Abatacept used in combination with non-methotrexate disease-modifying antirheumatic drugs: a descriptive analysis of data from interventional trials and the real-world setting.
ABSTRACT: BACKGROUND:Methotrexate (MTX) remains the anchor drug in rheumatoid arthritis (RA) treatment, but is poorly tolerated or contraindicated in some patients. There is a wealth of data supporting the use of abatacept in combination with MTX, but data on alternative conventional synthetic disease-modifying antirheumatic drug (csDMARD) combinations with abatacept are scarce. METHODS:In this post-hoc exploratory analysis, efficacy and safety data were extracted from abatacept RA studies in which combination with csDMARDs other than MTX was permitted: three interventional trials (ATTAIN, ASSURE, and ARRIVE) and one real-world study (ACTION). Patients with moderate-to-severe RA received abatacept in combination with MTX, hydroxychloroquine, sulfasalazine, azathioprine, or leflunomide for 6 months to 2 years according to the study design. Change from baseline in physical function (Health Assessment Questionnaire-Disability Index (HAQ-DI); all studies) and 28-joint Disease Activity Score (C-reactive protein) (DAS28 (CRP); ATTAIN, ARRIVE, and ACTION), American College of Rheumatology response rates (ATTAIN), and safety were assessed for individual and pooled csDMARD combinations for each trial. A meta-analysis was also performed on pooled data for HAQ-DI and DAS28 (CRP) across interventional trials. RESULTS:Across all four studies, 731 patients received abatacept plus one non-MTX csDMARD (hydroxychloroquine n?=?152; sulfasalazine n?=?123; azathioprine n?=?59; and leflunomide n?=?397) and 2382 patients received abatacept plus MTX. Mean changes from baseline in HAQ-DI scores for abatacept plus MTX (all csDMARDs pooled) vs abatacept plus a non-MTX csDMARD were -0.54 vs -0.44 (ATTAIN), -0.43 vs -0.43 (ASSURE), and -0.39 vs -0.36 (ARRIVE). Mean changes from baseline in DAS28 (CRP) and ACR response rates were also similar with abatacept plus MTX or non-MTX csDMARDs. Data for individual non-MTX csDMARDs (pooled across studies) and real-world data were consistent with these findings. Rates of treatment-related adverse events and serious adverse events, respectively, for abatacept plus one non-MTX csDMARD vs abatacept plus MTX were 35.7% vs 41.7% and 2.4% vs 2.3% (ATTAIN), 58.0% vs 55.9% and 4.2% vs 1.7% (ASSURE), and 38.1% vs 44.3% and 0.6% vs 2.9% (ARRIVE). CONCLUSIONS:Abatacept in combination with non-MTX csDMARDs is clinically effective and well tolerated in patients with moderate-to-severe RA, providing similar benefits to those seen with abatacept plus MTX. TRIAL REGISTRATION:ClinicalTrials.gov NCT00048581 . Registered 2 November 2002. ClinicalTrials.gov NCT00048932 . Registered 11 November 2002. ClinicalTrials.gov NCT00124982 . Registered 30 June 2005. ClinicalTrials.gov NCT02109666 . Registered 8 April 2014.
Project description:BACKGROUND AND OBJECTIVE:Early seronegative rheumatoid arthritis (RA) is considered a specific entity, especially regarding diagnostic issues and prognosis. Little is known about its potentially different initial clinical presentation and outcome. We aimed to determine predictors of good response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) in seronegative RA patients with early inflammatory arthritis. PATIENTS AND METHODS:Patients from the ESPOIR cohort with early inflammatory arthritis fulfilling the 2010 ACR/EULAR classification criteria for RA despite negativity for both rheumatoid factor and anti-CCP antibodies. The primary endpoint was a good or moderate EULAR response assessed after 1?year of follow-up, given at least 3?months of treatment with a csDMARD. Secondary objectives were to compare the early therapeutic response to methotrexate (MTX) and leflunomide (LEF) versus other csDMARDs (hydroxychloroquine, sulfasalazine) and to identify factors associated with functional disability (Health Assessment Questionnaire-Disability Index [HAQ-DI]?>?0.5 at 1?year) and structural progression (van der Heijde-modified total Sharp score >?1 and >?5 points at 1?year). Logistic regression analysis was used to determine independent predictors of outcomes. RESULTS:One hundred seventy-two patients were analyzed. Overall, 98/172 (57%) patients received MTX during the first year of follow-up. A good or moderate EULAR response at 1?year was associated with early use of csDMARDs (i.e., within 3?months after the first joint swelling) on univariate and multivariable analysis (odds ratio?=?2.41 [95% confidence interval 1.07-5.42], p =?0.03). Response rates were not affected by other classical prognostic factors (i.e., baseline DAS28). Presence of erosions at baseline was associated with Sharp score progression >?1 point and >?5 points (both p =?0.03) at 1?year. HAQ-DI ??1 at inclusion and active smoking were significantly associated with HAQ-DI?>?0.5 at 1?year. CONCLUSION:Our results suggest that delay in initiation of csDMARD more than baseline clinical, biological, or imaging features predominantly affects the outcome in early seronegative RA. These findings confirm that the usual therapeutic concepts in RA (early treatment, tight control, and treat-to-target) should be applied similarly to both seropositive and seronegative disease forms. TRIAL REGISTRATION:ClinicalTrials.gov: NCT03666091. Registered September 11, 2018.
Project description:INTRODUCTION:To evaluate the comparative efficacy and safety of subcutaneous sarilumab 200 mg monotherapy administered every 2 weeks (q2w) versus other monotherapies of biologic, targeted and conventional synthetic disease-modifying antirheumatic drugs (bDMARDs, tsDMARDs, csDMARDs) at recommended doses for treatment of rheumatoid arthritis in patients who are intolerant of or inadequate responders to csDMARDs (csDMARD-IR). METHODS:A systematic literature review and network meta-analysis (NMA) were conducted on 24-week efficacy outcomes: Health Assessment Questionnaire Disability Index (HAQ-DI) score, American College of Rheumatology (ACR) 20/50/70 criteria, and European League Against Rheumatism Disease Activity Score 28-joint count erythrocyte sedimentation rate (DAS28) <?2.6. In addition, serious infections and serious adverse events (SI/SAE) were examined at 24 weeks. RESULTS:Nine trials were selected for the NMA. Sarilumab 200 mg showed superiority versus adalimumab monotherapy on all efficacy outcomes and versus tofacitinib monotherapy on ACR20. Compared with csDMARDs, sarilumab 200 mg showed superiority on ACR 20/50/70 criteria and DAS28 <?2.6 but had similar efficacy on HAQ-DI. Efficacy of sarilumab 200 mg was similar versus certolizumab, etanercept, tofacitinib and tocilizumab 8 mg/kg monotherapy across all efficacy outcomes. SI/SAE appeared similar for sarilumab 200 mg versus all comparators. CONCLUSION:In csDMARD-IR patients, sarilumab 200 mg monotherapy has superior efficacy and similar safety versus csDMARDs, superior efficacy and similar safety versus adalimumab, and similar efficacy and safety versus bDMARDs and tsDMARDs. FUNDING:Sanofi and Regeneron Pharmaceuticals, Inc.
Project description:BACKGROUND:United Kingdom guidelines for the use of biologic disease modifying anti-rheumatic drugs (bDMARDS) for rheumatoid arthritis (RA) require patients to have active disease (Disease Activity Score [DAS28] >5.1) and have failed ?2 previous conventional synthetic DMARDs (csDMARD). Patients with moderate disease activity (MDA) do not meet these criteria, yet often have poor outcomes. This study aimed to identify trajectory groups of disability scores over three years in RA patients with MDA. METHODS:The study included biologic-naïve patients receiving csDMARDs only with MDA (3.2 <DAS28? 5.1) when recruited to the control cohort of the British Society for Rheumatology Biologics Register-RA (BSRBR-RA). Disability scores, measured using the Health Assessment Questionnaire (HAQ), were recorded every six months for three years. Trajectories of HAQ scores over follow-up were assessed using latent class growth models (LCGMs). Baseline age, gender, DAS28, symptom duration, rheumatoid factor status, number of prior csDMARDs and co-morbidities were assessed as potential predictors of group membership. RESULTS:In total, 1274 patients were included (mean age: 61 years (standard deviation: 12), 71.4% women). The best fitting model included seven HAQ trajectories. These trajectories were horizontal over follow-up and were related to baseline HAQ: very-low (6.8%, baseline (BL) HAQ: 0.22), low (11.5%, BL HAQ: 0.41), low-moderate (17.0%, BL HAQ: 0.93), moderate (13.4%, BL HAQ: 1.09), high-moderate (19.5%, BL HAQ: 1.61), severe (23.2%, BL HAQ: 1.98) and very-severe (8.6%, BL HAQ: 2.54). Higher DAS28, older age, female gender, longer disease duration and more co-morbidities were independently associated with higher HAQ trajectory group. CONCLUSION:There is substantial heterogeneity in baseline HAQ scores in this population, and the trajectories of HAQ scores after baseline are, on average, relatively flat. As bDMARD therapy has been shown to improve HAQ scores, patients with MDA but high HAQ scores may benefit from a more aggressive approach to therapy.
Project description:To evaluate clinical remission with subcutaneous abatacept plus methotrexate (MTX) and abatacept monotherapy at 12?months in patients with early rheumatoid arthritis (RA), and maintenance of remission following the rapid withdrawal of all RA treatment.In the Assessing Very Early Rheumatoid arthritis Treatment phase 3b trial, patients with early active RA were randomised to double-blind, weekly, subcutaneous abatacept 125?mg plus MTX, abatacept 125?mg monotherapy, or MTX for 12?months. Patients with low disease activity (Disease Activity Score (DAS)28 (C reactive protein (CRP)) <3.2) at month 12 entered a 12-month period of withdrawal of all RA therapy. The coprimary endpoints were the proportion of patients with DAS28 (CRP) <2.6 at month 12 and both months 12 and 18, for abatacept plus MTX versus MTX.Patients had <2?years of RA symptoms, DAS28 (CRP) ?3.2, anticitrullinated peptide-2 antibody positivity and 95.2% were rheumatoid factor positive. For abatacept plus MTX versus MTX, DAS28 (CRP) <2.6 was achieved in 60.9% versus 45.2% (p=0.010) at 12?months, and following treatment withdrawal, in 14.8% versus 7.8% (p=0.045) at both 12 and 18?months. DAS28 (CRP) <2.6 was achieved for abatacept monotherapy in 42.5% (month 12) and 12.4% (both months 12 and 18). Both abatacept arms had a safety profile comparable with MTX alone.Abatacept plus MTX demonstrated robust efficacy compared with MTX alone in early RA, with a good safety profile. The achievement of sustained remission following withdrawal of all RA therapy suggests an effect of abatacept's mechanism on autoimmune processes.NCT01142726.
Project description:OBJECTIVE:To assess the cost-effectiveness of tofacitinib-containing treatment sequences versus sequences containing only standard biological therapies in patients with moderate-to-severe rheumatoid arthritis (RA) after the failure of conventional synthetic disease-modifying antirheumatic drugs (csDMARD-IR population) and in patients previously treated with methotrexate (MTX) who show an inadequate response to second-line therapy with any tumour necrosis factor inhibitor (TNFi-IR population). METHODS:A patient-level microsimulation model estimated, from the perspective of the Spanish Public NHS, lifetime costs and quality-adjusted life years (QALY) for treatment sequences starting with tofacitinib (5 mg twice daily) followed by biological therapies versus sequences of biological treatments only. Concomitant treatment with MTX was considered. Model's parameters comprised demographic and clinical inputs (initial Health Assessment Questionnaire [HAQ] score and clinical response to short- and long-term treatment). Efficacy was measured by means of HAQ score changes using mixed treatment comparisons and data from long-term extension (LTE) trials. Serious adverse events (SAEs) data were derived from the literature. Total cost estimation (€, 2018) included drug acquisition, parenteral administration, disease progression and SAE management. RESULTS:In the csDMARD-IR population, sequences starting with tofacitinib proved dominant options (more QALYs and lower costs) versus the corresponding sequences without tofacitinib. In the TNFi-IR population, first-line treatment with tofacitinib+MTX followed by scAbatacept+MTX?rituximab+MTX?certolizumab+MTX proved dominant versus scTocilizumab+MTX?scAbatacept+MTX?rituximab+MTX?certolizumab+MTX; and tofacitinib+MTX?scTocilizumab+MTX?scAbatacept+MTX?rituximab+MTX versus scTocilizumab+MTX?scAbatacept+MTX?rituximab+MTX?certolizumab+MTX was less effective but remained a cost-saving option. CONCLUSIONS:Inclusion of tofacitinib seems a dominant strategy in moderate-to-severe RA patients after csDMARDs failure. Tofacitinib, as initial third-line therapy, proved a cost-saving strategy (€-?337,489/QALY foregone) in moderate-to-severe TNFi-IR RA patients. Key points • Therapeutical approach in rheumatoid arthritis (RA) consisted in sequences of several therapies during patient lifetime. • Treatment sequences initiating with tofacitinib followed by biological drugs provided higher health effects in csDMARDs-IR population, compared with sequences containing only biological drugs. • In both csDMARD-IR and TNFi-IR RA populations, initiating treatment with tofacitinib was associated to lower treatment costs for the Spanish National Health System.
Project description:Aiming at rapid decrease of disease activity, there has been a trend to start with higher doses of methotrexate (MTX) in patients newly diagnosed with rheumatoid arthritis (RA), both as monotherapy and in combination with other antirheumatic drugs. We aimed to study the relationship between clinical response and MTX dose as monotherapy or combination therapy in patients with early RA.Disease-modifying anti-rheumatic drug (DMARD)-naive patients with early RA, from a large international observational database, the METEOR database, were selected if MTX was part of their initial treatment. Patients were divided into four groups: MTX monotherapy, MTX?+?convention synthetic (cs)DMARDs, MTX?+?glucocorticoids or MTX?+?biologic (b)DMARDs. MTX dose was dichotomized: low dose ?10 mg/week; high dose ?15 mg/week. Linear mixed model analyses for the Disease Activity Score (DAS), DAS in 28 joints (DAS28) and Health Assessment Questionnaire (HAQ) were performed in each medication group, with MTX dose and time as covariates. Outcomes were assessed from baseline until 3-6 months follow up. Associations were adjusted for potential confounding by indication using propensity score (PS) modelling.For patients starting MTX monotherapy (n?=?523), MTX?+?csDMARDs (n?=?266) or MTX?+?glucocorticoids (n?=?615), the PS-adjusted effects of MTX dose (high versus low) on the DAS, DAS28 and HAQ were small and not clinically meaningful. Patients starting MTX?+?bDMARDs were disregarded due to low numbers (n =11).In patients newly diagnosed with RA, no clinical benefit of high compared to low initial MTX doses was found for MTX monotherapy or for MTX combination therapy with csDMARDs or glucocorticoids.
Project description:INTRODUCTION:This study assessed if concomitant use of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or corticosteroids altered the response or safety outcomes to baricitinib in rheumatoid arthritis (RA) patients. METHODS:Patients with???6 swollen/tender joints and no prior biologic DMARD were eligible for study inclusion. In RA-BUILD, csDMARD-inadequate responder (IR) patients were randomized to placebo or baricitinib (2 or 4 mg) once daily (QD). In RA-BEAM, methotrexate (MTX)-IR patients were randomized to placebo QD, baricitinib 4-mg QD, or adalimumab 40-mg biweekly. Patients continued background csDMARD (including MTX) therapy. This post hoc analysis of placebo and baricitinib 4-mg patients assessed the number and type of concomitant csDMARDS and concurrent corticosteroid use. RESULTS:From 716 placebo patients, 71, 21, and 6% were taking MTX alone, MTX?+???1 csDMARD, and non-MTX csDMARDs, respectively; from 714 baricitinib patients, the rates were 74, 18, and 6%; 56% of placebo and 55% of baricitinib patients used corticosteroids at baseline (mean dose, 6.0 mg/day for both groups); patients continued use throughout the studies. The odds ratios for achieving American College of Rheumatology response at the 20% improvement level (ACR20) and Clinical Disease Activity Index (CDAI)???10 at week 12 favored baricitinib for most subgroups; no significant interactions were observed. Rates of adverse events were similar regardless of csDMARD group or corticosteroid use. There were numerically more serious adverse events in placebo patients taking corticosteroids (4.2 vs. 1.6%) and a higher rate of discontinuations in baricitinib patients taking corticosteroids (4.1 vs. 1.2%). CONCLUSIONS:Baricitinib was efficacious regardless of concomitant use of csDMARDs or corticosteroids; the incidence of adverse events was similar across all groups of patients. FUNDING:Eli Lilly and Company and Incyte Corporation.
Project description:OBJECTIVES: To update a previous systematic review assessing the efficacy of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in rheumatoid arthritis (RA). METHODS: Two systematic reviews of the literature using PubMed, Embase and the Cochrane library were performed from 2009 until January 2013 to assess the efficacy of csDMARDs (as monotherapy or combination therapy) in adults with RA, and the efficacy of glucocorticoids in early RA. A third systematic review was performed until March 2013 to assess the efficacy of tofacitinib by meta-analysis. RESULTS: For glucocorticoids, of 222 hits, five publications relating to four new trials were analysed for efficacy, confirming that initial treatment of RA with low-dose prednisone plus methotrexate (MTX) results in better clinical and structural outcomes at 1 and 2 years than treatment with MTX alone. For csDMARDs, of 498 studies, only two new studies were randomised controlled trials comparing MTX monotherapy with MTX in combination with another csDMARD without differences in glucocorticoid usage. Using tight control principles, clinical outcomes were no better with immediate triple therapy than with 'step-up' therapy. For tofacitinib, the pooled analysis of 10 trials showed that tofacitinib was more efficacious on signs and symptoms, disability and appeared to be more efficacious on structural damage than control treatment with placebo (OR (95% CI)--American College of Rheumatology 20% (ACR20) response: 2.44 (1.97 to 3.02)) or treatment with MTX (ACR20 response: 2.38 (1.66 to 3.43)). CONCLUSIONS: Addition of low-dose glucocorticoids to csDMARD therapy produces benefits in early RA. Under tight control conditions, combination therapy with csDMARDs is no better than MTX monotherapy. Tofacitinib is a new DMARD with proven efficacy.
Project description:Objectives:To evaluate efficacy and safety of abatacept+methotrexate (MTX) in biologic-naive, anticitrullinated protein antibody (ACPA)-positive Japanese patients with active rheumatoid arthritis (RA) and early erosion versus placebo+MTX. Methods:In this phase IV, multicentre, double-blind study (NCT01758198), patients were randomised (1:1) to receive intravenous abatacept (~10 mg/kg) or placebo, plus MTX (?6 mg/week). Primary efficacy objectives were to compare American College of Rheumatology 20 (ACR20) response rates at week 16 and mean change from baseline in van der Heijde-modified total Sharp score (vdH-mTSS) at week 24 between abatacept+MTX and placebo+MTX groups. Results:Overall, 203 and 202 patients received abatacept+MTX and placebo+MTX, respectively. At week 16, ACR20 response rates were higher in the abatacept (75.4%) versus placebo group (27.7%; p<0.001). Mean change from baseline in vdH-mTSS at week 24 was 0.84 in the abatacept and 1.26 in the placebo group (p=0.017). Radiographic non-progression rates (change in vdH-mTSS?smallest detectable change (2.4)) were 88.1% and 75.4% in abatacept and placebo groups, respectively. Adjusted mean change from baseline in Disease Activity Score 28 (C-reactive protein) (DAS28 (CRP)) at week 16 demonstrated a numerically greater reduction in the abatacept versus placebo group. Proportions of patients with DAS28 (CRP), Simplified Disease Activity Index and Clinical Disease Activity Index remission up to week 52 were higher in the abatacept versus placebo group. The abatacept safety profile was consistent with previous observations. Conclusions:Compared with MTX alone, abatacept+MTX improved clinical symptoms and inhibited structural damage progression in ACPA-positive, Japanese patients with RA, early erosion and inadequate response to MTX.
Project description:BACKGROUND:To assess the risks of malignancies, infections and autoimmune diseases in patients with rheumatoid arthritis (RA) treated with abatacept compared with other biologic (b) disease-modifying antirheumatic drugs (DMARDs) or conventional synthetic (cs)DMARDs, in a US-wide observational RA cohort METHODS: Data were reviewed from patients (≥ 18 years) with RA who were registered with FORWARD, the National Databank for Rheumatic Diseases, and who initiated abatacept, other bDMARDs or csDMARDs between 2005 and 2015. Patients who switched treatment during the study could be allocated to more than one group. The incidence rates (IRs) by treatment were calculated for malignancies, hospitalized infections and autoimmune diseases identified by six monthly questionnaires and medical records. The hazard ratios (HRs) (95% confidence intervals [CIs]) for all outcomes with abatacept compared with other bDMARDs or csDMARDs were determined using marginal structural models adjusted for clinical confounders. RESULTS:In the study sample, 1496 initiated abatacept, 3490 initiated another bDMARD and 1520 initiated a csDMARD. The risk of malignancies with abatacept was not statistically significant versus other bDMARDs (HR [95% CI)] 1.89 [0.93, 3.84]) or versus csDMARDs (HR [95% CI] 0.93 [0.20, 4.27]). Patients receiving abatacept versus other bDMARDs were at a lower risk of hospitalized infections (HR [95% CI] 0.37 [0.18, 0.75]); the risk versus csDMARDs was lower with wide CIs (HR [95% CI] 0.31 [0.09, 1.05]). The relative risks for psoriasis were similar between treatment groups (HR [95% CI] 1.46 [0.76, 2.81] and HR [95% CI] 2.05 [0.59, 7.16] for abatacept versus other bDMARDs and versus csDMARDS, respectively). The IR (95% CI) of severe infusion/injection reactions was lower with abatacept compared with other bDMARDs (1.57 [1.11, 2.17] vs 2.31 [1.87, 2.82] per 100 patient-years, respectively). CONCLUSIONS:In this analysis, abatacept was well tolerated and did not result in an overall increased risk of malignancies, infections or autoimmune diseases compared with other bDMARDs or csDMARDs.