A study on the risk of fungal infection with tofacitinib (CP-690550), a novel oral agent for rheumatoid arthritis

Abstract

Tofacitinib (CP-690550), an oral Janus kinase inhibitor, has shown significant efficacy in the treatment of rheumatoid arthritis through blocking the signaling pathways of pro-inflammatory cytokines. However, recent evidence suggests that long-term tofacitinib treatment is associated with increased risk of infection (e.g. tuberculosis) in patients. In the present study, we illustrate that tofacitinib administration significantly reduced the survival rate of mice given lethal or sub-lethal dose challenge with Candida albicans. This was related to the ability of tofacitinib to reverse TNFα- and IFNγ-enhanced candidacidal activity of murine polymorph nuclear cells (PMNs) and also to suppress chemokine CXCL5 expression and PMN infiltration in the infected tissues of mice. More importantly, tofacitinib significantly antagonized the ability of TNFα, IFNγ and GM-CSF to boost human PMNs in phagocytosis and direct killing of C. albicans in vitro. It also down-regulated reactive oxygen production and neutrophil extracellular trap formation by human PMNs stimulated with yeast-derived β-glucans in the presence of TNFα, IFNγ or GM-CSF. Our data emphasizes a significantly increased risk for opportunistic fungal infection associated long-term tofacitinib treatment in humans, likely through antagonizing the PMN-boosting effect of pro-inflammatory cytokines.

Cytologic identification of fungal arthritis in a Labrador Retriever with disseminated Talaromyces helicus infection

“…In people, Janus kinase inhibitors modulate cytokine expression and immune responses and are associated with an increased risk of infections, such as tuberculosis . In laboratory studies, survival was reduced in mice receiving tofacitinib (another Janus kinase inhibitor) compared with the control population, when challenged with Candida albicans . There is currently no evidence in the veterinary literature definitively linking oclacitinib administration to an increase in infections, but the manufacturer's label does advise monitoring for development of infections while taking the drug.…”

Risks of Ruxolitinib in STAT1 Gain-of-Function-Associated Severe Fungal Disease

“…However, mouse models show conflicting data on the effect of JAK inhibitors in invasive candidiasis [17, 18]. In 1 study, tofacitinib was associated with reduced survival [17].…”

“…However, mouse models show conflicting data on the effect of JAK inhibitors in invasive candidiasis [17, 18]. In 1 study, tofacitinib was associated with reduced survival [17]. In a different study, administration of ruxolitinib 50 mg/kg/d starting a day before Candida injection was associated with reduced survival, but administration of 6.25 mg/kg/d beginning on the second day of the infection was associated with increased survival [18].…”

Small-Molecule Protein Kinases Inhibitors and the Risk of Fungal Infections

“…Cytokine balance plays a pivotal role in adaptive and innate immune defences against fungal infections. JAK inhibition downregulates cytokine signalling, decreasing the activation and infiltration of NK cells and macrophages into infected tissues and impacting subsequent phagocytic activity [39]. IFN-γ cytokine secretion generates a proinflammatory and microbicidal environment.…”