J Rheum Dis.  2012 Jun;19(3):118-124. 10.4078/jrd.2012.19.3.118.

Small Molecule Inhibitors in Rheumatoid Arthritis

• Lee EB

• KMID: 2223092
• DOI: http://doi.org/10.4078/jrd.2012.19.3.118

Abstract

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease predominantly affecting diarthroidal joints. Following the successful application of biologic agents, several small molecule inhibitors are currently under clinical trials. Small molecule inhibitors have several strengths compared with biologics. First, they can target several inflammatory cytokines together by blocking common signal transduction pathways. Second, they can be taken orally. Third, the price can be made flexible. Among the several small molecule inhibitors in the development process, fostamatinib and tofacitinib are the closest to the clinics at the moment. Fostamatinib, which is a Syk inhibitor, showed superior efficacy over placebo with tolerable safety signals. Diarrhea, hypertension and infection are representative adverse events. Tofacitinib, which is JAK inhibitor, is now finishing phase 3 clinical trials. It showed clinical efficacy comparable to Adalimumab and similar adverse effect profiles to the biologics, which include opportunistic infections. For laboratory abnormalities, leukopenia, anemia, increase of LDL and serum Cr were reported, which, however, were stabilized with prolonged use. Other classes of small molecule inhibitors did not show impressive efficacy as these small molecule inhibitors. In conclusion, small molecule inhibitors are promising novel therapeutic agents for the treatment of RA. They will be able to change the treatment paradigm of RA if they can show long-term safety.

Keyword

Rheumatoid arthritis; Small molecule inhibitor

MeSH Terms

Anemia
Antibodies, Monoclonal, Humanized
Arthritis, Rheumatoid
Biological Agents
Cytokines
Diarrhea
Hypertension
Joints
Leukopenia
Opportunistic Infections
Oxazines
Piperidines
Pyridines
Pyrimidines
Pyrroles
Signal Transduction
Antibodies, Monoclonal, Humanized
Biological Agents
Cytokines
Oxazines
Piperidines
Pyridines
Pyrimidines
Pyrroles
Adalimumab

Figure

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  Figure 1 Pathogenesis of rheumatoid arthritis.

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  Figure 2 Signal transduction of Syk.

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  Figure 3 Janus activated kinase inhibitors.

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