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Objective Women with psoriatic arthritis (PsA) may have reduced tumor necrosis factor inhibitor (TNFi) effectiveness compared to men. We examined sex differences in treatment response and retention rates during 24 months of follow-up among patients with PsA initiating their first TNFi. Methods Data from patients with PsA across 13 European Spondyloarthritis Research Collaboration Network registries starting their first TNFi were pooled. Logistic regression was used to analyze the association between sex and treatment response using low disease activity (LDA) according to the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) (<3.2) at six months as the primary outcome. Analyses were adjusted for age, country, conventional synthetic disease-modifying antirheumatic drug treatment, and TNFi start year. Retention rates were explored using the Kaplan–Meier estimator. Results We analyzed the treatment response of 7,679 patients with PsA (50% women) with available data on LDA at six months. At baseline, women and men had similar characteristics, including mean DAS28-CRP (women vs men, 4.4 [SD 1.2] vs 4.2 [SD 1.2]), though patient-reported outcome measures were worse in women. At six months, 64% of women and 78% of men had LDA (relative risk [RR] 0.82; 95% confidence interval [CI] 0.80–0.84). This difference was similar after adjustment (RR 0.83; 95% CI 0.81–0.85). TNFi retention rates were evaluated in 17,842 patients with PsA. Women had significantly lower retention rates than men at all time points (women 79%, 64%, and 50% vs men 88%, 77%, and 64% at 6, 12, and 24 months, respectively). Conclusion Despite comparable disease characteristics at baseline, women with PsA have reduced treatment response and retention rates to their first TNFi, highlighting the need to consider sex differences in PsA research and management., Objective: Women with psoriatic arthritis (PsA) may have reduced tumor necrosis factor inhibitor (TNFi) effectiveness compared to men. We examined sex differences in treatment response and retention rates during 24 months of follow-up among patients with PsA initiating their first TNFi. Methods: Data from patients with PsA across 13 European Spondyloarthritis Research Collaboration Network registries starting their first TNFi were pooled. Logistic regression was used to analyze the association between sex and treatment response using low disease activity (LDA) according to the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) (<3.2) at six months as the primary outcome. Analyses were adjusted for age, country, conventional synthetic disease-modifying antirheumatic drug treatment, and TNFi start year. Retention rates were explored using the Kaplan–Meier estimator. Results: We analyzed the treatment response of 7,679 patients with PsA (50% women) with available data on LDA at six months. At baseline, women and men had similar characteristics, including mean DAS28-CRP (women vs men, 4.4 [SD 1.2] vs 4.2 [SD 1.2]), though patient-reported outcome measures were worse in women. At six months, 64% of women and 78% of men had LDA (relative risk [RR] 0.82; 95% confidence interval [CI] 0.80–0.84). This difference was similar after adjustment (RR 0.83; 95% CI 0.81–0.85). TNFi retention rates were evaluated in 17,842 patients with PsA. Women had significantly lower retention rates than men at all time points (women 79%, 64%, and 50% vs men 88%, 77%, and 64% at 6, 12, and 24 months, respectively). Conclusion: Despite comparable disease characteristics at baseline, women with PsA have reduced treatment response and retention rates to their first TNFi, highlighting the need to consider sex differences in PsA research and management.

Objectives In bio-naïve patients with PsA initiating a TNF inhibitor (TNFi), we aimed to identify baseline predictors of Disease Activity index for PsA in 28 joints (DAPSA28) remission (primary objective) and DAPSA28 moderate response at 6 months, as well as drug retention at 12 months across 13 European registries. Methods Baseline demographic and clinical characteristics were retrieved and the three outcomes investigated per registry and in pooled data, using logistic regression analyses on multiply imputed data. In the pooled cohort, selected predictors that were either consistently positive or negative across all three outcomes were defined as common predictors. Results In the pooled cohort (n = 13 369), 6-month proportions of remission, moderate response and 12-month drug retention were 25%, 34% and 63% in patients with available data (n = 6954, n = 5275 and n = 13 369, respectively). Five common baseline predictors of remission, moderate response and 12-month drug retention were identified across all three outcomes. The odds ratios (95% CIs) for DAPSA28 remission were: age, per year: 0.97 (0.96–0.98); disease duration, years (<2 years as reference): 2–3 years: 1.20 (0.89–1.60), 4–9 years: 1.42 (1.09–1.84), ≥10 years: 1.66 (1.26–2.20); men vs women: 1.85 (1.54–2.23); CRP of >10 vs ≤10 mg/l: 1.52 (1.22–1.89) and 1 mm increase in patient fatigue score: 0.99 (0.98–0.99). Conclusion Baseline predictors of remission, response and adherence to TNFi therapy were identified, of which five were common for all three outcomes, indicating that the predictors emerging from our pooled cohort may be considered generalizable from country level to disease level., Objectives: In bio-naïve patients with PsA initiating a TNF inhibitor (TNFi), we aimed to identify baseline predictors of Disease Activity index for PsA in 28 joints (DAPSA28) remission (primary objective) and DAPSA28 moderate response at 6 months, as well as drug retention at 12 months across 13 European registries. Methods: Baseline demographic and clinical characteristics were retrieved and the three outcomes investigated per registry and in pooled data, using logistic regression analyses on multiply imputed data. In the pooled cohort, selected predictors that were either consistently positive or negative across all three outcomes were defined as common predictors. Results: In the pooled cohort (n=13 369), 6-month proportions of remission, moderate response and 12-month drug retention were 25%, 34% and 63% in patients with available data (n=6954, n=5275 and n=13 369, respectively). Five common baseline predictors of remission, moderate response and 12-month drug retention were identified across all three outcomes. The odds ratios (95% CIs) for DAPSA28 remission were: age, per year: 0.97 (0.96-0.98); disease duration, years (<2 years as reference): 2-3 years: 1.20 (0.89-1.60), 4-9 years: 1.42 (1.09-1.84), ≥10 years: 1.66 (1.26-2.20); men vs women: 1.85 (1.54-2.23); CRP of >10 vs ≤10 mg/l: 1.52 (1.22-1.89) and 1mm increase in patient fatigue score: 0.99 (0.98-0.99). Conclusion: Baseline predictors of remission, response and adherence to TNFi therapy were identified, of which five were common for all three outcomes, indicating that the predictors emerging from our pooled cohort may be considered generalizable from country level to disease level.

Objective To investigate the prevalence of anxiety and depression among patients with inflammatory arthritis (IA) and evaluate the association of these mental health issues with self-management behaviour. Methods In this nationwide cross-sectional study, we analysed data from 12 713 adult Danish patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or spondyloarthritis (SpA). Patients received an electronic questionnaire covering sociodemographics, self-management behaviour and mental health status. Questionnaire data were linked to clinical data from the Danish Rheumatology database (DANBIO) and the Danish National Patient Registry. The prevalence of anxiety and depression (by the Hospital Anxiety and Depression Scale for Anxiety (HADS-A) and Depression (HADS-D)) was estimated separately for RA/PsA/SpA. The association between mental health status and low self-management behaviour (adherence to treatment, health activation and physical activity) was estimated using multivariable logistic regression, adjusting for age, sex, educational level and comorbidity. Results The prevalence of anxiety (HADS-A≥8) was highest for patients with SpA (34.5% (95% CI 32.4% to 36.6%)) and lowest for patients with RA (22.1% (95% CI 21.2% to 23.0%)), it was higher for women, younger (<55 years) and recently diagnosed (<3 years) patients and those with basic education. Similar prevalence estimates were found for depression. Across diagnoses, the clinically relevant symptoms of anxiety and depression (HADS≥8) were significantly associated with low self-management behaviour. Conclusion Patients with IA showed substantial levels of anxiety and depression. A statistically significant association between anxiety and depression and low self-management behaviour was identified. These findings call for a systematic approach to identifying mental health issues in patients with IA., OBJECTIVE: To investigate the prevalence of anxiety and depression among patients with inflammatory arthritis (IA) and evaluate the association of these mental health issues with self-management behaviour. METHODS: In this nationwide cross-sectional study, we analysed data from 12 713 adult Danish patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or spondyloarthritis (SpA). Patients received an electronic questionnaire covering sociodemographics, self-management behaviour and mental health status. Questionnaire data were linked to clinical data from the Danish Rheumatology database (DANBIO) and the Danish National Patient Registry. The prevalence of anxiety and depression (by the Hospital Anxiety and Depression Scale for Anxiety (HADS-A) and Depression (HADS-D)) was estimated separately for RA/PsA/SpA. The association between mental health status and low self-management behaviour (adherence to treatment, health activation and physical activity) was estimated using multivariable logistic regression, adjusting for age, sex, educational level and comorbidity. RESULTS: The prevalence of anxiety (HADS-A≥8) was highest for patients with SpA (34.5% (95% CI 32.4% to 36.6%)) and lowest for patients with RA (22.1% (95% CI 21.2% to 23.0%)), it was higher for women, younger (<55 years) and recently diagnosed (<3 years) patients and those with basic education. Similar prevalence estimates were found for depression. Across diagnoses, the clinically relevant symptoms of anxiety and depression (HADS≥8) were significantly associated with low self-management behaviour. CONCLUSION: Patients with IA showed substantial levels of anxiety and depression. A statistically significant association between anxiety and depression and low self-management behaviour was identified. These findings call for a systematic approach to identifying mental health issues in patients with IA.

Introduction Neoehrlichia mikurensis is a tick-borne bacterium that primarily causes disease in immunocompromised patients. The bacterium has been detected in ticks throughout Europe, with a 0%–25% prevalence. N. mikurensis infection presents unspecific symptoms, which can easily be mistaken for inflammatory disease activity. We aimed to determine the prevalence of N. mikurensis in rheumatological patients receiving tumour necrosis factor inhibitors (TNFi) and a cohort of healthy individuals. Materials and methods This retrospective cohort study included 400 rheumatological patients treated with TNFi and 400 healthy blood donors. Plasma samples were retrieved from the Danish Rheumatological Biobank and the Danish Blood Donor Study between 2015 and 2022. Age, sex, diagnosis and duration of TNFi treatment were recovered from the Danish Rheumatological Database, DANBIO. Data on age and sex were available for the blood donors. One plasma sample per individual was tested for N. mikurensis DNA-specific real-time PCR targeting the groEL gene. Results In the rheumatological patients, the median age was 61 years (IQR 55–68 years), 62% were women, and 44% had a diagnosis of seropositive rheumatoid arthritis. In total, 54% of the patients were treated with infliximab. The median time from TNFi initiation to blood sampling was 20 months (IQR, 5–60 months). N. mikurensis DNA was not detected in any samples from patients or blood donors. Conclusion N. mikurensis infection does not appear to represent a prevalent risk in Danish rheumatological patients receiving TNFi or in blood donors., INTRODUCTION: Neoehrlichia mikurensis is a tick-borne bacterium that primarily causes disease in immunocompromised patients. The bacterium has been detected in ticks throughout Europe, with a 0%-25% prevalence. N. mikurensis infection presents unspecific symptoms, which can easily be mistaken for inflammatory disease activity. We aimed to determine the prevalence of N. mikurensis in rheumatological patients receiving tumour necrosis factor inhibitors (TNFi) and a cohort of healthy individuals. MATERIALS AND METHODS: This retrospective cohort study included 400 rheumatological patients treated with TNFi and 400 healthy blood donors. Plasma samples were retrieved from the Danish Rheumatological Biobank and the Danish Blood Donor Study between 2015 and 2022. Age, sex, diagnosis and duration of TNFi treatment were recovered from the Danish Rheumatological Database, DANBIO. Data on age and sex were available for the blood donors. One plasma sample per individual was tested for N. mikurensis DNA-specific real-time PCR targeting the groEL gene. RESULTS: In the rheumatological patients, the median age was 61 years (IQR 55-68 years), 62% were women, and 44% had a diagnosis of seropositive rheumatoid arthritis. In total, 54% of the patients were treated with infliximab. The median time from TNFi initiation to blood sampling was 20 months (IQR, 5-60 months). N. mikurensis DNA was not detected in any samples from patients or blood donors. CONCLUSION: N. mikurensis infection does not appear to represent a prevalent risk in Danish rheumatological patients receiving TNFi or in blood donors.

OBJECTIVE: To investigate real-world effectiveness of tumor necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (axSpA) and the association with 1) treatment line (second and third TNFi-series) and 2) reason for withdrawal from the preceding TNFi (lack of efficacy (LOE) versus adverse events (AE)). METHODS: Prospectively collected routine care data from 12 European registries were pooled. Rates for 12-month drug retention and 6-month remission (Ankylosing Spondylitis Disease Activity Score C-reactive protein inactive disease (ASDAS-ID)) were assessed in second and third TNFi-series and stratified by withdrawal reason. RESULTS: We included 8254 s and 2939 third TNFi-series; 12-month drug retention rates were similar (71%). Six-month ASDAS-ID rates were higher for the second (23%) than third TNFi (16%). Twelve-month drug retention rates for patients withdrawing from the preceding TNFi due to AE versus LOE were similar for the second (68% and 67%) and third TNFi (both 68%), while for the second TNFi, rates were lower in primary than secondary non-responders (LOE < 26 versus ≥26 weeks) (58% versus 71%, p< 0.001). Six-month ASDAS-ID rates for the second TNFi were higher if the withdrawal reason was AE (27%) versus LOE (17%), p< 0.001, while similar for the third TNFi (19% versus 13%, p= 0.20). CONCLUSION: A similar proportion of axSpA patients remained on a second and third TNFi after one year, but with low remission rates for the third TNFi. Remission rates on the second TNFi (but not the third) were higher if the withdrawal reason from the preceding TNFi was AE versus LOE.

This is the first report comparing EULAR and national treatment recommendations for PsA patients across Europe, and the first this decade to compare ASAS-EULAR and national treatment recommendations in axSpA patients. An electronic survey was completed from October 2021-April 2022 by rheumatologists in 15 European countries. One and four countries followed all EULAR and ASAS-EULAR recommendations, respectively. Five countries had no national treatment recommendations for PsA and/or axSpA, but followed other regulations. In several countries, national treatment recommendations predated the most recent EULAR/ASAS-EULAR recommendations. Entry criteria for starting biologic/targeted synthetic disease-modifying anti-rheumatic drugs varied considerably. In several countries, for PsA patients with significant skin involvement, interleukin-17 inhibitors were not given preference. The positioning of Janus Kinase inhibitors differed and Phosphodiesterase-4 inhibitors were not in use/reimbursed in most countries. This study may motivate European countries to update their national treatment recommendations, to align them better with the latest international recommendations.

Objectives The positioning of secukinumab in the treatment of axial SpA (axSpA) and PsA is debated, partly due to a limited understanding of the comparative safety of the available treatments. We aimed to assess the risk of the key safety outcome infections during treatment with secukinumab and TNF inhibitors (TNFi). Methods Patients with SpA and PsA starting secukinumab or TNFi year 2015 through 2018 were identified in four Nordic rheumatology registers. The first hospitalized infection during the first year of treatment was identified through linkage to national registers. Incidence rates (IRs) with 95% CIs per 100 patient-years were calculated. Adjusted hazard ratios were estimated through Cox regression, with secukinumab as the reference. Several sensitivity analyses were performed to investigate confounding by indication. Results Among 7708 patients with SpA and 5760 patients with PsA, we identified 16 229 treatment courses of TNFi (53% bionaïve) and 1948 with secukinumab (11% bionaïve). For secukinumab, the first-year risk of hospitalized infection was 3.5% (IR 5.0; 3.9–6.3), compared with 1.7% (IR 2.3; 1.7–3.0) during 3201 courses with adalimumab, with the IRs for other TNFi lying in between these values. The adjusted HR for adalimumab, compared with secukinumab, was 0.58 (0.39–0.85). In sensitivity analyses, the difference from secukinumab was somewhat attenuated and in some analyses no longer statistically significant. Conclusion When used according to clinical practice in the Nordic countries, the observed first-year absolute risk of hospitalized infection was doubled for secukinumab compared with adalimumab. This excess risk seemed largely explained by confounding by indication., Objectives. The positioning of secukinumab in the treatment of axial SpA (axSpA) and PsA is debated, partly due to a limited understanding of the comparative safety of the available treatments. We aimed to assess the risk of the key safety outcome infections during treatment with secukinumab and TNF inhibitors (TNFi). Methods. Patients with SpA and PsA starting secukinumab or TNFi year 2015 through 2018 were identified in four Nordic rheumatology registers. The first hospitalized infection during the first year of treatment was identified through linkage to national registers. Incidence rates (IRs) with 95% CIs per 100 patient-years were calculated. Adjusted hazard ratios were estimated through Cox regression, with secukinumab as the reference. Several sensitivity analyses were performed to investigate confounding by indication. Results. Among 7708 patients with SpA and 5760 patients with PsA, we identified 16 229 treatment courses of TNFi (53% bionaïve) and 1948 with secukinumab (11% bionaïve). For secukinumab, the first-year risk of hospitalized infection was 3.5% (IR 5.0; 3.9–6.3), compared with 1.7% (IR 2.3; 1.7–3.0) during 3201 courses with adalimumab, with the IRs for other TNFi lying in between these values. The adjusted HR for adalimumab, compared with secukinumab, was 0.58 (0.39–0.85). In sensitivity analyses, the difference from secukinumab was somewhat attenuated and in some analyses no longer statistically significant. Conclusion. When used according to clinical practice in the Nordic countries, the observed first-year absolute risk of hospitalized infection was doubled for secukinumab compared with adalimumab. This excess risk seemed largely explained by confounding by indication.

Objective Precision medicine in rheumatoid arthritis (RA) requires a good understanding of treatment outcomes and often collaborative efforts that call for data harmonisation. We aimed to describe how harmonisation across study cohorts can be achieved and investigate how the observed proportions reaching remission vary across remission criteria, study types, disease-modifying antirheumatic drugs (DMARDs) and countries, and how they relate to other treatment outcomes. Methods We used data from eight existing large-scale, clinical RA registers and a pragmatic trial from Sweden, Denmark and Norway. In these, we defined three types of treatment cohorts; methotrexate monotherapy (as first DMARD), tumour necrosis factor inhibitors (TNFi) (as first biological DMARD) and rituximab. We developed a harmonised study protocol defining time points during 36 months of follow-up, collected clinical visit data on treatment response, retention, persistence and six alternative definitions of remission, and investigated how these outcomes differed within and between cohorts, by treatment. Results Cohort sizes ranged from ∼50 to 22 000 patients with RA. The proportions reaching each outcome varied across outcome metric, but with small to modest variations within and between cohorts, countries and treatment. Retention and persistence rates were high (>50% at 1 year), yet <33% of patients starting methotrexate or TNFi, and only 10% starting rituximab, remained on drug without other DMARDs added and achieved American Congress of Rheumatology/European Alliance of Associations for Rheumatology or Simplified Disease Activity Index remission at 1 year. Conclusion Harmonisation of data from different RA data sources can be achieved without compromising internal validity or generalisability. The low proportions reaching remission, point to an unmet need for treatment optimisation in RA.

Objective Evidence indicates reduced treatment effectiveness of TNFi in women with axial spondyloarthritis (axSpA) compared with men. We aimed to investigate sex differences in treatment response and retention rates over 24 months of follow-up in axSpA patients initiating their first TNFi. Methods Data from axSpA patients initiating a TNFi in 1 of 15 registries within EuroSpA collaboration were pooled. We investigated the association of sex with treatment response using logistic regression. The primary outcome was clinically important improvement (CII) at 6 months according to Ankylosing Spondylitis Disease Activity Score with C-reactive protein (CRP) (≥1.1 decrease). We adjusted for age, country and TNFi start year. A secondary outcome was retention rates over 24 months of follow-up assessed by Kaplan-Meier estimator. Results In total, 6451 axSpA patients with data on CII were assessed for treatment response; 2538 (39%) were women and 3913 (61%) were men. Women presented at baseline with lower CRP levels but had higher scores on patient-reported outcome measures. At 6 months, 53% of the women and 66% of the men had CII. Women had a lower relative risk of CII compared with men (0.81; 95% CI 0.77 to 0.84). This sex difference was similar in adjusted analysis (0.85; 95% CI 0.82 to 0.88). Retention rates were evaluated in 27 702 patients. The TNFi 6/12/24 months retention rates were significantly lower among women (79%/66%/53%) than men (88%/79%/69%). Conclusion Treatment response and retention rates are lower among women with axSpA initiating their first TNFi. Sex differences in treatment effectiveness were present regardless of the outcome measure used for treatment response, and differences in retention rates transpired early and increased as time progressed., Objective Evidence indicates reduced treatment effectiveness of TNFi in women with axial spondyloarthritis (axSpA) compared with men. We aimed to investigate sex differences in treatment response and retention rates over 24 months of follow-up in axSpA patients initiating their first TNFi. Methods Data from axSpA patients initiating a TNFi in 1 of 15 registries within EuroSpA collaboration were pooled. We investigated the association of sex with treatment response using logistic regression. The primary outcome was clinically important improvement (CII) at 6 months according to Ankylosing Spondylitis Disease Activity Score with C-reactive protein (CRP) (≥1.1 decrease). We adjusted for age, country and TNFi start year. A secondary outcome was retention rates over 24 months of follow-up assessed by Kaplan-Meier estimator. Results In total, 6451 axSpA patients with data on CII were assessed for treatment response; 2538 (39%) were women and 3913 (61%) were men. Women presented at baseline with lower CRP levels but had higher scores on patient-reported outcome measures. At 6 months, 53% of the women and 66% of the men had CII. Women had a lower relative risk of CII compared with men (0.81; 95% CI 0.77 to 0.84). This sex difference was similar in adjusted analysis (0.85; 95% CI 0.82 to 0.88). Retention rates were evaluated in 27 702 patients. The TNFi 6/12/24 months retention rates were significantly lower among women (79%/66%/53%) than men (88%/79%/69%). Conclusion Treatment response and retention rates are lower among women with axSpA initiating their first TNFi. Sex differences in treatment effectiveness were present regardless of the outcome measure used for treatment response, and differences in retention rates transpired early and increased as time progressed.

Background We aimed to describe the uptake of newer biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in psoriatic arthritis (PsA) in the Nordic countries and to compare their retention and effectiveness. Methods Patients with PsA starting a b/tsDMARD in 2012-2020 in five Nordic rheumatology registers were included. Uptake and patient characteristics were described, with comorbidities identified from linkages to national patient registries. One-year retention and 6-month effectiveness (proportions achieving low disease activity (LDA) on the Disease Activity Index for PSoriatic Arthritis based on 28-joint evaluation) for the newer b/tsDMARDs (abatacept/apremilast/ixekizumab/secukinumab/tofacitinib/ustekinumab) were compared with adalimumab through adjusted regression models stratified by treatment course (first, second/third, and fourth or more). Results In total, 5659 treatment courses with adalimumab (56% biologic-naïve) and 4767 courses with a newer b/tsDMARD (21% biologic-naïve) were included. The uptake of newer b/tsDMARDs increased from 2014 and plateaued in 2018. Patient characteristics appeared similar across treatments at treatment start. Adalimumab was more often used as the first course and newer b/tsDMARDs more often in biologic-experienced patients. Used as a second/third b/tsDMARD, the retention rate and the proportion achieving LDA were significantly better for adalimumab (rate 65%, proportion 59%) compared with abatacept (45%, 37%), apremilast (43%, 35%), ixekizumab (LDA only, 40%) and ustekinumab (LDA only, 40%), but not significantly different from other b/tsDMARDs. Conclusion Uptake of newer b/tsDMARDs occurred mainly in biologic-experienced patients. Regardless of mode of action, only a minority of patients starting a second or later b/tsDMARD course remained on drug and achieved LDA. Superior outcomes for adalimumab indicate that the positioning of newer b/tsDMARDs in the PsA treatment algorithm remains to be es

Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce., Funding Agencies|NORDFORSK [90825]; Swedish Research Council [2018-02803]; Swedish innovation Agency (Vinnova); Innovationsfonden; The Research Council of Norway; Region Stockholm-Karolinska Institutet; Region Vasterbotten (ALF); Danish Rheumatism Association [R194-A6956, A1923, A3037, A3570]; Swedish Brain Foundation; Nils and Bibbi Jensens Foundation; Knut and Alice Wallenberg Foundation; Margaretha af Ugglas Foundation; South-Eastern Heath Region of Norway; Health Research Fund of Central Denmark Region; Region of Southern Denmark; A.P. Moller Foundation for the Advancement of Medical Science; Colitis-Crohn Foreningen; Novo Nordisk Foundation [NNF15OC0016932]; Aase og Ejnar Danielsens Fond; Beckett-Fonden; Augustinus Fonden; Knud and Edith Eriksens Mindefond; Laege Sofus Carl Emil Friis and Hustru Olga Doris Friis Legat; Psoriasis Forskningsfonden; University of Aarhus; Region of Southern Denmarks PhD Fund [12/7725]; Department of Rheumatology, Frederiksberg Hospital; Research Council of Norway [229624, 223273]; South East and Western Norway Health Authorities; ERC AdG project SELECTionPREDISPOSED; Stiftelsen Kristian Gerhard Jebsen; Trond Mohn Foundation; Novo Nordisk Foundation; University of Bergen

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

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

ObjectivesTo assess how biological disease-modifying antirheumatic drugs (bDMARDs), glucocorticoids and disease activity affect risk of Staphylococcus aureus bacteraemia (SAB) in patients with rheumatoid arthritis (RA).MethodsIn a nationwide cohort of patients with RA from the DANBIO registry, we conducted a nested case-control study including first-time microbiologically verified SAB cases from 2010 to 2018 and incidence density matched controls (1:4 by sex, age). We interlinked Danish registries and identified antirheumatic treatments, RA-specific clinical characteristics, comorbidities and socioeconomic status. The relative risk of SAB was assessed by adjusted ORs with 95% CIs and number needed to harm (NNH) reflected the absolute risk.ResultsAmong 30 479 patients, we identified 180 SAB cases (incidence rate: 106.7/100 000 person-years) and matched 720 controls (57% women, median age 73 years, IQR: 65-80). Risk of SAB was increased in current (OR 1.8 (95% CI 1.1 to 3.2)) and former bDMARD users (OR 2.5 (95% CI 0.9 to 7.0)), and in current users of oral glucocorticoids 7.5 mg/day (OR 9.5 (95% CI 3.9 to 22.7)) (non-use as reference). ORs for moderate/high disease activity compared with remission were 1.6 (95% CI 0.8 to 3.3)/1.5 (95% CI 0.6 to 4.3). Risk was increased in patients with longstanding RA (>10 years vs 7.5 mg/day.ConclusionWe identified a dose-dependent increased risk of SAB in patients with RA currently using oral glucocorticoids. Daily use of >7.5 mg appeared to be a clinically relevant risk factor, whereas the absolute risk was low for bDMARDs. No clear impact of disease activity was found.

Aims In May 2020, a nationwide, web-based system for remote entry of patient-reported outcomes (PROs) in inflammatory rheumatic diseases was launched and implemented in routine care (DANBIO-from-home). After 1.5 years of use, we explored clinical characteristics of patients who did versus did not use the system, and the time to first entry of PROs. Methods All patients followed in DANBIO were informed about DANBIO-from-home by electronic invitations or when attending their clinic. Characteristics of patients who did/did not use DANBIO-from-home in the period after implementation were explored by multivariable logistic regression analyses including demographic and clinical variables (gender, age group, diagnosis, disease duration, use of biological disease-modifying agent (bDMARD), Health Assessment Questionnaire (HAQ), Patient Acceptable Symptom Scale (PASS)). Time from launch to first entry was presented as cumulative incidence curves by age group (<40/40-60/61-80/>80 years). Results Of 33 776 patients, 68% entered PROs using DANBIO-from-home at least once. Median (IQR) time to first entry was 27 (11-152) days. Factors associated with data entry in multivariate analyses (OR (95% CI)) were: female gender (1.19 (1.12 to 1.27)), bDMARD treatment (1.41 (1.33 to 1.50)), age 40-60 years (1.79 (1.63 to 1.97)), 61-80 years (1.87 (1.70 to 2.07), or age >80 years (0.57 (0.50 to 0.65)) (reference: age <40 years), lower HAQ (0.68 (0.65 to 0.71)) and PASS 'no' (1.09 (1.02 to 1.17). Diagnosis was not associated. Time to first entry of PROs was longest in patients <40 years of age (119 (24-184) days) and shortest in the 61-80 years age group (25 (8-139) days). Conclusion A nationwide online platform for PRO in rheumatology achieved widespread use. Higher age, male gender, conventional treatment and disability were associated with no use.

Objective To 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. Methods We 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). Results We 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). Conclusion PsA 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 f

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