**1. Introduction**

Rheumatoid arthritis (RA) is an autoimmune disease that is characterized by synovial proliferation and inflammatory responses, the presence of autoantibodies including rheumatoid factor and anti-citrullinated protein antibodies (ACPA) in sera, cartilage, and bone erosion with deformity, and co-occurring health conditions such as cardiovascular disease events, pulmonary, psychological, and metabolic bone disorders [1]. Proinflammatory cytokines that mediate the progression of RA disease include tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and IL-6. Current international guidelines for patients with early RA recommend starting disease-modifying antirheumatic drugs (DMARDs) as soon as possible, with methotrexate being the preferred choice [2]. Methotrexate is usually supplemented with short-term, low-dose oral or intra-articular glucocorticoids (GCs) for fast relief of pain and swelling and for arresting the inflammatory process. GCs must be carefully managed to prevent their inappropriate use and tapered as soon as possible to avoid long-term adverse effects [2]. The highly efficacious biologic DMARDs targeting the proinflammatory cytokines and Janus kinase inhibitors are intended for patients with persistently active

disease after initial methotrexate failure and, in some cases, another conventional DMARD [2]. However, although these novel medications help to control RA disease activity, they are not universally effective in all RA patients [3,4] and many will lose therapeutic responsiveness after a period of time [5]. More potent or complementary treatments are needed.

The anti-inflammatory and antioxidant effects ofmelatonin have proven beneficialin severalinflammatory autoimmune diseases [6]. Melatonin is also capable of regulating responses of T cell subsets, such as CD4<sup>+</sup> T helper (Th)1, Th17, and regulatory T cells (Tregs) [7]. However, numerous studies indicate that melatonin, instead of being beneficial, could exacerbate RA disease-related activities. Nevertheless, in recent years, some conflicting results show that melatonin is capable of alleviating RA through anti-inflammatory and immunoregulatory mechanisms. The aim of this review is to elucidate the complex reactions of melatonin in RA and determine whether melatonin could serve as a potential therapeutic agent.
