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Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled, dose-ranging study.

ABSTRACT: OBJECTIVES:To compare efficacy and safety of various doses of tofacitinib, an oral Janus kinase inhibitor, with placebo in patients with active ankylosing spondylitis (AS, radiographic axial spondyloarthritis). METHODS:In this 16-week (12-week treatment, 4-week washout), phase II, multicentre, dose-ranging trial, adult patients with active AS were randomised (N=51, 52, 52, 52, respectively) to placebo or tofacitinib 2, 5 or 10?mg twice daily. The primary efficacy endpoint was Assessment of SpondyloArthritis International Society 20% improvement (ASAS20) response rate at week 12. Secondary endpoints included objective measures of disease activity, patient-reported outcomes and MRI of sacroiliac joints and spine. Safety was monitored. RESULTS:Emax model analysis of the primary endpoint predicted a tofacitinib 10?mg twice daily ASAS20 response rate of 67.4%, 27.3% higher than placebo. Supportive normal approximation analysis demonstrated tofacitinib 5?mg twice daily ASAS20 response rate significantly higher than placebo (80.8% vs 41.2%; p<0.001); tofacitinib 2 and 10?mg twice daily demonstrated greater response rate than placebo (51.9% and 55.8%, respectively; not significant). Secondary endpoints generally demonstrated greater improvements with tofacitinib 5 and 10?mg twice daily than placebo. Objective (including MRI) endpoints demonstrated clear dose response. Adverse events were similar across treatment groups with no unexpected safety findings. Dose-dependent laboratory outcome changes returned close to baseline by week 16. CONCLUSIONS:Tofacitinib 5 and 10?mg twice daily demonstrated greater clinical efficacy versus placebo in reducing signs, symptoms and objective endpoints of active AS in adult patients with a similar 12-week safety profile as reported in other indications. TRIAL REGISTRATION NUMBER:NCT01786668.

SUBMITTER: van der Heijde D

PROVIDER: S-EPMC5738601 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled, dose-ranging study.

van der Heijde Désirée D Deodhar Atul A Wei James C JC Drescher Edit E Fleishaker Dona D Hendrikx Thijs T Li David D Menon Sujatha S Kanik Keith S KS

Annals of the rheumatic diseases 20170127 8

<h4>Objectives</h4>To compare efficacy and safety of various doses of tofacitinib, an oral Janus kinase inhibitor, with placebo in patients with active ankylosing spondylitis (AS, radiographic axial spondyloarthritis).<h4>Methods</h4>In this 16-week (12-week treatment, 4-week washout), phase II, multicentre, dose-ranging trial, adult patients with active AS were randomised (N=51, 52, 52, 52, respectively) to placebo or tofacitinib 2, 5 or 10 mg twice daily. The primary efficacy endpoint was Asse ...[more]

PMID: 28130206

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Project description:We have compared synovial biopsies from ankylosing spondylitis and undifferentiated spondylitis patients with healthy controls and osteoarthritis patients Objective: In spondylarthropies, whole-genome gene expression profiling studies have been limited to peripheral blood to date. By undertaking a study in knee synovial biopsies from spondylarthropy (SpA) and ankylosing spondylitis (AS) patients we aimed to identified joint-specific candidate genes and pathways. These pathways may mediate systemic inflammation driven joint damaging processes and more specifically, the osteoproliferation that is characteristic of these conditions. Methods: RNA was extracted from six seronegative SpA, two AS, three osteoarthritis (OA) and four normal control knee synovial biopsies. Whole genome expression profiling was undertaken using the Illumina DASL system, which assays 24000 cDNA probes. Differentially expressed candidate genes were then validated using quantitative PCR and immunohistochemistry. Results: 416 differentially expressed genes were identified that clearly delineated between AS/SpA and control groups. Pathway analysis showed altered gene-expression in oxidoreductase activity, osteoblast activity, B-cell associated, matrix catabolic, and metabolic pathways. The inflammatory mediator, MMP3, was strongly upregulated in AS/SpA samples and the Wnt pathway inhibitors DKK3 and Kremen1 were downregulated. Conclusion: Pathways mediating both systemic inflammation as well as local tissue changes were identified. This suggests initial systemic inflammation in spondylarthropies transfers to and persists in the local joint environment, subsequently mediating changes in genes directly involved in the destructive tissue remodelling. Fifteen knee synovial biopsy tissue samples consisting of six seronegative spondyloarthropy (SpA), two ankylosing spondylitis (AS), three osteoarthritis (OA) and four normal control biopsies were obtained from the Synovial Tissue Bank at the Repatriation General Hospital in Adelaide, South Australia with the appropriate ethical approval (Supplementary Table 1). All patients provided informed written consent.

Dataset Information

Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled, dose-ranging study.

Publications

Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled, dose-ranging study.

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