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Original Investigation
January 9, 2019

Assessment of Diagnostic Strategy for Early Recognition of Bullous and Nonbullous Variants of Pemphigoid

Author Affiliations
  • 1Center for Blistering Diseases, Department of Dermatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
JAMA Dermatol. Published online January 9, 2019. doi:10.1001/jamadermatol.2018.4390
Key Points

Question  What is the optimal diagnostic strategy for bullous and nonbullous variants of pemphigoid?

Findings  In this paired, multivariable, diagnostic accuracy study of 1125 patients with suspected bullous or nonbullous pemphigoid, 1 in 5 patients with a pemphigoid diagnosis had no skin blistering. Pemphigoid diagnosis could be made with positive direct immunofluorescence microscopy on a skin biopsy specimen and/or indirect immunofluorescence on human salt-split skin substrate in serum; results of the enzyme-linked immunosorbent assay for BP180 NC16A did not have added diagnostic value.

Meaning  Performing both direct immunofluorescence and indirect immunofluorescence on salt-split skin tests is recommended for pemphigoid diagnosis, along with BP180 NC16A enzyme-linked immunosorbent assay as an add-on test for disease activity monitoring; the proposed diagnostic criteria allow the diagnosis of all pemphigoid variants.

Abstract

Importance  A substantial number of patients with bullous pemphigoid do not develop skin blisters and may not have received the correct diagnosis. Diagnostic criteria and an optimal diagnostic strategy are needed for early recognition and trials.

Objectives  To assess the minimal requirements for diagnosis of bullous and nonbullous forms of pemphigoid and to evaluate the optimal diagnostic strategy.

Design, Setting, and Participants  This paired, multivariable, diagnostic accuracy study analyzed data from 1125 consecutive patients with suspected pemphigoid who were referred to the Groningen Center for Blistering Diseases from secondary and tertiary care hospitals throughout the Netherlands. Eligible participants were patients with paired data on at least (1) a skin biopsy specimen for the direct immunofluorescence (DIF) microscopy test; (2) indirect immunofluorescence on a human salt-split skin substrate (IIF SSS) test; and (3) 1 or more routine immunoserologic tests administered between January 1, 2002, and May 1, 2015. Samples were taken from patients at the time of first diagnosis, before introduction of immunosuppressive therapy, and within an inclusion window of a maximum of 4 weeks. Data analysis was conducted from October 1, 2015, to December 1, 2017.

Main Outcomes and Measures  Pairwise DIF, IIF SSS, IIF on monkey esophagus, BP180 and BP230 enzyme-linked immunosorbent assays, and immunoblot for BP180 and BP230 tests were performed. The results were reported in accordance with 2015 version of the Standards for Reporting Diagnostic Accuracy.

Results  Of the 1125 patients analyzed, 653 (58.0%) were women and 472 (42.0%) were men, with a mean (SD) age of 63.2 (19.9) years. In total, 343 participants received a pemphigoid diagnosis, with 782 controls. Of the 343 patients, 74 (21.6%, or 1 in 5) presented with nonbullous pemphigoid. The DIF microscopy was the most sensitive diagnostic test (88.3% [n = 303]; 95% CI, 84.5%-91.3%), whereas IIF SSS was less sensitive (77.0% [n = 263]; 95% CI, 72.2%-81.1%) but was highly specific (99.9%; 95% CI, 99.3%-100%) and complemented most cases with negative DIF findings. Results of the BP180 NC16A enzyme-linked immunosorbent assay did not add diagnostic value for initial diagnosis in multivariable logistic regression analysis of combined tests. These findings lead to the proposed minimal criteria for diagnosing pemphigoid: (1) pruritus and/or predominant cutaneous blisters, (2) linear IgG and/or C3c deposits (in an n-serrated pattern) by DIF on a skin biopsy specimen, and (3) positive epidermal side staining of IgG by IIF SSS on a serum sample; this proposal extends bullous pemphigoid with the unrecognized nonbullous form.

Conclusions and Relevance  Both DIF and IIF SSS tests should be performed for diagnosis of the bullous and nonbullous variants of pemphigoid, and the BP180 NC16A enzyme-linked immunosorbent assay is recommended as an add-on test for disease activity monitoring.

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