药学学报

IgG4相关疾病发病机制及治疗进展

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吉星 , 鲁晨阳 , 卿平英 , 赵毅 , 刘毅 , 谭淳予 ^* , 罗玉斌 ^*

药学学报 | 综述 2022,57(8): 2283-2291

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药学学报 | 综述 2022, 57(8): 2283-2291

IgG4相关疾病发病机制及治疗进展

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吉星, 鲁晨阳, 卿平英, 赵毅, 刘毅, 谭淳予^*, 罗玉斌^*

作者信息

四川大学华西医院风湿免疫科, 四川成都 610041

通讯作者:

*谭淳予Tel: 13308002889, E-mail: annaquintessence@163.com

罗玉斌Tel: 18980606550, E-mail: luoyubin2016@163.com

Progress on the pathogenesis and treatment of IgG4-related disease

Xing JI, Chen-yang LU, Ping-ying QING, Yi ZHAO, Yi LIU, Chun-yu TAN^*, Yu-bin LUO^*

Affiliations

Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China

出版时间: 2022-08-12 doi: 10.16438/j.0513-4870.2022-0074

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摘要

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IgG4相关疾病是近20年才被广泛认识的一种自身免疫相关的纤维炎性疾病, 它几乎可以累及全身任何部位, 多发病于泪腺、唾液腺、胆道、胰腺、腹膜后组织等。其主要临床表现为累及部位的肿胀或占位, 导致受累组织脏器的正常功能受损。如果未得到有效治疗, 终末期纤维化会造成患者多个器官功能衰竭, 极大地影响患者的生存质量。在过去, 该病常被漏诊或误诊为炎症或肿瘤, 近年来随着对其认识的深入及诊断水平的提高, 临床确诊病例数逐渐增多, 这些患者也在接受早期治疗后获益。目前, IgG4相关疾病的主要治疗方法包括药物控制和手术切除, 其中药物治疗处于主导地位。虽然大部分患者使用激素或传统的改善病情抗风湿药物后能达到缓解, 但仍存在一些难以诱导缓解、反复复发、有激素或其他药物使用禁忌的病例, 这也是当前治疗IgG4相关疾病面临的主要难题。IgG4相关疾病发病机制的研究在近年来取得较大进展, 这不仅使得研究者对该病的认识更加深入, 同时为该病治疗提供了新的思路, 利妥昔单抗就是其中的典型代表。本文总结归纳了IgG4相关疾病发病机制研究进展和针对该病的治疗药物及其治疗原理, 并展望了具有发展潜力的治疗药物和药物开发方向, 以期对该病进行更好的临床治疗与管理。

关键词

IgG4相关疾病 / 发病机制 / 自身免疫 / 纤维化 / 治疗 / 生物制剂

Abstract

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IgG4-related disease (IgG4-RD) is a newly recognized fibro-inflammatory condition of autoimmune etiology in recent twenty years, mainly manifesting as mass-forming lesions in single or multiple organs. In the past, it was often missed or misdiagnosed as inflammation or tumor. Patients may die from multiple organ failure due to end-stage fibrosis if they are not treated promptly. However, the number of clinically confirmed cases has gradually increased with the improvement of diagnostic level in recent years, and these patients have benefited greatly after receiving early treatment. Although patients generally respond well to traditional immunosuppressors including glucocorticoids and disease-modifying anti-rheumatic drugs, refractory and recurrent cases, even patients with glucocorticoid contraindication are common. Important mechanistic insights have been derived from studies of B-cell depletion therapy, but greater awareness of the pathophysiology of IgG4-RD is still badly needed to identify novel therapeutic targets. In this article, we reviewed the pathogenesis progress and promising therapy of IgG4-RD to seek better clinical management of IgG4-RD.

Key words

IgG4-related disease / pathogenesis / autoimmunity / fibrosis / treatment / biological agent

引用本文

吉星, 鲁晨阳, 卿平英, 赵毅, 刘毅, 谭淳予, 罗玉斌. IgG4相关疾病发病机制及治疗进展. 药学学报, 2022 , 57 (8) : 2283 -2291 . DOI: 10.16438/j.0513-4870.2022-0074

Xing JI, Chen-yang LU, Ping-ying QING, Yi ZHAO, Yi LIU, Chun-yu TAN, Yu-bin LUO. Progress on the pathogenesis and treatment of IgG4-related disease[J]. Acta Pharmaceutica Sinica, 2022 , 57 (8) : 2283 -2291 . DOI: 10.16438/j.0513-4870.2022-0074

正文

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IgG4相关疾病(IgG4-RD) 是一种与自身免疫相关的慢性纤维炎性疾病, 近年来随着对其认识的不断深入, 过去很多被认为是孤立的单器官疾病, 现在已被统一为IgG4相关疾病, 其中包括自身免疫性胰腺炎(AIP)、Küttner's肿瘤、Mikulicz's病等。IgG4-RD具有其独特的临床特点及病理表现: 中老年男性发病率较其他人群更高, 且大多呈亚急性起病, 可累及几乎全身任何部位, 同时也具有器官倾向性, 多发病于泪腺、唾液腺、淋巴结、胆道、胰腺、腹膜后等部位, 主要表现为组织肿胀或占位。部分患者的血清学表现为总IgG、IgE、IgG4浓度升高。其典型的病理特点包括淋巴细胞、浆细胞尤其是IgG4阳性浆细胞的浸润、席纹状纤维化及闭塞性静脉炎。IgG4-RD患者往往对激素及B细胞清除治疗十分敏感^[1]。上述特点是IgG4-RD与其他疾病鉴别诊断的重要依据, 同时也提示其作为一类新兴的疾病种类存在特殊的发病机制及进展模式。目前, 已有不少研究对IgG4-RD的发病机制在不同层面进行了阐述, 针对该疾病发生发展过程中的关键细胞和分子的靶向治疗也成为研究热点。本文将重点围绕IgG4-RD的发病机制、治疗方案及其治疗原理等几个方面展开论述, 并对该疾病未来的治疗前景进行展望。

1 IgG4-RD发病机制的研究进展

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遗传和环境因素都参与了IgG4-RD的发生发展, 其发病机制主要与免疫系统功能紊乱相关, 包括固有免疫及适应性免疫。B细胞及T细胞的互作在IgG4-RD发病机制中处于核心地位, 但纤维化过程近年来也逐渐受到关注, 而有关IgG4-RD肠道菌群方面的研究目前仍较少。下面将从遗传与环境、免疫、纤维化及肠道菌群几个方面分别阐述IgG4-RD发病机制的研究进展。

1.1 遗传、环境因素

IgG4-RD具有一定的遗传倾向, 且与某些环境因素相关, 但相关研究证据较少。有关家族性IgG4-RD的报道国内外均只发现1例, 且均累及胰腺^{[2, 3]}。同时, 研究发现不同种族人群罹患IgG4-RD的临床表现也不相同: 亚洲血统倾向于仅在头颈部发病, 而白种人更容易患胰肝胆疾病和腹膜后和主动脉疾病, 这可能与遗传背景及环境因素有关^[4]。基因组研究分析发现, 人类白细胞抗原(HLA) 区域的两个关键基因DRB1*0405-DQB1*0401单倍型和ABCF1基因区决定AIP的易感性^[5]; AIP是否合并泪腺、唾液腺部位病变与基因KLF7、FRMD4、MPPED2呈正相关, 与LOC101928923基因呈负相关^[6], 提示存在易感基因与IgG4-RD是否发病及发病部位相关。另外, 来自荷兰的研究团队发现, 长期接触溶剂、工业和金属粉尘及汽车工业中使用的颜料和油类的“蓝领工作”是IgG4相关的胆管和胰腺疾病的潜在危险因素, 这些物质可能成为持续的抗原刺激, 诱发和维持IgG4-RD的发生发展^[7]。

1.2 固有性免疫

现有研究发现多种固有免疫细胞参与IgG4-RD的发病过程, 这些细胞主要通过产生细胞因子, 促进B细胞及T细胞活化, 从而参与炎症及纤维化过程。组织学观察及体外实验发现, IgG4-RD患者单核细胞及嗜碱性粒细胞的Toll样受体(TLR) 和核苷酸寡聚结构域样受体(NLR) 接受某种抗原刺激, 介导了大量活化因子的产生, 其中包括B细胞激活因子(BAFF) 和增殖诱导配体(APRIL) 家族, 它们可以促进B细胞增殖、成熟、分化及IgE抗体类别转换为IgG4^[8-12]。IgG4-RD患者活化的M2型巨噬细胞可以通过TLR7/IL-33信号通路, 异常激活Th2免疫应答, 且通过分泌IL-10、IL-13、CCL-18促进组织纤维化, 参与IgG4-RD的发病过程^[13-15]。肥大细胞在受累组织中通过分泌IL-4、IL-10及转化生长因子β1 (TGF-β1) 促进疾病进程, 同时, IgG4-RD患者血清中升高的IgE可能参与介导了这些肥大细胞的免疫级联反应^[16]。另外, 在实验性AIP模型中, 浆细胞样树突状细胞(pDC) 的干扰素调节因子7 (IRF-7) 激活, 产生IFN-α参与慢性炎症过程^{[17, 18]}。然而, 其他固有免疫细胞在IgG4-RD发病机制中的作用仍需要进一步探索。

1.3 适应性免疫

目前, 普遍认为B细胞与T细胞之间的互作在IgG4-RD发生发展过程中发挥着核心作用。IgG4-RD患者在抗原驱动下自身免疫耐受被打破, 继而诱发了一种异常的免疫应答, 在此过程中, 相关表型的B、T细胞活化、克隆增殖, 并迁移至病变部位集聚, 与组织固有细胞相互作用, 同时分泌促炎因子及促纤维化分子, 最终导致疾病的发生。

1.3.1 自身抗原/抗体

多种证据表明IgG4-RD是抗原驱动的疾病, 探寻其特异性抗原一直是研究者们努力的方向, 这对揭示IgG4-RD完整的发病机制十分重要。目前, 在IgG4-RD患者中已经发现多种自身抗原, 包括乳铁蛋白、分泌型胰蛋白酶抑制物(PSTI)、胰蛋白酶原(PRSS1、PRESS2)、碳酸酐酶、淀粉酶α2A、抑制素(prohibition)、膜联蛋白A11 (annexin-A11)、半乳糖凝集素3 (galectin-3)、在胰腺腺泡细胞中高表达的UBR2肽、胰腺细胞外基质中的层黏连蛋白511-E8 (laminin 511-E8) 等, 但这些自身抗原主要集中在IgG4相关的AIP病例中, 且均为小样本的观察性研究, 只能说明患者血清中存在针对这些抗原的自身抗体, 无法解释各抗原介导免疫反应、导致疾病的发生的具体过程, 故其普适性受到限制^[19-28]。在未来可能会发现更多IgG4-RD的自身抗原抗体, 它们将成为新的生物标记, 用于该病的诊断和疗效评估。

1.3.2 IgG4

IgG4作为IgG4-RD中诊断疾病、评估疾病活动度、预测复发风险的重要生物标志物, 其敏感性、特异性均不高^[29]。一些感染、肿瘤性疾病患者血清中IgG4也会升高, 而且针对前述自身抗原的抗体类别主要是IgG1、IgE, IgG4反而很少。IgG4相较于其他IgG亚类, 具有其特殊的结构特点: 它可以通过半分子交换, 即Fab臂交换, 将自身呈现为具有两个不同抗原结合位点的不对称双特异性分子, 这种现象导致IgG4的高度可变性, 从而阻止IgG4形成免疫复合物。而且IgG4本身对C1q亲和力低, 不能激活经典的补体途径, 反而会通过竞争抑制其他抗体的活性, 所以目前认为IgG4具有抗炎活性^{[30, 31]}。IgG4在IgG4-RD中发挥的作用仍不清楚, 是该病发病的起源还是疾病发展进程中的副产物, 这仍需要相关基础研究的开展。

1.3.3 B细胞

活动性IgG4-RD患者外周血中表型为CD19⁺CD27⁺CD20^-CD38^hi的循环浆母细胞数量增加, 且含有高滴度的Ig和IgG4, 组织病理学显示IgG4阳性浆细胞浸润, 这些临床特征均提示该疾病发展过程中存在大量浆细胞活化现象^{[1, 32]}。B细胞清除治疗的有效性是证明B细胞参与IgG4-RD致病过程最直接有力的证据^[33], 且认为B细胞清除治疗后疾病复发与B细胞库重建相关^[34]。现有研究证据表明, B细胞在IgG4-RD的炎症和纤维化过程中均发挥重要作用: 首先, B细胞作为抗原提呈细胞, 可以促进多种T细胞活化, 这些T细胞本身可以通过表达各种生物活性分子加速疾病的炎症及纤维化进程, 同时可以反过来促进B细胞类别转换、体细胞突变、生发中心形成等免疫应答, 最终促进IgG4产生(具体机制见T细胞)。另外, 浆细胞产生的相关自身抗体通过与自身抗原结合也会引起组织损伤, 从而诱发炎症反应和纤维沉积。研究发现, B细胞本身还可以通过产生血小板源性生长因子B (PDGF-B)、赖氨酸氧化酶同源物(LOXL2) 及趋化因子CCL4、CCL5、CCL11促进成纤维细胞活化增殖, 直接参与组织纤维化^[35], 也可间接通过激活肌成纤维细胞的分泌表型, 促进持续的胶原沉积^[36]。总之, B细胞在IgG4发病过程中发挥不可或缺的作用。

1.3.4 T细胞

IgG4-RD寡克隆扩增的浆母细胞具有体细胞高频突变的特点, 这表明该免疫应答反应是T细胞依赖的过程^[32], 主要包括Th2、Treg、Tfh等T细胞。研究发现, 受累组织中Th2型细胞因子包括IL-4、IL-5、IL-10的表达增多; Treg细胞浸润到受累组织器官产生IL-10和TGF-β, 这些细胞因子可以协同刺激促进浆细胞产生IgG4^{[14, 16, 37, 38]}; Tfh细胞特别是Tfh2细胞产生IL-21在B细胞增殖、成熟、分化及生发中心形成、IgG4类别转换过程中发挥重要作用^[39-43]; 另外, 有研究发现表达跨膜表面分子淋巴细胞活化分子信号F7 (SLAMF7) 的CD4阳性细胞毒性T细胞(CD4⁺ CTL) 在外周血和IgG4-RD炎症组织中明显扩增, 此类细胞可以通过分泌穿孔素、颗粒酶介导细胞死亡, 同时分泌TGF-β、IFN-γ、IL-1β促进组织重塑, 以填补细胞凋亡后留下的组织空缺^[44-48]。上述T细胞与B细胞协同作用, 引发组织损伤及纤维化。

1.4 纤维化

IgG4-RD的纤维化机制尚在进一步研究中, 但可以肯定的是, 该阶段包括多种免疫细胞及细胞因子、趋化因子、酶等生物分子的相互作用。其中, B细胞、M2型巨噬细胞、CD4⁺ CTL在纤维化进程中发挥的作用如前述。另外, 研究人员通过体外实验还发现IgG4-RD患者成纤维细胞表面的IL-6R在受到IL-6刺激后, 可以通过激活JAK2/STAT3、JAK1/STAT3、JAK2/Akt通路, 介导IL-7、IL-12、IL-23和B细胞活化因子的释放等, 参与致病性生发中心的形成及纤维化过程^[49], 这为抑制IgG4-RD纤维化进程提供了新思路。

1.5 肠道微生物

有关IgG4-RD肠道菌群的研究很少, Plichta等^[50]使用粪便DNA宏基因组测序的方法比较了系统性硬化症(SSc) 和IgG4-RD的肠道菌群与正常对照之间的差异后发现: 许多机会致病性梭状芽孢杆菌和典型的口腔链球菌物种在IgG4-RD和SSc患者粪便中显著增加, 而Alistipes、拟杆菌和产生丁酸盐的物种减少, 且IgG4-RD和SSc患者表现出编码cgr位点的Th17诱导菌株的扩增。而Hamada等^[51]通过对IgG4相关的AIP患者和慢性胰腺炎(CP) 患者的肠道菌群进行二代测序发现, 拟杆菌属(Bacteroides)、链球菌属(Streptococcus) 和梭状芽孢杆菌属(Clostridium) 在AIP患者中的比例较CP低。这两项研究结果的差异可能与选取的病例样本及对照组样本有关。另外, 一些研究发现动物模型持续暴露于肠道共生菌抗原, 可诱导AIP的发生^{[52, 53]}。使用广谱抗生素进行肠道消毒可抑制实验性AIP小鼠中产生IFN-α和IL-33的pDCs在胰腺部位的积累, 从而抑制AIP的发展^[54]。目前, 亟待肠道菌群方面更多的研究以进一步阐明IgG4-RD的发病机制, 同时寻找可能的治疗方案。

2 IgG4-RD诊断

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IgG4-RD为多器官系统受累的疾病, 临床表现多种多样, 尚缺乏特异性的生物标志物, 故其诊断仍有一定困难。临床上需整合临床表现、血清学、影像学和病理学特征综合评估诊断。其中, 组织病理学证据是诊断的金标准, 但某些器官的特异性临床及影像学表现对诊断提示作用较强, 如AIP在影像学上表现为腊肠样肿胀。PET-CT可用于评估器官受累程度, 也有助于监测治疗后的疾病活动^[55]。2011年日本学者^[56]提出IgG4-RD的诊断标准有助于临床上快速判断, 而2019年美国风湿病学会/欧洲抗风湿病联盟(ACR/EULAR)^[57]制定的分类标准, 具有更高的特异性, 目前两种诊断方法均在临床上广泛应用。

3 IgG4-RD现有治疗药物

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2015年发表的关于IgG4-RD管理和治疗的国际共识指导声明^[58]中提出, 所有有症状的、活跃的IgG4-RD患者均需要启动治疗, 慢性炎症和纤维化在疾病晚期会造成不可逆的损害, 所以早期诊断及治疗十分重要。现有的主要治疗方案包括糖皮质激素、传统改变病情抗风湿药及B细胞清除治疗。

3.1 糖皮质激素

糖皮质激素是目前治疗IgG4-RD的一线药物, 通常治疗效果明显^[1]。事实上, 在2019年的IgG4-RD分类标准中, 对激素无客观反应已经成为诊断IgG4相关疾病的一条排除标准^[57]。激素治疗有效性可能与其本身抗炎、抑制免疫的作用相关, 不具有特异性。另外, 有研究发现糖皮质激素受体在IgG4-RD受累组织中的纤维细胞/肌成纤维细胞、CD4阳性T细胞和IgG4阳性浆细胞中大量表达, 这可能与该疾病的激素高反应性有关^[59]。

3.2 传统改变病情抗风湿药

传统改变病情抗风湿药物目前在治疗IgG4-RD时主要作为激素辅助用药。其作用靶点及作用机制各不相同, 多为非特异性地调节自身免疫系统及抑制淋巴细胞的增殖。已报道过用于治疗IgG4-RD的传统免疫抑制剂包括硫唑嘌呤(AZA)^[60]、霉酚酸酯(MMF)^[61]、甲氨蝶呤(MTX)^[62]、环磷酰胺(CTX)^[63]、来氟米特(LEF)^[64]、艾拉莫德(Iguratimod)^[65]等, 上述药物均能有效降低疾病复发率或减少激素用量。

3.3 利妥昔单抗(rituximab, RTX)

利妥昔单抗治疗又称B细胞清除治疗, 是最早应用于治疗IgG4-RD, 且目前研究证据最多、效果最确切的生物制剂。RTX是一种人鼠嵌合的单克隆抗体, 可特异性结合前体B细胞、成熟B细胞和记忆B细胞表面表达的CD20抗原, 通过抗体依赖细胞介导的细胞毒作用、抗体依赖的细胞吞噬作用和补体依赖的细胞毒作用杀伤B淋巴细胞^{[66, 67]}。RTX主要抑制了B细胞在IgG4-RD起病进展过程中发挥的作用, 但有学者发现CD4⁺ CTL细胞数量在使用RTX后也显著下降, 这说明B细胞还可能参与了体内CD4⁺ CTL细胞数量的维持^[47]。目前RTX主要用于治疗难治性和复发性IgG4-RD病例, 可以实现激素的减药停药, 维持更长的无复发生存时间, 甚至达到完全缓解^{[33, 68-75]}。

4 IgG4-RD新的治疗方向

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使用激素及免疫抑制剂可以使大部分IgG4-RD患者达到临床缓解, 但复发率高^[76], 且由于罹患IgG4-RD的患者多为中老年人, 多不能耐受激素长期使用带来的不良反应。RTX治疗相关不良反应报道较少^{[71, 77]}, 但并不能完全抑制IgG4-RD的复发, 且仍有RTX治疗无效的IgG4-RD病例报道^{[34, 78, 79]}, 故寻找新的治疗靶点及治疗药物是十分必要的。目前已经取得一些进展, 包括针对B细胞、T细胞、细胞因子及纤维化进程的相关药物。

4.1 针对B细胞的治疗方案

B细胞是IgG4-RD发病过程中的关键细胞, 且B细胞清除治疗效果确切, 使得靶向B细胞的其他表面分子如CD19、B细胞受体(BCR) 和B细胞激活因子BAFF/APRIL的治疗具有可能性。目前, 已有相关药物在临床试验或个案报道中证实有效, 另外一些新的治疗方案则需要进一步的临床研究。

4.1.1 Obexelimab (XmAb5871)

Obexelimab是一种人工合成的单克隆抗体, 可特异性结合B细胞表面的FcγRIIb和CD19抗原, 通过多种通路抑制B细胞活化、增殖、抗原提呈等功能^[80]。Stone等^[81]在马萨诸塞州综合医院进行了一项XmAb5871治疗IgG4-RD临床研究, 在活动性IgG4-RD患者中具有良好的耐受性, 被认为是一种很有前景的治疗方法。

4.1.2 Inebilizumab

Inebilizumab是一种人源化的抗CD19单克隆抗体, 通过抗体依赖的细胞介导的细胞毒性作用清除表达CD19的B细胞群, 目前主要用于治疗AQP4-IgG阳性的视神经脊髓炎谱系疾病^[82]。美国Viela Bio公司正在积极探索其用于治疗IgG4相关疾病的可能性。

4.1.3 硼替佐米

硼替佐米属于蛋白酶体抑制剂, 是多发性骨髓瘤的一线用药, 其主要作用机制是通过抑制泛素-蛋白酶体途径, 导致多泛素化标记的蛋白质累积, 从而诱导肿瘤细胞凋亡。硼替佐米成功治疗IgG4-RD仅见于一位有眼眶假瘤和肺部浸润的患者的个案报道^[83], 作者认为治疗成功的关键在于消除了产生致病性自身抗体的浆细胞。

4.1.4 Bruton酪氨酸激酶(BTK) 抑制剂

BTK抑制剂可通过抑制BCR激活所介导的信号通路转导, 调节B细胞的增殖和分化。BTK抑制剂目前主要用于B细胞相关的血液系统肿瘤的治疗^[84]。近年来, BTK抑制剂在自身免疫相关疾病包括类风湿关节炎和系统性红斑狼疮中的应用也开始受到关注^[85-87]。其用于治疗IgG4-RD的临床试验也正在开展之中。

4.1.5 贝利木单抗(belimumab)

贝利木单抗是一种抑制可溶性BAFF与B细胞结合的人IgG1γ单克隆抗体, 其目前主要应用于治疗系统性红斑狼疮^[88]。Yamamoto等^[89]报道了1例belimumab有效治疗系统性红斑狼疮合并IgG4-RD的病例, 但belimumab单独用于治疗IgG4-RD是否有效仍需要更多临床研究来证实。

4.1.6 泰它西普(telitacicept)

泰它西普是一种由人IgG1-Fc与跨膜激活剂和钙调节配体相互作用物(TACI) 的可溶性胞外区域融合组成的新型重组蛋白, 它可以结合并中和BAFF和APRIL的活性, 使循环B细胞、促炎细胞因子和免疫球蛋白水平均降低^{[90, 91]}。目前, 泰它西普用于治疗类风湿性关节炎、系统性红斑狼疮的临床试验已经取得一定成果^{[90, 92]}, 其对IgG4-RD患者的治疗效果也值得进一步研究。

4.2 针对T细胞的治疗方案

IgG4-RD的发病过程中有多种类型的T细胞参与, 包括Th2、Tfh、CD4⁺ CTL、Treg等, 但靶向针对相关T细胞的治疗方案较少, 其在IgG4-RD中的应用也十分有限。

4.2.1 阿巴西普(abatacept)

阿巴西普是一种重组融合蛋白, 其细胞毒性T淋巴细胞相关蛋白4 (CTLA4) 结构域可以与CD28竞争结合CD80或CD86, 从而抑制T细胞的活化。Yamamoto及其同事^{[78, 93]}描述了1例难治性IgG4-RD患者在使用阿巴西普治疗后病情得到有效缓解, 且8个月内未出现复发。遗憾的是, 该患者活检标本中没有CD28的表达, 故阿巴西普的作用靶点目前仍存在一定争议。

4.2.2 埃罗妥珠单抗(elotuzumab)

埃罗妥珠单抗是一种针对SLAMF7的单克隆抗体, 可靶向抑制IgG4-RD发病过程中表达SLAMF7的CD4⁺ CTL^{[47, 94]}。该药物已经应用于多发性骨髓瘤的治疗^[95], 其在IgG4-RD的应用目前也受到极大关注。

4.3 针对细胞因子的治疗方案

各种免疫细胞通过分泌多种细胞因子参与了IgG4-RD的发病过程, 其中已有相关个案报道证明针对TNF-α、IL-4的单克隆抗体的治疗有效性。

4.3.1 英夫利昔单抗(infliximab)

英夫利昔单抗是一种人鼠嵌合型单克隆抗体, 可特异性地与可溶型及膜结合型的TNF-α结合, 其在炎症性肠病患者中应用广泛^[96], 也可用于治疗类风湿性关节炎^[97]。目前已有2例报道英夫利昔单抗用于IgG4-RD, 包括: 特发性眼眶炎(IOI) 和难治性IgG4相关眼部附件疾病的严重病例, 患者最终都得到良好的治疗效果^{[98, 99]}。

4.3.2 Dupilumab

Dupilumab是全人源化的抗IL-4Rα单克隆抗体, 能够与IL-4Rα高亲和力结合, 从而竞争性抑制IL-4、IL-13与IL-4Rα的结合, 阻断其介导的下游信号转导。在Simpson等^[100]的报道中, dupilumab的使用显著改善了IgG4-RD的严重特应性表现及腹膜后纤维化, 并伴有IgG4血清浓度的显著下降, 虽然该结论得到一些专家的质疑^[101], 但为进一步临床治疗和研究提供了参考。

4.4 针对纤维化的治疗方案

IgG4-RD的纤维化过程有多种细胞及细胞因子共同参与, 病理表现为独特的席纹状纤维化, 经治疗后纤维化呈现可逆表现。但某些长期的、高度纤维化的病变可能对现有治疗方案应答不佳, 此时手术减积治疗成为较好的选择^[58]。Ji等^[49]还发现, 在IgG4-RD患者中成纤维细胞的IL-6/IL-6R信号可以通过JAK-STAT信号通路转导介导多种细胞因子的产生, 促进纤维细胞的活化参与纤维化过程, 这提示JAK1/2抑制剂可能对IgG4-RD的抗纤维化治疗有效。另外, 目前尚无将靶向抗纤维药物如吡非尼酮、尼达尼布等用于治疗IgG4-RD的临床报道, 其是否能改善受累器官的纤维化程度需要临床研究来证实。

5 展望

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虽然目前已有不少有关IgG4-RD的机制研究, 但主要停留在组织和细胞水平。未来全面揭示IgG4-RD的发病机制可能需要多组学研究的整合, 包括基因组学、表观遗传学、转录组学、蛋白组学、代谢组学等。对其发病机制的深入研究, 不仅能寻找新的血清标志物用于临床早期诊断、干预及疗效的评价, 也有助于新的治疗靶点的探究。采用现有的治疗方案进行治疗, 仍存在疾病反复复发及不良反应大等缺点, 其最佳治疗方案的制定也缺少循证学依据, 临床上主要根据医生的临床经验选择用药。另外, 新的治疗药物主要见于个案报道, 缺乏足够的临床试验验证和数据支撑, 目前仍无法广泛应用。因此, 积极开展相关药物的随机临床试验是推动IgG4-RD治疗改进的重要方式。同时, 针对有效药物治疗机制及作用靶点的深入研究也对IgG4-RD疾病机制的揭示具有重要意义。总的来说, IgG4-RD的发病机制及临床管理亟待相关研究的开展。

作者贡献: 吉星负责文献查阅及论文撰写; 鲁晨阳、卿平英负责文献整理分类及修改文章; 赵毅、刘毅负责提供思路并编排文章; 谭淳予、罗玉斌负责文章选题、指导写作、修改及校对文章。

利益冲突: 本文作者均声明无利益冲突。

基金

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国家自然科学基金资助项目(81973540)

参考文献

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文献

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参考文献引证文献

排序方式：

[1]

Kamisawa T, Zen Y, Pillai S, et al. IgG4-related disease[J]. Lancet, 2015, 385: 1460-1471.

https://doi.org/10.1016/S0140-6736(14)60720-0

[2]

Dai YM, Xu HW, Xu ZH, et al. Two cases of IgG4-related diseases in immediate relatives[J]. Chin J Pancreatol (中华胰腺病杂志), 2019, 19: 465-467. https://www.cnki.com.cn/Article/CJFDTOTAL-SDYW200602002.htm

[3]

Watanabe T, Maruyama M, Ito T, et al. Two siblings with type 1 autoimmune pancreatitis[J]. Int Med, 2013, 52: 895-899.

https://doi.org/10.2169/internalmedicine.52.9078

[4]

Wallace ZS, Zhang Y, Perugino CA, et al. Clinical phenotypes of IgG4-related disease: an analysis of two international cross-sectional cohorts[J]. Ann Rheum Dis, 2019, 78: 406-412.

https://doi.org/10.1136/annrheumdis-2018-214603

[5]

Ota M, Katsuyama Y, Hamano H, et al. Two critical genes (HLA-DRB1 and ABCF1) in the HLA region are associated with the susceptibility to autoimmune pancreatitis[J]. Immunogenetics, 2007, 59: 45-52.

[6]

Oguchi T, Ota M, Ito T, et al. Investigation of susceptibility genes triggering lachrymal/salivary gland lesion complications in Japanese patients with type 1 autoimmune pancreatitis[J]. PLoS One, 2015, 10: e0127078.

https://doi.org/10.1371/journal.pone.0127078

[7]

de Buy Wenniger LJM, Culver EL, Beuers U. Exposure to occupational antigens might predispose to IgG4-related disease[J]. Hepatology, 2014, 60: 1453-1454.

https://doi.org/10.1002/hep.26999

[8]

Watanabe T, Yamashita K, Fujikawa S, et al. Involvement of activation of toll-like receptors and nucleotide-binding oligomerization domain-like receptors in enhanced IgG4 responses in autoimmune pancreatitis[J]. Arthritis Rheum, 2012, 64: 914-924.

https://doi.org/10.1002/art.33386

[9]

Fukui Y, Uchida K, Sakaguchi Y, et al. Possible involvement of Toll-like receptor 7 in the development of type 1 autoimmune pancreatitis[J]. J Gastroenterol, 2015, 50: 435-444.

https://doi.org/10.1007/s00535-014-0977-4

[10]

Watanabe T, Yamashita K, Sakurai T, et al. Toll-like receptor activation in basophils contributes to the development of IgG4-related disease[J]. J Gastroenterol, 2013, 48: 247-253.

https://doi.org/10.1007/s00535-012-0626-8

[11]

Yanagawa M, Uchida K, Ando Y, et al. Basophils activated via TLR signaling may contribute to pathophysiology of type 1 autoimmune pancreatitis[J]. J Gastroenterol, 2018, 53: 449-460.

https://doi.org/10.1007/s00535-017-1390-6

[12]

Kiyama K, Kawabata D, Hosono Y, et al. Serum BAFF and APRIL levels in patients with IgG4-related disease and their clinical significance[J]. Arthritis Res Ther, 2012, 14: R86.

https://doi.org/10.1186/ar3810

[13]

Ishiguro N, Moriyama M, Furusho K, et al. Activated M2 macrophages contribute to the pathogenesis of IgG4-related disease via Toll-like receptor 7/interleukin-33 signaling[J]. Arthritis Rheumatol, 2020, 72: 166-178.

[14]

Furukawa S, Moriyama M, Miyake K, et al. Interleukin-33 produced by M2 macrophages and other immune cells contributes to Th2 immune reaction of IgG4-related disease[J]. Sci Rep, 2017, 7: 42413.

https://doi.org/10.1038/srep42413

[15]

Furukawa S, Moriyama M, Tanaka A, et al. Preferential M2 macrophages contribute to fibrosis in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease[J]. Clin Immunol, 2015, 156: 9-18.

https://doi.org/10.1016/j.clim.2014.10.008

[16]

Takeuchi M, Sato Y, Ohno K, et al. T helper 2 and regulatory T-cell cytokine production by mast cells: a key factor in the pathogenesis of IgG4-related disease[J]. Mod Pathol, 2014, 27: 1126-1136.

https://doi.org/10.1038/modpathol.2013.236

[17]

Minaga K, Watanabe T, Arai Y, et al. Activation of interferon regulatory factor 7 in plasmacytoid dendritic cells promotes experimental autoimmune pancreatitis[J]. J Gastroenterol, 2020, 55: 565-576.

https://doi.org/10.1007/s00535-020-01662-2

[18]

Arai Y, Yamashita K, Kuriyama K, et al. Plasmacytoid dendritic cell activation and IFN-α production are prominent features of murine autoimmune pancreatitis and human IgG4-related autoimmune pancreatitis[J]. J Immunol, 2015, 195: 3033-3044.

https://doi.org/10.4049/jimmunol.1500971

[19]

Frulloni L, Lunardi C, Simone R, et al. Identification of a novel antibody associated with autoimmune pancreatitis[J]. New Engl J Med, 2009, 361: 2135-2142.

https://doi.org/10.1056/NEJMoa0903068

[20]

Endo T, Takizawa S, Tanaka S, et al. Amylase alpha-2A autoantibodies: novel marker of autoimmune pancreatitis and fulminant type 1 diabetes[J]. Diabetes, 2009, 58: 732-737.

https://doi.org/10.2337/db08-0493

[21]

Kino-Ohsaki J, Nishimori I, Morita M, et al. Serum antibodies to carbonic anhydrase I and II in patients with idiopathic chronic pancreatitis and Sjögren's syndrome[J]. Gastroenterology, 1996, 110: 1579-1586.

https://doi.org/10.1053/gast.1996.v110.pm8613065

[22]

Löhr JM, Faissner R, Koczan D, et al. Autoantibodies against the exocrine pancreas in autoimmune pancreatitis: gene and protein expression profiling and immunoassays identify pancreatic enzymes as a major target of the inflammatory process[J]. Am J Gastroenterol, 2010, 105: 2060-2071.

https://doi.org/10.1038/ajg.2010.141

[23]

Asada M, Nishio A, Uchida K, et al. Identification of a novel autoantibody against pancreatic secretory trypsin inhibitor in patients with autoimmune pancreatitis[J]. Pancreas, 2006, 33: 20-26.

https://doi.org/10.1097/01.mpa.0000226881.48204.fd

[24]

Okazaki K, Uchida K, Ohana M, et al. Autoimmune-related pancreatitis is associated with autoantibodies and a Th1/Th2-type cellular immune response[J]. Gastroenterology, 2000, 118: 573-581.

https://doi.org/10.1016/S0016-5085(00)70264-2

[25]

Shiokawa M, Kodama Y, Sekiguchi K, et al. Laminin 511 is a target antigen in autoimmune pancreatitis[J]. Sci Transl Med, 2018, 10: eaaq0997.

https://doi.org/10.1126/scitranslmed.aaq0997

[26]

Perugino CA, AlSalem SB, Mattoo H, et al. Identification of galectin-3 as an autoantigen in patients with IgG-related disease[J]. J Allergy Clin Immunol, 2019, 143: 736-745.e6.

https://doi.org/10.1016/j.jaci.2018.05.011

[27]

Hubers LM, Vos H, Schuurman AR, et al. Annexin A11 is targeted by IgG4 and IgG1 autoantibodies in IgG4-related disease[J]. Gut, 2018, 67: 728-735.

[28]

Du H, Shi L, Chen P, et al. Prohibitin is involved in patients with IgG4 related disease[J]. PLoS One, 2015, 10: e0125331.

https://doi.org/10.1371/journal.pone.0125331

[29]

Tang J, Cai S, Ye C, et al. Biomarkers in IgG4-related disease: a systematic review[J]. Semin Arthritis Rheum, 2020, 50: 354-359.

https://doi.org/10.1016/j.semarthrit.2019.06.018

[30]

Koneczny I. A new classification system for IgG4 autoantibodies[J]. Front Immunol, 2018, 9: 97.

https://doi.org/10.3389/fimmu.2018.00097

[31]

Maslinska M, Dmowska-Chalaba J, Jakubaszek M. The role of IgG4 in autoimmunity and rheumatic diseases[J]. Front Immunol, 2021, 12: 787422.

[32]

Mattoo H, Mahajan VS, Della-Torre E, et al. De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease[J]. J Allergy Clin Immunol, 2014, 134: 679-687.

https://doi.org/10.1016/j.jaci.2014.03.034

[33]

Carruthers MN, Topazian MD, Khosroshahi A, et al. Rituximab for IgG4-related disease: a prospective, open-label trial[J]. Ann Rheum Dis, 2015, 74: 1171-1177.

[34]

Stone JH, Carruthers MN, Topazian MD, et al. Response to: 'is rituximab effective for IgG4-related disease in the long term? Experience of cases treated with rituximab for 4 years' by Yamamoto et al[J]. Ann Rheum Dis, 2015, 74: e47.

https://doi.org/10.1136/annrheumdis-2015-207640

[35]

Della-Torre E, Rigamonti E, Perugino C, et al. B lymphocytes directly contribute to tissue fibrosis in patients with IgG-related disease[J]. J Allergy Clin Immunol, 2020, 145: 968-981.e14.

https://doi.org/10.1016/j.jaci.2019.07.004

[36]

Della-Torre E, Feeney E, Deshpande V, et al. B-cell depletion attenuates serological biomarkers of fibrosis and myofibroblast activation in IgG4-related disease[J]. Ann Rheum Dis, 2015, 74: 2236-2243.

https://doi.org/10.1136/annrheumdis-2014-205799

[37]

Zen Y, Fujii T, Harada K, et al. Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis[J]. Hepatology, 2007, 45: 1538-1546.

https://doi.org/10.1002/hep.21697

[38]

Tanaka A, Moriyama M, Nakashima H, et al. Th2 and regulatory immune reactions contribute to IgG4 production and the initiation of Mikulicz disease[J]. Arthritis Rheum, 2012, 64: 254-263.

https://doi.org/10.1002/art.33320

[39]

Grados A, Ebbo M, Piperoglou C, et al. T cell polarization toward T2/T2 and T17/T17 in patients with IgG4-related disease[J]. Front Immunol, 2017, 8: 235.

[40]

Chen Y, Lin W, Yang H, et al. Aberrant expansion and function of follicular helper T cell subsets in IgG4-related disease[J]. Arthritis Rrheumatol, 2018, 70: 1853-1865.

https://doi.org/10.1002/art.40556

[41]

Kamekura R, Takano K, Yamamoto M, et al. Cutting edge: a critical role of lesional T follicular helper cells in the pathogenesis of IgG4-related disease[J]. J Immunol, 2017, 199: 2624-2629.

https://doi.org/10.4049/jimmunol.1601507

[42]

Akiyama M, Yasuoka H, Yamaoka K, et al. Enhanced IgG4 production by follicular helper 2 T cells and the involvement of follicular helper 1 T cells in the pathogenesis of IgG4-related disease[J]. Arthritis Res Ther, 2016, 18: 167.

https://doi.org/10.1186/s13075-016-1064-4

[43]

Akiyama M, Suzuki K, Yamaoka K, et al. Number of circulating follicular helper 2 T cells correlates With IgG4 and interleukin-4 levels and plasmablast numbers in IgG4-related disease[J]. Arthritis Rheumatol, 2015, 67: 2476-2481.

https://doi.org/10.1002/art.39209

[44]

Mattoo H, Stone JH, Pillai S. Clonally expanded cytotoxic CD4 T cells and the pathogenesis of IgG4-related disease[J]. Autoimmunity, 2017, 50: 19-24.

https://doi.org/10.1080/08916934.2017.1280029

[45]

Maehara T, Mattoo H, Ohta M, et al. Lesional CD4⁺ IFN-γ⁺ cytotoxic T lymphocytes in IgG4-related dacryoadenitis and sialoadenitis[J]. Ann Rheum Dis, 2017, 76: 377-385.

https://doi.org/10.1136/annrheumdis-2016-209139

[46]

Della-Torre E, Bozzalla-Cassione E, Sciorati C, et al. A CD8α- subset of CD4⁺SLAMF7⁺ cytotoxic T cells is expanded in patients with IgG4-related disease and decreases following glucocorticoid treatment[J]. Arthritis Rheumatol, 2018, 70: 1133-1143.

https://doi.org/10.1002/art.40469

[47]

Mattoo H, Mahajan VS, Maehara T, et al. Clonal expansion of CD4⁺ cytotoxic T lymphocytes in patients with IgG4-related disease[J]. J Allergy Clin Immunol, 2016, 138: 825-838.

https://doi.org/10.1016/j.jaci.2015.12.1330

[48]

Pillai S, Perugino C, Kaneko N. Immune mechanisms of fibrosis and inflammation in IgG4-related disease[J]. Curr Opin Rheumatol, 2020, 32: 146-151.

https://doi.org/10.1097/BOR.0000000000000686

[49]

Ji ZF, Chen RY, Cui XM, et al. IL-6/IL-6R trans-signaling in fibroblasts releases cytokines that may be linked to the pathogenesis of IgG4-related disease[J]. Front Immunol, 2020, 11: 1272.

https://doi.org/10.3389/fimmu.2020.01272

[50]

Plichta DR, Somani J, Pichaud M, et al. Congruent microbiome signatures in fibrosis-prone autoimmune diseases: IgG4-related disease and systemic sclerosis[J]. Genome Med, 2021, 13: 35.

https://doi.org/10.1186/s13073-021-00853-7

[51]

Hamada S, Masamune A, Nabeshima T, et al. Differences in gut microbiota profiles between autoimmune pancreatitis and chronic pancreatitis[J]. Tohoku J Exp Med, 2018, 244: 113-117.

https://doi.org/10.1620/tjem.244.113

[52]

Yanagisawa N, Haruta I, Shimizu K, et al. Identification of commensal flora-associated antigen as a pathogenetic factor of autoimmune pancreatitis[J]. Pancreatology, 2014, 14: 100-106.

https://doi.org/10.1016/j.pan.2014.01.004

[53]

Haruta I, Yanagisawa N, Kawamura S, et al. A mouse model of autoimmune pancreatitis with salivary gland involvement triggered by innate immunity via persistent exposure to avirulent bacteria[J]. Lab Invest, 2010, 90: 1757-1769.

https://doi.org/10.1038/labinvest.2010.153

[54]

Kamata K, Watanabe T, Minaga K, et al. Intestinal dysbiosis mediates experimental autoimmune pancreatitis via activation of plasmacytoid dendritic cells[J]. Int Immunol, 2019, 31: 795-809.

[55]

Orozco-Gálvez O, Fernández-Codina A, Simó-Perdigo M, et al. Response to treatment in IgG4-related disease assessed by quantitative PET/CT scan[J]. Clin Nuclear Med, 2021, 46: e307-e311.

https://doi.org/10.1097/RLU.0000000000003537

[56]

Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011[J]. Mod Rheumatol, 2012, 22: 21-30.

https://doi.org/10.3109/s10165-011-0571-z

[57]

Wallace ZS, Naden RP, Chari S, et al. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease[J]. Ann Rheum Dis, 2020, 79: 77-87.

[58]

Khosroshahi A, Wallace ZS, Crowe JL, et al. International consensus guidance statement on the management and treatment of IgG4-related disease[J]. Arthritis Rheumatol, 2015, 67: 1688-1699.

https://doi.org/10.1002/art.39132

[59]

Iguchi T, Takaori K, Mii A, et al. Glucocorticoid receptor expression in resident and hematopoietic cells in IgG4-related disease[J]. Mod Pathol, 2018, 31: 890-899.

https://doi.org/10.1038/s41379-018-0036-4

[60]

de Pretis N, Amodio A, Bernardoni L, et al. Azathioprine maintenance therapy to prevent relapses in autoimmune pancreatitis[J]. Clin Transl Gastroenterol, 2017, 8: e90.

https://doi.org/10.1038/ctg.2017.17

[61]

Fei YY, Peng Y, Zhang PP, et al. Efficacy and safety of low dose mycophenolate mofetil treatment for immunoglobulin G4-related disease: a randomized clinical trial[J]. Rheumatology, 2019, 58: 52-60.

https://doi.org/10.1093/rheumatology/key227

[62]

Della-Torre E, Campochiaro C, Bozzolo EP, et al. Methotrexate for maintenance of remission in IgG4-related disease[J]. Rheumatology, 2015, 54: 1934-1936.

https://doi.org/10.1093/rheumatology/kev244

[63]

Fei YY, Ceng Y, Zhang PP, et al. Efficacy of cyclophosphamide treatment for immunoglobulin G4-related disease with addition of glucocorticoids[J]. Sci Rep, 2017, 7: 6195.

https://doi.org/10.1038/s41598-017-06520-5

[64]

Wang Y, Li K, Gao D, et al. Combination therapy of leflunomide and glucocorticoids for the maintenance of remission in patients with IgG4-related disease: a retrospective study and literature review[J]. Int Med J, 2017, 47: 680-689.

https://doi.org/10.1111/imj.13430

[65]

Liu Y, Zhang Y, Bian W, et al. Efficacy and safety of iguratimod on patients with relapsed or refractory IgG4-related disease[J]. Clin Rheumatol, 2020, 39: 491-497.

https://doi.org/10.1007/s10067-019-04880-z

[66]

Banchereau J, Rousset F. Human B lymphocytes: phenotype, proliferation, and differentiation[J]. Adv Immunol, 1992, 52: 125-262.

[67]

Weiner GJ. Rituximab: mechanism of action[J]. Semin Hematol, 2010, 47: 115-123.

https://doi.org/10.1053/j.seminhematol.2010.01.011

[68]

Della-Torre E, Lanzillotta M, Campochiaro C, et al. Efficacy and safety of rituximab biosimilar (CT-P10) in IgG4-related disease: an observational prospective open-label cohort study[J]. Eur J Intern Med, 2021, 84: 63-67.

https://doi.org/10.1016/j.ejim.2020.12.006

[69]

Hart PA, Topazian MD, Witzig TE, et al. Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo clinic experience[J]. Gut, 2013, 62: 1607-1615.

https://doi.org/10.1136/gutjnl-2012-302886

[70]

Khosroshahi A, Carruthers MN, Deshpande V, et al. Rituximab for the treatment of IgG4-related disease: lessons from 10 consecutive patients[J]. Medicine, 2012, 91: 57-66.

https://doi.org/10.1097/MD.0b013e3182431ef6

[71]

Ebbo M, Grados A, Samson M, et al. Long-term efficacy and safety of rituximab in IgG4-related disease: data from a French nationwide study of thirty-three patients[J]. PLoS One, 2017, 12: e0183844.

https://doi.org/10.1371/journal.pone.0183844

[72]

McMahon BA, Novick T, Scheel PJ, et al. Rituximab for the treatment of IgG4-related tubulointerstitial nephritis: case report and review of the literature[J]. Medicine, 2015, 94: e1366.

https://doi.org/10.1097/MD.0000000000001366

[73]

Topazian M, Witzig TE, Smyrk TC, et al. Rituximab therapy for refractory biliary strictures in immunoglobulin G4-associated cholangitis[J]. Clin Gastroenterol Hepatol, 2008, 6: 364-366.

https://doi.org/10.1016/j.cgh.2007.12.020

[74]

Wallace ZS, Mattoo H, Mahajan VS, et al. Predictors of disease relapse in IgG4-related disease following rituximab[J]. Rheumatology, 2016, 55: 1000-1008.

https://doi.org/10.1093/rheumatology/kev438

[75]

Wallwork R, Wallace Z, Perugino C, et al. Rituximab for idiopathic and IgG4-related retroperitoneal fibrosis[J]. Medicine, 2018, 97: e12631.

https://doi.org/10.1097/MD.0000000000012631

[76]

Hart PA, Kamisawa T, Brugge WR, et al. Long-term outcomes of autoimmune pancreatitis: a multicentre, international analysis[J]. Gut, 2013, 62: 1771-1776.

https://doi.org/10.1136/gutjnl-2012-303617

[77]

Della-Torre E, Conti A, Berti A, et al. Rituximab hypersensitivity in IgG4-related disease: successful desensitization in a patient with IgG4 rheumatoid factor[J]. Int J Rheum Dis, 2017, 20: 276-279.

https://doi.org/10.1111/1756-185X.13021

[78]

Yamamoto M, Takahashi H, Takano K, et al. Efficacy of abatacept for IgG4-related disease over 8 months[J]. Ann Rheum Dis, 2016, 75: 1576-1578.

https://doi.org/10.1136/annrheumdis-2016-209368

[79]

Yamamoto M, Awakawa T, Takahashi H. Is rituximab effective for IgG4-related disease in the long term? Experience of cases treated with rituximab for 4 years[J]. Ann Rheum Dis, 2015, 74: e46.

https://doi.org/10.1136/annrheumdis-2015-207625

[80]

Horton HM, Chu SY, Ortiz EC, et al. Antibody-mediated coengagement of FcγRIIb and B cell receptor complex suppresses humoral immunity in systemic lupus erythematosus[J]. J Immunol, 2011, 186: 4223-4233.

https://doi.org/10.4049/jimmunol.1003412

[81]

Stone JH, Wallace ZS, Perugino CA, et al. Final results of an open label phase 2 study of a reversible B cell inhibitor, Xmab® 5871, in IgG4-related disease [EB/OL]. Arthritis Rheumatol, 2017, 69[2022-3-17]. https://acrabstracts.org/abstract/final-results-of-an-open-label-phase-2-study-of-a-reversible-b-cell-inhibitor-xmab5871-in-igg4-related-disease

[82]

Frampton JE. Inebilizumab: first approval[J]. Drugs, 2020, 80: 1259-1264.

https://doi.org/10.1007/s40265-020-01370-4

[83]

Khan ML, Colby TV, Viggiano RW, et al. Treatment with bortezomib of a patient having hyper IgG4 disease[J]. Clin Lymphoma Myeloma Leuk, 2010, 10: 217-219.

https://doi.org/10.3816/CLML.2010.n.034

[84]

Pal Singh S, Dammeijer F, Hendriks RW. Role of Bruton's tyrosine kinase in B cells and malignancies[J]. Mol Cancer, 2018, 17: 57.

https://doi.org/10.1186/s12943-018-0779-z

[85]

Crofford LJ, Nyhoff LE, Sheehan JH, et al. The role of Bruton's tyrosine kinase in autoimmunity and implications for therapy[J]. Expert Rev Clin Immunol, 2016, 12: 763-773.

https://doi.org/10.1586/1744666X.2016.1152888

[86]

Lv J, Wu J, He F, et al. Development of Bruton's tyrosine kinase inhibitors for rheumatoid arthritis[J]. Curr Med Chem, 2018, 25: 5847-5859.

[87]

Lorenzo-Vizcaya A, Fasano S, Isenberg DA. Bruton's tyrosine kinase inhibitors: a new therapeutic target for the treatment of SLE?[J]. Immunotargets Ther, 2020, 9: 105-110.

https://doi.org/10.2147/ITT.S240874

[88]

Blair HA, Duggan ST. Belimumab: a review in systemic lupus erythematosus[J]. Drugs, 2018, 78: 355-366.

https://doi.org/10.1007/s40265-018-0872-z

[89]

Yamamoto M, Aochi S, Suzuki C, et al. A case with good response to belimumab for lupus nephritis complicated by IgG4-related disease[J]. Lupus, 2019, 28: 786-789.

https://doi.org/10.1177/0961203319840430

[90]

Chen X, Zhao Q, Hou Y, et al. Pharmacokinetics, pharmacodynamics, short term efficacy and safety of RCT-18, a novel BLyS/APRIL fusion protein, in patients with rheumatoid arthritis[J]. Br J Clin Pharmacol, 2016, 82: 41-52.

https://doi.org/10.1111/bcp.12908

[91]

Wu Y, Bressette D, Carrell JA, et al. Tumor necrosis factor (TNF) receptor superfamily member TACI is a high affinity receptor for TNF family members APRIL and BLyS[J]. J Biol Chem, 2000, 275: 35478-35485.

https://doi.org/10.1074/jbc.M005224200

[92]

Zhao Q, Chen X, Hou Y, et al. Pharmacokinetics, pharmacodynamics, safety, and clinical activity of multiple doses of RCT-18 in Chinese patients with systemic lupus erythematosus[J]. J Clin Pharmacol, 2016, 56: 948-959.

https://doi.org/10.1002/jcph.686

[93]

Carvajal Alegria G, Pochard P, Pers JO, et al. Could abatacept directly target expanded plasmablasts in IgG4-related disease?[J]. Ann Rheum Dis, 2016, 75: e73.

https://doi.org/10.1136/annrheumdis-2016-210400

[94]

Higashioka K, Ota Y, Maehara T, et al. Association of circulating SLAMF7Tfh1 cells with IgG4 levels in patients with IgG4-related disease[J]. BMC Immunol, 2020, 21: 31.

https://doi.org/10.1186/s12865-020-00361-0

[95]

Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma[J]. New Engl J Med, 2015, 373: 621-631.

https://doi.org/10.1056/NEJMoa1505654

[96]

Meyer A, Rudant J, Drouin J, et al. Effectiveness and safety of reference infliximab and biosimilar in Crohn disease: a French equivalence study[J]. Ann Inter Med, 2019, 170: 99-107.

https://doi.org/10.7326/M18-1512

[97]

Markham A, Lamb HM. Infliximab: a review of its use in the management of rheumatoid arthritis[J]. Drugs, 2000, 59: 1341-1359.

https://doi.org/10.2165/00003495-200059060-00010

[98]

Balaskas K, de Leval L, La Corte R, et al. Infliximab therapy for a severe case of IgG4-related ocular adnexal disorder recalcitrant to corticosteroid treatment[J]. Ocul Immunol Inflamm, 2012, 20: 478-480.

https://doi.org/10.3109/09273948.2012.714045

[99]

Karim F, Paridaens D, Westenberg LEH, et al. Infliximab for IgG4-related orbital disease[J]. Ophthalmic Plast Reconstr Surg, 2017, 33: S162-S165.

https://doi.org/10.1097/IOP.0000000000000625

[100]

Simpson RS, Lau SKC, Lee JK. Dupilumab as a novel steroid-sparing treatment for IgG4-related disease[J]. Ann Rheum Dis, 2020, 79: 549-550.

https://doi.org/10.1136/annrheumdis-2019-216368

[101]

Ebbo M, De Sainte-Marie B, Muller R, et al. Comment on article: 'dupilumab as a novel steroid-sparing treatment for IgG-related disease' by Simpson[J]. Ann Rheum Dis, 2020, 81: e27.

2022年第57卷第8期

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doi: 10.16438/j.0513-4870.2022-0074

接收时间：2022-01-05
首发时间：2025-12-23
出版时间：2022-08-12

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收稿日期：2022-01-05
修回日期：2022-03-18

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国家自然科学基金资助项目(81973540)

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四川大学华西医院风湿免疫科, 四川成都 610041

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*谭淳予Tel: 13308002889, E-mail: annaquintessence@163.com

罗玉斌Tel: 18980606550, E-mail: luoyubin2016@163.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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