Correspondence Clinical Letter
Clinical Letter Treatment of anti-laminin γ1 pemphigoid with mycophenolate mofetil
DOI: 10.1111/ddg.12564
Dear Editors, Autoimmune blistering diseases are a group of disorders characterized by autoantibodies, primarily IgG, directed against cutaneous adhesion molecules, thus leading to blister formation in the skin and mucous membranes. Autoantibodies may be directed against desmosomal structures of the epidermis (pemphigus diseases) on the one hand, or against hemidesmosomes and components of the dermoepidermal basement membrane (pemphigoid group) or against dermal anchoring fibrils (acquired epidermolysis bullosa) on the other hand. The second group includes bullous pemphigoid (BP), which, with an incidence of 10–30/1,000,000 per year, is the most common autoimmune bullous dermatosis [1]. We report on a 69-year-old patient who was admitted to our hospital with a suspected diagnosis of bullous pemphigoid. He had had a history of psoriasis for more than 30 years. For about three months prior to his admission, he had been increasingly affected by blisters, primarily developing over the joints and associated with severe pruritus. Comorbidities were immune thrombocytopenia (Werlhof’s disease) and hepatitis C. Clinically, the entire integument was covered by livid-red areas of erythema – partially showing widespread confluence – with yellow crusts, fine scaling, and marked lichenification. On the arms and legs, especially distally, there were tense blisters on an erythematous base, measuring approximately 3 mm in diameter, partly hemorrhagic, partly oozing and erosive (Figure 1a). Histology showed a subepidermal cleft with neutrophils and isolated eosinophils. Direct immunofluorescence analysis of perilesional skin revealed IgG and C3 deposits along the dermoepidermal basement membrane. Salt-split skin examination using the patient’s serum, in order to further differentiate the subepidermal blister formation, showed IgG and C3 binding to the dermal side of the artificial cleft (Figure 1b). Conventional electron microscopy revealed an electron-dense band beneath the lamina densa, which corresponded to the immunoglobulin deposits. Immunoblotting showed IgG antibodies against 200 kDa laminin γ1 (Figure 1c) [2]. IgG autoantibodies against the pemphigoid autoantigens, BP180 and BP230, collagen VII
696
Figure 1 Tense blisters (arrows) on an erythematous, partly urticarial base (a). Salt-split skin examination: IgG reactivity at the bottom of the cleft (b). Immunoblot: IgG reactivity with the 200 kDa laminin-γ1 chain (c).
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1307
Correspondence Clinical Letter
or laminin 332 were not found. In view of these results, we diagnosed anti-laminin γ1 pemphigoid. Due to elevated transaminases caused by initial therapy with azathioprine, the patient was switched to mycophenolate mofetil (MMF) at a dose of 2 g every day. In addition, he received systemic prednisolone therapy at an initial dose of 1 mg/kg, which was subsequently rapidly reduced. On this treatment, blister formation ceased and the skin lesions on the entire integument healed rapidly. The patient was referred to our outpatient clinic, and after three years, he is asymptomatic on MMF 2 g daily and prednisolone 7.5 mg daily. For our patient, MMF is an adequate long-term treatment option given his intolerance to azathioprine. Laminin γ1 is a glycoprotein of the extracellular matrix, which is located beneath the lamina lucida and is a structural component of the basement membrane [3, 4]. In anti-laminin γ1 pemphigoid, the autoantibodies therefore bind to the lamina densa of the dermoepidermal junction [4, 5], resulting in a subepidermal cleft. As the patients’ IgG autoantibodies react with a 200 kDa protein in the immunoblot using a keratinocyte extract, the autoantigen of this disorder was originally referred to as p200, before it was identified as laminin γ1 [6]. Anti-laminin γ1 pemphigoid is a very rare autoimmune bullous disorder that mainly affects patients between the ages of 50 and 70 [7, 8]. An association with psoriasis has been reported on multiple occasions [3, 5, 9]; our patient also had a more than 30-year history of psoriasis. It is suspected that altered laminin γ1 expression in psoriatic skin leads to activation of neutrophils and metalloproteinase (MMP) 9 with subsequent production of antibodies against laminin γ1 [3]. The pathogenetic role played by anti-laminin γ1 IgG autoantibodies is still unclear. Unlike anti-BP180 and anti-BP230, the classic pemphigoid autoantibodies, they do not directly cause subepidermal blisters [10]. Available treatment options include systemic corticosteroids in combination with dapsone or azathioprine [5]. We successfully treated our patient with mycophenolate mofetil. Conflict of interest None.
Correspondence to Prof. Dr. med. Martin Schaller Universitäts-Hautklinik Tübingen Liebermeisterstraße 25 72076 Tübingen Germany E-mail: [email protected]
References 1
Kneisel A, Hertl M. Autoimmune bullous skin diseases. Part 2: diagnosis and therapy. J Dtsch Dermatol Ges 2011; 9: 927–47. 2 Ishii N, Yoshida M, Hisamatsu Y et al. Epidermolysis bullosa acquisita sera react with distinct epitopes on the NC1 and NC2 domains of type VII collagen: study using immunoblotting of domain-specific recombinant proteins and postembedding immunoelectron microscopy. Br J Dermatol 2004; 150: 843–51. 3 Dainichi T, Koga H, Tsuji T et al. From anti-p200 pemphigoid to anti-laminin gamma1 pemphigoid. J Dermatol 2010; 37: 231–8. 4 Goletz S, Hashimoto T, Zillikens D, Schmidt E. Anti-p200 pemphigoid. J Am Acad Dermatol 2014; 71: 185–91. 5 Dainichi T, Kurono S, Ohyama B et al T. Anti-laminin gamma-1 pemphigoid. Proc Natl Acad Sci U S A 2009; 106: 2800–5. 6 Shimizu A, Funakoshi T, Ishibashi M et al. Immunoglobulin G deposition to nonhemidesmosomal lamina lucida and early neutrophil involvement are characteristic features in a case of anti-p200 pemphigoid. Br J Dermatol 2013; 168: 647–55. 7 Schmidt E, Zillikens D. Research in practice: diagnosis of subepidermal autoimmune bullous disorders. J Dtsch Dermatol Ges 2009; 7: 296–300. 8 Shimanovich I, Rose C, Hirako Y et al. Anti-p200 pemphigoid – a new bullous autoimmune dermatosis. J Dtsch Dermatol Ges 2004; 2: 7–14. 9 Yasuda H, Tomita Y, Shibaki A, Hashimoto T. Two cases of subepidermal blistering disease with anti-p200 or 180-kD bullous pemphigoid antigen associated with psoriasis. Dermatology 2004; 209: 149–55. 10 Vafia K, Groth S, Beckmann T et al. Pathogenicity of autoantibodies in anti-p200 pemphigoid. PLoS One 2012; 7: e41769.
Andrea Gawaz1, Gisela Metzler 1, Michael Hertl2, Takashi Hashimoto3, Martin Schaller 1 (1) Department of Dermatology, University of Tuebingen (2) Department of Dermatology and Allergology, University of Marburg (3) Department of Dermatology, Kurume University, Kurume, Japan
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1307
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Clinical Letter Treatment of anti-laminin γ1 pemphigoid with mycophenolate mofetil
DOI: 10.1111/ddg.12564
Dear Editors, Autoimmune blistering diseases are a group of disorders characterized by autoantibodies, primarily IgG, directed against cutaneous adhesion molecules, thus leading to blister formation in the skin and mucous membranes. Autoantibodies may be directed against desmosomal structures of the epidermis (pemphigus diseases) on the one hand, or against hemidesmosomes and components of the dermoepidermal basement membrane (pemphigoid group) or against dermal anchoring fibrils (acquired epidermolysis bullosa) on the other hand. The second group includes bullous pemphigoid (BP), which, with an incidence of 10–30/1,000,000 per year, is the most common autoimmune bullous dermatosis [1]. We report on a 69-year-old patient who was admitted to our hospital with a suspected diagnosis of bullous pemphigoid. He had had a history of psoriasis for more than 30 years. For about three months prior to his admission, he had been increasingly affected by blisters, primarily developing over the joints and associated with severe pruritus. Comorbidities were immune thrombocytopenia (Werlhof’s disease) and hepatitis C. Clinically, the entire integument was covered by livid-red areas of erythema – partially showing widespread confluence – with yellow crusts, fine scaling, and marked lichenification. On the arms and legs, especially distally, there were tense blisters on an erythematous base, measuring approximately 3 mm in diameter, partly hemorrhagic, partly oozing and erosive (Figure 1a). Histology showed a subepidermal cleft with neutrophils and isolated eosinophils. Direct immunofluorescence analysis of perilesional skin revealed IgG and C3 deposits along the dermoepidermal basement membrane. Salt-split skin examination using the patient’s serum, in order to further differentiate the subepidermal blister formation, showed IgG and C3 binding to the dermal side of the artificial cleft (Figure 1b). Conventional electron microscopy revealed an electron-dense band beneath the lamina densa, which corresponded to the immunoglobulin deposits. Immunoblotting showed IgG antibodies against 200 kDa laminin γ1 (Figure 1c) [2]. IgG autoantibodies against the pemphigoid autoantigens, BP180 and BP230, collagen VII
696
Figure 1 Tense blisters (arrows) on an erythematous, partly urticarial base (a). Salt-split skin examination: IgG reactivity at the bottom of the cleft (b). Immunoblot: IgG reactivity with the 200 kDa laminin-γ1 chain (c).
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1307
Correspondence Clinical Letter
or laminin 332 were not found. In view of these results, we diagnosed anti-laminin γ1 pemphigoid. Due to elevated transaminases caused by initial therapy with azathioprine, the patient was switched to mycophenolate mofetil (MMF) at a dose of 2 g every day. In addition, he received systemic prednisolone therapy at an initial dose of 1 mg/kg, which was subsequently rapidly reduced. On this treatment, blister formation ceased and the skin lesions on the entire integument healed rapidly. The patient was referred to our outpatient clinic, and after three years, he is asymptomatic on MMF 2 g daily and prednisolone 7.5 mg daily. For our patient, MMF is an adequate long-term treatment option given his intolerance to azathioprine. Laminin γ1 is a glycoprotein of the extracellular matrix, which is located beneath the lamina lucida and is a structural component of the basement membrane [3, 4]. In anti-laminin γ1 pemphigoid, the autoantibodies therefore bind to the lamina densa of the dermoepidermal junction [4, 5], resulting in a subepidermal cleft. As the patients’ IgG autoantibodies react with a 200 kDa protein in the immunoblot using a keratinocyte extract, the autoantigen of this disorder was originally referred to as p200, before it was identified as laminin γ1 [6]. Anti-laminin γ1 pemphigoid is a very rare autoimmune bullous disorder that mainly affects patients between the ages of 50 and 70 [7, 8]. An association with psoriasis has been reported on multiple occasions [3, 5, 9]; our patient also had a more than 30-year history of psoriasis. It is suspected that altered laminin γ1 expression in psoriatic skin leads to activation of neutrophils and metalloproteinase (MMP) 9 with subsequent production of antibodies against laminin γ1 [3]. The pathogenetic role played by anti-laminin γ1 IgG autoantibodies is still unclear. Unlike anti-BP180 and anti-BP230, the classic pemphigoid autoantibodies, they do not directly cause subepidermal blisters [10]. Available treatment options include systemic corticosteroids in combination with dapsone or azathioprine [5]. We successfully treated our patient with mycophenolate mofetil. Conflict of interest None.
Correspondence to Prof. Dr. med. Martin Schaller Universitäts-Hautklinik Tübingen Liebermeisterstraße 25 72076 Tübingen Germany E-mail: [email protected]
References 1
Kneisel A, Hertl M. Autoimmune bullous skin diseases. Part 2: diagnosis and therapy. J Dtsch Dermatol Ges 2011; 9: 927–47. 2 Ishii N, Yoshida M, Hisamatsu Y et al. Epidermolysis bullosa acquisita sera react with distinct epitopes on the NC1 and NC2 domains of type VII collagen: study using immunoblotting of domain-specific recombinant proteins and postembedding immunoelectron microscopy. Br J Dermatol 2004; 150: 843–51. 3 Dainichi T, Koga H, Tsuji T et al. From anti-p200 pemphigoid to anti-laminin gamma1 pemphigoid. J Dermatol 2010; 37: 231–8. 4 Goletz S, Hashimoto T, Zillikens D, Schmidt E. Anti-p200 pemphigoid. J Am Acad Dermatol 2014; 71: 185–91. 5 Dainichi T, Kurono S, Ohyama B et al T. Anti-laminin gamma-1 pemphigoid. Proc Natl Acad Sci U S A 2009; 106: 2800–5. 6 Shimizu A, Funakoshi T, Ishibashi M et al. Immunoglobulin G deposition to nonhemidesmosomal lamina lucida and early neutrophil involvement are characteristic features in a case of anti-p200 pemphigoid. Br J Dermatol 2013; 168: 647–55. 7 Schmidt E, Zillikens D. Research in practice: diagnosis of subepidermal autoimmune bullous disorders. J Dtsch Dermatol Ges 2009; 7: 296–300. 8 Shimanovich I, Rose C, Hirako Y et al. Anti-p200 pemphigoid – a new bullous autoimmune dermatosis. J Dtsch Dermatol Ges 2004; 2: 7–14. 9 Yasuda H, Tomita Y, Shibaki A, Hashimoto T. Two cases of subepidermal blistering disease with anti-p200 or 180-kD bullous pemphigoid antigen associated with psoriasis. Dermatology 2004; 209: 149–55. 10 Vafia K, Groth S, Beckmann T et al. Pathogenicity of autoantibodies in anti-p200 pemphigoid. PLoS One 2012; 7: e41769.
Andrea Gawaz1, Gisela Metzler 1, Michael Hertl2, Takashi Hashimoto3, Martin Schaller 1 (1) Department of Dermatology, University of Tuebingen (2) Department of Dermatology and Allergology, University of Marburg (3) Department of Dermatology, Kurume University, Kurume, Japan
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1307
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