A novel drug combination of Tofacitinib and Iguratimod alleviates rheumatoid arthritis and secondary osteoporosis

Jie Chen; Qincheng Che; Yuying Kou; Xing Rong; Xiaojie Zhang; Minqi Li; Qiang Shu

doi:10.1016/j.intimp.2023.110913

A novel drug combination of Tofacitinib and Iguratimod alleviates rheumatoid arthritis and secondary osteoporosis

Int Immunopharmacol. 2023 Nov;124(Pt B):110913. doi: 10.1016/j.intimp.2023.110913. Epub 2023 Sep 16.

Authors

Jie Chen¹, Qincheng Che¹, Yuying Kou², Xing Rong², Xiaojie Zhang¹, Minqi Li², Qiang Shu³

Affiliations

¹ Qilu Hospital, Cheeloo College of Medicine, Shandong University, Department of Rheumatology, Jinan, China; Shandong Provincial Clinical Research Center for Immune Diseases and Gout, Department of Rheumatology, Qilu Hospital, Jinan, China.
² Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, China; Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China.
³ Qilu Hospital, Cheeloo College of Medicine, Shandong University, Department of Rheumatology, Jinan, China; Shandong Provincial Clinical Research Center for Immune Diseases and Gout, Department of Rheumatology, Qilu Hospital, Jinan, China. Electronic address: shuqiang@sdu.edu.cn.

PMID: 37717316
DOI: 10.1016/j.intimp.2023.110913

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Iguratimod; Osteoporosis; Pyroptosis; Rheumatoid arthritis; Tofacitinib.

MeSH terms

Animals
Arthritis, Experimental* / pathology
Arthritis, Rheumatoid* / drug therapy
Arthritis, Rheumatoid* / pathology
Drug Combinations
Humans
Osteoporosis* / drug therapy
Rats
Tumor Necrosis Factor-alpha
X-Ray Microtomography

Substances

iguratimod
tofacitinib
Tumor Necrosis Factor-alpha
Drug Combinations