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Review
. 2021 May 28:12:680043.
doi: 10.3389/fphar.2021.680043. eCollection 2021.

The Therapeutic Landscape of Rheumatoid Arthritis: Current State and Future Directions

Shahin Shams  1 , Joseph M Martinez  2 , John R D Dawson  3 , Juan Flores  4 , Marina Gabriel  1 , Gustavo Garcia  1 , Amanda Guevara  2 , Kaitlin Murray  5 , Noah Pacifici  1 , Maxemiliano V Vargas  6 , Taylor Voelker  3 , Johannes W Hell  2 , Judith F Ashouri  7
Affiliations
Review

The Therapeutic Landscape of Rheumatoid Arthritis: Current State and Future Directions

Shahin Shams et al. Front Pharmacol. .

Abstract

Rheumatoid arthritis (RA) is a debilitating autoimmune disease with grave physical, emotional and socioeconomic consequences. 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. 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. 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. 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.

Keywords: JAK-STAT signaling; adenosine receptor; autoimmune disease; biological therapies; disease modifying anti-rheumatic drugs; inflammatory cytokines and chemokines; nanoparticles; rheumatoid arthritis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
MTX toxicity mechanism of action. Oligonucleotide synthesis is suppressed two-fold by MTXglu (methotrexate polyglutamate) via thymidylate synthase and dihydrofolate reductase inhibition.
FIGURE 2
FIGURE 2
MTX impact on adenosine secretion. MTX is polyglutamylated (MTXglu) after active transport of MXT into intracellular space. MTXglu inhibits AMP/adenosine deaminase (AMPDA/ADA respectively) and thus IMP/inosine production through accumulation of aminoimidazole carboxamidoribonucleotide (AICAR) and aminoimidazole carboxamidoribonucleoside (AICAside), the intermediate metabolites of purine biosynthesis. This results in increased cellular release of adenine nucleotides which are quickly converted into adenosine in the extracellular space. Adenosine triphosphate – ATP; adenosine diphosphate – ADP; adenosine monophosphate – AMP; adenylate deaminase – AMPDA; dihydrofolate polyglutamate - DHFglu; formyl AICAR - FAICAR; Inosine monophosphate – IMP; inosine triphosphate – ITP; inosine triphosphate pyrophosphatase – ITPA; reverse folate carrier 1 – RFC1; adenosine kinase – AK; nucleoside triphosphate phosphohydrolase – NTPDase; ecto-5’ nucleotidase – Ecto-5’ NT.
FIGURE 3
FIGURE 3
Adenosine receptors and their respective proinflammatory and anti-inflammatory responses upon extracellular adenosine binding. All adenosine receptors are a part of the G-protein coupled receptor family. Respective G-protein signaling partners are indicated on each subtype of adenosine receptor.
FIGURE 4
FIGURE 4
Select signaling pathways in RA. TNF-α signaling pathways required either TNFR1 or TNFR2 trimers. Signaling via TNFR1 pathway, upon TRADD binding without TNFR2, triggers cell death by either Casp-8 or MLKL. The recruiting of TRAF2 activates multiple signaling pathway cascade activation – including MAPK, NF-kB, and PKB. IL-6 signaling can occur through either mIL-6R classic signaling and of sIL-6R trans signaling. JAK activation occurs through both signaling mechanism and activating STAT and RAS/MAPK. IL-1 signaling through IL-1R1 via MyD88 which activates IRAK4 and subsequently IRAK1 bound to TRAF6 – leading to the activation of NFkB and AP1. IL-17 binds to an IL-17RA and IL-17RC receptor dimer. The SEFIR conserved signaling domain recruits Act1, which recruits TRAF6 and subsequently activates NF-kB, MAPK, and PI3K signaling pathways. IL-15 signaling can occur through JAK/STAT activation resulting in STAT3/STAT5 heterodimer formation, or activation through SHC which then results in activating MAPK and AKT. IL-12 signaling occurs through a heterodimer receptor consisting of IL-12Rβ1 and IL-12Rβ2 which activates JAK2 and TRK2 – leading to STAT4 dimer activation. IL-18 signaling results from the recruiting of MdD88 to the IL-18Rα and IL-18Rβ heterodimer, activating IRAK4 and thus TRAF6, which subsequently activates NF-kB and MAPK pathways. IL-4 signaling occurs the JAK/STAT activation via JAK1 and JAK3 binding to the IL-4Rα and common gamma-chain, respectively. IL-10 signal transduction results from both JAK1 binding to IL-10Rα and TYK2 binding to IL-10Rβ – which activates STAT3 in homodimer form.
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References

    1. Administration USFD (2020). New Drug Application (NDA): 009768, Original Approvals or Tentative Approvals. Silver Spring, MD: US Food and Drug Administration; Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview... (Accessed May 3, 2020).
    1. Ahmed M. S., Bae Y. S. (2016). Dendritic Cell-Based Immunotherapy for Rheumatoid Arthritis: from Bench to Bedside. Immune Netw. 16, 44–51. 10.4110/in.2016.16.1.44 - DOI - PMC - PubMed
    1. Akira S., Hirano T., Taga T., Kishimoto T. (1990). Biology of Multifunctional Cytokines: IL 6 and Related Molecules (IL 1 and TNF). FASEB J. 4, 2860–2867. 10.1096/fasebj.4.11.2199284 - DOI - PubMed
    1. Alamanos Y., Drosos A. (2005). Epidemiology of Adult Rheumatoid Arthritis. Autoimmun. Rev. 4, 130–136. 10.1016/j.autrev.2004.09.002 - DOI - PubMed
    1. Albrecht K., Müller-Ladner U. (2010). Side Effects and Management of Side Effects of Methotrexate in Rheumatoid Arthritis. Clin. Exp. Rheumatol. 28, S95–S101. - PubMed