JAK inhibitors and infections risk: focus on herpes zoster

Abstract

Currently, there is a growing interest in Janus kinase (JAK) intracellular signalling since targeted inhibitors against these pathways are proving effective in the treatment of a range of immune-mediated diseases, such as rheumatoid arthritis (RA), psoriasis, psoriatic arthritis (PsA), inflammatory bowel disease and atopic dermatitis. In particular, post marketing experience and the increasing development of new pharmacological inhibitors of broad and increasingly selective JAK pathways provide new insights into the JAK pathway role in viral infections as well as their pathogenic role in immune-mediated inflammatory diseases. Herein we provide an overview of the biological role of JAK signalling and its role in immunity against viruses, with particular regard to herpes zoster reactivation. Thereafter, we will discuss the evidence currently available on the principal JAK inhibitors and their association with viral infections.

Filgotinib, a novel JAK1-preferential inhibitor for the treatment of rheumatoid arthritis: An overview from clinical trials

“…As more treatment options become available, the question of how different jakinibs might compare with one another becomes increasingly pertinent for guiding clinical decisions. In an attempt to address this, some recent publications tabulated, side-by-side, the efficacy and safety data of different jakinibs from their respective phase 2/3 trials that were not done head-to-head [2,8,38]. Of course, such comparisons are tenuous at best.…”

“…Potentially serious events such as malignancy and thromboembolic events have also been reported with jakinibs. Side-by-side tabulation of across-trial data, which it is important to note were not head-to-head comparisons have suggested that filgotinib might have lower incidence rates of herpes zoster infection and venous thrombotic events than other jakinibs approved to date [8,38]. Nevertheless, as mentioned above, whether filgotinib has a more favorable safety profile remains to be demonstrated definitively and at this stage should be considered with caution in clinical practice.…”

“…These JAK isoforms form homo-and hetero-dimers and one heterotrimer that facilitate the signal transduction of various type I/II cytokines and growth factors implicated in inflammatory and hematopoietic pathways (Figure 1) [6,7]. Remarkable signaling versatility and complexity arise from the array of JAK dimers, as well as the numerous 'cytokine-JAK dimer-signal transducer and activator of transcription (STAT) effector' combinations, which present both opportunities and challenges in the endeavor of treating RA through JAK inhibition [6,8]. For example, JAK1 inhibition may simultaneously block the signaling of IL-6 and IFNa, both of which are implicated in RA pathology.…”

A comparison of Janus kinase inhibitor safety in rheumatoid arthritis

“…Reactivation of the varicella‐zoster virus had been observed with all JAKi studied in the treatment of RA 4 . The incidence of herpes zoster with JAKi appears to be higher than with either csDMARDs or bDMARDs 31 . Reactivation of the varicella‐zoster virus is thought to be a class effect caused by the inhibition of the anti‐viral cytokines interferon and interleukin‐15, which signal through JAK1, JAK2, and JAK3 (Table 8).…”

How important is JAK1 selectivity?

“…For the scientist, new therapies can increase understanding of the importance of particular cytokines in disease. For example, the reliance of IFNs on JAK signalling pathways is highlighted by the increased incidence of infections such as herpes zoster associated with many JAKis [ 3 ]. Several questions remain about JAKis in general and JAK1 selective inhibitors specifically.…”