Acta Dermato-Venereologica 99-6CompleteContent | Page 19

602 INVESTIGATIVE REPORT Gliptin-associated Bullous Pemphigoid and the Expression of Dipeptidyl Peptidase-4/CD26 in Bullous Pemphigoid Outi LINDGREN 1,2 , Outi VARPULUOMA 2 , Jussi TUUSA 2 , Jorma ILONEN 3 , Laura HUILAJA 2 , Nina KOKKONEN 2 and Kaisa TASANEN 2 1 Department of Pathology, MRC Oulu, University of Oulu and Oulu University Hospital, 2 Department of Dermatology, PEDEGO Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, and 3 Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku and Clinical Microbiology, Turku University Hospital, Turku, Finland Dipeptidyl peptidase-4 inhibitors (DPP-4i or gliptins) increase the risk of developing bullous pemphigoid. To clarify, whether gliptin-associated bullous pemphigoid has special features, we analyzed the clinical, histo- pathological and immunological features of 27 bullous pemphigoid patients, 10 of which previously used glip- tin medication. Compared to those who had not pre- viously received gliptins, subjects who had, showed higher BP180-NC16A ELISA (enzyme-linked immuno- sorbent assay) values, fewer neurological co-morbi- dities and shorter time to remission, but differences were not statistically significant. The HLA-DQB1*03:01 allele was more commonly present among the bullous pemphigoid patients than the control population, but was not more common in those with gliptin history. To determine the effect of gliptins on the expression of the DPP-4/CD-26 protein we performed immunohisto­ chemistry, which showed that the skin expression of DPP-4/CD-26 was increased in bullous pemphigoid patients, but not affected by prior gliptin treatment. We conclude that DPP-4i medication is common among bullous pemphigoid patients and prior gliptin treat- ment may be associated with some specific features. Key words: bullous pemphigoid; BP180; collagen XVII; CD26; dipeptidyl-4-peptidase. Accepted Mar 8, 2019; E-published Mar 8, 2019 Acta Derm Venereol 2019; 99: 602–609. Corr: Kaisa Tasanen, Department of Dermatology, Medical Research Center Oulu, University of Oulu, Aapistie 5A, FIN-90220 OULU, Finland. E-mail: [email protected] B ullous pemphigoid (BP) is the most frequently oc- curring autoimmune blistering skin disease. It is mainly seen in elderly people and manifests as severe pruritus, blisters, erosions and crusts on the skin (1). BP autoantibodies target the BP180 protein (also known as collagen XVII), the non-collagenous (NC) 16A domain being its main epitope (2). A diagnosis of BP is based on the clinical criteria, direct immunofluorescence (DIF) analysis of a perilesional skin, serological assays, including BP180-NC16A enzyme-linked immunosor- bent assay (ELISA), and indirect immunofluorescence analysis (1). The incidence of BP is growing (3–5) and neurological diseases, especially multiple sclerosis and dementias, increase the risk for subsequent BP (6–8). doi: 10.2340/00015555-3166 Acta Derm Venereol 2019; 99: 602–609 SIGNIFICANCE Bullous pemphigoid is a blistering skin disease, generally seen in the elderly patients. Bullous pemphigoid is caused by an autoimmune reaction against the BP180 protein, but the exact reason is currently unknown. Several epidemiolo- gical studies have shown that the use of gliptins increases the risk for bullous pemphigoid, but it is unclear whether gliptin-associated bullous pemphigoid has specific clinical or immunological characteristics. Our study demonstrates that compared to “classical” bullous pemphigoid, gliptin- associated bullous pemphigoid may have some specific features, but the differences are not as striking as pre- viously reported in Japanese patients. The anti-diabetic medications in bullous pemphigoid patients must be moni- tored carefully and gliptins should be replaced by another anti-diabetic medication. Since BP typically affects the elderly and has several comorbidities, polypharmacy is common among BP patients (9) and over 50 drugs have been reported to induce BP (10). Both case reports and registry studies have added to a growing body of evidence, showing an association between dipeptidyl peptidase-4 inhibitors (DPP-4i or gliptin) and BP (11–20). In addition to being an aminopeptidase, DPP-4 acts also as CD26, which is a cell surface antigen present on T lymphocytes (21). This is of interest with regard to the association between DPP-4i use and BP because autoreactive T cells have been associated to BP pathomechanism (1, 2). It has been shown that in gliptin-associated BP autoan- tibodies target parts of the BP180 other than the NC16A domain (20, 22, 23). Furthermore, gliptin-associated cases have been suggested to represent a “non-inflamma- tory” phenotype with less erythema and fewer urticarial lesions on the skin, fewer eosinophils infiltrating the skin lesions and a strong association with the HLA- DQB1*03:01 allele (20, 24). However, gliptin-associated BP cases that lacked any of the aforementioned special characteristics have been described (17, 18, 25, 26). The aim of our study was to analyze the clinical and immunological features of BP in patients with a history of DPP-4i use and those without. We also explored the ex- pression of DPP-4/CD26, BP180 and its binding partner laminin-γ2 in the skin of BP patients as well as the effect of gliptins on their expression in cultured keratinocytes. This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica.