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Methotrexate effect on immunogenicity and long-term maintenance of adalimumab in axial spondyloarthritis: a multicentric randomised trial.

ABSTRACT: OBJECTIVES:Anti-drug antibodies (ADA) are responsible for decreased adalimumab efficacy in axial spondyloarthritis (SpA). We aimed to evaluate the ability of methotrexate (MTX) to decrease adalimumab immunisation. METHODS:A total of 110 patients eligible to receive adalimumab 40?mg subcutaneously (s.c.) every other week were randomised (1:1 ratio) to receive, 2 weeks before adalimumab (W-2) and weekly, MTX 10?mg s.c. (MTX+) or not (MTX-). ADA detection and adalimumab serum concentration were assessed at weeks 4 (W4), 8 (W8), 12 (W12) and 26 (W26) after starting adalimumab (W0). The primary outcome was the proportion of patients with ADA at W26. Four years after the study completion, we retrospectively analysed adalimumab maintenance in relation with MTX co-treatment duration. RESULTS:We analysed data for 107 patients (MTX+; n=52; MTX-; n=55). ADA were detected at W26 in 39/107 (36.4%) patients: 13/52 (25%) in the MTX+ group?and 26/55 (47.3%) in the MTX- group (p=0.03). Adalimumab concentration was significantly higher in the MTX+ than MTX- group at W4, W8, W12 and W26. The two groups did not differ in adverse events or efficacy. In the follow-up study, MTX co-treatment >W26 versus no MTX or ?W26 was significantly associated with adalimumab long-term maintenance (p=0.04). CONCLUSION:MTX reduces the immunogenicity and ameliorate the pharmacokinetics of adalimumab in axial SpA. A prolonged co-treatment of MTX>W26 seems to increase adalimumab long-term maintenance.

SUBMITTER: Ducourau E

PROVIDER: S-EPMC7046954 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Methotrexate effect on immunogenicity and long-term maintenance of adalimumab in axial spondyloarthritis: a multicentric randomised trial.

Ducourau Emilie E Rispens Theo T Samain Marine M Dernis Emmanuelle E Le Guilchard Fabienne F Andras Lucia L Perdriger Aleth A Lespessailles Eric E Martin Antoine A Cormier Grégoire G Armingeat Thomas T Devauchelle-Pensec Valérie V Gervais Elisabeth E Le Goff Benoit B de Vries Annick A Piver Eric E Paintaud Gilles G Desvignes Céline C Ternant David D Watier Hervé H Goupille Philippe P Mulleman Denis D

RMD open 20200109 1

<h4>Objectives</h4>Anti-drug antibodies (ADA) are responsible for decreased adalimumab efficacy in axial spondyloarthritis (SpA). We aimed to evaluate the ability of methotrexate (MTX) to decrease adalimumab immunisation.<h4>Methods</h4>A total of 110 patients eligible to receive adalimumab 40 mg subcutaneously (s.c.) every other week were randomised (1:1 ratio) to receive, 2 weeks before adalimumab (W-2) and weekly, MTX 10 mg s.c. (MTX+) or not (MTX-). ADA detection and adalimumab serum concent ...[more]

PMID: 31958280

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Project description:BACKGROUND:Adalimumab was effective in treating patients with nonradiographic axial spondyloarthritis (nr-axSpA) in the 12-week ABILITY-1 trial. We present long-term efficacy and safety results of adalimumab from the open-label ABILITY-1 extension, including the relationship between clinical and magnetic resonance imaging (MRI) remission and impact of sustained clinical remission on physical function. METHODS:Patients received adalimumab 40 mg every other week or placebo for 12 weeks, then open-label adalimumab for up to 144 weeks. Clinical and safety data were collected through 3 years, and MRI data were collected until 2 years. Analyses were performed in the total population and subpopulation with positive MRI and/or elevated C-reactive protein (MRI/CRP-positive) at baseline. Clinical and MRI remission definitions included Ankylosing Spondylitis Disease Activity Score inactive disease (ASDAS ID; score <?1.3) and Spondyloarthritis Research Consortium of Canada (SPARCC) MRI score <?2 for sacroiliac joints (SIJs), spine, or both. Physical function was assessed using the Bath Ankylosing Spondylitis Functional Index. RESULTS:Overall, 185 patients were included in the total population and 142 in the MRI/CRP-positive subpopulation; 65% and 68%, respectively, completed 3 years. Clinical, functional, and MRI improvements were similar and equally sustainable in both populations. At year 3, the percentages of patients in ASDAS ID in the MRI/CRP-positive subpopulation were 30%/33% (nonresponder imputation) and 46%/49% (observed) for those initially receiving adalimumab/placebo. At years 1 and 2, patients in ASDAS ID vs not had significantly greater improvements in SPARCC SIJ scores from baseline (P < 0.001). Among patients with baseline MRI scores ??2 who achieved ASDAS ID at year 2, 44-68% also had MRI remission. Significantly more patients with sustained ASDAS ID through year 2 or 3 vs without achieved normal physical function (100% vs 48%; 100% vs 44%; both P < 0.001). No new safety concerns were observed. CONCLUSIONS:In the ABILITY-1 study of nr-axSpA, adalimumab therapy provided sustained clinical and functional improvements through 3 years, as well as suppression of MRI axial inflammation, which was greater in patients who achieved clinical remission. Sustained clinical remission was associated with increased attainment of normal physical function. The safety profile of adalimumab was consistent with prior studies. TRIAL REGISTRATION:ClinicalTrials.gov , NCT00939003 ; registered on July 10, 2009.

Project description:PurposeTo evaluate the efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis (nr-axSpA).MethodsPatients fulfilled Assessment of Spondyloarthritis international Society (ASAS) criteria for axial spondyloarthritis, had a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of ≥ 4, total back pain score of ≥ 4 (10 cm visual analogue scale) and inadequate response, intolerance or contraindication to non-steroidal anti-inflammatory drugs (NSAIDs); patients fulfilling modified New York criteria for ankylosing spondylitis were excluded. Patients were randomised to adalimumab (N=91) or placebo (N=94). The primary endpoint was the percentage of patients achieving ASAS40 at week 12. Efficacy assessments included BASDAI and Ankylosing Spondylitis Disease Activity Score (ASDAS). MRI was performed at baseline and week 12 and scored using the Spondyloarthritis Research Consortium of Canada (SPARCC) index.ResultsSignificantly more patients in the adalimumab group achieved ASAS40 at week 12 compared with patients in the placebo group (36% vs 15%, p<0.001). Significant clinical improvements based on other ASAS responses, ASDAS and BASDAI were also detected at week 12 with adalimumab treatment, as were improvements in quality of life measures. Inflammation in the spine and sacroiliac joints on MRI significantly decreased after 12 weeks of adalimumab treatment. Shorter disease duration, younger age, elevated baseline C-reactive protein or higher SPARCC MRI sacroiliac joint scores were associated with better week 12 responses to adalimumab. The safety profile was consistent with what is known for adalimumab in ankylosing spondylitis and other diseases.ConclusionsIn patients with nr-axSpA, adalimumab treatment resulted in effective control of disease activity, decreased inflammation and improved quality of life compared with placebo. Results from ABILITY-1 suggest that adalimumab has a positive benefit-risk profile in active nr-axSpA patients with inadequate response to NSAIDs.

Project description:ObjectiveTo evaluate long-term clinical, functional and radiographic outcomes in an open-label extension (OLE) study in patients with rheumatoid arthritis (RA) receiving adalimumab monotherapy or adalimumab+methotrexate following attainment of low disease activity (LDA) with adalimumab+methotrexate.MethodsMethotrexate-naive patients with early RA were randomised to adalimumab, methotrexate or adalimumab +methotrexate in a double-blind, 2-year study. Patients who completed the study and achieved LDA (28-joint Disease Activity Score using C reactive protein (DAS28(CRP)<3.2) could receive adalimumab monotherapy for up to 8 additional years in the OLE; open-label methotrexate could be added per investigator's discretion. This post hoc analysis included data up to OLE year 3 (study year 5) from patients receiving adalimumab+methotrexate who achieved LDA at year 2 followed by adalimumab monotherapy or methotrexate reinitiation. Normal physical function was defined as Disability Index of the Health Assessment Questionnaire <0.5 and radiographic non-progression as change in modified total Sharp score ≤0.5.ResultsOf 140 patients initiating adalimumab monotherapy, 84 (60%) received adalimumab only (methotrexate non-use) and 56 (40%) reinitiated methotrexate (methotrexate use) during OLE treatment. Median (IQR) time to first methotrexate use was 5.1 (0.1-31.4) weeks. Among methotrexate users, 61% retained LDA, 48% achieved DAS28(CRP) <2.6, 45% had normal physical function and 46% had no radiographic progression at year 5; for non-users, 63%, 50%, 58% and 50%, respectively, achieved these milestones. Adverse event rates were similar between methotrexate non-use and use patients.ConclusionsAdalimumab monotherapy effectively maintained good clinical, functional and radiographic outcomes for up to 3 additional years in ≥50% of patients who attained LDA after 2 years of adalimumab+methotrexate therapy.Trial registration numberNCT00195663; Post-results.

Project description:BackgroundIdentification of predictive clinical factors of long-term treatment response may contribute to improved management of non-radiographic axSpA (nr-axSpA) patients. This analysis aims to identify whether any baseline characteristics or Week 12 clinical outcomes in nr-axSpA patients with elevated C-reactive protein (CRP) and/or sacroiliitis on magnetic resonance imaging (MRI) enrolled in the C-axSpAnd study are predictive of achieving clinical response after 1 year of certolizumab pegol (CZP).MethodsC-axSpAnd (NCT02552212) was a phase 3, multicentre study, including a 52-Week double-blind, placebo-controlled period. Enrolled patients were randomised to CZP 200 mg Q2W or placebo. Predictors of Week 12 (CZP group only) and Week 52 clinical response were identified using a multivariate stepwise logistic regression analysis. Response variables included Ankylosing Spondylitis Disease Activity Score major improvement (ASDAS-MI), Assessment of SpondyloArthritis International Society 40% response (ASAS40), Bath Ankylosing Spondylitis Disease Activity Index 50% response (BASDAI50) and ASDAS inactive disease (ASDAS-ID). Predictive factors assessed included demographic and baseline characteristics and clinical outcomes at Week 12. A p-value <0.05 was required for forward selection into the model and p ≥0.1 for backward elimination. Missing data or values collected after switching to open-label treatment were accounted for using non-responder imputation. Sensitivity analyses accounted for patients with changes in non-biologic background medication.ResultsOf 317 enrolled patients, 159 and 158 were randomised to CZP and placebo, respectively. Younger age and male sex were identified as predictors of Week 12 response across all assessed efficacy outcomes in CZP-treated patients. Consistent predictors of Week 52 response, measured by ASDAS-MI, ASAS40 and BASDAI50, included human leukocyte antigen (HLA)-B27 positivity and sacroiliitis on MRI at baseline. MRI positivity was also predictive of achieving ASDAS-ID at Week 52. Sensitivity analyses were generally consistent with the primary analysis. In placebo-treated patients, no meaningful predictors of Week 52 response were identified.ConclusionsIn this 52-Week, placebo-controlled study in nr-axSpA patients with elevated CRP and/or active sacroiliitis on MRI at baseline, MRI sacroiliitis and HLA-B27 positivity, but not elevated CRP or responses at Week 12, were predictive of long-term clinical response to CZP. Findings may support rheumatologists to identify patients suitable for TNFi treatment.Trial registrationClinicalTrials.gov, NCT02552212 . Registered on 15 September 2015.

Dataset Information

Methotrexate effect on immunogenicity and long-term maintenance of adalimumab in axial spondyloarthritis: a multicentric randomised trial.

Publications

Methotrexate effect on immunogenicity and long-term maintenance of adalimumab in axial spondyloarthritis: a multicentric randomised trial.

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