Disease-modifying antirheumatic drugs and risk of thyroxine-treated autoimmune thyroid disease in patients with rheumatoid arthritis.

BACKGROUND: Autoimmune thyroid disease (AITD) and rheumatoid arthritis (RA) share a genetic background, and the prevalence of AITD in RA patients is increased. Whereas immunomodulatory treatments are used in RA, they are rarely used in AITD. OBJECTIVES: We hypothesized that disease-modifying antirheumatic drugs (DMARDs) as used in RA might lower the risk of incident AITD. METHODS: A nationwide cohort study including 13,731 patients with new-onset RA from the Swedish Rheumatology Quality Register 2006-2018 and 63,201 matched general population comparators linked to national registers to identify AITD. We estimated relative risks (hazard ratios) of AITD after RA diagnosis in RA patients compared to the general population, and in relation to DMARD treatment, using Cox regression. RESULTS: Following RA diagnosis, 321 (2.3%) of the RA patients and 1838 (2.9%) of the population comparators developed AITD, corresponding to an incidence of 3.7 versus 4.6 per 1000 person-years, hazard ratio, 0.81; 95% CI, 0.72-0.91. The decreased risk of incident AITD among RA patients compared to the general population was most pronounced among biologic DMARD (bDMARD) treated patients, with a hazard ratio of 0.54; 95% CI, 0.39-0.76. Among RA patients, subgrouped by bDMARD use, TNF-inhibitors were associated with the most pronounced decrease, hazard ratio, 0.67; 95% CI, 0.47-0.96. CONCLUSIONS: In contrast to the increased prevalence of AITD in RA patients at diagnosis, our results indicate that the risk of AITD decreases following RA diagnosis. This decrease is especially pronounced in RA patients treated with bDMARDs. These findings support the hypothesis that DMARDs might have a preventive effect on AITD.

Are JAKis more effective among elderly patients with RA, smokers and those with higher cardiovascular risk? A comparative effectiveness study of b/tsDMARDs in Sweden.

OBJECTIVES: To investigate whether the relative effectiveness of janus kinase inhibitors (JAKis) versus tumour necrosis factor inhibitors (TNFi) or other biological disease-modifying antirheumatic drugs in rheumatoid arthritis differ by the presence or absence of risk factors for cardiovascular (CV) disease, age, sex and smoking. METHODS: Through Swedish registers, we identified 13 493 individuals with 3166 JAKi, 5575 non-TNFi and 11 286 TNFi treatment initiations 2016-2022. All lines of therapy were included, with the majority in second line or higher. Treatment response was defined as the proportion reaching European Alliance of Associations for Rheumatology (EULAR) good response and Clinical Disease Activity Index (CDAI) remission, respectively, within 6 months. Crude percentage point differences in these proportions (JAKis, and non-TNFis, vs TNFis) overall and by risk factors were observed, and adjusted for confounders using linear regression models. Predicted probabilities of response and remission were estimated from adjusted Poisson models, and presented across CV risk and age. RESULTS: Overall, adjusted percentage point differences indicated higher response (+5.0%, 95% CI 2.2% to 7.9%) and remission (+5.8%, 95% CI 3.2% to 8.5%) with JAKis versus TNFis. The adjusted percentage point differences for response in those above 65, at elevated CV risk, and smokers were +5.9% (95% CI 2.7% to 9.0%), +8.3% (95% CI 5.3% to 11.4%) and +6.0% (95% CI 3.3% to 8.7%), respectively. The corresponding estimates for remission were +8.0% (95% CI 5.3% to 10.8%), +5.6% (95% CI 3.0% to 8.2%) and +7.6% (95% CI 5.5% to 9.7%). CONCLUSIONS: As used in clinical practice, response and remission at 6 months with JAKis are higher than with TNFi. Among patients with risk factors of concern, effectiveness is similar or numerically further increased. For individualised benefit-to-risk ratios to guide treatment choice, safety and effectiveness in specific patient segments should be considered.

Comorbidities and chance of remission in patients with early rheumatoid arthritis receiving methotrexate as first-line therapy: a Swedish observational nationwide study.

OBJECTIVES: This study aims to examine whether comorbidities affect the likelihood of reaching primary remission on methotrexate monotherapy as the first disease-modifying antirheumatic drug (DMARD) in early rheumatoid arthritis (RA). METHODS: We used nationwide Swedish clinical and quality registers to collect RA disease activity measures and comorbidity data for patients diagnosed with RA 2007-2020 (n=11 001). The primary outcome was failure to reach 28-joint Disease Activity Score (DAS28) remission at 3 months. Secondary outcomes included Boolean, Simplified Disease Activity Index/Clinical Disease Activity Index remission, European Alliance of Associations for Rheumatology response and no swollen joint count at 3 and 6 months. For each comorbidity, and for combinations thereof, we calculated adjusted relative risks (RRs) of failure to reach remission, using modified Poisson regression. RESULTS: In total, 53% (n=4019/7643) failed to reach DAS28 remission after 3 months of methotrexate monotherapy, ranging from 66% (n=25/38) among patients with chronic kidney disease to 48% (n=154/319) in patients with previous cancer. The risk of not reaching DAS28 remission at 3 months (RR adjusted for sex and age) was increased among patients with endocrine (RR 1.08, 95% CI 1.01 to 1.15), gastrointestinal (RR 1.16, 95% CI 1.03 to 1.30), infectious (RR 1.21, 95% CI 1.06 to 1.38), psychiatric (RR 1.24, 95% CI 1.15 to 1.35) and respiratory comorbidities (RR 1.16, 95% CI 1.01 to 1.32). Having three or more comorbidity categories was associated with a 27% higher risk of DAS28 remission failure at 3 months. A similar pattern was observed for the secondary outcomes. CONCLUSIONS: Comorbidities decrease the chance of reaching remission on methotrexate as DMARD monotherapy in patients with early RA and are important to consider when assessing treatment outcomes.

Comparative cardiovascular safety with janus kinase inhibitors and biological disease-modifying antirheumatic drugs as used in clinical practice: an observational cohort study from Sweden in patients with rheumatoid arthritis.

OBJECTIVES: To compare the incidence of cardiovascular (CV) events in rheumatoid arthritis (RA) treated with janus kinase inhibitors (JAKi), tumour necrosis factor inhibitors (TNFi), or other biological disease-modifying antirheumatic drugs (bDMARDs), in clinical practice, and to contextualise these findings by comparing to the Swedish RA population and general population at large. METHODS: Patients with RA initiating JAKi, TNFi and non-TNFi bDMARDs were identified in the Swedish Rheumatology Quality Register between 2016 and 2021. Through linkages to national registers, a cohort of patients with RA, general population comparators, as well as covariates and incident major acute CV event (MACE, including myocardial infarction, stroke and fatal CV events) were identified until 2022. Crude and age-sex standardised rates were calculated and HRs estimated from multivariable Cox regression models using TNFi as reference. RESULTS: We identified 13 492 patients with RA initiating a JAKi, non-TNFi bDMARD or TNFi treatment. Among 3037 JAKi-initiators, 59 MACE events were observed. The age-sex standardised rates for MACE were similar in the JAKi (0.88 per 100 person years) and TNFi (0.91) cohorts. Fully adjusted models showed no increased rate of MACE with JAKi (HR=0.71, 95% CI 0.51 to 0.99), or non-TNFi bDMARD (HR=0.98; 95% CI 0.78 to 1.23) in comparison to TNFi. We found no evidence that this HR changed over time since treatment initiation. In a CV-enriched subset, we observed higher rates but similar HRs. CONCLUSIONS: As used in present clinical practice in Sweden, we found no evidence that CV risk is higher with JAKis than TNFis in RA.

How does current disease activity in rheumatoid arthritis affect the short-term risk of acute coronary syndrome? A clinical register based study from Sweden and Norway.

OBJECTIVES: To estimate short-term risks of acute coronary syndrome (ACS) in patients with rheumatoid arthritis (RA) as a function of current RA disease activity including remission. METHODS: Data from clinical visits of RA patients in Sweden (SE) and Norway (NO) between January 1st 2012 until December 31st 2020 were used. At each visit, patient's disease activity was assessed including remission status (measured with several metrics). Through linkage to national health and death registers, patients were followed up for incident ACS up to six months from each visit. We compared the short-term risk of ACS in patients not in remission vs. in remission using Cox regression analyses with robust standard errors, adjusted for country and covariates (e.g., age, sex, prednisolone use, comorbidities). We also explored disease activity categories as exposure. RESULTS: We included 212,493 visits (10,444 from Norway and 202,049 from Sweden) among 41,250 patients (72% women, mean age at visit 62 years). During the 6-month follow-ups, we observed 524 incident ACS events. Compared to patients in remission, patients currently not in remission had an increased rate of ACS: adjusted hazard ratio (95% confidence interval) 1.52 (1.24-1.85) with DAS28 metric. The crude absolute six-month risks were 0.2% for patients in remission vs. 0.4% for patients with DAS28 high disease activity. The use of alternative RA disease activity and remission metrics provided similar results. CONCLUSION: Failure to reach remission is associated with elevated short-term risks of ACS, underscoring the need for CV risk factor optimization in these patients.

Risk of Psychiatric Disorders in Juvenile Idiopathic Arthritis: Population- and Sibling-Controlled Cohort and Cross-Sectional Analyses.

OBJECTIVE: The objective of this study was to examine the incidence and accumulated burden of psychiatric disorders in juvenile idiopathic arthritis (JIA) relative to the general population (GP) and to their same-sex siblings. METHODS: We performed an observational register-based study from July 1, 2006, to December 31, 2020, with three different study population contrasts: 1) patients with incident JIA versus five age- and sex-matched GP individuals (cohort), 2) patients with incident JIA versus full same-sex siblings (cohort), and 3) patients with prevalent JIA at age 18 versus matched GP individuals (cross-sectional). We investigated six groups of psychiatric disorders defined via International Classification of Diseases, Tenth Revision codes: mood and anxiety, suicidal behavior, eating, sleeping, substance use, psychotic, plus an overall combined outcome (ie, at least one of the six). Incidences rates were compared through Cox regression (contrasts 1 and 2) and logistic regression (contrast 3), all adjusted for demographics, comorbidities, and proxies for socioeconomic status. RESULTS: During 25,141 person-years of follow-up of 4939 incident patients with JIA, the incidence of the overall combined outcome was 20.1 per 1000 person-years in patients with JIA versus 13.1 per 1000 person-years in the GP (adjusted hazard ratio [HR] = 1.49 [95% confidence interval: 1.35-1.65]). The three most elevated HRs were obtained for sleeping disorder (1.91 [1.41-2.59]), suicidal behavior (1.60 [1.23-2.07]), and mood and anxiety disorders (1.46 [1.30-1.64]). The comparison of patients with JIA (n = 1815) with their siblings (n = 2050) for the overall combined outcome resulted in a nonstatistically significant HR (1.16 [0.82-1.64]). By age 18, patients with JIA were more likely to have been diagnosed with any psychiatric disorder (adjusted odds ratio = 1.37 [1.25-1.50]). CONCLUSION: There is an increased burden of psychiatric morbidity in JIA, which holds both individual and familial components.

Exposure to specific tumour necrosis factor inhibitors and risk of demyelinating and inflammatory neuropathy in cohorts of patients with inflammatory arthritis: a collaborative observational study across five Nordic rheumatology registers.

OBJECTIVE: To compare incidences of neuroinflammatory events, including demyelinating disease (DML), inflammatory polyneuropathies (IPN) and multiple sclerosis (MS), in patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA; including psoriatic arthritis) starting a tumour necrosis factor inhibitor (TNFi), investigating whether monoclonal TNFi antibodies (other TNFis (oTNFis)) confer higher risk than etanercept. METHODS: This is an observational cohort study including patients from the five Nordic countries starting a TNFi in 2001-2020. Time to first neuroinflammatory event was identified through register linkages. We calculated crude incidence rates (cIR) per 1000 person-years and used multivariable-adjusted Cox regression to compare incidences of neuroinflammatory events overall and for DML, IPN and MS with oTNFi versus etanercept. We further examined individual TNFis and indications. RESULTS: 33 883 patients with RA and 28 772 patients with SpA were included, initiating 52 704 and 46 572 treatment courses, respectively. In RA, we observed 135 neuroinflammatory events (65% DML) with cIR of 0.38 with oTNFi and 0.34 with etanercept. The HR of oTNFi versus etanercept was 1.07 (95% CI 0.74 to 1.54) for any neuroinflammatory event, 0.79 (95% CI 0.51 to 1.22) for DML, 2.20 (95% CI 1.05 to 4.63) for IPN and 0.73 (95% CI 0.34 to 1.56) for MS. In SpA, we observed 179 events (78% DML) with cIR of 0.68 with oTNFi and 0.65 with etanercept. The HR for any neuroinflammatory event, DML, IPN and MS was 1.06 (95% CI 0.75 to 1.50), 1.01 (95% CI 0.68 to 1.50), 1.28 (95% CI 0.61 to 2.69) and 0.94 (95% CI0.53 to 1.69), respectively. CONCLUSION: The cIRs of neuroinflammatory events are higher in SpA than in RA, but the choice of specific TNFi does not seem to play an important role in the risk of neuroinflammatory events.

Safety of biological and targeted synthetic disease-modifying antirheumatic drugs for rheumatoid arthritis as used in clinical practice: results from the ARTIS programme.

OBJECTIVE: Longitudinal clinical registry-infrastructures such as Anti-Rheumatic Therapies in Sweden (ARTIS) allow simultaneous comparison of the safety of individual immunomodulatory drugs used in clinical practice, with consistent definitions of treatment cohorts, follow-up and outcomes. Our objective was to assess and compare incidence rates of key safety outcomes for individual targeted synthetic or biological disease-modifying antirheumatic drugs (b/ts DMARDs) in rheumatoid arthritis (RA), updating previous reports and including newer treatments including Janus Kinase inhibitors (JAKi). METHODS: Nationwide register-based cohort study including all patients with RA in Sweden registered as starting any b/tsDMARD 1 January 2010 through 31 December 2020, followed until 30 June 2021 (N=20 117). The incidence rates of selected outcomes, identified through national healthcare registers, were compared between individual b/tsDMARDs, adjusted for confounding by demographics, RA disease characteristics and comorbidity. RESULTS: There were marked differences in treatment discontinuations due to adverse events (rates per 1000 person-years ranged from 18 on rituximab to 57 on tofacitinib), but few significant differences were observed for the serious adverse events under study. Neither cardiovascular events nor general serious infections were more frequent on baricitinib or tofacitinib versus bDMARDs, but JAKi were associated with higher rates of hospital-treated herpes zoster (HR vs etanercept, 3.82 (95% CI 2.05 to 7.09) and 4.00 (1.59 to 10.06)). Low number of events limited some comparisons, in particular for sarilumab and tofacitinib. CONCLUSION: Data from ARTIS supports that the b/tsDMARDs currently used to treat RA have acceptable and largely similar safety profiles, but differences exist in particular concerning tolerability and specific infection risks.

Glucocorticoid exposure and the risk of serious infections in rheumatoid arthritis: a marginal structural model application.

OBJECTIVE: Observational studies have reported an increased risk of infections associated with glucocorticoids in RA, not supported by evidence from randomized controlled trials. Inappropriately accommodating time-varying exposure and confounding in observational studies might explain the conflicting results. Therefore, we compared the incidence of serious infections between different oral glucocorticoid dose patterns over three years in a prospective inception cohort, adjusting for time-varying confounders in marginal structural models. METHODS: We included 9654 newly diagnosed RA patients from the Swedish Rheumatology Quality Register between 2007-2018 and followed them for three years after the first rheumatology visit. Follow-up was divided into 90-day periods. A mean oral prednisone daily dose was calculated for each period and categorized into 'no use', 'low' (≤10 mg/day) and 'high' (>10 mg/day) doses. The incidence of serious infections (hospitalization for infection) over follow-up periods was modelled by pooled logistic regression allowing separate effects for recent and past exposure. RESULTS: An increased incidence of serious infections was associated with higher compared with lower doses and with more recent compared with past glucocorticoid exposure. Over 3 years of follow-up, the marginal structural models predicted one additional serious infection for every 83 individuals treated with low GC doses for the first 6 months, and for every 125 individuals treated with high GC doses for the first 3 months, compared with no GC use. CONCLUSION: Our results broadly agree with previous observational studies showing a dose dependent increased risk of infection associated with (recent) use of oral glucocorticoids.

Federated analyses of multiple data sources in drug safety studies.

PURPOSE: Studies of rare side effects of new drugs with limited exposure may require pooling of multiple data sources. Federated Analyses (FA) allow real-time, interactive, centralized statistical processing of individual-level data from different data sets without transfer of sensitive personal data. METHODS: We review IT-architecture, legal considerations, and statistical methods in FA, based on a Swedish Medical Products Agency methodological development project. RESULTS: In a review of all post-authorisation safety studies assessed by the EMA during 2019, 74% (20/27 studies) reported issues with lack of precision in spite of mean study periods of 9.3 years. FA could potentially improve precision in such studies. Depending on the statistical model, the federated approach can generate identical results to a standard analysis. FA may be particularly attractive for repeated collaborative projects where data is regularly updated. There are also important limitations. Detailed agreements between involved parties are strongly recommended to anticipate potential issues and conflicts, document a shared understanding of the project, and fully comply with legal obligations regarding ethics and data protection. FA do not remove the data harmonisation step, which remains essential and often cumbersome. Reliable support for technical integration with the local server architecture and security solutions is required. Common statistical methods are available, but adaptations may be required. CONCLUSIONS: Federated Analyses require competent and active involvement of all collaborating parties but have the potential to facilitate collaboration across institutional and national borders and improve the precision of postmarketing drug safety studies.

A Healthy Lifestyle in Men at Increased Genetic Risk for Prostate Cancer.

BACKGROUND: Prostate cancer is the most heritable cancer. There is a need to identify possible modifiable factors for men at an increased risk of prostate cancer due to genetic factors. OBJECTIVE: To examine whether men at an increased genetic risk of prostate cancer can offset their risk of disease or disease progression by adhering to a healthy lifestyle. DESIGN, SETTING, AND PARTICIPANTS: We prospectively followed 12 411 genotyped men in the Health Professionals Follow-up Study (1993-2019) and the Physicians' Health Study (1983-2010). Genetic risk of prostate cancer was quantified using a polygenic risk score (PRS). A healthy lifestyle was defined by healthy weight, vigorous physical activity, not smoking, and a healthy diet. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall and lethal prostate cancer events (metastatic disease/prostate cancer-specific death) were analyzed using time-to-event analyses estimating hazard ratios (HRs) and lifetime risks. RESULTS AND LIMITATIONS: During 27 yr of follow-up, 3005 overall prostate cancer and 435 lethal prostate cancer events were observed. The PRS enabled risk stratification not only for overall prostate cancer, but also for lethal disease with a four-fold difference between men in the highest and lowest quartiles (HR, 4.32; 95% confidence interval [CI], 3.16-5.89). Among men in the highest PRS quartile, adhering to a healthy lifestyle was associated with a decreased rate of lethal prostate cancer (HR, 0.55; 95% CI, 0.36-0.86) compared with having an unhealthy lifestyle, translating to a lifetime risk of 1.6% (95% CI, 0.8-3.1%) among the healthy and 5.3% (95% CI, 3.6-7.8%) among the unhealthy. Adhering to a healthy lifestyle was not associated with a decreased risk of overall prostate cancer. CONCLUSIONS: Our findings suggest that a genetic predisposition for prostate cancer is not deterministic for a poor cancer outcome. Maintaining a healthy lifestyle may provide a way to offset the genetic risk of lethal prostate cancer. PATIENT SUMMARY: This study examined whether the genetic risk of prostate cancer can be attenuated by a healthy lifestyle including a healthy weight, regular exercise, not smoking, and a healthy diet. We observed that adherence to a healthy lifestyle reduced the risk of metastatic disease and prostate cancer death among men at the highest genetic risk. We conclude that men at a high genetic risk of prostate cancer may benefit from adhering to a healthy lifestyle.

Venous thromboembolism with JAK inhibitors and other immune-modulatory drugs: a Swedish comparative safety study among patients with rheumatoid arthritis.

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.

Comorbidities and treatment patterns in early rheumatoid arthritis: a nationwide Swedish study.

OBJECTIVE: To examine how comorbidities in patients with early rheumatoid arthritis (RA) associate with use of different disease-modifying antirheumatic drugs (DMARDs). METHODS: We used Swedish nationwide clinical and quality registers to collect comorbidity data for patients diagnosed with RA during 2006-2019 (n=13 505). We compared the use of DMARDs at diagnosis and after 1 year, in relation to comorbidity categories 5 years prior to RA diagnosis and overall comorbidity burden. For each comorbidity category, we also calculated adjusted ORs of being on treatment with other (or no) DMARDs compared with methotrexate (MTX) monotherapy 1 year after RA diagnosis. RESULTS: At RA diagnosis, 68% (n=9178) of all patients were treated with MTX monotherapy, with the lowest proportion in patients with chronic kidney (CKD, 48%, n=50) and respiratory diseases (57%, n=413). At 1 year, most patients still received MTX monotherapy (<11% decrease, across all comorbidity categories). At 1 year, 13% received biological/targeted synthetic DMARDs, with the lowest proportion among patients with malignant diseases (OR=0.69, 95% CI=0.51 to 0.95). Being without DMARD at 1 year was more common among patients with CKD (OR=3.25, 95% CI=2.20 to 4.81), respiratory diseases (OR=1.83, 95% CI=1.32 to 2.53) or a history of hospitalisation due to infection (OR=1.47, 95% CI=1.23 to 1.75), and among patients with higher comorbidity burden and older age. CONCLUSION: In a nationwide setting with universal healthcare, most comorbid conditions do not limit the initiation or continuation of MTX or other DMARDs in early RA, although patients with certain comorbid conditions, higher comorbidity burden and higher age were somewhat less intensively treated.

Haematological malignancies in patients with psoriatic arthritis overall and treated with TNF inhibitors: a Nordic cohort study.

OBJECTIVES: To evaluate the risk of haematological malignancies in patients with psoriatic arthritis (PsA) overall, and in relation to treatment with tumour necrosis factor inhibitors (TNFi). METHODS: We identified that patients with PsA starting a first TNFi from the clinical rheumatology registers (CRR) in the five Nordic countries (n=10 621) and biologics-naïve PsA patients from (1) the CRR (n=18 705) and (2) the national patient registers (NPR, n=27 286, Sweden and Denmark) from 2006 through 2019. For Sweden and Denmark, general population comparators were matched 5:1 to PsA patients on birth year, year at start of follow-up and sex. By linkage to the national cancer registers in all countries, we collected information on haematological malignancies overall, and categorised into lymphoid or myeloid types. We estimated incidence rate ratios (IRRs) with 95% CIs using modified Poisson regression for TNFi-treated versus biologics-naïve PsA patients and versus the general population adjusted for age, sex, calendar period and country. RESULTS: During 59 827 person-years, 40 haematological malignancies occurred among TNFi-treated patients with PsA resulting in a pooled IRR of 0.96 (0.68-1.35) versus biologics-naïve PsA from CRR and an IRR of 0.84 (0.64-1.10) versus biologics-naïve PsA from NPR. The IRR of haematological malignancies in PsA overall versus general population comparators was 1.35 (1.17-1.55). The estimates were largely similar for lymphoid and myeloid malignancies. CONCLUSIONS: Treatment with TNFi in patients with PsA was not associated with an increased incidence of haematological malignancies. Conversely, a moderately increased underlying risk was seen in patients with PsA compared with the general population.

Does persistence to methotrexate treatment in early rheumatoid arthritis have a familial component?

OBJECTIVES: To assess whether persistence to treatment with methotrexate (MTX) in early rheumatoid arthritis (RA) is shared among first-degree relatives with RA and to estimate any underlying heritability. METHODS: First-degree relative pairs diagnosed with RA 1999-2018 and starting MTX (in monotherapy) as their first disease-modifying anti-rheumatic drug (DMARD) treatment were identified by linking the Swedish Rheumatology Quality Register to national registers. Short- and long-term persistence to MTX was defined as remaining on treatment at 1 and 3 years, respectively, with no additional DMARDs added. We assessed familial aggregation through relative risks (RR) using log-binomial regression with robust standard errors and estimated heritability using tetrachoric correlations. We also explored the familial aggregation of EULAR treatment response after 3 and 6 months. To mimic the clinical setting, we also tested the association between having a family history of MTX persistence and persistence within the index patient. RESULTS: Familial persistence was not associated with persistence at 1 (RR=1.02, 95% CI 0.87-1.20), only at 3 (RR=1.41, 95% CI 1.14-1.74) years. Heritability at 1 and 3 years was estimated to be 0.08 (95% CI 0-0.43) and 0.58 (95% CI 0.27-0.89), respectively. No significant associations were found between family history and EULAR response at 3 and 6 months, neither overall nor in the clinical setting analysis. CONCLUSIONS: Our findings imply a familial component, including a possible genetic element, within the long-term persistence to MTX following RA diagnosis. Whether this component is reflective of characteristics of the underlying RA disease or determinants for sustained response to MTX in itself will require further investigation.

The impact of a csDMARD in combination with a TNF inhibitor on drug retention and clinical remission in axial spondyloarthritis.

OBJECTIVES: Many axial spondylarthritis (axSpA) patients receive a conventional synthetic DMARD (csDMARD) in combination with a TNF inhibitor (TNFi). However, the value of this co-therapy remains unclear. The objectives were to describe the characteristics of axSpA patients initiating a first TNFi as monotherapy compared with co-therapy with csDMARD, to compare one-year TNFi retention and remission rates, and to explore the impact of peripheral arthritis. METHODS: Data was collected from 13 European registries. One-year outcomes included TNFi retention and hazard ratios (HR) for discontinuation with 95% CIs. Logistic regression was performed with adjusted odds ratios (OR) of achieving remission (Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP < 1.3 and/or BASDAI < 2) and stratified by treatment. Inter-registry heterogeneity was assessed using random-effect meta-analyses, combined results were presented when heterogeneity was not significant. Peripheral arthritis was defined as ≥1 swollen joint at baseline (=TNFi start). RESULTS: Amongst 24 171 axSpA patients, 32% received csDMARD co-therapy (range across countries: 13.5% to 71.2%). The co-therapy group had more baseline peripheral arthritis and higher CRP than the monotherapy group. One-year TNFi-retention rates (95% CI): 79% (78, 79%) for TNFi monotherapy vs 82% (81, 83%) with co-therapy (P < 0.001). Remission was obtained in 20% on monotherapy and 22% on co-therapy (P < 0.001); adjusted OR of 1.16 (1.07, 1.25). Remission rates at 12 months were similar in patients with/without peripheral arthritis. CONCLUSION: This large European study of axial SpA patients showed similar one-year treatment outcomes for TNFi monotherapy and csDMARD co-therapy, although considerable heterogeneity across countries limited the identification of certain subgroups (e.g. peripheral arthritis) that may benefit from co-therapy.

Short-term, intermediate-term and long-term risks of acute coronary syndrome in cohorts of patients with RA starting biologic DMARDs: results from four Nordic countries.

OBJECTIVES: To compare the 1-year, 2-year and 5-year incidences of acute coronary syndrome (ACS) in patients with rheumatoid arthritis (RA) starting any of the biologic disease-modifying antirheumatic drugs (bDMARDs) currently available in clinical practice and to anchor these results with a general population comparator. METHODS: Observational cohort study, with patients from Denmark, Finland, Norway and Sweden starting a bDMARD during 2008-2017. Time to first ACS was identified through register linkages. We calculated the 1-year, 2-year and 5-year incidence rates (IR) (on drug and ever since treatment start) and used Cox regression (HRs) to compare ACS incidences across treatments taking ACS risk factors into account. Analyses were further performed separately in subgroups defined by age, number of previous bDMARDs and history of cardiovascular disease. We also compared ACS incidences to an individually matched general population cohort. RESULTS: 24 083 patients (75% women, mean age 56 years) contributing 40 850 treatment courses were included. During the maximum (5 years) follow-up (141 257 person-years (pyrs)), 780 ACS events occurred (crude IR 5.5 per 1000 pyrs). Overall, the incidence of ACS in RA was 80% higher than that in the general population. For all bDMARDs and follow-up definitions, HRs were close to 1 (etanercept as reference) with the exception of the 5-year risk window, where signals for abatacept, infliximab and rituximab were noted. CONCLUSION: The rate of ACS among patients with RA initiating bDMARDs remains elevated compared with the general population. As used in routine care, the short-term, intermediate-term and longer-term risks of ACS vary little across individual bDMARDs.

Do patient-reported measures of disease activity in rheumatoid arthritis vary between countries? Results from a Nordic collaboration.

OBJECTIVES: To investigate whether patient-reported outcomes vary across countries and are influenced by cultural/contextual factors. Specifically, we aimed to assess inter-country differences in tender joint count (TJC), pain and patient's global health assessment (PGA), and their impact on disease activity (DAS28-CRP) in RA patients from five Nordic countries. METHODS: We collected data (baseline, 3- and 12-months) from rheumatology registers in the five countries comprising RA patients starting a first ever MTX or a first ever TNF inhibitor (TNFi). In order to assess the role of context (=country), we separately modelled TJC, pain and PGA as functions of objective variables (CRP, swollen joint count, age, sex, calendar period and disease duration) with linear models. Analyses were performed at each time point and for both treatments. We further assessed the impact of inter-country differences on DAS28-CRP. RESULTS: A total of 27 645 RA patients started MTX and 19 733 started a TNFi. Crude inter-country differences at MTX start amounted to up to 4 points (28 points scale) for TJC, 10 and 27 points (0-100 scale) for pain and PGA, respectively. Corresponding numbers at TNFi start were 3 (TJC), 27 (pain) and 24 (PGA) points. All differences were reduced at 3- and 12-months, and attenuated when adjusting for the objective variables. The variation in predicted DAS28-CRP across countries amounted to <0.5 units. CONCLUSIONS: Inter-country differences in TJC, pain and PGA are greater than expected based on differences in objective measures, but have a small clinical impact on DAS28-CRP across countries.

Influenza outcomes in patients with inflammatory joint diseases and DMARDs: how do they compare to those of COVID-19?

OBJECTIVES: To estimate absolute and relative risks for seasonal influenza outcomes in patients with inflammatory joint diseases (IJDs) and disease-modifying antirheumatic drugs (DMARDs). To contextualise recent findings on corresponding COVID-19 risks. METHODS: Using Swedish nationwide registers for this cohort study, we followed 116 989 patients with IJD and matched population comparators across four influenza seasons (2015-2019). We quantified absolute risks of hospitalisation and death due to influenza, and compared IJD to comparators via Cox regression. We identified 71 556 patients with IJD on active treatment with conventional synthetic DMARDs and biological disease-modifying antirheumatic drugs (bDMARDs)/targeted synthetic disease-modifying antirheumatic drug (tsDMARDs) at the start of each influenza season, estimated risks for the same outcomes and compared these risks across DMARDs via Cox regression. RESULTS: Per season, average risks for hospitalisation listing influenza were 0.25% in IJD and 0.1% in the general population, corresponding to a crude HR of 2.38 (95% CI 2.21 to 2.56) that decreased to 1.44 (95% CI 1.33 to 1.56) following adjustments for comorbidities. For death listing influenza, the corresponding numbers were 0.015% and 0.006% (HR=2.63, 95% CI 1.93 to 3.58, and HR=1.46, 95% CI 1.07 to 2.01). Absolute risks for influenza outcomes were half (hospitalisation) and one-tenth (death) of those for COVID-19, but relative estimates comparing IJD to the general population were similar. CONCLUSIONS: In absolute terms, COVID-19 in IJD outnumbers that of average seasonal influenza, but IJD entails a 50%-100% increase in risk for hospitalisation and death for both types of infections, which is largely dependent on associated comorbidities. Overall, bDMARDs/tsDMARDs do not seem to confer additional risk for hospitalisation or death related to seasonal influenza.