Temporal trends in mortality in patients with systemic lupus erythematosus: a Danish population-based matched cohort study.

OBJECTIVE: Excess mortality has been demonstrated in patients with systemic lupus erythematosus (SLE) compared with the general population. We aimed to investigate the 5-year and 10-year all-cause mortality in patients with SLE compared with the general population in recent decades. METHODS: Nationwide population-based exposure matched cohort study. Incident cases of SLE diagnosed between 1996 and 2015 were identified using administrative health registries and followed until 2020, allowing for 5 and 10 years of follow-up. Patients with SLE were matched 1:5 on age and sex with individuals from the Danish general population. Time-to-event analyses were performed using the pseudo-observation approach. RESULTS: In total, 1351 incident cases of SLE and 6755 matched controls were identified. The crude risk difference (RD) for 5 years mortality decreased over the study period from 10.3% (95% CI 6.5-14.1%) to 4.6% (95% CI 1.4-7.8%) for patients with SLE compared with controls. The relative risk (RR) for 5-year mortality decreased similarly in the same period. Adjustment for comorbidities revealed lower RD and RR for mortality, but the decreasing trend remained. Crude and adjusted RD and RR for 10-year mortality did not change over calendar period. The 10-year RR was highest in young patients <50 years of age. CONCLUSION: Five-year mortality risk decreased over time for both patients with SLE and matched controls. However, excess 5-year mortality in the most recent calendar period and mortality late in the disease course remained. Continued focus on preventing disease progression and comorbidity is required.

Effectiveness of a novel digital patient education programme to support self-management of early rheumatoid arthritis: a randomised controlled trial.

OBJECTIVES: To evaluate the effectiveness of a novel digital patient education (PE) programme in improving self-management in patients newly diagnosed with rheumatoid arthritis (RA). METHODS: This was a parallel, open-label, two arms, randomised controlled trial with superiority design. Patients from five rheumatology clinics were randomised into digital PE (intervention) or face-to-face PE (control). The primary outcome was self-efficacy, measured by average difference in the Rheumatoid Arthritis Self-Efficacy (RASE) score from baseline to month 12. Secondary outcomes were RA knowledge, health literacy, adherence, and quality of life. Healthcare utilisation data and digital PE programme usage were recorded. Self-efficacy, knowledge, and health literacy data were analysed using mixed-effects repeated measures modelling; adherence using logistic regression, and quality of life and healthcare utilization using descriptive statistics with the Wilcoxon rank-sum test. RESULTS: Of the 180 patients randomised (digital PE, n = 89; face-to-face PE, n = 91), 175 had data available for analysis. Median age was 59.0 years, and 61% were women. The average difference in self-efficacy between groups from baseline to month 12 was significant by a -4.34 difference in RASE score, favouring the intervention group (95%CI -8.17 to -0.51; p= 0.026). RA knowledge, health literacy, and quality of life showed minor improvements over time but no difference between groups, except out-patient clinic contacts which were fewer in the intervention group. CONCLUSIONS: The findings suggest that digital PE is effective in improving self-efficacy and therefore self-management in patients with early RA. This intervention has potential to lower healthcare costs by decreasing out-patient clinic contacts. TRIAL REGISTRATION NUMBER: clinicaltrials.gov, NCT04669340.

Cancer risk with tocilizumab/sarilumab, abatacept, and rituximab treatment in patients with rheumatoid arthritis: a Danish cohort study.

OBJECTIVES: To investigate cancer risk in rheumatoid arthritis (RA) patients treated with tocilizumab/sarilumab, abatacept, or rituximab compared with those who received tumour necrosis factor inhibitors (TNFi) and compared with biological disease-modifying anti-rheumatic drugs (bDMARD) naïve RA patients. METHODS: Nationwide registry-based cohort study of RA patients initiating treatment with tocilizumab/sarilumab, abatacept, rituximab, TNFi, and bDMARD-naive patients their second type of conventional synthetic DMARD (csDMARD). Patients were identified in DANBIO and followed for cancer from 2006-2020. Patients could contribute multiple treatments, with person years (PYRS), deaths, and cancers allocated to each treatment group in a 'latest type of treatment' manner. Inverse probability of treatment weighting and weighted cause-specific Cox models were used to calculate hazard ratios (HRs) for cancer in each tocilizumab/sarilumab, abatacept, and rituximab group compared with TNFI and bDMARD naïve groups, respectively. RESULTS: In total, 21 982 treatment initiations, 96 475 PYRS, and 1423 cancers were identified. There were no statistically significant increased HRs for overall cancer in tocilizumab/sarilumab, abatacept, or rituximab treatment groups (HRs ranged from 0.7-1.1). More than five years of abatacept exposure showed a non-significantly increased HR compared with TNFi (HR 1.41, 95% confidence intervals CI 0.74-2.71). For hematological cancers, rituximab treatment showed non-significantly reduced HRs: vs TNFi (HR 0.09; 95%CI 0.00-2.06) and bDMARD-naïve (HR 0.13; 95%CI 0.00-1.89). CONCLUSION: Treatment with tocilizumab/sarilumab, abatacept, or rituximab in RA patients was not associated with increased risks of cancer compared with TNFi-treated and with bDMARD-naïve RA patients in a real-world setting.

Polyautoimmunity in Patients With Anticyclic Citrullinated Peptide Antibody-Positive and -Negative Rheumatoid Arthritis: a Nationwide Cohort Study From Denmark.

OBJECTIVE: This study aimed to compare the prevalence and incidence of polyautoimmunity between anticyclic citrullinated peptide antibody (anti-CCP)-positive and anti-CCP-negative patients with rheumatoid arthritis (RA). METHODS: In a nationwide register-based cohort study, patients with RA (disease duration ≤ 2 yrs) in the DANBIO rheumatology register with an available anti-CCP test in the Register of Laboratory Results for Research were identified. The polyautoimmunity outcome included 21 nonrheumatic autoimmune diseases identified by linkage between the Danish Patient Registry and Prescription Registry. The age- and sex-adjusted prevalence ratio (PR) was calculated by modified Poisson regression to estimate the prevalence at diagnosis in anti-CCP-positive vs anti-CCP-negative patients. The hazard ratio (HR) of polyautoimmunity within 5 years of entry into DANBIO was estimated in cause-specific Cox regression models. RESULTS: The study included 5839 anti-CCP-positive and 3799 anti-CCP-negative patients with RA. At first visit, the prevalence of prespecified polyautoimmune diseases in the Danish registers was 11.1% and 11.9% in anti-CCP-positive and anti-CCP-negative patients, respectively (PR 0.93, 95% CI 0.84-1.05). The most frequent autoimmune diseases were autoimmune thyroid disease, inflammatory bowel disease, and type 1 diabetes mellitus. During a mean follow-up of 3.5 years, only a few (n = 210) patients developed polyautoimmunity (HR 0.6, 95% CI 0.46-0.79). CONCLUSION: Polyautoimmunity as captured through the Danish National Patient Registry occurred in approximately 1 in 10 patients with RA at time of diagnosis regardless of anti-CCP status. In the years subsequent to the RA diagnosis, only a few and mainly anti-CCP-negative patients developed autoimmune disease.

Weight Loss for Patients With Gout and Concomitant Obesity: A Proof-of-Concept Randomized Trial.

OBJECTIVE: Despite scarce evidence, guidelines recommend weight loss as a management strategy for patients with gout. We investigated the effect of an intensive dietary intervention on body weight and clinical measures of gout severity in individuals with obesity and gout. METHODS: We conducted a 16-week randomized nonmasked parallel-group trial in Denmark, randomly assigning (one-to-one) individuals with obesity and gout to a low-energy diet or a control diet. The primary outcome was change in body weight. Key secondary outcomes were changes in serum urate (SU) level and visual analog scale-assessed pain and fatigue. RESULTS: Between December 1, 2018, and June 1, 2019, 61 participants were included in the intention-to-treat population and randomly assigned to the intensive diet group (n = 29) or control diet group (n = 32). Participants had a mean age of 60.3 (SD 9.9) years and mean body mass index of 35.6 (SD 5.0), and 59 (97%) were men. After 16 weeks, there was a significant difference in change in body weight between the diet and control groups (-15.4 vs -7.7 kg; difference -7.7 kg [95% confidence interval -10.7 to -4.7], P < 0.001). Despite results being potentially in favor of a low-energy diet, we could not confirm differences in SU level changes and fatigue between groups. No differences in pain and gout flares were observed between groups. No serious adverse events or deaths occurred during the trial. CONCLUSION: An intensive dietary intervention was safe and effectively lowered body weight in people with obesity and gout, but the weight loss did not directly translate into effects on SU level, fatigue, and pain.

Temporal trends in mortality in patients with rheumatoid arthritis: a Danish population-based matched cohort study.

OBJECTIVES: To investigate the 5-year all-cause mortality in patients with RA compared with the general population. METHODS: This was a nationwide population-based matched cohort study. RA patients diagnosed between 1996 and the end of 2015 were identified using administrative heath registries and followed until the end of 2020 allowing 5 years of follow-up. Patients with incident RA were matched 1:5 on year of birth and sex with non-RA individuals from the Danish general population. Time-to-event analyses were performed using the pseudo-observation approach. RESULTS: Compared with matched controls in 1996-2000, the risk difference for RA patients ranged from 3.5% (95% CI 2.7%, 4.4%) in 1996-2000 to -1.6% (95% CI -2.3%, -1.0%) in 2011-15, and the relative risk from 1.3 (95% CI 1.2, 1.4) in 1996-2000 to 0.9 (95% CI 0.8, 0.9) in 2011-15. The age-adjusted 5-year cumulative incidence proportion of death for a 60-year-old RA patient decreased from 8.1% (95% CI 7.3%, 8.9%) when diagnosed in 1996-2000 to 2.9% (95% CI 2.3%, 3.5%) in 2011-15, and for matched controls from 4.6% (95% CI 4.2%, 4.9%) to 2.1% (95% CI 1.9%, 2.4%). Excess mortality persisted in women with RA throughout the study period, while the mortality risk for men with RA in 2011-15 was similar to their matched controls. CONCLUSIONS: Enhanced improvement in mortality was found in RA patients compared with matched controls, but for sex-specific differences excess mortality was only persistent in women with RA.

Cancer risk in patients with rheumatoid arthritis treated with janus kinase inhibitors: a nationwide Danish register-based cohort study.

OBJECTIVES: We aimed to investigate the risk of first primary cancer in patients with RA treated with janus kinase inhibitors (JAKi) compared with those who received biologic DMARDs (bDMARDs) in a real-world setting. METHODS: We performed an observational cohort study using the nationwide registers in Denmark. Patients with RA aged 18+ years, without a previous cancer diagnosis, and who initiated treatment with JAKi or bDMARDs from 1 January 2017 to 31 December 2020 were followed for any cancer (except non-melanoma skin cancer). We applied inverse probability of treatment weighting (IPTW) to account for covariate differences between treatment groups. IPTW-generated weights were used with cause-specific Cox (CSC) models to calculate hazard ratios (HRs) for cancer incidence in JAKi-treated compared with bDMARD-treated patients with RA. RESULTS: We identified 875 and 4247 RA patients treated with JAKi and bDMARDs, respectively. The JAKi group contributed 1315 person years (PYRS) and 19 cancers, the bDMARD group contributed 8597 PYRS and 111 cancers, with corresponding crude incidence rates per 1000 PYRS of 14.4 and 12.9. Comparing the two groups using weighted CSC models, a HR of 1.41 (95% CI 0.76, 2.37, 95% CIs) was seen for JAKi- vs bDMARD-treated patients with RA. CONCLUSION: JAKi treatment in real-world patients with RA was not associated with a statistically significant increased risk of first primary cancer compared with those who received bDMARDs. However, several numerically increased risk estimates were detected, and a clinically important excess risk of cancer among JAKi recipients cannot be dismissed.

Evaluation of discontinuation for adverse events of JAK inhibitors and bDMARDs in an international collaboration of rheumatoid arthritis registers (the 'JAK-pot' study).

BACKGROUND: In a clinical trial setting, patients with rheumatoid arthritis (RA) taking the Janus kinase inhibitor (JAKi) tofacitinib demonstrated higher adverse events rates compared with those taking the tumour necrosis factor inhibitors (TNFi) adalimumab or etanercept. OBJECTIVE: Compare treatment discontinuations for adverse events (AEs) among second-line therapies in an international real-world RA population. METHODS: Patients initiating JAKi, TNFi or a biological with another mode of action (OMA) from 17 registers participating in the 'JAK-pot' collaboration were included. The primary outcome was the rate of treatment discontinuation due to AEs. We used unadjusted and adjusted cause-specific Cox proportional hazard models to compare treatment discontinuations for AEs among treatment groups by class, but also evaluating separately the specific type of JAKi. RESULTS: Of the 46 913 treatment courses included, 12 523 were JAKi (43% baricitinib, 40% tofacitinib, 15% upadacitinib, 2% filgotinib), 23 391 TNFi and 10 999 OMA. The adjusted cause-specific hazard rate of treatment discontinuation for AEs was similar for TNFi versus JAKi (1.00, 95% CI 0.92 to 1.10) and higher for OMA versus JAKi (1.11, 95% CI 1.01 to 1.23), lower with TNFi compared with tofacitinib (0.81, 95% CI 0.71 to 0.90), but higher for TNFi versus baricitinib (1.15, 95% CI 1.01 to 1.30) and lower for TNFi versus JAKi in patients 65 or older with at least one cardiovascular risk factor (0.79, 95% CI 0.65 to 0.97). CONCLUSION: While JAKi overall were not associated with more treatment discontinuations for AEs, subgroup analyses suggest varying patterns with specific JAKi, such as tofacitinib, compared with TNFi. However, these observations should be interpreted cautiously, given the observational study design.

Exploring disease-related and treatment-related issues and concerns experienced by adults with spondyloarthritis, inflammatory bowel disease and psoriasis to identify unmet needs: a qualitative clinical concept mapping study.

OBJECTIVES: Exploring patients' perspectives for significant factors of relevance in living with a chronic disease is important to discover unmet needs and challenges. The primary objective of this study was to explore disease-related and treatment-related issues and concerns experienced by adults with spondyloarthropathies (SpA) and associated diseases. As a secondary objective, we wanted to explore whether these factors were generic or disease dependent. DESIGN: We used group concept mapping (GCM), a validated qualitative method, to identify disease-related and treatment-related issues and concerns. Participants generated statements in the GCM workshops and organised them into clusters to develop concepts. Furthermore, participants rated each statement for importance from 1: 'not important at all' to 5: 'of great importance'. SETTING: Participants were recruited during routine care at the outpatient clinic at the hospitals in the period from May 2018 to July 2022. PARTICIPANTS: Eligible participants were adults ≥18 years and diagnosed with axial spondyloarthritis (AxSpA), psoriatic arthritis (PsA), psoriasis (PsO) or inflammatory bowel disease -split into Crohn's disease (CD) and ulcerative colitis (UC). RESULTS: 52 patients participated in the 11 workshops divided into groups according to their diagnosis. They created a total of 1275 statements that generated 10 AxSpA concepts, 7 PsA concepts, 7 PsO concepts, 10 CD concepts and 11 UC concepts. The highest rated concepts within each disease group were: AxSpA, 'lack of understanding/to be heard and seen by healthcare professionals' (mean rating 4.0); PsA, 'medication (effects and side effects)' (mean rating 3.8); PsO, 'social and psychological problems, the shame' (mean rating 4.0); CD, 'positive attitudes' (mean rating 4.3) and UC; 'take responsibility and control over your life' (mean rating 4.0). CONCLUSION: People with SpA and associated diseases largely agree on which concepts describe their disease-related and treatment-related issues and concerns with a few of them being more disease-specific.

Polyautoimmunity in patients with cutaneous lupus erythematosus: A nationwide sex- and age-matched cohort study from Denmark.

Background: Polyautoimmunity is defined as having 2 or more autoimmune diseases. Little is known about polyautoimmunity in patients with cutaneous lupus erythematosus (CLE). Objectives: To estimate prevalence and 5-year incidence of non-lupus erythematosus (LE) autoimmune diseases in patients with CLE. Methods: Patients with CLE were identified In the Danish National Patient Registry and each patient was age- and sex-matched with 10 general population controls. Outcome information on non-LE autoimmune diseases was obtained by register-linkage between Danish National Patient Registry and the National Prescription Register. The risk ratio (RR) for prevalent non-LE autoimmune disease at time of CLE diagnosis was calculated in modified Poisson regression; and hazard ratios (HRs) for incident non-LE autoimmune disease were estimated in Cox regression analyses. Results: Overall, 1674 patients with CLE had a higher prevalence of a non-LE autoimmune disease than the comparators (18.5 vs 7.9%; RR 2.4; 95% CI, 2.1 to 2.6). Correspondingly, the cumulative incidence of a non-LE autoimmune disease during 5 years of follow-up was increased for the patients with CLE: HR 3.5 (95% CI, 3.0 to 4.0). Limitations: Risk of detection and misclassification bias, mainly pertaining to the CLE group. Conclusion: Patients with CLE had higher prevalence and 5-year cumulative incidence of a non-LE autoimmune disease than the general population.

Tolerability and comparative effectiveness of TNF-, IL-17-, and IL-23(p19) inhibitors in psoriatic arthritis: A target trial emulation study.

OBJECTIVES: To compare tolerability and effectiveness of two different classes of biological Disease-Modifying Anti-Rheumatic Drugs (bDMARDs; interleukin (IL)-17- and IL-23(p19) inhibitors) relative to tumour necrosis factor inhibitors (TNFi) regarding the drug survival rates and treatment outcomes in patients with psoriatic arthritis (PsA). METHODS: We emulated a target trial on comparative effectiveness using observational data from a prospective cohort study based on the Parker Institute's PsA cohort - the PIPA cohort. All patients underwent interview and clinical examination programme at baseline and at follow-up visits at four and twelve months. The primary endpoint, drug survival, was assessed up to 12 months from baseline. We estimated hazard ratios from proportional hazards model and used propensity score adjustment in an attempt to deconfound and emulate a random treatment assignment. RESULTS: We included a total of 109 patients in the intention-to-monitor population at baseline initiating either TNFi (75 patients), IL17i (26 patients), or IL23(19)i (8 patients). Hazard ratios in the propensity adjusted model comparing IL-17i and IL-23(p19)i to TNFi were 1.36 (95% CI 0.59-3.14) and 0.56 (95% CI 0.10-3.24), respectively. TNFi and IL-17i had comparable effects regarding response rates and changes in clinical outcomes after 12 months, whereas IL-23(p19)i tended to perform better overall. CONCLUSION: No decisive differences between drugs were observed at group level regarding drug survival and clinical outcomes after 12 months. TNFi, IL-17i, and IL-23(p19)i may all be considered equally effective in the treatment of patients with PsA, advocating for investigating more in personalised treatment strategies.

Adherence to therapy of ixekizumab and secukinumab in psoriatic arthritis patients using first- or second-line IL-17A inhibitor treatment: A Danish population-based cohort study.

OBJECTIVES: To assess the effectiveness and tolerability of first- and second-line interleukin (IL)-17A inhibitor treatment in patients with psoriatic arthritis (PsA) from 2014 to 2021, using data from the Danish Rheumatology Registry (DANBIO) by investigating adherence to therapy. METHOD: PsA patients recorded in DANBIO who received a first- or second-line IL-17A inhibitor treatment were included in this study. All patients included had previously received ≥1 TNFi treatment. Baseline characteristics were analyzed in subgroups: first-line IL-17A inhibitor treatment and second-line IL-17A inhibitor treatment. adherence to therapy of first- or second-line IL-17A inhibitor treatments were reported as Kaplan-Meier plots. RESULTS: 534 patients were included in the study; first-line switchers: 534 (secukinumab: 510, ixekizumab: 24), second-line switchers: 102 (secukinumab: 35, ixekizumab: 67). Baseline characteristics showed a similar Health Assessment questionnaire (HAQ) and Visual Analogue Scale (VAS) pain. VAS global, Disease Assessment Score-28CRP and previous number of bDMARD treatments are similar with a greater value for second-line switchers. First-line ixekizumab treated patients present a younger age, greater percentage of females, a lower disease duration and a lower CRP value. Concomitant MTX use was greater for the first-line secukinumab treated patients. First- and second-line switchers had a similar adherence to therapy. Second-line secukinumab and second-line ixekizumab switchers showed a similar adherence to treatment. CONCLUSION: PsA patients receiving first- or second-line IL-17A inhibitors showed homogeneous baseline characteristics and similar adherence to therapy. Treatment failure of the first IL-17A inhibitor treatment should not preclude a second-line IL-17A inhibitor treatment.

Outcomes following SARS-CoV-2 infection in individuals with and without inflammatory rheumatic diseases: a Danish nationwide cohort study.

OBJECTIVE: In a setting with an extensive SARS-CoV-2 test strategy and availability of effective vaccines, we aimed to investigate if patients with inflammatory rheumatic diseases (IRD) face greater risk of contracting SARS-CoV-2 and have a worse prognosis of increased risk of hospitalisation, assisted ventilation and death compared with the general population. METHODS: This was a nationwide, population-based register study that compared outcomes of SARS-CoV-2 infection in Danish patients with IRD (n=66 840) with matched population controls (n=668 400). The study period was from March 2020 to January 2023. Cox regression analyses were used to calculate incidence rate ratios (IRRs) for SARS-CoV-2-related outcomes. RESULTS: We observed a difference in time to first and second positive SARS-CoV-2 test in patients with IRD compared with the general population (IRR 1.06, 95% CI 1.05 to 1.07) and (IRR 1.21, 95% CI 1.15 to 1.27). The risks of hospital contact with COVID-19 and severe COVID-19 were increased in patients with IRD compared with population controls (IRR 2.11, 95% CI 1.99 to 2.23) and (IRR 2.18, 95% CI 1.94 to 2.45). The risks of assisted ventilation (IRR 2.33, 95% CI 1.89 to 2.87) and COVID-19 leading to death were increased (IRR 1.98, 95% CI 1.69 to 2.33). Patients with IRD had more comorbidities compared with the general population. A third SARS-CoV-2 vaccination was associated with a reduced need for hospitalisation with COVID-19 and reduced the risk of death. CONCLUSION: Patients with IRD have a risk of SARS-CoV-2, which nearly corresponds to the general population but had a substantial increased risk of hospitalisation with COVID-19, severe COVID-19, requiring assisted ventilation and COVID-19 leading to death, especially in patients with comorbidities.

JAK-inhibitors and risk on serious viral infection, venous thromboembolism and cardiac events in patients with rheumatoid arthritis: A protocol for a prevalent new-user cohort study using the Danish nationwide DANBIO register.

Janus Kinase inhibitors (JAKis) are targeted synthetic disease-modifying antirheumatic drugs and represent an important alternative to treat patients with moderate to high rheumatoid arthritis (RA) disease activity. Safety concerns associated with increased risk for venous thromboembolism (VTE), serious viral infection, and, more recently, major adverse cardiovascular events (MACE) in JAKi users have emerged worldwide. However, as the exact mechanisms to explain these safety concerns remain unclear, the increased risk of VTE, MACE, and serious viral infection in JAKi users is heavily debated. In light of the need to enrich the safety profile of JAKis in real-world data, we aim to quantify the incidence and risk of MACE, VTE, and serious viral infections in RA patients registered in the Danish DANBIO registry, a nationwide registry of biological therapies used in rheumatology. Therefore, we will conduct a population-based cohort study using a prevalent new-user design. We will identify all RA patients in the DANBIO, ≥ 18 years old, receiving a JAKi or a tumor necrosis factor α inhibitor (TNF-αi) from January 2017 to December 2022. Prevalent and new users of JAKis will be matched to TNF-αi comparators with similar exposure history using time-conditional propensity scores (TCPS). We will describe the cumulative incidence of the outcomes (VTE, MACE, serious viral infection) in each exposure group (JAKi users; TNF-αi users), stratified by outcome type. Additionally, the Aalen-Johansen method will be used to estimate the time-to-event survival function stratified by outcome type. We will also estimate the hazard ratio (HR) with 95% confidence interval (CI) of each outcome in both exposure groups using the time-dependent Cox proportional hazards model. Results will enrich the safety profile of JAKis in real-world data.

Absolute risk estimation of new-onset proteinuria in patients with systemic lupus erythematosus: a Danish nationwide cohort study.

OBJECTIVES: Kidney involvement and medical compliance are frequent challenges in systemic lupus erythematosus (SLE). Additional data reporting such as absolute risk estimates may strengthen risk stratification and compliance. This study provides absolute risk estimations of risk of new-onset proteinuria among SLE patients. METHODS: Danish SLE centres provided clinical data on first time observations of proteinuria and other clinical parameters listed in the 1997 American College of Rheumatology Classification Criteria for SLE. Time from first occurring non-renal manifestation to new-onset proteinuria or censoring defined time at risk. Multivariate Cox-regression models were used to identify risk factors for new-onset proteinuria and to calculate risk of proteinuria stratified by risk factor debut age, duration, and sex. RESULTS: The patient population consisted of 586 patients with SLE, mainly Caucasian (94%) women (88%), mean age at inclusion of 34.6 years (standard deviation, SD=14.4 years), observed for a mean of 14.9 years (SD=11.2 years). The cumulative prevalence of proteinuria was 40%. Discoid rash, HR =0.42 (p=0.01) and lymphopenia HR=1.77 (p=0.005) were associated with new-onset proteinuria. Male patients with lymphopenia had the highest predictive risks of proteinuria with a 1-, 5- and 10-year risk of proteinuria ranging from 9-27%, 34-75% and 51-89%, depending on the age at presentation (debut at 20, 30, 40 or 50 years). The corresponding risk profiles for women with lymphopenia were 3-9%, 8-34% and 12-58%, respectively. CONCLUSIONS: Large differences in absolute risk estimates for new-onset proteinuria were identified. The differences may aid risk stratification and patient compliance among high-risk individuals.

Lymphocyte activation gene 3 is increased and affects cytokine production in rheumatoid arthritis.

BACKGROUND: Lymphocyte activation gene-3 (LAG-3) inhibits T cell activation and interferes with the immune response by binding to MHC-II. As antigen presentation is central in rheumatoid arthritis (RA) pathogenesis, we studied aspects of LAG-3 as a serological marker and mediator in the pathogenesis of RA. Since Galectin-3 (Gal-3) is described as an additional binding partner for LAG-3, we also aimed to study the functional importance of this interaction. METHODS: Plasma levels of soluble (s) LAG-3 were measured in early RA patients (eRA, n = 99) at baseline and after 12 months on a treat-to-target protocol, in self-reportedly healthy controls (HC, n = 32), and in paired plasma and synovial fluid (SF) from chronic RA patients (cRA, n = 38). Peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) were examined for LAG-3 expression by flow cytometry. The binding and functional outcomes of LAG-3 and Gal-3 interaction were assessed with surface plasmon resonance (SPR) and in cell cultures using rh-LAG3, an antagonistic LAG-3 antibody and a Gal-3 inhibitor. RESULTS: Baseline sLAG-3 in the plasma was increased in eRA compared to HC and remained significantly elevated throughout 12 months of treatment. A high level of sLAG-3 at baseline was associated with the presence of IgM-RF and anti-CCP as well as radiographic progression. In cRA, sLAG-3 was significantly increased in SF compared with plasma, and LAG-3 was primarily expressed by activated T cells in SFMCs compared to PBMCs. Adding recombinant human LAG-3 to RA cell cultures resulted in decreased cytokine secretion, whereas blocking LAG-3 with an antagonistic antibody resulted in increased cytokine secretion. By SPR, we found a dose-dependent binding between LAG-3 and Gal-3. However, inhibiting Gal-3 in cultures did not further change cytokine production. CONCLUSIONS: sLAG-3 in the plasma and synovial fluid is increased in both early and chronic RA patients, particularly in the inflamed joint. High levels of sLAG-3 are associated with autoantibody seropositivity and radiographic progression in eRA, and LAG-3 plays a biologically active role in cRA by decreasing inflammatory cytokine production. This functional outcome is not affected by Gal-3 interference. Our results suggest that LAG-3 is a faceted regulator of inflammation in early and chronic RA.

Predicting successful biologics tapering in patients with inflammatory arthritis: Secondary analyses based on the BIOlogical Dose OPTimisation (BIODOPT) trial.

AIMS: To evaluate predictors for successful biologic tapering among patients with inflammatory arthritis using baseline characteristics from the BIODOPT trial. METHODS: Adult patients with rheumatoid arthritis, psoriatic arthritis or axial spondyloarthritis on stable biologic dose and in low disease activity ≥12 months were enrolled. Participants were randomized (2:1) to disease activity-guided biologic tapering or continuation of baseline biologic. Patients achieving successful tapering reduced their biologic dose by ≥50%, had no protocol deviations and were in low disease activity at 18 months. Modified Poisson regression with robust variance estimator was applied. RESULTS: In total, 142 patients were randomized to tapering (n = 95) or control (n = 47). Successful tapering was achieved by 32 and 2%, respectively. Tapering group was the only statistically significant independent predictor for successful tapering, risk ratio (RR): 14.0 (95% confidence interval [CI]: 1.9 to 101.3, P = .009). However, higher Short Form Health Survey 36 mental component summary (SF-36 MCS) was observed to be a predictor of potential importance, RR: 1.06 (95% CI: 0.99 to 1.13, P = .097). When limiting the analyses to the tapering group only, none of the baseline variables were statistically significant independent predictors but SF-36 MCS was still considered to be of potential importance, RR: 1.05 (95% CI: 0.99 to 1.12, P = .098). CONCLUSION: Successful tapering is a reachable target for 1 in 3 patients with inflammatory arthritis who are interested in reducing their biological therapy. No statistically significant predictors (besides allocation to tapering) were identified. Future research on mental health and tapering is encouraged.

Effect of a 12-week high-intensity exercise intervention: a comparison of cardiac exercise adaptations during biological disease-modifying antirheumatic drug treatment (TNF inhibitors vs IL-6 signalling inhibitors) in patients with rheumatoid arthritis - study protocol for a randomised controlled trial.

INTRODUCTION: The chronic inflammatory state in rheumatoid arthritis (RA) augments the risk of cardiovascular disease (CVD), with pro-inflammatory cytokines tumour necrosis factor (TNF) and interleukin 6 (IL-6) playing a vital role. Consequently, biological disease-modifying antirheumatic drugs (bDMARDs) may attenuate that risk. IL-6 is also a myokine, secreted from exercising skeletal muscles, where IL-6 exhibits anti-inflammatory effects that may ameliorate the risk of CVD. In healthy humans treated with IL-6 signalling inhibitors (IL-6i), exercise induced loss of visceral fat mass and cardiac adaptations were abolished. We hypothesise that IL-6 signalling inhibition will impair the cardiac and metabolic adaptions to exercise training compared with TNF inhibition in RA patients. METHODS AND ANALYSIS: 80 RA patients treated with IL-6i (n=40) or TNF inhibitors (n=40) are included in a 12-week randomised investigator-blinded 4×4 min high-intensity interval training (HIIT) study. Patients are stratified for medical treatment and sex and allocated 1:1 to an exercise or a no exercise control group (four groups). The supervised exercise intervention comprises 3 weekly HIIT sessions on an ergometer bicycle. The primary outcome is the change in left ventricular mass (LVM), and key secondary outcome is change in visceral fat mass. Both outcomes are measured by MRI. Primary statistical analysis will evaluate LVM at follow-up in a regression model. Intention-to-treat and per protocol analyses will be conducted. The latter necessitates a minimum attendance rate of 80%, adherence to bDMARDs treatment of ≥80% and minimum 8 min (50%) of maximal heart rate above 85% per session. ETHICS AND DISSEMINATION: The study has been approved by the Capital Region Ethics Committee (H-21010559 amendments 86424, 87463 and 88044) and the Danish Medicines Agency (2021-b005287-21). The trial will follow ICH-GCP guidelines. Regardless of outcome, results will be published in relevant peer-reviewed journals. TRIAL REGISTRATION NUMBERS: Eudra-CT: 2021-b005287-21 and NCT05215509.

VEXAS syndrome as a cause of debilitating fatigue and intermittent fever.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly discovered complicated autoinflammatory syndrome associated with haematological and rheumatological manifestations, recognized for the first time in 2020. In this case report, we describe the first case of VEXAS syndrome in the North Denmark Region. A 76-year-old male was briefly admitted with COVID-19 and a myriad of symptoms including jaw pain, arthralgia, skin rash, malaise, intermittent fever and weight loss. After a prolonged diagnostic evaluation, VEXAS syndrome was suspected and confirmed with the presence of a mutated ubiquitin-like modifier activating enzyme 1 (UBA1) gene.