RESUMO
Objective: To evaluate the efficacy and safety of tofacitinib in combination with methotrexate (MTX) versus MTX monotherapy in patients with active rheumatoid arthritis (RA). Methods: Trials were identified from four electronic databases: PubMed, Web of science, Cochrane Library and EMBASE from inception to April 2022. Two independent reviewers evaluated each database to scan the title, abstract and keywords of each record retrieved. Full articles were further assessed when the information suggested that the study was a randomized clinical trial (RCT) comparing tofacitinib combined with MTX vs. MTX monotherapy in patients with active RA. Data were extracted from the literature, and the methodological quality of the included literature were evaluated and screened by two reviewers independently. The results were analyzed using RevMan5.3 software. The full text of the studies and extracted data were reviewed independently according to PRISMA guidelines. The outcome indicators were ACR 20, ACR 50, ACR 70, Disease activity score 28 (DAS28), erythrocyte sedimentation Rate (ESR) and adverse events (AEs). Results: Of 1152 studies yielded by the search, 4 were retained, totaling 1782 patients (1345 treated with tofacitinib combined with MTX vs 437 received MTX. In the trial of insufficient response to MTX treatment, tofacitinib combined with MTX had significant advantages compared with MTX monotherapy. Numerically higher ACR20, ACR50 and ACR70 response rates were observed in the tofacitinib combined with MTX groups versus MTX monotherapy. ACR20 (odds ratio (OR), 3.62; 95% CI, 2.84-4.61; P < 0.001), ACR50 (OR, 5.17; 95% CI, 3.62-7.38; P < 0.001), and ACR70 (OR, 8.44; 95% CI, 4.34-16.41; P < 0.001), DAS28 (ESR) < 2.6 (OR, 4.71, 95% CI, 2.06-10.77; P < 0.001). The probability of adverse events of tofacitinib combined with MTX was lower than that of MTX monotherapy (OR, 1.42; 95% CI, 1.08-1.88; P = 0.01). The number of cases discontinued due to lack of efficacy or adverse events was similar in both groups (OR, 0.93; 95% CI, 0.52-1.68). The probability of abnormal liver enzymes in the treatment of tofacitinib combined with MTX was significantly lower than that of MTX monotherapy (OR, 1.86; 95% CI, 1.35-2.56). However, there was no significant difference between the two groups in severe adverse reactions, neutropenia, anemia and cardiovascular disease. Conclusions: In terms of ACR20/50/70 and DAS28 (ESR), tofacitinib combined with MTX demonstrated superiority to MTX monotherapy in the treatment of patients with refractory RA. Considering the hepatoprotective and observably therapeutic efficacy, tofacitinib combined with MTX could be effective in treating refractory RA. However, in terms of hepatoprotective, it requires further large-scale and high-quality clinical trials to confirm.
RESUMO
Systemic lupus erythematosus (SLE) is a devastating autoimmune disorder associated with severe organ damage. The abnormality of T cell apoptosis is considered as an important pathogenetic mechanism of SLE. Norcantharidin (NCTD), a derivative of Cantharidin, is an efficacious anti-cancer drug by inhibiting cell proliferation and inducing cell apoptosis. Besides, NCTD has also been proved to protect the function of kidneys, while damaged renal function is the most important predictor of morbidity and mortality in SLE. All these suggest the potential effects of NCTD in SLE treatment. In this study we investigated whether NCTD exerted therapeutic effects in a mouse SLE model. Lupus prone female MRL/lpr mice were treated with NCTD (1, 2 mg·kg-1·d-1, ip) for 8 weeks. We showed that NCTD administration significantly decreased mortality rate, diminished the expression of anti-dsDNA IgG antibody, a diagnostic marker for SLE, as well as restored renal structure and function in MRL/lpr mice. Moreover, NCTD administration dose-dependently inhibited lymphoproliferation and T cell accumulation in the spleens of MRL/lpr mice. We further revealed that NCTD specifically inhibited DN T cell proliferation and Th17 cell differentiation both via blocking activation of signal transducer and activator of transcription 3 (STAT3) signaling pathway. On the other hand, NCTD did not affect T cell apoptosis in MRL/lpr mice. Taken together, our data suggest that NCTD may be as a promising therapeutic drug through targeting T cells for the treatment of SLE.
