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Tofacitinib is associated with attainment of the minimally important reduction in axial magnetic resonance imaging inflammation in ankylosing spondylitis patients.

ABSTRACT: Objectives:Minimally important changes (MICs) for SPondyloArthritis Research Consortium of Canada (SPARCC) MRI scores are ?2.5 for SI joint and ?5 for spine. This post hoc analysis assessed achievement of MIC in SPARCC scores in biologic-naïve patients with AS treated with tofacitinib or placebo, and correlation with clinical responses. Methods:Adult AS patients in a 12-week phase 2 study (n = 207) were randomized 1: 1: 1: 1 to tofacitinib 2, 5 or 10 mg twice daily (BID) or placebo. MIC in SPARCC SI joint and spine scores were assessed for patients with available MRI data (N = 164; 79%). Clinical endpoints at week 12, including Assessment of SpondyloArthritis international Society 20% improvement (ASAS20), were compared between patients achieving/not achieving MIC. Results:A greater proportion of patients achieved MIC with tofacitinib 2, 5 and 10 mg BID vs placebo for SI joint (28.6, 38.6, 29.6 vs 11.8%) and spine scores (29.3, 36.4, 40.9 vs 11.8%). Generally, a greater proportion of patients treated with tofacitinib 2, 5 and 10 mg BID or placebo, respectively, who achieved MIC for SI joint and spine scores achieved ASAS20 (SI joint: 75.0, 88.2, 69.2, 75.0%; spine: 91.7, 85.7, 72.2, 75.0%) vs patients who did not achieve MIC (SI joint: 51.7, 84.0, 58.1, 48.3%; spine: 46.4, 85.7, 53.8, 48.3%). Numerically greater responses were seen in those patients achieving vs not achieving MIC across a range of other efficacy assessments. Conclusion:Approximately one-third of tofacitinib-treated AS patients experienced clinically meaningful reductions in spinal MRI inflammation at week 12. Patients achieving MIC for MRI inflammation had greater clinical response.

SUBMITTER: Maksymowych WP

PROVIDER: S-EPMC6055606 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Tofacitinib is associated with attainment of the minimally important reduction in axial magnetic resonance imaging inflammation in ankylosing spondylitis patients.

Maksymowych Walter P WP van der Heijde Désirée D Baraliakos Xenofon X Deodhar Atul A Sherlock Sarah P SP Li David D Fleishaker Dona D Hendrikx Thijs T Kanik Keith S KS

Rheumatology (Oxford, England) 20180801 8

<h4>Objectives</h4>Minimally important changes (MICs) for SPondyloArthritis Research Consortium of Canada (SPARCC) MRI scores are ⩾2.5 for SI joint and ⩾5 for spine. This post hoc analysis assessed achievement of MIC in SPARCC scores in biologic-naïve patients with AS treated with tofacitinib or placebo, and correlation with clinical responses.<h4>Methods</h4>Adult AS patients in a 12-week phase 2 study (n = 207) were randomized 1: 1: 1: 1 to tofacitinib 2, 5 or 10 mg twice daily (BID) or placeb ...[more]

PMID: 29718421

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Project description:BackgroundAnkylosing spondylitis (AS) is characterised by immune-mediated arthritis and osteoproliferation, ultimately leading to joint ankylosis. Whether inflammation is necessary for osteoproliferation is controversial, fuelled by the unclear efficacy of anti-inflammatory treatments on radiographic progression. In proteoglycan-induced spondylitis (PGISp), a mouse model of AS, inflammation is the prerequisite for osteoproliferation as osteoproliferation was only observed following inflammation-driven intervertebral disc (IVD) destruction. We hypothesised that early intervention with a potent anti-inflammatory therapy would protect IVD integrity and consequently alter disease progression.MethodsPGISp mice received vehicle or a combination of etanercept (ETN) plus prednisolone (PRD) therapy for 2 or 6 weeks initiated at an early disease stage. Peripheral arthritis was scored longitudinally. Spinal disease was assessed using a semi-quantitative histological scoring regimen including inflammation, joint destruction and excessive tissue formation.ResultsETN + PRD therapy significantly delayed the onset of peripheral arthritis. IVD integrity was significantly protected when treatment was commenced in early disease. Six-weeks of treatment resulted in trends towards reductions in intervertebral joint damage and excessive tissue formation. IVD score distribution was dichotomized, likely reflecting the extent of axial disease at initiation of therapy. In the sub-group of mice with high IVD destruction scores, ETN + PRD treatment significantly reduced IVD destruction severity, inflammation and bone erosion and reduced cartilage damage and excessive tissue formation.ConclusionsEarly intervention with anti-inflammatory treatment not only improved inflammatory symptoms but also ameliorated structural damage of spine in PGISp mice. This preclinical observation suggests that early anti-inflammatory intervention may slow radiographic progression in AS patients.

Project description:This study aimed to assess the relationship between bone marrow edema (BME) on magnetic resonance imaging (MRI) and bone mineral density (BMD) in patients with ankylosing spondylitis (AS).The study included 333 patients with AS who underwent BMD measurements and axial MRI. Additionally, 106 normal controls were included. The modified New York criteria were used as the classification criteria of AS. Clinical, laboratory, and imaging data were collected and analyzed. Lumbar spine and proximal femur BMD were assessed using dual-energy X-ray absorptiometry. Low BMD was defined by a Z-score ?-2. The Spondyloarthritis Research Consortium of Canada (SPARCC) MRI index was used to assess inflammation at the sacroiliac joint (SIJ) and spine.Among the 333 patients, the male:female ratio was 4.6:1, mean patient age was 28.5±10.6 years, and mean disease duration was 7.3±6.8 years. The prevalences of low BMD, osteopenia, and osteoporosis were significantly higher among AS patients than among controls (19.8%, 62.8%, and 5.7% vs. 4.7%, 33.0%, and 0%, respectively, P = 0.000). The BMD values were significantly lower and prevalences of low BMD at both the spine and femur were significantly higher among patients with BME on MRI than among those without BME. Multivariate logistic regression analysis showed that male sex (OR 3.87, 95% CI 1.21-7.36, P = 0.023), high ASDAS-CRP score (OR 2.83, 95% CI 1.36-4.76, P = 0.015), the presence of BME on sacroiliac MRI (OR 2.83, 95% CI 1.77-6.23, P = 0.000) and spinal MRI (OR 4.06, 95% CI 1.96-8.46, P = 0.000), and high grade of sacroiliitis (OR 2.93, 95% CI 1.82-4.45, P = 0.002) were risk factors for low BMD (any site). The SPARCC scores of the SIJ were negatively correlated with femoral BMD (r = -0.22, 95% CI -0.33 to -0.10, P = 0.000). Additionally, the SPARCC scores of the spine were negatively correlated with BMD values (r = -0.23, 95% CI -0.36 to -0.09, P = 0.003) and Z-scores (r = -0.24, 95% CI -0.36 to -0.12, P = 0.001) at the spine.Low BMD is common in AS patients. BME on MRI is highly associated with low BMD at both the spine and femur.

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 is associated with attainment of the minimally important reduction in axial magnetic resonance imaging inflammation in ankylosing spondylitis patients.

Publications

Tofacitinib is associated with attainment of the minimally important reduction in axial magnetic resonance imaging inflammation in ankylosing spondylitis patients.

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