Background: Methotrexate (MTX), sulfonamides, hydroxychloroquine, and leflunomide have consistently resulted in remission with relatively mild to moderate adverse effects in patients with rheumatoid arthritis (RA). Modern medications outperform traditional treatments in that they target the pathological processes that underlie the development of RA. Methods: Following PRISMA guidelines, the authors accomplished a systematic review of the clinical efficacy of RA drugs, including the biologics such as Tumor Necrosis Factor-alpha inhibitors (TNF-α i) like Etanercept, Infliximab, Golimumab, and Adalimumab, kinase inhibitors (JAK inhibitors including Baricitinib and Tofacitanib), SyK inhibitors like Fos-tamatinib, MAPK inhibitors such as Talmapimod, T-cell inhibitors (Abatacept), IL6 blockers (Tocilizumab), and B cells depleters (Rituximab). These drugs have been found to increase remission rates when combined with MTX. A bioinformatics-based network was designed applying STRING-MODEL and the DrugBank database for the aforementioned drugs and MTX and, finally, employed for this systematic review. Results: Current research demonstrates that non-TNF-α inhibitor biologicals are particularly helpful in treating patients who did not respond well to conventional medications and TNF-α inhibitors. Despite being effective, these innovative drugs have a higher chance of producing hazardous side effects. The in silico investigations suggested an uncovered molecular interaction in combining MTX with other biological drugs. The STRING-MODEL showed that DHFR, TYMS, and ATIC, as the receptors of MTX, interact with each other but are not connected to the major interacted receptors. Conclusions: New game-changing drugs including Mavrilimumab, Iguratimod, Upadacitinib, Fenebrutinib, and nanoparticles may be crucial in controlling symptoms in poorly managed RA patients. Emerging therapeutic targets like Toll-like 4 receptors, NLRP3 inflammasome complexes, and mesenchymal stem cells can further transform RA therapy.
