Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA): 16-week outcomes of a stratified, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial.
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SUBMITTER: Humby F
PROVIDER: S-EPMC7829614 | biostudies-literature | 2021 Jan
REPOSITORIES: biostudies-literature
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Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA): 16-week outcomes of a stratified, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial.
Humby Frances F Durez Patrick P Buch Maya H MH Lewis Myles J MJ Rizvi Hasan H Rivellese Felice F Nerviani Alessandra A Giorli Giovanni G Mahto Arti A Montecucco Carlomaurizio C Lauwerys Bernard B Ng Nora N Ho Pauline P Bombardieri Michele M Romão Vasco C VC Verschueren Patrick P Kelly Stephen S Sainaghi Pier Paolo PP Gendi Nagui N Dasgupta Bhaskar B Cauli Alberto A Reynolds Piero P Cañete Juan D JD Moots Robert R Taylor Peter C PC Edwards Christopher J CJ Isaacs John J Sasieni Peter P Choy Ernest E Pitzalis Costantino C
Lancet (London, England) 20210101 10271
<h4>Background</h4>Although targeted biological treatments have transformed the outlook for patients with rheumatoid arthritis, 40% of patients show poor clinical response, which is mechanistically still unexplained. Because more than 50% of patients with rheumatoid arthritis have low or absent CD20 B cells-the target for rituximab-in the main disease tissue (joint synovium), we hypothesised that, in these patients, the IL-6 receptor inhibitor tocilizumab would be more effective. The aim of this ...[more]
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Project description:ObjectiveTo compare the effectiveness and safety of three non-tumour necrosis factor (TNF) α inhibitors (rituximab, abatacept, and tocilizumab) in the treatment of rheumatoid arthritis.DesignPopulation based prospective study.Setting53 university and 54 non-university clinical centres in France.Participants3162 adults (>18 years) with rheumatoid arthritis according to 1987 American College of Rheumatology criteria, enrolled in one of the three French Society of Rheumatology registries; who had no severe cardiovascular disease, active or severe infections, or severe immunodeficiency, with follow-up of at least 24 months.InterventionInitiation of intravenous rituximab, abatacept, or tocilizumab for rheumatoid arthritis.Main outcome measureThe primary outcome was drug retention without failure at 24 months. Failure was defined as all cause death; discontinuation of rituximab, abatacept, or tocilizumab; initiation of a new biologic or a combination of conventional disease modifying antirheumatic drugs; or increase in corticosteroid dose >10 mg/d compared with baseline at two successive visits. Because of non-proportional hazards, treatment effects are presented as life expectancy difference without failure (LEDwf), which measures the difference between average duration of survival without failure.ResultsAverage durations of survival without failure were 19.8 months for rituximab, 15.6 months for abatacept, and 19.1 months for tocilizumab. Average durations were greater with rituximab (LEDwf 4.1, 95% confidence interval 3.1 to 5.2) and tocilizumab (3.5, 2.1 to 5.0) than with abatacept, and uncertainty about tocilizumab compared with rituximab was substantial (-0.7, -1.9 to 0.5). No evidence was found of difference between treatments for mean duration of survival without death, presence of cancer or serious infections, or major adverse cardiovascular events.ConclusionAmong adults with refractory rheumatoid arthritis followed-up in routine practice, rituximab and tocilizumab were associated with greater improvements in outcomes at two years compared with abatacept.
| S-EPMC6344892 | biostudies-literature
Project description:BackgroundObservational studies have suggested that patients with rheumatoid arthritis (RA) who experience inadequate response to anti-tumour necrosis factor (anti-TNF) agents respond more favourably to rituximab (RTX) than to an alternative anti-TNF agent. However, the relative effectiveness of these agents on long-term outcomes, particularly in radiographic damage, remains unclear.ObjectiveTo compare the effectiveness of RTX against anti-TNF agents in preventing joint damage in patients with RA who have experienced inadequate response to at least one prior anti-TNF agent.MethodsThis is a prospective cohort study within the Swiss registry of patients with RA who discontinued at least one anti-TNF agent and subsequently received either RTX or an alternative anti-TNF agent. The primary outcome, progression of radiographic joint erosions (Ratingen erosion score)over time, and the secondary outcome, functional disability (Health Assessment Questionnaire Disability Index), were analysed using regression models for longitudinal data and adjusted for potential confounders.ResultsOf the 371 patients included, 104 received RTX and 267 received an alternative anti-TNF agent. During the 2.6-year median follow-up period, the rates of Ratingen erosion score progression were similar between patients taking RTX and patients taking an alternative anti-TNF agent (p=0.67). The evolution of the Health Assessment Questionnaire score was statistically significantly better in the RTX group (p=0.016), but the magnitude of the effect was probably not clinically relevant.ConclusionThis observational study suggests that RTX is as effective as an alternative anti-TNF agent in preventing erosions in patients with RA who have previously experienced inadequate response to anti-TNF agents.
| S-EPMC3500530 | biostudies-literature
Project description:Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not respond to individual biologic therapies and 5-20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA; n = 164), patients with low/absent synovial B cell molecular signature had a lower response to rituximab (anti-CD20 monoclonal antibody) compared with that to tocilizumab (anti-IL6R monoclonal antibody) although the exact mechanisms of response/nonresponse remain to be established. Here, in-depth histological/molecular analyses of R4RA synovial biopsies identify humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to all medications. Post-treatment changes in synovial gene expression and cell infiltration highlighted divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms. Using ten-by-tenfold nested cross-validation, we developed machine learning algorithms predictive of response to rituximab (area under the curve (AUC) = 0.74), tocilizumab (AUC = 0.68) and, notably, multidrug resistance (AUC = 0.69). This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatment-response phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients.
| S-EPMC9205785 | biostudies-literature
Project description:ObjectivesThe objective of this study was to evaluate the cost-effectiveness of abatacept, tocilizumab, and tumor necrosis factor (TNF) inhibitors as compared with rituximab in Finnish rheumatoid arthritis patients, who have previously been treated with TNF inhibitors.MethodsA patient-level simulation model was developed to predict costs and outcomes associated with four biological drugs (abatacept, tocilizumab, rituximab and TNF inhibitors) in the treatment of rheumatoid arthritis. Following lack of efficacy or adverse events, the patients were switched to another biological drug until all four options were exhausted. After that, the patients were assumed to receive a 6th line treatment until death. The patients' baseline characteristics and regression models used in the simulation were based on observational data from the National Register for Biological Treatments in Finland. Direct costs comprised drug costs, administration costs, costs of switching, and outpatient and inpatient care, while indirect costs included disability pension and sick leaves due to rheumatoid arthritis. Several subgroup and deterministic sensitivity analyses were conducted.ResultsDrug costs were the lowest for rituximab, but when administration costs and costs of switching were included, drug costs were the lowest for TNF inhibitors. Abatacept was associated with the highest drug costs, whereas rituximab was associated with the highest healthcare costs. In total, TNF inhibitors had the lowest direct costs, while rituximab had the highest direct costs. The amount of quality-adjusted life years (QALY) gained ranged from 9.405 for rituximab to 9.661 for TNF inhibitors. TNF inhibitors, abatacept, and tocilizumab were dominant in comparison to RTX.ConclusionsTNF inhibitors, abatacept, and tocilizumab had lower costs and higher QALYs than rituximab, and therefore, they were dominant in comparison to rituximab. As TNF inhibitors had the lowest costs and highest QALYs, they were the most cost-effective treatment option.
| S-EPMC6656352 | biostudies-literature
Project description:ObjectiveIn patients with active rheumatoid arthritis (RA) despite methotrexate, to compare the efficacy of adding tocilizumab to that of switching to tocilizumab monotherapy.MethodsDouble-blind, 2-year study in which adults with active RA (DAS28 >4.4) despite methotrexate were randomly assigned either to continue methotrexate with the addition of tocilizumab (MTX+TCZ) 8 mg/kg every 4 weeks or switch to tocilizumab and placebo (TCZ+PBO). The primary endpoint was the DAS28-erythrocyte sedimentation rate (ESR) remission rate at week 24. Secondary objectives included other symptomatic outcomes, quality of life and progression of structural damage.ResultsOf 556 randomly assigned patients, 512 (92%) completed 24 weeks. DAS28-ESR remission rates were 40.4% for TCZ+MTX and 34.8% for TCZ+PBO (p=0.19); American College of Rheumatology 20/50/70/90 rates were 71.5%/45.5%/24.5%/5.8% (TCZ+MTX) and 70.3%/40.2%/25.4%/5.1% (TCZ+PBO; differences not significant). A significant difference between groups was seen for low DAS28 (61.7% vs 51.4%). Radiographic progression was small and not different between groups (Genant-Sharp score progression ≤ smallest detectable change in 91% (TCZ+MTX) and 87% (TCZ+PBO)). Rates per 100 patient-years of serious adverse events and serious infections were 21 and six, respectively, for TCZ+MTX and 18 and six, respectively, for TCZ+PBO. Alanine aminotransferase elevations greater than threefold the upper limit of normal occurred in 7.8% and 1.2% of TCZ+MTX and TCZ+PBO patients, respectively.ConclusionNo clinically relevant superiority of the TCZ+MTX add-on strategy over the switch to tocilizumab monotherapy strategy was observed. The combination was more commonly associated with transaminase increases. Meaningful clinical and radiographic responses were achieved with both strategies, suggesting that tocilizumab monotherapy might be a valuable treatment strategy in suitable RA patients.
| S-EPMC3551223 | biostudies-literature
Project description:ObjectiveTo compare the efficacy and safety between tocilizumab added to methotrexate and tocilizumab switched from methotrexate in patients with active rheumatoid arthritis (RA).MethodsThis is a 2-year randomised, controlled study. RA patients with moderate or high disease activity despite methotrexate were randomly assigned either to tocilizumab added to methotrexate (add-on) or tocilizumab switched from methotrexate (switch). The primary endpoint was the DAS28 remission rate at week 24. Secondary objectives included other clinical efficacy indices, radiological outcomes assessed with the van der Heijde-modified total Sharp scoring system (mTSS), and safety.ResultsOf 223 randomised patients, 83% completed 52 weeks. DAS28 remission rates at week 24 were 70% for add-on and 55% for switch (p=0.02), but they became comparable at week 52 (72% vs 70%, p=0.86). Structural remission rates (mTSS≤0.5) at week 52 were not different (66% vs 64%, p=0.92). However, clinically relevant radiographic progression rates (CRRP; mTSS≥3) tended to be higher with the switch than with the add-on (15% vs 7%, p=0.07). Radiographic progression in the CRRP patients was larger with the switch than with the add-on (9.0/year vs 5.0/year, p=0.04). The difference in the mean C-reactive protein of the CRRP patients was significant for the first 24 weeks (1.56 vs 0.49, p=0.001) but not for the following 28 weeks (0.10 vs 0.04, p=0.1). Overall safety was preferable in the switch group.ConclusionsIn RA patients with inadequate response to methotrexate, tocilizumab added to methotrexate more rapidly suppressed inflammation than tocilizumab switched from methotrexate, leading to superior clinical efficacy and prevention of joint destruction.Trial registration numberNCT01120366.
| S-EPMC5099201 | biostudies-literature
Project description:ObjectiveTo compare work loss after starting tumour necrosis factor inhibitors (TNFi), rituximab, abatacept or tocilizumab in patients with rheumatoid arthritis (RA).MethodsWe used data from the Swedish Rheumatology Quality Register to identify patients aged 19-62 years who were treated with TNFi (n=15 093), rituximab (n=2123), abatacept (n=1877) or tocilizumab (n=1720) between 2007 and 2020. Data on work loss (0-365 days per year) from sick leave and disability pension were retrieved from linkage to the Social Insurance Agency. Patients in the different treatment arms were balanced regarding baseline covariates using inverse probability weighting (IPTW).ResultsWork loss increased for patients with RA until drug treatment initiation, reached a peak in the month after treatment initiation and then levelled off. Following IPTW, at 3 years before starting the treatment, there were no statistically significant differences in the mean annual adjusted work loss days between rituximab, abatacept or tocilizumab vs TNFi (mean difference vs TNFi: rituximab 1.1 days, 95% CI -4.5 to 6.7; abatacept 3.3, 95% CI -2.6 to 9.2; tocilizumab 1.2, 95% CI -4.9 to 7.3). At 3 years after starting the treatment (latest January 2021), there were also no statistically significant differences in the mean annual adjusted work loss days (mean difference: rituximab -4.8 days, 95% CI -11.3 to 1.7; abatacept 5.3, 95% CI -1.8 to 12.3; tocilizumab -0.6, 95% CI -7.7 to 6.5).ConclusionsTaking channelling into account, patients with RA treated with TNFi, rituximab, abatacept or tocilizumab had similar trajectories of work loss from sick leave and disability pension until treatment initiation, and similar trend breaks and plateau 3 years thereafter.
| S-EPMC11867670 | biostudies-literature
Project description:BackgroundEquivalent efficacy and comparable pharmacokinetic, immunogenicity, and safety profiles of the biosimilar BAT1806/BIIB800 and reference tocilizumab (TCZ) in participants with moderate-to-severe rheumatoid arthritis (RA) have been reported up to week 24 (treatment period [TP] 1) of the phase 3 study. Here we present results for TP2 (study weeks 24-48).MethodsIn this phase 3, multicenter, multiregional, double-blind, active-controlled, equivalence study, participants with active RA despite methotrexate were randomized (1:1:2) to intravenous administration of 8 mg/kg TCZ every 4 weeks to week 48 (TCZ group), or TCZ to week 24 followed by BAT1806/BIIB800 to week 48 (TCZ to BAT1806/BIIB800 group), or BAT1806/BIIB800 to week 48 (BAT1806/BIIB800 group). Efficacy in TP2 was evaluated using American College of Rheumatology (ACR) response criteria (ACR20/50/70) and change from baseline in Disease Activity Score on 28 joints (DAS28). Pharmacokinetics (trough levels), safety, and immunogenicity were also evaluated.ResultsOf 621 randomized participants, 577 (92.9%) completed TP1 and entered TP2 (TCZ: N = 145 [93.5%]; TCZ to BAT1806/BIIB800: N = 142 [92.2%]; BAT1806/BIIB800: N = 290 [92.9%]). Proportions of ACR20 responders were similar between treatment groups throughout TP2 (87.8%, 90.3%, and 90.4%, respectively, at week 48), as were proportions of ACR50 and ACR70 responders, and reduction in DAS28. Drug trough levels and antidrug antibody incidences were comparable between the treatment groups. Adverse events were balanced across the treatment groups and no fatal events were reported.ConclusionIn TP2, efficacy, safety, immunogenicity, and pharmacokinetic profiles were comparable between the TCZ, TCZ to BAT1806/BIIB800, and BAT1806/BIIB800 groups.Trial registrationNCT03830203 and EudraCT 2018-002202-31.
| S-EPMC11380339 | biostudies-literature
Project description:BackgroundUveitis associated with juvenile idiopathic arthritis is a cause of major ocular morbidity. A substantial proportion of children are refractory to systemic methotrexate and TNF inhibitors. Our aim was to study the safety and efficacy of tocilizumab in children with juvenile idiopathic arthritis-associated uveitis refractory to both methotrexate and TNF inhibitors.MethodsThis multicentre, single-arm, phase 2 trial was done following a Simon's two-stage design at seven tertiary hospital sites in the UK. Patients aged 2-18 years with active juvenile idiopathic arthritis-associated uveitis were eligible. All patients had been on a stable dose of methotrexate for at least 12 weeks and had not responded to treatment with a TNF inhibitor. Patients weighing 30 kg or more were treated with 162 mg subcutaneous tocilizumab every 2 weeks for 24 weeks, and participants weighing less than 30 kg were treated with 162 mg every 3 weeks for 24 weeks. The primary outcome was treatment response defined as a two-step decrease, or decrease to zero, from baseline in the level of inflammation (anterior chamber cells) at week 12, per the standardisation of uveitis nomenclature criteria. A phase 3 trial would be justified if more than seven patients responded to treatment. An interim analysis was planned to assess whether the trial would be stopped for futility, with futility defined as two or fewer treatment responses among ten participants. Adverse events were collected up to 30 calendar days after treatment cessation. The primary analysis was done in the intention-to-treat population and the safety analysis was done in all patients who started the treatment. This trial is registered with the International Standard Randomised Controlled Trial Number registry (ISRCTN95363507) and EU Clinical Trials Register (EudraCT 2015-001323-23).Findings22 participants were enrolled to the trial between Dec 3, 2015, and March 9, 2018, and 21 participants received treatment. One participant was found to be ineligible immediately after enrolment and was therefore withdrawn. Seven of 21 (median unbiased estimate of proportion 34% [95% CI 25-57]) responded to treatment (p=0·11). Safety results were consistent with the known safety profile of tocilizumab.InterpretationThe primary endpoint was not met, and thus the results do not support a phase 3 trial of tocilizumab in patients with juvenile idiopathic arthritis-associated uveitis. Importantly, data on the use of tocilizumab in clinical practice is now captured in national registries. Despite this trial not meeting the threshold required to justify a larger phase 3 trial, several patients responded to treatment; as such, tocilzumab might still be a therapeutic option in some children with uveitis refractory to anti-TNF drugs, given the absence of other treatment options.FundingVersus Arthritis and the National Institute for Health Research Clinical Research Network: Children.
| S-EPMC7134526 | biostudies-literature
Project description:ObjectivesAround 30% of patients with RA have an inadequate response to MTX. We aimed to use routine clinical and biological data to build machine learning models predicting EULAR inadequate response to MTX and to identify simple predictive biomarkers.MethodsModels were trained on RA patients fulfilling the 2010 ACR/EULAR criteria from the ESPOIR and Leiden EAC cohorts to predict the EULAR response at 9 months (± 6 months). Several models were compared on the training set using the AUROC. The best model was evaluated on an external validation cohort (tREACH). The model's predictions were explained using Shapley values to extract a biomarker of inadequate response.ResultsWe included 493 therapeutic sequences from ESPOIR, 239 from EAC and 138 from tREACH. The model selected DAS28, Lymphocytes, Creatininemia, Leucocytes, AST, ALT, swollen joint count and corticosteroid co-treatment as predictors. The model reached an AUROC of 0.72 [95% CI (0.63, 0.80)] on the external validation set, where 70% of patients were responders to MTX. Patients predicted as inadequate responders had only 38% [95% CI (20%, 58%)] chance to respond and using the algorithm to decide to initiate MTX would decrease inadequate-response rate from 30% to 23% [95% CI: (17%, 29%)]. A biomarker was identified in patients with moderate or high activity (DAS28 > 3.2): patients with a lymphocyte count superior to 2000 cells/mm3 are significantly less likely to respond.ConclusionOur study highlights the usefulness of machine learning in unveiling subgroups of inadequate responders to MTX to guide new therapeutic strategies. Further work is needed to validate this approach.
| S-EPMC10321123 | biostudies-literature