like acute cutaneous lupus erythematosus often have significant systemic disease activity (eg, lupus nephritis or cerebritis).

Physical

• Morphology of bullous systemic lupus erythematosus skin lesions
  • Blisters range from large, tense bullae (resembling bullous pemphigoid) to small, grouped vesicles (resembling dermatitis herpetiformis). They often arise on erythematous skin and may be preceded by urticarial papules and plaques. An annular or figurate configuration is occasionally observed. Bullae contain clear or hemorrhagic fluid. Rupture results in erosions and crusts, which typically heal with postinflammatory hyperpigmentation or hypopigmentation.

• • Although bullous systemic lupus erythematosus was initially defined as a nonscarring bullous disease, a mechanobullous presentation resembling classic epidermolysis bullosa acquisita has been reported. In such patients, vesicles and bullae arise within noninflamed skin of trauma-prone sites (reflecting skin fragility) and heal with milia and scarring.
• Distribution of bullous systemic lupus erythematosus
  • Bullous systemic lupus erythematosus frequently manifests as a widespread, symmetric distribution of skin lesions. The eruption favors the upper part of the trunk, proximal upper extremities (flexural and extensor aspects), neck, and face, but blisters can occur anywhere on the cutaneous surface. Usually, no clear association exists between sun exposure and the development of lesions, which involve both sun-protected and sun-exposed sites.
  • Lesions of classic epidermolysis bullosa acquisita–like bullous systemic lupus erythematosus are localized to trauma-prone areas such as the dorsal hands, feet, elbows, and knees.
  • Blisters and erosions can also affect the oral, pharyngeal, nasal, and vulvar mucous membranes.
• Lupus erythematosus–specific vesiculobullous skin disease
  • These vesiculobullous lesions are distinct from bullous systemic lupus erythematosus, representing severe variants of acute, subacute, or (rarely) discoid cutaneous lupus erythematosus. The eruptions can develop rapidly or evolve over several weeks.
  • In toxic epidermal necrolysis–like acute cutaneous lupus erythematosus, photodistributed diffuse or patchy erythema evolves (usually rapidly) into flaccid bullae (positive Nikolsky sign, unlike bullous systemic lupus erythematosus) and widespread sheetlike, full-thickness epidermal detachment.
  • Toxic epidermal necrolysis–like subacute cutaneous lupus erythematosus manifests as widespread blistering and full-thickness epidermal detachment in the context of preexisting photodistributed annular or papulosquamous skin lesions and anti-Ro/SS-1 and/or anti-La/SS-2 antibody production.
  • Involvement the oral, conjunctival, and genital mucosae occurs in some cases of toxic epidermal necrolysis–like lupus erythematosus.
  • Erythema multiforme–like lesions occurring in the context of acute, subacute, or (as initially described by Rowell and colleagues in 1963) discoid cutaneous lupus erythematosus have been referred to as Rowell syndrome. The development of these targetoid erythematous plaques with central (or, in the setting of subacute cutaneous lupus erythematosus, peripheral) blistering and erosions is thought to represent a limited form of toxic epidermal necrolysis–like lupus erythematosus. Mucosal involvement is often observed.^16,17,18,19
  • Vesicles or erosions at the advancing edge of active annular subacute lupus erythematosus lesions represent a relatively common observation.
• Other mucocutaneous findings
  • Specific cutaneous lesions of acute, subacute, and chronic (discoid) cutaneous lupus are observed in a minority of patients with bullous systemic lupus erythematosus. See Lupus Erythematosus, Acute; Lupus Erythematosus, Subacute Cutaneous; and Lupus Erythematosus, Discoid for information on these forms of cutaneous lupus erythematosus.
  • Nonspecific cutaneous findings of lupus erythematosus, such as periungual telangiectasias, livedo reticularis, and nonscarring alopecia, also may be present. See Lupus Erythematosus, Acute; Lupus Erythematosus, Subacute Cutaneous; and Lupus Erythematosus, Discoid for details.
  • Chilblain lupus can occur in association with Rowell syndrome.
• General examination: Extracutaneous findings of systemic lupus erythematosus may include joint tenderness and swelling, pallor or petechiae (reflecting hematologic abnormalities), and auscultation evidence of a pulmonary or pericardial effusion. See Systemic Lupus Erythematosus in eMedicine's Internal Medicine section for details.

Causes

• Certain individuals may have a genetic predisposition to develop autoimmunity to BMZ antigens and to systemic lupus erythematosus. For example, epidermolysis bullosa acquisita, bullous systemic lupus erythematosus, and systemic lupus erythematosus are all associated with an increased prevalence of the HLA class II DR2 haplotype. The antigen-presenting protein encoded by the DR2-associated DRB1*1501 allele (found in both epidermolysis bullosa acquisita and bullous systemic lupus erythematosus patients) has been postulated to be involved in presenting type VII collagen epitopes to T lymphocytes.
• Toxic epidermal necrolysis–like lupus erythematosus can be triggered by intensive ultraviolet exposure.

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