Previous studies have confirmed the as sociation of methotrexate with infections, hematological problems and hepatotoxicity. Still, all the in cluded studies in the meta analysis have allowed stable doses of low dose corticosteroids as a background regi men. thus costicosterioids could also have contributed for the tofacitinib associated infection and immune sup pressions. While, as verified by a randomized double blind study, the elevated level of LDL choles terol in tofacitinib treated patients with rheumatoid arthritis seem to be managed by adding statins to the regimens. Nevertheless, this meta analysis has also shown that the number of tofacitinib treated patients who discon tinued medication due to adverse events were not differ ent from placebo treated groups.

Moreover, the included studies in this meta analysis were not primarily designed to assess tofacitinib related adverse events. As a result, the significant association of tofacitinib with infections and laboratory abnormalities might not be conclusive. A meta analysis including studies which were not designed to assess adverse events and have had small sample sizes may not have an adequate power to test rare adverse events. As limitations, first, this meta analysis has noted a sig nificant heterogeneity among the included studies. The possible explanation for the significant heterogeneity among the included studies could be 1 the differences in the baseline demographic and clinical characteristics of the patients recruited in the studies. 2 The variation in the duration of therapy and the drug regimens across studies.

Nonetheless, these assumptions were not supported by either the subgroup analysis or meta regres sion. that is to say, the treatment outcome did not seem to be affected by the duration of therapy Entinostat and by the use of tofacitinib as monotherapy or in combination with metho trexate. Second, since most of the included studies did not report values for ACR50, and ACR70 responses, meta ana lyses were not conducted with these outcome indicators. Third, all the primary studies included in this meta analysis were sponsored by a pharmaceutical company. Studies sponsored by pharmaceutical companies were more likely to have outcomes favoring the sponsor interests. Fourth, this meta analysis did not to incorporate studies written in other languages. Conclusion In conclusion, tofacitinib monotherapy or in combination with background methotrexate was effective in the treat ment of active rheumatoid arthritis in patients with an in adequate response or intolerance to at least one of the nonbiologic or biologic DMARDs. Additionally, the num ber of patients who discontinued medication in the tofa citinib treatment groups was not different from placebo groups.