Objectives To investigate rates of key safety outcomes in patients with rheumatoid arthritis (RA) initiating biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) and in reference cohorts, presented over time since the market entry of each b/tsDMARD class and over calendar period at treatment start. Methods This was a nationwide register-based cohort study conducted from 2006 to 2022. From the Swedish Rheumatology Quality Register and national registers, we identified treatment initiators of b/tsDMARDs (n = 33,550 initiations), an early bionaive RA cohort (n = 16,011), and a matched general population cohort (n = 111,074). The main outcome was first of either major adverse cardiovascular event, venous thromboembolism, cancer, or serious infection. We stratified rates by time since market entry of each b/tsDMARD class at treatment start, and by calendar year of treatment start. We calculated incidence rates (IRs) and hazard ratios (HRs) using Cox regression and adjusted for patient characteristics. Results Overall, 5862 events were observed in the b/tsDMARD initiator cohort. b/tsDMARD treatments initiated >5 (vs <2) years since market entry of that class were associated with lower outcome rates (unadjusted HR = 0.74; 95% CI = 0.67-0.81). This association was attenuated once adjusting for patient characteristics (adjusted HR = 0.93; 95% CI = 0.84-1.03). By contrast, during our study period, adjusted rates declined (adjusted HR = 0.74 and 95% CI = 0.69-0.80 for b/tsDMARDs initiated 2016-2021 vs 2006-2010), despite a constant rate in the background population. Conclusions Modest channelling makes the safety profile of b/tsDMARDs appear worse when new on the market. Declining incidences of typical RA comorbidities in b/tsDMARD initiators during recent years suggest that the bar defining an “acceptable” safety profile for new b/tsDMARDs for use in RA should be lower(ed).

Background: In recent years, there have been concerns regarding an increased risk of major adverse cardiovascular events (MACE), venous thromboembolism (VTE) and cancer in RA patients treated with JAK inhibitors (JAKi). Such signals were initially picked up in data from the clinical development programs, and further strengthened by results from the ORAL Surveillance safety trial, pointing to the need for careful safety monitoring of these drugs as used post-approval in clinical practice. When a new drug class is introduced on the market, it is likely to be initially prescribed to “difficult to treat“ RA patients, with a higher burden of comorbidities and limited remaining treatment options. Such selection may introduce confounding by indication, and make new drugs appear more hazardous than drugs that have been on the market for several years. Although studies on drug safety usually aim to minimize confounding by indication, it is considered to be one of the major limitations of observational studies. In an era of rapid drug development and safety concerns such as those exemplified by treatment with JAKi, there is a need to directly understand the impact of any such new-on-the-market channeling on the observed rates of safety outcomes. Objectives: To investigate the impact of and variation in the strength of channeling bias on the observed safety profile of b/tsDMARDs in RA patients, as a function of time since market entry of each b/tsDMARD class. Methods: Cohort study from 1st of January 2006 up until 31st of December 2022. Clinical characteristics and b/tsDMARD treatment initiations (first ever by drug) among patients with prevalent RA were identified using the Swedish rheumatology quality register (SRQ). Data on the safety outcomes under study, comorbid conditions and their treatments were obtained from linkage to Swedish national registers. We used a composite safety outcome defined as time to first of i) MACE, ii) VTE, iii) cancer or iv) serious infection. We assessed the rates for this outcome for b/tsDMARD overall, stratified by the time from market entry of the b/tsDMARD class under study until the start of the treatment episode in question. Thereafter, we plotted these rates (age- and sex standardized) using a flexible parametric model. We also calculated hazard ratios (HR) per time period (market entry of drug class until treatment start) using a flexible parametric model. Finally, we assessed the rates for individual b/tsDMARD classes by calendar period of treatment start, and plotted these (crude) rates using Poisson regression. Results: We identified 43 571 b/tsDMARD initiations in 24 162 individuals with RA, and 2 861 composite safety outcome events with a corresponding incidence rate of 56 (95% CI 54-58) per 1 000 person-years on active treatment. Figure 1 demonstrates some but limited difference the estimated overall age- and sex-standardized rates by time since treatment start, stratified by time from market entry for each class of b/tsDMARD until start of the treatment episode. Using <2 years from market entry until treatment start as reference, the corresponding crude HRs were 0.96 (95% CI 0.82-1.13) for 2-5 years, and 0.79 (95% CI 0.69-0.90) for > 5 years. Figure 2 demonstrates a general decrease in estimated 1-year crude rates for the safety outcome over calendar time. Conclusion: We found some but limited decline in observed rates of our composite safety outcome by time since drug class market entry. By contrast, we noted a general trend - across all b/tsDMARDs under study - towards declining rates of the same safety outcomes during the calendar period of our study. These findings de-emphasize the role of confounding by indication as a major cause of the increase in observed rates of adverse events for JAK inhibitors in observational studies, secular trends seem more important. REFERENCES: NIL. Acknowledgements: We would like to thank all RA patients and rheumatologists in Sweden for entering data into the Swedish Rheumatology Quality Register. Disclosure of Interests: Viktor Molander: None declared, Hannah Bower: None declared, Thomas Frisell: None declared, Johan Askling Karolinska Institutet, with JA as principal investigator, has or has had research agreements with Abbvie, Astra-Zeneca, BMS, Eli Lilly, Galapagos, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB, mainly in the context of safety monitoring of biologics via ARTIS/Swedish Biologics Register.Figure 1Estimated age- and sex standardized 5-year rates of composite safety outcome for b/tsDMARDs overall, stratified by time from market entry for each class of b/tsDMARD to treatment start. Figure 2Crude estimated 1-year rates of composite safety outcome by b/tsDMARD class.

Individuals with rheumatoid arthritis (RA) are at around 50-100% increased risk of venous thromboembolism (VTE). In 2019, signals emerged suggesting an increased risk of VTE in RA patients treated with JAK inhibitors (JAKi), a new and highly efficacious class of disease- modifying antirheumatic drug (DMARD). In this thesis, we aimed to further disentangle the associations between RA, its treatment, and VTE risk in a series of observational studies. We used data from the Swedish rheumatology quality register and other national registers, thereby including a majority of all Swedish patients with RA, as well as a general population comparator cohort. Study I was a study validating International classification of diseases (ICD) 10 codes for VTE registered in the National patient register specifically in patients with RA, through manual review of medical records. Based on review of 269 registered VTE events at hospitals in Region Stockholm from 2009 through 2018, 235 were confirmed as incident VTE. This resulted in a positive predictive value (PPV) of 87% for incident VTE, which ranged from 80% to 98% when we applied various restrictions to our definition of VTE. The majority of the confirmed events were diagnosed independently of RA (only 17 cases involved initial work- up by a rheumatologist, and in 3 cases there was an initial suspicion af an RA-related symptom). This study demonstrates a high validity for registered ICD-10 codes for VTE specifically in patients with RA, and suggests a low degree of surveillance or diagnostic bias. Study II was a cohort study on the association between RA disease activity, measured by the Disease activity score 28 (DAS28), and the risk of VTE. Based on 322,601 rheumatologist visits in 46,316 patients with RA from 2006 through 2018, we identified 2,241 incident VTE events during the year following the rheumatologist visit. This resulted in a cumulative 1- year incidence of 0.52% for DAS28 remission, and 1.08% for high disease activity, with a corresponding adjusted risk ratio of 2.03 (95% CI 1.73-2.38) for high DAS28 vs. remission. Compared to the general population, the risk ratio of VTE for the overall RA population was 1.88 (95% CI 1.65-2.05). The study demonstrates a significant association between RA disease activity and VTE risk, thereby underscoring the importance of VTE risk stratification in patients with RA, and that treating RA to remission is important to minimize VTE risk. Study III was an active comparator, new user design cohort study on the risk of VTE in patients with RA treated with JAKi, TNFi and other biologic DMARDs (bDMARDs) from 2010 through 2021. Based on 32,737 treatment episodes and 559 incident VTE events, the adjusted hazard ratio (HR) for the risk of VTE for JAKi vs. TNFi was 1.73 (95% CI 1.24-2.42). Regarding VTE subtypes, the corresponding HR was 3.21 (95% CI 2.11-4.88) for pulmonary embolism and 0.83 (95% CI 0.47-1.45) for deep vein thrombosis. The incidence of VTE was doubled with use of JAKi compared to the entire RA population, and tripled compared to the general population. The study demonstrates an increased risk of VTE for patients with RA treated with JAKi in clinical practice, an increase confined to pulmonary embolism rather than deep vein thrombosis. Study IV was a cohort study on the potential impact of channeling bias for biologic and targeted synthetic DMARD (b/tsDMARD) drug classes when new on the market, compared to when established, in patients with RA from 2006 through 2022. We identified 33,550 b/tsDMARD initiations and 5,862 composite safety events (first of: major adverse cardiovascular event, VTE, cancer or serious infection). b/tsDMARD treatments initiated >5 years since market entry of the drug class in question (vs. < 2 years) were associated with lower rates of the composite safety outcome (unadjusted HR 0.74 (95% CI 0.67-0.81)). This association was attenuated after adjusting for patient characteristics (HR 0.93 (95% CI 0.84- 1.03)). By contrast, rates of the composite safety outcome decreased gradually for b/tsDMARD initiations during the study period, although these rates were stable in bionaïve RA and the general population. The study demonstrates a relatively modest level of channeling, although it makes b/tsDMARD drug classes appear more harmful when new on the market. Since the rates of these composite safety outcomes gradually decreased over calendar time for RA patients treated with b/tsDMARD, this suggests that the bar that defines acceptable rates of safety events for new and future b/tsDMARD should be lower. List of scientific papers I. Validation and characterization of venous thromboembolism diagnoses in the Swedish National Patient Register among patients with rheumatoid arthritis. Viktor Molander, Hannah Bower, Johan Askling. Scand J Rheumatol 2023;52:111-117. https://doi.org/10.1080/03009742.2021.2001907 II. Risk of venous thromboembolism in rheumatoid arthritis, and its association with disease activity: a nationwide cohort study from Sweden. Viktor Molander, Hannah Bower, Thomas Frisell, Johan Askling. Annals of the Rheumatic Diseases 2021;80:169-175. https://doi.org/10.1136/annrheumdis-2020-218419 III. Risk of venous thromboembolism with JAK inhibitors and other immune- modulatory drugs: a Swedish comparative safety study among patients with rheumatoid arthritis. Viktor Molander, Hannah Bower, Thomas Frisell, Bénédicte Delcoigne, Daniela Di Giuseppe, Johan Askling. Annals of the Rheumatic Diseases 2023;82:189-197. https://doi.org/10.1136/ard-2022-223050 IV. Do newly approved drugs have a worse observed safety profile than once established? A study on time-trends in observed risks of key safety outcomes with immune-modulatory drugs against rheumatoid arthritis. Viktor Molander, Hannah Bower, Thomas Frisell, Johan Askling. [Manuscript]

Objective To assess and compare the incidence of venous thromboembolism (VTE) in patients with rheumatoid arthritis (RA) treated with Janus kinase inhibitors (JAKi), tumour necrosis factor inhibitors (TNFi) or other biological disease modifying antirheumatic drugs (bDMARDs). For contextualisation, to assess VTE incidences in the Swedish general population and in the RA source population. Methods We performed a nationwide register-based, active comparator, new user design cohort study in Sweden from 2010 to 2021. The Swedish Rheumatology Quality Register was linked to national health registers to identify treatment cohorts (exposure) of initiators of a JAKi, a TNFi, or a non-TNFi bDMARD (n=32 737 treatment initiations). We also identified a general population cohort (matched 1:5, n=92 108), and an 'overall RA' comparator cohort (n=85 722). Outcome was time to first VTE during the follow-up, overall and by deep vein thrombosis (DVT) and pulmonary embolism (PE). We calculated incidence rates (IR) and multivariable-adjusted HRs using Cox regression. Results Based on 559 incident VTE events, the age- and sex-standardised (to TNFi) IR (95% CI) for VTE was 5.15 per 1000 person-years (4.58 to 5.78) for patients treated with TNFi, 11.33 (8.54 to 15.04) for patients treated with JAKi, 5.86 (5.69 to 6.04) in the overall RA cohort and 3.28 (3.14 to 3.43) in the general population. The fully adjusted HR (95% CI) for VTE with JAKi versus TNFi was 1.73 (1.24 to 2.42), the corresponding HR for PE was 3.21 (2.11 to 4.88) and 0.83 (0.47 to 1.45) for DVT. Conclusions Patients with RA treated with JAKi in clinical practice are at increased risk of VTE compared with those treated with bDMARDs, an increase numerically confined to PE.

Objective To assess the validity of venous thromboembolism (VTE) diagnoses registered in the Swedish National Patient Register (NPR) in patients with rheumatoid arthritis (RA). Method We performed a validation study using manual chart reviews to validate ICD-10 codes for VTE from the NPR. We took a random sample of 269 VTE events registered at hospitals in Region Stockholm from 2009 to 2018 in patients with RA. Results Medical records for all 269 VTE events were available for review. Overall, the positive predictive value (PPV) for a VTE diagnosis was 95%. For incident VTE events, the PPV was 87% and ranged from 80% to 98% across six more or less restricted alternative definitions of incident VTE event. Out of 235 confirmed incident VTE events, the vast majority were diagnosed independently of the RA disease (three cases occurred as a result of clinical work-up for a presumed RA-related sign or symptom, and in 17 cases did the work-up involve a rheumatologist). Conclusions This study demonstrates high validity for VTE diagnoses recorded in the NPR for patients with RA, thus confirming that the NPR may be used to identify prevalent VTE as well as incident VTE events in patients with RA. Our results further demonstrate that in patients with RA, diagnoses of VTE are only marginally influenced by work-up related to the rheumatic disease, suggesting a modest impact of surveillance or diagnostic bias.

Background: Patients with rheumatoid arthritis (RA) are at increased risk for venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE) (1). Several established risk factors of VTE, such as age, immobilization and comorbid conditions, occur more often patients with RA (2). In addition, inflammation may in itself also increase VTE risk by upregulating procoagolatory factors and causing endothelial damage (3). Recent reports indicate an increased risk of VTE in RA patients treated with JAK-inhibitors (4), pointing to the need to better understand how inflammation measured as clinical RA disease activity influences VTE risk. Objectives: To investigate the relationship between clinical RA disease activity and incidence of VTE. Methods: Patients with RA were identified from the Swedish Rheumatology Quality Register (SRQ) between July 1 st 2006 and December 31 st 2017. Clinical rheumatology data for these patients were obtained from the visits recorded in SRQ, and linked to national registers capturing data on VTE events and comorbid conditions. For each such rheumatologist visit, we defined a one-year period after the visit and determined whether a VTE event had occurred within this period or not. A visit followed by a VTE event was categorized as a case, all other visits were used as controls. Each patient could contribute to several visits. The DAS28 score registered at the visit was stratified into remission (0-2.5) vs. low (2.6-3.1), moderate (3.2-5.1) and high (>5.1) disease activity. Logistic regression with robust cluster standard errors was used to estimate the association between the DAS28 score and VTE. Results: We identified 46,311 patients with RA who contributed data from 320,094 visits. Among these, 2,257 visits (0.7% of all visits) in 1345 unique individuals were followed by a VTE within the one-year window. Of these, 1391 were DVT events and 866 were PE events. Figure 1 displays the absolute probabilities of a VTE in this one-year window, and odds ratios for VTE by each DAS28 category, using DAS28 remission as reference. The one-year risk of a VTE increased from 0.5% in patients in DAS28 remission, to 1.1% in patients with DAS28 high disease activity (DAS28 above 5.1). The age- and sex-adjusted odds ratio for a VTE event in highly active RA compared to RA in remission was 2.12 (95% CI 1.80-2.47). A different analysis, in which each patient could only contribute to one visit, yielded similar results. Figure 1. Odds ratios (OR) comparing the odds of VTE for DAS28 activity categories versus remission. Grey estimates are from unadjusted logistic regression models, black estimates are from logistic regression models adjusted for age and sex. Absolute one-year risk of VTE are estimated from unadjusted models. Conclusion: This study demonstrates a strong association between clinical RA inflammatory activity as measured through DAS28 and risk of VTE. Among patients with high disease activity one in a hundred will develop a VTE within the coming year. These findings highlight the need for proper VTE risk assessment in patients with active RA, and confirm that patients with highly active RA, such as those recruited to trials for treatment with new drugs, are already at particularly elevated risk of VTE. References: [1]Holmqvist et al. Risk of venous thromboembolism in patients with rheumatoid arthritis and association with disease duration and hospitalization. JAMA. 2012;308(13):1350-6. [2]Cushman M. Epidemiology and risk factors for venous thrombosis. Semin Hematol. 2007;44(2):62-9. [3]Xu J et al. Inflammation, innate immunity and blood coagulation. Hamostaseologie. 2010;30(1):5-6, 8-9. [4]FDA. Safety trial finds risk of blood clots in the lungs and death with higher dose of tofacitinib (Xeljanz, Xeljanz XR) in rheumatoid arthritis patients; FDA to investigate. 2019. Acknowledgments: Many thanks to all patients and rheumatologists persistently filling out the SRQ. Disclosure of Interests: Viktor Molander: None declared, Hannah Bower: None declared, Johan Askling Grant/research support from: JA acts or has acted as PI for agreements between Karolinska Institutet and the following entities, mainly in the context of the ARTIS national safety monitoring programme of immunomodulators in rheumatology: Abbvie, BMS, Eli Lilly, Merck, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB Pharma

Objective To assess the incidence of venous thromboembolism (VTE) in rheumatoid arthritis (RA) relative to individuals without RA, and to investigate the relationship between aspects of clinical disease activity in RA and the risk of VTE. Methods We conducted a nationwide register-based cohort study 2006 through 2018 using the Swedish Rheumatology Quality Register linked to other national patient registers to identify all patients with RA with at least one registered rheumatologist visit during the study period (n=46 316 patients, 322 601 visits). The Disease Activity Score 28 erythrocyte sedimentation rate (ESR) (DAS28 ESR) and its components served as the exposure, and a VTE event within the year following the visit was the main outcome. We also included general population referents (1:5) matched on age, sex and residential area. Results Based on 2241 incident VTE events within 1 year of each included visit, and 5301 VTE events in the general population cohort, the risk ratio for VTE in RA was 1.88 (95% CI 1.65 to 2.15). Among patients with RA, the risk (and risk ratio) increased with increasing RA disease activity, from 0.52% following visits in remission to 1.08% following visits with DAS28 ESR high disease activity, RR compared with remission=2.03, 95% CI 1.73 to 2.38. Compared with the general population, also patients with RA in DAS28 ESR remission were at elevated VTE risk. Conclusions This study demonstrates a strong association between clinical RA disease activity measured by DAS28 ESR and the risk of VTE. RA disease activity can be used as an additional tool for VTE risk stratification in patients with RA.

We report a case of chronic empyema in a 63-year-old man with a history of asbestos exposure and alcohol overconsumption. In 2009, he presented with dyspnoea, exudative pleurisy on the right side with no symptoms of infection or malignancy. In 2013, the patient presented with increased dyspnoea and a massive chronic empyema had evolved. Culture of the pleural fluid was positive for Escherichia coli and anaerobic bacteria, and he was treated with antibiotics, chest drainage as well as surgical evacuation. After surgery, as the lung failed to expand, growth of opportunistic bacteria and rising C reactive protein obliged long-time treatment with broad-spectrum antibiotics as well as chest drainage with daily saline flushes. The patient still suffers from fatigue, poor nutritional status and anaemia, and further treatment with chest drainage and antibiotics is planned. Advanced chronic empyema is a difficult condition with poor response to treatment, and diagnostic delay is the main cause of complications.