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Bullous systemic lupus erythematosus

Author: Dr Sophie Rolls, Specialist Registrar in Dermatology, Glamorgan House, University Hospital of Wales, Cardiff and Vale University Health Board, Cardiff, United Kingdom. DermNet NZ Editor in Chief: Adjunct A/Prof Amanda Oakley, Dermatologist, Hamilton, New Zealand. Copy edited by Gus Mitchell. October 2019.


What is bullous systemic lupus erythematosus?

Bullous systemic lupus erythematosus (SLE) is an autoimmune subepidermal blistering disease that occurs in patients with SLE. It is associated with antibodies against type VII collagen.

Bullous SLE is also called bullous eruption of SLE and vesiculobullous SLE.

Bullous systemic lupus erythematosus

Who gets bullous systemic lupus erythematosus?

The incidence of bullous SLE was estimated to be 0.22 and 0.26 cases per million per year in France and Singapore. In a large cohort of sera taken from patients with immunobullous disorders, 1–2% were identified as bullous SLE [1,2].

Like SLE, bullous SLE typically occurs in women of African descent in their thirties. It can, however, occur in all ages, sexes, and ethnicities.

What causes bullous systemic lupus erythematosus?

Bullous SLE is classified into type 1 and type 2.

  • Most patients have type I bullous SLE where auto-antibodies are targeted against type VII collagen, specifically the non-collagenous type 1 and type 2 (NC1 and NC2) domains.
  • The NC1 domain plays an important role in maintaining the structure of the dermal-epidermal junction (DEJ) [3–5].
  • In type II bullous SLE, antibodies are targeted against other antigens of the DEJ including BP130, BP280 and lamina 332.

Predisposing factors include adverse drug reactions to hydralazine, penicillamine, methimazole; and exposure to ultraviolet (UV) B radiation.

Bullous SLE is immuno-genetically related to epidermolysis bullous acquista (EBA). In both, the expression of autoimmunity to type VII collagen is associated with human leukocyte antigen class II allele [6].

What are the clinical features of bullous systemic lupus erythematosus?

In bullous SLE, tense vesicles, bullae and erosions arise on normal or erythematous skin, usually in sun-exposed sites.

  • The face is often affected; mucosal surfaces can also be involved.
  • The onset of bullous eruption does not correlate with the activity of the systemic disease.
  • The bullae may have clear or haemorrhagic content.
  • The blisters heal without scarring.
  • Pruritus is absent or mild.
  • Milia are not a prominent feature.
  • Erythematous annular urticarial plaques may arise.

What are the complications of bullous systemic lupus erythematosus?

No complications have been described.

How is bullous systemic lupus erythematosus diagnosed?

Most patients with bullous SLE have already been diagnosed with SLE. Investigations are necessary to distinguish bullous SLE from SLE with a concomitant blistering disorder. Rarely, bullous SLE can be the initial clinical manifestation of SLE.

Histopathological findings resemble dermatitis herpetiformis, in that they both possess:

  • Subepidermal splitting
  • A neutrophil predominant infiltrate in the upper dermis
  • Papillary micro-abscesses
  • Leucocytoclasis
  • Mucin deposition in the dermis.

Basal layer vacuolation, characteristic for other forms of cutaneous LE, is not present.

The characteristic direct immunofluorescence (DIF) finding in a perilesional skin biopsy in bullous SLE is linear or granular immunoglobulin (Ig)G, IgM, IgA or C3 at the dermoepidermal junction (DEJ).

Serum autoantibodies, detected via the indirect immunofluorescence test or enzyme-linked immunosorbent assay (ELISA), are against type VII collagen (type I bullous SLE). BP 230, BP 180, or lamina 322 can also be targeted (type II bullous SLE).

Serration pattern analysis of DIF microscopy differentiates tissue bound auto-antibodies against type VII collagen, where a u-serrated pattern is seen, from all other anti-DEJ antibodies where an n-serrated pattern is seen [7].

Diagnostic criteria for bullous SLE requires:

  1. A diagnosis of SLE based upon American College of Rheumatology criteria
  2. An acquired vesiculobullous eruption
  3. Histopathology evidence of a subepidermal blister and neutrophil-predominant dermal infiltrate
  4. DIF microscopy showing linear or granular deposits of immunoglobulin (Ig)G or IgM and often IgA at the basement membrane zone
  5. Antibodies to type VII collagen via indirect immunofluorescence on salt-split skin or ELISA.

What is the differential diagnosis for bullous systemic lupus erythematosus?

Other blistering conditions that may resemble bullous SLE include:

What is the treatment for bullous systemic lupus erythematosus?

Dapsone, at a dose of 1.0–1.5 mg/kg/day, is considered the treatment of choice. It is effective in the vast majority of patients and leads to rapid clinical improvement within days or a few weeks. This rapid response differentiates bullous SLE from SLE with a concomitant autoimmune blistering disease.

Where dapsone fails, prednisolone (systemic steroids) and azathioprine are used. Patients successfully treated with methotrexate or rituximab have been reported [8–10].

What is the outcome for bullous systemic lupus erythematosus?

Bullous SLE is transient in the majority of cases and usually completely regresses with no further flares, irrespective of the activity of the systemic disease.

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References

  1. Bernard P, Vaillant L, Labeille B, et al. Incidence and distribution of subepidermal autoimmune bullous skin diseases in three French regions. Bullous Diseases French Study Group. Arch Dermatol 1995; 131: 48–52. PubMed
  2. Wong SN, Chua SH. Spectrum of subepidermal immunobullous disorders seen at the National Skin Centre, Singapore: a 2‐year review. Br J Dermatol 2002; 147: 476–80. PubMed
  3. Chan LS, Lapiere JC, Chen M, Traczyk T, et al. Bullous systemic lupus erythematosus with autoantibodies recognizing multiple skin basement membrane components, bullous pemphigoid antigen 1, laminin-5, laminin-6, and type VII collagen. Arch Dermatol 1999; 135: 569. PubMed
  4. Yell JA, Allen J, Wonjnarowska F, Kirtschig G, Burge AM. Bullous systemic lupus erythematosus: revised criteria for diagnosis. Br J Dermatol 1995; 132: 921–8. PubMed
  5. Gammon WR, Murrell DF, Jenison MW, et al. Autoantibodies to type VII collagen recognize epitopes in a fibronectin‐like region of the noncollagenous (NC1) domain. J Invest Dermatol 1993; 100: 618–22. PubMed
  6. Gammon WR, Heise ER, Burke WA, Fine JD, et al. Increased frequency of HLA-DR2 in patients with autoantibodies to epidermolysis bullosa acquisita antigen: evidence that the expression of autoimmunity to type VII collagen is HLA class II allele associated. J Invest Dermatol 1988; 91: 228–32. PubMed
  7. Vodegel RM, Jonkman MF, Pas HH, de Jong MC. U‐serrated immunodeposition pattern differentiates type VII collagen targeting bullous diseases from other subepidermal bullous autoimmune diseases. Br J Dermatol 2004; 151: 112–18. PubMed
  8. Malcangi G, Brandozzi G, Giangiacomi M, Zampetti M, Danieli MG. Bullous SLE: response to methotrexate and relationship with disease activity. Lupus 2003; 12: 63–6. PubMed
  9. Alsanafi S, Kovarik C, Mermelstein AL, Werth VP. Rituximab in the treatment of bullous systemic lupus erythematosus. J Clin Rheumatol 2011; 17: 142–4. PubMed
  10. Aude Risi-Pugliese T, Cohen Aubart F, Haroche J, Moguelet P et al. Clinical, histological, immunological presentations and outcomes of bullous systemic lupus erythematosus: 10 New cases and a literature review of 118 cases. Arthritis Rheum 2018; 48: 83. PubMed

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