Leflunomide

“ 点击蓝字 关注我们 王琛 中国药科大学生命科学与技术学院二级教授、博士生导师。国家杰出青年基金获得者（2002）、国务院政府特殊津贴获得者、中科院“百人计划”获得者、新世纪百千万人才工程国家级人选、国务院突出贡献中青年专家、国家重点研发计划项目负责人、江苏省“双创团队”领军人才、中国药科大学兴药杰出科学家。曾任上海市第十三、十四届人大代表和第十一届全国青年委员。现任中国病理生理学会蛋白质修饰与疾病专业委员会副主委、江苏省生物技术学会副理事长（第八届）等。长期聚焦于发现并解析宿主模式识别受体的特异性识别、细胞信号转导关键通路的组成与动态变化、早期免疫应答反应的时空特性，阐释固有免疫与急性炎症相关的分子调控机制。特别关注泛素与类泛素化修饰调控固有免疫和炎症的新功能与新机制，并从天然小分子化合物库中筛选并研究调控相关通路的先导化合物。在 Nature，Cell，Immunity，Nat Immunol 等期刊发表研究性论文 100 余篇，他引超过 8 000 余次；主编《泛素家族介导的蛋白质降解和细胞自噬》等著作。 洪泽 南京中医药大学中药制药过程控制与智能制造技术全国重点实验室副教授，硕士生导师。研究主要围绕固有免疫信号通路中的关键调控蛋白，探索其在自身免疫性疾病和代谢性疾病中发挥的作用及其调控机制，靶向相关蛋白进行药物开发，旨在为相关疾病的精准治疗提供新的药物靶点和治疗策略。目前已发表高水平 SCI 学术论文 10 余篇，其中以第一或共同第一作者在 PNAS，Cell Rep，Sci China Life Sci 等杂志发表研究性论文多篇，相关研究成果被 BioWorld 报道。 干扰素基因刺激蛋白相关婴儿期发病血管病变研究进展PPS  陈赛花 1，穆妮热·麦麦提 1，仲梓维 1，洪泽 2*，王琛 1** （1. 中国药科大学生命科学与技术学院，江苏 南京 211198；2. 南京中医药大学中药制药过程控制与智能制造技术全国重点实验室，江苏 南京 210046） [摘要]干扰素基因刺激蛋白（STING）相关婴儿期发病血管病变（SAVI）是一种由 STING 基因发生功能获得性突变所诱发的罕见的自身炎症疾病。随着近年临床报道的 SAVI 病例逐渐增多、相关小鼠疾病模型的建立，研究人员对于该疾病的发病机制和治疗策略的认识逐渐深入。综述对已报道的 SAVI 病例进行系统性回顾，简述其病理机制和治疗策略，以期为该罕见病的临床治疗提供参考。 干扰素基因刺激蛋白（stimulator of interferon genes，STING）相关婴儿期发病血管病变（STINGassociatedvasculopathy with onset in infancy，SAVI）是一种由 STING1 基因发生功能获得性突变引起的自身炎症性疾病 [1]。SAVI 多发于婴儿期，主要临床特征包括早发的系统性炎症、高烧、反复冻疮样皮炎、关节炎、间质性肺疾病（interstitial lung disease，ILD）导致的肺纤维化和晚期呼吸功能衰竭 [2]。目前针对 SAVI 患者的临床病例报道较少，SAVI 疾病在临床上具有以下特征：不同 STING 突变体的 SAVI 患者间的疾病表现不同，且现有治疗方案对于不同SAVI患者的疗效差异显著。本文从疾病的发病机制、临床表现、治疗策略等方面对目前报道的 SAVI 病例进行系统回顾，以期为该罕见病的早期诊断和治疗提供参考。 1 SAVI 疾病的发病机制 作为 STING 突变诱发的自身炎症性疾病，SAVI 的发病机制与 STING 信号通路异常持续激活密切相关。下文将从 STING 蛋白的结构及 STING 信号通路介导的固有免疫功能阐释 SAVI 相关 STING 突变体异常激活的分子机制。 1.1 STING 蛋白及其介导的固有免疫信号通路 STING1 基因编码的人源 STING 蛋白（也称为MITA，ERIS 或 MPYS）由 379 个氨基酸组成，包含 N 端 4 次跨内质网膜结构域（NTD，又称 TM1-TM4，含 1-137 aa 基序），铰链结构域（含 138-149 aa 基序），胞浆环二核苷酸（cyclic dinucleotide，CDNs）结合域（CBD，含 150-340 aa 基序）和 C 末端尾巴结构域（CTT，含 341-379 aa 基序）[3-6]。静息状态下 STING 蛋白以二聚体的形式稳定存在于内质网膜表面。二聚化的 CBD 结构域在胞浆内形成“V” 形疏水口袋用于 CDNs 配体的结合 [7]。  病原微生物感染与细胞损伤会导致双链 DNA（dsDNA）在胞浆异常聚积。胞浆 dsDNA 受体环鸟苷酸-腺苷酸合成酶（cyclic GMP-AMP synthase，cGAS）在结合 dsDNA 后，以三磷酸腺苷（denosine triphosphate，ATP） 和 三 磷 酸 鸟 苷（guanosine triphosphate，GTP）为底物合成第二信使分子2'3'-cGAMP[8-9]。2'3'-cGAMP 结合到 STING 二聚体的“V”形口袋内，诱导其发生构象变化形成 “U”形口袋，促进胞浆 CBD 结构域相对于跨膜结构域发生 180 度旋转，解除 CTT 结构域自身抑制作用，进而 STING 蛋白以“背对背”的方式多聚化激活。激活的 STING 蛋白从内质网转移至高尔基体的过程中招募并激活下游效应蛋白 TANK 结合激酶 1（TANK binding kinase1，TBK1）、κB 抑制因子激酶（inhibitor of κB kinase，IKK）、干扰素调控因子 3（interferon regulatory factor 3，IRF3）和核转录因子 κB（nuclear factor-κB，NF-κB），诱导一型干扰素和炎症因子的表达，激活机体的固有免疫反应 [10]。 1.2 SAVI 相关STING 突变体的异常激活 对 SAVI 患者的基因组测序及相关功能研究发现，编码 STING 蛋白的 STING1 基因发生功能获得性突变。根据突变氨基酸所在 STING 蛋白序列中位置的不同，可将 SAVI 相关的 STING 突变体分为以下 3 类：1）位于 NTD- 铰链 -CBD 结构交互区域的突变体，包括 H72N、V147L、V147M、F153V、N154S、V155M 和 G158A，该类突变体能调控STING CBD 结构域相对于跨膜区的 180 度旋转；2）位于 STING 二聚体的配体识别口袋内（G166E），促进二聚体的稳定；3）位于 STING 二聚体与相邻二聚体形成多聚体的互作表面，包括 C206Y、G207E、R281Q、R281W 和 R284G，参与 CTT 的释放，解除静息状态下 STING 蛋白的自身抑制作用，促进 STING 蛋白的多聚化激活。上述 SAVI 相关 STING突变体均能在不依赖上游 2'3'-cGAMP 配体结合下自发多聚化激活，提示诱导下游免疫和炎症信号通路的持续异常激活是SAVI疾病发病的根本原因[11]。STING 信号通路及 SAVI 相关 STING 突变体异常激活的分子机制如图 1 所示。 1.3 SAVI 的病理机制 为了阐明 SAVI 疾病的病理机制，研究人员利用规律成簇间隔短回文重复序列（clustered regularly interspaced short palindromic repeats，CRISPR）技术，对小鼠基因组中的 STING1 基因进行定点突变，已建立了 2 种常见的 SAVI 相关 STING 突变体的小鼠模型，即 STING N153S 小鼠（相当于人 STINGN154S 突变）和 STING V154M 小 鼠（ 相 当 于人STING V155M 突变）[12-13]。  纯合子的 STING N153S 小鼠在妊娠期不能存活，成年的杂合子 STING N153S 小鼠自发脾肿大、胸腔积液、皮肤溃疡性病变、肺部血管炎症伴随呼吸窘迫，血清中免疫球蛋白 M（immunoglobulin M，IgM）、肿瘤坏死因子 α（tumor necrosis factor alpha，TNF-α）、 白 介 素 17（interleukin-17，IL17）和单核细胞趋化因子-1（monocytechemoattractantprotein-1，MCP-1）等显著升高，大部分小鼠过早死亡。对小鼠脾脏细胞分析发现，STINGN153S 突变诱导髓系细胞增殖、T 细胞减少。值得注意的是，在 STING N153S 小鼠中 STING 蛋白下游 IRF3 介导的一型干扰素信号并不参与介导小鼠肺部病变、髓系细胞增生和 T 细胞减少，且该小鼠模型并未表现出临床 SAVI 患者中的肺纤维化和一型干扰素相关的基因表型 [12]。  与 STING N153S 小 鼠 相 似， 杂合子 STING V154M 雌性小鼠不育，只能用杂合子 STING V154M 雄鼠与野生型雌鼠进行繁育。杂合子 STING V154M 小鼠相比于正常小鼠体质量显著下降，且大部分小鼠过早死亡；病变的组织主要表现为肺炎、肾炎和脾脏肿大。对小鼠血液和脾脏白细胞分析发现，淋巴细胞（T淋巴细胞和自然杀伤细胞）占比显著降低，粒细胞和单核细胞的占比显著增加；STING V154M 小鼠血清炎症性细胞因子 TNF-α 和 IL-6 升高，免疫球蛋白 G（immunoglobulin G，IgG） 和 IgM 的水平显著 升高；在 STING V154M 小鼠中 STING 蛋白下游 IRF3 介导的一型干扰素信号也不参与介导淋巴细胞的减少和髓系细胞的增加；同时，在STING V154M 小鼠中并未检测到与临床 SAVI 患者相似的皮肤炎症病变的表型 [13]。在另外一项 STING N153S 和 V154M 小鼠的平行对比研究中发现，相比于 N153S 小鼠，V154M 小鼠的疾病程度更加严重，其表现为出生率更低（35%）、体质量更低、淋巴细胞减少和髓系细胞增加更严重、仅 V154M 小鼠出现肺纤维化症状，也进一步确认了一型干扰素通路并不参与肺部病变和免疫系统紊乱等 SAVI 疾病表型的进展 [14]。此外，Stinson 等 [15] 利用 SAVI N153S 小鼠分别与一型、二型和三型干扰素受体敲除的小鼠进行杂交后发现，SAVI 导致的肺部炎症和淋巴细胞减少症是由 T 细胞产生的二型干扰素介导的，而非一型干扰素。Gao 等 [16] 对 SAVI V154M小鼠进一步研究发现，SAVI 疾病的肺部炎症是由二型干扰素和肺部内皮细胞以及 T 细胞共同作用引起的。 综上，SAVI 相关小鼠疾病模型的研究结果表明：1）尽管现有的 SAVI 小鼠模型能自发产生多种与临床 SAVI 患者相似的疾病症状如免疫和炎症因子的升高、淋巴细胞减少症等，但并不能完全重现临床 SAVI 患者的肺纤维化（STING N153S 小鼠）和皮肤病变（STING V154M 小鼠）等疾病表型；2）相比于 STING 下游 IRF3 介导的一型干扰素信号通路，STING 下游激活的炎症信号通路、淋巴细胞死亡和二型干扰素信号通路在疾病的进展过程中发挥更加重要的调控作用。 2 SAVI 疾病的临床表现 PubMed 数据库和中国知网目前报道的 69 例SAVI 患者（见表 1）的疾病特征初步统计如下：31 例患者疾病初期表现为皮肤皮疹，伴随反复冻疮症状；38 例患者疾病初期表现为呼吸困难，肺部受损症状；10 例患者疾病初期表现为多发性关节炎。 2.1 突变基因型和遗传性 SAVI 患者存在多种 STING1 突变基因型，且不同基因型的遗传性存在差异。本次统计的 69 例SAVI 患者中，共计 15 种 STING1 基因突变，其中STING V155M 突变体 27 例，N154S 突变体 7 例，R281W 突变体 8 例，G207E 突变体 6 例，G166E突变体 5 例，H72N 突变体 3 例，V147L、C206Y、R281G 和 R281Q 突变体各 2 例，R284G、V147M、F153V、F279L 和 G158A 突变体各 1 例 [1, 17-36]。在 69 例 SAVI 患者中，有 6 例患者无法确定遗传方式（没有来自父母双方的可用 DNA），其余患者中有 34 例为新发突变，21 例为常染色体显性遗传突变，8 例为常染色体隐性遗传突变。其中，常染色体隐性遗传突变为 R281W 突变 [17, 19]，该突变报道在近亲结合的阿拉伯民族家庭中。STING R281W 家系中存在杂合携带者和纯合患者，杂合携带者无明显症状，纯合患者的症状较其他突变体患者更轻，这与细胞水平转染 STING R281W 突变体质粒后诱导低水平的一型干扰素和炎症因子一致。 2.2 发病时间  作为罕见的自身炎症疾病，SAVI 通常发病于婴幼儿时期，该疾病的平均发病年龄约为 2.28 岁，多数患者（47 例）在 1 周岁之前出现疾病症状，极少数患者成年后发病。列入统计的患者平均年龄为 17.8 岁，其中包含 2 个病情较轻、寿命较长的家系（G166E、G207E）；去除这 2 个家系后，患者平均年龄为 12.63 岁。目前报道的患者中仅有 22 例 SAVI 患者生长至成年，包括 4 例成年后死亡的患者。SAVI 婴幼儿患者发病后诱发生长障碍和身高受限等伴随疾病。SAVI 疾病临床少见成年患者的报道，可能与疾病的诊断困难、致死性和目前治疗策略的不成熟有关。 2.3 皮肤病变 SAVI 患者表现出不同程度的皮肤病变：53 例患者表现出轻度皮疹和冻疮样皮炎；31 例患者表现出严重的皮肤溃疡，主要表现在鼻子、脸颊、耳朵、口腔黏膜、手指和脚趾；9 例患者表现出广泛的组织损失；12 例患者出现鼻中隔穿孔症状；多例患者由于远端皮肤组织损失和反复冻疮导致截肢。不同 STING 突变体 SAVI 患者的皮肤病变程度存在显著差异。与 V155M 突变患者相比，N154S 突变患者更早出现疾病表型且皮肤病变更严重。与其他患者的复杂疾病表型不同，G166E、G207E 基因突变患者主要表现为皮肤病变，未见肺部和其他疾病症状 [27-28]。G166E 家系 SAVI 新发病例报道时年龄已达 86 岁，疾病程度较轻，是目前已有报道的 SAVI 患者中最长寿的病例。 2.4 肺部病变 肺部病变是 SAVI 疾病致死的主要因素。除上述提及的 G166E 和 G207E 突变患者外，几乎所有患者均表现出不同程度的肺部病变，临床表现为婴幼儿期 SAVI 患者出现早发性进行性呼吸困难、呼吸急促和咳嗽症状。胸部 X 线计算机断层扫描结果显示，肺部出现毛玻璃样浑浊，小叶间隔增厚和限制性肺气肿。本次统计的 69 例 SAVI 患者中，49 例患者表现出 ILD，其中 25 例进展为肺纤维化，更有 14 例进一步进展为终末期肺衰竭。终末期肺衰竭是 SAVI 疾病患者死亡的关键原因。 2.5 关节和肌肉病变 SAVI 患者易表现出多发性关节炎及肌炎，这是SAVI 婴幼儿患者生长障碍和身高受限的原因之一。对于 SAVI 婴幼儿患者，不明原因的多发性关节炎和早发家族性关节炎是此类患者的初始临床表现。SAVI 患者存在明显的关节疼痛，临床检验显示患者骨龄受限并伴随类风湿因子表达。随着 SAVI 疾病的进展，肌炎症状加重为肌肉萎缩，严重影响患者的生活质量。 2.6 免疫功能紊乱 SAVI 患者血中高表达干扰素与炎症因子，这些免疫和炎症因子作用于多种组织和器官，加剧组织的炎症损伤。分析 SAVI 患者的伴随疾病发现：3例 SAVI 患者发生肾小球肾炎 [20-22]；2 例 SAVI 患者发生肝炎 [25, 31]。值得注意的是，在疾病治疗进行器官移植过程中，SAVI 患者的高免疫反应状态会加剧器官移植的排异反应，使病情进一步恶化。1 例 SAVI 患者在肺移植 2 个月后出现全身多器官衰竭死亡 [29]；1 例 SAVI 患者在肝移植后肝炎症加剧 [32]，出现多发胆道囊肿及炎性细胞浸润；1 例患者在骨髓移植后发生心功能紊乱 [31]，出现血管充血性皮疹和鼻穿孔症状。 2.7 脑部和中枢神经系统的异常 多种 SAVI 相关 STING 突变体患者出现神经系统紊乱的症状。其中，1 例 C206Y 突变患者表现为松果体钙化 [25]；1 例 V147M 患者表现为颅内苍白球钙化 [29]；2 例 N154S 患者分别表现为痉挛性双瘫和癫痫的症状 [29]；1 例 F279L 突变患者脑部磁共振成像（magnetic resonance imaging，MRI）显示双侧顶枕皮质、皮质下和深部白质斑块性高信号，表现为癫痫；2 例患者出现视网膜血管/毛细血管扩张压迫视觉神经导致失明的症状 [31]。 2.8 血生化指标的异常 血液指标检查显示，多种 SAVI 相关 STING 突变体患者自身免疫抗体阳性并伴随免疫因子表达的显著增高，具体表现为炎性标志物红细胞沉降率（erythrocyte sedimentation rate，ESR）和 C-反应蛋白（C-reaction protein，CRP）升高。多例 SAVI 患者检测到自身抗体阳性以及 IgG、IgA 水平高于正常值；6 例患者自身抗 DNA 抗体阳性；31 例患者自身抗核抗体（antinuclear antibody，ANA）阳性；19 例患者抗中性粒细胞胞浆抗体阳性；15 例患者类风湿因子阳性。  目前临床诊断 SAVI 疾病主要依赖于该疾病在皮肤、血管和肺部引起的特征性疾病表型，疾病的确证需要结合患者基因组 STING1 的测序结果。 3 SAVI 疾病的临床治疗策略 3.1 现有治疗策略 目前 SAVI 疾病临床主要使用类固醇激素（强的松龙）联合多种免疫抑制剂与酪氨酸激酶（Janus kinase，JAK）抑制剂进行治疗。针对发热、关节疼痛、血管充血等症状使用钙通道阻滞剂、茶碱类药物、解热镇痛药辅助治疗。 3.1.1 类固醇激素和免疫抑制剂  69 例 SAVI 患者中，38 例接受类固醇激素治疗，40 例接受免疫抑制剂治疗，其中 27 例为类固醇激素联用免疫抑制剂治疗。类固醇激素包括强的松龙、甲基强的松龙、尼泊松龙和地塞米松等。免疫抑制剂包括羟氯喹、霉酚酸酯、硫唑嘌呤、来氟米特、甲氨喋呤、环孢素 A、利妥昔单抗、妥珠单抗、依那西普、英夫利昔单抗、阿那白滞素等。由于 SAVI 疾病与系统性红斑狼疮（systemic lupus erythematosus，SLE）、类风湿性关节炎等自身免疫性疾病症状类似，SAVI 患者发病入院时主要通过类固醇联合免疫抑制剂进行经验性治疗，在基因检测确诊为 SAVI 疾病后使用 JAK 抑制剂进一步治疗。 3.1.2 JAK 抑制剂  SAVI 疾病是由 STING 信号通路异常持续激活引起的。STING 信号通路下游激活一型干扰素为主的免疫信号和 TNF-α/IL-1/IL-6 为主的炎症信号。JAK 抑制剂能够抑制一型干扰素下游的 JAK/STAT 信号通路，提示 SAVI 疾病可使用JAK 抑制剂抑制免疫系统的激活 [37-41]。69 例 SAVI患者中，38 例使用 JAK 抑制剂（卢可替尼、巴西替尼、托法替尼）进行治疗。JAK 抑制剂治疗后，SAVI 患者呼吸急促等现象明显改善。需要注意的是，JAK 抑制剂的疗效在不同患者间存在差异，托法替尼治疗仅能改善 SAVI 患者的肺部症状，对皮疹未见明显疗效，且 1 例 SAVI 患者在治疗过程中死亡 [33]。 3.1.3 辅助治疗药物  SAVI 疾病的辅助治疗主要缓解发热、关节疼痛、呼吸急促、血管充血等症状。使用阿司匹林、萘普生、乙酰水杨酸、伊洛前列素、双氯芬酸钠等非甾体抗炎药解热镇痛；使用硝苯地平、氨氯地平等钙通道阻滞剂舒张血管平滑肌；使用几酮茶碱舒张气管平滑肌从而改善呼吸急促症状。 对上述药物治疗后 SAVI 患者的预后进一步分析发现，类固醇激素、钙通道阻滞剂、茶碱类药物和解热镇痛药在缓解患者发热、关节疼痛、血管充血、急性呼吸困难等方面具有显著的作用，应对患者的急性发作和维持患者生命体征具有不可替代的作用。JAK 抑制剂的联用能够进一步改善部分 SAVI 患者呼吸急促症状及运动能力。本次研究统计的 31 例使用 JAK 抑制剂治疗的 SAVI 患者中，有 21 例服用 JAK 抑制剂后症状改善，6 例服用后症状未有改变，4 例服用后症状仍然恶化甚至出现死亡。 3.2 临床治疗困境 目前 SAVI 疾病临床主要使用免疫抑制剂联合JAK 抑制剂进行治疗。长期给药会引发以下几个问题：1）药代动力学（pharmacokinetics，PK）和药效学（pharmacodynamics，PD）是高度可变，给药剂量必须适应患者体质量和肾功能的变化。然而 SAVI 疾病多发于婴幼儿时期，且需长期给药。婴幼儿的体质量变化较大，给药剂量需要根据患者的生长状况随时进行调整，这使得患者的依从性差。同时，SAVI 疾病会导致患者出现肝肾损伤，影响药物的经肝肾代谢与体内消除，增加药物不良反应。更重要的是，长期服用 JAK 抑制剂可能会加重肝肾损伤，使患者病情加重。2）在 SAVI 疾病的治疗过程中，通常会使用类固醇激素以及多种免疫抑制剂。这些免疫抑制剂的使用使患者病原体感染的风险增大，增加常见致病原感染，如带状疱疹、病毒性呼吸道感染、金黄色葡萄球菌感染和铜绿假单胞菌感染等；3）JAK 抑制剂仅能抑制 STING 介导的一型干扰素信号，但不能抑制 STING 介导的炎症反应和淋巴细胞死亡等，在治疗效果上存在局限性。因此，亟需开发治疗 SAVI 疾病的特异性药物并制定合理的治疗策略。 3.3 潜在治疗方法 目前针对 SAVI 疾病的基础和临床研究仍处于起步阶段，临床治疗手段有限。根据现有的医疗条件、技术手段和药物开发进展，多种潜在的治疗方法或可成为 SAVI 临床治疗的新手段。 3.3.1 个体化治疗  SAVI 疾病表型复杂，是涉及全身多个组织器官的疾病。目前临床已发现 15 种与SAVI 疾病相关的 STING 突变体间的临床表型差异明显。因此，阐明不同 STING 突变体与疾病表征的相关性及其病理机制是 SAVI 疾病临床治疗的基础。临床上可根据突变体种类的不同对患者进行个体化治疗。对于 N154S 突变体患者严重的皮肤病变在治疗过程中需要着重考虑使用免疫抑制剂控制皮肤损伤，对于 V155M 突变体患者中凸显肺部和肾脏功能紊乱在治疗中应首先考虑改善肺和肾脏的功能。然而对于 G166E 和 G207E 突变体患者，其疾病症状较轻，只有皮肤病变，治疗过程中仅需控制局部皮肤症状即可，减少糖皮质激素等系统性免疫制剂的长期使用。 3.3.2 基因治疗  基因治疗在基因突变诱发的罕见病治疗中广泛应用。囊性纤维化、血友病和肌萎缩侧索硬化症的治疗中均有基因治疗的应用。作为STING1 基因功能获得性突变诱发的罕见自身炎症疾病，目前尚未见报道SAVI疾病基因治疗的相关研究。后续对 SAVI 疾病的基因治疗可以通过基因编辑疗法和基因沉默疗法开展，通过 CRISPR/Cas9 技术切除致病细胞内的突变基因或使用 RNA 干扰技术沉默 STING1 基因的表达，抑制自身免疫反应，从而改善症状。 3.3.3 靶向 STING 蛋白抑制剂  考虑到 SAVI 疾病发病的分子机制，开发靶向 STING 蛋白突变体的抑制剂对 SAVI 疾病治疗展现出良好的前景。目前STING 小分子抑制剂的开发聚焦于阻断配体分子2'3'-cGAMP 对 STING 蛋白激活，并没有特异性针对 SAVI 相关 STING 突变体抑制剂的开发 [42-45]。小分子抑制剂 Compound 18 和 SN-011 结合 STING 的 CBD 口袋内抑制配体分子诱导的 STING 蛋白的激活。小分子抑制剂 H-151 和 BB-CL-amidine 分别共价结合到 STING 蛋白的第 91 和 148 位半胱氨酸残基上，抑制 STING 蛋白的多聚化激活。SN-011 在体外能显著抑制多种 SAVI 相关 STING 突变体的自激活，阻断下游免疫和炎症信号的表达，展现出潜在的治疗作用，但仍需进一步评价体内的药效学作用。Compound18、H-151 和 BB-CL-amidine 对 STING 突变体异常激活的抑制作用有待进一步研究。此外，随着 STING 蛋白与其下游接头蛋白 TBK1 相互作用的冷冻电镜结构的解析，可以开发特异性抑制 STING-TBK1 相互作用的小分子抑制剂阻断 STING 蛋白的信号转导。  相比于临床使用的 JAK 抑制剂，STING 突变体小分子抑制剂在 SAVI 疾病的治疗中具有以下潜在的优势：1）能直接靶向致病蛋白，从源头上抑制细胞功能的紊乱；2）不仅能抑制下游干扰素依赖的免疫功能紊乱，且能阻断干扰素非依赖的病理过程；3）不影响其他固有免疫信号通路的激活，降低了疾病治疗过程中的感染风险。因此，能够有效调控 SAVI 相关 STING 突变体激活的小分子抑制剂具有广泛的应用前景。 3.3.4 药物开发的体内外模型评价方法  在药物开发的临床前药效学评价阶段可使用 SAVI 的疾病模型小鼠（V154M、N153S）进行体内外活性评价：在体外检测受试药物对疾病小鼠的巨噬细胞、淋巴细胞和肺内皮细胞等多种细胞功能紊乱的调控作用；在体内评价长期给药对疾病小鼠皮肤、肺和肾脏等多组织病变的影响；此外，可以从临床上收集 SAVI患者的外周血单核细胞（PBMC）用于受试药物的体外活性评价。考虑到小鼠模型的局限性和人体组织样本获得的困难性，采用 SAVI 患者体细胞进行诱导多能干细胞（induced pluripotent stem cell，iPSC）的分化表现出巨大优势。iPSC 可分化为多种肺细胞，如 Ⅱ 型肺泡上皮细胞、内皮细胞和肺泡巨噬细胞，且具有进一步形成肺部类器官的潜力。利用 iPSC 诱导的 SAVI 肺部病变的体外模型可以进行更有效的小分子活性评价，且能避免种属差异、患者特异性以及伦理问题 [40, 46]。 4 结语 从 2014 年首次报道 SAVI 疾病以来，至今经过近 10 年的研究，临床上已初步确定了该疾病的诊断策略和治疗方案。作为危及生命且婴儿期发病的严重自身炎症疾病，临床确诊的 SAVI 患者的数量也逐渐增多。随着疾病模型小鼠的建立，对 SAVI 发病机制的研究也逐渐深入。在此契机下，开发 SAVI 疾病的特异性治疗药物的条件已基本成熟且为临床亟需。本综述通过分析临床报道的 SAVI 病例的发病症状及其治疗方案和患者预后的情况，归纳了目前治疗方案下存在的问题，结合病理机制的相关研究，为该罕见病后续的药物开发和临床治疗提供参考和思路。 参考文献： [1]  Liu Y, Jesus A A, Marrero B, et al. 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Human induced pluripotent stem cells generated from STING-associated vasculopathy with onset in infancy (SAVI) patients with a heterozygous mutation in the STING gene[J]. Stem Cell Res, 2022, 65: 102974. DOI: 10.1016/j.scr.2022.102974. 美编排版：朱玲欣 感谢您阅读《药学进展》微信平台原创好文，也欢迎各位读者转载、引用。本文选自《药学进展》2025年第2期。 《药学进展》杂志由国家教育部主管、中国药科大学和中国药学会共同主办，中国科技核心期刊（中国科技论文统计源期刊）。刊物以反映药学科研领域的新方法、新成果、新进展、新趋势为宗旨，以综述、评述、行业发展报告为特色，以药学学科进展、技术进展、新药研发各环节技术信息为重点，是一本专注于医药科技前沿与产业动态的专业媒体。 《药学进展》注重内容策划、加强组稿约稿、深度挖掘、分析药学信息资源、在药学学科进展、科研思路方法、靶点机制探讨、新药研发报告、临床用药分析、国际医药前沿等方面初具特色；特别是医药信息内容以科学前沿与国家战略需求相合，更加突出前瞻性、权威性、时效性、新颖性、系统性、实战性。根据最新统计数据，刊物篇均下载率连续三年蝉联我国医药期刊榜首，复合影响因子1.216，具有较高的影响力。 《药学进展》编委会由国家重大专项化学药总师陈凯先院士担任主编，编委由新药研发技术链政府监管部门、高校科研院所、制药企业、临床医院、CRO、金融资本及知识产权相关机构近两百位极具影响力的专家组成。 联系《药学进展》↓↓↓ 编辑部官网：pps.cpu.edu.cn； 邮箱：yxjz@163.com； 电话：025-83271227。 欢迎投稿、订阅！ 往期推荐 聚焦“兴药为民·2023生物医药创新融合发展大会”“兴药为民·2023生物医药创新融合发展大会”盛大启幕！院士专家齐聚杭城，绘就生物医药前沿赛道新蓝图“兴药强刊”青年学者论坛暨《药学进展》第二届青年编委会议成功召开“兴药为民·2023生物医药创新融合发展大会”路演专场圆满收官！校企合作新旅程已启航 我知道你在看哟

The arrival of biosimilars like Celltrion's STEQEYMA and Biocon's YESINTEK is shaking up the psoriatic arthritis market, challenging blockbuster biologics with cost-effective alternatives. As competition intensifies, these biosimilars are reshaping treatment choices and driving a shift in the market landscape. LAS VEGAS, March 12, 2025 /PRNewswire/ -- Psoriatic arthritis (PsA) is a chronic inflammatory condition that affects approximately 112 per 100,000 adults worldwide. It is more prevalent in Europe and North America than in Asia and South America. In patients with psoriasis, the prevalence of psoriatic arthritis can range from 6% to 34% in Western populations. Despite its impact, many individuals with psoriatic arthritis remain undiagnosed or receive inadequate treatment, highlighting the need for increased awareness and access to specialized care. As per DelveInsight analysis, among the 7MM, the United States accounted for the highest number of prevalent cases of psoriatic arthritis in 2023, and these cases are expected to increase by the end of 2034 due to several key factors such as an increase in awareness and diagnosis, as well as the rapid prevalence of PsA. Psoriatic arthritis, occurring in approximately 20% of individuals with psoriasis, is a chronic inflammatory arthritis intricately linked to psoriatic arthritis. This aggressive condition is characterized by potential significant morbidity and compromised quality of life. Treatment approaches for psoriatic arthritis encompass a variety of strategies aimed at managing symptoms, slowing disease progression, and improving the overall quality of life. These approaches typically involve a combination of pharmacological therapies, lifestyle modifications, and, in severe cases, surgical interventions. Psoriatic arthritis treatment is highly individualized based on disease severity, response to therapy, and patient preferences, with multidisciplinary care from rheumatologists, dermatologists, and physical therapists playing a key role. Pharmacological treatment for psoriatic arthritis primarily targets inflammation and pain relief. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen, are often the first line of defense, helping to reduce pain and inflammation. Disease-modifying antirheumatic drugs (DMARDs) like methotrexate, sulfasalazine, and leflunomide are commonly prescribed to prevent joint damage and suppress the inflammatory process. For individuals with mild-to-moderate psoriatic arthritis, oral small molecules (OSMs) like OTEZLA (apremilast) offer a convenient, non-injectable option by modulating inflammatory pathways. Biologic agents have revolutionized the treatment landscape for psoriatic arthritis. These medications specifically inhibit key molecules in the inflammatory cascade. TNF inhibitors like HUMIRA (adalimumab), ENBREL (etanercept), and REMICADE (infliximab) are frontline biologics that target tumor necrosis factor, a crucial driver of inflammation. Patients who do not respond to TNF inhibitors may benefit from IL-17 inhibitors like COSENTYX (secukinumab) and TALTZ (ixekizumab) or IL-12/23 inhibitors such as STELARA (ustekinumab). Learn more about the FDA-approved psoriatic arthritis drugs @ Drugs for Psoriatic Arthritis Treatment SKYRIZI (risankizumab), developed by AbbVie, is a humanized IgG1 monoclonal antibody that acts as an interleukin-23 (IL-23) antagonist. It can be used on its own or in conjunction with non-biologic DMARDs. In June 2022, the FDA approved SKYRIZI as the first and only targeted IL-23 inhibitor for adults with active psoriatic arthritis. Another biologic, TREMFYA (guselkumab by Janssen), was approved by the FDA in July 2020 as the first monoclonal antibody that selectively binds to the p19 subunit of IL-23, further expanding treatment options for psoriatic arthritis patients. BIMZELX (bimekizumab), developed by UCB Biopharma, is a humanized monoclonal antibody that targets IL-17A and IL-17F. It received European Commission approval in June 2023 for adults with active psoriatic arthritis and axial spondyloarthritis. On September 23, 2024, the FDA approved BIMZELX for treating adults with active psoriatic arthritis, non-radiographic axial spondyloarthritis (nr-axSpA) with objective inflammation, and active ankylosing spondylitis. In Phase III studies, BIMZELX showed meaningful responses in patients with inadequate TNF inhibitor responses and those new to biologics, indicating its potential as an important treatment option for psoriatic arthritis. In cases where joint damage becomes severe and unresponsive to medical therapies, surgical interventions like joint replacement surgery may be necessary to restore function and alleviate pain. Lifestyle changes, such as regular exercise, joint protection techniques, and weight management, are also critical in managing psoriatic arthritis, as excess weight can worsen symptoms and increase disease severity. The treatment landscape for psoriatic arthritis continues to evolve, offering hope to patients with more targeted therapies and improved outcomes. As companies like UCB Biopharma, AbbVie, and Janssen advance their biologic portfolios, the future looks promising for psoriatic arthritis management. The competition in the biosimilar market is intensifying as companies introduce cost-effective alternatives to blockbuster biologics. In December 2024, Celltrion announced FDA approval for STEQEYMA (ustekinumab-stba), a biosimilar to STELARA, for subcutaneous injection or intravenous infusion in adult and pediatric patients with plaque psoriasis and psoriatic arthritis, as well as adult patients with Crohn's disease and ulcerative colitis. Simultaneously, Biocon Biologics Ltd. is strengthening its position with positive Phase III results for YESINTEK, its biosimilar to ustekinumab, in adult patients with moderate to severe chronic plaque psoriasis. The pivotal randomized, double-blind, parallel-group study demonstrated comparable efficacy and safety to the reference biologic, STELARA, and the findings are being presented at the 2025 American Academy of Dermatology (AAD) Annual Meeting in Orlando, Florida. With the approval of STEQEYMA and the promising clinical outcomes for YESINTEK, these biosimilars are poised to challenge STELARA by offering cost-effective alternatives in key immunology indications. As pricing pressures and healthcare sustainability concerns drive the demand for biosimilars, these developments mark a significant shift in the treatment landscape, providing greater accessibility and affordability for patients while increasing competition in the immunology market. To know more about psoriatic arthritis treatment options, visit @ New Treatment for Psoriatic Arthritis The psoriatic arthritis market is buzzing with numerous companies advancing treatments to cater to the growing patient base. Several therapies are expected to enter the market during the forecast period, providing new hope for patients. Some of these potential therapies include ACELYRIN Inc.'s Izokibep, Novartis Pharmaceuticals' Secukinumab, UCB Biopharma SRL's Bimekizumab, and Bristol-Myers Squibb's Deucravacitinib. Additionally, AbbVie's Upadacitinib and Risankizumab, as well as Eli Lilly and Company's Ixekizumab, are also part of the promising pipeline. Other noteworthy therapies include Sun Pharma's ILUMYA/ILUMETRI, Bristol-Myers Squibb's SOTYKTU, and Affibody's Izokibep in collaboration with Acelyrin and Inmagene. With these advancements, the psoriatic arthritis treatment landscape is set for a major shift, offering patients more tailored and effective options. The companies involved in developing biosimilars include Alvotech, Teva, Biocon Biologics, Celltrion, Fresenius Kabi, and others. Discover which therapies are expected to grab major psoriatic arthritis market share @ Psoriatic Arthritis Market Report ILUMYA/ILUMETRI by Sun Pharma is an interleukin-23 (IL-23) inhibitor classified as a humanized, anti-IL-23p19 monoclonal antibody. It works by blocking inflammatory proteins (cytokines and chemokines) in the body. By inhibiting the effects of IL-23, ILUMYA helps control the release of other inflammatory proteins, including IL-17 and TNF-α. This mechanism reduces inflammation, decreases the number of inflammatory cells in psoriatic lesions, helps prevent plaque formation, and resolves tissue damage. The drug is currently undergoing evaluation in Phase III clinical development, actively recruiting subjects with active psoriatic arthritis who have prior exposure to anti-TNF agents, as well as those who are anti-TNF naïve. SOTYKTU, developed by Bristol-Myers Squibb, is the first and only novel oral selective tyrosine kinase 2 (TYK2) inhibitor being studied across multiple immune-mediated diseases. Deucravacitinib binds to the regulatory domain of the TYK2 enzyme, inhibiting its activation. This selective inhibition reduces the release of proinflammatory cytokines and chemokines, helping to control the inflammation associated with psoriatic arthritis and alleviating its signs and symptoms. Currently, the drug is being investigated for the treatment of psoriatic arthritis in a Phase III clinical trial. Izokibep, developed by Affibody in partnership with Acelyrin and Inmagene, is a unique antibody mimetic and a novel bispecific agent that potentially targets both subunits of the IL-17A homo-dimer and serum albumin. Affibody has entered into a partnership agreement with Acelyrin for the development and commercialization of izokibep and has completed a Phase II trial. As part of this agreement, Acelyrin obtained worldwide rights to izokibep, excluding selected Asian countries, where rights have been granted to Inmagene Biopharmaceuticals. In March 2024, Acelyrin announced the release of positive top-line results from the Phase IIb/III trial, indicating that izokibep was well-tolerated with a favorable safety profile. This drug is currently in Phase III clinical trial. Discover more about drugs for psoriatic arthritis in development @ Psoriatic Arthritis Clinical Trials The anticipated launch of these emerging therapies for psoriatic arthritis is poised to transform the market landscape in the coming years. As these cutting-edge treatments continue to mature and gain regulatory approval, they are expected to reshape the psoriatic arthritis market landscape, offering new standards of care and unlocking opportunities for medical innovation and economic growth. DelveInsight estimates that the psoriatic arthritis market size was USD 9 billion in 2021 and is expected to grow significantly in the coming years. This growth can be attributed to the introduction of upcoming therapies and the rising prevalence of the condition. The anticipated launch of these therapies is also expected to attract new entrants to the psoriatic arthritis market, resulting in increased competition and innovation. DelveInsight's latest published market report titled " Psoriatic Arthritis Market Insight, Epidemiology, and Market Forecast – 2034" will help you discover which market leader is set to capture the largest market share. The report provides comprehensive insights into country-specific treatment guidelines, patient pool analysis, and epidemiology forecasts to help understand key opportunities and assess the market's underlying potential. The psoriatic arthritis market report offers epidemiological analysis for the study period 2020–2034 in the 7MM, segmented into: Total Prevalent Cases of Psoriatic Arthritis Total Diagnosed Prevalent Cases of Psoriatic Arthritis Gender-specific Diagnosed Prevalent Cases of Psoriatic Arthritis Severity-specific Diagnosed Prevalent Cases of Psoriatic Arthritis The report provides an edge while developing business strategies by understanding trends shaping and driving the 7MM Psoriatic Arthritis market. Highlights include: 10-year Forecast 7MM Analysis Epidemiology-based Market Forecasting Historical and Forecasted Market Analysis upto 2034 Emerging Drug Market Uptake Peak Sales Analysis Key Cross Competition Analysis Industry Expert's Opinion Access and Reimbursement Download this psoriatic arthritis market report to assess the epidemiology forecasts, understand patient journeys, gain insights into KOLs' opinions about upcoming treatment paradigms, and identify the factors contributing to changes in the psoriatic arthritis market. Additionally, stay informed about the mitigating factors that can enhance your market position in the psoriatic arthritis therapeutic space. Related Reports Psoriatic Arthritis Pipeline Psoriatic Arthritis Pipeline Insight – 2025 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key schizophrenia companies, including Affibody, Kymera, Selection Therapeutics GmbH, Jiangsu HengRui Medicine Co., Ltd., Nimbus Lakshmi, Inc., Hansoh BioMedical R&D Company, Bio-Thera Solutions, ACELYRIN Inc., among others. Psoriatic Arthritis Epidemiology Forecast Psoriatic Arthritis Epidemiology Forecast – 2034 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, and Psoriatic Arthritis epidemiology trends. 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About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED