JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines

Danese, Silvio; Grisham, Matthew B.; Hodge, Jennifer; Telliez, Jean‐Baptiste

doi:10.1152/ajpgi.00311.2015

Cited by 150 publications

(103 citation statements)

References 82 publications

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“…Tofacitinib is a potent inhibitor of JAK1 and JAK3. 14 A phase II study, 15 and two identical phase III studies, 16 demonstrated that patients with moderately to severely active UC receiving tofacitinib were more likely to achieve remission at 8 weeks than those receiving placebo. A previous 4-week phase II study, carried out in patients with moderate-to-severe CD, did not show efficacy for tofacitinib 1, 5 or 15 mg twice daily in inducing clinical response; however, a surprisingly high placebo response was observed.…”

Section: Significance Of This Studymentioning

confidence: 99%

Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials

Panés

Sandborn

Schreiber

et al. 2017

Gut

310

220

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ObjectiveTofacitinib is an oral, small-molecule Janus kinase inhibitor that is being investigated for IBD. We evaluated the efficacy and safety of tofacitinib for induction and maintenance treatment in patients with moderate-to-severe Crohn's disease (CD).DesignWe conducted two randomised, double-blind, placebo-controlled, multicentre phase IIb studies. Adult patients with moderate-to-severe CD were randomised to receive induction treatment with placebo, tofacitinib 5 or 10 mg twice daily for 8 weeks. Those achieving clinical response-100 or remission were re-randomised to maintenance treatment with placebo, tofacitinib 5 or 10 mg twice daily for 26 weeks. Primary endpoints were clinical remission at the end of the induction study, and clinical response-100 or remission at the end of the maintenance study.Results180/280 patients randomised in the induction study were enrolled in the maintenance study. At week 8 of induction, the proportion of patients with clinical remission was 43.5% and 43.0% with 5 and 10 mg twice daily, respectively, compared with 36.7% in the placebo group (p=0.325 and 0.392 for 5 and 10 mg twice daily vs placebo). At week 26 of maintenance, the proportion of patients with clinical response-100 or remission was 55.8% with tofacitinib 10 mg twice daily compared with 39.5% with tofacitinib 5 mg twice daily and 38.1% with placebo (p=0.130 for 10 mg twice daily vs placebo). Compared with placebo, the change in C-reactive protein from baseline was statistically significant (p<0.0001) with 10 mg twice daily after both induction and maintenance treatments.ConclusionsPrimary efficacy endpoints were not significantly different from placebo, although there was evidence of a minor treatment effect. No new safety signals were observed for tofacitinib.Trial registration numbersNCT01393626 and NCT01393899.

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Section: Significance Of This Studymentioning

confidence: 99%

Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials

Panés

Sandborn

Schreiber

et al. 2017

Gut

310

220

View full text Add to dashboard Cite

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“…Inflammatory bowel disease (IBD) is an intricate multifactorial, chronic, and relapsing disease that involves inflammation of the gastrointestinal tract [1, 2]. It comprises ulcerative colitis (UC) and Crohn’s disease (CD) triggered through various genetic and environmental elements [3–5].…”

Section: Introductionmentioning

confidence: 99%

Disruption of GPR35 Exacerbates Dextran Sulfate Sodium-Induced Colitis in Mice

Farooq

Hou

et al. 2018

Dig Dis Sci

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“…In mammals, four JAK families of enzymes (JAK1, JAK2, JAK3 and tyrosine kinase 2) and seven STAT family members (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6) are employed by over 50 cytokines and growth factors to mediate intracellular signalling . Janus kinase inhibitors are being developed and utilized for the treatment of a variety of inflammatory, autoimmune and haematological disorders in humans …”

Section: Introductionmentioning

confidence: 99%

Immunomodulatory in vitro effects of oclacitinib on canine T‐cell proliferation and cytokine production

Banović

Tarigo

Gordon

et al. 2018

Veterinary Dermatology

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Background Oclacitinib is a Janus kinase inhibitor used to control pruritus and skin lesions in canine allergic skin disease; its effect on canine T cells is not well‐characterized. Hypothesis/Objectives To evaluate the impact of oclacitinib on cultured T cells using peripheral blood mononuclear cells from dogs. Animals Six bluetick coonhounds. Methods and materials Lymphocyte‐enriched cells were incubated with or without the T‐cell mitogen concanavalin A (Con A), oclacitinib (0.5, 1 or 10 μM), ciclosporin (200 ng/mL), Con A + oclacitinib 1 μM and Con A + ciclosporin. We assessed both T‐cell proliferation and the secretion of cytokines. Results Ciclosporin and oclacitinib both inhibited the spontaneous proliferation of T cells; this effect was significant only after incubation with oclacitinib at 10 μM. At this concentration, oclacitinib significantly reduced the spontaneous secretion of clonal activator cytokines [interleukin (IL)‐2, IL‐15], pro‐inflammatory cytokines (interferon‐gamma (IFN‐γ), IL‐18) and the regulatory cytokine IL‐10; tumour necrosis factor alpha (TNF‐α) and IL‐6 cytokine production was mildly inhibited. After Con A stimulation, only T cells co‐treated with ciclosporin achieved a significant proliferation inhibition and reduction of IL‐2, IL‐10, IL‐15, IL‐18, IFN‐γ and TNF‐α. Surprisingly, oclacitinib at 1 μM (337 ng/mL, corresponding to the oral dosage of 0.4–0.6 mg/kg) did not significantly affect Con A‐stimulated T‐cell proliferation nor cytokine production (IL‐2, IL‐10, IL‐15, IL‐18, IFN‐γ and TNF‐α). Conclusions Although a limited number of dogs were investigated, these preliminary results suggest that oclacitinib appears to have immunosuppressive properties, but only at dosages above those used to treat allergic pruritus in dogs.

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JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines

Abstract: Danese S, Grisham M, Hodge J, Telliez J-B. JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines.

Cited by 150 publications

References 82 publications

Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials

Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials

Disruption of GPR35 Exacerbates Dextran Sulfate Sodium-Induced Colitis in Mice

Immunomodulatory in vitro effects of oclacitinib on canine T‐cell proliferation and cytokine production

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