Induction maintenance with tumour necrosis factor-inhibitor combination therapy with discontinuation versus methotrexate monotherapy in early rheumatoid arthritis: a systematic review and meta-analysis of efficacy in randomised controlled trials.
ABSTRACT: To determine whether an induction-maintenance strategy of combined therapy (methotrexate (MTX)+tumour necrosis factor (TNF) inhibitor (TNFi)) followed by withdrawal of TNFi could yield better long-term results than a strategy with MTX monotherapy, since it is unclear if the benefits from an induction phase with combined therapy are sustained if TNFi is withdrawn.We performed a meta-analysis of trials using the initial combination of MTX+TNFi in conventional synthetic disease-modifying antirheumatic drug-naïve patients with early rheumatoid arthritis (RA). A systematic literature search was performed for induction-maintenance randomised controlled trials (RCTs) where initial combination therapy was compared with MTX monotherapy in patients with clinically active early RA. Our primary outcome was the proportion of patients who achieved low disease activity (LDA; Disease Activity Score (DAS)28<3.2) and/or remission (DAS28<2.6) at 12-76 weeks of follow-up. A random-effects model was used to pool the risk ratio (RR) for LDA and remission and heterogeneity was explored by subgroup analyses.We identified 6 published RCTs, 4 of them where MTX+adalimumab was given as initial therapy and where adalimumab was withdrawn in a subset of patients after LDA/remission had been achieved. 2 additional trials used MTX+infliximab as combination therapy. The pooled RRs for achieving LDA and clinical remission at follow-up after withdrawal of TNFi were 1.41 (95% CI 1.05 to 1.89) and 1.34 (95% CI 0.95 to 1.89), respectively. There was significant heterogeneity between trials due to different treatment strategies, which was a limitation to this study.Initial therapy with MTX+TNFi is associated with a higher chance of retaining LDA and/or remission even after discontinuation of TNFi.
Project description:OBJECTIVE:To assess the efficacy and safety of adalimumab plus methotrexate (ADA+MTX) compared with methotrexate monotherapy in achieving stable low disease activity (LDA; disease activity score (DAS28(CRP)) <3.2 at weeks 22 and 26) and clinical, radiographic and functional outcomes in methotrexate-naive patients with early rheumatoid arthritis (RA). METHODS:1032 patients with active RA were randomly assigned 1:1 to ADA+MTX or placebo plus methotrexate (PBO+MTX) for 26 weeks. Treatment modifications were to be made in a subsequent study period based on the achievement of DAS28(CRP) <3.2 at weeks 22 and 26. Post-hoc analyses compared patients achieving stable remission using DAS28 and 2010 ACR/EULAR criteria with those achieving LDA but not remission. RESULTS:Among patients completing 6 months, 44% (207/466) ADA+MTX versus 24% (112/460) PBO+MTX patients achieved stable LDA at weeks 22 and 26 (p<0.001). Combination therapy was statistically superior to methotrexate in obtaining higher ACR20/50/70 responses, more clinical remissions, greater mean reductions in DAS28(CRP), no radiographic progression, and normal functional status at week 26 (p<0.001 for all). The only factor predicting stable LDA was disease activity at week 12. Patients achieving ACR/EULAR remission, particularly in the PBO+MTX group, had some advantage in radiographic outcomes compared with patients who only achieved LDA (but not remission). The overall frequency of adverse events was comparable between groups. There were more serious infections and deaths in the ADA+MTX group, with a possible age effect. CONCLUSIONS:Treatment with ADA+MTX was significantly superior to methotrexate alone with respect to clinical, radiographic and functional outcomes in patients with early active RA. Before initiating treatment with adalimumab, individual patient evaluation of the benefit/risk ratio should be carefully considered.
Project description:INTRODUCTION:Controlled clinical studies have shown that the efficacy of tocilizumab (TCZ) monotherapy is superior to that of tumor necrosis factor inhibitor (TNFi) monotherapy and comparable to that of TCZ plus methotrexate (MTX) for the treatment of rheumatoid arthritis (RA). This study compared the real-world effectiveness of TCZ monotherapy vs. TNFis plus MTX in US patients with RA. METHODS:TCZ-naïve patients from the Corrona RA registry with prior exposure to???1 TNFi who initiated TCZ monotherapy or TNFi?+?MTX were included. Outcomes included mean change in Clinical Disease Activity Index (CDAI), achievement of low disease activity (LDA; CDAI???10), achievement of modified American College of Rheumatology (mACR) 20/50 responses, and mean change in modified Health Assessment Questionnaire (mHAQ) at 6 months. Patients initiating TNFi?+?MTX were grouped by MTX dose (??10 mg;?>?10 to???15 mg;?>?15 to???20 mg;?>?20 mg); outcomes in each group were compared with TCZ monotherapy using trimmed populations (excluding patients outside the propensity score distribution overlap). RESULTS:Patients in all groups experienced improvement in CDAI at 6 months (mean change, - 6.9 to - 9.7), with no significant differences between the TCZ monotherapy and TNFi?+?MTX groups. Achievement of LDA and mACR responses at 6 months were comparable between the TCZ monotherapy and TNFi?+?MTX groups; overall, 26.8-38.0% of patients achieved LDA, 24.3-37.6% achieved mACR20 response and 13.2-20.8% achieved mACR50 response. The mean change in mHAQ at 6 months was - 0.1 in all groups. CONCLUSIONS:In this real-world population of US patients with RA who had prior TNFi exposure, there was no evidence of a difference in the effectiveness of TCZ monotherapy compared with that of TNFi?+?MTX, regardless of MTX dose, at 6 months for improving RA disease activity. FUNDING:Corrona, LLC. Plain language summary available for this article.
Project description:BACKGROUND:If TNF inhibitors are initiated in the early stages of psoriatic arthritis, this could potentially modulate disease and therefore allow us to discontinue the TNF inhibitor after achieving remission. OBJECTIVE:To investigate whether remission induced by tumour necrosis factor alpha inhibitor (TNFi) and methotrexate in patients with early psoriatic arthritis is sustained after withdrawal of TNFi. METHODS:Open-label extension of a recently published double-blind, randomized placebo-controlled trial. Patients with psoriatic arthritis fulfilling the CASPAR criteria and with active disease at baseline (swollen and tender joint count ??3) were randomized to either golimumab and methotrexate or matched placebo and methotrexate. Patients in Disease Activity Score (DAS) remission at week 22 continued in the open-label extension on methotrexate monotherapy. The primary end point was the percentage of patients in DAS-CRP remission (DAS <?1.6) at week 50. RESULTS:Eight patients from the original placebo group and 18 patients from the original TNFi group continued in the extension phase. At week 50, 6 out of 8 (75%) patients from the original MTX (methotrexate) group versus 10 out of 18 (56%) patients from the original MTX+TNFi group were in DAS-CRP remission (p =?0.347). Considering the total study population, 6 out of 24 (25%) of the original MTX group versus 10 out of 26 (38.5%) of the original MTX+TNFi group were in DAS remission at week 50 (p =?0.308). CONCLUSIONS:Remission achieved by initial combination treatment with TNFi and methotrexate in early psoriatic arthritis is maintained on methotrexate monotherapy in approximately half of the patients. TRIAL REGISTRATION:Registered at Clinicaltrials.gov with number NCT01871649 on June 7, 2013.
Project description:OBJECTIVES:To investigate the frequency and predictors of sustained 28-joint DAS (DAS28) remission and low disease activity (LDA) in patients receiving anti-TNF therapy and changes in responses over a 12 year period. METHODS:Data from the British Society for Rheumatology Biologics Registry for Rheumatoid Arthritis were used. Sustained remission and LDA were defined according to DAS28-ESR thresholds sustained for 6 months. The dataset was dichotomized into sequential chronological subgroups (2001-2010 and 2010-2013). Predictive variables were identified from a previous systematic review and modelled using multivariable logistic regression. RESULTS:Overall, 2144 (14.9%) and 3802 (26.3%) patients achieved sustained remission or LDA, respectively. Positive predictors of sustained remission/LDA included adalimumab (vs etanercept), greater patient global assessment, never- and ex-smoker status (vs current smoking), greater swollen joint count, more recent commencement of anti-TNF and MTX co-prescription (except in the 2010-2013 subgroup). Negative predictors of sustained remission and LDA included poor baseline functional status (HAQ), female gender, older age at starting anti-TNF, infliximab use (vs etanercept), increasing BMI and greater baseline ESR. Increasing tender joint count was negatively associated with sustained LDA only. The overall proportion of patients achieving sustained remission and LDA has increased significantly over time. CONCLUSION:Sustained remission/LDA on anti-TNF treatment remains uncommon. Adalimumab use, greater patient global assessment, never- and ex-smoker status, greater swollen joint count, more recent commencement of anti-TNF and MTX co-prescription are associated with achievement of sustained remission/LDA. However, co-prescription of MTX was not associated with an increased likelihood of achieving sustained remission or LDA in the analysis of more recent anti-TNF responses.
Project description:INTRODUCTION:No published studies exist comparing the effectiveness of tofacitinib with other advanced therapies for the treatment of rheumatoid arthritis (RA) in real-world clinical practice. Here, we report differences in effectiveness of tofacitinib compared with standard of care, tumor necrosis factor inhibitors (TNFi), with or without concomitant methotrexate (MTX), using US Corrona registry data. METHODS:This observational cohort study included RA patients receiving tofacitinib (from 6 November 2012; N?=?558) or TNFi (from 1 November 2001; N?=?8014) with or without MTX until 31 July 2016. Efficacy outcomes at 6 months included modified American College of Rheumatology 20% responses, Clinical Disease Activity Index (CDAI) and Pain. Outcomes were compared between patients receiving TNFi and tofacitinib with or without MTX and by line of therapy. Outcomes within therapy lines were compared using propensity-score matching; between-group differences were estimated using mixed-effects regression models. RESULTS:Patients receiving tofacitinib had longer RA duration and a greater proportion had previously received biologics than those receiving TNFi; other baseline characteristics were comparable. In patients receiving second- and third-line TNFi therapy, CDAI low disease activity/remission response rates were significantly better with concomitant MTX. Too few patients received tofacitinib as second line for meaningful assessment. No significant differences were observed in outcomes between tofacitinib as monotherapy and tofacitinib with concomitant MTX. CONCLUSIONS:In clinical practice, TNFi efficacy is improved with concomitant MTX in the second and third line. In the third/fourth line, patients are likely to achieve similar efficacy with tofacitinib monotherapy, or TNFi or tofacitinib in combination with MTX. FUNDING:Pfizer Inc.
Project description:OBJECTIVE:The objective was to determine if dose reduction is non-inferior to full-dose TNFi to maintain low disease activity (LDA) in patients already in remission with TNFi, in axial spondyloarthritis. METHODS:Randomized, parallel, non-inferiority, open-label multicentre clinical trial. Patients were eligible if they had axial spondyloarthritis and had been in clinical remission for ??6?months with any available TNFi (adalimumab, etanercept, infliximab, golimumab) at the dose recommended by product labelling. Patients were randomized by automated central allocation to continue the same TNFi dose schedule, or to reduce the dose by roughly half according to the protocol. The main outcome was the proportion of subjects with LDA after 1?year. Serious adverse reactions or infections were recorded. RESULTS:The trial stopped due to end of the funding period, after 126 patients were randomized; 113 patients (84.1% male, mean age (SD) 45.6 (13.0) years) were included in the main per-protocol subset. Non-inferiority was concluded for LDA at 1?year (47/55 (83.8%) patients in the full-dose and 48/58 (81.3%) patients in the reduced-dose arm, adjusted difference (95% CI) -?2.5% (-?16.6% to 11.7%)). Serious adverse reactions or infections were reported in 7/62 patients (11.3%) assigned to full dose and 2/61 patients (3.3%) assigned to reduced dose (p value?=?0.164). CONCLUSION:In patients with ankylosing spondylitis in clinical remission for at least 6?months, dose reduction is non-inferior to full TNF inhibitor doses to maintain LDA after 1?year. Serious adverse events may be less frequent with reduced doses. TRIAL REGISTRATION:EU Clinical Trials Registry, EudraCT 2011-005871-18 and ClinicalTrials.gov, NCT01604629 .
Project description:The effect of five approved tumour necrosis factor inhibitors (TNFi: infliximab, etanercept, adalimumab, certolizumab, and golimumab) on joint destruction in rheumatoid arthritis (RA) have been compared versus methotrexate (MTX) in randomized controlled trials (RCTs) but have not been compared directly to each other or to an otherwise untreated placebo control. The present analysis compares effects of standard doses, high doses, and low doses of TNFis on radiographic joint destruction in RA and relate these effects to MTX and placebo by means of a Bayesian network meta-analysis. We identified 31 RCTs of the effect of TNFis on joint destruction and 5 RCTs with controls, which indirectly could link otherwise untreated placebo controls to the TNFi treatments in the network. The previously untested comparison with placebo was performed to estimate not only the effect relative to another drug, but also the absolute attainable effect. Compared to placebo there was a highly significant inhibitory effect on joint destruction of infliximab, etanercept, adalimumab, certolizumab, and golimumab, which was about 0.9% per year as monotherapy and about 1.2% per year when combined with MTX. Although significantly better than MTX and placebo, golimumab seemed inferior to the remaining TNFis. There was no difference between original reference drugs (Remicade, Enbrel) and the almost identical copy drugs (biosimilars).
Project description:To evaluate the impact of methotrexate (MTX) dosage on clinical, functional and quality of life outcomes in patients with rheumatoid arthritis (RA) from two previous etanercept (ETN) trials after 24 months of treatment.Patients with active RA in the ETN+MTX combination treatment arms of the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) and COmbination of Methotrexate and ETanercept in Active Early Rheumatoid Arthritis (COMET) studies were pooled in this post hoc analysis and stratified by MTX dosage at 24 months, having MTX monotherapy groups as control: low dose, <10.0 mg/week; medium dose, 10.0-17.5 mg/week; and high dose, >17.5 mg/week. Data from these patient subgroups were included in descriptive summaries of demographic and disease characteristics at baseline. The following outcomes at 24 months were also evaluated for each subgroup: Disease Activity Score in 28 joints (DAS28) low disease activity (LDA) and remission; American College of Rheumatology 20%, 50% and 70% improvement criteria (ACR20, 50 and 70) responses; and changes from baseline in DAS28, Health Assessment Questionnaire Disease Index (HAQ-DI) and EuroQol 5-dimensions visual analogue scale (EQ-5D VAS).Baseline demographics were similar between the low, medium and high MTX dose groups in the ETN+MTX combination and MTX monotherapy arms, with the exception of disease duration (ETN+MTX low 5.5; medium 5.1; high 0.8 years vs MTX low 8.3; medium 4.7; high 0.8 years). Responses to ETN+MTX combination therapy at 24 months were consistently high across MTX dosage groups, with very similar rates of DAS28 LDA/remission and ACR20/50/70. Improvements in DAS28, HAQ-DI and EQ-5D VAS were also not dependent on MTX dosage in the combination treatment arm.Patients with RA in the TEMPO and COMET trials who received ETN+MTX showed similar efficacy outcomes at 24 months, regardless of MTX dosage.NCT00195494 (COMET) and NCT00393471 (TEMPO).
Project description:INTRODUCTION:There is insufficient evidence regarding the appropriate dose of methotrexate (MTX) required to achieve specific treatment goals in patients with rheumatoid arthritis (RA) receiving biologic drugs in Japan. The present study aimed to assess the dose-response effect of MTX in combination with adalimumab (ADA) to achieve low disease activity (LDA) and/or remission at 24 weeks in RA patients. METHODS:This analysis used data of the ADA all-case survey in Japan (n = 7740), and 5494 patients who received ADA and MTX were classified into five groups by weighted average MTX dose (>0-<4, 4-<6, 6-<8, 8-< 10, and ?10 mg/week). Of the 5494 patients, 3097 with baseline 28-joint disease activity score based on erythrocyte sedimentation rate >3.2 were analyzed for effectiveness by MTX dose. RESULTS:In biologic-naïve patients (n = 1996/3097), LDA/remission rates increased with MTX up to 6-<8 mg/week and then plateaued at higher doses (LDA, p = 0.0440; remission, p = 0.0422). In biologic-exposed patients (n = 1101/3097), LDA/remission rates increased with MTX dose (LDA, p = 0.0009; remission p = 0.0143). The incidences of serious adverse drug reactions (ADRs) and serious infections did not differ by MTX dose, but total ADRs and infections were significantly higher (p < 0.05) with increased MTX doses. CONCLUSION:The appropriate MTX doses in combination with ADA to achieve LDA and/or remission at week 24 were different between biologic-naïve and biologic-exposed patients with RA, suggesting that 8 mg/week of MTX would be enough for biologic-naïve patients. TRIAL REGISTRATION:ClinicalTrials.gov identifier, NCT01076959. FUNDING:AbbVie and Eisai Co., Ltd.
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.