Novel small-molecular therapeutics for rheumatoid arthritis

Curr Opin Rheumatol. 2012 May;24(3):335-41. doi: 10.1097/BOR.0b013e32835190ef.


Purpose of review: Since the introduction of biologic therapies into the treatment paradigm of rheumatoid arthritis (RA), there has been hope that oral small molecule immune modulators would be developed that would have a risk : benefit profile at least similar to biologic therapies, be more convenient for the patient and, hopefully, be less expensive. This article reviews the progress made in the development of these compounds over the past year.

Recent findings: Additional information has become available in the past year on five oral compounds including kinase inhibitors (tofacitinib, fostamatinib, VX-509), an S1P lyase inhibitor (LX 3305) and a chemokine receptor-1 antagonist (CCX354-C). Efficacy has been shown in phase III with tofacitinib and in phase II with fostamatinib and VX-509; safety was the primary endpoint of the trials of CCX354-C and LX3305. Regarding side effects, liver test elevation and neutropenia occurred with tofacitinib, VX-509 and fostamatinib; lipid elevation with tofacitinib and VX-509; creatinine elevation and anemia with tofacitinib, and hypertension and diarrhea with fostamatinib.

Summary: Compounds that inhibit tyrosine kinase pathways involved in cellular signalling have been shown to be effective in the treatment of RA with a reasonable risk : benefit ratio. It is too early to tell about inhibitors of other pathways.

Publication types

  • Review

MeSH terms

  • Aminopyridines
  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Rheumatoid / drug therapy*
  • Humans
  • Janus Kinases / antagonists & inhibitors
  • Molecular Targeted Therapy / methods
  • Morpholines
  • Oxazines / therapeutic use
  • Piperidines
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Pyridines / therapeutic use
  • Pyrimidines / therapeutic use
  • Pyrroles / therapeutic use


  • Aminopyridines
  • Antirheumatic Agents
  • Morpholines
  • Oxazines
  • Piperidines
  • Protein Kinase Inhibitors
  • Pyridines
  • Pyrimidines
  • Pyrroles
  • tofacitinib
  • Protein-Tyrosine Kinases
  • Janus Kinases
  • fostamatinib