Abstract
The development of biological disease-modifying antirheumatic drugs (bDMARDs) and target synthetic DMARDs (tsDMARDs), also known as small molecule inhibitors, represent a breakthrough in rheumatoid arthritis (RA) treatment. The tsDMARDs are a large family of small molecules targeting mostly the several types of kinases, which are essential in downstream signaling of pro-inflammatory molecules. This review highlights current challenges associated with the treatment of RA using small molecule inhibitors targeting intracellular JAKs/MAPKs/NF-κB/SYK-BTK signaling pathways. Indeed, we have provided the latest update on development of small molecule inhibitors, their clinical efficacy and safety as a strategy for RA treatment. On the other hand, we have highlighted the risk and adverse effects of tsDMARDs administration including, among others, infections and thromboembolism. Therefore, performance of blood tests or viral infection screening should be recommended before the tsDMARDs administration. Interestingly, recent events of SARS-CoV-2 outbreak have demonstrated the potential use of small molecule inhibitors not only in RA treatment, but also in fighting COVID-19 via blocking the viral entry, preventing of hyperimmune activation and reducing cytokine storm. Thus, small molecule inhibitors, targeting wide range of pro-inflammatory singling pathways, may find wider implications not only for the management of RA but also in the controlling of COVID-19.
Highlights
Rheumatoid arthritis (RA) is an aggressive immune-mediated disease with a worldwide prevalence of approximately 0.5–1% of population
The canonical pathway responds to diverse stimuli, including ligands of cytokine receptors, pattern recognition receptors (PRRs), TNF receptor superfamily (TNFRSF), T-cell receptor (TCR) and
As spleen tyrosine kinase (SYK) functions as a key molecule in B cell receptor signaling, while Bruton’s tyrosine kinase (BTK) is fundamental for regulation of B cell proliferation and activation process; both kinases were proposed as therapeutic target in rheumatoid arthritis (RA) treatment [28]
Summary
Rheumatoid arthritis (RA) is an aggressive immune-mediated disease with a worldwide prevalence of approximately 0.5–1% of population. In 2012 FDA approved new class of targeted synthetic DMARDs (tsDMARDs), which were developed to target a particular molecular structure This class of drugs is known as small molecule inhibitors. Rheumatism (EULAR) guidelines have recommend the use of bDMARDs and tsDMARDs to treat patients with moderate-to-severe disease activity [5] These treat-to-target medicines are usually recommended only for patients that do not respond to methotrexate or other conventional synthetic DMARDs (csDMARDs), due to high cost of treatment. “cell survival” pathway are probably responsible for the apoptosis resistance, characteristic for RA inflamed synovial tissue [8] Molecules building these signaling pathways attractive targets for the building development new therapies on RA inflamed synovialbecome tissue [8]. The red rectangles, tsDMARDs are terminated are highlighted byrectangles the whitewith rectangles dashed line
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