Tyrosine kinase inhibitors for the treatment of rheumatoid arthritis: phase I to Ⅱ clinical trials

ABSTRACT

Introduction: Rheumatoid arthritis (RA) is a chronic, refractory disorder caused by autoimmunity in the synovial joints. Disease-modifying anti-rheumatic drugs (DMARDs) and biologicals offer remission in only two-thirds of RA patients within 3 months, hence new therapeutic approaches are necessary. Tyrosine kinase inhibitors (TKIs) are newly developed small molecule drugs which have demonstrated encouraging results in this disease.

Areas covered: The key findings from phase I and II clinical trials that have investigated the use of novel TKIs in the treatment of RA are discussed. We examined the literature published between January 2014 to January 2019 using electronic databases including PubMed, Web of Science, Medline, Embase, and Google Scholar. Additional information about phase I and II trials on the ClinicalTrial.gov website up to January 2019 was also retrieved.

Expert opinion: JAK inhibitors are promising drugs with sound efficacy and acceptable safety and may be beneficial to patients who do not respond to DMARDs and biologicals. The response rates among RA patients to TKIs are diverse; genetic and environmental factors may be involved in the varying responses which are closely related to the pathogenesis of RA. Future studies may reveal the underlying mechanisms of resistance and non-response.

KEYWORDS:

• Rheumatoid arthritis
• disease-modifying anti-rheumatic drugs
• tyrosine kinase inhibitor
• Janus kinase
• Bruton’s tyrosine kinases
• spleen tyrosine kinases

Article Highlights

• Tyrosine kinase inhibitors (TKIs) are newly developed small molecule drugs that have demonstrated clinical benefits in the treatment of rheumatoid arthritis (RA) in phase I and II trials.

• TKIs have therapeutic potential for RA patients who are unresponsive to disease-modifying antirheumatic drugs (DMARDs) and biological agents.

• Numerous Bruton tyrosine kinases (BTK) inhibitors are being developed for the treatment of RA.

• JAK inhibitors have showed robust effecacies in the treatment of RA and have an acceptable safety profile.

• Clinical trials assessing numerous spleen tyrosine kinase (SYK) inhibitors have been terminated because of infection or undisclosed reasons.

• Genetic and environmental factors may be involved in the various responses to TKIs which are also closely related to the pathogenesis of RA. Future studies are required to reveal the underlying mechanisms of the resistance and non-response to TKIs.

This box summarizes the key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One peer reviewer has received research support and/or honoraria from Mitsubishi-Tanabe Pharma, Glaxo-Smithkline, Pfizer, Teijin Pharma, Eisai Pharma, Chugai Pharma, Asahi-kasei Pharma Corp. Ono Pharma. Abbvie, Takeda Industrial Pharma, Astellas Pharma Inc, Bristol-Myers Squibb, Eli lilly Japan, Janssen Pharma, Actelion Pharmaceuticals Japan, Otsuka Pharma, Nippon Shinyaku, Gilead G.K, Daiichi-Sankyo, Boehringer Ingelheim Japan. Japan Tobacco Inc. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

Additional information

Funding

The work of the authors is funded by Clinical Research Startup Program of Southern Medical University by High-level University Construction Funding of Guangdong Provincial Department of Education LC2019ZD015 and National Natural Science Foundation of China 81773532.