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.

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.

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.

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.

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.

Effectiveness of TNF-inhibitors, abatacept, IL6-inhibitors and JAK-inhibitors in 31 846 patients with rheumatoid arthritis in 19 registers from the 'JAK-pot' collaboration.

BACKGROUND: JAK-inhibitors (JAKi), recently approved in rheumatoid arthritis (RA), have changed the landscape of treatment choices. We aimed to compare the effectiveness of four current second-line therapies of RA with different modes of action, since JAKi approval, in an international collaboration of 19 registers. METHODS: In this observational cohort study, patients initiating tumour necrosis factor inhibitors (TNFi), interleukin-6 inhibitors (IL-6i), abatacept (ABA) or JAKi were included. We compared the effectiveness of these treatments in terms of drug discontinuation and Clinical Disease Activity Index (CDAI) response rates at 1 year. Analyses were adjusted for patient, disease and treatment characteristics, including lines of therapy and accounted for competing risk. RESULTS: We included 31 846 treatment courses: 17 522 TNFi, 2775 ABA, 3863 IL-6i and 7686 JAKi. Adjusted analyses of overall discontinuation were similar across all treatments. The main single reason of stopping treatment was ineffectiveness. Compared with TNFi, JAKi were less often discontinued for ineffectiveness (adjusted HR (aHR) 0.75, 95% CI 0.67 to 0.83), as was IL-6i (aHR 0.76, 95% CI 0.67 to 0.85) and more often for adverse events (aHR 1.16, 95% CI 1.03 to 1.33). Adjusted CDAI response rates at 1 year were similar between TNFi, JAKi and IL-6i and slightly lower for ABA. CONCLUSION: The adjusted overall drug discontinuation and 1 year response rates of JAKi and IL-6i were similar to those observed with TNFi. Compared with TNFi, JAKi were more often discontinued for adverse events and less for ineffectiveness, as were IL-6i.

COVID-19 infection and hospitalization risk according to vaccination status and DMARD treatment in patients with rheumatoid arthritis.

OBJECTIVES: The objectives of this study were to investigate the incidence of COVID-19 hospitalization in unvaccinated and vaccinated patients with RA compared with matched controls, and in patients with RA according to DMARD treatment. METHODS: This was a Danish nationwide matched-cohort study from January to October 2021. Patients with RA were identified in the DANBIO register and matched 1:20 with individuals from the general population on age, sex, and vaccination status. Primary and secondary outcomes were COVID-19 hospitalization (Danish National Patient Register) and first-time positive SARS-CoV-2 PCR test (Danish COVID-19 Surveillance Register), respectively. Stratified by vaccination status, incidence rates (IRs) per 1000 person years (PYs) and comorbidity-adjusted hazard ratios (aHRs) in cause-specific Cox models were calculated with 95% confidence intervals. RESULTS: In total, 28 447 unvaccinated patients and 568 940 comparators had IRs for COVID-19 hospitalization of 10.4 (8.0-13.4) and 4.7 (4.3-5.1) per 1000 PYs, respectively (aHR 1.88, 1.44-2.46). When fully vaccinated, corresponding IRs were 0.9 (0.5-1.6) and 0.5 (0.4-0.6) per 1000 PYs (aHR 1.94, 1.03-3.66). Unvaccinated RA patients had an aHR of 1.22 (1.09-1.57) for testing positive for SARS-CoV-2 and 1.09 (0.92-1.14) among vaccinated RA patients. Vaccinated rituximab-treated patients had increased crude IR of COVID-19 hospitalization compared with conventional DMARD-treated patients. CONCLUSION: The incidence of COVID-19 hospitalization was increased for both unvaccinated and vaccinated patients with RA compared with controls. Importantly, the parallel decreasing risk for patients with RA suggests a comparable relative benefit of vaccination in most patients.

Incidence and severeness of COVID-19 hospitalization in patients with inflammatory rheumatic disease: a nationwide cohort study from Denmark.

OBJECTIVES: To estimate the incidence of COVID-19 hospitalization in patients with inflammatory rheumatic disease (IRD); in patients with RA treated with specific DMARDs; and the incidence of severe COVID-19 infection among hospitalized patients with RA. METHODS: A nationwide cohort study from Denmark between 1 March and 12 August 2020. The adjusted incidence of COVID-19 hospitalization was estimated for patients with RA; spondyloarthritis including psoriatic arthritis; connective tissue disease; vasculitides; and non-IRD individuals. Further, the incidence of COVID-19 hospitalization was estimated for patients with RA treated and non-treated with TNF-inhibitors, HCQ or glucocorticoids, respectively. Lastly, the incidence of severe COVID-19 infection (intensive care, acute respiratory distress syndrome or death) among hospital-admitted patients was estimated for RA and non-IRD sp - individudals. RESULTS: Patients with IRD (n = 58 052) had an increased partially adjusted incidence of hospitalization with COVID-19 compared with the 4.5 million people in the general population [hazard ratio (HR) 1.46, 95% CI: 1.15, 1.86] with strongest associations for patients with RA (n = 29 440, HR 1.72, 95% CI: 1.29, 2.30) and vasculitides (n = 4072, HR 1.82, 95% CI: 0.91, 3.64). There was no increased incidence of COVID-19 hospitalization associated with TNF-inhibitor, HCQ nor glucocorticoid use. COVID-19 admitted patients with RA had a HR of 1.43 (95% CI: 0.80, 2.53) for a severe outcome. CONCLUSION: Patients with IRD were more likely to be admitted with COVID-19 than the general population, and COVID-19 admitted patients with RA could be at higher risk of a severe outcome. Treatment with specific DMARDs did not affect the risk of hospitalization.

Methotrexate and risk of interstitial lung disease and respiratory failure in rheumatoid arthritis: a nationwide population-based study.

OBJECTIVES: MTX is the most commonly recommended DMARD for first-line treatment of RA, however, it has been hypothesized to cause lung disease as an adverse effect. We investigated the risk of interstitial lung disease (ILD) and acute and chronic respiratory failure in persons with RA treated with MTX and other medications. METHODS: From the Danish National Patient Register (NPR) and the DANBIO register for rheumatic diseases, we retrieved data on 30 512 persons with RA registered in 1997-2015. Information on ILD and respiratory failure was obtained from the NPR. Information on age and sex for all Danish citizens was obtained from the Danish Civil Registration System. MTX and other medication purchases were retrieved from the Danish Prescription Registry. Associations between MTX and lung disease outcomes were analysed in Cox regression models with adjustment for age, calendar time, sex and other medications. Standardized incidence ratios (SIRs) of lung disease were calculated to compare the RA population with the general population. RESULTS: There was no increased risk of lung disease with MTX treatment [one or more purchases compared with no purchases; HR 1.00 (95% CI 0.78, 1.27) for ILD and 0.54 (95% CI 0.43, 0.67) for respiratory failure] at the 5 year follow-up. The SIR was three to four times higher for ILD in MTX-treated persons with RA, but similar to the whole RA population compared with the background population. CONCLUSION: Persons with RA had an increased risk of ILD compared with the general population, but there was no further increased risk associated with MTX treatment.

Is pain associated with premature mortality in patients with psoriatic arthritis? A nested case-control study using the DANBIO Register.

OBJECTIVES: It has been hypothesized that the presence of chronic pain causes excess mortality. Since chronic pain is prevalent among patients with PsA this potential association should be explored. We aimed to investigate whether higher cumulative pain intensity is associated with an excess mortality risk in patients with PsA. METHODS: A nested case-control study using data from the nationwide DANBIO Register (Danish Database for Biological Therapies in Rheumatology) Register and Danish healthcare registers. Cases were patients who died and corresponding to the date of death, matched on sex, year of birth and calendar period at the time of death with up to five controls. Exposure of interest was mean pain intensity reported during the time followed in routine rheumatology practice. Pain intensity was measured using a visual analogue scale from 0 to 100 and conditional logistic regression was used to calculate odds of mortality per 5 unit increase in pain while adjusting for confounders. RESULTS: The cohort consisted of 8019 patients. A total of 276 cases were identified and matched with 1187 controls. Higher mean pain intensity was associated with increased odds of mortality [odds ratio 1.06 (95% CI 1.02, 1.10)] in the crude model, but there was no association [odds ratio 0.99 (95% CI 0.95, 1.03)] when adjusting for additional confounders. Factors shown to increase the odds of mortality were recent glucocorticoid use, concomitant chronic obstructive pulmonary disease, diabetes mellitus, cancer and cardiovascular disease. CONCLUSION: These results indicate that experienced pain in itself is not associated with premature mortality in patients with PsA. However, recent glucocorticoid use and concurrent comorbidities were.

Risk of solid cancers overall and by subtypes in patients with psoriatic arthritis treated with TNF inhibitors - a Nordic cohort study.

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.

Increased cancer risk in patients with cutaneous lupus erythematosus and systemic lupus erythematosus compared with the general population: A Danish nationwide cohort study.

OBJECTIVES: To investigate if patients with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) have an increased risk of cancer compared with the general population, and furthermore to identify specific cancer types associated with increased risk. METHODS: This is an observational cohort study of 5310 patients with CLE or SLE identified in the Danish National Patient Register from 1 January 1995 to 31 December 2014. The cohort was followed up for cancer by linkage to the Danish Cancer Registry. Based on the age, sex, and calendar specific cancer rates of the general population of Denmark, standardised incidence ratios (SIRs) were calculated. RESULTS: The patients with CLE or SLE were followed for 40.724 person-years, each group's average duration of follow-up being 6.9 and 8.1 years. The SIR for overall cancer (except non-melanoma skin cancer (NMSC)) was increased in patients with CLE 1.35 (95%CI 1.15 to 1.58) and patients with SLE 1.45 (95%CI 1.30 to 1.62). Both groups had high risks of hematological - including a 3-4-fold increased risk of non-Hodgkin lymphoma -, pancreatic, and lung cancers. Several cancers associated with oncogenic viruses as liver and tongue/mouth/pharynx were increased in the SLE group, while the risk of ovarian cancer was increased 2-4-fold only in the CLE group. CONCLUSION: The overall risk of cancer was significantly increased in both patients with CLE and SLE. SIRs for hematological, pancreatic and lung cancers were elevated in both groups. Extra awareness of cancer in patients with SLE and patients with CLE should be considered.

Risk of neuroinflammatory events in arthritis patients treated with tumour necrosis factor alpha inhibitors: a collaborative population-based cohort study from Denmark and Sweden.

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

Incidence and time trends of joint surgery in patients with psoriatic arthritis: a register-based time series and cohort study from Denmark.

OBJECTIVE: To investigate time-trends and cumulative incidence of joint surgery among patients with psoriatic arthritis (PsA) compared with the general population. METHODS: In this nationwide register-based cohort study, The Danish National Patient Registry was used to identify incident PsA patients. The 5-year incidence rates (IR) and incidence rate ratios (IRR) of joint surgery were calculated in four calendar-period defined cohorts. Each patient was matched with ten non-PsA individuals from the general population cohort (GPC). The cumulative incidences of any joint and joint-sacrificing surgery, respectively, were estimated using the Aalen-Johansen method. RESULTS: From 1996 to 2017, 11 960 PsA patients (mean age 50 years; 57% female) were registered. The IRR of any joint surgery was twice as high for PsA patients compared with GPCs across all calendar periods. Among patients with PsA, 2, 10 and 29% required joint surgery at 5, 10 and 15 years after diagnosis. The risk of surgery in PsA patients diagnosed at 18-40 years was higher (22%) than in GPC 60+ year old (20%) after 15 years of follow-up. CONCLUSIONS: The use of joint surgery among PsA patients remained around twofold higher from 1996 to 2012 compared with GPC. After 15 years of follow-up, nearly 30% of the PsA patients had received any surgery, and even a person diagnosed with PsA at the age of 18-40 years had a higher risk of surgery than GPCs of 60+ year old. Thus, the high surgical rates represent an unmet need in the current treatment of PsA.

Secular trends in the incidence and prevalence of gout in Denmark from 1995 to 2015: a nationwide register-based study.

OBJECTIVE: To investigate temporal trends in the incidence and prevalence of gout in the adult Danish population. METHODS: Using the nationwide Danish National Patient Registry, we calculated the number of incident gout patients (per 100 000 person-years) within each 1 year period from 1995 to 2015 and the prevalence of gout in 2000 and 2015. Further, we calculated age- and gender-specific incidence rates of gout from 1995 to 2015. RESULTS: We identified a total of 45 685 incident gout patients (72.9% males) with a mean age of 65 years (s.d. 16) at diagnosis. In both genders, an increase in age-standardized incidence rates was observed from 32.3/100 000 (95% CI 30.7, 33.9) in 1995 to 57.5/100 000 (95% CI 55.6, 59.5) in 2015 (P < 0.001). Similar trends were observed for 8950 cases diagnosed in rheumatology departments. We likewise observed an increase in the prevalence of gout from 0.29% (95% CI 0.29, 0.30) in 2000 to 0.68% (95% CI 0.68, 0.69) in 2015. CONCLUSIONS: The annual incidence rate of gout increased by almost 80% in Denmark between 1995 and 2015. The prevalence increased by nearly 130% between 2000 and 2015. Reasons for this are unknown but may include an increase in risk factors (e.g. obesity, diabetes mellitus), longer life expectancy and increased awareness of the disease among patients and/or health professionals.

Impact of TNF inhibitor therapy on joint replacement rates in rheumatoid arthritis: a matched cohort analysis of BSRBR-RA UK registry data.

OBJECTIVES: Previous ecological data suggest a decline in the need for joint replacements in RA patients following the introduction of TNF inhibitor (TNFi) therapy, although patient-level data are lacking. Our primary aim was to estimate the association between TNFi use and subsequent incidence of total hip replacement (THR) and total knee replacement. METHODS: A propensity score matched cohort was analysed using the British Society for Rheumatology Biologics Registry (2001-2016) for RA data. Propensity score estimates were used to match TNFi users to similar conventional synthetic DMARD users (with replacement) using a 1:1 ratio. Weighted multivariable Cox regression was used to estimate the impact of TNFi on study outcomes. Effect modification by baseline age and disease severity were investigated. Joint replacement at other sites was also analysed. An instrumental variable sensitivity analysis was also performed. RESULTS: The matched analysis contained a total of 19 116 patient records. Overall, there was no significant association between TNFi use vs conventional synthetic DMARD on rates of THR (hazard ratios = 0.86 [95% CI: 0.60, 1.22]) although there was significant effect modification by age (P < 0.001). TNFi was associated with a reduction in THR among those >60 years old (hazard ratio = 0.60 [CI: 0.41, 0.87]) but not in younger patients. No significant associations were found for total knee replacement or other joint replacement. CONCLUSION: Overall, no association was found between the use of TNFi and subsequent incidence of joint replacement. However, TNFi was associated with a 40% relative reduction in THR rates among older patients.

Risk of second malignant neoplasm and mortality in patients with rheumatoid arthritis treated with biological DMARDs: a Danish population-based cohort study.

OBJECTIVE: To study the risk of a second malignant neoplasm (SMN) and mortality in patients with rheumatoid arthritis (RA) with a history of a primary cancer diagnosis and treated with biological disease-modifying antirheumatic drugs (bDMARD). METHODS: Among patients with RA (n=15 286) registered in the DANBIO Register during 2000-2011, 1678 had a primary cancer according to the Danish Cancer Registry. HRs for SMN and death were calculated. RESULTS: During follow-up there were 279 patients with RA contributing person-years to the bDMARDs use before their primary cancer diagnosis, 220 to the only after, 92 to the both before and after, while 1203 patients with RA contributed to the non-use strata. Ever use of bDMARDs was associated with a HR of 1.11 (95% CI 0.74 to 1.67) for developing a SMN compared with non-use (cancer site adjusted). The HR for death associated with bDMARD use before the primary cancer diagnosis was increased 1.53 (95% CI 1.13 to 2.09). After further adjustment for extent of the primary cancer, the HR for death was 1.20 (95% CI 0.88 to 1.63) for bDMARDs use before cancer, 1.36 (95% CI 0.78 to 2.39) for bDMARD use only after cancer and 1.22 (95% CI 0.70 to 2.13) for use both before and after the cancer. CONCLUSIONS: Among patients with RA with a history of cancer, treatment with bDMARDs was not associated with increased risk of SMN. No clear conclusion can be drawn regarding mortality in bDMARD-treated patients with RA.

Predictors of revision, prosthetic joint infection and mortality following total hip or total knee arthroplasty in patients with rheumatoid arthritis: a nationwide cohort study using Danish healthcare registers.

OBJECTIVES: To investigate predictors of 10-year risk of revision and 1-year risk of prosthetic joint infection (PJI) and death following total hip/total knee arthroplasty (THA/TKA) in (1) patients with rheumatoid arthritis (RA) compared with patients with osteoarthritis (OA); and (2) patients with RA treated with biological disease-modifying antirheumatic drugs (bDMARD) within 90 days preceding surgery compared with non-treated. METHODS: Register-based cohort study using the Danish National Patient Register, the DANBIO rheumatology register (RA-specific confounders and treatment episodes) and the Danish Hip and Knee Arthroplasty Registers. Survival analyses were used to calculate confounder-adjusted sub-HRs (SHR) and HRs. RESULTS: In total, 3913 patients with RA with THA/TKA were compared with 120 499 patients with OA. Patients with RA had decreased risk of revision (SHR 0.71 (0.57-0.89)), but increased risk of PJI (SHR=1.46 (1.13-1.88)) and death (HR=1.25 (1.01-1.55)). In DANBIO, 345 of 1946 patients with RA with THA/TKA had received bDMARD treatment within 90 days preceding surgery. bDMARD-treated patients did not have a statistically significant increased risk of revision (SHR=1.49 (0.65-3.40)), PJI (SHR=1.61 (0.70-3.69)) nor death (HR=0.75 (0.24-2.33)) compared with non-treated. Glucocorticoid exposure (HR=2.87 (1.12-7.34)) and increasing DAS28 (HR=1.49 (1.01-2.20)) were risk factors for mortality. CONCLUSION: Patients with RA had a decreased 10-year risk of revision while the risk of death and PJI was increased compared with patients with OA following THA/TKA. bDMARD exposure was not associated with statistically significant increased risk of neither PJI nor death in this study. Glucocorticoid exposure and increased disease activity were associated with an increased risk of death.

Incidence of hip and knee replacement in patients with rheumatoid arthritis following the introduction of biological DMARDs: an interrupted time-series analysis using nationwide Danish healthcare registers.

OBJECTIVES: To study the impact of the introduction of biological disease-modifying anti-rheumatic drugs (bDMARDs) and associated rheumatoid arthritis (RA) management guidelines on the incidence of total hip (THR) and knee replacements (TKR) in Denmark. METHODS: Nationwide register-based cohort and interrupted time-series analysis. Patients with incident RA between 1996 and 2011 were identified in the Danish National Patient Register. Patients with RA were matched on age, sex and municipality with up to 10 general population comparators (GPCs). Standardised 5-year incidence rates of THR and TKR per 1000 person-years were calculated for patients with RA and GPCs in 6-month periods. Levels and trends in the pre-bDMARD (1996-2001) were compared with the bDMARD era (2003-2016) using segmented linear regression interrupted by a 1-year lag period (2002). RESULTS: We identified 30 404 patients with incident RA and 297 916 GPCs. In 1996, the incidence rate of THR and TKR was 8.72 and 5.87, respectively, among patients with RA, and 2.89 and 0.42 in GPCs. From 1996 to 2016, the incidence rate of THR decreased among patients with RA, but increased among GPCs. Among patients with RA, the incidence rate of TKR increased from 1996 to 2001, but started to decrease from 2003 and throughout the bDMARD era. The incidence of TKR increased among GPCs from 1996 to 2016. CONCLUSION: We report that the incidence rate of THR and TKR was 3-fold and 14-fold higher, respectively among patients with RA compared with GPCs in 1996. In patients with RA, introduction of bDMARDs was associated with a decreasing incidence rate of TKR, whereas the incidence of THR had started to decrease before bDMARD introduction.

Gender differences in biologic treatment outcomes-a study of 1750 patients with psoriatic arthritis using Danish Health Care Registers.

Objective: We aimed to investigate gender differences in disease manifestations, patient-reported outcomes, comorbidities and treatment effectiveness among patients with PsA treated with their first TNFα inhibitor (TNFI). Methods: In this observational cohort study, the DANBIO register provided prospectively collected data on PsA patients who initiated their first TNFI in 2000-15. Comorbidity information was achieved from the Danish Nationwide Patient Register. Response to treatment was assessed according to EULAR and ACR criteria at 3 and 6 months. Cox and logistic regression models analysed the impact of gender on TNFI persistence and response, respectively, while adjusting for a priori selected confounders including clinical-, laboratory- and patient-reported factors, comorbidities and lifestyle characteristics. Results: A total of 1750 PsA patients (935 women) were included. At baseline, women were older (49 years/47 years), more often smokers (32%/26%), had worse patient-reported scores (e.g. global score 71 mm/65 mm) and higher frequencies of hospital-diagnosed anxiety or depression (7%/4%) and chronic pulmonary disease (7%/3%) than men (all P < 0.01). Median TNFI persistence was 3.8 years (95% CI: 3.0, 5.7) in men vs 1.4 (1.1, 1.8) in women (P < 0.001). Men had higher odds of achieving response after 3 and 6 months, for example, adjusted odds ratio = 3.2 (1.6, 6.1) for EULAR good/moderate response (vs women) at 6 months. Conclusion: Male gender was strongly associated with greater TNFI treatment effectiveness. Adjustment for baseline risk factors including patient-reported outcomes, disease activity, comorbidities and lifestyle factors did not influence this relationship, which suggests a role of biological factors.