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Fate of lymphocytes after withdrawal of tofacitinib treatment.

ABSTRACT: Tofacitinib (Tofa) is an inhibitor of Janus Kinase 3, developed for the treatment of autoimmune diseases and for the prevention of transplant rejection. Due to its selective action on proliferating cells, Tofa can offer a way to block T cell activation, without toxic effects on resting cells. However, few studies have investigated the effects of Tofa on lymphocyte activation in vitro. Our aim was to study the action of Tofa on different lymphocyte subsets after in vitro stimulation and to track the behaviour of treated cells after interruption of the treatment. Peripheral blood lymphocytes were stimulated in vitro with mitogen and treated with two concentrations of Tofa. After a first period in culture, cells were washed and further incubated for an additional time. Lymphocyte subsets, activation phenotype and proliferation were assessed at the different time frames. As expected, Tofa was able to reduce the activation and proliferation of lymphocytes in the first four days of treatment. In addition the drug led to a relative decrease of Natural Killer, B cells and CD8 T cells compared to CD4 T cells. However, treated cells were still viable after the first period in culture and begun to proliferate, strikingly, in a dose dependent manner when the drug was removed from the environment by replacing the culture medium. This novel data does not necessarily predict a similar behaviour in vivo, but can warn about the clinical use of this drug when a discontinuation of treatment with Tofa is considered for any reason.

SUBMITTER: Piscianz E

PROVIDER: S-EPMC3887061 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Fate of lymphocytes after withdrawal of tofacitinib treatment.

Piscianz Elisa E Valencic Erica E Cuzzoni Eva E De Iudicibus Sara S De Lorenzo Elisa E Decorti Giuliana G Tommasini Alberto A

PloS one 20140109 1

Tofacitinib (Tofa) is an inhibitor of Janus Kinase 3, developed for the treatment of autoimmune diseases and for the prevention of transplant rejection. Due to its selective action on proliferating cells, Tofa can offer a way to block T cell activation, without toxic effects on resting cells. However, few studies have investigated the effects of Tofa on lymphocyte activation in vitro. Our aim was to study the action of Tofa on different lymphocyte subsets after in vitro stimulation and to track ...[more]

PMID: 24416411

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Project description:IntroductionThe objective of this analysis was to assess disease activity metrics using a variety of disease outcome measures following methotrexate (MTX) withdrawal in ORAL Shift, a phase 3b/4 study of tofacitinib with/without MTX, in patients with rheumatoid arthritis (RA) achieving Clinical Disease Activity Index (CDAI)-defined low disease activity (LDA).MethodsPatients aged ≥ 18 years with active RA and an inadequate response to MTX received open-label tofacitinib modified-release 11 mg once daily plus MTX for 24 weeks. In the double-blind MTX withdrawal phase, those who had achieved CDAI LDA (≤ 10) at week 24 were randomised 1:1 to receive tofacitinib monotherapy or continued tofacitinib plus MTX. Efficacy analyses were performed in subgroups defined by whether remission and/or LDA had been achieved at week 24 with: Disease Activity Score in 28 joints, erythrocyte sedimentation rate [DAS28-4(ESR)], Routine Assessment of Patient Index Data 3 (RAPID3), CDAI and Simplified Disease Activity Index (SDAI); or DAS28-4[C-reactive protein(CRP)] < 2.4/ < 2.6/ < 2.9/ ≤ 3.2.ResultsFive hundred and thirty patients received treatment in the double-blind MTX withdrawal phase. Proportions of patients achieving each disease activity criterion at week 24 varied by metric. Across disease activity metrics [excluding DAS28-4(ESR) remission], 58-89% of patients per group, and numerically more patients receiving tofacitinib plus MTX, achieved the same criterion at week 48 as at week 24. Differences between groups in least squares mean change from baseline (Δ) DAS28-4(ESR) from week 24-48 favoured tofacitinib plus MTX (nominal p values < 0.05). RAPID3 and DAS28-4(CRP) estimated a higher proportion of patients with acceptable disease state versus DAS28-4(ESR), CDAI remission and SDAI remission.ConclusionResponse rates at the beginning of the double-blind phase varied across metrics. A consistent trend towards higher response rates with tofacitinib plus MTX was observed across metrics after randomisation, with nominal differences in DAS28-4(ESR) responses. Compared with continued combination therapy, MTX withdrawal did not lead to a clinically meaningful reduction in the response to tofacitinib. DAS28-4(CRP) and RAPID3 were the least stringent metrics.Trial registrationClinicalTrials.gov identifier: NCT02831855.

Dataset Information

Fate of lymphocytes after withdrawal of tofacitinib treatment.

Publications

Fate of lymphocytes after withdrawal of tofacitinib treatment.

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