Objectives Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by the synovitis and bone erosion. The combination therapy of glucocorticoids (GCs) and methotrexate (MTX) is recommended in early RA management, although the precise underlying mechanism of action remains unclear. This study is aimed to clarify the mechanism of MTX in combined with GC in treating RA. Methods GC-induced osteoporosis (GIOP) mouse model was used to investigate the bone-protective role of MTX. Lipopolysaccharide-induced arthritis mouse model was used to evaluate the anti-inflammatory effects of GCs and MTX. Functional role of MTX on osteoclastogenesis was assessed by trap staining and micro-computer tomography. Western blot, RT-qPCR and coimmunoprecipitation were used to explore the underlying mechanisms. Results We demonstrate that GCs, but not MTX, rapidly inhibited synovitis in arthritis model. MTX treatment was observed to inhibit osteoclastogenesis induced by GC in vitro and mitigate bone loss attributed by GIOP. GCs were found to augment the interaction between the membrane GC receptor (mGR) and signal transducer and activator of transcription 1 (STAT1), leading to the suppression of IFN-γR/STAT1 signalling pathways. Interestingly, MTX was found to inhibit osteoclastogenesis induced by GCs through the enhancement of the A2AR and IFN-γR interaction, thereby activating the IFN-γR/STAT1 signalling cascade. Consequently, this process results in a reduction in the mGR and STAT1 interaction. Conclusions Our study provides compelling evidence that MTX can make GCs effectively to suppress synovitis and reduce bone loss induced by GCs. This sheds light on the potential mechanistic insights underlying the efficacy of GCs in conjunction with MTX for treating RA.

Bladder cancer is the ninth most common cancer in the world; fewer than 15% of transitional-cell carcinoma patients survive 2 years if left untreated. Although radical cystectomy is the standard treatment of choice, much of them relapse and the necessity of adjuvant chemotherapy is still under debate. The aim of the study was to evaluate the efficacy of adjuvant intraarterial chemotherapy (IAC) with gemcitabine and cisplatin (GC) on locally advanced bladder cancer. This is a retrospective study on 60 patients with locally advanced bladder carcinoma who underwent radical cystectomy between May 2000 and June 2011. Patients were studied in two groups based on IAC and followed up for up to 5 years. Among 60 patients, there were 25 patients who underwent IAC (GC) after radical cystectomy (the IAC group) and 35 patients who underwent radical cystectomy alone (the control group). Although not significant, the relapse rates were slightly reduced in the IAC group than in the control group. Patients with IAC had a reduction in mortality compared with patients without IAC over 5 years. Specifically, IAC significantly reduced about 82% of mortality within the first year (hazard ratio = 0.18, 95% CI 0.03-0.97, P = 0.04). Additionally, IAC was well tolerated and safe. The most common adverse effect was transient myelosuppression (10/25, 40%), which was resolved by various medical treatments. Compared with radical cystectomy alone, radical cystectomy in combination with adjuvant IAC moderately but significantly reduces 1-year mortality. Our preliminary data showed only marginal benefit for the early survival. However, a randomized clinical study is needed to determine the long-term survival benefit.

Methotrexate (MTX) remains a cornerstone in the management of rheumatoid arthritis (RA). Extensive basic pharmacological research has consistently demonstrated the e cacy of MTX in treating RA, while there is still insu cient understanding about the potential mechanisms. In this review, current knowledge on the mechanisms by which MTX acts in bone erosion and synovitis is summarized, and MTX-based combination therapies are discussed. Additionally, the bone-protective and anti-in%am matory roles of adenosine receptors are described, and biomarkers associated with MTX responders in RA are explored. This review sheds new light on future research directions for RA, as well as o ers evidence-based recommendations to enhance the clinical utilization of MTX in RA treatment. Cite this article as: Teng Y, Jiang L, Yin H, Deng G. The role and mechanistic e ects of methotrexate in the treatment of rheumatoid arthritis. Eur J Rheumatol. 2025:12(4), -0086, 10.5152/ eurjrheum.2025.24086.