Severe acral contractures and nail loss in a patient with mechano-bullous Epidermolysis bullosa acquisita

ARTICLE

Auteur(s) : Carl Meissner¹, Marc Hoefeld-Fegeler¹, Robert Vetter¹, Michael Bellutti¹, Artem Vorobyev³, Harald Gollnick¹, Martin Leverkus^1,2

¹Department of Dermatology and Venereology, Otto-von-Guericke-University Magdeburg, Germany
²Department of Dermatology, Venereology, and Allergology, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
³Department of Dermatology, University of Lübeck

Epidermolysis bullosa acquisita (EBA) is a chronic acquired autoimmune blistering disease with highly variable clinical manifestations [1]. The classic mechano-bullous non-inflammatory type presents with acral blisters and erosions. Inflammatory variants of EBA can resemble bullous or cicatricial pemphigoid, and severe mucosal involvement may be present, leading to severe complications, such as oesophageal stenosis [2]. Therapeutically, EBA represents a major challenge, requiring high dose long term immunosuppressive therapy, with modest long term success [3].

We describe a 50-year-old patient in whom a mechano-bullous form of EBA was diagnosed 12 years ago [4]. First symptoms were blister formation on mechanically stressed areas (figure 1A). Furthermore, aggravated blister formation of the hands was evident within hours after sun exposure. Histopathology of biopsies revealed subepidermal bullae and a dense inflammatory infiltrate in the upper dermis. Direct immunofluorescence (DIF) microscopy showed linear depositions of IgG and C3 at the basement membrane zone, and indirect IF microscopy showed binding of circulating IgG (figure 1F), but not IgA antibodies to the dermal side of the split (figures 1G, H). Immunoblot analysis with IgG4 isotype-specific secondary antibodies showed that the patient's serum specifically reacted with the recombinant NC-1 domain of type VII collagen. ELISA using recombinant BP230, BP180 NC16A domains, as well as ANA, ENA, or Abs against single or double stranded DNA, were negative. We diagnosed a predominantly mechano-bullous form of EBA. The patient refused consent for an oral corticosteroid therapy and did not present again for several years. He noted an aggravation of the symptoms upon intensive manual work. 9 years after diagnosis he noted progressive atrophic scarring of his hands (figure 1B). After the initial diagnosis 12 years before, therapy with intravenous immunoglobulins (1.2 g kg^-1 in monthly intervals over a total of 18 months) was initiated. Subsequently, he was treated with mycophenolate mofetil (2 g daily p.o.) and colchicine (1 mg daily) [5] for several years. Later, recurrent oesophageal strictures required balloon dilation. 12 years after the initial diagnosis, the patient presented with severe contractures of the hands and feet (figures 1C-E). The palmar side of his hands demonstrated severe dermatogenic contractures and nail loss (figure 1E). For this we started systemic corticosteroid treatment in combination with azathioprine (1.5 mg/kg body weight). Based upon previous successful reports [6, 7], we initiated 4 cycles of a B-cell depleting therapy with Rituximab (375 mg/m² infusion once a week) and achieved remission of the inflammatory clinical symptoms over 4 months. Circulating autoantibody titers against the immuno-dominant (NC-1) domains of type VII collagen (titer of 1:1600 at presentation) were undetectable within 4-6 months, and the skin vulnerability was substantially improved.

A loss of function of type VII collagen due to mutations within the COL7A1 gene leads to different forms of epidermolysis bullosa [8]. We demonstrate that over the prolonged course presented here a predominantly mechano-bullous EBA can lead to severe contractures and mutilations that may resemble a dystrophic form of Epidermolysis bullosa. To the best of our knowledge, this is the first documented case of such major skin complications of EBA in the literature, arguing for an early aggressive immunosuppression for such forms of EBA. Although the patient was not continuously affected in his daily life by the extent of active disease, the mechano-bullous form of EBA can lead to serious acral complications. We will now aim to mobilize the patient once clinical activity of the disease is controlled by immunosuppressive and B-cell depleting therapy. Future studies will evaluate the effectiveness of immunosuppression, not only for acute inflammation [9], but also for prevention of mutilations. We speculate that immunosuppression and thus reduction of circulating and tissue-bound autoantibodies to collagen type VII may delay the scarring and contractions that we document in this report.

Acknowledgement

Financial support: none. Conflict of interest: none.

References

2 Shipman AR, Agero AL, Cook I, et al. Epidermolysis bullosa acquisita requiring multiple oesophageal dilatations. ClinExpDermatol 2008; 33: 787-9.

3 Schmidt E, Brocker EB, Goebeler M. Rituximab in treatment-resistant autoimmune blistering skin disorders. ClinRevAllergy Immunol 2008; 34: 56-64.

4 Jappe U, Zillikens D, Bonnekoh B, Gollnick H. Epidermolysis bullosa acquisita with ultraviolet radiationsensitivity. BrJ Dermatol 2000; 142: 517-20.

5 Bibas R, Gaspar NK. Ramos-e-Silva. Colchicine for dermatologic diseases. JDrugs Dermatol 2005; 4: 196-204.

6 Niedermeier A, Eming R, Pfutze M, et al. Clinical response of severe mechanobullous epidermolysis bullosa acquisita to combined treatment with immunoadsorption and rituximab (anti-CD20 monoclonal antibodies). Arch Dermatol 2007; 143: 192-8.

7 Schmidt E, Benoit S, Brocker EB, Zillikens D, Goebeler M. Successful adjuvant treatment of recalcitrant epidermolysis bullosa acquisita with anti-CD20 antibody rituximab. Arch Dermatol 2006; 142: 147-50.

8 Dang N, Murrell DF. Mutation analysis and characterization of COL7A1 mutations in dystrophic epidermolysis bullosa. Exp Dermatol 2008; 17: 553-68.

9 Takae Y, Nishikawa T, Amagai M. Pemphigus mouse model as a tool to evaluate various immunosuppressive therapies. Exp Dermatol 2009; 18: 252-60.