Pos1015 a Novel Drug Combination of Iguratimod and Tofacitinib Alleviates Rheumatoid Arthritis and Secondary Osteoporosis

Abstract

BackgroundAt present, specific immune targeted therapeutics including biologics and kinase inhibitors has made significant progress in Rheumatoid arthritis (RA). However, the irresponse to targeted therapies in some refractory RA patients suggests more attention should be paid on cell death pathways, such as pyroptosis. TNF-α is a proinflammatory cytokine that plays a fundamental role in the pathogenesis of RA, which could induce pyroptosis in monocytes and macrophages and cause the destruction of bone and cartilage. Iguratimod (IGU) has been confirmed as a highly efficacious and safe conventional synthetic disease-modifying anti-rheumatic drug for RA in Asia. Whether the combination of IGU and Tofacitinib (TOF), the Janus kinase inhibitor, would be better partner need to be elucidated.ObjectivesTo evaluate the therapeutic effect of IGU and TOF on active RA and secondary osteoporosis in collagen-induced arthritis (CIA)+TNF model.MethodsIn this study, hematoxylin and eosin (HE) staining were used to evaluate the pathological changes in ankle joints of CIA+TNF model. Immunohistochemistry (IHC) were used to evaluate the level of pyroptosis related proteins in synovial tissue. We performed Micro-computed tomography (Micro-CT), HE staining and IHC to analyze the trabecular bone changes in distal femoral metaphyses to investigate the destruction of knee joint.ResultsAfter 6 weeks treatment of IGU and/or TOF, the diameter of ankle joint and the level of interleukin (IL)-18, IL-1 of CIA+TNF model. Immunohistochemistry (IHC) were used to evaluate the level of pyroptosis related proteins in synovial tissue. We performed M group. HE staining showed that only a small amount of inflammatory cell infiltration and less pannus were seen in synovial tissue of both monotherapy and combination group, when compared with the CIA+TNF group. Of importance, the pyroptosis related proteins, such as gasdermin D (GSDMD), nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3), caspase-1, and IL-1β were significantly less expression in synovial tissue of combination group compared with the CIA+TNF group. Both the osteoblast bone formation and osteoclast bone absorption were sharply ruined in CIA+TNF model. However the bone destruction was significantly alleviated and bone turnover rate was remarkably increased in combination group, detected by Micro-CT, HE staining and IHC.ConclusionThe TOF-IGU combination synergistically alleviated the disease severity of the CIA model, including relieving joint inflammation and bone erosion, with suppressing the activation of the NLRP3 inflammasome and reducing GSDMD-mediated pyroptosis. The combined application of TOF and IGU may have a stronger therapeutic effect on RA and secondary osteoporosis bone remodeling.Figure 1.Therapeutic effects of TOF and IGU on the disease severity in CIA+TNF model.(A) The diameter of ankle joint; (B) HE staining in synovial tissue; (C) IHC staining of pyroptosis related proteins in synovial tissue; (D) Micro-CT analysis in distal femurs; (E) HE staining in knee joint; (F) IHC staining of ALP and TRAP staining in knee joint.Acknowledgementsthe ECCM Program of Clinical Research Center of Shandong University (No. 2021SDUCRCB010) and the Natural Science Foundation of Shandong Province (ZR2022MH177)Disclosure of InterestsNone Declared.