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Interleukin-6 receptor blockade or TNF? inhibition for reducing glycaemia in patients with RA and diabetes: post hoc analyses of three randomised, controlled trials.

ABSTRACT: BACKGROUND:Diabetes is common in patients with rheumatoid arthritis (RA). Interleukin (IL)-6 is implicated in both the pathogenesis of RA and in glucose homeostasis; this post hoc analysis investigated the effects of IL-6 receptor vs. tumour necrosis factor inhibition on glycosylated haemoglobin (HbA1c) in patients with RA with or without diabetes. METHODS:Data were from two placebo-controlled phase III studies of subcutaneous sarilumab 150/200?mg q2w?+?methotrexate or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and a phase III monotherapy study of sarilumab 200?mg q2w vs. adalimumab 40?mg q2w. Patients with diabetes were identified by medical history or use of antidiabetic medication (patients with HbA1c ??9% were excluded from all three studies). HbA1c was measured at baseline and weeks 12/24. Safety and efficacy were assessed in RA patients with or without diabetes. RESULTS:Patients with diabetes (n?=?184) were older, weighed more and exhibited higher RA disease activity than patients without diabetes (n?=?1928). Regardless of diabetes status, in patients on background csDMARDs, least squares (LS) mean difference (95% CI) in change from baseline in HbA1c for sarilumab 150?mg/200?mg vs. placebo at week 24 was -?0.28 (-?0.40, -?0.16; nominal p?

SUBMITTER: Genovese MC

PROVIDER: S-EPMC7488252 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Interleukin-6 receptor blockade or TNFα inhibition for reducing glycaemia in patients with RA and diabetes: post hoc analyses of three randomised, controlled trials.

Genovese Mark C MC Burmester Gerd R GR Hagino Owen O Thangavelu Karthinathan K Iglesias-Rodriguez Melitza M John Gregory St GS González-Gay Miguel A MA Mandrup-Poulsen Thomas T Fleischmann Roy R

Arthritis research & therapy 20200909 1

<h4>Background</h4>Diabetes is common in patients with rheumatoid arthritis (RA). Interleukin (IL)-6 is implicated in both the pathogenesis of RA and in glucose homeostasis; this post hoc analysis investigated the effects of IL-6 receptor vs. tumour necrosis factor inhibition on glycosylated haemoglobin (HbA1c) in patients with RA with or without diabetes.<h4>Methods</h4>Data were from two placebo-controlled phase III studies of subcutaneous sarilumab 150/200 mg q2w + methotrexate or conventiona ...[more]

PMID: 32907617

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Project description:OBJECTIVE:Randomised controlled trials (RCT) are the gold standard to provide unbiased data. However, when patients have a treatment preference, randomisation may influence participation and outcomes (eg, external and internal validity). The aim of this study was to assess the influence of patients' preference in RCTs by analysing partially randomised patient preference trials (RPPT); an RCT and preference cohort combined. DESIGN:Systematic review and meta-analyses. DATA SOURCES:MEDLINE, Embase, PsycINFO and the Cochrane Library. ELIGIBILITY CRITERIA FOR SELECTING STUDIES:RPPTs published between January 2005 and October 2018 reporting on allocation of patients to randomised and preference cohorts were included. DATA EXTRACTION AND SYNTHESIS:Two independent reviewers extracted data. The main outcomes were the difference in external validity (participation and baseline characteristics) and internal validity (lost to follow-up, crossover and the primary outcome) between the randomised and the preference cohort within each RPPT, compared in a meta-regression using a Wald test. Risk of bias was not assessed, as no quality assessment for RPPTs has yet been developed. RESULTS:In total, 117 of 3734 identified articles met screening criteria and 44 were eligible (24 873 patients). The participation rate in RPPTs was >95% in 14 trials (range: 48%-100%) and the randomisation refusal rate was >50% in 26 trials (range: 19%-99%). Higher education, female, older age, race and prior experience with one treatment arm were characteristics of patients declining randomisation. The lost to follow-up and cross-over rate were significantly higher in the randomised cohort compared with the preference cohort. Following the meta-analysis, the reported primary outcomes were comparable between both cohorts of the RPPTs, mean difference 0.093 (95% CI -0.178 to 0.364, p=0.502). CONCLUSIONS:Patients' preference led to a substantial proportion of a specific patient group refusing randomisation, while it did not influence the primary outcome within an RPPT. Therefore, RPPTs could increase external validity without compromising the internal validity compared with RCTs. PROSPERO REGISTRATION NUMBER:CRD42019094438.

Project description:BackgroundThe development of autoantibodies in patients with rheumatoid arthritis (RA) has potential as a marker of treatment response. This analysis assessed the association of an autoantibody response to carbamylated vimentin (anti-CarbV) and to vimentin modified by citrullination (anti-MCV) with response to treatment and structural damage progression in the phase III study RA-BEGIN.MethodsData from patients in the modified intent-to-treat population of RA-BEGIN were included for analysis; these patients received methotrexate (MTX), baricitinib 4 mg once daily, or baricitinib plus MTX during the 52-week study period. Endpoints analyzed were clinical response to treatment, assessed using change from baseline (CFB) in Simplified Disease Activity Index (SDAI) and Disease Activity Score for 28-joint count with serum high-sensitivity C-reactive protein (DAS28-hsCRP), and structural damage progression, assessed using CFB greater than the smallest detectable change in the van der Heijde-modified Total Sharp Score. The anti-CarbV and anti-MCV isotypes assessed were immunoglobulin (Ig) A, IgG, and IgM. Multivariable mixed-effect models for repeated measures (MMRMs) were used for the longitudinal analysis of treatment response, and multivariable logistic regression models were used for the analysis of structural damage progression at week 52.ResultsAnalysis of the association between autoantibodies and treatment response showed that high titers of anti-CarbV (IgA and IgG) were associated with a greater clinical response as measured by SDAI and DAS28-hsCRP. Anti-CarbV IgA and IgG, but not IgM, demonstrated an association after adjustment for other factors included in the MMRMs. High titers of anti-CarbV IgM were associated with a poor response to MTX monotherapy, whereas a nonsignificant trend toward a better response to baricitinib and baricitinib plus MTX was observed. There was no association between anti-MCV antibodies and treatment response. High titers of anti-CarbV IgA were associated with a greater probability of radiographic progression, but no association between anti-MCV antibodies and radiographic progression was observed.ConclusionsHigh titers of anti-CarbV IgA and IgG isotypes, but not anti-MCV isotypes, may be useful prognostic biomarkers for identifying the likelihood of the response to treatment and structural damage progression in patients with RA.

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Interleukin-6 receptor blockade or TNF? inhibition for reducing glycaemia in patients with RA and diabetes: post hoc analyses of three randomised, controlled trials.

Publications

Interleukin-6 receptor blockade or TNFα inhibition for reducing glycaemia in patients with RA and diabetes: post hoc analyses of three randomised, controlled trials.

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