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100 Publications visible to you, out of a total of 100
Incidence of Major Adverse Cardiovascular Events in Patients With Rheumatoid Arthritis Treated With JAK Inhibitors Compared With Biologic Disease-Modifying Antirheumatic Drugs: Data From an International Collaboration of Registries

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OBJECTIVE: Our objective was to assess the incidence of major adverse cardiovascular events (MACEs) in patients with rheumatoid arthritis (RA) treated with JAK inhibitors (JAKi), tumor necrosis factor … inhibitors (TNFi), or biologic disease-modifying antirheumatic drugs with other modes of action (bDMARD-OMA) in a multicountry, real-world population. METHODS: Patients with RA from 15 registries in the JAK-pot collaboration were included. MACE incidence was analyzed using two approaches: a within-registry analysis aggregating country-specific estimates from registers with >25 incident MACEs through meta-analysis and an individual-level data combined analysis. We used adjusted linear mixed Poisson regression to obtain incidence rate ratios (IRRs) of MACEs between treatment groups, accounting for multiple treatment courses. RESULTS: The study included 73,008 treatment courses (16,417 JAKi, 35,373 TNFi, and 21,218 bDMARD-OMA) and 828 incident MACEs among 51,233 patients. Median follow-up time was 1.3 years, with most of the follow-up concentrated in the first two years of treatment. Incidence rates were 7.0, 7.6, and 11.8 per 1,000 person-years for JAKi, TNFi, and bDMARD-OMA, respectively. Compared to TNFi, JAKi (within-registry adjusted IRR 0.89, 95% confidence interval [CI] 0.63-1.25) had similar incidence rates of MACEs and bDMARD-OMA had higher rates (within-registry adjusted IRR 1.35, 95% CI 1.10-1.66). Combined analysis showed similar results. CONCLUSION: Observational data from the JAK-pot collaboration show no evidence of an increase in cardiovascular events during the first two years of use with JAKi compared to TNFi in the general RA population.

Authors: R. Aymon, D. Mongin, R. Guemara, Z. Salis, J. Askling, D. Choquette, C. Codreanu, D. Di Giuseppe, I. Flouri, D. Huschek, K. L. Hyrich, F. Iannone, T. K. Kvien, B. F. Leeb, D. Nordstrom, L. Otero-Varela, K. Pavelka, M. Pombo-Suarez, A. Rodrigues, Z. Rotar, P. Sidiropoulos, S. A. Provan, A. Strangfeld, T. Nina, J. Zavada, L. Kearsley-Fleet, D. S. Courvoisier, A. Finckh, K. Lauper

Date Published: 2025

Publication Type: Journal

Comparative risk of incident malignancies in rheumatoid arthritis patients treated with Janus kinase inhibitors or bDMARDs: observational data from the German RABBIT register

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ABSTRACT Objectives To estimate the effects of Janus kinase inhibitors (JAKis) vs biologic disease-modifying antirheumatic drugs (bDMARDs) on the risk of incident malignancies (excluding nonmelanoma … skin cancer) in patients and patient subgroups with rheumatoid arthritis. Methods Episodes of disease-modifying antirheumatic drug (DMARD) treatment initiated between January 2017 and December 2020 and followed up to June 2024 in RABBIT, the German register for the long-term observation of therapy with biologics and targeted disease-modifying antirheumatic drugs in adult patients with rheumatoid arthritis, were analysed. Incidence rates (IRs) per 1000 patient-years with 95% CIs were calculated, and incident malignancy risk was estimated as hazard ratios (HRs) by inverse probability weighted adjusted Cox models. Results Among 2285 JAKi and 4259 bDMARD treatment episodes, 88 and 135 malignancies occurred, respectively. JAKi treatments were dominated by baricitinib and tofacitinib, while most bDMARD treatments comprised tumour necrosis factor inhibitors. IRs were 11.6 (95% CI: 9.3, 14.3) in JAKi- and 8.9 (95% CI: 7.4, 10.5) in bDMARD-treated groups. The adjusted HR comparing JAKis with bDMARDs was 1.40 (95% CI: 1.09, 1.80). An increase in the malignancy risk for JAKi vs bDMARD treatment could only be observed in treatment episodes lasting longer than 16 months. The risk appeared higher in some subgroups of patients, including those who started treatment aged ≥60 years, patients with ≥3 prior conventional synthetic DMARD treatments, and patients with high disease activity. Conclusions In this German observational cohort study, an overall small increase in malignancy risk for JAKi vs bDMARD treatment was observed, with more pronounced risks in some subgroups of patients. The observed risk should be carefully counterbalanced to the known malignancy risk associated with insufficient disease control.

Authors: Martin Schaefer, Alina Purschke, Vera Zietemann, Tatjana Rudi, Yvette Meissner, Adrian Richter, Sylvia Berger, Karin Rockwitz, Klaus Krüger, Karl Matthias Schneider, Anne C. Regierer, Anja Strangfeld

Date Published: 2025

Publication Type: Journal

Evaluation of discontinuation for adverse events of JAK inhibitors and bDMARDs in an international collaboration of rheumatoid arthritis registers (the ’JAK-pot’ study)

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BACKGROUND: In a clinical trial setting, patients with rheumatoid arthritis (RA) taking the Janus kinase inhibitor (JAKi) tofacitinib demonstrated higher adverse events rates compared with those taking … the tumour necrosis factor inhibitors (TNFi) adalimumab or etanercept. OBJECTIVE: Compare treatment discontinuations for adverse events (AEs) among second-line therapies in an international real-world RA population. METHODS: Patients initiating JAKi, TNFi or a biological with another mode of action (OMA) from 17 registers participating in the ’JAK-pot’ collaboration were included. The primary outcome was the rate of treatment discontinuation due to AEs. We used unadjusted and adjusted cause-specific Cox proportional hazard models to compare treatment discontinuations for AEs among treatment groups by class, but also evaluating separately the specific type of JAKi. RESULTS: Of the 46 913 treatment courses included, 12 523 were JAKi (43% baricitinib, 40% tofacitinib, 15% upadacitinib, 2% filgotinib), 23 391 TNFi and 10 999 OMA. The adjusted cause-specific hazard rate of treatment discontinuation for AEs was similar for TNFi versus JAKi (1.00, 95% CI 0.92 to 1.10) and higher for OMA versus JAKi (1.11, 95% CI 1.01 to 1.23), lower with TNFi compared with tofacitinib (0.81, 95% CI 0.71 to 0.90), but higher for TNFi versus baricitinib (1.15, 95% CI 1.01 to 1.30) and lower for TNFi versus JAKi in patients 65 or older with at least one cardiovascular risk factor (0.79, 95% CI 0.65 to 0.97). CONCLUSION: While JAKi overall were not associated with more treatment discontinuations for AEs, subgroup analyses suggest varying patterns with specific JAKi, such as tofacitinib, compared with TNFi. However, these observations should be interpreted cautiously, given the observational study design.

Authors: R. Aymon, D. Mongin, S. A. Bergstra, D. Choquette, C. Codreanu, D. De Cock, L. Dreyer, O. Elkayam, D. Huschek, K. L. Hyrich, F. Iannone, N. Inanc, L. Kearsley-Fleet, S. S. Koca, T. K. Kvien, B. F. Leeb, G. Lukina, D. C. Nordstrom, K. Pavelka, M. Pombo-Suarez, A. Rodrigues, Z. Rotar, A. Strangfeld, P. Verschueren, R. Westermann, J. Zavada, D. S. Courvoisier, A. Finckh, K. Lauper

Date Published: 2024

Publication Type: Journal

Multiple morbidities are associated with serious infections in patients with rheumatoid arthritis

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OBJECTIVE: To assess the association between a comprehensive list of morbidities and serious infection (SI) in patients with rheumatoid arthritis (RA). METHODS: This study evaluated SI risk associated … with 55 comorbidities using a population-based inception cohort including all adult patients with incident RA from 1999 through 2014 with follow up through 2021. Morbidities and SI were ascertained using previously validated international classification of disease (ICD)-9 and ICD-10 codes. Conditional frailty models were utilized to analyze the association between each morbidity and SI: Model 1 adjusted for age, sex, and calendar year; Model 2 adjusted for factors in Model 1 and the Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT) Risk Score of Infections; and Model 3 adjusted for factors in Model 1 and the Mayo SI Risk Score. RESULTS: 911 patients (70 % female, mean age 56 years, 66 % seropositive) were included. There were 293 SI among 155 patients (17 %), corresponding to an incidence of 3.9 SI per 100 person-years. Eighteen SI were fatal. Risk of SI was significantly increased in 27 of 55 morbidities in Model 1, 11 morbidities in Model 2, and 23 morbidities in Model 3. Additionally, several morbidities included in the RABBIT and Mayo risk scores continued to have large effect sizes despite adjustment. Serious infection risk increased by 11-16 % per morbidity in the three models. CONCLUSIONS: Several morbidities are associated with an increased risk for SI. Future risk scores may include morbidities identified in this study for improved SI risk assessment.

Authors: B. A. Kimbrough, C. S. Crowson, R. J. Lennon, J. M. Davis, A. Strangfeld, E. Myasoedova

Date Published: 2024

Publication Type: Journal

Impact of systemic inflammation and disease activity on the incidence of interstitial lung disease in patients with rheumatoid arthritis - a nested case-control study within the German biologics register RABBIT

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BACKGROUND: To investigate the association between the development of incident interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) and the disease activity of RA with its various … components, especially C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). METHODS: We analysed data from RA patients, observed in the German biologics register RABBIT between 2001 and 2021. In a nested case-control study, patients with a reported incident ILD diagnosis during follow-up were matched 1:5 to patients without ILD. Matching criteria were sex, age, RA duration, date of enrolment and observation time. Defined by a directed acyclic graph (DAG), we adjusted the conditional logistic regression models for rheumatoid factor, smoking, chronic obstructive pulmonary disease and tuberculosis/chronic viral infections to investigate the impact of disease activity/systemic inflammation. Mean and categorized values were analysed within 12 months prior to ILD and during the entire observation time. Additionally, two sensitivity analyses were performed, using validated ILD cases only and considering ILD cases with an observation time of more than 12 months. RESULTS: We identified 139 RA patients with incident ILD and matched them to 686 controls. In 94 cases the diagnosis could be validated, and 98 cases had a follow-up of > 12 months. The averaged DAS28 composite score (including ESR or CRP) was not associated with developing RA-ILD (odds ratios 1.16 [95% confidence interval: 0.97-1.40] and 1.06 [0.86-1.29], respectively). However, single measures of inflammation, log ESR (1.86 [1.35-2.57]) and log CRP (1.55 [1.21-1.97]), were significantly associated with an increased RA-ILD risk. A higher risk for ILD was also revealed for persistently high inflammation. Other DAS28 components showed no significant associations with RA-ILD. These results were consistent for values over the entire observation time of a patient and within 12 months prior to the ILD. Sensitivity analyses confirmed these findings. CONCLUSION: Higher levels of systemic inflammation, as indicated by ESR and CRP, but not joint counts or patient’s global assessment, were significantly associated with the occurrence of incident ILD in patients with RA. As possible predictor for the development of RA-ILD, systemic inflammation should be monitored closely and independently of joint count results.

Authors: R. Ramien, T. Rudi, R. Alten, A. Krause, M. Schneider, M. Schaefer, A. Strangfeld, Y. Meissner

Date Published: 2024

Publication Type: Journal

Impact of DMARD treatment and systemic inflammation on all-cause mortality in patients with rheumatoid arthritis and interstitial lung disease: a cohort study from the German RABBIT register

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OBJECTIVES: To investigate the impact of disease activity and treatment with disease-modifying antirheumatic drugs (DMARDs) on all-cause mortality in patients with rheumatoid arthritis and prevalent … interstitial lung disease (RA-ILD). METHODS: Patients with RA-ILD were selected from the biologics register Rheumatoid Arthritis: Observation of Biologic Therapy (RABBIT). Using time-varying Cox regression, the association between clinical measures and mortality was investigated. The impact of DMARDs was analysed by (1) Cox regression considering cumulative exposure (ie, treatment months divided by total months) and (2) time-varying Cox regression as main approach (treatment exposures at monthly level). RESULTS: Out of 15 566 participants, 381 were identified as RA-ILD cases with 1258 person-years of observation and 2.6 years median length of follow-up. Ninety-seven patients (25.5%) died and 34 (35.1%) of these were not receiving DMARD therapy at the time of death. Higher inflammatory biomarkers but not swollen and tender joint count were significantly associated with mortality. Compared with tumour necrosis factor inhibitors (TNFi), non-TNFi biologic DMARDs (bDMARDs) exhibited adjusted HRs (aHRs) for mortality below 1, lacking statistical significance. This finding was stable in various sensitivity analyses. Joint aHR for non-TNFi biologics and JAKi versus TNFi was 0.56 (95% CI 0.33 to 0.97). Receiving no DMARD treatment was associated with a twofold higher mortality risk compared with receiving any DMARD treatment, aHR 2.03 (95% CI 1.23 to 3.35). CONCLUSIONS: Inflammatory biomarkers and absence of DMARD treatment were associated with increased risk of mortality in patients with RA-ILD. Non-TNFi bDMARDs may confer enhanced therapeutic benefits in patients with RA-ILD.

Authors: T. Rudi, V. Zietemann, Y. Meissner, A. Zink, A. Krause, H. M. Lorenz, C. Kneitz, M. Schaefer, A. Strangfeld

Date Published: 2024

Publication Type: Journal

Abatacept and non-melanoma skin cancer in patients with rheumatoid arthritis: a comprehensive evaluation of randomised controlled trials and observational studies

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OBJECTIVES: This study aims to evaluate non-melanoma skin cancer (NMSC) risk associated with abatacept treatment for rheumatoid arthritis (RA). METHODS: This evaluation included 16 abatacept RA clinical … trials and 6 observational studies. NMSC incidence rates (IRs)/1000 patient-years (p-y) of exposure were compared between patients treated with abatacept versus placebo, conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) and other biological/targeted synthetic (b/ts)DMARDs. For observational studies, a random-effects model was used to pool rate ratios (RRs). RESULTS:  49 000 patients receiving abatacept were analysed from clinical trials ( 7000) and observational studies ( 42 000). In randomised trials (n=4138; median abatacept exposure, 12 (range 2-30) months), NMSC IRs (95% CIs) were not significantly different for abatacept (6.0 (3.3 to 10.0)) and placebo (4.0 (1.3 to 9.3)) and remained stable throughout the long-term, open-label period (median cumulative exposure, 28 (range 2-130 months); 21 335 p-y of exposure (7044 patients over 3 years)). For registry databases, NMSC IRs/1000 p-y were 5-12 (abatacept), 1.6-10 (csDMARDs) and 3-8 (other b/tsDMARDs). Claims database IRs were 19-22 (abatacept), 15-18 (csDMARDs) and 14-17 (other b/tsDMARDs). Pooled RRs (95% CIs) from observational studies for NMSC in patients receiving abatacept were 1.84 (1.00 to 3.37) vs csDMARDs and 1.11 (0.98 to 1.26) vs other b/tsDMARDs. CONCLUSIONS: Consistent with the warnings and precautions of the abatacept label, this analysis suggests a potential increase in NMSC risk with abatacept use compared with csDMARDs. No significant increase was observed compared with b/tsDMARDs, but the lower limit of the 95% CI was close to unity.

Authors: T. A. Simon, L. Dong, S. Suissa, K. Michaud, S. Pedro, M. Hochberg, M. Boers, J. Askling, T. Frisell, A. Strangfeld, Y. Meissner, V. Khaychuk, A. Dominique, M. A. Maldonado

Date Published: 2024

Publication Type: Journal

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