Search

ObjectivesTo 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.MethodsUsing 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.ResultsPer 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.ConclusionsIn 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.

Objectives To compare trajectories of marriage and parenthood in individuals with JIA vs the general population. Methods Patients with JIA (n = 4399) were identified in the Swedish National Patient Register (2001–2016) and individually matched to up to five general population comparators on birthyear, sex and residence county (n = 21 981). Marriage and parenthood data were retrieved from the Total Population Register from age 18 y, and parenthood from the Multigeneration Register from age 15 y, respectively. Hazard ratios (HRs) were estimated using Cox regression adjusted for parental education, parental marital status and number of siblings. Results During a median of 6.3 years of follow-up, 362 patients with JIA and 1744 comparators got married (12.9 vs. 12.5 per 1000 person-years; HR 1.03, 95%CI 0.93-1.15). During a median of 8.8 years of follow-up, 680 patients with JIA and 3477 matched comparators became parents (17.1 vs 17.8 per 1000 person-years; HR 0.94, 95%CI 0.87-1.01). In the subgroup of patients with systemic onset JIA (SJIA), the adjusted hazard ratios for marriage and parenthood were 0.79 (95%CI 0.53-1.17) and 0.73 (95%CI 0.55-0.97), respectively. Conclusion The times to first marriage and first parenthood are similar for patients with JIA and the general population, suggesting that adolescents with JIA transition into family life along a trajectory resembling their community peers. One exception is the subgroup of patients with systemic onset JIA, who become parents for the first time at a lower rate than general population comparators.

BackgroundThe effect of interleukin 17-inhibitors on anterior uveitis (AU) in spondyloarthritis (SpA) is poorly understood. This study aimed to compare the risk of AU during treatment with secukinumab versus tumour necrosis factor inhibitors (TNFi).MethodsPatients with SpA starting secukinumab or a TNFi 2015 through 2018 were identified in the Swedish Rheumatology Quality Register. Occurrence of AU was identified based on diagnosis codes in outpatient ophthalmology care in the National Patient Register. The main outcomes were crude rates of AU-diagnoses per 100 patient-years, and adjusted HRs for AU, during treatment, in patients without AU during the year before treatment start (in order to reduce confounding by indication). HRs were adjusted for age, sex, history of AU and patient global assessment of disease activity.ResultsBased on 4851 treatment starts (456 secukinumab; 4395 any TNFi), the rate of AU-diagnoses per 100 patient-years was 6.8 (95% CI 5.2 to 8.7) for secukinumab. Among the TNFi, the rate varied from 2.9 (95% CI 2.1 to 3.7) for infliximab and 4.0 (95% CI 3.3 to 4.9) for adalimumab to 7.5 (95% CI 6.7 to 8.4) for etanercept. The adjusted HRs for first AU (adalimumab as reference) were: secukinumab 2.32 (95% CI 1.16 to 4.63), infliximab 0.99 (95% CI 0.49 to 1.96), etanercept 1.82 (95% CI 1.13 to 2.93), golimumab 1.59 (95% CI 0.90 to 2.80) and certolizumab 1.12 (95% CI 0.44 to 2.83). Sensitivity analyses confirmed the pattern of higher AU rates with secukinumab and etanercept versus monoclonal TNFi.ConclusionAs used in clinical practice in SpA, secukinumab appears to be associated with a higher risk of AU, compared with the monoclonal TNFi and a similar risk compared with etanercept.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/., Background: Comedication with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) during treatment with tumour necrosis factor inhibitors (TNFi) is extensively used in psoriatic arthritis (PsA), although the additive benefit remains unclear. We aimed to compare treatment outcomes in patients with PsA treated with TNFi and csDMARD comedication versus TNFi monotherapy. Methods: Patients with PsA from 13 European countries who initiated a first TNFi in 2006-2017 were included. Country-specific comparisons of 1 year TNFi retention were performed by csDMARD comedication status, together with HRs for TNFi discontinuation (comedication vs monotherapy), adjusted for age, sex, calendar year, disease duration and Disease Activity Score with 28 joints (DAS28). Adjusted ORs of clinical remission (based on DAS28) at 12 months were calculated. Between-country heterogeneity was assessed using random-effect meta-analyses, combined results were presented when heterogeneity was not significant. Secondary analyses stratified according to TNFi subtype (adalimumab/infliximab/etanercept) and restricted to methotrexate as comedication were performed. Results: In total, 15 332 patients were included (62% comedication, 38% monotherapy). TNFi retention varied across countries, with significant heterogeneity precluding a combined estimate. Comedication was associated with better remission rates, pooled OR 1.25 (1.12-1.41). Methotrexate comedication was associated with improved remission for adalimumab (OR 1.45 (1.23-1.72)) and infliximab (OR 1.55 (1.21-1.98)) and improved retention for infliximab. No effect of comedication was demonstrated for etanercept. Conclusion: This large observational study suggests that, as used in clinical practice, csDMARD and TNFi comedication are associated with improved remission rates, and specifically, comedication with methotrexate increases remission rates for both adalimumab and infliximab.

Objective Patients with rheumatoid arthritis (RA) are at increased risk of coronary artery disease (CAD) and seem to develop more severe acute coronary syndromes (ACS) than the general population. Because few studies have investigated the CAD distribution in the context of acute or stable CAD in RA, the objective was to investigate whether this risk is due to a different distribution and severity of coronary stenoses (versus non-RA), resulting in clinical manifestation of CAD. Methods We performed a population-based study using linkages of nationwide clinical, health, and demographics registers. We compared 1 cohort of patients with RA, and 1 matched cohort of patients without RA, undergoing a first coronary angiography from 2006 through 2015. Cardiovascular (CV) characteristics and the presence and distribution of clinically significant stenoses were compared (through odds ratios [ORs]), stratified by indication (stable CAD, ST-elevation myocardial infarction [STEMI], and non–ST-elevation ACS [NSTACS]), using logistic regression. Results We identified 2,985 patients with RA and 10,290 patients without RA who underwent a first coronary angiography. A higher proportion of patients with RA (75% versus 69%) had STEMI and NSTACS as indication for angiography. We found no difference in the presence and distribution of clinically significant coronary stenoses in RA compared with the patients without RA, regardless of the CAD type (for having any significant stenosis in stable CAD OR 0.9, STEMI OR 0.8, and NSTACS OR 1.1), stratification by RA duration, sex, or burden of concomitant CV risk factors. Conclusion Although RA may accelerate the development of clinical CAD events, the underlying angiographic characteristics are similar to those in patients without RA.

The 6‐month infection risk was 43% lower in patients with sarcoidosis who initiated methotrexate compared to those who started azathioprine. Our findings suggest that unless contraindications exist, methotrexate should be preferred over azathioprine as the primary steroid‐sparing choice in individuals with sarcoidosis., Background and objective No clinical trial has examined the risk of infection associated methotrexate and azathioprine, two advocated treatments for sarcoidosis. We aimed to compare the 6‐month risk of infection after the initiation of methotrexate or azathioprine. Methods We conducted a retrospective target trial emulation using Swedish pre‐existing data. We searched for eligible participants who were dispensed methotrexate or azathioprine in the Prescribed Drug Register (PDR) every day between January 2007 and June 2013. Adults were eligible if they had ≥2 ICD‐coded visits for sarcoidosis in the National Patient Register (NPR) and were dispensed ≥1 systemic corticosteroid but no methotrexate or azathioprine in the past 6 months (PDR). Within 6 months of methotrexate or azathioprine initiation, diagnosis of infectious disease was identified (visit in the NPR where infectious disease was the primary diagnosis). We estimated RR and risk differences comparing methotrexate (n = 667) to azathioprine initiations (n = 259) using targeted maximum likelihood estimation (TMLE) adjusting for demographic factors, comorbidity and sarcoidosis severity proxies. Results There were 43 infections in the methotrexate group (adjusted 6‐month risk 6.8%) and 29 infections in the azathioprine group (12.0%). The RR for infectious disease at 6 months associated with methotrexate compared to azathioprine initiation was 0.57 (95% CI: 0.39, 0.82) and the risk difference was −5.2% (95% CI: −8.5%, −1.8%). The RR at 9 months was attenuated to 0.77 (95% CI: 0.52, 1.14). Conclusion Methotrexate appears to be associated with a lower risk of infection in sarcoidosis than azathioprine, but randomized trials should confirm this finding.

Background and Aims Patients with inflammatory bowel disease [IBD] are subject to more work disability than the general population. We aimed to estimate the monetary cost of IBD for the individual through assessment of earnings in relation to diagnosis. Methods Through linkage of national registers, we identified patients aged 30–55 years at first IBD diagnosis in Sweden in 2002–2011, and same-sex IBD-free siblings. We estimated taxable earnings and disposable income from 5 years before to 5 years after diagnosis. Results The 5961 patients [27% Crohn’s disease, 68% ulcerative colitis, 4.3% IBD unclassified] had similar taxable earnings to their 7810 siblings until the year of diagnosis, when earnings decreased and remained lower than for siblings during follow-up. The adjusted difference in earnings over the entire 5-year period after diagnosis was −5% [−8212€; 95% confidence interval: −11 458 to −4967€]. The difference was greater in women than in men, and greater in Crohn’s disease than in ulcerative colitis. When stratifying for sex and IBD subtype and comparing earnings during each year of follow-up, median annual earnings were lower in women with Crohn’s disease and ulcerative colitis than in their sisters during all years of follow-up, whereas the men had similar annual taxable earnings to their brothers. Disposable income was similar between patients and siblings during the investigated time period. Conclusion From the year of diagnosis and at least 5 years onwards, patients with IBD had 5% lower earnings than siblings, mainly explained by differences between women with IBD and their sisters. However, there were no differences in disposable income.

Objectives To estimate the incidence and strength of association of extra-articular manifestations [EAMs, here: anterior uveitis (AU), IBD and psoriasis] in patients with AS, undifferentiated SpA (uSpA) and PsA, compared with controls. Methods Three mutually exclusive cohorts of patients aged 18–69 years with AS (n = 8517), uSpA (n = 10 245) and PsA (n = 22 667) were identified in the Swedish National Patient Register 2001–2015. Age-, sex- and geography-matched controls were identified from the Swedish Population Register. Follow-up began 1 January 2006, or six months after the first SpA diagnosis, whichever occurred later, and ended at the first date of the EAM under study, death, emigration, 70 years of age, and 31 December 2016. Incidence rates (IRs) and incidence rate ratios were calculated for each EAM, and stratified by sex and age. Results Incidence rate ratios for incident AU, IBD and psoriasis were significantly increased in AS (20.2, 6.2, 2.5), uSpA (13.6, 5.7, 3.8) and PsA (2.5, 2.3, n.a) vs controls. Men with AS and uSpA had significantly higher IRs per 1000 person-years at risk for incident AU than women with AS (IR 15.8 vs 11.2) and uSpA (IR 10.1 vs 6.0), whereas no such sex difference was demonstrated in PsA or for the other EAMs. Conclusions AU, followed by IBD and psoriasis, is the EAM most strongly associated with AS and uSpA. Among the SpA subtypes, AS and uSpA display a largely similar pattern of EAMs, whereas PsA has a considerably weaker association with AU and IBD.

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

Although cirrhosisis a major cause of liver-related mortality globally, validation studies of the administrative coding for diagnoses associated with cirrhosis are scarce. We aimed to determine the validity of the International Classification of Diseases, 10th revision (ICD-10) codes corresponding to cirrhosis and its complications in the Swedish National Patient Register (NPR).We randomly selected 750 patients with ICD codes for either alcohol-related cirrhosis (K70.3), unspecified cirrhosis (K74.6) oesophageal varices (I85.0/I85.9), hepatocellular carcinoma (HCC, C22.0) or ascites (R18.9) registered in the NPR from 72 healthcare centres in 2000-2016. Hospitalisation events and outpatient visits in specialised care were included. Positive predictive values (PPVs) were calculated using the information in the patient charts as the gold standard.Complete data were obtained for 630 (of 750) patients (84%). For alcohol-related cirrhosis, 126/136 cases were correctly coded, corresponding to a PPV of 93% (95% confidence interval, 95%CI: 87-96). The PPV for cirrhosis with unspecified aetiology was 91% (121/133, 95%CI: 85-95) and 96% for oesophageal varices (118/123, 95%CI: 91-99). The PPV was lower for HCC, 84% (91/109, 95%CI: 75-90). The PPV for liver-related ascites was low, 43% (56/129, 95%CI: 35-52), as this category often consisted of non-hepatic ascites. When combining the ascites code with a code for chronic liver disease, the PPV for liver-related ascites increased to 93% (50/54, 95%CI: 82-98).The validity of ICD-10 codes for cirrhosis, oesophageal varices and HCC is high. However, coding for ascites should be combined with a code of chronic liver disease to have an acceptable validity.

Objectives To estimate the association between biological DMARDs (bDMARDs; overall and by drug) as used in RA and the risk of malignant lymphomas including subtypes. Methods By linking nationwide Swedish registers we identified cohorts of patients with RA initiating treatment with a bDMARD (n = 16 392), bDMARD-naïve (n = 55 253), an age- and sex-matched general population comparator cohort (n = 229 047), and all incident lymphomas 2001–16. We used Cox regression to calculate hazard ratios (HRs) of lymphoma taking calendar period and other factors into account. Results There were 82 lymphomas among the bDMARD-treated patients with RA, crude incidence rate 76/100 000 person-years, and 310 lymphomas among the bDMARD-naïve patients with RA, crude incidence rate 90/100 000 person-years. This resulted in an adjusted HR (aHR) associated with bDMARD treatment (vs not) of 1.08 (95% CI: 0.83, 1.41). The corresponding aHR for bDMARD-treated and bDMARD-naïve vs the general population was 1.65 (95% CI: 1.31, 2.08) and 1.56 (95% CI: 1.37, 1.78) respectively. Restricting follow-up period to after 2006, the aHR of lymphoma for patients with RA starting a first bDMARD vs bDMARD-naïve was 0.69 (95% CI: 0.47, 1.00), and for bDMARD treated vs patients with RA switching from one conventional synthetic DMARDs to another, aHR was 0.46 (95% CI: 0.28, 0.73). There were no signals of different risks with any particular TNF inhibitor (TNFi) agent. We found no different lymphoma subtype pattern following bDMARD therapy. Conclusion Treatment with bDMARDs, including both TNFi and non-TNFi bDMARDs, does not further increase the lymphoma risk in RA; instead, bDMARD treatment may actually reduce the excess lymphoma risk in RA.

Summary Background Crohn's disease is a risk factor for colorectal cancer (CRC). However, available studies reflect older treatment and surveillance strategies, and most have assessed risks for incident CRC without taking surveillance and lead-time bias into account. Such biases can be accounted for by assessing CRC incidence by tumour stage and CRC mortality by tumour stage. We aimed to assess rates of incident CRC and CRC mortality among patients with Crohn's disease compared with the general population. Methods For this nationwide register-based cohort study, we used International Classification of Disease codes in national patient registers and pathology reports to identify incident cases of Crohn's disease. In Denmark we searched for incident cases between January, 1977, and December, 2011, and in Sweden between January, 1969, and December, 2017. For each patient with Crohn's disease, we identified up to ten reference individuals in national population registers and matched them by sex, age, calendar year, and place of residence. Matched reference individuals had to be alive and free of inflammatory bowel disease at the start of follow-up of index patients with Crohn's disease, and stopped contributing to reference person-years if they were diagnosed with inflammatory bowel disease. Our main outcome was death from CRC (main or contributory cause of death) as captured in the cause-of-death registers. Our secondary outcome was incident CRC, as defined by the cancer registers. We used Cox regression to estimate hazard ratios (HRs) for incident CRC and CRC mortality, taking tumour stage into account. We used a series of Cox models to estimate cause-specific HRs of the different competing outcomes (CRC diagnosis, CRC death, and other causes of death) and adjusted for tumour stage at CRC diagnosis. Findings During the 1969–2017 study period, we identified 47 035 patients with incident Crohn's disease (13 056 in Denmark and 33 979 in Sweden) and 463 187 matched reference individuals. During follow-up, 296 (0·47 per 1000 person-years) CRC deaths occurred among individuals with Crohn's disease compared with 1968 (0·31 per 1000 person-years) in reference individuals, corresponding to an overall adjusted HR of 1·74 (1·54–1·96). 499 (0·82 per 1000 person-years) cases of incident CRC were diagnosed in patients with Crohn's disease compared with 4084 (0·64 per 1000 person-years) cases in reference individuals, corresponding to an overall adjusted HR of 1·40 (95% CI 1·27–1·53). Patients with Crohn's disease who were diagnosed with CRC were at increased risk of CRC mortality compared with reference individuals also diagnosed with CRC (HR 1·42 [1·16–1·75] when adjusted for tumour stage), and tumour stage at CRC diagnosis did not differ between groups (p=0·27). Patients with Crohn's disease who had follow-up of 8 years or longer or who were diagnosed with primary sclerosing cholangitis (PSC) and hence were potentially eligible for CRC surveillance had an increased overall risk of CRC death (HR 1·40 [1·16–1·68]) or CRC diagnosis (HR 1·12 [0·98–1·28]). However, in patients potentially eligible for CRC surveillance we only found significantly increased risks in patients diagnosed with Crohn's disease before the age of 40 years, patients with disease activity in the colon only, or patients with PSC. Interpretation Patients with Crohn's disease are at increased risk of CRC diagnosis and CRC death. Patients with Crohn's disease who have CRC have a higher mortality than patients without Crohn's disease who are also diagnosed with CRC. CRC surveillance should likely be focused on patients diagnosed with Crohn's disease before the age of 40 years, on patients with colon inflammation, and on those who have PSC. Funding Swedish Medical Society, Karolinska Institutet, Regional Agreement on Medical Training and Clinical Research between Stockholm County Council and Karolinska Institutet (ALF), Forte Foundation, Swedish Cancer Foundation, and Independent Research Fund Denmark.

ObjectivesTo investigate whether tumour necrosis factor alpha inhibitors (TNFis) are associated with an increased risk of neuroinflammatory diseases among patients with arthritic diseases.MethodsCohorts of patients with rheumatoid arthritis (RA, n=25 796), psoriatic arthritis (PsA, n=8586) and ankylosing spondylitis (AS, n=9527) who initiated a TNFi treatment year 2000–2017 were identified from nationwide clinical rheumatology registers in Sweden and Denmark. Information on demyelinating disease and inflammatory neuropathy diagnoses was retrieved from prospective linkage to National Patients Register. A Cox proportional hazard model was used to estimate HRs and 95% CI comparing TNFi exposed and non-exposed, by disease and country.ResultsAmong 111 455 patients with RA, we identified 270 (Sweden) and 51 (Denmark) events (all types of neuroinflammatory diseases combined), corresponding to crude incidence rates (per 1000 person-years) of 0.37 (Sweden) and 0.39 (Denmark) in TNFi-treated patients vs 0.39 (Sweden) and 0.28 (Denmark) in unexposed patients, and an age-sex-calendar-period-adjusted HR (95% CI) of 0.97 (0.72 to 1.33) (Sweden) and 1.45 (0.74 to 2.81) (Denmark) in TNFi exposed compared with non-exposed patients. For a total of 64 065 AS/PsA patients, the corresponding numbers were: 196 and 32 events, crude incidence rates of 0.59 and 0.87 in TNFi-treated patients vs 0.40 and 0.19 in unexposed patients, and HRs of 1.50 (1.07 to 2.11) and 3.41 (1.30 to 8.96), for Sweden and Denmark, respectively. For multiple sclerosis, the patterns of HRs were similar.ConclusionsUse of TNFi in AS/PsA, but not in RA, was associated with increased risk of incident neuroinflammatory disease, though the absolute risk was below one in 1000 patients/year.

Objective: Novel, highly effective disease-modifying therapies have revolutionized multiple sclerosis (MS) care. However, evidence from large comparative studies on important safety outcomes, such as cancer, is still lacking. Methods: In this nationwide register-based cohort study, we linked data from the Swedish MS register to the Swedish Cancer Register and other national health care and census registers. We included 4,187 first-ever initiations of rituximab, 1,620 of fingolimod, and 1,670 of natalizumab in 6,136 MS patients matched for age, sex, and location to 37,801 non-MS general population subjects. Primary outcome was time to first invasive cancer. Results: We identified 78 invasive cancers among treated patients: rituximab 33 (incidence rate [IR] per 10,000 person-years = 34.4, 95% confidence interval [CI] = 23.7–48.3), fingolimod 28 (IR = 44.0, 95% CI = 29.2–63.5), and natalizumab 17 (IR = 26.0, 95% CI = 15.1–41.6). The general population IR was 31.0 (95% CI = 27.8–34.4). Adjusting for baseline characteristics, we found no difference in risk of invasive cancer between rituximab, natalizumab, and the general population but a possibly higher risk with fingolimod compared to the general population (hazard ratio [HR] = 1.53, 95% CI = 0.98–2.38) and rituximab (HR = 1.68, 95% CI = 1.00–2.84). Interpretation: In this first large comparative study of 3 highly effective MS disease-modifying therapies, no increased risk of invasive cancer was seen with rituximab and natalizumab, compared to the general population. However, there was a borderline-significant increased risk with fingolimod, compared to both the general population and rituximab. It was not possible to attribute this increased risk to any specific type of cancer, and further studies are warranted to validate these findings.

Background Growth retardation is well described in childhood-onset inflammatory bowel disease (IBD). Aims To study if childhood-onset IBD is associated with reduced final adult height. Methods We identified 4201 individuals diagnosed with childhood-onset IBD 1990-2014 (Crohn's disease: n = 1640; ulcerative colitis: n = 2201 and IBD-unclassified = 360) in the Swedish National Patient Register. Results Patients with IBD attained a lower adult height compared to reference individuals (adjusted mean height difference [AMHD] -0.9 cm [95% CI -1.1 to -0.7]) and to their healthy siblings (AMHD -0.8 cm [-1.0 to -0.6]). Patients with Crohn's disease (CD) were slightly shorter than patients with ulcerative colitis (UC; -1.3 cm vs -0.6 cm). Lower adult height was more often seen in patients with pre-pubertal disease onset (AMHD -1.6 cm [-2.0 to -1.2]), and in patients with a more severe disease course (AMHD -1.9 cm, [-2.4 to -1.4]). Some 5.0% of CD and 4.3% of UC patients were classified as growth retarded vs 2.5% of matched reference individuals (OR 2.42 [95% CI 1.85-3.17] and 1.74 [1.36-2.22] respectively). Conclusion Patients with childhood-onset IBD on average attain a slightly lower adult height than their healthy peers. Adult height was more reduced in patients with pre-pubertal onset of disease and in those with a more severe disease course.

First of all, we would like to thank Dr Kaltsonoudis et al for their interest in our study. Dr Kaltsonoudis et al 1 have raised an interesting suggestion in their correspondence based on their study from 2014.2 They suggest that all patients who are candidates for tumour necrosis factor alpha inhibitor (TNFi) therapy should have a thorough neurological assessment (including brain MRI and neurophysiological tests) before commencing TNFi treatment. Moreover, they believe that the risk of neuroinflammatory events following treatment with TNFis is not disease-dependent, but agent-dependent, and that part of the observed risks following treatment …

Findings from molecular studies suggesting that several infectious agents cause sarcoidosis are intriguing yet conflicting and likely biased due to their cross-sectional design. As done in other inflammatory diseases to overcome this issue, prospectively-collected register data could be used, but reverse causation is a threat when the onset of disease is difficult to establish. We investigated the association between infectious diseases and sarcoidosis to understand if they are etiologically related. We conducted a nested case–control study (2009–2013) using incident sarcoidosis cases from the Swedish National Patient Register (n = 4075) and matched general population controls (n = 40,688). Infectious disease was defined using inpatient/outpatient visits and/or antimicrobial dispensations starting 3 years before diagnosis/matching. Adjusted odds ratios (aOR) of sarcoidosis were estimated using conditional logistic regression and tested for robustness assuming the presence of reverse causation bias. The aOR of sarcoidosis associated with history of infectious disease was 1.19 (95% confidence interval [CI] 1.09, 1.29; 21% vs. 16% exposed cases and controls, respectively). Upper respiratory and ocular infections conferred the highest OR. Findings were similar when we altered the infection definition or varied the infection-sarcoidosis latency period (1–7 years). In bias analyses assuming one in 10 infections occurred because of preclinical sarcoidosis, the observed association was completely attenuated (aOR 1.02; 95% CI 0.90, 1.15). Our findings, likely induced by reverse causation due to preclinical sarcoidosis, do not support the hypothesis that common symptomatic infectious diseases are etiologically linked to sarcoidosis. Caution for reverse causation bias is required when the real disease onset is unknown. Electronic supplementary material The online version of this article (10.1007/s10654-020-00611-w) contains supplementary material, which is available to authorized users.

Background Crohn’s disease (CD) is associated with increased risk of small bowel cancer (SBC), but previous studies were limited by a small number of cases, short follow-up, lack of individually matched comparators, and over-representation of tertiary referral centres, leading to exaggerated relative risks and incidence data. Data on ulcerative colitis (UC) and SBC are scarce. Methods In a binational, population-based cohort study from Sweden and Denmark of patients diagnosed with inflammatory bowel disease (IBD) during 1969–2017 and matched reference individuals from the general population, we evaluated the risk of incident SBC, including SBC subtypes (small bowel adenocarcinoma, neuroendocrine tumours, and sarcoma). Cox regression was used to compute adjusted hazard ratios (aHRs) as a measure of relative risks for incident SBC and SBC subtypes. Results We identified 161,896 individuals with IBD (CD: 47,370; UC: 97,515; unclassified IBD:17,011). During follow-up, 237 cases of SBC were diagnosed in patients with IBD (CD: 24.4/100,000 person-years; UC: 5.88/100,000 person-years), compared with 640 cases in reference individuals (2.81/100,000 person-years and 3.32/100,000 person-years, respectively, Table). This corresponded to one extra case of for small bowel cancer in 385 CD patients, and one extra case in 500 UC patients, followed-up for 10 years. The aHR for incident SBC of 9.09 (95% CI = 7.34–11.3) in CD patients and 1.85 (95% CI = 1.43–2.39) in UC patients (Figure). When the first year after IBD diagnosis was excluded, the aHRs for incident SBC decreased to 4.96 in CD patients and 1.69 in UC patients. Among CD patients, relative risks were highest for recently diagnosed, childhood-onset, ileal, and stricturing CD; among UC patients, relative risks were highest for those with extensive colitis and primary sclerosing cholangitis (PSC). In CD patients, the risk of all SBC subtypes was increased (aHR 15.8 for adenocarcinoma, 5.51 for neuroendocrine tumours, and 4.04 for sarcoma) whereas in UC patients only the risk of adenocarcinoma (aHR 1.99) and neuroendocrine tumours (aHR 2.01) were increased. Conclusion SBC was more common in IBD patients, particularly among patients with CD, although absolute risks were low. Further studies should evaluate the utility of SBC surveillance in selected populations such as those with ileal CD, extensive colitis, or UC-PSC.

ObjectivesTo examine all-cause and cause-specific mortality in adult-onset and elderly-onset IBD and to describe time trends in mortality over the past 50 years.DesignSwedish nationwide register-based cohort study 1964–2014, comparing mortality in 82 718 incident IBD cases (inpatient and non-primary outpatient care) with 10 times as many matched general population reference individuals (n=801 180) using multivariable Cox regression to estimate HRs. Among patients with IBD, the number of participants with elderly-onset (≥60 years) IBD was 17 873.ResultsDuring 984 330 person-years of follow-up, 15 698/82 718 (19%) of all patients with IBD died (15.9/1000 person-years) compared with 121 095/801 180 (15.1%) of reference individuals, corresponding to an HR of 1.5 for IBD (95% CI=1.5 to 1.5 (HR=1.5; 95% CI=1.5 to 1.5 in elderly-onset IBD)) or one extra death each year per 263 patients. Mortality was increased specifically for UC (HR=1.4; 95% CI=1.4 to 1.5), Crohn’s disease (HR=1.6; 95% CI=1.6 to 1.7) and IBD-unclasssified (HR=1.6; 95% CI=1.5 to 1.8). IBD was linked to increased rates of multiple causes of death, including cardiovascular disease (HR=1.3; 1.3 to 1.3), malignancy (HR=1.4; 1.4 to 1.5) and digestive disease (HR=5.2; 95% CI=4.9 to 5.5). Relative mortality during the first 5 years of follow-up decreased significantly over time. Incident cases of 2002–2014 had 2.3 years shorter mean estimated life span than matched comparators.ConclusionsAdult-onset and elderly-onset patients with UC, Crohn’s disease and IBD-unclassified were all at increased risk of death. The increased mortality remained also after the introduction of biological therapies but has decreased over time.

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. Electronic supplementary material The online version of this article (10.1186/s13075-019-1908-9) contains supplementary material, which is available to authorized users.

OBJECTIVES To investigate absolute and relative risk of serious infections in adult/elderly inflammatory bowel disease (IBD) diagnosed 2002-2017. METHODS Nationwide, register-based cohort study of Swedish patients with IBD compared with general population matched reference individuals with regard to time to first serious infection, equal to hospital admission. Multivariable Cox regression estimated hazard ratios (HRs) for any serious infection. Secondary outcomes included site-specific infections, opportunistic infections and sepsis. RESULTS We identified 47 798 individuals with IBD. During a follow-up of 329 000 person-years, they had 8752 first serious infections (26.6 per 1000 person-years). This compared with an incidence rate of 10.7 per 1000 person-years in matched reference individuals, corresponding to a 2.53-fold increased hazard of serious infections (95%CI = 2.47-2.59). The HR for serious infection in elderly-onset IBD was 2.01 (95%CI = 1.95-2.08). The relative hazard of serious infection was somewhat higher in Crohn's disease (2.94; 95%CI = 2.81-3.06) than in ulcerative colitis (2.24; 95%CI = 2.17-2.31). The HR for serious infections was high in the first year of follow-up (5.17; 95%CI = 4.93-5.42). Individuals with IBD were at a particularly high relative hazard of gastrointestinal and opportunistic infections. The HR for sepsis was 2.47 (95%CI = 2.32-2.63). The relative rates for serious infections in IBD increased in recent years. CONCLUSIONS Patients with adult-onset IBD are at increased risk of serious infections, particularly gastrointestinal and opportunistic infections. Relative rates were highest just after IBD diagnosis, and seem to have increased in recent years.

The authors would like to thank Giuffrida and colleagues for their interest in our manuscript, ‘Inflammatory Bowel Disease and Risk of Small Bowel Cancer: A binational population-based cohort study from Denmark and Sweden’.1 2 In contrast to previous studies focused on small bowel adenocarcinoma death with short follow-up time, we provide an age-adjusted composite risk of death due to multiple small bowel cancer subtypes, including adenocarcinoma, neuroendocrine tumours and sarcoma, with over 20 years of follow-up.3–6 We adjusted for cancer heredity and in sensitivity analyses, excluded patients with coeliac disease in …

Background: Inflammatory bowel disease (IBD) has been associated with hepatobiliary cancer, but existing evidence is poor. We evaluated risk of death from hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and extrahepatic cholangiocarcinoma (ECC) among patients with IBD. Methods: This Swedish/Danish population-based cohort study (1969–2017) followed patients with IBD and 1:10 matched population comparators from their diagnosis/match date until death, emigration, or end of follow-up. Results: Among the 97,496 patients with ulcerative colitis/963,026 comparators, we found 66/390 HCC-deaths, 120/173 ICC-deaths, and 91/220 ECC-deaths (median follow-up 10 years); the 10-year-mortality was 0.5‰ (per mille) for HCC, 0.6‰ for ICC, and 0.4‰ for ECC, which decreased to 0.3‰, 0.4‰, and 0.2‰, respectively, in 2003–2017. Overall hazard ratios (HR) were 1.83 [95% confidence interval (CI), 1.41–2.38] for HCC-, 7.33 (95% CI, 5.81–9.25) for ICC-, and 4.46 (95% CI, 3.49–5.70) for ECC-deaths. A total of 22/66 HCC-deaths, 87/120 ICC-deaths, and 55/91 ECC-deaths occurred among patients with ulcerative colitis with primary sclerosing cholangitis (PSC), corresponding to 10-year-mortality of 6.7‰, 26.2‰, and 17.2‰, respectively. Among 47,399 patients with Crohn's disease (median follow-up 11 years), 10-year-mortality from HCC (n = 28), ICC (n = 28), and ECC (n = 24) were 0.3‰, 0.1‰, and 0.3‰, respectively, and corresponding HRs were 1.96 (95% CI, 1.31–2.93), 3.33 (95% CI, 2.19–5.09), and 3.10 (95% CI, 1.97–4.87). One of 28 HCC-deaths, 14/28 ICC-deaths (10-year-mortality 19‰), and 12/24 ECC-deaths (10-year-mortality 14‰) occurred after PSC. Conclusions: Risk of HCC-, ICC-, and ECC-deaths was low in patients with IBD and decreased over time. However, a large proportion of deaths occurred after PSC. Impact: Guidelines on specific surveillance strategies for patients with IBD with PSC, but not those without PSC, are needed.

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.

ObjectiveIn rheumatoid arthritis (RA), evidence regarding the effectiveness of a second biologic disease-modifying antirheumatic drug (bDMARD) in patients whose first-ever bDMARD was a non–tumor necrosis factor inhibitor (TNFi) bDMARD is limited. The objective of this study was therefore to assess the outcome of a second bDMARD (non-TNFi: rituximab [RTX], abatacept [ABA], or tocilizumab [TCZ], separately; and TNFi) after failure of a non-TNFi bDMARD as first bDMARD.MethodsWe identified patients with RA from the 5 Nordic biologics registers who started treatment with a non-TNFi as first-ever bDMARD but switched to a second bDMARD. For the second bDMARD, we assessed drug survival (at 6 and 12 months) and primary response (at 6 months).ResultsWe included 620 patients starting a second bDMARD (ABA 86, RTX 40, TCZ 67, and TNFi 427) following failure of a first non-TNFi bDMARD. At 6 and 12 months after start of their second bDMARD, approximately 70% and 60%, respectively, remained on treatment, and at 6 months, less than one-third of patients were still on their second bDMARD and had reached low disease activity or remission according to the Disease Activity Score in 28 joints. For those patients whose second bMDARD was a TNFi, the corresponding proportion was slightly higher (40%).ConclusionThe drug survival and primary response of a second bDMARD in patients with RA switching due to failure of a non-TNFi bDMARD as first bDMARD is modest. Some patients may benefit from TNFi when used after failure of a non-TNFi as first bDMARD.

Objective To estimate the occurrence and relative risks of first-ever-incident non-cutaneous cancer overall and for 16 sites in patients with RA treated with biologic and targeted synthetic DMARDs (b/tsDMARDs), by time since treatment start, attained age, and duration of active treatment. Methods This is an observational nationwide and population-based cohort study of patients with RA (n = 69 308), treated with TNF inhibitors (TNFi; adalimumab, certolizumab, etanercept, golimumab, infliximab) or other b/tsDMARDs (abatacept, rituximab, baricitinib, tofacitinib and tocilizumab) compared with RA patients not treated with b/tsDMARDs, and matched general population referents (n = 109 532), 2001–2018. The study was based on prospectively collected data from the Swedish Rheumatology Quality Register and from other registers, linked to the national Swedish Cancer Register. Incidence rates and hazard ratios were estimated via Cox regression adjusted for co-morbidities and other health characteristics. Results Based on 8633 incident cancers among RA patients, the overall relative risk of cancer with TNFi [hazard ratio (HR) = 1.0] was neither increased nor did it change with time since treatment start, duration of active treatment, or attained age, when compared with b/tsDMARD-naïve RA. For other b/tsDMARDs, we noted no consistent signal of increased overall risks (HRs ranged from 1.0 to 1.2), but there were statistically significant estimates above 1 for abatacept with 2–5 years of active treatment, for older age groups, and between several of the bDMARDs and urinary tract cancer. Conclusion TNFis, as used long term in clinical practice against RA, are not linked to increased risks for cancer overall. For other b/tsDMARDs, and for site-specific risks, our results are generally reassuring but contain signals that call for replication.

Objectives RF and ACPA are used as diagnostic tools and their presence has been associated with clinical response to some biologic DMARDs (bDMARDs) in RA. This study compared the impact of seropositivity on drug discontinuation and effectiveness of bDMARDs in patients with RA, using head-to-head comparisons in a real-world setting. Methods We conducted a pooled analysis of 16 observational RA registries. Inclusion criteria were a diagnosis of RA, initiation of treatment with rituximab (RTX), abatacept (ABA), tocilizumab (TCZ) or TNF inhibitors (TNFis) and available information on RF and/or ACPA status. Drug discontinuation was analysed using Cox regression, including drug, seropositivity, their interaction, adjusting for concomitant and past treatments and patient and disease characteristics and accounting for country and calendar year of bDMARD initiation. Effectiveness was analysed using the Clinical Disease Activity Index evolution over time. Results Among the 27 583 eligible patients, the association of seropositivity with drug discontinuation differed across bDMARDs (P for interaction Conclusion Seropositivity was associated with increased effectiveness of non-TNFi bDMARDs, especially RTX and ABA, but not TNFis.

Objectives: To investigate whether low social support or low decision latitude at work correlate with risk of rheumatoid arthritis (RA), and whether and how those factors are associated with known ...

Objectives To investigate whether TNF inhibitors (TNFi) are associated with increased risk of solid cancer in patients with psoriatic arthritis (PsA). Methods From the Nordic clinical rheumatology registers (CRR) here: SRQ/ARTIS (Sweden), DANBIO (Denmark), NOR-DMARD (Norway), ROB-FIN (Finland) and ICEBIO (Iceland) we identified PsA patients who started a first TNFi 2001–2017 (n = 9655). We identified patients with PsA not treated with biologics from (i) the CRR (n = 14 809) and (ii) the national patient registers (PR, n = 31 350). By linkage to the national cancer registers, we collected information on incident solid cancer overall and for eight cancer types. We used Cox regression to estimate hazard ratio (HR) with 95% CI of cancer (per country and pooled) in TNFi-exposed vs biologics-naïve, adjusting for age, sex, calendar period, comorbidities and disease activity. We also assessed standardized incidence ratios (SIR) in TNFi-exposed PsA vs the general population (GP). Results We identified 296 solid cancers among the TNFi-exposed PsA patients (55 850 person-years); the pooled adjusted HR for solid cancer overall was 1.0 (0.9–1.2) for TNFi-exposed vs biologics-naïve PsA from the CRR, and 0.8 (0.7–1.0) vs biologics-naïve PsA from the PRs. There were no significantly increased risks for any of the cancer types under study. The pooled SIR of solid cancer overall in TNFi treated PsA vs GP was 1.0 (0.9–1.1). Conclusion In this large cohort study from five Nordic countries, we found no increased risk of solid cancer in TNFi-treated PsA patients, neither for solid cancer overall nor for eight common cancer types.

Objectives To estimate absolute and relative risks for all-cause mortality and for severe COVID-19 in inflammatory joint diseases (IJDs) and with antirheumatic therapies. Methods Through Swedish nationwide multiregister linkages, we selected all adult patients with rheumatoid arthritis (RA, n=53 455 in March 2020), other IJDs (here: spondyloarthropathies, psoriatic arthritis and juvenile idiopathic arthritis, n=57 112), their antirheumatic drug use, and individually matched population referents. We compared annual all-cause mortality March-September 2015 through 2020 within and across cohorts, and assessed absolute and relative risks for hospitalisation, admission to intensive care and death due to COVID-19 March-September 2020, using Cox regression. Results During March-September 2020, the absolute all-cause mortality in RA and in other IJDs was higher than 2015-2019, but relative risks versus the general population (around 2 and 1.5) remained similar during 2020 compared with 2015-2019. Among patients with IJD, the risks of hospitalisation (0.5% vs 0.3% in their population referents), admission to intensive care (0.04% vs 0.03%) and death (0.10% vs 0.07%) due to COVID-19 were low. Antirheumatic drugs were not associated with increased risk of serious COVID-19 outcomes, although for certain drugs, precision was limited. Conclusions Risks of severe COVID-19-related outcomes were increased among patients with IJDs, but risk increases were also seen for non-COVID-19 morbidity. Overall absolute and excess risks are low and the level of risk increases are largely proportionate to those in the general population, and explained by comorbidities. With possible exceptions, antirheumatic drugs do not have a major impact on these risks. Funding Agencies|Swedish research CouncilSwedish Research CouncilEuropean Commission; Swedish Heart-Lung foundationSwedish Heart-Lung Foundation; Swedish Cancer SocietySwedish Cancer Society; NordForsk; Foundation for Research in Rheumatology (FOREUM); Region Stockholm; Karolinska Institutet (ALF)Karolinska Institutet

Objectives Comorbidities contribute to the morbidity and mortality in RA, and are thus important to capture and treat early. In contrast to the well-studied comorbidity risks in established RA, less is known about the comorbidity pattern up until diagnosis of RA. We therefore compared whether the occurrence of defined conditions, and the overall comorbidity burden at RA diagnosis, is different from that in the general population, and if it differs between seropositive and seronegative RA. Methods Using Swedish national clinical and demographic registers, we identified new-onset RA patients (n = 11 086), and matched (1:5) to general population controls (n = 54 813). Comorbidities prior to RA diagnosis were identified in the Patient and Prescribed Drug Registers, and compared using logistic regression. Results At diagnosis of RA, respiratory (odds ratio (OR) = 1.58, 95% CI: 1.44, 1.74), endocrine (OR = 1.39, 95% CI: 1.31, 1.47) and certain neurological diseases (OR = 1.73, 95% CI: 1.59, 1.89) were more common in RA vs controls, with a similar pattern in seropositive and seronegative RA. In contrast, psychiatric disorders (OR = 0.87, 95% CI: 0.82, 0.92) and malignancies (OR = 0.88, 95% CI: 0.79, 0.97) were less commonly diagnosed in RA vs controls. The comorbidity burden was slightly higher in RA patients compared with controls (P Conclusion We found several differences in comorbidity prevalence between patients with new-onset seropositive and seronegative RA compared with matched controls from the general population. These findings are important both for our understanding of the evolvement of comorbidities in established RA and for early detection of these conditions.

Objective: To describe baseline characteristics and to compare treatment effectiveness of secukinumab versus tumor necrosis factor inhibitors (TNFi) in patients with spondyloarthritis (SpA) using adalimumab as the main comparator. Methods: This was an observational, prospective cohort study. Patients with SpA (clinical ankylosing spondylitis, nonradiographic axial SpA, or undifferentiated SpA) starting secukinumab or a TNFi during 2015–2018 were identified from 5 Nordic clinical rheumatology registries. Data on comorbidities and extraarticular manifestations (psoriasis, uveitis, and inflammatory bowel disease) were captured from national registries (data available in 94% of patients) and included in multivariable analyses. We assessed 1-year treatment retention (crude survival curves, adjusted hazard ratios [HRadj] for treatment discontinuation) and 6-month response rates (Ankylosing Spondylitis Disease Activity Score [ASDAS] score adj 1.43 [95% CI 1.12–1.81]). Across treatment lines, secukinumab had poorer estimates for 6-month response rates than adalimumab, statistically significantly only for the third-plus line (adjusted analyses: ASDAS score

Publisher's version (útgefin grein), Objective: To investigate the relationship between anti–citrullinated protein antibodies (ACPAs), specific ACPA subspecificities, rheumatoid factor (RF) isotypes, and incident cardiovascular (CV) events in patients with rheumatoid arthritis (RA). Methods: Serum samples from Swedish patients with new-onset RA (diagnosed within 1 year of symptom onset between 1996 and 2009) were centrally typed for anti–cyclic citrullinated peptide 2 (anti-CCP2) antibodies, 20 ACPA subspecificities, and RF isotypes. Patients were followed up longitudinally in nationwide registers to monitor the occurrence of acute coronary syndrome (ACS), stroke, CV-related death, and major adverse CV events (MACE). The association between each serologic marker and CV outcome, and the impact of adjustment for the Disease Activity Score in 28 joints (DAS28), smoking status, and income at baseline, were assessed using Cox proportional hazards models. In addition, associations of serologic markers with all-cause mortality were explored. Results: In total, 2,814 patients with RA were included in the study. The median follow-up was 13 years, during which the CV end points of ACS, stroke, or CV-related death were reported to occur in 375 patients. Occurrence and/or levels of anti-CCP2 were associated with risk of incident ACS (hazard ratio [HR] 1.46, 95% confidence interval [95% CI] 1.03–2.06), stroke (HR 1.47, 95% CI 1.03–2.10), CV-related death (P = 0.024 for association with anti-CCP2 levels), and MACE (HR 1.34, 95% CI 1.06–1.70). Similarly, an association with the number of ACPA subspecificities was observed; however, this could not be attributed to any individual or group of ACPA subspecificities. Presence of IgM-RF was associated with all CV end points except ACS, and IgA-RF was exclusively associated with CV-related death. Adjustment for smoking status, income, and DAS28 scores decreased most of the HRs, whereas IgA-RF remained associated with CV-related death (HR 1.61, 95% CI 1.05–2.48). All of the assessed serologic makers were associated with all-cause mortality. Conclusion: RF isotypes and ACPAs are associated with future CV events in patients with RA. ACPA levels and number of subspecificities seem more important than the occurrence of particular subspecificities, and these associations were not explained by a history of ever smoking., Karolinska institutet (strategic research area epidemiology), The nordic research council (nordforsk), The rheumatology research foundation (foreum), Stiftelsen för Strategisk Forskning, Vetenskapsrådet, Stockholms Läns Landsting, The swedish heart lung foundation

Publisher's version (útgefin grein), [No abstract available], This study was partly funded by grants from Nord-Forsk and FOREUM.

Background & Aims Mutations in the HFE gene can lead to hereditary haemochromatosis (HH) and have been suggested to increase the risk of extra-hepatic diseases, especially breast and colorectal cancer. Here we investigated long-term outcomes of Swedish patients with HFE mutations. Methods We identified 3645 patients with a homozygous p.C282Y (62%) or a compound heterozygous p.C282Y/p.H63D (38%) mutation from eight centres in Sweden between 1997 and 2017. These were matched 1:10 by age, sex and county of residence to reference individuals from the general population. We ascertained incident outcomes until the end of 2017 by linkage to national registers. Studied outcomes were HH, cirrhosis, hepatocellular carcinoma (HCC), breast cancer (in women), colorectal cancer, type 1 and 2 diabetes, hypothyroidism, Parkinsons disease and mortality. Cox proportional hazards regression was used to estimate hazard ratios for these outcomes. Results Median age at diagnosis was 52 years, 44% were females. During a mean follow-up of 7.9 years, we found an increased risk for HCC, HH, cirrhosis, type 2 diabetes, osteoarthritis and death. Excess mortality was only seen in men. No increased risk was seen for colorectal or breast cancer. Liver-related outcomes were rare, with a cumulative incidence of HFE mutation carriers in a university hospital setting had an increased risk for mortality in men, along with increased risks of cirrhosis, HCC, diabetes type 2, and osteoarthritis. In general, the absolute risk for adverse outcomes was low and no increased risk for colon or breast cancer was observed. Funding Agencies|Stockholm Count Council; Swedish Gastrointestinal Foundation; Tore Nilssons Foundation for medical research; Ruth and Richard Julin Foundation; Stockholm County CouncilStockholm County Council [K2017-4579, ALF LS 2019-0064]; Center for innovative medicine [CIMED 20180889]; Swedish Cancer SocietySwedish Cancer Society [170690]

Objectives To compare treatment retention and response to secukinumab vs adalimumab, including the other four TNF inhibitors (TNFi) as comparators, in PsA. Methods All patients with PsA starting secukinumab or a TNFi in 2015–2018 were identified in the biologic registers of the Nordic countries. Data on comorbidities were linked from national registers. One-year treatment retention and hazard ratios (HRs) for treatment discontinuation were calculated. The proportion achieving a 6 month 28-joint Disease Activity Index for Psoriatic Arthritis (DAPSA28) remission was determined together with odds ratios (ORs) for remission (logistic regression). Both HRs and ORs were calculated with adalimumab as the reference and adjusted for baseline characteristics and concurrent comorbidities. All analyses were stratified by the line of biologic treatment (first, second, third+). Results We identified 6143 patients contributing 8307 treatment courses (secukinumab, 1227; adalimumab, 1367). Secukinumab was rarely used as the first biologic, otherwise baseline characteristics were similar. No clinically significant differences in treatment retention or response rates were observed for secukinumab vs adalimumab. The adjusted HRs for discontinuation per the first, second and third line of treatment were 0.98 (95% CI 0.68, 1.41), 0.94 (0.70, 1.26) and 1.07 (0.84, 1.36), respectively. The ORs for DAPSA28 remission in the first, second and third line of treatment were 0.62 (95% CI 0.30, 1.28), 0.85 (0.41, 1.78) and 0.74 (0.36, 1.51), respectively. In the subset of patients previously failing a TNFi due to ineffectiveness, the results were similar. Conclusion No significant differences in treatment retention or response were observed between secukinumab and adalimumab, regardless of the line of treatment. This suggests that even in patients who have failed a TNFi, choosing either another TNFi or secukinumab may be equally effective.

Background: There are limited data on population-wide assessment of cost in Crohn's disease (CD) and ulcerative colitis (UC). Aim: To estimate the societal cost of actively treated CD and UC in Sweden. Methods: We identified 10 117 prevalent CD and 19 762 prevalent UC patients, aged ≥18 years on 1 January 2014 and 4028 adult incident CD cases and 8659 adult incident UC cases (2010-2013) from Swedish Patient Register. Each case was matched to five population comparators. Healthcare costs were calculated from medications, outpatient visits, hospitalisations and surgery. Cost of productivity losses was derived from disability pension and sick leave. Results: The mean annual societal costs per working-age patient (18-64 years) with CD and UC were $22 813 (vs $7533 per comparator) and $14 136 (vs $7351 per comparator) respectively. In patients aged ≥65 years, the mean annual costs of CD and UC were $9726 and $8072 vs $3875 and $4016 per comparator respectively. The majority of cost for both CD (56%) and UC (59%) patients originated from productivity losses. Higher societal cost of working-age CD patients as compared to UC patients was related to greater utilisation of anti-TNF (22.2% vs 7.4%) and increased annual disability pension (44 days vs 25 days). Among incident CD and UC patients, the mean total cost over the first year per patient was over three times higher than comparators. Conclusion: In Sweden, the societal cost of incident and prevalent CD and UC patients was consistently two to three times higher than the general population. (Less)

Objectives To study clinical characteristics, mortality, and secondary prevention, after a first incident acute myocardial infarction (AMI) in patients with ankylosing spondylitis (AS) compared with the general population. Methods In total, 292 subjects with AS and a first AMI between Jan 2006 and Dec 2014 were identified using the Swedish national patient register. Each subject was matched with up to 5 general population comparators per AS-patient (n = 1276). Follow-up started at the date of admission for AMI and extended until death or 365 days of follow-up. Cox regression was used to assess mortality in two time intervals: days 0–30 and days 31–365. For a subgroup with available data, clinical presentation at admission, course, treatment for AMI, and secondary prevention were compared. Results During the 365-day follow-up, 56/292 (19%) AS patients and 184/1276 (14%) comparators died. There were no difference in mortality due to cardiovascular-related causes, although the overall mortality day 31–365 was increased among patients with AS compared with comparators (HR [95% CI] = 2.0 [1.3;3.0]). At admission, AS patients had a higher prevalence of cardiovascular comorbidities compared with comparators. At discharge, patients with AS were less often prescribed lipid-lowering drugs and non-aspirin antiplatelet therapy. Conclusions Patients with AS tend to have a higher comorbidity burden at admission for first AMI. The mortality after a first AMI due to cardiovascular-related causes does not seem to be elevated, despite an increased overall mortality during days 31–365 among patients with AS compared with the general population. Key Points• The all-cause mortality after a first AMI was higher in patients with AS.• Mortality after a first AMI due to CVD-related causes does not seem to be elevated for patients with AS.• In patients with AS suffering a first AMI, more attention should be given to other comorbidities causing an excess in mortality.

ObjectivesTo investigate a potential shared susceptibility between rheumatoid arthritis (RA) and acute coronary syndrome (ACS) by estimation of the risk of ACS among full siblings of patients with RA.MethodsBy linking nation-wide Swedish registers, we identified a cohort of patients with new-onset RA 1996–2016, age- and sex-matched (5:1) general population comparator subjects, full siblings of RA and comparator subjects, and incident ACS events through 31 December 2016. We used Cox regression to estimate the HR of ACS among patients with RA and the siblings of patients with RA versus the general population, overall and stratified by RA serostatus. We explored the impact of traditional cardiovascular (CV) risk factors on the observed associations.ResultsWe identified 8109 patients with incident RA, and 11 562 full siblings of these. Compared with the general population, the HR of ACS in RA was 1.46 (95% CI 1.28 to 1.67) and 1.22 (95% CI 1.09 to 1.38) among their siblings. The increased risks seemed confined to seropositive RA (patients: 1.52 [1.30 to 1.79], their siblings: 1.27 [1.10 to 1.46]); no significant risk increase was observed among siblings of patients with seronegative RA (HR 1.13 [95% CI 0.92 to 1.39]). Adjustment for 19 traditional CV risk factors did not appreciably alter these associations.ConclusionSiblings of patients with RA are at increased risk of ACS, suggesting shared susceptibility between RA and ACS, indicating the need and potential for additional cardio-preventive measures in RA (and their siblings).

Background & aims Childhood-onset inflammatory bowel disease (IBD) is believed to be a more severe disease than adult-onset IBD, but there is little information on all-cause and cause-specific mortality in patients with childhood-onset IBD. We performed a population-based cohort study, with 50 years of follow-up, to estimate absolute and relative risks for overall and cause-specific mortality in patients with childhood-onset IBD, during childhood and adulthood. Methods We identified children with a diagnosis of IBD (younger than 18 years) in the Swedish nationwide health registers (1964–2014; n = 9442) and individuals from the general population matched for sex, age, calendar year, and place of residence (reference group; n = 93,180). Hazard ratios (HR) for death were estimated using Cox regression separately in patients with ulcerative colitis (n = 4671), Crohn's disease (n = 3780), and IBD unclassified (n = 991). HRs were compared among calendar periods. Results During 138,690 person-years of follow-up, 294 deaths (2.1/1000 person-years) occurred among the patients with IBD compared with 940 deaths in the reference group (0.7/1000 person-years; adjusted HR, 3.2; 95% confidence interval [CI] 2.8–3.7). Mean age at end of follow-up was 30 years. HRs were increased for patients with ulcerative colitis 4.0, 95% CI 3.4–4.7; Crohn's disease 2.3, 95% CI 1.8–3.0; and IBD unclassified 2.0, 95% CI 1.2–3.4. Among patients younger than 18 years, there were 27 deaths from IBD 4.9, 95% CI 3.0–7.7. Among young adults with IBD, we found no evidence that HRs for death decreased from 1964 through 2014 (P = .90). Conclusions Children with IBD have a 3-fold increase in risk of death when followed through adulthood. The relative risk for death has not decreased with development of new drugs for treatment of IBD.

Objective The link and interplay between different airway exposures and rheumatoid arthritis (RA) risk are unclear. This study was undertaken to determine whether respiratory disease is associated with development of RA, and specifically to examine this relationship by RA serostatus and smoking exposure. Methods Using data from the Epidemiological Investigation of Rheumatoid Arthritis study, this analysis included 1,631 incident RA cases and 3,283 matched controls recruited from 2006 to 2016. Linking these individuals to the National Patient Register provided information on past acute or chronic, upper or lower respiratory disease diagnoses. For each disease group, we estimated adjusted odds ratios (ORadj ) with 95% confidence intervals (95% CI) for RA, using logistic regression models adjusted for age, sex, residential area, body mass index, and education both overall and stratified by anti-citrullinated protein antibody (ACPA)/rheumatoid factor (RF) status and by smoking status. Results Respiratory disease diagnoses were associated with risk of RA, with an ORadj of 1.2 for acute upper respiratory disease (95% CI 0.8-1.7), 1.4 for chronic upper respiratory disease (95% CI 1.1-1.9), 2.4 for acute lower respiratory disease (95% CI 1.5-3.6), and 1.6 for chronic lower respiratory disease (95% CI 1.5-3.6). These associations were present irrespective of RF or ACPA status, though the association was somewhat stronger for ACPA/RF-positive than ACPA/RF-negative RA. The association between any respiratory disease and RA was stronger for nonsmokers (ORadj 2.1 [95% CI 1.5-2.9]) than for smokers (ORadj 1.2 [95% CI 0.9-1.5]). Conclusion Respiratory diseases increase the risk for both seropositive and seronegative RA, but only among nonsmokers. These findings raise the hypothesis that smoking and airway disease are associated with RA development through partly different mechanisms.

Most studies on fractures in inflammatory bowel disease (IBD) are based on patients from tertiary centers or patients followed up before the introduction of immunomodulators or biologics. In addition, the role of corticosteroids in fracture risk has rarely been examined.We conducted a nationwide population-based cohort study of 83,435 patients with incident IBD (ulcerative colitis [UC]: n = 50,162, Crohn's disease [CD]: n = 26,763, and IBD unclassified: 6,510) and 825,817 reference individuals from 1964 to 2014. Using multivariable Cox regression, we estimated hazard ratios (HRs) for hip fracture and any fracture and the association with cumulative corticosteroid exposure.During 1,225,415 person-years of follow-up in patients with IBD, there were 2,491 first-time hip fractures (203/100,000 person-years) compared with 20,583 hip fractures during 12,405,642 person-years in reference individuals (159/100,000 person-years). This corresponded to an HR of 1.42 (95% confidence interval [CI] = 1.36-1.48). The risk for hip fracture was higher in CD compared with UC (P0.001). Inflammatory bowel disease was also associated with any fracture (IBD: HR = 1.18; 95% CI = 1.15-1.20). Hazard ratios for hip fracture had not changed since the introduction of immunomodulators or biologics. Increasing exposure to corticosteroids was associated with hip fracture in both IBD and non-IBD individuals (P0.001), but only in elderly (60 years) patients with IBD. The association between IBD and hip fracture was nonsignificant among individuals without corticosteroids (HR = 1.11; 95% CI = 0.86-1.44).Inflammatory bowel disease (CD and UC) is associated with an increased risk of hip fracture and any fracture, but not in individuals without a history of corticosteroid treatment. The association between corticosteroids and hip fracture was restricted to elderly patients with IBD.

Background Patients with inflammatory bowel disease (IBD) have an increased risk of cancer.Aim To assess the risk of pancreatic cancer in IBD compared to the general population.Methods Patients with incident IBD 1969-2017 were identified in Danish and Swedish National Patient Registers and through biopsy data, and were matched to IBD-free reference individuals by sex, age, place of residence and year of IBD diagnosis. We linked data to Cancer and Causes of Death Registers and examined the absolute and relative risks of pancreatic cancer and pancreatic cancer death.Results Among 161 926 patients followed for 2 000 951 person years, 442 (0.27%) were diagnosed with pancreatic cancer compared to 3386 (0.21%) of the 1 599 024 reference individuals. The 20-year cumulative incidence was 0.34% (95% confidence interval 0.30-0.38) vs 0.29% (0.28-0.30). The incidence rate was 22.1 (20.1-24.2)/100 000 person years in the patients (excluding the first year of follow-up: 20.8 [18.8-23.0]), and 16.6 (16.0-17.2) in the reference individuals. The hazard ratio (HR) for pancreatic cancer was increased overall: 1.43 (1.30-1.58), in subtypes (Crohn's disease: 1.44 [1.18-1.74]; ulcerative colitis: 1.35 [1.19-1.53]; IBD unclassified: 1.99 [1.50-2.64]) and especially in IBD patients with primary sclerosing cholangitis: 7.55 (4.94-11.5). Patients and reference individuals with pancreatic cancer did not differ in cancer stage (P = 0.17) or pancreatic cancer mortality (HR 1.07 [0.95-1.21]).Conclusions Patients with IBD had an excess risk of pancreatic cancer, in particular patients with primary sclerosing cholangitis. However, the cumulative incidence difference after 20 years was small: 0.05%, that is, one extra pancreatic cancer per 2000 IBD patients.

Use of tumor necrosis factor inhibitors (TNFi) in patients with a history of cancer remains a clinical dilemma.To investigate whether TNFi treatment in rheumatoid arthritis (RA) is associated with increased risk for cancer recurrence.Population-based cohort study based on linkage of nationwide registers.Sweden.Patients with RA who started TNFi treatment between 2001 and 2015, after being diagnosed with cancer, and matched patients with RA and a history of the same cancer who had never received biologics.The primary outcome was the first recurrence of cancer. Adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs), taking into account time, cancer type, and whether the cancer was invasive or in situ (or tumor, node, metastasis [TNM] classification system stage in a subset of patients).Among 467 patients who started TNFi treatment (mean time after cancer diagnosis, 7.9 years), 42 had cancer recurrences (9.0%; mean follow-up, 5.3 years); among 2164 matched patients with the same cancer history, 155 had recurrences (7.2%; mean follow-up, 4.3 years) (HR, 1.06 [95% CI, 0.73 to 1.54). Hazard ratios were close to 1 in analyses of patient subsets matched on cancer stage or with similar time from index cancer diagnosis to the start of TNFi treatment, as well as in unmatched analyses. Several CIs had upper limits close to 2.The outcome algorithm was partly nonvalidated, and channeling bias was possible if patients with a better index cancer prognosis were more likely to receive TNFi.The findings suggest that TNFi treatment is not associated with increased risk for cancer recurrence in patients with RA, although meaningful risk increases could not be ruled out completely.ALF (an agreement in Stockholm County Council concerning medical education and research in health and medical care), the Swedish Cancer Society, the Swedish Foundation for Strategic Research, and the Swedish Research Council.

Background and aims Crohn's disease may affect the ability to work and lead to permanent disability. We aimed to investigate work loss in prevalent patients. Methods We identified patients with Crohn's disease and general population comparators matched by sex, birth year, healthcare region and education. We assessed days of sick leave and disability pension retrieved from the Swedish Social Insurance Agency and estimated the absolute and relative risk of receiving disability pension [minimum 25% work impairment]. Results In 2014, the 20638 Crohn's disease patients [median age 44 years] had more than twice as many mean lost workdays [disability pension: 44; sick leave: 19] as the 102038 comparators [disability pension: 20; sick leave: 8], mean difference 35 days [95% confidence interval 33-37]. However, the majority had no lost workdays [68% of patients and 85% of comparators]. The proportion of patients receiving disability pension was 15% (6.5% in the comparators, risk ratio 2.34 [2.25-2.43]) and was higher in all subgroups, especially in female patients [28% vs 13% in the comparators], in those with ≤9 years of education [41% vs 23%] and in ages 60-64 years [46% vs 25%]. The relative risk of disability pension within the patient cohort [adjusted for age, sex, region and education] was higher in patients with complicated disease behaviour, extraintestinal manifestations, need of surgery or treatment with biologics. The differences between patients and comparators remained when comparing other calendar years [2006-2013]. Conclusion Work loss was found in approximately one-third of patients. The mean number of lost workdays was twice as high as in the comparators.

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. Electronic supplementary material The online version of this article (10.1186/s13075-018-1680-2) contains supplementary material, which is available to authorized users.

Background:Rheumatoid Arthritis (RA) is associated with increased cardiovascular co-morbidity including acute coronary syndrome (ACS), partly due to effects of systemic inflammation. Disease-modifying anti-rheumatic drugs (DMARDs) may reduce RA disease activity, but act through several pathways and may themselves have an impact on cardiovascular risks. Whether the risks of ACS associated with biologic (b) and targeted synthetic (ts) DMARDs differ is still unknown.Objectives:To assess and compare incidences of ACS during treatment of RA with etanercept (ETA), adalimumab (ADA), infliximab (INF), certolizumab pegol (CTZ), golimumab (GOL), rituximab (RIT), abatacept (ABA), tocilizumab (TCZ), baricitinib (BAR) or tofacitinib (TOF).Methods:We defined and pooled treatment cohorts of patients starting any of the above treatments between 2008 and 2017 from clinical rheumatology registers in Denmark (DK), Finland (FI), Norway (NO), and Sweden (SE). One patient could contribute several treatment episodes. Age, sex, co-medication (methotrexate, prednisolone), number of previous b/tsDMARDs, CRP, comorbidities (cardiovascular (including ACS (defined as ICD-10: I20.0, I21.0-4, I21.9) and cerebrovascular disease, thromboembolic events, diabetes, hospitalized infection, cancer, kidney failure, COPD) and associated drugs were extracted and used as adjustment in Cox regression analyses comparing the incidence of ACS between treatments. We used several follow-up lengths (1, 2, and up to 5 years) and two different risk windows (ACS on drug [ending follow-up on treatment discontinuation] and ACS ever since treatment start [disregarding any treatment discontinuation]). We also stratified by age and number of previous b/tsDMARDs.Results:We included 40850 treatment courses in 24083 patients (DK 7271, FI 3732, NO 1540, and SE 11540; around 75% women). ETA was the most common treatment (27%) whereas BAR and TOF comprised We found 780 incident ACS events during 141 326 person-years (pyrs) in the 5-year follow-up time and “ACS ever since treatment start” risk window, resulting in a crude incidence rate of 5.5 events per 1000 pyrs. No event was recorded for BAR nor TOF, which also had the shortest follow-up. Adjusted hazard ratios (HR) increased slightly with longer follow-up times, but the two risk windows provided similar HRs. For the 5-year follow-up, RIT was associated with an increased risk of ACS compared to ETA (Table), while no association was observed for shorter follow-up times. Stratifying on age did not modify the associations. Separate analyses by number of previous b/tsDMARDs suggested that ABA (HR=1.8, 95% CI 1.0-3.3), INF (HR=2.2, 95% CI 1.0-4.6) and RIT (HR=1.9, 95% CI 1.1-3.4) were associated with increased risks of ACS compared to ETA in the subgroup of patients with two or more previous bDMARDs (Figure), whereas no differences were found among patients starting either drug as 1st/2nd bDMARD.Table 1.Comparisons of risks for ACS during a 5-year follow-up since start of bDMARD treatment.DrugN eventspyrsCrude incidence rate/ 1000 pyrsHR (95% CI)1ETA175359174.9ref.ADA115240934.81.0 (0.8-1.3)CTZ54141583.80.9 (0.6-1.2)GOL4090064.41.1 (0.8-1.5)INF106178036.01.2 (0.9-1.5)ABA70107956.51.1 (0.8-1.4)RIT158166229.51.3 (1.0-1.6)TCZ62128664.80.9 (0.5-1.2)BAR036TOF030Pyrs: person-years; HR: hazards ratio1 adjustment: see text.Conclusion:In this cohort including ≥ 24,000 patients followed for up to 5 years, the ACS incidence rate was 5.5/1000 pyrs, with RIT showing an increased risk compared to ETA. In clinical practice, the choice of bDMARD does not seem to influence ACS risk in the short term. In the longer term, differences in ACS risk between bDMARDs may reflect channeling to these, or truly differential effects in subpopulations of patients.Acknowledgements:Partly funded by Nordforsk and ForeumDisclosure of Interests:Bénédicte Delcoigne: None declared, Lotta Ljung: None declared, Sella Aa. Provan Speakers bureau: Novartis, Consultant of: Novartis, Grant/research support from: Boehringer- Ingelheim, Bente Glintborg Grant/research support from: Pfizer, BMS, AbbVie, Kathrine Lederballe Gron Grant/research support from: BMS, Merete L. Hetland Consultant of: Abbvie, Biogen, BMS, Celltrion, Eli Lilly, Janssen Biologics B.V, Lundbeck Fonden, MSD, Pfizer, Roche, Samsung Biopies, Sandoz, Novartis, Grant/research support from: Abbvie, Biogen, BMS, Celltrion, Eli Lilly, Janssen Biologics B.V, Lundbeck Fonden, MSD, Pfizer, Roche, Samsung Biopies, Sandoz, Novartis, Niels Steen Krogh: None declared, Nina Trokovic: None declared, Heikki Relas Speakers bureau: Abbvie, Celgene, Pfizer, Grant/research support from: Abbvie, Celgene, Pfizer, Carl Turesson Speakers bureau: Abbvie, Bristol-Myers Squibb, Medac, Pfizer, Roche, Consultant of: Roche, Brigitte Michelsen Consultant of: Novartis (paid to employer), Grant/research support from: Novartis (paid to employer), Johan Askling Consultant of: Abbvie, Astra-Zeneca, BMS, Eli Lilly, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB. These entities have entered into agreements with Karolinska Institutet with JA as principal investigator, mainly in the context of safety monitoring of biologics via the ARTIS national safety monitoring system.

Background:The role of psychosocial conditions on the disease course of rheumatoid arthritis (RA) is getting increased attention. In our previous study, low social support and low decision latitude at work were associated with known modifiable risk factors for RA disease development, such as smoking and low educational level (1). Further, smoking and low educational level have previously been shown to be associated with worse RA disease outcome (2-4). Whether psychosocial characteristics are related to RA disease outcome needs further investigation.Objectives:To investigate the relationship between two psychosocial characteristics: low social support and low decision latitude at work, and achievement of remission in patients with RA.Methods:At inclusion in the Swedish EIRA study, incident RA cases (N=3724) and controls (N=5937), matched for age, sex and residential area, responded to a questionnaire including questions on social support and decision latitude at work. The answers were recoded into separate scores and the distribution of the scores among controls were used to define the exposures. Low social support and low decision latitude at work, respectively, among patients, were set as the level corresponding to the lowest quartile among controls, and were compared with scores corresponding to the remaining three quartiles.The outcome, disease activity score 28-joint count (DAS28) remission, defined as DAS28Logistic regression was used to evaluate the association between low social support or low decision latitude at work, respectively, and the chance of remission at the time-points 3 months, 12 months and 60 months after inclusion. All results were adjusted for age, sex and residential area and the fully adjusted models were also adjusted for smoking, obesity, physical activity and educational level.Results:Low social support (n=655) was associated with a reduced chance for remission at all three time points in the model adjusted for age, sex and residential area; OR 3 months 0.77 (95% CI 0.61-0.97), OR 12 months 0.78 (95% CI 0.64-0.95) OR 60 months 0.77 (95% CI 0.59-0.99). This association was diminished after further adjustment. After stratifying for sex, this association was enhanced in women but inverse among men (Figure 1).No association between low decision latitude at work (n=166) and chance for remission was observed neither in the analyses stratified for matching variables, nor in the full model. This result was only marginally changed after stratifying for sex (Figure 1).Conclusion:Low social support was associated with lower chance of remission in early RA, but the association was not independent of other risk factors for worse outcome (smoking, physical activity, obesity and low educational level).The interrelationship between social stressors and previously known risk factors for worse outcome highlights the importance of supportive actions at many levels to increase the possibility for the individual to make healthy decisions.References:[1]Hedenstierna. et al. Scand J Rheumatol. 2021:1-5.[2]Saevarsdottir, et al. Ann Rheum Dis. 2011;70(3):469-75.[3]Saevarsdottir, et al. Arthritis Rheum. 2011;63(1):26-36.[4]Jiang, et al. Arthritis Res Ther. 2015;17:317.Figure 1.Odds ratios for assiciation between social stressors and DAS 28 remissionAcknowledgements:We want to thank all the participants of the EIRA study and the clinical collaborators for their valuable contribution. We also want to thank the staff for their dedicated work with the data collection.Disclosure of Interests:None declared

Background:Studies from COVID-19 case-repositories among patients with rheumatic diseases have assessed associations (relative risks) between characteristics of the disease and adverse COVID-19 outcomes. Such designs are susceptible to bias from selection of cases reported. Few studies have assessed absolute and relative risks for COVID-19 outcomes in population-based cohorts of patients with inflammatory joint diseases, nor compared these risks to those in the general population.Objectives:To estimate all-cause mortality, absolute and relative risks for severe COVID-19 in patients with chronic inflammatory joint diseases, compared over time and to the general population.Methods:We updated a multi-register nationwide linkage (“ARTIS”) on adults with RA, PsA, AS, SpA or JIA and population referents (matched on sex, age, and region), with data on hospitalizations, admission to intensive care (ICU), and deaths due to COVID-19. We calculated all-cause mortality March-September 2015-2020, and absolute and relative risks for COVID-19 outcomes March-September 2020. Patients were compared to population referents using hazard ratios (HR) from Cox models adjusted for comorbidities and socio-economy.Results:We identified 110567 individuals with inflammatory joint disease (53455 with RA) in Sweden on March 1st 2020, and 484277 matched general population subjects. In all cohorts, the absolute risk of death from any cause in 2020 was higher than 2015-2019 (Figure 1), with a peak in mid-April, but the relative risks of death (vs. the general population) 2020 remained similar to HRs for 2015-2019 (HR for 2020 in Table 1).Among all individuals with inflammatory joint disease in 2020, the risk for hospitalization, admission to ICU, and death due to COVID-19 was 0.5%, 0.04% and 0.1%, respectively (Table 1). HRs (vs. the general population) were elevated for almost all outcomes. HRs for COVID-19 related outcomes (Table 1) were higher than for non-COVID-19 outcomes; adjustment for co-morbidities and socio-economy explained much of these increases, somewhat less so for the former.Figure 1.All-cause mortality in Swedish individuals with inflammatory joint disease and general population, March-September 2020 and the average 2015-2019Table 1.Absolute and relative risks for COVID-19 outcomes in Swedish individuals with inflammatory joint disease compared to general population comparators March-September 2020OutcomeEvents(risk, %)Events (risk, %), general populationHR1*HR2**AllHospitalization, all causes8971 (8.1%)24273 (5.0%)1.65(1.61, 1.69)1.18 (1.15, 1.21)Hospitalization, COVID-19581 (0.5%)1443 (0.3%)1.77 (1.61, 1.95)1.32 (1.19, 1.46)ICU, COVID-1945 (0.04%)162 (0.03%)1.22 (0.88, 1.70)1.17 (0.82, 1.66)Death, all causes1310 (1.2%)3036 (0.6%)1.90 (1.78, 2.02)1.13 (1.05, 1.21)Death, COVID-19161 (0.1%)338 (0.07%)2.09 (1.73, 2.52)1.18 (0.97, 1.44)RAHospitalization, all causes5275 (9.9%)13072 (5.9%)1.71 (1.66, 1.77)1.21 (1.17, 1.25)Hospitalization, COVID-19379 (0.7%)784 (0.4%)2.02 (1.78, 2.28)1.40 (1.23, 1.60)ICU, COVID-1931 (0.06%)79 (0.04%)1.63 (1.08, 2.48)1.53 (0.98, 2.40)Death, all causes968 (1.8%)2026 (0.9%)1.99 (1.85, 2.15)1.18 (1.09, 1.28)Death, COVID-19134 (0.3%)245 (0.11%)2.28 (1.85, 2.81)1.27 (1.02, 1.59)PsA AS SpA JIAHospitalization, all causes3696 (6.5%)11201 (4.3%)1.54 (1.48, 1.59)1.16 (1.11, 1.20)Hospitalization, COVID-19202 (0.4%)659 (0.3%)1.41 (1.20, 1.65)1.20 (1.02, 1.41)ICU, COVID-1914 (0.02%)83 (0.03%)0.78 (0.44, 1.37)0.76 (0.43, 1.37)Death, all causes342 (0.6%)1010 (0.4%)1.56 (1.38, 1.76)0.98 (0.86, 1.12)Death, COVID-1927 (0.05%)93 (0.04%)1.34 (0.87, 2.05)0.83 (0.54, 1.28)*HR1 unadjusted, matched (age, sex, and region)**HR2, as HR1 but adjusted for comorbidities and socio-economyConclusion:Risks of severe COVID-19 were increased among patients with inflammatory joint diseases, but similar increases were seen for non-COVID-19 morbidity. Co-morbidities and socio-economy explain much of this increase.Disclosure of Interests:Hannah Bower: None declared, Thomas Frisell: None declared, Daniela Di Giuseppe: None declared, Bénédicte Delcoigne: None declared, Gerd-Marie Alenius: None declared, Eva Baecklund: None declared, Katerina Chatzidionysiou Speakers bureau: Eli Lilly, AbbVie and Pfizer, Consultant of: Eli Lilly, AbbVie and Pfizer, Nils Feltelius Employee of: Nils Feltelius is employed by the Medical Products Agency (MPA), which is a governmental body. The views in this abstract may not represent the views of the MPA, Helena Forsblad-d’Elia: None declared, Alf Kastbom Employee of: Former employee of Sanofi, Lars Klareskog: None declared, Elisabet Lindqvist: None declared, Ulf Lindström: None declared, Carl Turesson Speakers bureau: Roche, AbbVie and Pfizer, Consultant of: Roche, Grant/research support from: Research grant from Bristol-Myers Squibb, Christopher Sjowall: None declared, Johan Askling Grant/research support from: PI for agreements between Karolinska Institutet and Abbvie, BMS, Eli Lilly, Pfizer, Roche, Samsung Bioepis, and Sanofi for safety monitoring of anti-rheumatic therapies (ARTIS).

Background:Knowledge of changes over time in baseline characteristics and tumor necrosis factor inhibitor (TNFi) response in bio-naïve axial spondyloarthritis (axSpA) patients treated in routine care is limited.Objectives:To investigate secular trends in baseline characteristics and retention, remission and response rates in axSpA patients initiating a first TNFi.Methods:Prospectively collected data on bio-naïve axSpA patients starting TNFi in routine care from 15 European countries were pooled. According to year of TNFi initiation, three groups were defined a priori based on bDMARD availability: Group A (1999–2008), Group B (2009–2014) and Group C (2015–2018). Retention rates (Kaplan-Meier), crude and LUNDEX adjusted1 remission (Ankylosing Spondylitis Disease Activity Score (ASDAS) Results:In total, 27189 axSpA patients were included (5945, 11255 and 9989 in groups A, B and C).At baseline, patients in group A were older, had longer disease duration and a larger proportion of male and HLA-B27 positive patients compared to B and C, whereas disease activity was similar across groups.Retention rates at 6, 12 and 24 months were highest in group A (88%/81%/71%) but differed little between B (84%/74%/64%) and C (85%/76%/67%).In all groups, median ASDAS and BASDAI had decreased markedly at 6 months (Table 1). The ASDAS values at 12 and 24 months and BASDAI at 24 months were higher in group A compared with groups B and C. Similarly, crude remission and response rates were lowest in group A. After adjustments for drug retention (LUNDEX), remission and response rates showed less pronounced between-group differences regarding ASDAS measures and no relevant differences regarding BASDAI measures.Conclusion:Nowadays, axSpA patients initiating TNFi are younger with shorter disease duration and more frequently female and HLA-B27 negative than previously, while baseline disease activity is unchanged. Drug retention rates have decreased, whereas crude remission and response rates have increased. This may indicate expanded indication but also a stable disease activity threshold for TNFi initiation over time, an increased focus on targeting disease remission and more available treatment options.References:[1]Arthritis Rheum 2006; 54: 600-6.Table 1.Secular trends in baseline characteristics, treatment retention, remission and response rates in European axSpA patients initiating a 1st TNFiBaseline characteristicsGroup A(1999–2008)Group B(2009–2014)Group C(2015–2018)Age, years, median (IQR)57 (49–66)51 (42–60)46 (37–56)Male, %666057HLA-B27, %877772Years since diagnosis, median (IQR)5 (1–12)2 (0–8)2 (0–7)Smokers, %232425ASDAS, median (IQR)3.5 (2.8–4.1)3.4 (2.8–4.1)3.5 (2.8–4.1)BASDAI, median, (IQR)57 (42–71)59 (43–72)57 (41–71)TNFi drug, % (Adalimumab /Etanercept / Infliximab /Certolizumab / Golimumab)22 / 35 / 43 / 0 / 037 / 21 / 20 / 4 / 1827 / 28 / 24 / 8 / 13Follow up6 months12 months24 monthsGr AGr BGr CGr AGr BGr CGr AGr BGr CRetention rates, %, (95% CI)88 (88–89)84 (83–85)85 (84–86)81 (80–82)74 (74–75)76 (75–76)71 (70–72)64 (63–65)67 (66–68)ASDAS, median, (IQR)1.8 (1.2–2.8)1.9 (1.2–2.8)1.8 (1.2–2.6)1.9 (1.3–2.6)1.7 (1.2–2.5)1.6 (1.1–2.4)1.9 (1.4–2.6)1.7 (1.1–2.4)1.5 (1.1–2.2)ASDAS inactive disease, %, c/L28 / 2528 / 2430 / 2624 / 1932 / 2434 / 2623 / 1634 / 2039 / 23ASDAS CII, %, c/L57 / 5159 / 5063 / 5461 / 5063 / 4767 / 5159 / 4168 / 4074 / 45ASDAS MI, %, c/L31 / 2732 / 2737 / 3232 / 2637 / 2741 / 3130 / 2042 / 2546 / 28BASDAI, median, (IQR)23 (10–40)26 (11–48)24 (10–44)21 (10–38)23 (10–42)20 (8–39)22 (9–40)20 (8–39)16 (6–35)BASDAI remission, %, c/L44 / 4040 / 3443 / 3645 / 3645 / 3450 / 3844 / 3048 / 2956 / 34BASDAI 50 response, %, c/L53 / 4750 / 4253 / 4557 / 4656 / 4258 / 4457 / 3960 / 3563 / 38Gr, Group; c/L, crude/LUNDEX adjusted.Acknowledgements:Novartis Pharma AG and IQVIA for supporting the EuroSpA Research Collaboration Network.Disclosure of Interests:Lykke Midtbøll Ørnbjerg Grant/research support from: Novartis, Sara Nysom Christiansen Speakers bureau: BMS and GE, Grant/research support from: Novartis, Simon Horskjær Rasmussen: None declared, Anne Gitte Loft Speakers bureau: AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, UCB, Consultant of: AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, UCB, Grant/research support from: Novartis, Ulf Lindström: None declared, Jakub Zavada: None declared, Florenzo Iannone: None declared, Fatos Onen: None declared, Michael J. Nissen Speakers bureau: Novartis, Eli Lilly, Celgene, and Pfizer, Consultant of: Novartis, Eli Lilly, Celgene, and Pfizer, Brigitte Michelsen Consultant of: Novartis, Grant/research support from: Novartis, Maria Jose Santos Speakers bureau: AbbVie, Novartis, Pfizer, Gary Macfarlane Grant/research support from: GlaxoSmithKline, Dan Nordström Consultant of: Abbvie, BMS, MSD, Novartis, Pfizer, Roche, UCB, Manuel Pombo-Suarez: None declared, Catalin Codreanu Speakers bureau: AbbVie, Amgen, Egis, Novartis, Pfizer, UCB, Grant/research support from: AbbVie, Amgen, Egis, Novartis, Pfizer, UCB, Matija Tomsic Speakers bureau: Abbvie, Amgen, Biogen, Medis, MSD, Novartis, Pfizer, Consultant of: Abbvie, Amgen, Biogen, Medis, MSD, Novartis, Pfizer, Irene van der Horst-Bruinsma Speakers bureau: Abbvie, BMS, MSD, Novartis, Pfizer, Lilly, UCB, Björn Gudbjornsson Speakers bureau: Amgen and Novartis, Johan Askling: None declared, Bente Glintborg Grant/research support from: Pfizer, Biogen, AbbVie, Karel Pavelka Speakers bureau: AbbVie, Roche, MSD, UCB, Pfizer, Novartis, Egis, Gilead, Eli Lilly, Consultant of: AbbVie, Roche, MSD, UCB, Pfizer, Novartis, Egis, Gilead, Eli Lilly, Elisa Gremese: None declared, Nurullah Akkoc: None declared, Adrian Ciurea Speakers bureau: Abbvie, Eli-Lilly, MSD, Novartis, Pfizer, Eirik kristianslund: None declared, Anabela Barcelos: None declared, Gareth T. Jones Grant/research support from: Pfizer, AbbVie, UCB, Celgene, Amgen, GSK, Anna-Mari Hokkanen Grant/research support from: MSD, Carlos Sánchez-Piedra: None declared, Ruxandra Ionescu Speakers bureau: Abbvie, Amgen, Boehringer-Ingelheim Eli-Lilly,Novartis, Pfizer, Sandoz, UCB, Ziga Rotar Speakers bureau: Abbvie, Amgen, Biogen, Medis, MSD, Novartis, Pfizer, Consultant of: Abbvie, Amgen, Biogen, Medis, MSD, Novartis, Pfizer, Marleen G.H. van de Sande: None declared, Arni Jon Geirsson: None declared, Mikkel Østergaard Speakers bureau: AbbVie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Centocor, GSK, Hospira, Janssen, Merck, Mundipharma, Novartis, Novo, Orion, Pfizer, Regeneron, Schering-Plough, Roche, Takeda, UCB and Wyeth, Consultant of: AbbVie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Centocor, GSK, Hospira, Janssen, Merck, Mundipharma, Novartis, Novo, Orion, Pfizer, Regeneron, Schering-Plough, Roche, Takeda, UCB and Wyeth, Merete L. Hetland Speakers bureau: Abbvie, Biogen, BMS, Celltrion, Eli Lilly, Janssen Biologics B.V, Lundbeck Fonden, MSD, Pfizer, Roche, Samsung Biopies, Sandoz, Novartis.