针对一些类风湿性关节炎（RA）患者对目前治疗不足的问题需要进行解决。难治性RA（RRA）患者通常伴有较高的肿瘤坏死因子（TNF）表达。我们评估了Iguratimod（IGU）和Tofacitinib（TOF）联合治疗对RRA和继发性骨质疏松症的协同治疗效果。应用血红染色和嗜酸性染色评估胶原诱导关节炎（CIA）+TNF模型大鼠踝关节的病理变化。采用免疫组织化学（IHC）和免疫荧光（IF）评估滑膜组织中与焦亡相关蛋白水平。此外，通过HE染色、IHC和微计算机断层扫描研究了膝关节。此外，体外实验采用免疫印迹和酶联免疫吸附测定（ELISA）检测了TOF和IGU对RA样纤维样滑膜细胞中TNF-α诱导的焦亡的影响。经TOF和/或IGU处理后，CIA + TNF模型的关节炎评分、滑膜组织中的炎症细胞浸润以及血浆中白介素（IL）-18、IL-1β和IL-6的水平在联合组中显著增加，而显著减少于CIA + TNF模型组。联合组中焦亡相关蛋白的表达显著低于CIA + TNF组，体外实验结果一致。骨破坏在联合组中得到显著缓解，骨转换率较CIA + TNF模型组明显增加。TOF + IGU减轻了CIA + TNF模型中RRA的严重程度，缓解了关节炎炎症，减少了骨侵蚀，抑制了焦亡。TOF和IGU的联合应用可能在RRA和继发性骨质疏松性骨重塑方面具有叠加的治疗效果。版权所有© 2023该作者。由Elsevier B.V.出版。

The inadequate response of some patients with rheumatoid arthritis (RA) to current therapies is an issue that needs to be addressed. Patients with refractory RA (RRA) are often accompanied by high Tumor necrosis factor (TNF) expression. We evaluated the synergistic therapeutic effects of the combination of Iguratimod (IGU) and Tofacitinib (TOF) on RRA and secondary osteoporosis.Pathological changes in the ankle joints of collagen-induced arthritis (CIA) + TNF model rats were assessed using hematoxylin and eosin (HE) staining. Immunohistochemistry (IHC) and immunofluorescence (IF) were used to evaluate pyroptosis-related protein levels in the synovial tissues. Moreover, the knee joint was investigated by performing HE staining, IHC, and micro-computed tomography. Furthermore, in vitro, western blotting and enzyme-linked immunosorbent assay (ELISA) were performed to detect the effects of TOF and IGU on TNF-α-induced pyroptosis in fibroblast-like synoviocytes of RA.After treatment with TOF and/or IGU, the arthritis scores, inflammatory cell infiltration in synovial tissues, and levels of interleukin (IL)-18, IL-1β, and IL-6 in the plasma were remarkably increased in the CIA + TNF model and dramatically decreased in the combination group. The expression of pyroptosis-related proteins was significantly lower in the combination group than in the CIA + TNF group, and a consistent trend was observed in vitro. Bone destruction was significantly alleviated, and the bone turnover rate was remarkably increased in the combination group compared to that in the CIA + TNF model.TOF + IGU alleviated the severity of RRA in the CIA + TNF rat model, relieving joint inflammation, reducing bone erosion, and suppressing pyroptosis. The combined application of TOF and IGU may have a superimposed therapeutic effect on RRA and secondary osteoporotic bone remodeling.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.