table_1_Gliptin Accountability in Mucous Membrane Pemphigoid Induction in 24 Out of 313 Patients.PDF

Mucous membrane pemphigoids (MMPs) and bullous pemphigoid (BP) are autoimmune bullous diseases that share physiopathological features: both can result from autoantibodies directed against BP180 or BP230 antigens. An association has been reported between BP and intake of gliptins, which are dipeptidyl peptidase-IV inhibitors used to treat type 2 diabetes mellitus. Clinical and immunological differences have been reported between gliptin-induced BPs and classical BPs: mucosal involvement, non-inflammatory lesions, and target BP180 epitopes other than the NC16A domain. Those findings accorded gliptins extrinsic accountability in triggering MMP onset. Therefore, we examined gliptin intrinsic accountability in a cohort of 313 MMP patients. To do so, we (1) identified MMP patients with gliptin-treated (challenge) diabetes; (2) selected those whose interval between starting gliptin and MMP onset was suggestive or compatible with gliptin-induced MMP; (3) compared the follow-ups of patients who did not stop (no dechallenge), stopped (dechallenge) or repeated gliptin intake (rechallenge); (4) compared the clinical and immunological characteristics of suggestive-or-compatible-challenge patients to 121 never-gliptin-treated MMP patients serving as controls; and (5) individually scored gliptin accountability as the trigger of each patient’s MMP using the World Health Organization-Uppsala Monitoring Center, Naranjo- and Begaud-scoring systems. 17 out of 24 gliptin-treated diabetic MMP patients had suggestive (≤12 weeks) or compatible challenges. Complete remission at 1 year of follow-up was more frequent in the 11 dechallenged patients. One rechallenged patient’s MMP relapsed. These 17 gliptin-treated diabetic MMP patients differed significantly from the MMP controls by more cutaneous, less buccal, and less severe involvements and no direct immunofluorescence IgA labeling of the basement membrane zone. Multiple autoantibody-target antigens/epitopes (BP180–NC16A, BP180 mid- and C-terminal parts, integrin α6β4) could be detected, but not laminin 332. Last, among the 24 gliptin-treated diabetic MMP patients, five had high (I4–I3), 12 had low (I2-I1) and 7 had I0 Begaud intrinsic accountability scores. These results strongly suggest that gliptins are probably responsible for some MMPs. Consequently, gliptins should immediately be discontinued for patients with a positive accountability score. Moreover, pharmacovigilance centers should be notified of these events.

黏膜类天疱疮（Mucous membrane pemphigoids, MMPs）与大疱性类天疱疮（bullous pemphigoid, BP）均为自身免疫性大疱病，二者具有共同的病理生理特征：发病均与针对BP180或BP230抗原的自身抗体相关。已有研究报道BP的发病与格列汀类药物的使用存在关联，此类药物为临床用于治疗2型糖尿病的二肽基肽酶-IV抑制剂。
研究显示，格列汀诱导型BP与经典型BP存在临床及免疫学差异，包括黏膜受累、非炎症性皮损，以及靶表位为NC16A结构域外的BP180抗原。上述结果提示格列汀可能作为外源性诱因参与MMP的发病。为此，本研究针对313例MMP患者队列，探讨了格列汀在MMP发病中的内在致病责任，并开展了如下研究：（1）筛选合并糖尿病且接受格列汀治疗的MMP患者（即激发试验队列）；（2）选取从开始使用格列汀至MMP发病的时间间隔符合或提示格列汀诱导型MMP的病例；（3）对比未停药、停药（去激发）及再次服用格列汀（再激发）患者的随访结局；（4）将符合/提示激发条件的患者与121例未接受过格列汀治疗的MMP对照患者进行临床及免疫学特征比较；（5）采用世界卫生组织-乌普萨拉监测中心评分法、Naranjo评分法及Begaud评分系统，对每位患者的MMP发病与格列汀的关联责任进行独立评分。
24例合并糖尿病且接受格列汀治疗的MMP患者中，有17例的时间间隔符合或提示格列汀诱导型MMP（间隔≤12周）。在11例接受停药处理的患者中，随访1年时的完全缓解率更高；1例再次接受格列汀治疗的患者出现MMP复发。与对照组相比，这17例格列汀暴露的糖尿病合并MMP患者存在显著差异：皮肤受累更广泛、颊黏膜受累更少、病情严重程度更低，且未出现基底膜区直接免疫荧光IgA染色阳性。本研究可检测到多种自身抗体靶抗原/表位（BP180-NC16A、BP180中段及C端区域、整合素α6β4），但未检测到层粘连蛋白332。最后，在24例接受格列汀治疗的糖尿病合并MMP患者中，5例Begaud内在责任评分为高（I4~I3）、12例为低（I2~I1）、7例为I0。
上述结果强烈提示，格列汀可能是部分MMP的致病诱因。因此，对于评分显示存在明确关联的患者，应立即停用格列汀；此外，应将此类事件通报给药物警戒中心。