Proteomic analysis to define predictors of treatment response to adalimumab or methotrexate in rheumatoid arthritis patients.
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SUBMITTER: Ling SF
PROVIDER: S-EPMC7253356 | biostudies-literature | 2020 Jun
REPOSITORIES: biostudies-literature
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Project description:ObjectivesMethotrexate is considered to be first-line therapy for rheumatoid arthritis (RA). However, a substantial proportion of treated patients do not achieve the desired goals of therapy. This analysis aimed to identify predictors of insufficient response to methotrexate in patients with early RA.MethodsThe Optimal Protocol for Treatment Initiation with Methotrexate and Adalimumab (OPTIMA) and PREMIER studies in patients with RA for <1 and <3 years, respectively, examined the efficacy of methotrexate and adalimumab in methotrexate-naive patients. This post hoc analysis included patients for whom initial methotrexate monotherapy was not successful after 6 months. Candidate predictors of insufficient response and clinically relevant radiographic progression (CRRP) included demographics, baseline disease characteristics and time-averaged disease variables over a 12-week interval. In OPTIMA, adalimumab was added to therapy after insufficient treatment response; in PREMIER, initial methotrexate therapy was continued; clinical, functional and radiologic outcomes were assessed after 1 year.ResultsBaseline 28-joint Disease Activity Score based on C-reactive protein (DAS28(CRP)) and time-averaged DAS28(CRP) over 4, 8 and 12 weeks were the strongest predictors of insufficient response to methotrexate and CRRP. Addition of adalimumab to methotrexate therapy was associated with better clinical, functional and radiographic outcomes after 1 year compared with continuing on methotrexate monotherapy.ConclusionsIn patients with early RA, baseline disease characteristics and early disease activity can predict response to methotrexate treatment and radiographic progression at 6 months. The addition of adalimumab at 6 months after methotrexate failure is associated with improved outcomes. These results support treatment-to-target strategies and timely adaptation of therapy in patients with early RA.Trial registration numberNCT00420927, NCT00195663; Post-results.
| S-EPMC6225797 | biostudies-literature
Project description:BackgroundTreatment of rheumatoid arthritis (RA) with a combination of methotrexate (MTX)+adalimumab (ADA) is more effective than ADA monotherapy. We assessed the toxicity of different doses of MTX and treatment efficacy of ADA+MTX in two trials.MethodsData originated from CONCERTO, in patients with early RA initiating ADA+ 2.5, 5, 10 or 20 mg/week MTX for 26 weeks; and MUSICA, in patients with an inadequate response to MTX initiating ADA+ 7.5 or 20 mg/week MTX for 24 weeks. Efficacy was assessed by the American College of Rheumatology 50 (ACR50). Patient-reported MTX-related toxicity information was collected at each visit on 18 prespecified MTX-related adverse events (AE) in the MTX label.ResultsIn CONCERTO, ACR50 rates increased over time, ranging from 54% to 68% at week 26, while AE rates remained steady, ranging from 2.4% to 17.8% at week 26. Of 395 patients, 113 (28.6%) reported 345 MTX-related AEs, including one serious AE (SAE, excessive fatigue and/or malaise); 10 AEs (in two patients) led to study discontinuation. In MUSICA, ACR50 rates increased over time, and were 32.3% and 37.5% at week 24, while MTX-related AE rates remained steady and were 6.5% at week 24. Of 309 patients, 71 (23%) reported 185 MTX-related AEs, including 5 SAEs (four infections and one fever/chills); six AEs (in four patients) led to study discontinuation.ConclusionIn patients with RA initiating ADA+MTX combination, treatment efficacy was achieved and increased throughout both trials, while rates of MTX-related AEs remained steady. MTX-related AEs were observed in up to 30% of patients and most were mild. MTX was discontinued by 0.5%-1.3% of patients.Trial registration numberMUSICA (NCT01185288), CONCERTO (NCT01185301), Post results.
| S-EPMC5604722 | biostudies-literature
Project description:To assess joint disease activity by ultrasound (US) in patients with rheumatoid arthritis (RA) initiating treatment with adalimumab (ADA) plus methotrexate (MTX).Data for this post hoc analysis originated from the MUSICA trial (ClinicalTrials.gov identifier: NCT01185288), which evaluated the efficacy of initiating ADA (40 mg every other week) plus 7.5 or 20 mg/week MTX in 309 patients with RA with an inadequate response to MTX. Synovial vascularization over 24 weeks was assessed bilaterally at metacarpophalangeal joint 2 (MCP2), MCP3, MCP5, metatarsophalangeal joint 5, and the wrists by power Doppler US (PDUS). A semiquantitative 4-grade scale was used. Disease activity was assessed using the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) and Simplified Disease Activity Index (SDAI). The correlation between continuous variables was assessed using Pearson's correlation coefficient.After 24 weeks of treatment with ADA plus MTX, rapid improvements in the mean synovial vascularity score were observed; the greatest improvements were in MCP2 (-0.5), MCP3 (-0.4), and the wrist (-0.4). At week 24, patients with the lowest DAS28-CRP (<2.6) had the lowest mean 5-joint and 3-joint composite synovial vascularity scores. The 5-joint and 3-joint scores were strongly correlated (??>?0.9). Synovial vascularity scores correlated poorly with DAS28, swollen joint count in 66 joints (SJC66), SJC28, tender joint count in 68 joints (TJC68), TJC28, Clinical Disease Activity Index (CDAI), SDAI, physician's global assessment, patient's global assessment of pain, and disease duration (??<?0.2). Thirty-two (70%) of 46 patients with a DAS28-CRP of <2.6, and 11 (58%) of 19 patients with an SDAI indicating remission had at least 1 joint with a synovial vascularity score of ?1.PDUS detects changes in synovial vascularity in RA patients treated with ADA plus MTX, and residual synovial vascularity in patients in whom clinical disease control has been achieved.
| S-EPMC5129587 | biostudies-literature
Project description:OBJECTIVE:To evaluate the achievement of comprehensive disease control (CDC) following 1?year of treatment with adalimumab+methotrexate?versus methotrexate alone and whether early achievement of remission (at week 24 or 26) is associated with CDC at week 52 in patients with either early or established rheumatoid arthritis (RA). METHODS:Post hoc analyses were conducted in three clinical studies assessing treatment with adalimumab+methotrexate: DE019 (NCT00195702) enrolled patients with established RA who were methotrexate inadequate responders; OPTIMA (NCT00420927) and PREMIER (NCT00195663) enrolled methotrexate-naive patients with early RA. In OPTIMA, patients not achieving stable low disease activity at weeks 22 and 26 in the placebo+methotrexate?group could receive open-label adalimumab+methotrexate for 52 weeks (Rescue ADA arm). CDC was defined as the simultaneous achievement of clinical remission (DAS28(CRP)<2.6), normal function (HAQ-DI<0.5) and absence of radiographic progression (?mTSS?0.5). RESULTS:Regardless of disease duration, significantly more patients receiving adalimumab+methotrexate achieved CDC compared with methotrexate alone. In the adalimumab+methotrexate?group, a numerically greater proportion of patients with early RA (~25%) versus established RA (14%) achieved CDC at 1?year; achievement of CDC was notably greater among patients who met criteria for remission at week 24 or 26 (~50% of patients with early RA and 39% with established RA). CONCLUSION:Treatment with adalimumab+methotrexate increases the likelihood of achieving CDC in patients with either early or established RA. Clinical remission at week 24 or 26 is associated with achievement of CDC at week 52. TRIAL REGISTRATION NUMBER:DE019 (NCT00195702), OPTIMA (NCT00420927), PREMIER (NCT00195663); Post-results.
| S-EPMC5623327 | biostudies-literature
Project description:ObjectiveTo evaluate the efficacy and safety of the Janus kinase-1-preferential inhibitor filgotinib versus placebo or tumour necrosis factor-α inhibitor therapy in patients with active rheumatoid arthritis (RA) despite ongoing treatment with methotrexate (MTX).MethodsThis 52-week, multicentre, double-blind, placebo-controlled and active-controlled phase III trial evaluated once-daily oral filgotinib in patients with RA randomised 3:3:2:3 to filgotinib 200 mg (FIL200) or filgotinib 100 mg (FIL100), subcutaneous adalimumab 40 mg biweekly, or placebo (through week 24), all with stable weekly background MTX. The primary endpoint was the proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Additional efficacy outcomes were assessed sequentially. Safety was assessed from adverse events and laboratory abnormalities.ResultsThe proportion of patients (n=1755 randomised and treated) achieving ACR20 at week 12 was significantly higher for FIL200 (76.6%) and FIL100 (69.8%) versus placebo (49.9%; treatment difference (95% CI), 26.7% (20.6% to 32.8%) and 19.9% (13.6% to 26.2%), respectively; both p<0.001). Filgotinib was superior to placebo in key secondary endpoints assessing RA signs and symptoms, physical function and structural damage. FIL200 was non-inferior to adalimumab in terms of Disease Activity Score in 28 joints with C reactive protein ≤3.2 at week 12 (p<0.001); FIL100 did not achieve non-inferiority. Adverse events and laboratory abnormalities were comparable among active treatment arms.ConclusionsFilgotinib improved RA signs and symptoms, improved physical function, inhibited radiographic progression and was well tolerated in patients with RA with inadequate response to MTX. FIL200 was non-inferior to adalimumab.Trial registration numberNCT02889796.
| S-EPMC8237199 | biostudies-literature
Project description:To 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.Methotrexate-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.Of 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.Adalimumab 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.NCT00195663; Post-results.
| S-EPMC6018859 | biostudies-literature
Project description:IntroductionThe objective of this study was to evaluate the real-world safety and effectiveness of adalimumab with methotrexate (MTX) in disease-modifying antirheumatic drug (DMARD)- and biologic-naïve Japanese patients with rheumatoid arthritis (RA) at risk of progressive structural joint damage.MethodsThis multicenter, prospective, observational, postmarketing surveillance study was conducted between February 2013 and April 2015 at 84 centers in Japan. Patients with RA at risk of progressive structural joint damage were enrolled and initiated treatment with adalimumab and MTX. Adverse events were recorded up to week 28. Effectiveness/disease activity was assessed using the Disease Activity Score based on a 28-joint count with erythrocyte sedimentation rate and C-reactive protein (DAS28-4ESR and DAS28-4CRP), Clinical Disease Activity Index, and Simplified Disease Activity Index at 0, 4, 12, and 24 weeks. DAS28-4CRP response was evaluated in the low-dose (<8 mg/week) and high-dose (≥8 mg to ≤16 mg/week) MTX groups at week 24.ResultsOne hundred fifty-seven of 163 patients comprised the safety cohort: mean (SD) age, 56.5 (13.9) years; females, 65.6%; rheumatoid factor positive, 73.2%; anti-cyclic citrullinated peptide antibody positive, 66.9%; bone erosions, 51.6%; mean disease duration, 9.5 months. The majority of patients (≥80%) had moderate or high disease activity at baseline, and ≥50% with available data achieved remission or low disease activity at week 24 (DAS28-4CRP <3.2). Five serious adverse drug reactions occurred in four patients, including pyelonephritis, Pneumocystis jiroveci pneumonia, interstitial lung disease, pleurisy, and pericarditis; the outcomes were either recovered or recovering. Significant improvements/reductions in disease activity over 24 weeks were noted in all effectiveness measures (P < 0.0001). Most of the population achieved DAS28-4CRP remission (<2.6) at week 24 regardless of the MTX dose.ConclusionAdalimumab in combination with MTX could be a beneficial treatment option for DMARD- and biologic-naïve Japanese patients with RA at risk of progressive structural joint damage.FundingAbbVie GK and Eisai.Trial registrationClinicalTrials.gov identifier, NCT01783730.
| S-EPMC5443728 | biostudies-literature
Project description:BackgroundMethotrexate is the preferred initial disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis (RA). However, clinically useful tools for individualized prediction of response to methotrexate treatment in patients with RA are lacking. We aimed to identify clinical predictors of response to methotrexate in patients with rheumatoid arthritis (RA) using machine learning methods.MethodsRandomized clinical trials (RCT) of patients with RA who were DMARD-naïve and randomized to placebo plus methotrexate were identified and accessed through the Clinical Study Data Request Consortium and Vivli Center for Global Clinical Research Data. Studies with available Disease Activity Score with 28-joint count and erythrocyte sedimentation rate (DAS28-ESR) at baseline and 12 and 24 weeks were included. Latent class modeling of methotrexate response was performed. The least absolute shrinkage and selection operator (LASSO) and random forests methods were used to identify predictors of response.ResultsA total of 775 patients from 4 RCTs were included (mean age 50 years, 80% female). Two distinct classes of patients were identified based on DAS28-ESR change over 24 weeks: "good responders" and "poor responders." Baseline DAS28-ESR, anti-citrullinated protein antibody (ACPA), and Health Assessment Questionnaire (HAQ) score were the top predictors of good response using LASSO (area under the curve [AUC] 0.79) and random forests (AUC 0.68) in the external validation set. DAS28-ESR ≤ 7.4, ACPA positive, and HAQ ≤ 2 provided the highest likelihood of response. Among patients with 12-week DAS28-ESR > 3.2, ≥ 1 point improvement in DAS28-ESR baseline-to-12-week was predictive of achieving DAS28-ESR ≤ 3.2 at 24 weeks.ConclusionsWe have developed and externally validated a prediction model for response to methotrexate within 24 weeks in DMARD-naïve patients with RA, providing variably weighted clinical features and defined cutoffs for clinical decision-making.
| S-EPMC9248180 | biostudies-literature
Project description:Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). The aim of this study was to explore the safety and efficacy of open-label tofacitinib following blinded treatment with adalimumab or tofacitinib for moderate to severe RA.Analyses included patients treated with adalimumab 40 mg once every 2 weeks or tofacitinib 10 mg twice daily (BID) with background methotrexate (MTX) in a 12-month randomized study (NCT00853385), who subsequently received tofacitinib 10 mg BID (with/without background MTX) in an open-label extension (NCT00413699). Patients with treatment-related serious adverse events (AEs) and serious or recurrent infections in the index study were excluded from the extension study. Exposure-adjusted incidence rates of safety-related events were assessed in 3-month and 12-month periods in the year before and in the year after switching. Efficacy was assessed 3 months before, at the time of, and 3 months after switching.There were 233 (107 adalimumab to tofacitinib 10 mg BID, 126 blinded to open-label tofacitinib 10 mg BID) patients included in these analyses. Patients in both treatment sequences had similar incidence rates (per 100 patient-years) of discontinuation due to AEs, serious AEs, and serious infections in the year before and in the year after switching. Incidence rates of AEs were increased in the first 3 months after switching compared with the last 3 months before switching in both treatment groups. Switching from either blinded adalimumab or tofacitinib to open-label tofacitinib resulted in numerically higher incidence of responders for signs and symptoms of disease and improved physical function.Treatment can be directly switched from adalimumab to tofacitinib. A similar safety and efficacy profile was seen when patients received open-label tofacitinib after receiving either blinded adalimumab or tofacitinib.ClinicalTrials.gov Identifiers: NCT00853385 , registered 27 February 2009; NCT00413699 , registered 18 December 2006.
| S-EPMC4918072 | biostudies-literature
Project description:Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). However, despite its efficacy and affordability, additional DMARDs or biologic agents are often required in order to achieve the recommended goals of low disease activity or remission. Although well tolerated by most, some patients develop important side effects such as cytopenias, gastrointestinal adverse events (stomatitis, nausea), or abnormal liver function tests, which may limit its use and may result in additional health care costs. Given the clinical implications of widespread use of MTX in RA, various studies have evaluated the role of potential biomarkers in predicting treatment effectiveness of MTX. These biomarkers include RBC MTX polyglutamate (PG) levels; genetic variation in genes from relevant biological and metabolic pathways; gene expression profiles; serum proteins. This paper provides an update on the current data regarding biomarkers of treatment response to MTX.
| S-EPMC3400362 | biostudies-literature