Objective To estimate the effect of denosumab compared with oral bisphosphonates on reducing the risk of type 2 diabetes in adults with osteoporosis. Design Population based study involving emulation of a randomized target trial using electronic health records. Setting IQVIA Medical Research Data primary care database in the United Kingdom, 1995-2021. Participants Adults aged 45 years or older who used denosumab or an oral bisphosphonate for osteoporosis. Main outcome measures The primary outcome was incident type 2 diabetes, as defined by diagnostic codes. Cox proportional hazards models were used to estimate adjusted hazard ratios and 95% confidence intervals, comparing denosumab with oral bisphosphonates using an as treated approach. Results 4301 new users of denosumab were matched on propensity score to 21 038 users of an oral bisphosphonate and followed for a mean of 2.2 years. The incidence rate of type 2 diabetes in denosumab users was 5.7 (95% confidence interval 4.3 to 7.3) per 1000 person years and in oral bisphosphonate users was 8.3 (7.4 to 9.2) per 1000 person years. Initiation of denosumab was associated with a reduced risk of type 2 diabetes (hazard ratio 0.68, 95% confidence interval 0.52 to 0.89). Participants with prediabetes appeared to benefit more from denosumab compared with an oral bisphosphonate (hazard ratio 0.54, 0.35 to 0.82), as did those with a body mass index ≥30 (0.65, 0.40 to 1.06). Conclusions In this population based study, denosumab use was associated with a lower risk of incident type 2 diabetes compared with oral bisphosphonate use in adults with osteoporosis. This study provides evidence at a population level that denosumab may have added benefits for glucose metabolism compared with oral bisphosphonates.
In daily clinical practice, the DAS28 and RAPID3 definitions identified remission about twice as often as the ACR/EULAR Boolean, SDAI, and CDAI. Predictors of remission were similar across remission definitions. These findings provide additional evidence to follow treatment recommendations and treat RA early with a DMARD.
ObjectiveThe objective of this study was to compare achievement of remission in 2 early rheumatoid arthritis (RA) treat‐to‐target (TTT) cohorts, a tight control cohort with a target of stringent remission in a randomized controlled trial and an observational cohort targeting a looser definition of remission in clinical practice.MethodsWe analyzed data from the Aiming for Remission in Rheumatoid Arthritis: a randomised trial examining the benefit of ultrasound in a Clinical Tight Control regimen (ARCTIC) trial and the Norwegian Very Early Arthritis Clinic (NOR‐VEAC) observational study. Both were Norwegian multicenter studies that included disease‐modifying antirheumatic drug (DMARD)–naive RA patients and implemented TTT. The target in the ARCTIC trial was remission defined as a Disease Activity Score (DAS) of <1.6 plus 0 swollen joints on a 44‐joint count, while the target in the NOR‐VEAC study was the less stringent remission target of a DAS28 of <2.6. We assessed achievement of the study‐specific targets and compared the odds of achieving the American College of Rheumatology(ACR)/European League Against Rheumatism (EULAR) Boolean remission during 2 years of follow‐up.ResultsWe included 189 patients from the ARCTIC trial and 330 patients from the NOR‐VEAC study. The study‐specific target had been achieved in more than half of the patients in each cohort at 6 months, increasing to >60% at 12 and 24 months. The odds of achieving ACR/EULAR Boolean remission during follow‐up were higher in the ARCTIC trial than in the NOR‐VEAC study, with significant differences at 3 months (odds ratio 1.73 [95% confidence interval 1.03–2.89]), 12 months (odds ratio 1.97 [95% confidence interval 1.21–3.20]), and 24 months (odds ratio 1.82 [95% confidence interval 1.05–3.16]).ConclusionA majority of patients in both cohorts reached the study‐specific treatment targets. More patients in the ARCTIC trial than in the NOR‐VEAC study achieved ACR/EULAR Boolean remission during follow‐up, suggesting that targeting a more stringent definition of remission provides further potential for favorable outcomes of a TTT strategy.
ObjectiveWhen initiating a new therapy in patients with rheumatoid arthritis (RA), current treatment recommendations suggest escalating therapy in case of poor clinical improvement by 3 months or if the treatment target has not been reached by 6 months. We investigated which disease activity improvement levels at 3 months predicted achievement of the treatment targets at 6 months in a real-life clinical setting.MethodsWe included 1610 patients with RA enrolled in the NOR-DMARD study between 2000 and 2012. Analyses were performed for the total group of patients and repeated for subgroups stratified by baseline disease activity, disease duration or treatment with methotrexate or a tumour necrosis factor inhibitor. We used a diagnostic test approach to explore the associations between 3-month response and 6-month outcome.ResultsNot achieving 50% improvement in Simplified Disease Activity Index (SDAI) by 3 months significantly decreased the likelihood of reaching remission at 6 months in all subgroups (negative likelihood ratios (LRs−) 0.15–0.36). Patients with high disease activity when initiating treatment were likely to fail reaching remission if they achieved less than SDAI 70% response by 3 months (LR− 0.25 and negative predictive value 0.98). Achieving a major response (SDAI 85%) at 3 months significantly increased the likelihood of reaching remission at 6 months (LRs+ 6.56).ConclusionLevels of 3-month disease activity improvement can inform clinicians when deciding to continue or adjust ongoing therapy in a treat-to-target strategy aiming for remission or low disease activity within 6 months. The required levels of 3-month improvement varied with baseline disease activity.
Objective Little is known about acute calcium pyrophosphate (CPP) crystal arthritis flare rates and risk factors for recurrence. We characterized flares and determined the rate and predictors of acute CPP crystal arthritis flares in an academic medical center cohort. Methods We performed a retrospective cohort study among a random sample of patients with acute CPP crystal arthritis identified in the Partners HealthCare electronic medical record, 1991–2017. Flare was defined as self-limited, acute-onset synovitis with synovial fluid CPP crystals and/or chondrocalcinosis, not better explained by another cause. We calculated incidence rates (IR) for acute CPP crystal arthritis flare among all subjects and by sex. We estimated HR for recurrent flare using univariate Cox models that accounted for within-person correlated data. Results We identified 70 patients with acute CPP crystal arthritis with a total of 111 flares. Recurrent flares occurred in 24% of patients; half of flares occurred in a previously unaffected joint. The acute CPP crystal arthritis flare rate was 11.4 per 100 person-years overall (95% CI 8.2–15.4), 14.2 in women (95% CI 9.6–0.1), and 7.1 in men (95% CI 3.4–13.0). Cancer (HR 2.98, 95% CI 1.33–6.68) and chronic kidney disease (HR 2.92, 95% CI 1.10–7.76) were associated with a higher rate for recurrent flare. Conclusion Recurrent flares occurred in about one-fourth of patients with acute CPP crystal arthritis and often occurred in previously unaffected joints. The acute CPP crystal arthritis flare rate was twice as high in women as in men.
Background Observational data are increasingly being used to conduct external comparisons to clinical trials. In this study, we empirically examined whether different methodological approaches to longitudinal missing data affected study conclusions in this setting. Methods We used data from one clinical trial and one prospective observational study, both Norwegian multicenter studies including patients with recently diagnosed rheumatoid arthritis and implementing similar treatment strategies, but with different stringency. A binary disease remission status was defined at 6, 12, and 24 months in both studies. After identifying patterns of longitudinal missing outcome data, we evaluated the following five approaches to handle missingness: analyses of patients with complete follow-up data, multiple imputation (MI), inverse probability of censoring weighting (IPCW), and two combinations of MI and IPCW. Results We found a complex non-monotone missing data pattern in the observational study (N = 328), while missing data in the trial (N = 188) was monotone due to drop-out. In the observational study, only 39.0% of patients had complete outcome data, compared to 89.9% in the trial. All approaches to missing data indicated favorable outcomes of the treatment strategy in the trial and resulted in similar study conclusions. Variations in results across approaches were mainly due to variations in estimated outcomes for the observational data. Conclusions Five different approaches to handle longitudinal missing data resulted in similar conclusions in our example. However, the extent and complexity of missing observational data affected estimated comparative outcomes across approaches, highlighting the need for careful consideration of methods to account for missingness in this setting. Based on this empirical examination, we recommend using a prespecified advanced missing data approach to account for longitudinal missing data, and to conduct alternative approaches in sensitivity analyses.
BackgroundWhen initiating therapy with synthetic disease-modifying anti-rheumatic drugs (sDMARDs) in patients with rheumatoid arthritis (RA), the recommended target is remission or low disease activity (LDA). Limited data exist on the impacts of reaching remission rather than LDA on long-term outcomes.ObjectivesTo compare RA-patients who achieved Simplified Disease Activity Index (SDAI) remission versus LDA 6 months after initiating sDMARD therapy, with regard to physical function, Health Related Quality of Life (HRQoL) and disease activity during 5 years of follow-up in a routine clinical setting.MethodsData were provided NOR-DMARD, a prospective multicentre longitudinal observational study. We selected DMARD-naïve patients with RA enrolled between December 2000 and April 2009 who had a registered visit with available SDAI status 6 months after initiating sDMARD therapy. Data on each patient were collected at baseline, after 3, 6 and 12 months, and yearly thereafter, including the modified Health Assessment Questionnaire (MHAQ), the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) with Physical and Mental Components Summary scores (PCS and MCS, respectively) and SF-6D, and assessments that allowed the calculation of the composite disease activity scores SDAI, Clinical Disease Activity Index (CDAI) and the Disease Activity Score based on 28 joint counts (DAS28). Multivariate linear mixed models were used to explore the effect of SDAI status at 6 months on physical function (MHAQ), HRQoL (SF-36 PCS and MCS, SF-6D) and disease activity (SDAI, CDAI, DAS28) during 5 year follow-up. The statistical models were adjusted for age, gender, disease duration and baseline disease activity. Furthermore, we performed mixed model analyses separately for patients in LDA, MDA and HDA at baseline, exploring the impact of SDAI status at 6 months on long-term disease activity in each sub-group.ResultsOf 1148 eligible patients, 867 patients (75.5%) started with methotrexate in monotherapy and 281 (24.5%) started with another sDMARD or sDMARD combination. Patients in SDAI remission (n=145; 16.6%) rather than LDA (n=454; 39.5%) 6 months after initiating therapy had better physical function (MHAQ, estimated mean difference 0.11–0.20, p<0.02), higher SF-36 PCS (4.13–8.16, p<0.003) and SF-6D (0.06–0.12, p<0.0001), and lower disease activity (SDAI, 2.24–5.15, p<0.05) for all visits during 5 years of follow-up. Stratified mixed models analyses of patients in SDAI LDA, MDA and HDA at baseline, resulted in an overall significant long-term beneficial effect of achieving remission rather than LDA at 6 months; however, the differences were less distinct for patients who were already in a state of LDA at baseline.ConclusionsThe achievement of SDAI remission 6 months after initiating DMARD-therapy was associated with favourable long-term outcomes compared with the achievement of SDAI low disease activity. The results from the study support that stringent remission is the optimal treatment target in patients with RA.Disclosure of Inte...
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