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Although therapeutic options are increasing, many patients continue to have an inadequate response to therapy or intolerable side effects ( Alonso-Ruiz et al., 2008 Wang et al., 2018). It has been suggested that these high treatment costs may negatively affect medication adherence in patients with RA ( Heidari et al., 2018).įinal common mediators of disease, including tumor necrosis factor-α (TNF-α) and interleukin (IL)-6, are well studied and have yielded breakthrough therapeutics. The yearly cost of care for the chronic treatment of RA in the United States is estimated at $12,509 (direct treatments costs of $3,725) in patients using non-biologic treatments, and $36,053 (direct treatment costs of $20,262) in patients using biologic agents ( Hresko et al., 2018). In North America, the overall prevalence of RA is ∼1% ( Myasoedova et al., 2010 Tobón et al., 2010) though some groups show higher prevalence rates – with the highest prevalence affecting the Chippewa Native American people at 7% ( Alamanos and Drosos, 2005 Ferucci et al., 2005). Risk factors for RA include smoking, gender (females show higher incidence), obesity, old age, and genetics with genetic and epigenetic factors comprising ∼30% of risk (reviewed in ( Ollier and MacGregor, 1995 Scott et al., 2010 Smolen et al., 2018 Mikhaylenko et al., 2020 Smolen et al., 2020)).

Additionally, autoantibodies to rheumatoid factor (RF) and citrullinated protein are often present. It can also affect extra-articular organs (e.g., heart, lungs, eyes, blood vessels) and reduce life span ( Hakala, 1988 Young and Koduri, 2007 Koduri et al., 2010 Widdifield et al., 2018). It is characterized by inflammation of the synovial membrane lining joints, frequently resulting in bone erosion and eventual joint destruction if left untreated. Rheumatoid Arthritis (RA) is a chronic, destructive autoimmune disease that afflicts over one percent of the world population and causes substantial pain, joint deformity, and functional disability ( Helmick et al., 2008). Finally, we turn to the emerging fields of bioengineering and cell therapy to illuminate possible future targeted therapeutic options that combine material and biological sciences for localized therapeutic action with the potential to greatly reduce side effects seen in systemically applied treatment modalities. Here we present an up-to-date accounting of both emerging and approved pharmacological treatments for RA, detailing their discovery, mechanisms of action, efficacy, and limitations. In this review, we detail multiple biomolecular pathways involved in RA disease pathogenesis to elucidate and highlight pathways that have been therapeutic targets in managing this systemic autoimmune disease. Despite advances in targeted biologic and pharmacologic interventions that have recently come to market, many patients with RA continue to have inadequate response to therapies, or intolerable side effects, with resultant progression of their disease. Rheumatoid arthritis (RA) is a debilitating autoimmune disease with grave physical, emotional and socioeconomic consequences. Engleman Rheumatology Research Center, Department of Medicine, University of California, San Francisco, CA, United States 6Department of Chemistry, University of California, Davis, Davis, CA, United States.5Department of Anatomy, Physiology, and Cell Biology, University of California, Davis, Davis, CA, United States.4Center for Neuroscience, University of California, Davis, Davis, CA, United States.3Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA, United States.

2Department of Pharmacology, University of California, Davis, Davis, CA, United States.1Department of Biomedical Engineering, University of California, Davis, Davis, CA, United States.Dawson 3, Juan Flores 4, Marina Gabriel 1, Gustavo Garcia 1 †, Amanda Guevara 2, Kaitlin Murray 5, Noah Pacifici 1, Maxemiliano V.