OBJECTIVES:This study aimed to investigate whether ultrasound (US)-detected features preceding Doppler-active synovitis are associated with progression to clinical arthritis in anticitrullinated protein antibody (ACPA)-positive individuals with musculoskeletal (MSK) symptoms. METHODS:In this prospective cohort study, 309 ACPA-positive individuals with MSK symptoms but without clinical arthritis and Doppler-active synovitis were included. US assessments evaluated minimal US findings, including synovial thickening, tendon sheath involvement, bursal effusions, and bone surface cortical irregularities. Longitudinal within-individual trajectories of US findings were analysed over time. Anticyclic citrullinated peptide 2 immunoglobulin G (IgG) and IgM rheumatoid factor (IgM RF) were measured at inclusion. The primary outcome was development of clinical arthritis over 3 years. Associations were analysed using Cox regression and logistic regression models. RESULTS:During a median follow-up of 13 months (IQR 7-22), 117 of 309 participants (38%) developed clinical arthritis, of whom 97 of 117 (83%) fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism rhematoid arthritis classification criteria. Any US finding at baseline (75/309) was associated with a 3-fold increased risk of arthritis development (51/117 progressors vs 24/192 nonprogressors; hazard ratio [HR] 3.3, 95% CI 2.3-4.8). Among these, tendon sheath involvement showed the strongest association (HR 3.6, 95% CI 2.4-5.4), especially in combination with IgM RF positivity (HR 4.2, 95% CI 2.7-6.4). Longitudinal trajectories demonstrated progressive accumulation of US findings prior to arthritis onset, whereas such findings remained infrequent among nonprogressors. Tendon involvement frequently preceded synovial changes. CONCLUSIONS:Minimal US findings preceding Doppler-active synovitis, particularly tendon involvement, were strongly associated with progression to clinical arthritis in ACPA-positive individuals and support an US-identified 'presynovitis' phase of rheumatoid arthritis development and early risk stratification.

OBJECTIVES:This study aims to assess the risks of primary and second primary keratinocyte cancers (KCs) in patients with rheumatoid arthritis (RA) and in relation to treatment with biologic disease-modifying antirheumatic drugs (bDMARDs) or targeted synthetic disease-modifying antirheumatic drugs. METHODS:Nationwide cohort study of patients treated with Janus kinase inhibitors (JAKi), tumour necrosis factor inhibitor (TNFi), or non-TNFi bDMARDs, using data from the Swedish Rheumatology Quality Register linked to other registers including the National Cancer Register, 2012 through 2023. Adjusted hazard ratios (HRs) were estimated via Cox regression using TNFi as reference. RESULTS:We identified 21,756 unique patients with RA. Based on 155 incident KC with JAKi, 458 with non-TNFi and 766 with TNFi, the HR for JAKi vs TNFi was 1.39 (1.16-1.68), corresponding to 1 extra KC case per every 244 patients per year. For non-TNFi vs TNFi, the HR was 0.96 (0.86-1.08). By subtype, the HR for JAKi vs TNFi was 1.41 (1.13-1.75) for basal cell carcinoma and 1.49 (1.09-2.05) for squamous cell carcinoma (SCC). For abatacept vs etanercept, the HR for SCC was 1.48 (1.11-1.97). The HR for a second primary KC was 1.31 (0.94-1.82) for JAKi and 0.94 (0.75-1.17) for non-TNFi bDMARD vs TNFi. CONCLUSIONS:Patients treated with JAKi have an elevated risk of KC compared with patients treated with TNFi. Although the class of non-TNFi bDMARDs is not associated with increased KC risk, we repeated a drug-specific signal of increased risk for SCC with abatacept.

Background /Aims: Few studies have explored how family history of colorectal cancer (CRC) affects CRC incidence in inflammatory bowel disease (IBD). We estimated CRC incidence rates (IRs) and IR differences, by family history of CRC, and the interaction between IBD and family history. Methods Nationwide, register-based cohort study 1996-2023, including patients with IBD and matched (age, sex, parish, year) comparators from the general population. The exposure was family history, defined as the number of first-degree relatives (parent, sibling, or child) and their age at CRC diagnosis (<50 or ≥50 years). Results During a median follow-up of 11 years, 1,882 CRC events occurred in 124,387 patients with IBD (IR 1.17[95%CI:1.12-1.23]/1,000 person-years) and 14,177 CRC events in 1,213,641 comparators (IR 0.88[95%CI:0.86-0.89]/1,000 person-years). In IBD, the greatest CRC risk increase was seen in those with ≥2 affected relatives: 2.69(95%CI:0.60-4.78) additional cases per 1,000 person-years versus no family history, while risk increase with early-onset CRC heredity was modest: 0.42(95%CI: -0.47-1.31)/1,000 person-years. The IRs were comparable between patients and matched comparators with the same family history, except among those without family history of CRC, where the CRC incidence was higher in IBD. The relative effect of family history was weaker in IBD, where the baseline CRC risk was already elevated. Conclusion On the absolute scale, family history of CRC increased CRC incidence similarly in IBD and matched comparators, with the greatest increase in individuals with multiple affected relatives. Guidelines advise special attention to patients with family history of early-onset CRC; our findings raise the question if surveillance strategies should instead prioritize patients with multiple affected relatives.

OBJECTIVES:The purpose of this paper is to investigate baseline predictors of unacceptable pain, overall and in patients with low inflammatory activity, as well as of pain over time, in patients with early rheumatoid arthritis (RA). METHODS:We studied patients newly diagnosed with RA in Sweden in 2012-2020 (N = 10297), using data from several national registers. Pain was assessed by a Visual Analogue Scale (VAS; 0-100 mm). Unacceptable pain was defined as VAS pain > 40 mm, and low inflammation as C-reactive protein < 10 mg/L. Baseline predictors of unacceptable pain and unacceptable pain with low inflammation were evaluated using logistic regression analysis. Predictors of pain over time, from baseline to the 2-year follow-up, were investigated using linear mixed-effect models. RESULTS:Of the 3427 patients with data at 2 years, 1143 (33%) had unacceptable pain, and 808 (26%) had unacceptable pain with low inflammation. Female sex, worse patient-reported outcomes (PROs), low parameters of inflammation, and having many tender compared with swollen joints were baseline predictors of unacceptable pain and unacceptable pain with low inflammation at 1 and 2 years, and of more pain over time. Smoking, non-European origin, and having a psychiatric or pain-related comorbidity were also associated with more pain over time. CONCLUSIONS:Factors beyond inflammation contribute significantly to unacceptable pain at follow-up in RA. Physicians should be aware of the increased risk of unacceptable pain in patients with worse PROs and with discrepancies between the number of tender and swollen joints. Sex and cultural differences also need to be considered in future pain interventions in early RA.

OBJECTIVES:Rheumatoid arthritis (RA) is a disease with a heterogeneous phenotype. Partly, this heterogeneity may be concealed by metrics such as 28-joint disease activity score (DAS28) that may assign similar scores to dissimilar phenotypes. To explore how individual patient profiles may be separated, we developed three classification schemes and compared these with DAS28 in newly diagnosed RA. METHODS:We selected patients aged 18-100 years, newly diagnosed with RA between 2012 and 2022 and registered in the Swedish Rheumatology Quality Register. We devised three alternative classifications based on (i) a subjective-objective decomposition of the DAS28 (seven levels), (ii) clinical experience-based cut-offs for each of the DAS28 components (five levels) and (iii) a data-driven Gaussian Mixture Model (five clusters). For each classification, we calculated descriptive statistics for clinical characteristics, demographic variables and comorbidity histories, and contrasted these with those based on DAS28 categories in our study population. RESULTS:We identified 6624 patients with complete data on all included variables. In each of the alternative classifications, subjectively dominated and objectively dominated subsets captured differences regarding comorbidity histories not detectable in the DAS28 categories. Across all alternative classifications, subjectively dominated subsets had lower work ability than objectively dominated subsets and included 50%-300% more patients with pain and psychiatric diagnoses prior to RA diagnosis. CONCLUSIONS:Separating subjective and objective dimensions reveals different RA patient profiles that are grouped together by DAS28, demonstrating the extent to which DAS28 is confounded by factors beyond RA disease activity. Disentangling and treating heterogeneous RA patient profiles may therefore require more granular disease activity classification systems.

RA is associated with a markedly increased risk of venous thromboembolism (VTE), reflecting a complex interplay between chronic inflammation, immune dysregulation and haemostatic imbalance. Large population-based studies consistently demonstrate a 50-100% excess risk of deep vein thrombosis and pulmonary embolism in RA, with the highest incidence early after diagnosis and during flares. Mechanistically, inflammatory cytokines, endothelial dysfunction, platelet activation, impaired fibrinolysis and autoantibody-driven immune responses promote a state of chronic immunothrombosis. RA-specific factors such as disease activity, seropositivity, disability and treatment exposures further modify thrombotic risk; some targeted therapies may amplify the risk in a subset of patients. Despite these insights, current VTE risk stratification and prevention strategies are extrapolated from the general population and fail to incorporate RA-specific factors. Improved understanding of the reason(s) behind the increased VTE risks reported with certain immune-modulatory drugs, and development of integrated clinical and biomarker-based stratification tools, are therefore both essential to enable effective thromboprophylaxis in RA.

Objectives Newly diagnosed patients with rheumatoid arthritis (RA) often ask whether diet can influence disease activity, yet evidence remains limited. We investigated whether prediagnosis adherence to a Mediterranean diet is associated with remission 6 months after diagnosis. Methods We included incident RA cases from the Swedish Epidemiological Investigation of Rheumatoid Arthritis study, with follow-up through the Swedish Rheumatology Quality Register. Remission at 6 months was defined using 5 alternative criteria (eg, 28-joint Disease Activity Score [DAS28], Boolean or combinations of their components). Prediagnosis diet was measured with a 124‑item food‑frequency questionnaire, and Mediterranean diet adherence was scored from 0 to 9. Modified Poisson regression estimated adjusted risk ratios (RRs) and 95% CIs for remission, comparing the highest vs the lowest Mediterranean diet tertiles. Analyses were stratified by RA autoantibody status (rheumatoid factor and/or anticitrullinated protein antibodies). Results Among 1510 incident RA cases (77% autoantibody-positive), higher Mediterranean diet adherence was associated with DAS28 remission in autoantibody-positive RA (59% vs 49%, RR: 1.24; CI: 1.07-1.44), but not in autoantibody-negative RA (49% vs 58%, RR: 0.84; CI: 0.65-1.09). A similar pattern appeared for Boolean remission (autoantibody-positive: 35% vs 28%, RR: 1.24; CI: 0.98-1.57; autoantibody-negative: 31% vs 32%, RR: 1.00; CI: 0.67-1.49). In contrast, Mediterranean diet adherence was not associated with minimal objective inflammatory activity (28-swollen joint count ≤ 1 and C-reactive protein ≤ 1 mg/dL). Conclusions Greater adherence to a Mediterranean diet at RA onset is associated with higher chances of remission in autoantibody-positive, but not in autoantibody‑negative RA.

INTRODUCTION:Real-world data quantifying absolute cancer risk in Crohn's disease (CD) by treatment status are lacking but are essential for patient counselling. METHODS:We linked nationwide Swedish register data and assessed incident cancers overall and by type in patients with CD 2007-2023. We estimated age-stratified incidence rate (IR) differences compared with the general population in a once-exposed-always-exposed design. Treatment cohorts comprised new users of thiopurine, tumor necrosis factor inhibitors (TNFi), thiopurine + TNFi, vedolizumab, ustekinumab, and patients naïve to immunomodulatory drugs. RESULTS:We followed 38,733 patients and 360,616 comparator subjects for a median 7.3 years. The IR differences for any cancer (number of excess cancers in each treatment cohort per 1,000 person-years versus the matched population) were 2.43 (95% CI: 1.92; 2.94) for the naive cohort; 3.14 (95% CI: 2.50; 3.78) for thiopurine-treated, 2.42 (95% CI: 1.63; 3.22) for TNFi-treated, 2.59 (95% CI: 1.53; 3.64) for thiopurine + TNFi, 2.61 (95% CI: -0.08; 5.30) for vedolizumab, and 1.54 (95% CI: -1.34; 4.41) for ustekinumab. The excess cancer incidence was primarily because of nonmelanoma skin cancer (squamous cell and basal cell carcinoma). After exclusion of nonmelanoma skin cancers, the excess overall cancer incidence was 1.27 to 0.96 cases/1,000 person-years in the naïve, thiopurine, and TNFi-treated groups, but not significantly increased in the other. IR differences for overall cancer increased and hazard ratios decreased with increasing patient age. DISCUSSION:Elevated overall cancer incidence was observed across all treatment cohorts, also in treatment-naïve patients. After exclusion of nonmelanoma skin cancer, the excess cancer incidence in CD was around 1 extra case per 1,000 person-years because of lung, small bowel, hepatobiliary, and hematologic cancers.

OBJECTIVES:The European Alliance of Associations for Rheumatology (EULAR) recently proposed a framework for 'difficult-to-manage' (D2M) and 'treatment-refractory' disease in psoriatic arthritis (PsA). We explored real-world prevalence and characteristics of patients fulfilling registry-based components inspired by EULAR's framework among patients with PsA initiating biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARD). METHODS:Cohort study from 5 Nordic biologics registries with follow-up of patients initiating first b/tsDMARD 1999 to 2020. First (step 1a), 3 cohorts were defined: discontinuation of ≥2, ≥3, or ≥4 b/tsDMARDs, respectively. Additional components were added sequentially to each cohort: (1b) b/tsDMARD-discontinuation reason (inefficacy/side effects); (1c) discontinuation of ≥2 different mechanisms of action (with 1a+1b+1c providing nuanced understanding of switching patterns); (2) problematic signs/symptoms (patient global score ≥ 30 mm); (3) persistent disease activity (tender/swollen joint count ≥1, C-reactive protein [CRP] > 10 mg/L, or Disease Activity index in PSoriatic Arthritis 28-joint counts >14). Treatment-refractory disease required primary/secondary b/tsDMARD inefficacy (not side-effects/intolerability/contraindications), and objective inflammation (tender/swollen joint count ≥ 1, or CRP > 10 mg/L). RESULTS:Among 14,362 patients, discontinuation of ≥2/≥3/≥4 b/tsDMARDs occurred in 36%/18%/10%, respectively, during a median(IQR) follow-up of 6.3 years (2.4-10.7). Applying all components (1a-3), D2M prevalences were 2%/3%/3%, respectively. Corresponding treatment-refractory prevalences were 1.2%/1.2%/0.8%, respectively. Female sex, depression, and opioid use increased with the number of b/tsDMARD discontinuations. CONCLUSIONS:In routine care, multiple b/tsDMARD discontinuations were common. Two percent were D2M, and 1.2% were treatment-refractory, both characterised by a higher prevalence of women, depression, and opioid use. Although our retrospective design did not allow testing of the EULAR definitions, our findings highlight the complexity of D2M and treatment-refractory PsA and underline the need for prospective studies.

OBJECTIVES:This study aimed to identify types of care trajectories leading to rheumatoid arthritis (RA) diagnosis, and to identify if, and when, such trajectories deviate from those in the general population. METHODS:We included patients with a first-ever RA diagnosis between 2016 and 2020 in the Swedish nationwide multiregister system and matched general population controls. We performed group-based multitrajectory modelling on 9 healthcare components over the 10 years preceding the index date, grouping patients based on their pattern of healthcare use. We described these groups, or 'types of trajectories', and compared these to those of the matched population controls. RESULTS:Based on 6824 patients with seropositive RA, we describe 5 trajectories: (i) Healthy (60%), low healthcare use across all care components; (ii) High sick leave (18%), no musculoskeletal (MSK) or infection-related inpatient care but high sick leave; (iii) Chronic pain (10%), high use of analgesics with frequent MSK-related inpatient care; (iv) High infection (9%), frequent infection-related inpatient use; and (v) High burden (3%), with an overall high use of healthcare. Deviations from the 'expected' trajectories in the general population emerged as early as 10 (types 1, 3, 5), 3 (type 4), and 2 years (type 2) before the index date. CONCLUSIONS:Individuals with new-onset RA can be grouped into clusters, each with its own signature in terms of pre-RA healthcare resource utilisation and deviation from the expected years before the RA diagnosis. Our results open for identification of individuals at elevated risk, for potential preventive action, and may highlight aetiopathologically important events.

OBJECTIVES:Rheumatoid arthritis (RA) has been associated with substantial work loss, but advances in treatment have improved clinical outcomes for patients over time calling for an updated assessment. We therefore aimed to examine calendar trends in the association between RA diagnosis and work loss. METHODS:This study included 3850 patients with RA, diagnosed between 2006 and 2020, aged 30-60 years, and their 4422 same-sex siblings. Data on work loss (the sum of sick leave and disability days) were retrieved from the Swedish Social Insurance Agency, from 3 years before up to 10 years after diagnosis. Analyses were stratified by diagnosis period (2006-2011 vs 2012-2020). RESULTS:Starting 13 months before RA diagnosis and peaking in the year thereafter, patients with RA experienced more work loss than their same-sex siblings. This excess was smaller during 2012-2020 than 2006-2011 (26 vs 47 days annually, P < 0.001). Patients diagnosed in 2012-2020 also had faster declines in work loss 2-10 years post-diagnosis than those diagnosed 2006-2012, with a smaller difference vs same-sex siblings (11 vs 29 days annually; P = 0.001). Work loss was highly skewed, with a small proportion of patients contributing most of the work loss days. CONCLUSION:Compared with their same-sex siblings as a surrogate for the counterfactual ideal, RA is still associated with considerable work loss. This difference has, however, declined in recent years, possibly due to earlier diagnosis and improved treatment.

Standardized definitions of autoimmune disease (AD) are lacking. Therefore, we aim to propose a definition of AD for register-based research and estimate the burden of AD in Sweden as registered in the National Patient Register (NPR) from 1980 to 2023. Leveraging the NPR, we defined AD as having at least two relevant International Classification of Diseases (ICD) codes representing AD. These codes could either represent the same disease or two different diseases. Age-standardized and age-specific incidence rates (IRs) of AD were calculated, along with prevalence on December 31, 2023. From 1980 to 2023, the mean age-standardized IR of AD was 318 cases per 100,000 person-years (95

OBJECTIVES:The objective of the study is to compare care pathways of patients with musculoskeletal (MSK) complaints-from first presentation in primary care to referral and follow-up in rheumatology-across 5 European healthcare systems, and to explore how healthcare system characteristics influence these pathways. METHODS:Routinely collected healthcare data from 5 European countries (UK, Sweden, the Netherlands, Spain, and Hungary) were analysed. Primary care data included > 4 million adults with at least 1 MSK encounter, and secondary rheumatology data included > 600,000 patients. Primary care consultation rates, referral rates to specialist care, and rheumatology follow-up duration were compared across countries. Healthcare characteristics were extracted from the literature. RESULTS:The distribution of MSK complaints in primary care was similar across countries, with 25% to 30% of residents visiting their general practitioner annually for an MSK complaint (UK data not available). In contrast, referral of such patients with MSK complaints to rheumatology varied considerably (5%-38%). Among those referred, 46% to 70% were discharged within 3 months, whereas only 13% to 43% remained in long-term rheumatology care. We observed that countries with a high proportion of sustained long-term rheumatology care (UK and Sweden) had lower referral rates, fewer rheumatologists per capita, and employed a selective triaging system, whereas countries where referrals more frequently resulted in short-term rheumatology care (the Netherlands, Spain, and Hungary) had higher referral rates and employed nonselective triaging. CONCLUSIONS:Substantial cross-country variation exists in the management of MSK complaints. Although primary care MSK presentations are similar, referral rates and the patient-mix reaching rheumatology differ widely between countries-an important consideration for developing cross-national clinical guidelines and diagnostic tools.

Objectives To investigate if psoriatic arthritis (PsA) itself and if biological disease-modifying antirheumatic drugs (bDMARDs) used in PsA are associated with increased risks of nonmelanoma skin cancer (NMSC). Methods From nationwide health and clinical rheumatology registers in 4 Nordic countries, we identified patients with PsA who between 2010 and 2021 started a: (i) tumour necrosis factor inhibitor (TNFi), or (ii) non-TNFi bDMARD, or were (iii) b/targeted synthetic (ts)DMARD naïve. For Sweden and Denmark, we identified incident patients with PsA (2010-2021) and corresponding general population (GP) comparator subjects. Using ever-treated follow-up, incidence rates and adjusted hazards ratios (aHRs) with 95% CIs were calculated for NMSC overall, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC), respectively. Results We identified 619 NMSCs among incident patients with PsA (n = 23,553). We observed 221 NMSCs in TNFi-treated (n = 9999), 34 NMSCs in non-TNFi bDMARD-treated (n = 2200), and 433 NMSCs in b/tsDMARD-naïve (n = 19,089) PsA. The aHR of NMSC for incident PsA vs GP was 1.20 (1.11-1.31). Pooled aHRs for NMSC overall were 1.24 (1.03-1.50) with TNFi and 1.11 (0.75-1.63) with non-TNFi bDMARDs vs b/tsDMARD-naïve PsA. Corresponding aHRs of BCC were 1.21 (0.93-1.58) for TNFi and 0.85 (0.42-1.69) for non-TNFi bDMARDs, whereas aHRs for SCC were 1.46 (0.84-2.56) and 2.37 (0.95-5.90). Conclusions Increased risks of NMSC (SCC in particular) were found in patients with PsA compared with the GP. Compared with b/tsDMARD-naïve PsA, TNFi was associated with an increased risk of NMSC overall, whereas a nonsignificantly increased risk of SCC was seen for non-TNFi bDMARDs. However, causality between bDMARD use and NMSC in PsA remains uncertain.

BACKGROUND:Women with chronic inflammatory disorders such as rheumatoid arthritis (RA) and spondyloarthritis (SpA) are at increased risk for cervical precancer (CIN2+). It is unknown whether their human papillomavirus (HPV) status differs compared with a general screening population. OBJECTIVES:To determine whether cervical screening reliant on HPV16/18 detection would be appropriate also in RA/SpA. METHODS:We included women with (1) RA (n = 53 816) or (2) SpA (n = 25 496) who were naïve to biologic-/targeted synthetic-disease-modifying anti-rheumatic drugs (b/tsDMARD), (3) women with RA (n = 14 033) or (4) SpA (n = 8297) starting a first b/tsDMARD, and matched (1:5) general population comparators, n = 504 290). Incident HPV infection was categorized as positive for HPV16/18, and/or other (non-16/18) HPV types. Relative risks (RRs) were assessed through log-binomial regression. RESULTS:Women with RA, whether exposed to b/tsDMARDs or not, had a higher prevalence of HPV (statistically significant RR of 1.17-1.18 vs comparators). Among women with SpA, risks were elevated in b/tsDMARD-exposed, as were other (non-16/18) HPV types. B/tsDMARD-naïve women with RA (but not those with bionaïve SpA) had higher risk for CIN2+ than comparators (RR = 1.20, 95% CI = 1.07 to 1.34). However, the proportion of women with CIN2+ positive for HPV16/18 or other HPV types did not differ vs comparators, neither in RA nor in SpA and whether b/tsDMARD-exposed or not. CONCLUSION:Although some women with RA or SpA have higher risks for HPV and CIN2+ than the general population, their proportions of HPV16/18 vs other HPV types in CIN2+ do not differ. This is reassuring for cervical screening risk-stratifying women based on HPV16/18 detection.

OBJECTIVES:This study aims to provide an update of the European Alliance of Associations for Rheumatology (EULAR) rheumatoid arthritis (RA) management recommendations addressing the most recent insights. METHODS:An International Task Force was formed with a wide expertise and solicited 2 systemic literature research activities on the safety and efficacy of disease-modifying antirheumatic drugs (DMARDs). New evidence was discussed, considering the update from 2022. A voting process was applied to each item. Levels of evidence and strengths of recommendation were assigned, and participants voted on the levels of agreement. RESULTS:The task force agreed on 5 overarching principles and reduced the number of recommendations to 9 concerning use of conventional synthetic DMARDs (methotrexate [MTX], leflunomide, sulfasalazine); glucocorticoids (GCs); biological (b)DMARDs (tumour necrosis factor inhibitors [adalimumab, certolizumab pegol, etanercept, golimumab, infliximab], abatacept, rituximab, tocilizumab, sarilumab, including biosimilars) and targeted synthetic [ts]DMARDs (namely the Janus kinase inhibitors [JAKi] tofacitinib, baricitinib, filgotinib, upadacitinib). Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target), and tapering following clinical remission is provided. Safety aspects, including risk of major cardiovascular events (MACEs) and malignancies, costs and sequencing of b/tsDMARDs were considered. Initially, MTX ideally in combination with short-term GCs is recommended; upon insufficient response after 3 to 6 months, a bDMARD should be added; after careful consideration of risks, including MACEs, malignancies and/or thrombo-embolic events, JAKi may also be considered. If the first bDMARD (or JAKi) fails, any other bDMARD (from another or the same class) or JAKi (considering risks) is recommended. With sustained remission, DMARDs may be tapered, but caution is required as stopping often leads to a flare. Levels of evidence and levels of agreement were high for most recommendations. CONCLUSIONS:These updated EULAR recommendations provide consensus on RA management based on currently available evidence regarding efficacy, safety, and cost.

To investigate the long-term risk of rheumatoid arthritis (RA) among individuals with autism spectrum disorder (ASD), addressing potential immune comorbidity in ASD populations. A population-based matched cohort was assembled using Swedish registers, including 46,164 individuals diagnosed with ASD between 1987 and 2017, matched to 4,634,895 controls by sex and birth year. Cohort members were followed from age 18 until RA diagnosis, death, emigration, or end of follow-up, providing up to 30 years of observation into adulthood. Cox proportional hazards models estimated hazard ratios (HR) for RA, with sensitivity analyses adjusting for parental autoimmune, psychiatric history, and socioeconomic status. RA diagnosis rates were similar between individuals with ASD (n = 58, 0.13%) and controls (n = 5484, 0.12%), with no increased risk: overall HR = 1.06 (95% CI 0.82-1.37), seropositive HR = 1.00 (0.67-1.48), and seronegative HR = 1.12 (0.79-1.57). Complementary analyses adjusting for parental psychiatric history, autoimmune conditions, and socioeconomic factors yielded consistent null findings (HR = 1.34, 95% CI 0.97-1.84). Sensitivity analyses, including accelerated failure time models and alternative RA subtype definitions, confirmed these results. This large-scale population study does not suggest an increased RA risk in individuals with ASD. Despite suggested immune dysfunction in ASD and shared genetic pathways with autoimmune conditions, we did not observe evidence that ASD is associated with elevated RA risk during adulthood; In conclusion, these findings inform understanding of autoimmune comorbidity patterns in autism and may guide evidence-based clinical monitoring for autistic adults.

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:Data on the association between non-steroidal anti-inflammatory drugs (NSAIDs) and kidney cancer (KC) are conflicting. This study aimed to evaluate this association in the general population and in patients with extensive NSAID use: rheumatoid arthritis (RA) and spondyloarthritis (SpA). METHODS:We conducted a nationwide register-based cohort study of the Swedish general population and among patients with RA or SpA, among whom NSAID use was around five times higher. In each of these cohorts, we assessed the incidence of KC 2010 through 2021 by NSAID exposure as defined by repeated prescriptions. We also evaluated KC mortality in individuals treated (vs. not) with NSAIDs, taking the cancer stage into account. Adjusted hazard ratios (HRs) were calculated through Cox regression, taking age, sex, educational level, comorbidities and family history of KC into account. RESULTS:Based on 751 incident cases of KC among 393,709 individuals in the general population (33% NSAID-exposed), the HR for NSAID-exposure was 1.32 (95% confidence interval [CI] 1.13-1.54), with the highest HRs during the first year of follow-up (HR thereafter 1.20). The corresponding cancer stage-adjusted HR for mortality from KC with NSAID-exposure was 1.26 (95%CI 0.87-1.82). In RA and SpA, the HRs for KC incidence with NSAID exposure were 0.83 (95%CI 0.58-1.18) and 1.60 (95%CI 0.78-3.29), respectively. CONCLUSIONS:We found up to a 30% increase in the overall incidence and mortality from KC with NSAID in the general population. This association was attenuated beyond the first year of follow-up and inconsistent in populations with much higher NSAID use.

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.