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To evaluate pregnancy outcomes in relation to antirheumatic treatment before and during pregnancy, as a proxy of disease severity in pregnant women with psoriatic arthritis (PsA), compared to those without PsA.Our study focused on a Swedish nationwide registry-based cohort study that included 921 PsA pregnancies and 9,210 non-PsA pregnancies occurring between 2007 and 2017 (matched 1:10 based on maternal age, year of delivery, and parity). We estimated adjusted odds ratios (ORs) overall, with 95% confidence intervals (95% CIs), and stratified by presence, timing, and type of antirheumatic treatment. Adjustments were made for maternal body mass index, smoking, education level, and country of birth. The outcome of preterm birth was also stratified by parity.Pregnant women with PsA versus those without PsA were more obese, more often smokers, and more frequently had a diagnosis of pregestational hypertension and diabetes mellitus. Increased risks in PsA pregnancies versus non-PsA pregnancies were primarily preterm birth (adjusted OR 1.69 [95% CI 1.27-2.24]) and cesarean delivery (adjusted OR 1.77 [95% CI 1.43-2.20] for elective delivery, and adjusted OR 1.42 [95% CI 1.10-1.84] for emergency delivery). The risks differed according to the presence, timing, and type of antirheumatic treatment, with the most increased risk in PsA pregnancies (versus non-PsA) occurring with antirheumatic treatment during pregnancy (adjusted OR 2.30 [95% CI 1.49-3.56] for preterm birth). The corresponding adjusted OR for preterm birth in women with PsA who were exposed specifically to biologic treatment during pregnancy was 4.49 [95% CI 2.60-7.79]. Risk of preterm birth was primarily increased in first pregnancies.Compared to non-PsA pregnancies, risks of preterm birth and cesarean delivery were mostly increased in those exposed to antirheumatic treatment during pregnancy, especially biologic treatments. As parity influences the risk of preterm birth in women with PsA, special attention to first pregnancies is warranted. Women with PsA should receive individualized monitoring during pregnancy.

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

Objectives To explore the association of maternal RA to pregnancy outcomes, especially preterm birth (PTB) and small for gestational age (SGA), in relation to disease activity and anti-rheumatic treatment before and during pregnancy. Methods By linking prospective clinical rheumatology registers (CRR) in Sweden (the Swedish Rheumatology Quality Register, SRQ) and Denmark (the Danish clinical quality register, DANBIO) with medical birth registers, we identified 1739 RA-pregnancies and 17 390 control-pregnancies (matched 1:10 on maternal age, birth year, parity) with delivery 2006–18. Disease activity (DAS28, CRP, HAQ score) and anti-rheumatic treatment 9 months before and during pregnancy were identified through CRR and prescribed drug registers. Using logistic regression, we estimated adjusted odds ratios (aOR) with 95% CI for PTB and SGA overall and stratified by disease activity and anti-rheumatic treatment before and during pregnancy, adjusting for maternal characteristics. Results We found increased aOR of PTB [1.92 (1.56–2.35)] and SGA [1.93 (1.45–2.57)] in RA-pregnancies vs control-pregnancies. For RA-pregnancies with DAS28-CRP ≥4.1 vs Conclusion During pregnancy, disease activity rather than treatment seems to be the most important risk factor for PTB and SGA in RA. Women with RA should be carefully monitored during pregnancy, especially if they have moderate to high disease activity or/and are treated with extensive anti-rheumatic treatment.

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

Familial associations can be indicators of shared genetic susceptibility between two diseases. Previous data on familial autoimmunity in patients with idiopathic inflammatory myopathies (IIM) are scarce and inconsistent.To investigate which autoimmune diseases (ADs) may share genetic susceptibility with IIM, we examined the familial associations between IIM and different ADs.In this Swedish population-based family study, we assembled 7615 first-degree relatives (FDRs) of 1620 patients with IIM and 37,309 relatives of 7797 matched individuals without IIM. Via register linkages, we ascertained rheumatoid arthritis, other rheumatic inflammatory diseases (RIDs), multiple sclerosis, inflammatory bowel diseases (IBD), type 1 diabetes mellitus, autoimmune thyroid diseases (AITD), coeliac disease (CeD) and myasthenia gravis among the FDRs. We estimated the familial association between IIM and each AD using conditional logistic regression and performed subgroup analyses by kinship.Patients with IIM had significantly higher odds of having ≥1 FDR affected by other RIDs (adjusted odds ratio [aOR] = 1.40, 95% confidence interval [CI] 1.11-1.78) and greater odds of having ≥2 FDRs affected by CeD (aOR = 3.57, 95% CI 1.28-9.92) compared to the individuals without IIM. In the analyses of any FDR pairs, we observed familial associations for other RIDs (aOR = 1.34, 95% CI 1.14-1.56), IBD (aOR = 1.20, 95% CI 1.02-1.41), AITD (aOR = 1.10, 95% CI 1.02-1.19) and CeD (aOR = 1.37, 95% CI 1.08-1.74) while associations for other ADs were not statistically significant.The observed familial associations may suggest that IIM shares genetic susceptibility with various ADs, information that may be useful for clinical counselling and guiding future genetic studies of IIM.

ObjectivesThe magnitude of the genetic contribution to idiopathic inflammatory myopathies (IIMs) is unknown. In this project, we aimed to investigate the familial aggregation and heritability of IIM.MethodsThis is a family-based study using nationwide healthcare register data in Sweden. We matched each patient with IIM to individuals without IIM, identified their first-degree relatives and determined the IIM status among all first-degree relatives. We estimated the adjusted ORs (aORs) of familial aggregation of IIM using conditional logistic regression. In addition, we used tetrachoric correlation to estimate the heritability of IIM.ResultsWe included 7615 first-degree relatives of 1620 patients with IIM diagnosed between 1997 and 2016 and 37 309 first-degree relatives of 7797 individuals without IIM. Compared with individuals without IIM, patients with IIM were more likely to have ≥1 first-degree relative affected by IIM (aOR=4.32, 95% CI 2.00 to 9.34). Furthermore, the aOR of familial aggregation of IIM in full siblings was 2.53 (95% CI 1.62 to 3.96). The heritability of IIM was 22% (95% CI 12% to 31%) among any first-degree relatives and 24% (95% CI 12% to 37%) among full siblings.ConclusionsIIM has a familial component with a risk of aggregation among first-degree relatives and a heritability of about 20%. This information is of importance for future aetiological studies and in clinical counselling.

ObjectiveAssess cancer risks with Janus kinase inhibitors (JAKi) versus biological disease-modifying antirheumatic drugs (bDMARDs) in clinical practice.MethodsCohort study of patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA) initiating treatment with JAKi, tumour necrosis factor inhibitors (TNFi) or other (non-TNFi) bDMARDs 2016–2020 using prospectively collected data from the Swedish Rheumatology Quality Register linked to other registers including the Cancer Register. We estimated incidence rates, and HRs via Cox regression, for all cancers excluding non-melanoma skin cancer (NMSC), and for individual cancer types including NMSC.ResultsWe identified 10 447 patients with RA and 4443 patients with PsA who initiated treatment with JAKi, a non-TNFi bDMARD or a TNFi. Median follow-up times in RA were 1.95, 2.83 and 2.49 years, respectively. In RA, based on 38 incident cancers other than NMSC with JAKi vs 213 with TNFi the overall HR was 0.94 (95% CI 0.65 to 1.38). Based on 59 vs 189 incident NMSC, the HR was 1.39 (95% CI 1.01 to 1.91). At 2 or more years since treatment start, the HR for NMSC was 2.12 (95% CI 1.15 to 3.89). In PsA, based on 5 vs 73 incident cancers other than NMSC, and 8 vs 73 incident NMSC, the corresponding HRs were 1.9 (95% CI 0.7 to 5.2) and 2.1 (95% CI 0.8 to 5.3).ConclusionIn clinical practice, the short-term risk of cancer other than NMSC in individuals initiating treatment with JAKi is not higher than for TNFi, but we found evidence of increased risk for NMSC.

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.

Objectives To examine pregnancy outcomes among births to women with idiopathic inflammatory myopathy (IIM) in relation to time of IIM diagnosis using population-based data. Methods This study used Swedish nationwide registers to identify all singleton births that occurred between 1973 and 2016 among women diagnosed with IIM between 1998 and 2016 and among women unexposed to IIM. We classified births according to the IIM status of the mother at time of delivery: post-IIM (n = 68), 1–3 years pre-IIM (n = 23), >3 years pre-IIM (n = 710) and unexposed to IIM (n = 4101). Multivariate regression models were used to estimate relative risks of adverse pregnancy outcomes in post-IIM births and pre-IIM births separately, in comparison with their non-IIM comparators. Results We found that post-IIM births had increased risks of caesarean section [adjusted relative risk (aRR) = 1.98; 95% CI: 1.08, 3.64], preterm birth (aRR = 3.35; 95% CI: 1.28, 8.73) and low birth weight (aRR = 5.69; 95% CI: 1.84, 17.55) compared with non-IIM comparators. We also noticed higher frequencies of caesarean section and instrumental delivery in 1–3 years pre-IIM births than in the non-IIM comparators. Conclusion Women who gave birth after IIM diagnosis had higher risks of caesarean section, preterm birth and low birth weight. These results further underline the importance of special care and close monitoring of women with IIM. Higher frequencies of caesarean section and instrumental delivery in pre-IIM births highlight the need for future research on the influence of subclinical features of IIM on pregnancy outcomes.

ObjectiveTo explore the risk of pre-eclampsia in rheumatoid arthritis (RA), axial spondyloarthritis (AxSpA) and psoriatic arthritis (PsA), focusing on the impact of treatment and disease activity.MethodsWe identified RA, AxSpA and PsA singleton pregnancies (2006–2018) by linking medical birth registers to Swedish (SRQ) and Danish (DANBIO) rheumatology registers. Control pregnancies from the medical birth registers were matched 1:10 on maternal age, parity and birth year.We obtained information on antirheumatic treatment before and during pregnancy and disease activity during pregnancy. Risks of pre-eclampsia in RA, AxSpA and PsA pregnancies, compared with control pregnancies, were estimated overall and by antirheumatic treatment (conventional synthetic disease-modifying antirheumatic drug (DMARD)/biological DMARD/corticosteroids, as monotherapy or combination therapy) and disease load (Health Assessment Questionnaire≥1/C-reactive protein≥10/Disease Activity Score in 28 joints≥3.2) through logistic regression (adjusted ORs (aORs) with 95% CI).ResultsWe observed 69, 34, and 26 pre-eclampsia events among RA (n=1739), AxSpA (n=819) and PsA (n=489), resulting in a risk of pre-eclampsia of, respectively, aOR 1.27 (95% CI 0.96 to 1.67), 1.17 (0.76 to 1.78) and 1.85 (1.10 to 3.12), compared with controls.For RA, maternal combination therapy before and during pregnancy was associated with increased risk (1.59; 1.07 to 2.37 and 1.53; 0.97 to 2.39, respectively). For PsA, maternal monotherapy before pregnancy was associated with pre-eclampsia (2.72; 1.4 to 5.13). In RA pregnancies with available information (43%), high disease load was associated with doubled risk of pre-eclampsia (aOR 1.96; 1.26 to 3.04).ConclusionPsA pregnancies, but not AxSpA pregnancies, were at increased risk of pre-eclampsia. For RA, combination therapy (potentially a surrogate for high disease activity both before and during pregnancy) and high disease load during pregnancy might be a risk factor for pre-eclampsia.

Objectives AS is known to be a highly heritable disease, but previous studies on the magnitude of the familial aggregation and heritability of AS have been small and inconclusive, with familial relative risks ranging from 17 to 94. We aimed to improve estimates of these factors by studying families of all subjects diagnosed with AS in Sweden over a period of 16 years and to investigate if familial risks vary by sex or type of relative. Methods In a nested case–control study, we identified AS index patients from the National Patient Register (NPR) and the Swedish Rheumatology Quality Register (SRQ) between 2001 and 2016. Each index patient was matched on age and sex to up to 50 general population controls. First-degree relatives of index patients and controls were identified through the Multi-Generation Register, with disease status ascertained in the NPR and SRQ. Familial risks were defined as odds ratios (ORs) of having AS when exposed to a first-degree relative with AS, using conditional logistic regression. Results The overall familial OR for AS was 19.4 (95% CI 18.1, 20.8). Estimates were similar for different relative types and by sex, but having more than one affected relative resulted in a higher risk [OR 68.0 (95% CI 51.3, 90.1)]. Heritability, estimated by assuming sibling risks were completely due to genetics, was 77% (95% CI 73, 80). Conclusion Although the familial risk and heritability of AS are higher than for most other diseases, we report estimates that are substantially lower than commonly referenced numbers for AS from other populations.

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.

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.

Objective: To determine whether a family history of spondyloarthritis (SpA) is associated with clinical presentation at the start of tumour necrosis factor inhibitor (TNFi) treatment, or predictive of TNFi drug survival and treatment response in patients with SpA. Method: Family history of SpA in patients with ankylosing spondylitis (AS), psoriatic arthritis (PsA), and undifferentiated SpA (uSpA) from the Swedish Rheumatology Quality register starting a TNFi as their first biologic in 2006���2018 was assessed through national registers. Clinical characteristics at treatment start were compared by family history status. We used Cox regression to estimate hazard ratios for drug discontinuation, and analysed treatment response at 3 and 12 months with linear regression. Multiple imputation was used to address missing data. Results: We included 9608 patients. Patients with family history had an earlier age at onset and longer disease duration at TNFi treatment start, but did not differ regarding disease activity and presence of SpA manifestations. Hazard ratios for drug discontinuation were 1.08 [95% confidence interval (CI) 0.89���1.31] for AS patients with a family history of AS, 1.02 (95% CI 0.89���1.18) for PsA patients with a family history of PsA, and 1.11 (95% CI 0.85���1.45) for uSpA patients with a family history of uSpA, after adjusting for demographic, socioeconomic, and SpA-related factors. Treatment response at 3 and 12 months was similar between groups. Conclusion: Family history of SpA was not found to be associated with clinical presentation at the start of TNFi treatment, nor was it associated with drug survival or treatment response in SpA patients starting a first TNFi.

Objective To examine the association between idiopathic inflammatory myopathy (IIM) and cancer before and after IIM diagnosis. Methods We used prospectively collected nationwide register data to design a case-control study to investigate the occurrence of cancer before IIM, and a cohort study to investigate the occurrence of cancer after IIM. Patients diagnosed with IIM between 2002 and 2016 in Sweden, were compared to the general population. The association between cancer and IIM was estimated before and after IIM diagnosis via logistic regression and Cox regression models, respectively. Results We included 1419 patients with IIM and 7045 individuals from the general population. The overall odds of cancer before IIM diagnosis were increased in IIM compared to the general population, adjusted odds ratio (AOR) 1.5, 95% confidence interval (CI) 1.3–1.8. This association was also noted after IIM diagnosis, adjusted hazard ratio (AHR) 1.7 (95% CI 1.4–2.0), or one additional cancer in every 125 IIM patients per year. Colorectal (AOR 2.1), lung (AOR 5.4) and ovarian (AOR 7.0) cancers were associated with IIM before diagnosis. Oropharyngeal (AHR 9.1) and cervical (AHR 3.8) cancers, malignant melanoma (AHR 3.2) and non-melanoma skin cancer (AHR 3.1) were associated with IIM after diagnosis. Adenocarcinomas were associated with dermatomyositis before diagnosis and squamous cell cancers after IIM diagnosis. Lymphatic hematopoietic cancers were associated with IIM both before and after diagnosis. Conclusions The cancer types that occur before IIM diagnosis differ from the ones that occur after diagnosis. This may have an impact on screening decisions for IIM.

Background: Most anti-tumour necrosis factor (anti-TNF) agents are transferred across the placenta and may increase paediatric susceptibility to infections. Aims: To assess the risk of paediatric infections after maternal anti-TNF treatment. Methods: Population-based cohort study in Denmark, Finland and Sweden 2006-2013 in which 1027 children born to women with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis or inflammatory bowel disease, treated with anti-TNF, and 9346 children to women with non-biologic systemic treatment, were compared to 1 617 886 children of the general population. Children were followed for 3 years. Results: Adjusted by maternal age, parity, smoking, body mass index, country and calendar year, the incidence rate ratios with 95% confidence interval (CI) for hospital admissions for infection in the first year were 1.43 (1.23-1.67) for anti-TNF and 1.14 (1.07-1.21) for non-biologic systemic treatment, and 1.29 (1.11-1.50) and 1.09 (1.02-1.15), respectively, when additionally adjusting for adverse birth outcomes. There was a slight increase in antibiotic prescriptions in the second year for anti-TNF, 1.19 (1.11-1.29), and for non-biologic systemic treatment, 1.10 (1.07-1.13). There was no difference among anti-TNF agents, treatment in the third trimester, or between mono/combination therapy with non-biologic systemic treatment. Conclusions: Both anti-TNF and non-biologic systemic treatment were associated with an increased risk of paediatric infections. However, reassuringly, the increased risks were present regardless of treatment in the third trimester, or with combination treatment, and were not persistent during the first 3 years of life. Our findings may indicate a true risk, but could also be due to unadjusted confounding by disease severity and healthcare-seeking behaviour. This may in turn shift the risk-benefit equation towards continuation of treatment even in the third trimester.

Purpose: To study the risk of preterm birth, caesarean section, and small for gestational age after anti-tumor necrosis factor agent treatment (anti-TNF) in pregnancy. Methods: Population-based study including women with inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and psoriasis, and their infants born 2006 to 2013 from the national health registers in Denmark, Finland, and Sweden. Women treated with anti-TNF were compared with women with nonbiologic systemic treatment. Adalimumab, etanercept, and infliximab were compared pairwise. Continuation of treatment in early pregnancy was compared with discontinuation. Odds ratios with 95% confidence intervals were calculated in logistic regression models adjusted for country and maternal characteristics. Results: Among 1 633 909 births, 1027 infants were to women treated with anti-TNF and 9399 to women with nonbiologic systemic treatment. Compared with non-biologic systemic treatment, women with anti-TNF treatment had a higher risk of preterm birth, odds ratio 1.61 (1.29-2.02) and caesarean section, 1.57 (1.35-1.82). The odds ratio for small for gestational age was 1.36 (0.96-1.92). In pairwise comparisons, infliximab was associated with a higher risk of severely small for gestational age for inflammatory joint and skin diseases but not for inflammatory bowel disease. Discontinuation of anti-TNF had opposite effects on preterm birth for inflammatory bowel disease and inflammatory joint and skin diseases. Conclusions: Anti-TNF agents were associated with increased risks of preterm birth, caesarean section, and small for gestational age. However, the diverse findings across disease groups may indicate an association related to the underlying disease activity, rather than to agent-specific effects.

Objective.To examine the reproductive pattern of women with idiopathic inflammatory myopathy (IIM) compared to the general population.Methods.Population-based, nationwide registers were used to identify offspring of women with IIM and comparators.Results.Women with IIM in general had similar reproductive patterns as the comparators, whereas in those diagnosed between 26 and 45 years of age, there was an overall trend for fewer children as well as a higher proportion of nulliparity and a lower fertility rate in women with dermatomyositis than their comparators.Conclusion.Reproductive attention should be paid to patients with IIM diagnosed during the childbearing period.

Background Tumour necrosis factor inhibitors (TNFi) effectively reduce inflammation in Psoriatic arthritis (PsA). However, a possible association between treatment with TNFi and an increased cancer risk has previously been suggested. Objectives To investigate the risk of cancer in TNFi treated PsA patients compared with standardized rates from the general population in Denmark, Finland, Iceland and Sweden. Methods TNFi-treated PsA patients were followed from first registration with TNFi-treatment in ARTIS (Sweden), DANBIO (Denmark), ICEBIO (Iceland) or ROB-FIN (Finland) and linked to the national Cancer Registry in each country. Patients with a cancer history prior to start of follow-up were excluded. We investigated the risk of primary cancer among TNFi-treated PsA patients compared with general population cancer rates standardized to age, sex and calendar period within each country. Standardized incidence ratios (SIRs) were estimated for each country and pooled SIRs were subsequently calculated for both any cancer and site-specific cancers of interest. Results A total of 5218, 2039, 270 and 526 patients were registered as ever TNFi-treated in ARTIS, DANBIO, ICEBIO and ROB-FIN, respectively, contributing a total of 44 041 patient years of follow-up across all 4 countries. For all cancers, the SIRs of TNFi-treated patients from ARTIS, DANBIO, ICEBIO and ROB-FIN were 0.94 (0.80 to 1.10), 0.99 (0.77 to 1.26), 1.71 (0.88 to 2.99) and 1.28 (0.82 to 1.90), respectively. The number of observed and expected cancers and the SIRs of any and selected site-specific cancers are listed in table 1. Conclusion Our results suggest that the overall cancer risk for TNFi-treated PsA patients is not increased compared to the general population. Further analysis of the risk of malignant lymphomas will inform on whether the increased risk we observed is attributed to the PsA disease or treatment with TNFi. Acknowledgement This study is funded by FOREUM and NordForsk. Disclosure of Interests Christine Ballegaard Speakers bureau: Janssen Pharmaceuticals., Karin Hellgren: None declared, Rene Cordtz: None declared, Benedicte Delcoigne: None declared, Bjorn Gudbjornsson: None declared, Thorvardur Jon Love Consultant for: Received reimbursment from Celgene for speaking about guidelines for the treatment of psoriatic arthritis, Kalle Aaltonen: None declared, Dan Nordstrom Grant/research support from: MSD, Pfizer, Consultant for: AbbVie, BMS, MSD, Novartis, Roche, Pfizer, UCB, Speakers bureau: Novartis, UCB, Sella Aarrestad Provan Consultant for: Novartis, Speakers bureau: Lilly, Johan Askling Grant/research support from: Karolinska Institutet (JA) has or has had research agreements with the following pharmaceutical companies, mainly in the context of the ATRIS national safety monitoring programme for rheumatology biologicals: Abbvie, BMS, MSD, Eli Lilly, Pfizer, Roche, Samsung Bioepis, and UCB., Consultant for: Karolinska Institutet has received remuneration for JA participating in ad boards arranged by Lilly, Novartis, and Pfizer., Kristian Zobbe: None declared, Lars Erik Kristensen Grant/research support from: UCB, Biogen, Janssen Pharmaceuticals, and Novartis, Consultant for: Consultant for AbbVie, Amgen, Biogen, BMS, Celgene, Eli Lilly, Janssen Pharmaceuticals, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB Pharma., Speakers bureau: Pfizer, AbbVie, Amgen, UCB, BMS, Biogen, MSD, Novartis, Eli Lilly and Company, and Janssen Pharmaceuticals, Lene Dreyer Consultant for: MSD, UCB and Janssen Pharmaceuticals, Speakers bureau: MSD, UCB and Janssen Pharmaceuticals, Speakers bureau: UCB, MSD, Eli Lilly and Janssen Pharmaceuticals.

Background: The optimal sequencing of biologic Disease Modifying Anti-Rheumatic Drugs (bDMARDs) in Rheumatoid Arthritis (RA) is unknown. Evidence regarding the effectiveness of a 2nd non-TNFi bDMARD, as well as of TNFi, in patients whose 1st bDMARD has been a non-TNFi is limited. Objectives: To characterize patients switching for medical reasons after failure of a non-TNFi used as 1st bDMARD, and to assess the effectiveness of rituximab (RTX), abatacept (ABA) or tocilizumab (TCZ) vs. a TNFi. Methods: Patients from 5 national registers (Sweden, Norway, Denmark, Iceland and Finland) with RA who started treatment with a non-TNFi as a 1st bDMARD after 2010 and switched to a 2nd bDMARD within 3 months after the discontinuation of the 1st (with the exception of RTX for which a 6-month window was used), were identified. Clinical effectiveness was assessed by DAS28 change at 6 months. Results: 611 patients were included in the analyses. 80% were female, the majority were positive for RF (76%) and anti-CCP (69%). The mean (±SD) age, DAS28 and HAQ at baseline was 58 (13), 4.5 (1.4) and 1.3 (0.7), respectively, while the median (IQR) disease duration was 5.0 (2.2-12.0) years. Baseline characteristics of patients and the clinical response for each switching strategy are shown in table 1. Moderate responses were observed for most switching strategies. 63% of patients were still on treatment with their 2nd bDMARD at 6 months after switch. Conclusion: The six-month drug retention for a 2nd bDMARD in patients with RA switching due to failure of a non-TNFi bDMARD as 1st ever bDMARD was lower than two thirds (63%). More detailed analyses are exploring potential subgroups of patients for whom specific switching strategies are more effective. Acknowledgement: The study was partly funded by a study grant from NordForsk and Foreum. Disclosure of Interests: Katerina Chatzidionysiou: None declared, Merete L. Hetland Grant/research support from: BMS, MSD, AbbVie, Roche, Novartis, Biogen, Pfizer, Consultant for: Eli Lilly, Speakers bureau: Orion Pharma, Biogen, Pfizer, CellTrion, Merck, Samsung Bioepis, Thomas Frisell: None declared, Daniela Di Giuseppe: None declared, Karin Hellgren: None declared, Bente Glintborg Grant/research support from: Biogen, Pfizer, AbbVie, Dan Nordstrom Grant/research support from: MSD, Pfizer, Consultant for: AbbVie, BMS, MSD, Novartis, Roche, Pfizer, UCB, Speakers bureau: Novartis, UCB, Kalle Aaltonen: None declared, Nina Trokovic: None declared, Eirik kristianslund: None declared, Tore K. Kvien Grant/research support from: AbbVie, BMS, MSD, Pfizer, Roche and UCB., Consultant for: AbbVie, Biogen, BMS, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Hospira, Merck-Serono, MSD, Novartis, Oktal, Orion Pharma, Pfizer, Roche, Sandoz, Sanofi, Mylan and UCB, Speakers bureau: AbbVie, Biogen, BMS, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Hospira, Merck-Serono, MSD, Novartis, Oktal, Orion Pharma, Pfizer, Roche, Sandoz, Sanofi and UCB, Sella Aarrestad Provan Consultant for: Novartis, Speakers bureau: Lilly, Bjorn Gudbjornsson: None declared, Gerdur Grondal : None declared, Lene Dreyer Consultant for: MSD, UCB and Janssen Pharmaceuticals, Speakers bureau: MSD, UCB and Janssen Pharmaceuticals, Speakers bureau: UCB, MSD, Eli Lilly and Janssen Pharmaceuticals., Lars Erik Kristensen Grant/research support from: UCB, Biogen, Janssen Pharmaceuticals, and Novartis, Consultant for: Consultant for AbbVie, Amgen, Biogen, BMS, Celgene, Eli Lilly, Janssen Pharmaceuticals, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB Pharma., Speakers bureau: Pfizer, AbbVie, Amgen, UCB, BMS, Biogen, MSD, Novartis, Eli Lilly and Company, and Janssen Pharmaceuticals, Tanja Schjodt Jorgensen Consultant for: Abbvie, Roche, Novartis, UCB, Biogen, Eli Lilly., Speakers bureau: Abbvie, Roche, Novartis, UCB, Biogen, Eli Lilly., Lennart T.H. Jacobsson Consultant for: LJ has received lecture and consulting fees from Pfizer, Abbvie, Novartis, Eli-Lily and Janssen, Johan Askling Grant/research support from: Karolinska Institutet (JA) has or has had research agreements with the following pharmaceutical companies, mainly in the context of the ATRIS national safety monitoring programme for rheumatology biologicals: Abbvie, BMS, MSD, Eli Lilly, Pfizer, Roche, Samsung Bioepis, and UCB., Consultant for: Karolinska Institutet has received remuneration for JA participating in ad boards arranged by Lilly, Novartis, and Pfizer.

Background Ankylosing spondylitis (AS) is known to have strong familial aggregation, but studies quantifying the familial risk are few and have reached varying results. Familial risks reported from population-based studies range from 17 to 94 in first-degree relatives of AS cases.1 2 The heritability (i.e., the proportion of variance in AS liability explained by genetic variation) has been reported to >90%, based on very small studies of twins.3 Objectives To assess the familial aggregation and heritability of AS among all Swedish AS patients, and to investigate if risks vary by type of first-degree relative or sex. Methods We identified all patients with an ICD-10 code of AS in the Swedish National Patient Register (NPR) between 1 January 2001 and 31 December 2016. To increase validity, index patients were required to have two or more visits listing an AS diagnosis, and at least one of the visits being to a specialist in rheumatology or internal medicine. Each index patient was matched on sex and birth year to 50 general population controls from the Total Population Register. First-degree relatives of index patients and controls were identified through the Multi-generation register. Their disease status was ascertained from the NPR in a similar manner as for index patients. Familial risks of AS among first-degree relatives were calculated as odds ratios (ORs) with conditional logistic regression. Based on the familial risks, the corresponding heritability was calculated for a range of plausible prevalence estimates. Results We identified 13 795 patients that met the inclusion criteria. Of their siblings, parents, and children, 3.6, 2.3, and 2.1% respectively also had AS. The overall familial OR when having one affected relative was 19.4 (95% CI 18.1-20.8). The estimates were similar for relatives of different kinds (see table), but having more than one affected relative resulted in a higher risk (OR 68.0 (95% CI 51.3-90.1)). Heritability, estimated from sibling risk, was 77%. There were no clear-cut differences between the sexes, but women tended to have an elevated familial risk if the affected relative was female, and slightly lower heritability compared to males. These estimates can be considered as an upper limit of heritability, as shared environmental factors have not been taken into account in calculations. Conclusion Familial risks of AS were similar between different types of first-degree relatives, and no significant gender difference was seen on the heritability scale. Although high compared to most other diseases, the familial risks and heritability were lower than previous reports from other countries, though in line with earlier Swedish findings using in part the same data source. The heritability proposed here might still be an overestimate of the true influence of genetics on disease risk. Thus, efforts should also be directed at identifying other risk factors for AS that are not of genetic origin. References [1] Sundquist K, et al. Rheumatology2008;47(8):1199-202. [2] Geirsson AJ, Kristjansson K, Gudbjornsson B. Ann Rheum Dis2010;69(7):1346-8. [3] Brown MA, et al. Arthritis Rheum1997;40(10):1823-8. Disclosure of Interests None declared

Background:Women with rheumatoid arthritis (RA) are at increased risks of adverse pregnancy outcomes, especially preterm birth (PTB) and small for gestational age (SGA). However, the link between RA disease activity, type and timing of anti-rheumatic treatment, and the risk of these outcomes remains unclear.Objectives:To explore the associations between maternal RA and PTB/SGA in relation to disease activity and use of anti-rheumatic treatment before and during pregnancy.Methods:By linking national medical birth registers to prospective clinical rheumatology registers (CRRs) in Sweden (SRQ) and Denmark (DANBIO), we identified 1739 RA-pregnancies and 17390 control-pregnancies (matched 1:10 on maternal age, birth year, and parity) with delivery 2006-2018. From CRRs and prescribed drug registers, we collected information on RA disease activity (DAS28, CRP and HAQ-score) and anti-rheumatic drugs (biologics, conventional synthetic (cs)DMARDs and oral steroids) nine months before and during pregnancy. Using logistic regression, we estimated adjusted odds ratios (ORs) with 95% confidence intervals (CI) for PTB and SGA in RA-pregnancies vs. control-pregnancies overall, and stratified by disease activity and type of anti-rheumatic treatment before and during pregnancy. Apart from the matching variables we adjusted for body mass index, smoking, educational level and country.Results:Overall, RA-pregnancies were associated with increased ORs of PTB (1.92, 95% CI 1.56-2.35) and SGA (1.93, 95% CI 1.45-2.57). High maternal disease activity during pregnancy strengthened the associations with both PTB and SGA, whereas the ORs approached 1 for low disease activity (control-pregnancies constituting the reference), Table 1. Among RA-pregnancies with available information on DAS28-CRP (n=686, 39%), OR was 2.69 (95% CI 1.37-5.26) for PTB, and 3.39 (95% CI 1.43-8.06) for SGA, comparing DAS28-CRP >=3.2 vs.Table 1.Adjusted odds ratios (ORs)1 for PTB and SGA in RA-pregnancies in relation to disease activity and functional status during pregnancy vs. control pregnanciesPreterm birthSmall for gestational age1Pregnancies, nEvents,n (%)Adjusted OR(95% CI)Pregnancies, nEvents,n (%)Adjusted OR(95% CI)Control-pregnancies217312794 (5)1 (REF)17184418 (2)1(REF)All RA pregnancies21734144 (8)1.92 (1.56-2.35)172275 (4)1.93 (1.45-2.57)DAS28-CRP3,445926 (6)1.05 (0.64-1.72)45613 (3)0.96 (0.49-1.91)3.2-5.118217 (9)2.40 (1.40-4.11)18113 (7)3.13 (1.64-5.97)>5.1435 (12)2.77 (0.86-8.87)434 (9)4.59 (1.59-13.2)No information105096 (9)2.18 (1.71-2.78)104245 (4)2.06 (1.46-2.90)HAQ-score333819 (6)1.31 (0.79-2.16)3358 (2)0.93 (0.41-2.12)0.5-0.916615 (9)2.37 (1.34-4.19)1655 (3)1.50 (0.60-3.74)≥119619 (10)1.85 (1.06-3.24)19518 (9)3.70 (2.05-6.67)No information103491 (9)2.06 (1.60-2.64)102744 (4)1.98 (1.39-2.82)CRP, mg/L345521 (5)0.91 (0.55-1.51)45214 (3)1.09 (0.57-2.07)10-2919122 (11)2.58 (1.52-4.38)19012 (6)2.68 (1.38-5.22)≥30579 (16)4.59 (2.28-9.22)575 (9)4.12 (1.68-10.1)No information103192 (9)2.10 (1.64-2.70)102344 (4)2.05 (1.44-2.90)1Missingness on small for gestational age in 12 RA-pregnancies and 128 control-pregnancies 2Only among live births, i.e. stillbirths excluded. 3Maximum value any time during pregnancy 4Defined as DAS28-CRP without patient’s global health VASConclusion:During pregnancy, disease activity rather than treatment, appears to be the most important risk factor for PTB and SGA in RA. The findings highlight the importance of monitoring RA during pregnancy, especially in women receiving extensive anti-rheumatic treatment or with residual disease activity.Acknowledgements:The Nordic clinical rheumatology registers for allowing us to use their clinical data. We also would like to acknowledge the NordForsk and FOREUM, especially the patient representatives of the NordForsk collaboration.Disclosure of Interests:Karin Hellgren Consultant of: UCB, Anne Emilie Secher: None declared, Bente Glintborg Grant/research support from: Pfizer, Biogen and BMS, Ane Lilleoere Rom: None declared, Björn Gudbjornsson Speakers bureau: Amgen and Novartis, Brigitte Michelsen Consultant of: Novartis, Grant/research support from: Novartis, Fredrik Granath: None declared, Merete Lund Hetland Speakers bureau: Biogen, Celltrion, Janssen Biologics B.V, MSD, Pfizer, Samsung Biopis, Consultant of: Biogen, Celltrion, Janssen Biologics B.V, MSD, Pfizer, Samsung Biopis, Grant/research support from: AbbVie, Biogen, BMS, Eli Lilly Danmark A/S, Lundbeck Fonden, Pfizer, Roche, Sandoz, Novartis

Background:Spondyloarthritis (SpA) is known to have high familial aggregation, with a positive family history of SpA being a strong risk factor for disease development, in particular for ankylosing spondylitis (AS). Despite this well-known characteristic of the disease, whether family history is associated with disease prognosis and treatment outcome has been much less studied. Patient characteristics predicting response to tumour necrosis factor alpha inhibitors (TNFi) in SpA include age, sex and high disease activity, but whether family history is predictive of TNFi treatment outcomes remains unclear.Objectives:To assess if a family history of psoriatic arthritis (PsA), AS, or SpA in general is associated with a different drug survival and treatment response to TNFi in patients with AS and PsA.Methods:Patients diagnosed with AS (N=1688) or PsA (N=3216) starting their first TNFi treatment between January 2006 and December 2017 were identified in the Swedish Rheumatology Quality Register (SRQ). Disease activity measures were extracted from SRQ at treatment start and at 3 and 12 months of treatment. Data on demographics and comorbidities were available through linkage to other national registries. Multiple imputation was applied to address missing data. Family history was defined as having at least one first-degree relative diagnosed with AS, PsA or any form of SpA in the National Patient Register at start of first TNFi. Analyses were made for AS and PsA index patients separately. Kaplan-Meier plots were used to compare drug survival, and hazard ratios for drug discontinuation were estimated with Cox regression adjusting for age, sex, disease duration and baseline disease activity. The change in disease activity from baseline to 3 months of treatment, and the proportion of patients remaining on treatment at 12 months and reaching low disease activity (LDA) with BASDAI (for AS) and DAS28-CRP (for PsA), were analysed in linear regression adjusting for age, sex, disease duration and baseline disease activity.Results:A positive family history of AS was found in 14% of AS patients, and 12% of PsA patients had a family history of PsA. Characteristics such as age, sex and baseline disease activity were similar in AS patients with and without a family history of AS. Among PsA patients, those with a family history of PsA were to a larger extent female, with lower CRP but longer disease duration. No significant differences were seen in drug survival among patients with and without a family history of their respective disease (Figure 1), with hazard ratios for drug discontinuation of 1.03 (95% CI 0.84 to 1.27) in AS patients and 1.08 (95% CI 0.94 to 1.25) in PsA patients. Using family history of any form of SpA as exposure did not change this conclusion. The changes in disease activity at 3 months of treatment compared to baseline were similar between groups. At 12 months, 55.2% of AS patients with a family history were still on treatment and had a BASDAI corresponding to LDA, compared to 56.4% of AS patients without a family history. Among PsA patients, 38.7% of patients with a family history had reached DAS28-CRP LDA, compared to 42.6% for those without a family history. For both AS and PsA, these differences were non-significant.Conclusion:While family history of SpA is a strong predictor of disease development, family history was not found to affect neither TNFi drug survival nor treatment response in patients with AS and PsA in this register-based study.Figure 1.Survival plots for time to TNFi discontinuation in patients diagnosed with AS and PsA respectively, by family history statusDisclosure of Interests:Matilda Morin: None declared, Karin Hellgren Speakers bureau: KH has received speakers fee from Abbvie and UCB Nordic., Ulf Lindström: None declared, Thomas Frisell: None declared

There are increasing needs for detailed real-world data on rheumatic diseases and their treatments. Clinical register data are essential sources of information that can be enriched through linkage to additional data sources such as national health data registers. Detailed analyses call for international collaborative observational research to increase the number of patients and the statistical power. Such linkages and collaborations come with legal, logistic and methodological challenges. In collaboration between registers of inflammatory arthritides in Sweden, Denmark, Norway, Finland and Iceland, we plan to enrich, harmonise and standardise individual data repositories to investigate analytical approaches to multisource data, to assess the viability of different logistical approaches to data protection and sharing and to perform collaborative studies on treatment effectiveness, safety and health-economic outcomes. This narrative review summarises the needs and potentials and the challenges that remain to be overcome in order to enable large-scale international collaborative research based on clinical and other types of data.

BackgroundLymphomas comprise a heterogeneous group of malignant diseases with highly variable prognosis. Rheumatoid arthritis (RA) is associated with a twofold increased risk of both Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL). It is unknown whether treatment with biologic disease-modifying antirheumatic drugs (bDMARDs) affect the risk of specific lymphoma subtypes.MethodsPatients never exposed to (bionaïve) or ever treated with bDMARDs from 12 European biologic registers were followed prospectively for the occurrence of first ever histologically confirmed lymphoma. Patients were considered exposed to a bDMARD after having received the first dose. Lymphomas were attributed to the most recently received bDMARD.ResultsAmong 124 997 patients (mean age 59 years; 73.7% female), 533 lymphomas were reported. Of these, 9.5% were HL, 83.8% B-cell NHL and 6.8% T-cell NHL. No cases of hepatosplenic T-cell lymphoma were observed. Diffuse large B-cell lymphoma (DLBCL) was the most frequent B-cell NHL subtype (55.8% of all B-cell NHLs). The subtype distributions were similar between bionaïve patients and those treated with tumour necrosis factor inhibitors (TNFi). For other bDMARDs, the numbers of cases were too small to draw any conclusions. Patients with RA developed more DLBCLs and less chronic lymphocytic leukaemia compared with the general population.ConclusionThis large collaborative analysis of European registries has successfully collated subtype information on 533 lymphomas. While the subtype distribution differs between RA and the general population, there was no evidence of any modification of the distribution of lymphoma subtypes in patients with RA treated with TNFi compared with bionaïve patients.

Objective. Data on lymphoma risk in ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are scarce. This study was undertaken to assess the risk of lymphoma in AS and PsA overall and in relat ...

Objective Patients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas with a strong correlation with RA disease severity. Given the changes in RA therapy over recent decades, this study was undertaken to assess whether lymphoma risk remains increased, and if so, to explore risk predictors and lymphoma subtypes. Methods We identified 12,656 cases of incident RA in the Swedish Rheumatology Quality Register 1997-2012 and obtained information on therapy and inflammatory activity during the first year after diagnosis. Each patient was matched to 10 population comparator subjects. Through linkage to the Swedish Cancer Register, lymphomas, including subtypes, were identified. We assessed hazard ratios (HRs) using Cox regression. Results Overall, the HR for lymphoma was increased in RA, to 1.6 (95% confidence interval [95% CI] 1.2-2.1). Taking RA duration into account, risks did not appear to have declined over successive calendar years of RA diagnosis. Neither use of methotrexate the first year after RA diagnosis nor ever use of tumor necrosis factor inhibitors (TNFi) increased lymphoma risk (HR 0.9 [95% CI 0.4-1.9]). Use of oral corticosteroids the first year after RA diagnosis was associated with a reduced risk (HR 0.5 [95% CI 0.3-0.9]). Inflammatory activity during the first year after RA diagnosis did not predict future lymphoma risk. Chronic lymphocytic leukemia occurred less frequently, and Hodgkin's lymphoma occurred more frequently, in RA patients than in the general population. Conclusion The average lymphoma risk in recently diagnosed RA is similar in magnitude to that reported in historical cohorts. Standard antirheumatic treatment including TNFi did not predict future lymphoma risk. Distribution of lymphoma subtypes warrants further investigation.

To search for a relationship between ultra-rapid metabolism catalysed by cytochrome P450 2C9 (CYP2C9) and its genotypes.DNA from a Swedish ultra-rapid metaboliser patient [losartan metabolic ratio (MR)0.13] and three healthy Swedes with normal CYP2C9 activity and a MR of about 1 were assessed for variation in the CYP2C9 gene. Direct DNA sequencing was performed for all exons and exon-intron junctions and also for -2100 bp of the 5′-flanking regions of the CYP2C9 gene. This analysis revealed four intronic mutations [single nucleotide polymorphisms (SNPs) 1-4] in the three samples with normal MR while no variation was observed in the ultra-rapid metaboliser. PCR/restriction fragment length polymorphism and allele-specific PCR methods were subsequently developed to screen 85 Swedes and 128 Koreans without CYP2C9*2 or *3.We found a significant relationship between SNP 4 (IVS8-109AT) and CYP2C9 activity (χ²-test, p=0.011) in the Swedes. Twenty Swedes with the lowest MR were compared with 20 Swedes with the highest MR, revealing a strong association (p00.001) between SNP4 and higher MR. For homozygous SNP 1 (IVS1+83TC), SNP 2 (IVS2+73TC), and SNP 3 (IVS6+95AG), no phenotype and genotype relationships were found, but theMRwas generally higher among the Swedes compared to the Koreans (Mann-Whitney test, p0.05).We found that the SNP 4 IVS8-109T allele is associated with a higher CYP2C9 MR in healthy Swedish subjects, but further investigations need to be carried out to establish a molecular explanation for ultra-rapid CYP2C9- catalysed metabolism. Haplotype based on SNPs 1-4 did not seem to contribute to variation in the MR of the Korean subjects nor play a role in determining the MR of the Swedish ones.

The cytochrome P450 enzyme CYP2C9 metabolizes several important drugs, such as warfarin and oral antidiabetic drugs. The enzyme is polymorphic, and all known alleles, for example, CYP2C9*2 and*3, give decreased activity. Ultra-high activity of the enzyme has not yet been reported.We present a patient with Behçet's disease who required treatment with high doses of phenytoin. When fluconazole, a potent inhibitor of CYP2C9, was added to the treatment regimen, the patient developed ataxia, tremor, fatigue, slurred speech and somnolence, indicating phenytoin intoxication. On suspicion of ultra-high activity of CYP2C9, a phenotyping test for CYP2C9 with losartan was performed.The patient was shown to have a higher activity of CYP2C9 than any of the 190 healthy Swedish Caucasians used as controls.Our finding of an ultrarapid metabolism of losartan and phenytoin may apply to other CYP2C9 substrates, where inhibition of CYP2C9 may cause severe adverse drug reactions.

BACKGROUND & AIMS: Safety data on anti-tumor necrosis factor (TNF) treatment during pregnancy are limited. We studied the risk of birth defects after anti-TNF treatment in early pregnancy.METHODS: We collected data on 1,272,424 live-born infants identified from the Danish (2004-2012) and Swedish (2006-2012) population-based health registers. We determined the prevalence of birth defects among infants born to women with chronic inflammatory disease (inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, or psoriasis), with (n=683) and without (n=21,549) anti-TNF treatment during early pregnancy, and in the general population. We compared the risk of any major birth defect and birth defect by organ system for infants to women with chronic inflammatory disease, with and without anti-TNF treatment. Risks were presented as odds ratios (OR) with 95% confidence intervals (CI). We adjusted for maternal age, parity, smoking, body mass index, multiple gestation, country, and chronic inflammatory diagnosis.RESULTS: Birth defects were more prevalent among infants born to women with chronic inflammatory disease, regardless of anti-TNF treatment status, than in the general population (4.8% vs 4.2%). Birth defects occurred in 43 of the infants born to the 683 women who received anti-TNF treatment (6.3%) and 1019 of the infants born to women with chronic inflammatory disease (4.7%). The OR for any defect in women receiving anti-TNF therapy was 1.32 (95% CI, 0.93-1.82); the ORs for a cardiovascular defect was 1.60 (95% CI, 0.93-2.58) and the OR for a urinary defect was 2.22 (95% CI, 0.86-4.71), respectively.CONCLUSIONS: Based on an analysis of data from the health registries in Denmark and Sweden, women who receive anti-TNF agents during pregnancy have a slightly (but not significantly) higher risks of having children with birth defects. Although larger studies are needed, the heterogeneity of the observed birth defects also does not indicate a common etiology.

First Results Of A European Registries Collaborative Project To Describe The Spectrum Of Lymphomas Across Different Drug Treatment Groups In Rheumatoid Arthritis

Patients with rheumatoid arthritis (RA), in particular those with the most severe disease, are at increased risk of developing malignant lymphoma. Whether this increase is entirely a consequence of the RA disease and/or its treatment or is reflective of shared susceptibility to the two diseases remains unclear. We undertook this study to assess whether patients with RA are already at increased risk of lymphoma or of other cancers before the diagnosis of RA, and if the relative risk increases with time since RA diagnosis.Patients with incident RA (symptom duration1 year) (n = 6,745) registered in the Swedish Early Arthritis Registry from 1997 through 2006 were identified. For each patient, 5 general population controls were randomly matched by sex, age, marital status, and residence (n = 33,657). For all study subjects, inclusion in the nationwide Swedish Cancer Register in 1958-2006 was determined. Relative risks (RRs) (with 95% confidence intervals [95% CIs]) of lymphoma and of cancer overall, before and after diagnosis of RA, were estimated using conditional logistic regression and Cox regression, respectively.Before diagnosis of RA, there was no observed increase in the risk of lymphoma (RR [odds ratio] 0.67 [95% CI 0.37-1.23]) or other cancers (RR 0.78 [95% CI 0.70-0.88]). During the first 10 years following diagnosis of RA, the overall RR (hazard ratio) of lymphoma development was 1.75 (95 % CI 1.04-2.96).These findings indicate that overall, a history of cancer, including lymphoma, does not increase the risk of subsequent RA development. Shared susceptibility to RA and lymphoma may thus be of limited importance. In contrast, increased lymphoma risks were observed within the first decade following RA diagnosis.

Benefits and risks of corticosteroid treatment in rheumatoid arthritis (RA) are debated. Patients with RA are at increased risk of malignant lymphomas. In a large case-control study of risk factors for lymphoma in RA, it was recently reported that steroid treatment was associated with decreased lymphoma risk.To further assess the nature of the association between steroid treatment in RA and the risk of lymphoma.In a cohort of 74 651 patients with RA, 378 patients with lymphoma and 378 matched RA controls were identified, and information on inflammatory activity and different aspects of steroid treatment (duration, therapeutic strategy and mode of administration) abstracted from their medical records. Lymphomas were reclassified (WHO classification) and examined for Epstein-Barr virus. Relative risks were assessed as adjusted odds ratios (ORs) through conditional logistic regression.A total duration of oral steroid treatment of2 years was not associated with lymphoma risk (OR=0.87; 95% CI 0.51 to 1.5), whereas total treatment2 years was associated with a lower lymphoma risk (OR=0.43; 95% CI 0.26 to 0.72). RA duration at the initiation of oral steroids did not affect lymphoma risk. Intra-articular steroids were associated with a reduced lymphoma risk, but only when used as swift flare treatment (OR=0.22; 95% CI 0.13 to 0.37). Analyses by lymphoma subtype showed a reduced risk of diffuse large B-cell lymphoma (crude OR=0.59; 95% CI 0.37 to 0.94).In this RA population, use of steroids was associated with reduced lymphoma risk. Whether this association is a generic effect of steroids or specific to the studied population remains unknown.

Background Although family history of arthritis-related diseases is routinely collected as part of the work-up for rheumatoid arthritis (RA) in clinical practice, the interpretation of such information is often difficult since the relative importance of a family history of different arthritic and inflammatory diseases - beyond the established familial association of RA itself - is little known. Further, recent studies suggest that seropositive and seronegative RA have unique as well as shared genetic risk factors. However, with the exception of the HLA region, little is known about which genes or pathways are different between the two disease subsets. Objectives To assess the difference in predictive value of a family history of arthritis-related conditions for seropositive and seronegative RA, incidentally exploring the possible genetic difference of these disease subsets. Methods Register-based nested case-control study in the Swedish total population. RA was ascertained through the nationwide Patient register and the Swedish Rheumatology Register. First degree relatives were ascertained through the Swedish Multi-Generation Register. Autoimmune and arthritis-related diseases in relatives were assessed through the Patient register. Familial risks where calculated using conditional logistic regression with robust standard errors. Results Family history of seropositive RA was the strongest predictor of RA in the proband, regardless of serostatus. Statistically significant familial co-aggregation with RA was found for every arthritis-related disease under study, but risk increases varied widely (Table). With the exception of family history of RA itself, the difference in familial co-aggregation was very small for seropositive and seronegative RA. When combinations of family histories were examined, no arthritis-related disease added information beyond that provided by a family history of RA. Conclusions Seropositive and seronegative RA does not appear to differ much in the genetic risk factors that are shared with other arthritis-related diseases. Although a family history of (either of) several non-RA arthritis-related diseases is predictive of RA, the impact of others (e.g., osteoarthritis, unspecified athralgia) is negligible. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1720

Does Biological Therapy Alter the Lymphoma Risk or Distribution of Lymphoma Subtypes in Patients with ra?