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Objective Autoantibodies serve as essential clinical biomarkers and may indicate etiological mechanisms in rheumatic diseases. In light of the increasing knowledge concerning the diversity and biologic implications of anti–citrullinated peptide/protein antibodies (ACPAs), we have re‐evaluated the association between the ACPA response and the HLA‐DRB1 allelic groups, known to represent a major genetic risk factor for rheumatoid arthritis (RA). Methods We explored a collection of 4,392 well‐characterized incident patients with RA of White European descent from the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) new‐onset RA study, as well as 1,199 cases of patients with RA of Southeast Asian origin from the Malaysian EIRA study. We focused on a quantitative analysis of the levels of anti–cyclic citrullinated peptide IgG antibodies, including those falling below the diagnostic threshold. Results Our data show that non‐shared epitope alleles HLA‐DRB1*09 and *15 exhibit significant associations with ACPA levels. Notably, these novel associations were independent of ethnicity. To validate our findings, we conducted an additional replication study in an independent pool of 4,109 patients with RA of White European origin. Conclusion These results indicate a new, previously overlooked, role for the HLA locus in the regulation of the levels of ACPA RA‐specific autoantibodies that goes beyond the shared epitope‐defined gene variants.

Objective To compare work loss after starting tumour necrosis factor inhibitors (TNFi), rituximab, abatacept or tocilizumab in patients with rheumatoid arthritis (RA).Methods We used data from the Swedish Rheumatology Quality Register to identify patients aged 19-62 years who were treated with TNFi (n=15 093), rituximab (n=2123), abatacept (n=1877) or tocilizumab (n=1720) between 2007 and 2020. Data on work loss (0–365 days per year) from sick leave and disability pension were retrieved from linkage to the Social Insurance Agency. Patients in the different treatment arms were balanced regarding baseline covariates using inverse probability weighting (IPTW).Results Work loss increased for patients with RA until drug treatment initiation, reached a peak in the month after treatment initiation and then levelled off. Following IPTW, at 3 years before starting the treatment, there were no statistically significant differences in the mean annual adjusted work loss days between rituximab, abatacept or tocilizumab vs TNFi (mean difference vs TNFi: rituximab 1.1 days, 95% CI −4.5 to 6.7; abatacept 3.3, 95% CI −2.6 to 9.2; tocilizumab 1.2, 95% CI −4.9 to 7.3). At 3 years after starting the treatment (latest January 2021), there were also no statistically significant differences in the mean annual adjusted work loss days (mean difference: rituximab −4.8 days, 95% CI −11.3 to 1.7; abatacept 5.3, 95% CI −1.8 to 12.3; tocilizumab −0.6, 95% CI −7.7 to 6.5).Conclusions Taking channelling into account, patients with RA treated with TNFi, rituximab, abatacept or tocilizumab had similar trajectories of work loss from sick leave and disability pension until treatment initiation, and similar trend breaks and plateau 3 years thereafter.

Abstract Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.

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.

Objective To assess associations between inflammatory remission, formal treatment targets and the likelihood of starting a new disease-modifying antirheumatic drug (DMARD), among patients with early rheumatoid arthritis (RA).Methods Patients newly diagnosed with RA were identified in the Swedish Rheumatology Quality Register (n=11 784). Disease Activity Score 28 (DAS28) and DMARD-treatment were assessed at RA diagnosis and 3, 6, 12 and 24 months thereafter. Inflammatory remission was defined as: swollen joints (0–28)=0 and C reactive protein

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.

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.

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.

Objective Precision medicine in rheumatoid arthritis (RA) requires a good understanding of treatment outcomes and often collaborative efforts that call for data harmonisation. We aimed to describe how harmonisation across study cohorts can be achieved and investigate how the observed proportions reaching remission vary across remission criteria, study types, disease-modifying antirheumatic drugs (DMARDs) and countries, and how they relate to other treatment outcomes.Methods We used data from eight existing large-scale, clinical RA registers and a pragmatic trial from Sweden, Denmark and Norway. In these, we defined three types of treatment cohorts; methotrexate monotherapy (as first DMARD), tumour necrosis factor inhibitors (TNFi) (as first biological DMARD) and rituximab. We developed a harmonised study protocol defining time points during 36 months of follow-up, collected clinical visit data on treatment response, retention, persistence and six alternative definitions of remission, and investigated how these outcomes differed within and between cohorts, by treatment.Results Cohort sizes ranged from ~50 to 22 000 patients with RA. The proportions reaching each outcome varied across outcome metric, but with small to modest variations within and between cohorts, countries and treatment. Retention and persistence rates were high (>50% at 1 year), yet

Abstract Introduction The aim of this work is to evaluate baricitinib safety with respect to venous thromboembolism (VTE), major adverse cardiovascular events (MACE), and serious infection relative to tumor necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA). Methods Patients with RA from 14 real-world data sources (three disease registries, eight commercial and three government health insurance claims databases) in the United States (n = 9), Europe (n = 3), and Japan (n = 2) were analyzed using a new user active comparator design. Propensity score matching (1:1) controlled for potential confounding. Meta-analysis of incidence rate ratios (IRR) and incidence rate differences (IRD) for each outcome, from each data source was executed using modified Poisson regression and Cochran–Mantel–Haenszel analysis. Results Of 9013 eligible baricitinib-treated patients, 7606 were propensity score-matched with TNFi-treated patients, contributing 5879 and 6512 person-years of baricitinib and TNFi exposure, respectively. Across data sources, 97 patients (56 baricitinib) experienced VTE during follow-up, 93 experienced MACE (54 baricitinib), and 321 experienced serious infection (176 baricitinib). Overall IRRs comparing baricitinib with TNFi treatment were 1.51 (95% CI 1.10, 2.08) for VTE, 1.54 (95% CI 0.93, 2.54) for MACE, and 1.36 (95% CI 0.86, 2.13) for serious infection. IRDs for VTE, MACE, and serious infection, respectively, were 0.26 (95% CI −0.04, 0.57), 0.22 (95% CI −0.07, 0.52), and 0.57 (95% CI −0.07, 1.21) per 100 person-years greater for baricitinib than TNFi. Conclusions Overall results suggest increased risk of VTE with baricitinib versus TNFi, with consistent point estimates from the two largest data sources. A numerically greater risk was observed for MACE and serious infection when comparing baricitinib versus TNFi, with different point estimates from the two largest data sources. Findings from this study and their impact on clinical practice should be considered in context of limitations and other evidence regarding the safety and efficacy of baricitinib and other Janus kinase inhibitors. Trial registration: EU PAS Register ( http://encepp.eu ), identifier #32271.

Abstract Objectives To investigate the association between psychosocial vulnerability, defined as either low social support or low decision latitude at work, and disease remission at 3, 12, and 60 months in patients with rheumatoid arthritis (RA). Methods This cohort study included all patients enrolled in both the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) 1996–2015 and the Swedish Rheumatology Quality Register (SRQ, n = 2820). Information on social support and decision latitude at work at RA diagnosis were identified from the EIRA questionnaire. Indexes for levels of social support and decision latitude at work, respectively, were calculated based on the questionnaire. Low social support and low decision latitude at work, respectively, were identified by a score in the lowest quartile and compared with the three other quartiles (not low). Disease-activity parameters were retrieved from SRQ at 3, 12, and 60 months. The associations between social support or decision latitude at work, respectively, and Disease Activity Score 28 joint count with C-reactive protein (DAS28-CRP) remission were analysed using logistic regression models adjusted for age, sex, smoking habits, alcohol habits, symptom duration, and educational level. Results Having low social support (n = 591) was not associated with DAS28-CRP remission at 3 (OR 0.93, 95% CI 0.74–1.16), 12 (OR 0.96, 95%CI 0.75–1.23), or 60 (OR 0.89, 95%CI 0.72–1.10) months compared to not low social support (n = 2209). No association was observed for low (n = 212) versus not low (n = 635) decision latitude at work and DAS28-CRP remission at 3 (OR 0.84, 95%CI 0.54–1.31), 12 (OR 0.81, 95%CI 0.56–1.16), or 60 (OR 1.37, 95%CI 0.94–2.01) months. Conclusion In a country with general access to healthcare, psychosocial vulnerability does not influence the likelihood of achieving remission in early RA.

Abstract 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.

Objectives To estimate the incidence of non-vertebral fractures in ankylosing spondylitis (AS) compared with the general population.Methods Nationwide register-based cohort study including patients with AS (n=11 611, 65% men, mean age 48 years), and matched general population controls (n=58 050). Five prespecified fracture outcomes: (1) non-vertebral; (2) fracture of the proximal humerus, distal forearm or hip; (3) proximal humerus; (4) distal forearm and (5) hip) were identified through register linkages with follow-up 2007–2016. We used Poisson regression to calculate incidence rates (IRs), number of fractures per 1000 person-years at risk and IR ratios (IRRs), overall and by sex and age. IRRs were adjusted for history of any prior fracture.Results IRs (men/women) for non-vertebral fracture in AS were 11.9 (95% CI 11.0 to 12.9)/14.5 (95% CI 13.1 to 16.1) and in controls 10.0 (95% CI 9.7 to 10.4)/11.8 (95% CI 11.1 to 12.4), IRR (men/women) 1.2 (95% CI 1.1 to 1.3)/1.2 (95% CI 1.1 to 1.4). IRs (men/women) for fractures of the humerus, forearm or hip in AS were 4.0 (95% CI 3.5 to 4.6)/6.3 (95% CI 5.4 to 7.3) and in controls 2.7 (95% CI 2.5 to 2.9)/5.5 (95% CI 5.1 to 6.0), IRR (men/women) 1.5 (95% CI 1.3 to 1.7)/1.1 (95% CI 0.9 to 1.3). IRRs were statistically significantly elevated in men with AS versus controls for forearm fracture (1.4 (95% CI 1.1 to 1.7)) and hip fracture (1.8 (95% CI 1.4 to 2.3)), whereas not in women with AS where the IRRs were 1.1 (95% CI 0.9 to 1.4) and 1.0 (95% CI 0.6 to 1.4). For humerus fracture, IRRs were 1.4 (95% CI 0.99 to 1.9) in men with AS versus controls and 1.1 (95% CI 0.8 to 1.6) in women.Conclusions Both men and women with AS have a slightly higher risk of non-vertebral fractures than the general population. A statistically significantly higher risk of fractures of the proximal humerus, distal forearm or hip was found in men with AS in comparison to general population, where the relative risk was especially pronounced for hip fracture.

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.

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 (

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.

Objective Lung cancer is a common malignancy in rheumatoid arthritis (RA). Since smoking is a risk factor for both (seropositive) RA and lung cancer, it remains unclear whether RA, in itself, increases lung cancer risk.Methods We performed a population-based cohort study of patients with RA and individually matched general population reference individuals identified in Swedish registers and from the Epidemiological Investigation of RA early RA study, prospectively followed for lung cancer occurrence 1995–2018. We calculated incidence rates and performed Cox regression to estimate HRs including 95% CIs of lung cancer, taking smoking and RA serostatus into account.Results Overall, we included 44 101 patients with RA (590 incident lung cancers, 56 per 100 000), and 216 495 matched general population individuals (1691 incident lung cancers, 33 per 100 000), corresponding to a crude HR (95% CI) of 1.76 (1.60 to 1.93). In subset analyses, this increased risk remained after adjustment for smoking (HR 1.77, 95% CI 1.06 to 2.97). Compared with general population subjects who were never smokers, patients with RA who were ever smokers had almost seven times higher risk of lung cancer. In RA, seropositivity was a significant lung cancer risk factor, even when adjusted for smoking, increasing the incidence 2–6 times. At 20 years, the risk in patients with RA was almost 3%, overall and over 4% for patients who were ever smokers and had at least one RA autoantibody.Conclusions Seropositive RA is a risk factor for lung cancer over and above what can be explained by smoking, although residual confounding by smoking or other airway exposures cannot be formally excluded. There is a need for increased awareness and potentially for regular lung cancer screening, at least in a subset of patients with RA.

Objective The objectives of this study were to assess the 1‐year persistence to methotrexate (MTX) initiated as the first ever conventional synthetic disease‐modifying antirheumatic drug in new‐onset rheumatoid arthritis (RA) and to investigate the marginal gains and robustness of the results by increasing the number and nature of covariates and by using data‐driven, instead of hypothesis‐based, methods to predict this persistence. Methods Through the Swedish Rheumatology Quality Register, linked to other data sources, we identified a cohort of 5475 patients with new‐onset RA in 2006‐2016 who were starting MTX monotherapy as their first disease‐modifying antirheumatic drug. Data on phenotype at diagnosis and demographics were combined with increasingly detailed data on medical disease history and medication use in four increasingly complex data sets (48‐4162 covariates). We performed manual model building using logistic regression. We also performed five different machine learning (ML) methods and combined the ML results into an ensemble model. We calculated the area under the receiver operating characteristic curve (AUROC) and made calibration plots. We trained on 90% of the data, and tested the models on a holdout data set. Results Of the 5475 patients, 3834 (70%) remained on MTX monotherapy 1 year after treatment start. Clinical RA disease activity and baseline characteristics were most strongly associated with the outcome. The best manual model had an AUROC of 0.66 (95% confidence interval [CI] 0.60‐0.71). For the ML methods, Lasso regression performed best (AUROC = 0.67; 95% CI 0.62‐0.71). Conclusion Approximately two thirds of patients with early RA who start MTX remain on this therapy 1 year later. Predicting this persistence remains a challenge, whether using hypothesis‐based or ML models, and may yet require additional types of data.

Objective To determine the association of allergic conditions with incident rheumatoid arthritis (RA), especially in relation to smoking history and anti-citrullinated peptide antibody (ACPA) status.Methods This case–control study included 3515 incident RA cases and 5429 matched controls from the Epidemiological Investigation of Rheumatoid Arthritis study 1995 to 2016, including questionnaire-based information on eight allergic conditions composed from a list of 59 unique allergies. We used logistic regression and adjusted ORs (aOR) to assess the association between allergic conditions and risk of RA, adjusting for age, sex, residential area, body mass index, education, and smoking, and stratified by smoking and ACPA.Results A history of any reported allergy was equally common in RA (n=1047, 30%) as among population controls (n=1540, 29%), aOR 1.04, 95% CI 0.95 to 1.15. Metal, respiratory, food, plant/pollen and chemical allergies were not associated with risk of RA. By contrast, statistically significant associations were observed for animal dander allergy (6% vs 5%, aOR 1.37, 95% CI 1.03 to 1.82), especially in ACPA-positive RA (aOR 1.46 95% CI 1.06 to 2.01) and for atopic dermatitis, in particular for older and ACPA-negative RA (aOR 2.33, 95% CI 1.37 to 3.96 at age 80). Never smokers with allergic rhinitis also had increased risk of developing RA (aOR 1.30, 95% CI 1.00 to 1.68).Conclusion Most common allergies do not increase risk of RA, nor do they protect against RA. However, some allergic conditions, notably animal dander allergy, atopic dermatitis and allergic rhinitis, were associated with an increased risk for RA.

Abstract Background There is substantial evidence that patients with ankylosing spondylitis (AS) have high response rates to tumour necrosis factor inhibitors (TNFi), a low likelihood of successful treatment termination, but yet a limited drug retention. Whereas several reports have assessed drug retention rates for TNFi in AS, there are few, if any, studies investigating the actual treatment trajectories on a patient level, including subsequent therapy changes and dose reductions, of individual patients. The aim of this study was to describe 5-year treatment trajectories in patients with ankylosing spondylitis (AS) starting a first TNFi. Methods Bio-naïve patients with AS starting a TNFi in 2006–2015 were identified in the nationwide Swedish Rheumatology Quality register and followed until 31 December 2015. All changes in their anti-rheumatic treatment during follow-up were recorded. To further increase precision, these data were complimented by information on the amount of prescribed subcutaneous TNFi collected from pharmacies during each year, retrieved from the Swedish Prescribed Drug Register. Results Two thousand five hundred ninety patients started a first TNFi 2006–2015, and after 1 year, 74% remained on their first TNFi. However, after 5 years, this figure was only 46%, although at that time 63% were still on treatment with any biologic, while 30% had no anti-rheumatic treatment at all. After discontinuing the first TNFi, 46% switched directly to a second TNFi, but the drug retention for the second and third TNFi grew successively shorter compared to that for the first TNFi. In contrast, patients remaining on treatment with their first subcutaneous TNFi gradually reduced the dose, so that during the fifth year of treatment only 66% had collected ≥ 75% of the defined daily doses for that year. Conclusion Less than half of patients with AS will remain on their first TNFi after 5 years, but most are still on a biologic. While patients remaining on treatment with their first TNFi appear to be able to reduce the dose over time, a large proportion cycle through several biologics, and 1/3 have no anti-rheumatic treatment after 5 years. This indicates the importance of thorough follow-up programs as well as a need for alternative therapeutic options.

Objectives To compare incidence rates of gastrointestinal (GI) perforations between patients with RA and the general population, and between patients treated with tumour necrosis factor inhibitors (TNFi) and non-TNFi biologics.Methods In this nationwide cohort study, a total of 63 532 patients with RA, with 26 050 biological treatment episodes (TNFi, rituximab, abatacept or tocilizumab) and 76 304 general population controls, were followed between 2009 and 2017 until the first outcome event. The main outcome was hospitalisation or death due to lower GI perforations, identified according to a prespecified list of ICD-10 (International Classification of Diseases, 10th revision) codes. Inverse probability of treatment weighting was used for adjustment.Results The sex-standardised and age-standardised incidence rates of lower GI perforations were 1.1 (95% CI 1.0 to 1.3) events per 1000 person-years among general population controls, 1.6 (1.5–1.7) among bionaïve patients and ranged from 1.8 (1.4–3.6) (TNFi) to 4.5 (2.7–10.4) (tocilizumab) among biologics-treated patients. After adjustment for glucocorticoid use, the risk in bionaïve, TNFi-treated, abatacept-treated or rituximab-treated patients with RA was no longer different from the general population, while for tocilizumab it remained significantly higher. Comparing tocilizumab to TNFi, the adjusted HR for lower GI perforations was 2.2 (1.3–3.8), corresponding to one additional GI perforation per 451 patient-years treated with tocilizumab instead of TNFi.Conclusion Tocilizumab was associated with a higher risk of lower GI perforations compared with alternative biologics. In absolute numbers, the risk remained low on all biologics commonly used to treat RA, but the accumulated evidence across settings and outcome definitions supports that this risk should be considered in treatment guidelines for RA.

Objective To investigate if autoimmune thyroid disease (AITD) impacts rheumatoid arthritis (RA) disease activity or response to methotrexate.Methods A nationwide register-based cohort study of 9 004 patients with new-onset RA from the Swedish Rheumatology Quality Register year 2006–2016, with linkage to other nationwide registers to identify comorbidity with AITD defined as thyroxine prescription before RA diagnosis, excluding non-autoimmune causes. We compared RA disease activity using 28-joint Disease Activity Score (DAS28) and its components, and EULAR response, between patients with and without AITD, using logistic regression.Results At diagnosis, patient reported outcome measures (PROMs; patient global, Health Assessment Questionnaire Disability Index and pain) but not objective disease activity measures (erythrocyte sedimentation rate and swollen joint count) were significantly higher (p

Abstract Background The Mediterranean diet has been associated with lower mortality and lower risk of cardiovascular diseases and cancer. Although its components have been analysed in several studies, only one study has specifically investigated the association between Mediterranean diet and risk of rheumatoid arthritis (RA), and reported no association. Methods Data on 1721 patients with incident RA (cases) and 3667 controls, matched on age, gender and residential area, from the Swedish epidemiological investigation of RA (EIRA), a population-based case-control study, were analysed using conditional logistic regression. The Mediterranean diet score, ranging from 0 to 9, was calculated from a 124-item food frequency questionnaire. Results In the EIRA study (median age of participants 53 years), 24.1% of the patients and 28.2% of the controls had high adherence to the Mediterranean diet (a score between 6 and 9). After adjustments for body mass index, educational level, physical activity, use of dietary supplements, energy intake, and smoking, high adherence reduced the odds of developing RA by 21% (OR 0.79; 95% CI 0.65–0.96) as compared to low adherence (a score between 0 and 2). The OR was even lower among men (OR 0.49; 95% CI 0.33–0.73), but no significant association was found among women (OR 0.94; 95% CI 0.74–1.18). An association between high diet score and low risk of RA was observed in rheumatoid factor (RF)-positive (OR 0.69; 95% CI 0.54–0.88), but not RF-negative RA (OR 0.96; 95% CI 0.68–1.34), and in RA characterised by presence of antibodies to citrullinated peptides (ACPA), but not in ACPA-negative RA. Conclusions In this large population-based case-control study, the Mediterranean diet score was inversely associated with risk of RA. However, an association was only found among men and only in seropositive RA.

Abstract Background To investigate the risk of first-time acute coronary syndrome (ACS), stroke and venous thromboembolism (VTE) in patients with ankylosing spondylitis (AS), psoriatic arthritis (PsA) and undifferentiated spondyloarthritis (uSpA), compared to each other and to the general population (GP). Methods This is a prospective nationwide cohort study. Cohorts with AS (n = 6448), PsA (n = 16,063) and uSpA (n = 5190) patients and a GP (n = 266,435) cohort, were identified 2001–2009 in the Swedish National Patient and Population registers. The follow-up began 1 January 2006, or 6 months after the first registered spondyloarthritis (SpA) diagnosis thereafter, and ended at ACS/stroke/VTE event, death, emigration or 31 December 2012. Crude and age- and sex-standardized incidence rates (SIRs) and hazard ratios (HRs) were calculated for incident ACS, stroke or VTE, respectively. Results Standardized to the GP cohort, SIRs for ACS were 4.3, 5.4 and 4.7 events per 1000 person-years at risk in the AS, PsA and uSpA cohort, respectively, compared to 3.2 in the GP cohort. SIRs for stroke were 5.4, 5.9 and 5.7 events per 1000 person-years at risk in the AS, PsA and uSpA cohort compared to 4.7 in the GP cohort. Corresponding SIRs for VTE were 3.6, 3.2 and 3.5 events per 1000 person-years at risk compared to 2.2 in the GP cohort. Age-and sex-adjusted HRs (95% CI) for ACS events were significantly increased in AS (1.54 (1.31–1.82)), PsA (1.76 (1.59–1.95)) and uSpA (1.36 (1.05–1.76)) compared to GP. Age-adjusted HRs for ACS was significantly decreased in female AS patients (0.59 (0.37–0.97)) compared to female PsA patients. Age-and sex-adjusted HRs for stroke events were significantly increased in AS (1.25 (1.06–1.48)) and PsA (1.34 (1.22–1.48)), and nonsignificantly increased in uSpA (1.16 (0.91–1.47)) compared to GP. For VTE the age-and sex-adjusted HRs for AS, PsA and uSpA were equally and significantly increased with about 50% compared to GP. Conclusions Patients with AS, PsA and uSpA are at increased risk for ACS and stroke events, which emphasizes the importance of identification of and intervention against cardiovascular risk factors in SpA patients. Increased alertness for VTE is warranted in patients with SpA.

Objectives To estimate the mortality among siblings of patients with rheumatoid arthritis (RA) and put any excess mortality among these in relation to the mortality among patients with RA.Methods Using prospective nation-wide registers, we identified patients diagnosed with new-onset RA 2001–2017 (n=8137), patients with prevalent RA 2006–2017 (n=25 464), matched general population comparator subjects to all RA patients (n=22 457/68 674) and full-siblings of all groups (n=28 878/91 546).We followed all cohorts until death, 31 December 2018, migration and (for non-RA subjects) RA diagnosis. We compared patients with RA versus the general population, and siblings of RA versus siblings of the general population using Cox regression, including adjustment for socio-economy.Results The HR of death versus the general population was 1.11 (95% CI 1.01 to 1.22) for incident and 1.46 (95% CI 1.39 to 1.52) for prevalent patients with RA. The siblings of these patient groups were also at increased risk of death (HR=1.10, 95% CI 1.01 to 1.20 and 1.09, 95% CI 1.04 to 1.13, respectively), with little impact of adjustment for socio-economy.Conclusion The mortality in RA is increased, but around one-fifth of this excess is present also among their siblings. Previous literature using general population rates for comparison has thus likely overestimated the direct impact on mortality attributable to RA. To bring down excess mortality in RA, optimal disease control is important but may not suffice.

IntroductionThe possible hypothesis of a link between periodontitis and rheumatoid arthritis (RA), specifically anti-citrullinated protein antibody (ACPA) positive RA, prompted us to investigate the prevalence of periodontitis in the Swedish Epidemiological Investigation of RA (EIRA), a well-characterised population-based RA case-control cohort.MethodsPeriodontal status of 2,740 RA cases and 3,942 matched controls was retrieved through linking EIRA with the National Dental Health Registry (DHR), where dental diagnostic- and treatment codes on the adult Swedish population have been registered. Dental records from 100 cases and controls were reviewed to validate the periodontal diagnostic codes in DHR.ResultsThe reviewed dental records confirmed 90% of the periodontitis diagnoses in DHR among RA cases, and 88% among controls. We found the positive predictive value of periodontitis diagnoses in the DHR to be 89% (95% CI 78 to 95%) with a sensitivity of 77% (95% CI: 65 to 86%). In total, 86% of EIRA participants were identified in DHR. The risk for periodontitis increased by age and current smoking status in both cases as well as controls. No significant differences in prevalence of periodontal disease in terms of gingivitis, periodontitis, peri-implantitis or increased risk for periodontitis or peri-implantitis were observed between RA cases and controls. In addition, there was no difference on the basis of seropositivity, ACPA or rheumatoid factor (RF), among patients with RA.ConclusionsOur data verify that smoking and ageing are risk factors for periodontitis, both in RA and controls. We found no evidence of an increased prevalence of periodontitis in patients with established RA compared to healthy controls, and no differences based on ACPA or RF status among RA subjects.

BACKGROUND: Ankylosing spondylitis (AS) is associated with several extra-articular manifestations. Nephrolithiasis (NL) has not been recognized as one of those, however, several factors known to increase the risk of NL are at play in AS patients. The objective was to estimate rates and predictors of NL in Swedish patients with AS compared to the general population. METHODS AND FINDINGS: We performed a prospective population-based nationwide cohort study based on linkage of data from Swedish registries. 8,572 AS patients were followed for 49,258 person-years (py) and 39,639 matched general population comparators were followed for 223,985 py. Patients were followed prospectively together with comparator subjects from January 2001 through December 2009. The first occurrence of NL during follow-up was the primary outcome. Hazard Ratios (HR) were used to compare these rates adjusting for comorbidities and treatment, and to assess predictors for NL. Mean age at study entry was 46 years (inter quartile range 36-56 years), 65% were males. Based on 250 vs. 466 NL events, the adjusted HR of NL in AS patients was 2.1 (95%CI 1.8 to 2.4). Predictors of NL within the AS group included prior diagnosis of inflammatory bowel disease (IBD) (HR 2.3; 95%CI 1.7 to 3.3), prior diagnosis of NL (HR 16.4; 95%CI 11.5 to 23.4), and patients receiving anti-TNF treatment (HR 1.6; 95%CI 1.2 to 2.1). Male sex was a risk factor for NL both in AS patients and in the general population. LIMITATIONS: The risk for residual confounding and inability to study the chemical nature of NL were considered the main limitations of the study. CONCLUSIONS: Patients with AS are at increased risk of NL, which may be considered a novel extra-articular manifestation. Previous history of NL, IBD, AS disease severity and male sex were identified as predictors of NL in AS.

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8 × 10(-8)), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3' UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1 × 10(-11) in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry.