Real-world Comparative Effectiveness of Tocilizumab Monotherapy vs. Tumor Necrosis Factor Inhibitors with Methotrexate in Patients with Rheumatoid Arthritis

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-naive patients from the Corrona RA registry with prior exposure to \u3e /= 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 \u3c /= 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 ( \u3c /= 10 mg; \u3e 10 to \u3c /= 15 mg; \u3e 15 to \u3c /= 20 mg; \u3e 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

Comparative effectiveness and safety of rituximab versus subsequent anti-tumor necrosis factor therapy in patients with rheumatoid arthritis with prior exposure to anti-tumor necrosis factor therapies in the United States Corrona registry

INTRODUCTION: Patients with active rheumatoid arthritis (RA) despite anti-tumor necrosis factor(anti-TNF)agent treatment can switch to either a subsequent anti-TNF agent or a biologic with an alternative mechanism of action, such as rituximab; however, there are limited data available to help physicians decide between these 2 strategies. The objective of this analysis was to examine the effectiveness and safety of rituximab versus a subsequent anti-TNF agent in anti-TNF-experienced patients with RA using clinical practice data from the Corrona registry. METHODS: Rituximab-naive patients from the Corrona registry with prior exposure to \u3e /=1 anti-TNF agent who initiated rituximab or anti-TNF agents (2/28/2006-10/31/2012) were included. Two cohorts were analyzed: the trimmed population (excluding patients who fell outside the propensity score distribution overlap) and the stratified-matched population (stratified by 1 vs \u3e /=2 anti-TNF agents, then matched based on propensity score). The primary effectiveness outcome was achievement of low disease activity (LDA)/remission (Clinical Disease Activity Index \u3c /=10) at 1 year. Secondary outcomes included achievement of modified American College of Rheumatology (mACR) 20/50/70 responses and meaningful improvement ( \u3e /=0.25) in modified Health Assessment Questionnaire (mHAQ) score at 1 year. New cardiovascular, infectious and cancer events were reported. RESULTS: Estimates for LDA/remission, mACR response and mHAQ improvement were consistently better for rituximab than for anti-TNF agent users in adjusted analyses. The odds ratio for likelihood of LDA/remission in rituximab versus anti-TNF patients was 1.35 (95 % CI, 0.95-1.91) in the trimmed population and 1.54 (95 % CI, 1.01-2.35) in the stratified-matched population. Rituximab patients were significantly more likely than anti-TNF patients to achieve mACR20/50 and mHAQ improvement in the trimmed population and mACR20 and mHAQ in the stratified-matched population. The rate of new adverse events per 100 patient-years was similar between groups. CONCLUSIONS: In anti-TNF-experienced patients with RA, rituximab was associated with an increased likelihood of achieving LDA/remission, mACR response and physical function improvement, with a comparable safety profile, versus subsequent anti-TNF agent users. TRIAL REGISTRATION: ClinicalTrials.gov NCT01402661. Registered 25 July 2011

Hydroxychloroquine and the risk of respiratory infections among RA patients

OBJECTIVES: To determine the effect of hydroxychloroquine on the incidence of new respiratory infections in a large registry of rheumatoid arthritis (RA) patients compared with a matched cohort receiving other conventional disease-modifying antirheumatic drugs (csDMARDs). METHODS: We reviewed physician-reported infections including upper respiratory infections (URI), bronchitis and pneumonia in the Corrona RA registry from June 2008 to February 2020 with the goal of comparing infections in biologic/targeted synthetic (b/ts) DMARDs naive HCQ starts compared with starts of other csDMARDs and no HCQ. Patients on different interventions were compared using time-varying adjusted Cox models adjusting for age, sex, duration of RA, BMI, disease activity, smoking status, concurrent medications, season of the year, year of onset and history of serious infections, diabetes or cardiovascular disease (CVD). A secondary analysis in a set of propensity-matched starts were also compared adjusting for time-varying covariates. The analysis was repeated including URI and bronchitis only and also for serious respiratory infections only. RESULTS: No evidence of differences was found in the incidence of any respiratory infection (URI, bronchitis, pneumonia) in patients receiving HCQ compared with other csDMARDs: HR=0.87 (0.70 to1.07) in adjusted analyses and HR=0.90 (0.70 to 1.17) in adjusted matched analysis. Similar results were found in the analysis of URI and bronchitis only and for serious respiratory infections only. CONCLUSIONS: In patients with RA, the risk for respiratory infections was similar among patients using HCQ as compared to other non-biologic DMARDs

Comparative effectiveness of abatacept versus tocilizumab in rheumatoid arthritis patients with prior TNFi exposure in the US Corrona registry

BACKGROUND: We compared the effectiveness of abatacept (ABA) vs tocilizumab (TCA) in tumor necrosis factor inhibitor (TNFi) experienced patients. METHODS: We identified rheumatoid arthritis (RA) patients from a large observational US cohort (1 January 2010-31 May 2014) who had discontinued at least one TNFi and initiated ABA or TCZ in moderate or high disease activity based on the Clinical Disease Activity Index (CDAI) and had no prior exposure to the comparator drug. Using propensity score matching (1:1) stratified by prior TNF use (1 TNFi vs ≥2 TNFis), effectiveness at 6 months after initiation was evaluated. Mean change in CDAI over 6 months following initiation was the primary outcome, with secondary outcomes of achievement of low disease activity/remission (CDAI ≤ 10) and mean change in modified Health Assessment Questionnaire (mHAQ) score. RESULTS: The 264 pairs of propensity score-matched ABA and TCZ initiators were well matched with no substantial differences in the baseline characteristics, defined as standardized differences \u3e0.1 in the stratification. Both treatment groups had similar mean change in CDAI at 6 months (-11.3 in ABA vs -9.9 in TCZ; mean difference -1.27, 95% CI -3.65, 1.11). Similar proportions of both treatment groups achieved low disease activity/remission (adjusted odds ratio for ABA vs TCZ 0.99, 95% CI 0.69, 1.43). Mean change in mHAQ was -0.12 in ABA initiators vs -0.11 in TCZ initiations (mean difference -0.01, 95% CI -0.09, 0.06). CONCLUSIONS: Patients receiving either ABA or TCZ had substantial improvement in clinical disease activity. In this propensity score-matched sample, similar outcomes were observed for both treatment cohorts

The comparative effectiveness of abatacept versus anti-tumour necrosis factor switching for rheumatoid arthritis patients previously treated with an anti-tumour necrosis factor

OBJECTIVE: We compared the effectiveness of abatacept (ABA) versus a subsequent anti-tumour necrosis factor inhibitor (anti-TNF) in rheumatoid arthritis (RA) patients with prior anti-TNF use. METHODS: We identified RA patients from a large observational US cohort (2/1/2000-8/7/2011) who had discontinued at least one anti-TNF and initiated either ABA or a subsequent anti-TNF. Using propensity score (PS) matching (n:1 match), effectiveness was measured at 6 and 12 months after initiation based on mean change in Clinical Disease Activity Index (CDAI), modified American College of Rheumatology (mACR) 20, 50 and 70 responses, modified Health Assessment Questionnaire (mHAQ) and CDAI remission in adjusted regression models. RESULTS: The PS-matched groups included 431 ABA and 746 anti-TNF users at 6 months and 311 ABA and 493 anti-TNF users at 12 months. In adjusted analyses comparing response following treatment with ABA and anti-TNF, the difference in weighted mean change in CDAI (range 6-8) at 6 months (0.46, 95% CI -0.82 to 1.73) and 12 months was similar (-1.64, 95% CI -3.47 to 0.19). The mACR20 responses were similar at 6 (28-32%, p=0.73) and 12 months (35-37%, p=0.48) as were the mACR50 and mACR70 (12 months: 20-22%, p=0.25 and 10-12%, p=0.49, respectively). Meaningful change in mHAQ was similar at 6 and 12 months (30-33%, p=0.41 and 29-30%, p=0.39, respectively) as was CDAI remission rates (9-10%, p=0.42 and 12-13%, p=0.91, respectively). CONCLUSIONS: RA patients with prior anti-TNF exposures had similar outcomes if they switched to a new anti-TNF as compared with initiation of ABA

Effectiveness of Rituximab for the Treatment of Rheumatoid Arthritis in Patients with Prior Exposure to Anti-TNF: Results from the CORRONA Registry

OBJECTIVE: To characterize the real-world effectiveness of rituximab (RTX) in patients with rheumatoid arthritis. METHODS: Clinical effectiveness at 12 months was assessed in patients who were prescribed RTX based on the Clinical Disease Activity Index (CDAI). Change in CDAI was calculated (CDAI at 12 mos minus at initiation). Achievement of remission or low disease activity (LDA; CDAI \u3c /= 10) among those with moderate/high disease activity at the time of RTX initiation was compared based on prior anti-tumor necrosis factor agent (anti-TNF) use (1 vs \u3e /= 2) using logistic regression models. RESULTS: Patients (n = 265) were followed for 12 months with a mean change in CDAI of -8.1 (95% CI -9.8 - -6.4). Of the 218 patients with moderate/high disease activity at baseline, patients with 1 prior anti-TNF (baseline CDAI 25.0) demonstrated a mean change in CDAI of -10.1 (95% CI -13.2 - -7.0); patients with \u3e /= 2 prior anti-TNF (baseline CDAI 30.0) demonstrated a mean change of -10.5 (95% CI -12.9 - -8.0). The unadjusted OR for achieving LDA/remission in patients with moderate/high disease activity at baseline exposed to \u3e /= 2 versus 1 prior anti-TNF was 0.40 (95% CI 0.22-0.73), which was robust to 4 different adjusted models (OR range 0.38-0.44). CONCLUSION: A good clinical response was observed in all patients; however, patients previously treated with 1 anti-TNF, who had lower baseline CDAI and a greater opportunity for clinical improvement compared with patients previously treated with \u3e /= 2 anti-TNF, were more likely to achieve LDA/remission

Model-Based Filtering of Combinatorial Test Suites

International audienceTobias is a combinatorial test generation tool which can efficiently generate a large number of test cases by unfolding a test pattern and computing all combinations of parameters. In this paper, we first propose a model-based testing approach where Tobias test cases are first run on an executable UML/OCL specification. This animation of test cases on a model allows to filter out invalid test sequences produced by blind enumeration, typically the ones which violate the pre-conditions of operations, and to provide an oracle for the valid ones. We then introduce recent extensions of the Tobias tool which support an incremental unfolding and filtering process, and its associated toolset. This allows to address explosive test patterns featuring a large number of invalid test cases, and only a small number of valid ones. For instance, these new constructs could mandate test cases to satisfy a given predicate at some point or to follow a given behavior. The early detection of invalid test cases improves the calculation time of the whole generation and execution process, and helps fighting combinatorial explosion

Impact of Tocilizumab Monotherapy on Clinical and Patient-Reported Quality-of-Life Outcomes in Patients with Rheumatoid Arthritis

INTRODUCTION: Tocilizumab (TCZ) monotherapy has been proven as an effective treatment for rheumatoid arthritis (RA) in clinical trials. However, there are limited data available regarding the effectiveness of TCZ monotherapy in real-world clinical settings in the United States. The objective of this study was to evaluate the impact of TCZ monotherapy on disease activity and patient-reported outcomes (PROs) in a US-based observational cohort of patients with RA seen in routine clinical practice. METHODS: Eligible patients had active RA, no prior use of TCZ, and initiated TCZ as monotherapy. Changes in disease activity and PROs were assessed 1 year after TCZ initiation for the overall cohort and stratified by number of prior tumor necrosis factor inhibitors (TNFis; 0, 1, or \u3e /=2). Primary outcomes were change in Clinical Disease Activity Index (CDAI); change in patient global disease activity, pain, fatigue; and the proportions of patients with improvement in modified Health Assessment Questionnaire (mHAQ), morning stiffness, and EQ-5D. RESULTS: Of 255 eligible TCZ monotherapy initiators, 9.4% were TNFi naive, 36.5% had one prior TNFi, and 54.1% had \u3e /=2 prior TNFis. Clinical and PRO measures indicated that patients were substantially impacted by their disease at baseline. The median decrease in CDAI from baseline to 1 year was 9.8 and median patient global and pain scores improved by 10 mm, indicative of clinically meaningful improvement; the median fatigue score improved by 5 mm. Approximately 26% of patients reported clinically meaningful improvement in mHAQ, 54% experienced improvement in morning stiffness, and 20% to 36% experienced improvement in EQ-5D domains (walking, self-care, usual activities, pain/discomfort, and anxiety/depression). Improvements were similar across TNFi groups. CONCLUSIONS: Patients with active, refractory RA who initiated TCZ monotherapy experienced improvements in both composite disease activity scores and PROs at 1 year, regardless of prior TNFi exposure. FUNDING: Corrona, LLC and Genentech

The rheumatoid arthritis treat-to-target trial: a cluster randomized trial within the Corrona rheumatology network

BACKGROUND: The treat-to-target (T2T) approach to the care of patients with rheumatoid arthritis involves using validated metrics to measure disease activity, frequent follow-up visits for patients with moderate to high disease activity, and escalation of therapy when patients have inadequate therapeutic response as assessed by standard disease activity scores. The study described is a newly launched cluster-randomized behavioral intervention to assess the feasibility and effectiveness of the T2T approach in US rheumatology practices. It is designed to identify patient and provider barriers to implementing T2T management. This initial paper focuses on the novel study design and methods created to provide these insights. METHODS/DESIGN: This trial cluster-randomizes rheumatology practices from the existing Corrona network of private and academic sites rather than patients within sites or individual investigators to provide either T2T or usual care (UC) for qualified patients who meet the 2010 revised American College of Rheumatology criteria for the diagnosis of rheumatoid arthritis and have moderate to high disease activity. Specific medication choices are left to the investigator and patient, rather than being specified in the protocol. Enrollment is expected to be completed by the end of 2013, with 30 practices randomized and enrolling a minimum of 530 patients. During the 12-month follow-up, visits are mandated as frequently as monthly in patients with active disease in the T2T group and every 3 months for the UC group. Safety data are collected at each visit. The coprimary endpoints include a comparison of the proportion of patients achieving low disease activity in the T2T and UC groups and assessment of the feasibility of implementing T2T in rheumatology practices, specifically assessment of the rates of treatment acceleration, frequency of visits, time to next visit conditional on disease activity, and probability of acceleration conditional on disease activity in the 2 groups. DISCUSSION: This cluster-randomized behavioral intervention study will provide valuable insights on the outcomes and feasibility of employing a T2T treatment approach in clinical practice in the United States. TRIAL REGISTRATION: NCT01407419

Immunosuppressive treatment and the risk of diabetes in rheumatoid arthritis

OBJECTIVE: Inflammation and anti-inflammatory treatments might influence the risk of diabetes. The objective of this study was to assess factors associated with incident diabetes in rheumatoid arthritis (RA). METHODS: The study population consisted of RA patients from a multi-center cohort study, Corrona. To assess risk associated with disease modifying antirheumatic drug (DMARD) exposure, we assessed five mutually exclusive DMARD groups. Additionally, we assessed the risk associated with body mass index (BMI, \u3c 25, 25-30, \u3e 30 kg/m2) and glucocorticoid usage. Incident cases of diabetes were confirmed through adjudication, and Cox regression models were fit to estimate the risk of incident diabetes. RESULTS: We identified 21,775 DMARD treatment regimens, the mean (SD) age at the index visit was 58 (13) years, disease duration 10 (10) years, and 30% used oral glucocorticoids at the time. Eighty-four incident cases of diabetes were confirmed within the treatment exposure periods. The hazard ratio (HR, 95% confidence interval) for diabetes was significantly reduced in patients receiving TNF inhibitors, HR 0.35 (0.13, 0.91), compared to patients treated with non-biologic DMARDs other than hydroxychloroquine and methotrexate. Hydroxychloroquine, methotrexate and use of other biologic DMARDs had a numerically reduced risk compared to the same group. Patients prescribed \u3e /=7.5 mg of glucocorticoids had a HR of 2.33 (1.68, 3.22) of incident diabetes compared with patients not prescribed oral glucocorticoids. RA patients with a BMI \u3e 30 had a HR of 6.27 (2.97, 13.25) compared to patients with BMI \u3c /=25. CONCLUSION: DMARDs, glucocorticoids and obesity influenced the risk of incident diabetes in a large cohort of RA patients. Monitoring for the occurrence of diabetes should be part of routine RA management with a focus on specific subgroups