Rheumatoid arthritis (RA) is a systemic, inflammatory autoimmune disorder with numerous manifestations caused due to intricate chain of events (Trouw et al., 2017). Cells of the leukocyte lineage such as: Monocytes-macrophages, neutrophils, mastocytes and subsets of T & B cells majorly contribute to the pathogenesis of RA by secreting various cytokines and chemokines (Shikhagaie et al., 2017). Tumor necrosis factor alpha (TNFα), interleukin 1 beta (IL-1β), interleukin 6 (IL-6) and interleukin 17 (IL-17) are the key mediators of RA pathogenesis (McInnes and Schett, 2017). Inhibiting the effect of these cytokines has been the target of interest, mainly aimed at alleviating the inflammation in the synovium (Burmester and Pope, 2017). Monoclonal antibodies (mAbs) against TNFα (Infliximab, etanercept and adalimumab) and IL-1β (anakinra and canakinumab) have been used in recent years in suppressing the inflammation at the joint space of RA patients (Cohen and Kay, 2017; Szondy and Pallai, 2017). Howbeit, due to several side effects after prolonged usage and ineffectiveness in curing the disease, the quest for effective and a safer therapy for RA are still an unsolved mystery. Interleukin 21 (IL-21), a dual role cytokine discovered during the year 2000 shares similar homology with IL-2 family of cytokines (IL-2, IL-4 and IL-15) (Leonard and Spolski, 2005). IL-21 interacts with gamma chain (γc) of IL-21 receptor (IL-21R) expressed in various immune cells of the leukocyte lineage. IL-21 is predominantly secreted by T helper 17 (Th17), follicular T helper (Tfh) and natural killer T (NKT) cells (Varicchi et al., 2016). In normal physiology, IL-21 helps in promoting NK cells activation, CD4+ T cell effector function and B cell proliferation to plasma cells for antibody production (Davis et al., 2007; Spolski and Leonard, 2008). IL-21/IL-21R have been shown to mediate various autoimmune disorders such as Sjögren’s syndrome, systemic lupus erythematosus (SLE), multiple sclerosis and type I diabetes (Kwok et al., 2015; Ferreira et al., 2015; Ghalamfarsa et al., 2016; Huang et al., 2016). In recent years, IL-21 has been found to be a key player in RA pathogenesis and progression (Kwok et al., 2012; Xing et al., 2016 (a); Xing et al., 2016 (b)). In RA pathogenesis, IL-21 receptor (IL-21R) is highly expressed on CD4+ T cell subsets, macrophages, dendritic cells and synovial fibroblasts (Lubberts, 2010).