Immunomodulatory effect of long‐term oclacitinib maleate therapy in dogs with atopic dermatitis

Abstract

Background -Canine atopic dermatitis (cAD) is a chronic disease characterised by hypersensitivity to environmental allergens. Oclacitinib maleate selectively inhibits pro-inflammatory mediators associated with cAD. However, the impact of chronic oclacitinib use on immunocompetence requires further investigation.Objectives -Herein, we examined the potential immunomodulatory effects of prolonged oclacitinib treatment in dogs.Animals -Thirteen privately owned dogs with cAD, treated with 0.4-0.6 mg/kg oclacitinib for 12 months.Methods and materials -Pruritus level was evaluated using a pruritus Visual Analog Scale (pVAS) and the canine atopic dermatitis extent and severity index, 4 th iteration (CADESI IV). Peripheral blood samples were collected for routine laboratory assays and lymphocyte subtypes were analysed using flow cytometry. Antigenspecific intracellular cytokine production from CD4+ and CD8+ T lymphocytes was analysed following in vitro stimulation by Dermatophagoides farinae antigens.Results -Oclacitinib treatment significantly reduced pVAS and CADESI-04 scores, by 51% and 86.7%, respectively. Flow cytometric analysis revealed increased CD4+ and CD14+ lymphocyte populations. The cytokine profile at 360 days after treatment initiation was similar to that before treatment and was not associated with clinical relapse.Conclusion -Oclacitinib, when administered at the currently labelled dose for one year, is associated with a significant increase in circulating CD4+ T cells, but does not alter cytokine production from antigen-stimulated T cells. The results reported do not support evidence for immunosuppression mediated by the mechanisms evaluated in this study.

Long‐term effects of ciclosporin and oclacitinib on mediators of tolerance, regulatory T‐cells, IL‐10 and TGF‐β, in dogs with atopic dermatitis

“…A single in vitro study showed no effect on cytokine production with oclacitinib at therapeutical concentration for canine AD 38 . A 12 months in vivo study with oclacitinib in atopic dogs showed no effect on the numbers of CD4+IL‐4+ and CD4+IFN‐β+ cells 37 . With oclacitinib preferably inhibiting JAK1, it could be theorised that the previously shown lack of effect on IL‐4 (signalling via JAK1 and JAK3) and IFN‐ (signalling via JAK1 and JAK2) production also could be extrapolated to IL‐2 (signalling via JAK1 and JAK3) and IL‐10 production (signalling via JAK1 and TYK2) 36 .…”

“…In dogs, two recent in vivo studies showed a reduction between pre‐ and post‐treatment percentages of Treg cells in dogs receiving an 8 day (20 mg/kg/day) and a 90 day (5 mg/kg/day) course of CSA, respectively 34,35 . These changes were, however, not statistically significant 36,37 . Suppressive effects of CSA on T‐cell proliferation and IL‐10 production in dogs were shown in vitro and in vivo, 38,39 although the in vivo study was performed only with high dosages (20 mg/kg/day) of CSA.…”

“…Studies and conclusive results about the effect of oclacitinib on Treg cells or T cells in general are limited in veterinary medicine. Only one in vivo study evaluated the long‐term usage of an approved oclacitinib dose in atopic dogs and showed a slight increase of CD4+ cells, yet Treg cells were not specifically measured 37 . In vitro studies on the effect of approved dosages of oclacitinib on T cells showed no effect on proliferation and CD25 and FOXP3 expression, although a cytoreductive effect on CD4+ and CD8+ cells was noted 38,42 .…”

“…34,35 These changes were, however, not statistically significant. 36,37 Suppressive effects of CSA on T-cell proliferation and IL-10 production in dogs were shown in vitro and in vivo, 38,39 although the in vivo study was performed only with high dosages (20 mg/ kg/day) of CSA. Conflicting results also were reported in studies with atopic humans in which a low-dose CSA treatment resulted in an increase or decrease in Treg cell counts.…”

A Comprehensive Overview of Globally Approved JAK Inhibitors

“…Banovic et al [ 134 ] have reported an immunosuppressive effect of oclacitinib in dogs when used at a dose higher than that used in the treatment of allergic pruritus. However, an increase in CD4+ lymphocyte populations in dogs was observed after long-term treatment with oclacitinib [ 135 ].…”