Detection of anti-BP180 NC16A autoantibodies after the onset of dipeptidyl peptidase-IV inhibitor-associated bullous pemphigoid: a report of three patients
Detection of anti-BP180 NC16A autoantibodies after the onset of dipeptidyl peptidase-IV inhibitor-associated bullous pemphigoid: a report of three patients
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二肽基肽酶-IV抑制剂相关性大疱性类天疱疮发病后抗BP180 NC16A自身抗体的检测：三例患者的报告
DOI：
10.1111/bjd.16656
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发表时间：
2018
影响因子：
10.3
通讯作者：
Shimizu H.
中科院分区：
文献类型：
--
作者：
Mai Y.;Nishie W.;Izumi K.;Yoshimoto N.;Morita Y.;Watanabe M.;Toyonaga E.;Ujiie H.;Iwata H.;Fujita Y.;Nomura T.;Sato-Matsumura K.C.;Shimizu S.;Shimizu H.
大疱性类天疱疮（BP）是一种常见的自身免疫性水疱性疾病，其中自身抗体（autoAb）靶向基底角质形成细胞中的两种半桥粒组分（BP 180/胶原XVII和BP 230），1 80-90%的BP患者具有靶向BP 180的跨膜细胞外NC 16 A结构域的autoAb（抗BP 180 NC 16 A autoAb）。1最近，越来越多的BP患者与二肽基肽酶-IV抑制剂（DPP 4 i）治疗2型糖尿病相关，2-4尽管这种相关性仍然存在争议。5我们最近的报道表明，DPP 4 i-BP（DPP 4 i-BP）倾向于表现出“非炎性”表型，其特征在于没有或轻度红斑，并且这些DPP 4 i-BP患者具有优先靶向BP 180胞外结构域中部而非NC 16 A结构域的自身抗体。6，7然而，Fania等人4报道了5例DPP 4 i-BP病例，这些病例具有经典BP的重叠特征，包括抗BP 180 NC 16 A自身抗体和炎性表型的存在。尚不确定抗BP 180 NC 16 A autoAb是否可能在最初检测不到抗BP 180 NC 16 A autoAb的患者中在DPP 4 i-BP过程中产生。在这份报告中，我们提出了三个病人与DPP 4 i-BP中的抗BP 180 NC 16 A autoAb最初检测不到，但成为积极的过程中的BP。所有3例患者（1例，77岁女性; 2例，75岁男性; 3例，81岁男性）均患有2型糖尿病，均接受过teneliglitazone或vildaglitazone治疗（表1）。这三名患者最初对BP 180 NC 16 A荧光酶免疫测定（CLEIA）或酶联免疫吸附测定（ELISA）呈阴性，而使用全长重组BP 180的ELISA在患者2和3中呈阳性。由于DPP 4 i与BP发作的相关性尚未得到很好的认识，因此所有患者的DPP 4 i均持续存在。红斑最初为轻度;然而，在病程期间，水疱和糜烂随着红斑的发展而恶化。有趣的是，BP 180 NC 16 A CLEIA在三名患者中结果为阳性（表1）。1例患者经米诺环素和停药后10个月达到完全缓解。患者2具有复发过程直到停止DPP 4 i，尽管全身治疗包括米诺环素和泼尼松龙施用。在患者3中，通过泼尼松龙解决了BP病变;然而，每隔几个月出现一次几个水泡，直到停用DPP 4 i。三名患者在DPP 4 i停药后均未复发，尽管抗BP 180 NC 16 A autoAb在患者2和3中持续存在。在这里，我们介绍了三名DPP 4 i-BP患者，其中抗BP 180 NC 16 A autoAb最初无法检测到。有趣的是，所有患者在BP发作后开始产生抗BP 180 NC 16 A autoAb。据我们所知，这是第一次报道表位在DPP 4 i-BP中扩展。表位扩散发生在各种自身免疫性疾病中，一项前瞻性多中心研究显示，49%的BP患者发生表位扩散，并与疾病严重程度相关。8值得注意的是，先前的一项研究报告，靶向BP的NC 16 A结构域的autoAb通常在疾病的初始阶段观察到。8然而，在我们的患者中，靶向BP 180的NC 16 A结构域的autoAb最初是不可检测的，并且它们是表位扩散的结果（表1）。Fania等人表明，具有抗BP 180 NC 16 A autoAb的DPP 4 i-BP具有靶向BP 180的多个表位的autoAb，4这也表明表位...
DEAR EDITOR, Bullous pemphigoid (BP) is a common autoimmune blistering disorder in which autoantibodies (autoAbs) target two hemidesmosomal components (BP180/collagen XVII and BP230) in basal keratinocytes, 1 and 80–90% of patients with BP have autoAbs targeting the juxtamembranous extracellular NC16A domain of BP180 (anti-BP180 NC16A autoAbs). 1 Recently, increasing numbers of patients with BP associated with the administration of dipeptidyl peptidase-IV inhibitors (DPP4i) for the treatment of type 2 diabetes have been reported, 2–4 although the association remains controversial. 5 Our recent reports suggested that DPP4i-associated BP (DPP4i-BP) tends to show a ‘noninflammatory’phenotype characterized by no or mild erythema, and these patients with DPP4i-BP have autoAbs that preferentially target the mid-portion of the extracellular domain of BP180 but not the NC16A domain. 6, 7 However, Fania et al. 4 reported five cases of DPP4i-BP that shared overlapping features of classical BP, including the presence of anti-BP180 NC16A autoAbs and the inflammatory phenotype. It is uncertain whether anti-BP180 NC16A autoAbs may develop during the course of DPP4i-BP in those patients in whom anti-BP180 NC16A autoAbs were initially undetectable. In this report, we present three patients with DPP4i-BP in whom anti-BP180 NC16A autoAbs were initially undetectable but became positive during the course of BP. All three patients (1, a 77-year-old female; 2, a 75-year-old male; 3, an 81-year-old male) had type 2 diabetes that had been treated with teneligliptin or vildagliptin (Table 1). These three patients were initially negative for BP180 NC16A chemiluminescent enzyme immunoassay (CLEIA) or enzyme-linked immunosorbent assay (ELISA), while ELISA using full-length recombinant BP180 was positive in patients 2 and 3. Because the association of DPP4i with BP onset was not well recognized, the DPP4i had continued in all patients. The erythema was initially mild; however, the blisters and erosions worsened in association with the development of erythema during the disease course. Interestingly, BP180 NC16A CLEIA turned out to be positive in the three patients (Table 1). In patient 1, it took 10months to achieve a complete remission by minocycline and the withdrawal of DPP4i. Patient 2 had a relapsing course until the cessation of DPP4i, despite systemic treatments including minocycline and prednisolone administration. In patient 3, BP lesions were resolved by prednisolone; however, a few blisters appeared once every few months until the DPP4i withdrawal. None of the three patients had recurrences after the DPP4i withdrawal, although anti-BP180 NC16A autoAbs persisted in patients 2 and 3. Here, we present three patients with DPP4i-BP in whom anti-BP180 NC16A autoAbs were initially undetectable. Interestingly, all patients started to produce anti-BP180 NC16A autoAbs after BP onset. To our knowledge, this is the first report of epitope spreading in DPP4i-BP. Epitope spreading occurs in various autoimmune diseases, and a prospective multicentre study showed it to occur in 49% of patients with BP and to correlate with the disease severity. 8 Notably, a previous study reported that autoAbs targeting the NC16A domain of BP are usually observed from the initial stage of the disease. 8 However, in our patients, the autoAbs targeting the NC16A domain of BP180 were not initially detectable, and they developed as a result of epitope spreading (Table 1). Fania et al. showed that DPP4i-BP with anti-BP180 NC16A autoAbs had autoAbs targeting multiple epitopes of BP180, 4 which also suggests that epitope …