JAK inhibitors for rheumatoid arthritis

ABSTRACT

Introduction

JAK (Janus kinase) is a type of non-receptor tyrosine kinase that includes JAK1, JAK2, JAK3, and Tyk2. Currently, there are five JAK inhibitors approved for treating rheumatoid arthritis. These inhibitors vary in their selectivity for different JAK isoforms.

Area covered

This review outlines the mode of actions and the results of Phase III trials of the JAK inhibitors which have been approved for the treatment of rheumatoid arthritis.

Expert commentary

JAK inhibitors have the potential to finely tune immunity and inflammation in patients with rheumatoid arthritis. The in vitro data indicates that IL-6 signaling is suppressed by all JAK inhibitors, while tofacitinib exhibits the most extensive suppression of cytokines via the JAK pathway. Peficitinib suppresses common gamma cytokines, and filgotinib suppresses interferon. Furthermore, baricitinib and upadacitinib appear to be inclined toward suppressing interferon and the IL-12 family. Despite their specific target profiles, any of these drugs can inhibit other JAKs if their blood levels surpass a certain threshold. As a result, predicting in vivo selectivity remains a challenging task. JAK inhibitor seems to be a vital treatment option for difficult-to-treat rheumatoid arthritis patients, and it is expected that precision medicine approaches will enhance its effectiveness in the future.

KEYWORDS:

• JAK-STAT pathway
• JAK inhibitor
• tofacitinib
• baricitinib
• peficitinib
• upadacitinib
• filgotinib

Article highlights

• The JAK selectivity varies among the five JAK inhibitors.

• Any of the JAK inhibitors are as effective or even more effective than biologics.

• The ORAL surveillance study reported higher incidence rates of both MACE and cancer in patients treated with JAK inhibitors compared to TNF inhibitors in patients over 65 years old.

• The mechanism by which JAK inhibitors may increase the risk of MACE or cancer is currently unknown from an immunological standpoint.

• It is crucial to conduct proactive screening for the risks of major adverse cardiovascular events (MACE) and malignancy before prescribing JAK inhibitors.

Declaration of interest

S. Kubo has received consulting fees, speaking fees, and/or honoraria from Eli Lilly, Bristol-Myers, GlaxoSmithKline, and research grants from Daiichi-Sankyo, AbbVie, Boehringer Ingelheim, and Astellas. S. Nakayamada has received consulting fees, speaking fees, and/or honoraria from Bristol-Myers, AstraZeneca, Pfizer, GlaxoSmithKline, Astellas, Asahi-Kasei, Sanofi, AbbVie, Eisai, Chugai, Gilead, Boehringer Ingelheim and has received research grants from Mitsubishi-Tanabe. Y. Tanaka has received speaking fees and/or honoraria from Behringer-Ingelheim, Eli Lilly, AbbVie, Gilead, AstraZeneca, Bristol-Myers, Chugai, Daiichi-Sankyo, Eisai, Pfizer, Mitsubishi-Tanabe, GlaxoSmithKline, received research grants from Asahi-Kasei, AbbVie, Chugai, Eisai, Takeda, Daiichi-Sankyo, Boehringer-Ingelheim.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

SK contributed to the overall review and writing of the manuscript. SN and YT participated in the overall review. All authors read and approved the final manuscript.

Additional information

Funding

This manuscript was funded by JSPS KAKENHI Grant Numbers 19K17919 and 20K08815.