Treatment-related changes in serum neutrophil gelatinase-associated lipocalin (NGAL) in psoriatic arthritis: results from the PIPA cohort study.

OBJECTIVES: Obesity and psoriatic arthritis (PsA) have a complicated relationship. While weight alone does not cause PsA, it is suspected to cause worse symptoms. Neutrophil gelatinase-associated lipocalin (NGAL) is secreted through various cell types. Our objective was to assess the changes and trajectories in serum NGAL and clinical outcomes in patients with PsA during 12 months of anti-inflammatory treatment. METHOD: This exploratory prospective cohort study enrolled PsA patients initiating conventional synthetic or biological disease-modifying anti-rheumatic drugs (csDMARDs/bDMARDs). Clinical, biomarker, and patient-reported outcome measures were retrieved at baseline, and 4 and 12 months. Control groups at baseline were psoriasis (PsO) patients and apparently healthy controls. The serum NGAL concentration was quantified by a high-performance singleplex immunoassay. RESULTS: In total, 117 PsA patients started a csDMARD or bDMARD, and were compared indirectly at baseline with a cross-sectional sample of 20 PsO patients and 20 healthy controls. The trajectory in NGAL related to anti-inflammatory treatment for all included PsA patients showed an overall change of -11% from baseline to 12 months. Trajectories in NGAL for patients with PsA, divided into treatment groups, showed no clear trend in clinically significant decrease or increase following anti-inflammatory treatment. NGAL concentrations in the PsA group at baseline corresponded to the levels in the control groups. No correlation was found between changes in NGAL and changes in PsA outcomes. CONCLUSION: Based on these results, serum NGAL does not add any value as a biomarker in patients with peripheral PsA, either for disease activity or for monitoring.

Exercise and education vs intra-articular saline for knee osteoarthritis: a 1-year follow-up of a randomized trial.

OBJECTIVE: To assess the longer-term effect of the Good Life with osteoarthritis in Denmark (GLAD) exercise and education program relative to open-label placebo (OLP) on changes from baseline in core outcomes in individuals with knee osteoarthritis (OA). METHODS: In this 1-year follow-up of an open-label, randomized trial, patients with symptomatic and radiographically confirmed knee OA were monitored after being randomized to either the 8-week GLAD program or OLP given as 4 intra-articular saline injections over 8 weeks. The primary outcome was the change from baseline in the Knee injury and Osteoarthritis Outcome Score questionnaire (KOOS) pain subscale after 1 year in the intention-to-treat population. Key secondary outcomes were the KOOS function and quality of life subscales, and Patients' Global Assessment of disease impact. RESULTS: 206 adults were randomly assigned: 102 to GLAD and 104 to OLP, of which only 137 (63/74 GLAD/OLP) provided data at 1 year. At one year the mean changes in KOOS pain were 8.4 for GLAD and 7.0 for OLP (Difference: 1.5 points; 95% CI -2.6 to 5.5). There were no between-group differences in any of the secondary outcomes. CONCLUSIONS: In this 1-year follow-up of individuals with knee OA, the 8-week GLAD program and OLP both provided minor longer-term benefits with no group difference. These results require confirmation given the significant loss to follow-up. TRIAL REGISTRATION NUMBER: NCT03843931.

Increased prevalence of sleep disturbance in psoriatic arthritis is associated with inflammatory and non-inflammatory measures.

OBJECTIVES: To examine the prevalence of sleep disturbances, quantified by the Pittsburgh Sleep Quality Index (PSQI), in patients with psoriatic arthritis (PsA), psoriasis (PsO) and healthy controls (HCs), explore associations between PSQI and clinical and patient-reported outcomes, and evaluate the effect of treatment on PSQI. METHOD: Patients were included from the Parker Institute's PsA patient cohort to evaluate the prevalence of sleep disturbances. Univariate and multivariate regression analyses were used to explore associations between sleep disturbance and outcome measures. Treatment effect in PsA patients was assessed with a mixed-effect model for repeated measures. RESULTS: In total, 109 PsA patients, 20 PsO patients, and 20 HCs were included. Sleep disturbances were reported by 66.1% of PsA patients, 45.0% of PsO patients, and 15.0% of HCs. Univariate regression analyses revealed statistically significant associations (p < 0.001) between PSQI and Disease Activity Score (DAS28CRP), tender points, visual analogue scale (VAS) patient global and pain, Psoriatic Arthritis Impact of Disease fatigue, Health Assessment Questionnaire (HAQ), and painDETECT score. Multivariate regression analysis demonstrated VAS patient global, VAS pain, and tender points as being independently associated with PSQI. The mixed-effect model revealed no effect of treatment. CONCLUSION: More PsA patients than PsO patients and HCs reported sleep disturbances. Sleep disturbances were associated with inflammatory and non-inflammatory measures possibly explaining the limited effect of treatment. This demonstrates the need for interdisciplinary approaches to improve the management of sleep disturbance in PsA.Trial registration: ClinicalTrials.gov (NCT02572700).

Who are likely to benefit from the Good Life with osteoArthritis in Denmark (GLAD) exercise and education program? An effect modifier analysis of a randomised controlled trial.

OBJECTIVE: To identify contextual factors that modify the treatment effect of the 'Good Life with osteoArthritis in Denmark' (GLAD) exercise and education programme compared to open-label placebo (OLP) on knee pain in individuals with knee osteoarthritis (OA). METHODS: Secondary effect modifier analysis of a randomised controlled trial. 206 participants with symptomatic and radiographic knee OA were randomised to either the 8-week GLAD programme (n = 102) or OLP given as 4 intra-articular saline injections over 8 weeks (n = 104). The primary outcome was change from baseline to week 9 in the Knee injury and Osteoarthritis Outcome Score questionnaire (KOOS) pain subscale (range 0 (worst) to 100 (best)). Subgroups were created based on baseline information: BMI, swollen study knee, bilateral radiographic knee OA, sports participation as a young adult, sex, median age, a priori treatment preference, regular use of analgesics (NSAIDs or paracetamol), radiographic disease severity, and presence of constant or intermittent pain. RESULTS: Participants who reported use of analgesics at baseline seem to benefit from the GLAD programme over OLP (subgroup contrast: 10.3 KOOS pain points (95% CI 3.0 to 17.6)). Participants with constant pain at baseline also seem to benefit from GLAD over OLP (subgroup contrast: 10.0 points (95% CI 2.8 to 17.2)). CONCLUSIONS: These results imply that patients who take analgesics or report constant knee pain, GLAD seems to yield clinically relevant benefits on knee pain when compared to OLP. The results support a stratified recommendation of GLAD as management of knee OA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03843931. EudraCT number 2019-000809-71.

The effect of risankizumab on achieving minimal clinically important differences in patient-reported outcomes in patients with psoriatic arthritis: results from KEEPsAKE 1 and 2.

BACKGROUND: Psoriatic arthritis (PsA) is a chronic inflammatory disease that reduces the quality of life. This study assessed the effects of risankizumab (RZB) on the achievement of minimal clinically important differences (MCID) in patient-reported outcomes (PROs). METHODS: KEEPsAKE-1 and -2 are randomized, placebo-controlled Phase 3 clinical studies assessing RZB (150 mg) vs. placebo (PBO) in adult patients with PsA with inadequate response or intolerance to disease-modifying antirheumatic drugs and/or biologics. Patients were randomized 1:1 to receive RZB or PBO for 24 weeks; starting at Week 24, all patients received RZB 150 mg through Week 52. PROs assessed were Patient's Global Assessment of Disease Activity (PtGA), Patient's Assessment of Pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), Short-Form 36 Physical and Mental Component Summary scores (PCS and MCS, respectively), 5-Level EQ-5D (EQ-5D-5L), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), and Work Productivity and Activity Impairment (WPAI). The proportion of patients achieving MCID at Weeks 24 and 52 are reported. Odds ratios of achieving MCID with RZB treatment at Week 24, relative to PBO, were estimated by logistic regression controlling for baseline and stratification factors. RESULTS: In KEEPsAKE-1, RZB- vs. PBO-treated patients were more likely to report MCID in all PROs at Week 24; similar results were obtained in KEEPsAKE-2, except for SF-36 MCS and WPAI presenteeism domain. In KEEPsAKE-1 and KEEPsAKE-2, 65% and 62% of RZB-treated patients, respectively, reported MCID in PtGA at Week 24, which increased to 74% and 68%, respectively, at Week 52. Approximately 48% of all PBO-treated patients reported MCID in PtGA at Week 24 and, after initiating RZB, >65% reported MCID at Week 52. Results were similar in the remaining PROs. CONCLUSIONS: These data demonstrate that patients with PsA receiving RZB treatment are more likely to report clinically important improvements in PROs compared with patients receiving PBO.

Agreement between self-reported and observed functioning in patients with rheumatoid arthritis, osteoarthritis, and fibromyalgia, and the influence of pain and fatigue: a cross-sectional study.

OBJECTIVE: To evaluate the relationship between self-reported and performance-based measures of functioning in rheumatoid arthritis (RA), knee osteoarthritis (OA), and fibromyalgia (FM), and the influence of pain and fatigue. METHOD: Self-reported functioning was assessed by the Stanford Health Assessment Questionnaire, Fibromyalgia Impact Questionnaire, and Knee injury and Osteoarthritis Outcome Score. Performance-based measures of task-related physical activity included grip strength and Six-Minute Walk Test (6MWT). Assessment of Motor and Process Skills (AMPS) was used to obtain performance-based measures of activities of daily living (ADL) ability. Pain and fatigue were assessed by 100 mm visual analogue scales. Spearman's rho correlation and regression modelling were applied. RESULTS: Correlations between self-reported functioning and performance-based measures of ADL ability were weak to moderate, and strongest in OA (r = 0.57, p = 0.002), and AMPS ADL ability measures did not enter regression models as explanatory factors for self-reported functioning. Correlations between AMPS ADL ability measures and measures of task-related physical activity were weak, except for a strong correlation between AMPS ADL motor ability and 6MWT in OA (r = 0.63, p = 0.000). The 6MWT was the only performance-based test explaining variance in AMPS motor ability (OA = 42%; FM = 11%). Pain explained variance in self-reported ability and contributed to variance in AMPS ADL motor ability measures in OA. CONCLUSION: Self-reported and observed measures of functioning assess partly different aspects of functioning, and both approaches may therefore be relevant in a structured assessment of patients with musculoskeletal disorders.

Inflammatory hallmarks of lesser prominence in psoriatic arthritis patients starting biologics: a Nordic population-based cohort study.

OBJECTIVES: To assess secular trends in baseline characteristics of PsA patients initiating their first or subsequent biologic DMARD (bDMARD) therapy and to explore prescription patterns and treatment rates of bDMARDs from 2006 to 2017 in the Nordic countries. METHODS: PsA patients registered in the Nordic rheumatology registries initiating any treatment with bDMARDs were identified. The bDMARDs were grouped as original TNF inhibitor [TNFi; adalimumab (ADA), etanercept (ETN) and infliximab (IFX)]; certolizumab pegol (CZP) and golimumab (GOL); biosimilars and ustekinumab, based on the date of release. Baseline characteristics were compared for the five countries, supplemented by secular trends with R2 calculations and point prevalence of bDMARD treatment. RESULTS: A total of 18 089 patients were identified (Denmark, 4361; Iceland, 449; Norway, 1948; Finland, 1069; Sweden, 10 262). A total of 54% of the patients were female, 34.3% of patients initiated an original TNFi, 8% CZP and GOL, 7.5% biosimilars and 0.3% ustekinumab as a first-line bDMARD. Subsequent bDMARDs were 25.2% original TNFi, 9% CZP and GOL, 12% biosimilars and 2.1% ustekinumab. From 2015 through 2017 there was a rapid uptake of biosimilars. The total of first-line bDMARD initiators with lower disease activity increased from 2006 to 2017, where an R2 close to 1 showed a strong association. CONCLUSION: Across the Nordic countries, the number of prescribed bDMARDs increased from 2006 to 2017, indicating a previously unmet need for bDMARDs in the PsA population. In recent years, PsA patients have initiated bDMARDs with lower disease activity compared with previous years, suggesting that bDMARDs are initiated in patients with a less active inflammatory phenotype.

Cause-specific mortality in patients with psoriasis and psoriatic arthritis.

BACKGROUND: There are limited data regarding causes of mortality in patients with psoriasis or psoriatic arthritis (PsA). OBJECTIVES: This retrospective cohort study evaluated the risk and leading causes of mortality in patients with psoriasis or PsA. METHODS: Individuals with a hospital-based diagnosis of PsA or psoriasis were identified using the Danish National Patient Registry. Matched control individuals were identified from the general population. The main outcome measures were risk of death and cause-specific mortality in patients with psoriasis or PsA. RESULTS: Death rates per 1000 patient-years (with 95% confidence intervals) vs. controls were 22·3 (19·7-24·9) vs. 13·9 (11·8-16·0) for patients with psoriasis and 10·8 (8·9-12·8) vs. 11·6 (9·6-13·6) for patients with PsA. Survival, according to stratified hazard ratios (HRs), was significantly lower in patients with psoriasis than in controls (HR 1·74, P < 0·001), but not in patients with PsA (HR 1·06, P = 0·19). Significantly increased risk of death was observed in patients with psoriasis vs. controls due to a number of causes; the highest risks were observed for diseases of the digestive system; endocrine, nutritional and metabolic diseases; and certain infectious and parasitic diseases (HRs 3·61, 3·02 and 2·71, respectively). In patients with PsA, increased mortality was observed only for certain infectious and parasitic diseases (HR 2·80) and diseases of the respiratory system (HR 1·46). Patients with psoriasis died at a younger age than controls (mean age 71·0 vs. 74·5 years, P < 0·001). CONCLUSIONS: Patients with severe psoriasis have increased mortality risk compared with matched controls, due to a number of causes. Evidence to support an increased risk for patients with PsA was less convincing.

Biological treatment in ankylosing spondylitis in the Nordic countries during 2010-2016: a collaboration between five biological registries.

OBJECTIVES: Large-scale observational cohorts may be used to study the effectiveness and rare side effects of biological disease-modifying anti-rheumatic drugs (bDMARDs) in ankylosing spondylitis (AS), but may be hampered by differences in baseline characteristics and disease activity across countries. We aimed to explore the research infrastructure in the five Nordic countries regarding bDMARD treatment in AS. METHOD: This observational cohort study was based on data from biological registries in Denmark (DANBIO), Sweden (SRQ/ARTIS), Finland (ROB-FIN), Norway (NOR-DMARD), and Iceland (ICEBIO). Data were collected for the years 2010-2016. Registry coverage, registry inventory (patient characteristics, disease activity measures), and national guidelines for bDMARD prescription in AS were described per country. Incident (first line) and prevalent bDMARD use per capita, country, and year were calculated. In AS patients who started first line bDMARDs during 2010-2016 (n = 4392), baseline characteristics and disease activity measures were retrieved. RESULTS: Registry coverage of bDMARD-treated patients ranged from 60% to 95%. All registries included extensive prospectively collected data at patient level. Guidelines regarding choice of first line drug and prescription patterns varied across countries. During the period 2010-2016 prevalent bDMARD use increased (p < 0.001), whereas incident use tended to decrease (p for trend < 0.004), with large national variations (e.g. 2016 incidence: Iceland 10.7/100 000, Finland 1.7/100 000). Baseline characteristics were similar regarding C-reactive protein, but differed for other variables, including the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (range 3.5-6.3) and Ankylosing Spondylitis Disease Activity Score (ASDAS) (2.7-3.8) (both p < 0.0001). CONCLUSION: Collaboration across the five Nordic biological registries regarding bDMARD use in AS is feasible but national differences in coverage, prescription patterns, and patient characteristics must be taken into account depending on the scientific question.

Burden of rheumatoid arthritis in the Nordic region, 1990-2015: a comparative analysis using the Global Burden of Disease Study 2015.

OBJECTIVE: To report mortality and disability due to rheumatoid arthritis (RA) in the Nordic region (Denmark, Finland, Greenland, Iceland, Norway, and Sweden) using data from the Global Burden of Disease Study (GBD) 2015. METHOD: Using the results of GBD 2015, we present rates and trends in prevalence, mortality, years of life lost, years lived with disability (YLD), and disability-adjusted life-years (DALYs) of RA in the Nordic region during 1990-2015. RESULTS: In 2015, the age-standardized prevalence of RA was higher in the Nordic region than the global level (0.44%, 95% uncertainty interval 0.40-0.48%, vs 0.35%, 0.32-0.38%). For women (men), DALYs increased by 2.4% (12.9%), from 29 263 (10 909) in 1990 to 29 966 (12 311) in 2015. The burden of RA as a proportion of total DALYs in women (men) increased from 0.90% (0.29%) in 1990 to 0.94% (0.36%) in 2015. Age-standardized DALY rates declined in all countries except Denmark and Greenland between 1990 and 2015. Of 315 conditions studied, RA was ranked as the 16th (37th) leading cause of YLD in women (men) in the region. Of 195 countries studied, Greenland, Finland, Denmark, Norway, Sweden, and Iceland had the 7th, 11th, 28th, 38th, 48th, and 78th highest age-standardized YLD rates for RA, respectively. CONCLUSIONS: The prevalence of RA in the Nordic region is higher than the global average. Current trends in population growth and ageing suggest a potential increase in RA burden in the coming decades in the region that should be considered in healthcare resources allocation.

Pain and pain mechanisms in patients with inflammatory arthritis: A Danish nationwide cross-sectional DANBIO registry survey.

BACKGROUND: Central pain mechanisms may be prominent in subsets of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and other spondyloarthritis (SpA). The painDETECT questionnaire (PDQ) identifies neuropathic pain features, which may act as a proxy for centrally mediated pain. The objectives were to quantify and characterize pain phenotypes (non-neuropathic vs. neuropathic features) among Danish arthritis patients using the PDQ, and to assess the association with on-going inflammation. METHODS: The PDQ was included onto the DANBIO touch screens at 22 departments of Rheumatology in Denmark for six months. Clinical data and patient reported outcomes were obtained from DANBIO. A PDQ-score >18 indicated neuropathic pain features, 13-18 unclear pain mechanism and <13 non-neuropathic pain. RESULTS: Pain data (visual analogue scale, VAS) was available for 15,978 patients. 7,054 patients completed the PDQ (RA: 3,826, PsA: 1,180, SpA: 1,093). 52% of all patients and 63% of PDQ-completers had VAS pain score ≥ 30 mm. The distribution of the PDQ classification-groups (<13/ 13-18/ >18) were; RA: 56%/24%/20%. PsA: 45%/ 27%/ 28%. SpA: 55% / 24%/ 21%. More patients with PsA had PDQ score >18 compared to RA and SpA (p<0.001). For PDQ > 18 significantly higher scores were found for all patient reported outcomes and disease activity scores. No clinical difference in CRP or swollen joint count was found. Logistic regression showed increased odds for having VAS pain ≥39 mm (the median) for a PDQ-score >18 compared to <13 (OR = 10.4; 95%CI 8.6-12.5). CONCLUSIONS: More than 50% of the Danish arthritis patients reported clinically significant pain. More than 20% of the PDQ-completers had indication of neuropathic pain features, which was related to a high pain-level. PDQ-score was associated with DAS28-CRP and VAS pain but not with indicators of peripheral inflammation (CRP and SJC). Thus, pain classification by PDQ may assist in mechanism-based pain treatment.

Surgical interventions for nephrolithiasis in ankylosing spondylitis and the general population.

OBJECTIVE: The aim of this study was to estimate rates and type of definitive surgical interventions for nephrolithiasis in Swedish patients with ankylosing spondylitis (AS) compared to the general population. MATERIALS AND METHODS: This national prospective cohort study linked data from Swedish population and healthcare registries. Incidence rates and interventions for nephrolithiasis during follow-up in patients with AS were compared to general population comparator (GPC) subjects. RESULTS: In total, 8572 AS patients were followed for 49,959 person-years and 39,639 matched GPCs were followed for 225,221 person-years. Mean age at study entry was 46 years [interquartile range (IQR) 36-56 years] and 65% were male. In AS patients with a diagnosis of nephrolithiasis during the study period, 29% (72/250) underwent similar intervention for nephrolithiasis compared to 24% (114/466) GPCs (p = 0.21). The incidence rate ratio (RR) in overall AS patients was 2.9 [95% confidence interval (CI) 2.1-3.8] during a median follow-up of 6.2 years (IQR 3.2-8.6 years). With prior diagnosis of nephrolithiasis, the RR for AS patients compared to GPCs was 3.7 (95% CI 1.8-7.7); without prior nephrolithiasis the RR was 2.1 (95% CI 1.5-3.0). Increasing age [odds ratio (OR) 1.02, 95% CI 1.01-1.03], prior nephrolithiasis diagnosis (OR 3.3, 95% CI 1.97-5.62) and atherosclerotic cardiac disease (OR 2.0, 95% CI 1.03-3.91) were identified as predictors of intervention for nephrolithiasis. CONCLUSIONS: Patients with AS have an almost three-fold increased risk of surgical intervention for kidney stones, with similar management, compared to the general population.

Effectiveness and survival-on-drug of certolizumab pegol in rheumatoid arthritis in clinical practice: results from the national Swedish register.

OBJECTIVES: Evidence regarding the efficacy and effectiveness of certolizumab pegol (CZP) in rheumatoid arthritis (RA) patients who have failed to respond to treatment with a tumour necrosis factor inhibitor (TNFi) is limited. The aim of this study was to describe the effectiveness and survival-on-drug of CZP in a real-life setting, both in TNFi-naïve patients and in patients who had previously failed TNFis, and in relation to disease activity at baseline. METHOD: The national Swedish Rheumatology Quality Register (SRQ) was used to identify patients with RA starting treatment with CZP between 2009 and 2013. The effectiveness of treatment was assessed using the 28-joint Disease Activity Score (DAS28), the Health Assessment Questionnaire (HAQ), measures of remission, the European League Against Rheumatism (EULAR) response during 0-6 months from start of treatment, and survival-on-drug during the first 30 months. RESULTS: A total of 945 RA patients started treatment with CZP. Of these, 540 (57.1%) received CZP as the first biological treatment, 215 (23%) had failed one previous TNFi, and 190 (20%) had failed at least two TNFis. Overall, 71% achieved at least a EULAR moderate response and 38% had a EULAR good response at 6 months from baseline. TNFi-naïve patients achieved significantly better results and had better survival-on-drug compared to patients who had failed previous TNFis. Around 20% of patients who had not responded to two or more prior TNFis achieved EULAR good response to therapy and a similar percentage achieved remission. Patients who had high baseline disease activity had a higher risk of discontinuing treatment compared to those without high disease activity. CONCLUSIONS: In this real-life RA cohort, CZP was associated with significant clinical improvement. The effectiveness and survival-on-drug vary markedly depending on the line of treatment.

Validity of ankylosing spondylitis and undifferentiated spondyloarthritis diagnoses in the Swedish National Patient Register.

OBJECTIVES: Epidemiological studies of spondyloarthritis (SpA), using ICD codes from the Swedish National Patient Register (NPR), offer unique possibilities but hinge upon an understanding of the validity of the codes. The aim of this study was to validate the ICD codes for ankylosing spondylitis (AS) and undifferentiated SpA (uSpA) in the NPR against the established classification criteria [modified New York (mNY), Assessment of SpondyloArthritis international Society (ASAS), Amor, and European Spondyloarthropathy Study Group (ESSG) criteria]. METHOD: All patients with an ICD-8/9/10 code of AS or uSpA in the NPR 1966-2009 at a visit to a specialist in rheumatology or internal medicine or corresponding hospitalization, alive and living in Sweden 2009, were identified (n=20,089). Following a structured procedure to achieve geographical representativeness, 500 random patients with a diagnosis of AS or uSpA in 2007-2009 were selected. Based on a structured review of clinical records, positive predictive values (PPVs) for fulfilling the criteria sets were calculated. RESULTS: For those having received an ICD code for AS, the PPVs for fulfilling the mNY criteria or any set of SpA criteria were 70% and 89%, respectively. For those with an uSpA diagnosis (and never an AS diagnosis), the corresponding PPVs were 20% and 79%. The subset with both AS and uSpA diagnoses (overlap=12%) were as likely to fulfil the mNY criteria as the group that had been coded as AS only. CONCLUSIONS: The diagnosis codes for AS or uSpA had high PPVs, suggesting that our case identification in the Swedish NPR can be used for nationwide, population-based, epidemiological studies of these diseases.

Safety of Etoricoxib, Celecoxib, and Nonselective Nonsteroidal Antiinflammatory Drugs in Ankylosing Spondylitis and Other Spondyloarthritis Patients: A Swedish National Population-Based Cohort Study.

OBJECTIVE: Safety data regarding the use of etoricoxib and other nonsteroidal antiinflammatory drugs (NSAIDs) in ankylosing spondylitis (AS) and other spondyloarthritis (SpA) patients are rather limited. Our objective was to estimate and compare rates of gastrointestinal, renovascular, and cardiovascular adverse events in patients exposed to etoricoxib, celecoxib, or nonselective NSAIDs or totally unexposed to NSAIDs. METHODS: We performed a national register-based cohort study on patients with AS or SpA (n = 21,872) identified in the Swedish national patient register from 1987-2009. Treatment exposure was assessed time dependently based on the prescription drug register from 2006-2009, adjusting for sociodemographics and comorbidities derived from national population-based registers. RESULTS: Exposure to etoricoxib, celecoxib, and nonselective NSAIDs was 7.6%, 3.9%, and 71.2%, respectively. No major risk differences for serious cardiovascular, gastrointestinal, or renal adverse events were seen among the 3 exposure groups. Patients unexposed to NSAIDs had more baseline comorbidities and an increased relative risk for congestive heart failure events during the study period (2.0, 95% confidence interval [95% CI] 1.3-3.2). The relative risk for atherosclerotic events was nonsignificant when compared to the nonselective NSAID group (1.0, 95% CI 0.7-1.5), while the relative risk for gastrointestinal events was lower for unexposed patients (0.5, 95% CI 0.4-0.7). CONCLUSION: Overall, serious adverse events related to nonselective NSAIDs, etoricoxib, and celecoxib were similar and in the range of what would be expected in a group of SpA patients. Patients unexposed to NSAIDs had considerably more baseline comorbidities and increased risk for congestive heart failure, reflecting a selection of patients being prescribed NSAIDs in clinical practice.

Drug survival on TNF inhibitors in patients with rheumatoid arthritis comparison of adalimumab, etanercept and infliximab.

OBJECTIVE: To compare drug survival on adalimumab, etanercept and infliximab in patients with rheumatoid arthritis (RA). METHODS: Patients with RA (n=9139; 76% women; mean age 56 years) starting their first tumour necrosis factor (TNF) inhibitor between 2003 and 2011 were identified in the Swedish Biologics Register (ARTIS). Data were collected through 31 December 2011. Drug survival over up to 5 years of follow-up was compared overall and by period of treatment start (2003-2005/2006-2009; n=3168/4184) with adjustment for age, sex, education, period, health assessment questionnaire (HAQ), disease duration, concomitant disease modifying antirheumatic drug (DMARD) treatment and general frailty (using hospitalisation history as proxy). RESULTS: During 20 198 person-years (mean/median 2.2/1.7 years) of follow-up, 3782 patients discontinued their first biological (19/100 person-years; 51% due to inefficacy, 36% due to adverse events). Compared with etanercept, infliximab (adjusted HR 1.63, 95% CI 1.51 to 1.77) and adalimumab initiators had higher discontinuation rates (1.26, 95% CI 1.16 to 1.37), and infliximab had a higher discontinuation rate than adalimumab (1.28, 95% CI 1.18 to 1.40). These findings were consistent across periods, but were modified by time for adalimumab versus etanercept (p<0.001; between-drug difference highest the 1st year in both periods). The discontinuation rate was higher for starters in 2006-2009 than 2003-2005 (adjusted HR 1.12, 95% CI 1.04 to 1.20). The composition of 1-year discontinuations also changed from 2003-2005 vs 2006-2009: adverse events decreased from 45% to 35%, while inefficacy increased from 43% to 53% (p<0.001). CONCLUSIONS: Discontinuation rates were higher for infliximab compared with adalimumab and etanercept initiators, and for adalimumab versus etanercept during the 1st year. Discontinuation rates increased with calendar period, as did the percentage discontinuations due to inefficacy.

Efficacy and drug survival of anti-tumour necrosis factor-alpha therapies in patients with non-radiographic axial spondyloarthritis: an observational cohort study from Southern Sweden.

OBJECTIVES: To evaluate the efficacy and drug survival of anti-tumour necrosis factor (anti-TNF) therapy in non-radiographic axial spondyloarthritis (nr-axSpA) patients treated in clinical practice in Southern Sweden. METHOD: In this cohort study we prospectively included 112 patients with nr-axSpA and high disease activity as well as inadequate response or intolerance to non-steroidal anti-inflammatory drugs (NSAIDs) receiving their first course of anti-TNF therapy. Patients fulfilling modified New York criteria for ankylosing spondylitis (AS) were excluded. The Assessment of SpondyloArthritis International Society (ASAS) criteria for axial SpA were fulfilled by 77% (n = 86) of the included patients. RESULTS: At baseline, the median age of the cohort was 38 years, 59% were males, 79% of the patients had imaging suggestive of sacroiliitis (primarily inflammation on magnetic resonance imaging, MRI), 71% were HLA-B27 positive, and the median disease duration was 6 years and 10 months. At 6 months of follow-up, the median Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) decreased from 5.6 to 3.2 (p = 0.002), the Bath Ankylosing Spondylitis Functional Index (BASFI) decreased from 3.9 to 1.8 (p = 0.005), and C-reactive protein (CRP) level decreased from 4.4 to 1.7 mg/L (p = 0.001). After 1 year of treatment the Kaplan-Meier estimated drug survival was 76%, and at 2 years of follow-up this value decreased to 65%. Patients with inflammatory MRI findings at baseline had significantly better drug survival [hazard ratio (HR) 0.24, 95% confidence interval (CI) 0.10-0.55, p = 0.001]. Male sex was also associated with higher drug survival (HR 0.45, 95% CI 0.24-0.85, p = 0.011). CRP level at baseline was not associated with drug survival. CONCLUSIONS: Anti-TNF treatment of patients with nr-axSpA in clinical practice resulted in reduced BASDAI and BASFI scores and good drug survival. The results from this study suggest that male gender and positive imaging at baseline are associated with a favourable treatment course.

Hypoglycaemia and QT interval prolongation in type 1 diabetes--bridging the gap between clamp studies and spontaneous episodes.

AIMS: We propose a study design with controlled hypoglycaemia induced by subcutaneous injection of insulin and matched control episodes to bridge the gap between clamp studies and studies of spontaneous hypoglycaemia. The observed prolongation of the heart rate corrected QT interval (QTc) during hypoglycaemia varies greatly between studies. METHODS: We studied ten adults with type 1 diabetes (age 41±15years) without cardiovascular disease or neuropathy. Single-blinded hypoglycaemia was induced by a subcutaneous insulin bolus followed by a control episode on two occasions separated by 4weeks. QT intervals were measured using the semi-automatic tangent approach, and QTc was derived by Bazett's (QTcB) and Fridericia's (QTcF) formulas. RESULTS: QTcB increased from baseline to hypoglycaemia (403±20 vs. 433±39ms, p<0.001). On the euglycaemia day, QTcB also increased (398±20 vs. 410±27ms, p<0.01), but the increase was less than during hypoglycaemia (p<0.001). The same pattern was seen for QTcF. Plasma adrenaline levels increased significantly during hypoglycaemia compared to euglycaemia (p<0.01). Serum potassium levels decreased similarly after insulin injection during both hypoglycaemia and euglycaemia. CONCLUSIONS: Hypoglycaemia as experienced after a subcutaneous injection of insulin may cause QTc prolongation in type 1 diabetes. However, the magnitude of prolongation is less than typically reported during glucose clamp studies, possible because of the study design with focus on minimizing unwanted study effects.

The number needed to treat for second-generation biologics when treating established rheumatoid arthritis: a systematic quantitative review of randomized controlled trials.

OBJECTIVE: To evaluate the number needed to treat (NNT) and the number needed to harm (NNH) of the second-generation biologics abatacept, certolizumab, golimumab, rituximab, and tocilizumab in patients with established rheumatoid arthritis (RA) taking concomitant methotrexate (MTX). METHODS: A systematic literature search of MEDLINE, EMBASE, Web of Science, and the Cochrane Register of Controlled Trials was conducted up to 1 November 2009. We selected any published randomized, double-blind, MTX-controlled study including RA patients with a mean disease duration of at least 5 years before entering a pivotal trial on second-generation biological therapy. Studies eligible for inclusion involved patients, who had previously shown inadequate response to conventional disease-modifying anti-rheumatic drug (DMARD) therapy. Pre-specified binary outcomes were extracted with a preference for 1-year data (6-month data were used if no data were available for 1 year). Two reviewers independently extracted the data necessary to estimate the absolute measures in a non-responder intention-to-treat (ITT) analysis. RESULTS: Five randomized controlled trials, one for each of the drugs, were selected and data extracted according to published data at endpoint for American College of Rheumatology 50% (ACR50)-responding patients, and withdrawals due to adverse events. NNT ranged from four to six treated patients to achieve one ACR50 response, while withdrawals due to adverse events were few and non-significant compared to the placebo group, except for rituximab administered as 1000 mg. CONCLUSION: Comparable efficacy was shown by the five biological agents studied, with few adverse events. However, for rituximab, tocilizumab, and golimumab, only 6-month data were available, hampering the external validity with regard to long-term efficacy and tolerability. A low dose (500 mg) of rituximab may be as effective as the recommended dose of 1000 mg.