Affecting the effectors: JAK inhibitors modulation of immune cell numbers and functions in patients with rheumatoid arthritis

ABSTRACT

Introduction

The Janus kinase family includes four members – JAK1, JAK2, JAK3, TYK2 - that are selectively associated with type I and II cytokine receptors. Jak-inhibitors (Jakinibs) are a new class of drugs for treating inflammatory diseases. Five Jakinibs are currently available for Rheumatoid Arthritis (RA): tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib. Considering the role of cytokines and growth factors in immune cell survival and activation, the anti-proliferative and suppressive effects of Jakinibs on these cells are predictable.

Areas covered

This review summarizes Jakinibs’ effects on immune populations in vitro and in vivo. In vitro, Jakinibs affected T and B lymphocytes, monocytes, neutrophils and dendritic cell proliferation. T helper, B cell differentiation, and cytokine secretion . Accordingly, changes in the number of lymphocytes, natural killer (NK) cells, and neutrophils have been reported during the randomized clinical trials with all the Jakinibs, reverting after drug withdrawal.

Expert opinion

In vitro and in vivo studies showed that the numbers and the function of immune cells are influenced by Jakinibs. Nonetheless, their effects do not seem to represent a major safety issue as these changes do not correlate with the onset of serious infection despite the increased rates of herpes zoster reactivation.

KEYWORDS:

• Adaptive immunity
• immune cells
• innate immunity
• JAK-STAT
• Jakinibs
• rheumatoid arthritis

Highlights

• Distinct pairs of JAKs are associated with cytokine receptors; since JAK proteins are shared among receptors, inhibiting a specific JAK could alter the signaling of several different cytokine receptors at the same time.

• The role of the JAK-STAT pathway in lymphocyte development, proliferation, and myelopoiesis accounts for the changes in immune cell number and function detectable upon Jakinib administration both in vitro and in vivo.

• In vivo, the effects of Jakinibs on immune cells are reversible upon drug discontinuation; although the duration of immunosuppression does not coincide with drug elimination, the short half-life of Jakinibs allows for a shorter withhold in case of infections or procedures at risk of infections.

• The changes in number and function of innate and adaptive immune cells does not seem to correlate with serious infectious adverse events in patients treated with Jakinibs; the effect of JAK inhibition on tumorigenesis and cardiovascular/thrombotic risk remains to be determined.

Declaration of interest

C Garufi declares speaker fees from Eli Lilly. F R Spinelli declares research grants from Pfizer, speaker fees from Eli Lilly and Galapagos. The authors have no other 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 apart from those disclosed.

Conflict of interest

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

Additional information

Funding

This paper was not funded.