Blisters Not Required to Diagnose Pemphigoid

By Will Boggs MD

January 18, 2019

NEW YORK (Reuters Health) - The presence of blisters is not required to make the diagnosis of pemphigoid, according to a new study of this common cutaneous autoimmune disease.

"The patients with nonbullous pemphigoid often have complaints of chronic itch and could be misdiagnosed as eczema, with a potential long delay until the diagnosis of pemphigoid is made," Dr. Joost Meijer of University Medical Center Groningen, in the Netherlands, told Reuters Health by email. "This recently recognized nonbullous disease variant contradicts the clinical image of the bullous disease that physicians have."

The findings were published online January 9 in JAMA Dermatology, along with two other studies on pemphigoid.

Minimal diagnostic criteria for pemphigoid have not yet been established, Dr. Meijer and colleagues note. And the more than 20% of patients with pemphigoid who do not present with typical skin blistering may often be misdiagnosed or overlooked, they add.

The team used data from the Groningen Center for Blistering Diseases to evaluate the diagnostic accuracy of direct immunofluorescence (DIF) microscopy on a skin biopsy specimen and various serologic tests in a retrospective study of 1,125 patients with suspected bullous or nonbullous pemphigoid.

Of the 343 individuals ultimately diagnosed with pemphigoid, 21.6% presented with nonbullous pemphigoid. The DIF test provided 88.3% sensitivity and 99.2% specificity for diagnosing pemphigoid.

Among patients with bullous pemphigoid, DIF on the perilesional skin was more sensitive than that on healthy skin or lesional skin. DIF sensitivity in patients without skin blisters was lower and did not differ significantly between biopsy sites.

DIF detected IgG deposition alone in 19.8% of specimens, IgG and C3c in 44.6% of specimens, IgG and IgA in 6.6% of specimens and deposition of all three in 20.5% of specimens.

Among immunoserological tests, indirect immunofluorescence on a human salt-split skin substrate (IIF SSS) proved most sensitive (77.0%) and specific (99.9%), with a positive predictive value of 99.6%.

Performing the widely used BP180 NC16A ELISA had no additional value for the initial diagnosis of pemphigoid and showed a high number of false-positives in this cohort.

In multivariable analysis, the presence of skin blisters had the highest predictive factor in diagnosing pemphigoid, while increasing age showed a smaller incremental link with pemphigoid above age 60. Pruritus was often a reason to suspect pemphigoid, but did not independently predict the diagnosis.

The researchers propose minimal diagnostic criteria for pemphigoid to include at least two positive results out of the following: 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 by IIF SSS on a serum sample.

"We aimed to establish diagnostic criteria for pemphigoid for the first time, including the complete spectrum of patients with bullous and nonbullous pemphigoid," Dr. Meijer said. "We provide evidence that the diagnosis of pemphigoid can be based on a blood sample, which is a great step forward in the diagnosis of pemphigoid."

The two other papers address different aspects of bullous pemphigoid. In the first, Dr. Khalaf Kridin and Dr. Reuven Bergman from Ramban Health Care Campus, in Haifa, Israel, report that mucosal lesions are common in patients with bullous pemphigoid.

Among the 328 patients in their retrospective study, 56 (17.1%) presented with mucosal lesions, most commonly on the oral mucosa. Lesions were also observed on the larynx, genital, anal and ocular mucosa.

Features associated with mucosal involvement included younger age, more extensive disease, less peripheral eosinophilia and treatment with higher doses of corticosteroids.

About one in six patients with mucosal involvement tended to develop bullous pemphigoid in association with the intake of dipeptidyl peptidase-4 (DPP-4) inhibitors. This is the subject of the third paper, by Dr. Dong Hyun Kim and colleagues from Bundang CHA Medical Center, CHA University School of Medicine, in Seongnam, South Korea.

Based on recent clinical reports suggesting an increased risk of developing bullous pemphigoid among patients using DPP-4 inhibitors, Dr. Kim's team used Korea's Health Insurance Review and Assessment Service database to investigate this association in a study of 670 patients with newly diagnosed bullous pemphigoid and type 2 diabetes and 670 matched controls.

Significantly more patients with bullous pemphigoid (38.9%) than controls (28.1%) were prescribed DPP-4 inhibitors.

In multivariate analysis, the odds of having bullous pemphigoid was 58% higher in patients with diabetes who were prescribed a DPP-4 inhibitor than in patients not prescribed a DPP-4 inhibitor.

In subgroup analyses, the risk of developing bullous pemphigoid in association with taking DPP-4 inhibitors with similar among patients younger and older than 75 years, but the association between DPP-4 inhibitor use and bullous pemphigoid was evident only among men.

Dr. Kim told Reuters Health by email, "Since DPP-4 inhibitors have been identified as a risk factor for the development of bullous pemphigoid (BP), it is important to ask BP patients whether they started taking DPP-4 inhibitors before the onset of BP. Especially, vildagliptin is considered to be highly associated with the development of BP among all DPP-4 inhibitors. If BP occurs in patients with diabetes, DPP-4 inhibitors can be changed to another anti-diabetic medication."

"In our study, we were not able to correlate the actual onset of BP symptoms and the duration of the use of DPP-4 inhibitors because of the study design," he explained. "Further studies are also needed to confirm whether BP symptoms improve when DPP-4 inhibitors are discontinued. It would be meaningful to do further research on why vildagliptin is a high-risk medication for development of BP and the precise pathogenetic mechanism. We will consider the study of these points."

Dr. Dedee F. Murrell of the University of New South Wales, in Sydney, Australia, who co-authored an editorial on the reports, told Reuters Health by email, "Pemphigoid - a serious condition usually in people with many comorbidities and a 10% mortality at one year - is becoming more common (and is) suspected to be triggered by medications and neurological conditions. One drug class with the most evidence is gliptins."

"Many patients present with protracted itch and then a nonspecific rash," she said. "It is important to suspect BP even when there are no blisters. Routine skin biopsies in formalin are not specific enough; skin biopsies in Michel media or fresh for DIF and serum for indirect IF on salt-split skin are needed in order not to delay the diagnosis. The mucosae are involved more often than the dogma suggests."

"Earlier diagnosis means less toxic treatments are likely to be needed," Dr. Murrell said. "Hopefully that will translate to less morbidly and mortality."

Senior author of the first paper, Dr. Marcel F. Jonkman, who first learned about the "atypical" patients with pemphigoid and complete absence of skin blisters approximately 15 years ago, passed away on January 14.

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JAMA Dermatol 2019.