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

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 PARTICIPANTSThis 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 MEASURESPairwise 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. RESULTSOf 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.

Diagnostic testing in gestational bullous pemphigoid: Has enzyme-linked immunosorbent assay replaced direct immunofluorescence as the new gold standard?

“…More research is required to establish the sensitivity and specificity for DIF in the diagnosis of GBP and compare DIF and BP180-NC16a ELISA. Barnadas et al, 7 Powell et al, 4 S ardy et al, 5 Meijer et al, 6 GBP and BP GBP BP BP 74 Combined C3/IgG: 99 73.2-76 77 96 NR 96.5-97.1 99 BP180-NC16A ELISA Barnadas et al, 7 Powell et al, 4 Sitaru et al, 8 GBP…”

Development of Bullous Pemphigoid after Tenckhoff Catheter Placement in a Peritoneal Dialysis Patient

“…Moreover, the patient’s serum revealed positivity for anti-BP180 NC16A antibodies (ELISA) while the anti-BP230 antibody was also detectable but below the positivity threshold (7.1 U/mL; normal values <9 U/mL). A diagnosis of BP was made according to both the 2015 European Dermatology Forum consensus recommendations [1] and the 2015 German guidelines [2], as well as to the recent criteria proposed by Meijer et al [3].…”

Pemphigoid variants affecting the skin

“…However, one in five patients lack blisters, a variant termed ‘nonbullous pemphigoid’ (NBP) (Fig. b) . Interestingly, autoantibodies in both BP and NBP target similar antigens (BP180 and BP230), and it is unknown why there is an absence of blisters in NBP .…”

“…6,7 Interestingly, autoantibodies in both BP and NBP target similar antigens (BP180 and BP230), and it is unknown why there is an absence of blisters in NBP. 6,7 NBP clinically may resemble various pruritic dermatoses, causing long diagnostic delays. 6,8 Histopathology has no diagnostic value, and most often shows a nonspecific perivascular infiltrate.…”