Efficacy of dupilumab reveals therapeutic target for IgG4-related disease- simultaneous control of inflammation and fibrosis.
Efficacy of dupilumab reveals therapeutic target for IgG4-related disease- simultaneous control of inflammation and fibrosis.
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dupilumab 的功效揭示了 IgG4 相关疾病的治疗靶点——同时控制炎症和纤维化。
DOI：
10.1136/annrheumdis-2020-217076
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发表时间：
2022
期刊：
影响因子：
27.4
通讯作者：
Tanaka H.
中科院分区：
文献类型：
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作者：
Yamamoto M;Yoshikawa N;Tanaka H.
我们怀着极大的兴趣阅读了Simpson et al关于dupilumab在IgG 4相关疾病（IgG 4-RD）患者中的临床疗效的文章。1糖皮质激素目前是IgG 4-RD的一线诱导治疗。2由于它通常抑制获得性免疫细胞，我们无法知道IgG 4-RD中的治疗靶点。到目前为止，利妥昔单抗的疗效，靶向B细胞，已被讨论，3但我们再次证实，2型辅助性T（Th 2）细胞可以是一个治疗靶点在IgG 4-RD。Tanaka等人此前披露，与干燥综合征患者和健康对照组相比，IgG 4-RD患者唇腺中Th 2细胞因子mRNA的表达升高。4我们已经证明，血清白细胞介素（IL）-5水平随着疾病的进展而升高，5并且ST 2+记忆T产生大量的IL-5。6由于ST 2是IL-33的受体，IL-33可诱导幼稚T细胞向Th 2细胞分化，因此我们认为IL-5可能是IgG 4-RD的治疗靶点。基于这一假设，我们用美泊利珠单抗（一种人源化抗IL-5单克隆抗体）治疗了几例IgG 4相关泪腺炎和涎腺炎（IgG 4-DS）支气管哮喘患者。他们经历了几次复发或出现难以逐渐减少糖皮质激素。结果，支气管哮喘得到改善，所有患者的外周血嗜酸性粒细胞计数均迅速降至0。但泪腺和唾液腺的增大没有改变，血清IgG 4浓度也没有改变或略有下降。类固醇减量效应有限，美泊利珠单抗不能导致IgG 4-DS的总体控制。因此，推测IL-4在Th 2细胞因子中更参与IgG 4-RD的发病机制。IL-4是形成生发中心不可或缺的细胞因子，特别是IgG 4-RD，它在体液免疫反应中也很重要，包括通过滤泡辅助T细胞和B细胞之间的接触产生IgG 4。[7]因此，从长远来看，我们不仅要关注临床改善，还要关注免疫学结果的变化，包括辛普森病例中的球蛋白水平。此外，dupilumab还可抑制IL-13信号，因为IL-13受体使用IL-4 R α。dupilumab的临床疗效最初在特应性皮炎中得到证实。8在特应性皮炎中，IL-13通过骨膜蛋白导致成纤维细胞的自我增殖。9 Ohta等报道在IgG 4-RD的受累器官中检测到IL-13和骨膜蛋白的产生。IL-13可能是IgG 4-RD纤维化机制中的关键参与细胞因子之一。因此，dupilumab具有抑制IgG 4-RD纤维化进展的潜力。长期有效性和安全性的证据需要进行大规模的临床试验，2016年我们在本刊报道了阿巴西普有效的IgG 4-RD病例。11患者已安全接受阿巴西普治疗超过5年，无复发。尽管此后接受阿巴西普治疗的患者数量有所增加，但没有患者发生继发性无应答。如果能够证明dupilumab给药的长期维持和安全性，可能将其视为T
We read with great interest the article from Simpson et al on the clinical efficacy of dupilumab in a patient with IgG4-related disease (IgG4-RD). 1 Glucocorticoid is currently the first-line induction therapy for IgG4-RD. 2 Since it generally suppresses acquired immune cells, we could not know the therapeutic targets in IgG4-RD. So far, the efficacy of rituximab, targeting B cells, has been discussed, 3 but we reconfirm that type 2 helper T (Th2) cells can be one of the therapeutic targets in IgG4-RD by this article. Tanaka et al previously disclosed that the expression of Th2 cytokine mRNA was elevated in the labial glands from patients with IgG4-RD, compared with the patients with Sjögren’s syndrome and healthy controls. 4 We have shown that the levels of serum interleukin (IL)-5 were elevated according to the disease progression, 5 and the ST2+ memory T produced large amount of IL-5. 6 Because ST2 is the receptor of IL-33, which could lead to differentiation from naïve T to Th2, we had considered that IL-5 would be a therapeutic target for IgG4-RD. Based on the hypothesis, we treated with mepolizumab—a humanised anti-IL-5 monoclonal antibody—for several IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) patients with bronchial asthma. They experienced several relapses or presented with difficult for tapering glucocorticoid. As a result, bronchial asthma was improved, and the peripheral counts of eosinophils promptly led to 0 in all patients. However, the enlargement of lacrimal and salivary glands was not changed, and the serum IgG4 concentration also unchanged or slightly decreased. The steroid tapering effect was limited and mepolizumab could not lead to overall control in IgG4-DS. For this reason, it was presumed that IL-4, among the Th2 cytokines, was more involved in the pathogenesis of IgG4-RD. IL-4 is indispensable cytokine for the formation of germinal centres, and in especially IgG4-RD, it is also important in humoral immune reactions including IgG4 production by the contact between follicular helper T cells and B cells. 7 So, in the long term, we want to focus not only on clinical improvement but also on changes in immunological findings including globulin levels in the case presented by Simpson. In addition, dupilumab can also inhibit IL-13 signal because IL-13 receptor uses IL-4Rα. Clinical efficacy of dupilumab was initially confirmed in atopic dermatitis. 8 In atopic dermatitis, IL-13 leads to selfproliferation of fibroblasts via periostin. 9 Ohta et al reported that the production of both IL-13 and periostin was detected in the involved organs of IgG4-RD. 10 It is possible that IL-13 is one of the key player cytokines in the mechanism of the fibrosis in IgG4-RD. For this reason, dupilumab has a potential to suppress the progression of the fibrosis in IgG4-RD. It is necessary to perform large-scale clinical trials for the evidence of long-term efficacy and safety.In 2016, we reported the IgG4-RD case that abatacept was effective in this journal. 11 The patient has been treated safely with abatacept for more than 5 years without the relapse. Although the number of patients treated with abatacept has increased since then, no patient experienced secondary non-response. If it can be proved the long-term maintenance and safety in dupilumab administration, it is probably regarded as one of the T