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Original Investigation |

Laboratory Diagnosis and Clinical Profile of Anti-p200 Pemphigoid

Joost M. Meijer, MD1; Gilles F. H. Diercks, MD, PhD1; Enno Schmidt, MD, PhD2; Hendri H. Pas, PhD1; Marcel F. Jonkman, MD, PhD1
[+] Author Affiliations
1Center for Blistering Diseases, Department of Dermatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
2Department of Dermatology, University of Lübeck, Lübeck, Germany
JAMA Dermatol. 2016;152(8):897-904. doi:10.1001/jamadermatol.2016.1099.
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Importance  Anti-p200 pemphigoid is a rare subepidermal autoimmune blistering disease characterized by autoantibodies against a 200-kDa protein in the basement membrane zone. Anti-p200 pemphigoid is probably often misdiagnosed because of low availability of diagnostic assays and expertise and classified as bullous pemphigoid or epidermolysis bullosa acquisita.

Objective  To clinically characterize patients with anti-p200 pemphigoid, identified by using indirect immunofluorescence microscopy on skin substrates deficient in type VII collagen and laminin-332 (knockout analysis), to validate this technique by immunoblot with dermal extract, and to incorporate direct immunofluorescence serration pattern analysis in the diagnostic algorithm.

Design, Setting, and Participants  This was a retrospective study performed from January 2014 to June 2015 with biobank patient materials and clinical data for the period 1998 to 2015 from the single national referral center on autoimmune bullous diseases. Patients were selected based on a dermal side binding on 1-mol/L salt (sodium chloride)-split human skin substrate by indirect immunofluorescence microscopy, not diagnosed epidermolysis bullosa acquisita or anti–laminin-332 mucous membrane pemphigoid.

Main Outcomes and Measures  Indirect immunofluorescence microscopy knockout analysis was performed and diagnosis of anti-p200 confirmed by immunoblot with dermal extract. Clinical, histological, and immunological findings were registered. Autoantibodies against laminin γ1 were determined by immunoblot.

Results  Twelve patients with anti-p200 pemphigoid (7 male and 5 female; mean age, 66.6 years) were identified using the indirect immunofluorescence microscopy knockout analysis. Direct immunofluorescence microscopy showed a linear n-serrated IgG deposition pattern along the basement membrane zone in 9 of 11 patients. The diagnosis was confirmed by immunoblot showing autoantibodies against 200-kDa protein in dermal extract in 12 of 12 patients. Autoantibodies against recombinant laminin γ1 were detected by immunoblot in 8 of 12 patients. Remarkable similarities were seen in clinical features with predominantly tense blisters on hands and feet, resembling dyshidrosiform pemphigoid. Mucosal involvement was seen in 6 (50%) of the patients.

Conclusions and Relevance  Predominance of blisters on hands and feet may be a clinical clue to the diagnosis of anti-p200 pemphigoid. Direct immunofluorescence microscopy serration pattern analysis and indirect immunofluorescence microscopy knockout analysis are valuable additional techniques to facilitate the diagnosis of anti-p200 pemphigoid.

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Figure 1.
Clinical Manifestations of Anti-p200 Pemphigoid

A and B, Tense blisters and desquamation of a palm and sole, respectively, resembling dyshidrosiform pemphigoid. C, Vesicles on the tongue. D, Circumscript monomorphic tense vesicles and blisters on the arm.

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Figure 2.
Indirect Immunofluorescence (IIF) Microscopy Knockout Analysis on Skin Substrate of a Patient With Epidermolysis Bullosa Completely Deficient of Type VII Collagen (RDEB) or Laminin-332 (JEB)

A and B, Test results for anti-laminin-332 mucous membrane pemphigoid (MMP). In absence of the target antigen, serum of a patient with anti–laminin-332 MMP is negative (neg) on laminin-332 deficient skin (A). C and D, Test results for epidermolysis bullosa acquisita (EBA). Similarly, serum of a patient with EBA is negative on type VII collagen deficient skin (D). E and F, Test results for anti-p200 pemphigoid. Serum of a patient with anti-p200 pemphigoid is positive (pos) on both skin substrates, therefore excluding autoantibodies to solely laminin-332 and type VII collagen.

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Figure 3.
Algorithm for Diagnosis of Anti-p200 Pemphigoid in Patients With Subepidermal Autoimmune Bullous Diseases (sAIBDs) and IgG Autoantibodies Binding to the Dermal Side on SSS by (IIF) Microscopy

The differential diagnosis includes anti-p200 pemphigoid, anti–laminin-332 mucous membrane pemphigoid (MMP) and epidermolysis bullosa acquisita (EBA). To distinguish between these sAIBDs, final diagnosis can be confirmed by using 1 or a combination of available laboratory techniques: immunoblotting with appropriate substrates, immunoprecipitation, enzyme-linked immunosorbent assay (ELISA), fluorescence overlay antigen mapping or IIF knockout analysis on type VII collagen and laminin-332–deficient skin. Reactivity to laminin γ1 is seen in 70% to 90% of patients with anti-p200 pemphigoid and can be used as a diagnostic marker. ECM indicates extracellular matrix; IF, immunofluorescence; IIF, indirect immunofluorescence; SSS, salt (sodium chloride)-split skin.

aDiagnosis of EBA can be made by direct immunofluorescence (DIF) microscopy alone, based on a linear u-serrated deposition pattern of IgG along the basement membrane zone (BMZ).

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