Does Older Age have an Impact on Rituximab Efficacy and Safety? Results from the NOR-DMARD Register.

OBJECTIVE: The objective of this study was to compare the efficacy and safety of rituximab in older vs younger patients with rheumatoid arthritis. METHODS: Data on 367 patients with rheumatoid arthritis treated with rituximab in the Norwegian Disease-Modifying Antirheumatic Drug (NOR-DMARD) register were analysed, comparing patients aged ≥ 65 years (n = 91) with patients aged < 65 years (n = 276). Drug survival was compared using a Kaplan-Meier analysis and Cox proportional hazard models. Disease activity, as assessed by the Disease Activity Score based on 28 joints and erythrocyte sedimentation rate (DAS28-ESR) and the Simplified Disease Activity Index, was analysed with linear mixed models. The occurrence of adverse events was analysed by quasi-Poisson regression models. RESULTS: Drug survival was similar in the two age groups. The proportion of patients who remained taking rituximab over 2 years was 72% in those under aged 65 years vs 74% in those aged ≥ 65 years. No statistically significant association with age was found for drug survival in either the unadjusted (hazard ratio 1.13, p = 0.65) or adjusted Cox proportional hazard analyses for the model with DAS28-ESR as a confounder (effect size 1.11, p = 0.73). Models including the Simplified Disease Activity Index instead of DAS28-ESR yielded similar results. Age was furthermore not significantly associated with disease activity over time, although there was a tendency towards a poorer response in older patients. In the older age group, there was a higher incidence of pneumonia (107 vs 51 per 1000 patient-years) and other serious infections (142 vs 66 per 1000 patient-years). CONCLUSIONS: Rituximab is a reasonable therapeutic option for older patients with rheumatoid arthritis although vigilance is needed with regard to the infection profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01581294.

What do we measure with 28-joint DAS in elderly patients? An explorative analysis in the NOR-DMARD study.

OBJECTIVE: Insight into the influence of ageing on disease outcomes is limited. The objective of this study was to examine the potential effect of age on disease activity using the 28-joint DAS (DAS28) and its components in patients with RA. METHODS: Baseline data of DMARD-naïve patients with RA from the Norwegian Register of DMARDs were used. Linear regression explored the strength of the association between age (<45, 45-65 and >65 years) and each DAS28 component while accounting for education and gender. Adjusted predicted scores for DAS28 components and total DAS28 score were calculated for each age category. RESULTS: Baseline data from 2037 patients [mean age 55.2 years (s.d. 14.0), 68% females] were available. Regression models had to be stratified for gender (P for interaction <0.001); education was a significant covariate. Males >65 years of age with an intermediate level of education have a 56% higher ESR and 25% higher 28-joint swollen joint count as compared with their younger counterparts (<45 years). For females, corresponding differences were 51% and 27%, respectively. The age effect on the 28-joint tender joint count and patient global assessment was negligible. In patients with an intermediate education level, DAS28 was 5.0 vs 5.5 (10% increase) in the youngest vs oldest age groups, independent of gender. CONCLUSION: The age-related increase in ESR and 28-joint swollen joint count scores without a relevant corresponding increase in 28-joint tender joint count and patient global assessment might imply that age-related processes (e.g. soft tissue changes, physiological ESR increase) contribute to a higher DAS28 in elderly patients.

Joint Distribution and Two-Year Outcome in 347 Patients With Monoarthritis of Less Than Sixteen Weeks' Duration.

OBJECTIVE: The present study was undertaken to investigate the joint distribution and 2-year outcome of patients with recent-onset monoarthritis. METHODS: Adult patients with clinically apparent monoarthritis of ≤16 weeks' duration were included in a multicenter 2-year longitudinal study. Clinical characteristics, joint distribution, development of chronic inflammatory rheumatic disease (CIRD), as well as classification criteria according to the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 criteria for RA were studied. Predictors for development of CIRD were analyzed by multivariable logistic regression analyses. RESULTS: The knee (49.3%), ankle (16.7%), and wrist (14.1%) were the most frequently affected joints among the 347 included patients. A total of 91 patients (26.2%) developed CIRD during follow-up; 21 (6.1%) were diagnosed with RA, and 16 (4.6%) with psoriatic arthritis. Longer duration of joint swelling, joint localization, and anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF) positivity were independent predictors of CIRD. Six of 58 patients (10.3%) with ankle monoarthritis and 21 of 49 patients (42.9%) with wrist monoarthritis developed CIRD during follow-up. The 2010 ACR/EULAR Criteria for RA identified all patients diagnosed with seropositive RA at an early stage, mostly within 3 months. CONCLUSION: Approximately one-fourth of patients with recent-onset monoarthritis developed CIRD over 2 years. Patients presenting with ankle arthritis rarely developed CIRD, whereas patients presenting with wrist arthritis more frequently did so. Longer duration of joint swelling and ACPA and RF positivity were also predictive of CIRD. Our findings facilitate the early identification of patients with monoarthritis who have an unfavorable prognosis.

Associations between certolizumab pegol serum levels, anti-drug antibodies and treatment response in patients with inflammatory joint diseases: data from the NOR-DMARD study.

OBJECTIVES: To identify a therapeutic target interval for certolizumab pegol drug levels and examine the influence of anti-drug antibodies in patients with inflammatory joint diseases. METHODS: Certolizumab pegol and anti-drug antibody levels were measured in serum samples collected after 3 months of certolizumab pegol treatment in 268 patients with inflammatory joint diseases (116 axial spondyloarthritis, 91 rheumatoid arthritis and 61 psoriatic arthritis) in the NOR-DMARD study. Treatment response was defined by Ankylosing Spondylitis Disease Activity Score Clinically important improvement in axial spondyloarthritis, European League Against Rheumatism good/moderate response in rheumatoid arthritis, and improvement in 28-joint Disease Activity Score of ≥ 0.6 in PsA. Serum drug levels and anti-drug antibodies were analysed using automated in-house assays. RESULTS: Certolizumab pegol serum levels varied considerably between individuals (median (IQR) 32.9 (17.3-43.9) mg/L). Certolizumab pegol level ≥ 20 mg/L was associated with treatment response for the total inflammatory joint disease population, with odds ratio (OR) 2.3 (95% CI 1.2-4.5, P = 0.01) and OR 1.9 (95% CI 1.0-3.5, P = 0.05) after 3 and 6 months of treatment, respectively. For individual diagnoses, this association was most consistent for axial spondyloarthritis, with OR 3.4 (95% CI 1.0-11.1, P < 0.05) and OR 3.3 (95% CI 1.0-10.8, P < 0.05), respectively. Certolizumab pegol level > 40 mg/L was not associated with any additional benefit for any of the diagnoses. Anti-drug antibodies were detected in 6.1% (19/310) of samples and were associated with low certolizumab pegol levels (P < 0.01). CONCLUSIONS: Serum certolizumab pegol levels 20-40 mg/L were associated with treatment response in inflammatory joint diseases. Our study is the first to show this association in axial spondyloarthritis and psoriatic arthritis patients. The results suggest a possible benefit of therapeutic drug monitoring in patients with inflammatory joint disease on certolizumab pegol treatment. TRIAL REGISTRATION: NCT01581294, April 2012.

Assessments of the unmet need in the management of patients with rheumatoid arthritis: analyses from the NOR-DMARD registry.

OBJECTIVE: To describe the outcomes of MTX and biologic DMARD (bDMARD) treatment in patients with RA and assess unmet needs in patients who fail treatment, using real-world data from the Norwegian DMARD (NOR-DMARD) registry. METHODS: Data included RA treatment courses from January 2007 until July 2016. Patients received MTX monotherapy (in MTX-naïve patients), bDMARD monotherapy, bDMARDs + MTX, or bDMARDs + other conventional synthetic DMARDs (csDMARDs). DAS28-4(ESR) was used to measure remission (<2.6) and inadequate response (>3.2) across all groups at Months 6 and 12. Estimated ACR20/50/70 and EULAR good and good/moderate response rates (based on DAS28-4[ESR] score) for bDMARDs were modelled at Months 6 and 12 using logistic mixed regression. DAS28-4(ESR) scores and changes from baseline, and rates and reasons for discontinuation, were evaluated for all groups over 24 months. RESULTS: The 2778 treatment courses in this analysis included 714 MTX monotherapy, 396 bDMARD monotherapy, 1460 bDMARDs + MTX and 208 bDMARDs + other csDMARDs. Of patients with DAS28-4(ESR) data at Months 6 and 12 (25.0-34.1%), 33.9-47.2% did not switch treatment and were inadequate-responders at Month 12. There were no significant differences in efficacy between bDMARD groups (bDMARD monotherapy, or bDMARDs + MTX or other csDMARDs). Lack of efficacy was the most common reason for stopping treatment across all groups (13.7-22.1% over 24 months). CONCLUSION: An unmet treatment need exists for patients still experiencing inadequate response to MTX monotherapy and bDMARDs as monotherapy or in combination with MTX/other csDMARDs after 12 months. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01581294.

Treat to target strategy in early rheumatoid arthritis versus routine care - A comparative clinical practice study.

OBJECTIVE: To assess the 2-year effect on disease activity and health-related quality of life (HRQoL) of implementing a clinical practice treat-to-target (T2T) strategy in patients with rheumatoid arthritis (RA). METHODS: Patients in the Norwegian Very Early Arthritis Cohort 2.0 (NOR-VEAC 2.0), included 2010-2015, were treated according to T2T principles with visits at baseline, 3, 6, 9, 12 months, then every 6 months plus monthly visits until DAS28 <2.6. These patients were compared to a pre-T2T cohort of patients included in the Norwegian Disease Modifying Anti-Rheumatic Drug (NOR-DMARD) register 2006-2009. Both groups had a clinical diagnosis of RA (≤1 year) and were DMARD naïve. Disease activity and HRQoL outcomes were analysed, and the primary outcome was SDAI remission (≤3.3) at 2years. RESULTS: The T2T cohort included 293 patients (mean (SD) age 54 (13) years, 66% females, disease duration median (25,75 perc) 98 (57,164) days) and the routine care cohort 392 patients (age 54 (13) years, 68% females, 4 (0,30) days since diagnosis). At 2years, the proportion of patients achieving SDAI remission was 46% in the T2T cohort compared to 31% in the routine care cohort. EQ-5D was similar at baseline, but differed significantly between groups at 2years (median (25,75 perc) 0.77 (0.69, 0.85) vs 0.73 (0.59, 0.80), p < 0.001). Methotrexate monotherapy was the dominant DMARD regimen used to achieve SDAI remission in both cohorts. CONCLUSION: Higher remission rates and better HRQoL were achieved in patients following a T2T strategy in clinical practice compared to routine care.

Comparing the disease course of patients with seronegative and seropositive rheumatoid arthritis fulfilling the 2010 ACR/EULAR classification criteria in a treat-to-target setting: 2-year data from the ARCTIC trial.

OBJECTIVES: Recent studies suggest that implementation of the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis (RA) leads to higher inflammatory activity in seronegative compared with seropositive patients at time of diagnosis. Our aim was to compare the disease course in seronegative and seropositive patients classified according to the 2010 criteria. METHODS: DMARD-naïve patients with RA fulfilling the 2010 criteria were included in the treat-to-target ARCTIC trial and followed for 24 months. We stratified patients as seropositive (rheumatoid factor (RF)+, anticitrullinated protein antibodies (ACPA)+ or both) or seronegative (RF- and ACPA-) and compared disease activity, radiographic progression, treatment response and remission rates across groups. RESULTS: 230 patients were included with mean (SD) age 51.4 (13.7) years, and 61% were female. 34 patients (15%) were seronegative. At 24 months, disease activity measures, radiographic progression and remission rates were similar between groups, despite more inflammatory activity in seronegative patients at baseline. Treatment response was slower in seronegative compared with seropositive patients. The groups received similar treatment. CONCLUSION: Our findings suggest that among patients with RA classified according to the 2010 ACR/EULAR criteria, seronegative patients respond well to modern treatment strategies. However, treatment response was somewhat slower in seronegative patients and radiographic progression was similar in seronegative and seropositive patients. Our results indicate that seronegative RA is not a mild form of the disease and requires intensive treat-to-target therapy similar to treatment of seropositive RA.

Associations between Cytokine Levels and CYP3A4 Phenotype in Patients with Rheumatoid Arthritis.

Systemic inflammation has been linked to suppressed CYP3A4 activity. The aim of this study was to examine associations between levels of a broad selection of cytokines and CYP3A4 phenotype in patients with rheumatoid arthritis (RA). The study included 31 RA patients treated with tumor necrosis factor (TNF)-α inhibitors. CYP3A4 phenotype was measured as serum concentration of 4ß-hydroxycholesterol (4ßOHC) by ultra-performance liquid chromatography-tandem mass spectrometry in samples collected prior to and 3 months after initiation of treatment with TNF-α inhibitors. Serum levels of the following 21 cytokines were determined in the same samples using a bead-based multiplex immunoassay (Luminex technology): CCL2, CCL3, CXCL8, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon γ, interleukin (IL)-1ß, IL-1 receptor antagonist (ra), IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-13, IL-15, IL-17A, IL-18, IL-23, and TNF-α Correlations between levels of cytokines and 4ßOHC were assessed by Spearman's rank correlation tests. Among the investigated cytokines, three were negatively correlated with CYP3A4 phenotype during treatment with TNF-α inhibitors: i.e., IL-1ra (r = -0.408, P = 0.023), IL-6 (r = -0.410, P = 0.022) and CXCL8 (r = -0.403, P = 0.025) (P ≥ 0.3 for all other cytokines). None of the analyzed cytokines were correlated with CYP3A4 phenotype prior to TNF-α inhibitor treatment (P > 0.1 for all cytokines). These findings suggest that immune responses associated with increased levels of IL-1ra, IL-6, and CXCL8 may suppress CYP3A4 metabolism. Further studies are required to evaluate these preliminary findings in different patient populations and also examine the possible molecular mechanisms behind our observations.

Effects of biometrics, location and persistent organic pollutants on blood clinical-chemical parameters in polar bears (Ursus maritimus) from Svalbard, Norway.

In the present study, blood clinical-chemical parameters (BCCPs) were analysed in 20 female and 18 male Svalbard polar bears (Ursus maritimus) captured in spring 2007. The aim was to study how age, body condition (BC), biometrics, plasma lipid content and geographical location may confound the relationship between persistent organic pollutants (POPs) including PCBs, HCB, chlordanes, DDTs, HCHs, mirex and OH-PCBs and the concentrations of 12 specific BCCPs (hematocrit [HCT], hemoglobin [HB], aspartate aminotransferase [ASAT], alanine aminotransferase [ALAT], γ-glutamyltransferase [GGT], creatine kinase [CK], triglycerides [TG], cholesterol [CHOL], high-density lipoprotein [HDL], creatinine (CREA], urea, potassium (K]), and to investigate if any of these BCCPs may be applied as potential biomarkers for POP exposure in polar bears. Initial PCA and O-PLS modelling showed that age, lipids, BC and geographical location (longitude and latitude) were important parameters explaining BCCPs in females. Following subsequent partial correlation analyses correcting for age and lipids, multiple POPs in females were still significantly correlated with HCT and HDL (all p < 0.05). In males, age, BM, BC and longitude were important parameters explaining BCCPs. Following partial correlation analyses correcting for age, biometrics, lipids and longitude in males, multiple POPs were significantly correlated with HCT, ASAT, GGT and CHOL (all p < 0.05). In conclusion, several confounding parameters has to be taken into account when studying the relations between BCCPs and POPs in polar bears. When correcting for these, in particular HCT may be used as a simple cost-efficient biomarker of POP exposure in polar bears. Furthermore, decreasing HDL concentrations and increasing CHOL concentration with increasing POP concentrations may indicate responses related to increased risk of cardiovascular disease. We therefore suggest to further study POP exposure and lipidome response to increase knowledge of the risk of cardiometabolic syndrome in polar bears.

The Impact of Ultrasound on the Use and Efficacy of Intraarticular Glucocorticoid Injections in Early Rheumatoid Arthritis: Secondary Analyses From a Randomized Trial Examining the Benefit of Ultrasound in a Clinical Tight Control Regimen.

OBJECTIVE: Intraarticular glucocorticoid injections are common in rheumatoid arthritis (RA) treatment. This study was undertaken to investigate whether ultrasound in combination with clinical examination is better than clinical examination alone at identifying joints that will benefit from intraarticular injections, and to compare the efficacy of ultrasound-guided versus palpation-guided procedures. METHODS: In the treat-to-target Aiming for Remission in Rheumatoid Arthritis: a Randomised Trial Examining the Benefit of Ultrasonography in a Clinical Tight Control Regimen (ARCTIC), patients with early RA were randomized 1:1 to follow-up with or without ultrasound. In addition to disease-modifying antirheumatic drugs, intraarticular glucocorticoids were used to treat inflamed joints. The distribution of injections was assessed in both study groups. The relationship of clinical and ultrasound findings at the time of injection with treatment efficacy was examined, with non-swollen joint at the next visit as the outcome measure. Treatment success was compared across study groups to evaluate ultrasound-guided versus palpation-guided procedures. RESULTS: More injections were administered in the ultrasound group than in the conventional strategy group (n = 770 versus 548), especially in intercarpal joints (n = 58 versus 5) and metatarsophalangeal joints (n = 200 versus 104). Injecting clinically swollen joints without power Doppler (PD) activity on ultrasound was not efficacious compared to not injecting (odds ratio [OR] 1.3; P = 0.59). Efficacy was best in swollen joints (OR 9.0; P = 0.001) and non-swollen joints (OR 8.4; P = 0.016) with moderate PD activity. Treatment success was similar for the ultrasound-guided and palpation-guided procedures. CONCLUSION: Our findings indicate that the efficacy of intraarticular glucocorticoid injections varies according to ultrasound findings at the time of injection, supporting the use of ultrasound as a tool to select joints that will benefit from intraarticular injections. However, ultrasound needle guidance was not superior to palpation guidance.

Deriving common comorbidity indices from the MedDRA classification and exploring their performance on key outcomes in patients with rheumatoid arthritis.

OBJECTIVE: To develop algorithms for calculating the Rheumatic Diseases Comorbidity Index (RDCI), Charlson-Deyo Index (CDI) and Functional Comorbidity Index (FCI) from the Medical Dictionary for Regulatory Activities (MedDRA), and to assess how these MedDRA-derived indices predict clinical outcomes, utility and health resource utilization (HRU). METHODS: Two independent researchers linked the preferred terms of the MedDRA classification into the conditions included in the RDCI, the CDI and the FCI. Next, using data from the Norwegian Register-DMARD study (a register of patients with inflammatory joint diseases treated with DMARDs), the explanatory value of these indices was studied in models adjusted for age, gender and DAS28. Model fit statistics were compared in generalized estimating equation (prediction of outcome over time) models using as outcomes: modified HAQ, HAQ, physical and mental component summary of SF-36, SF6D and non-RA related HRU. RESULTS: Among 4126 patients with RA [72% female, mean (s.d.) age 56 (14) years], median (interquartile range) of RDCI at baseline was 0.0 (1.0) [range 0-6], CDI 0.0 (0.0) [0-7] and FCI 0.0 (1.0) [0-6]. All the comorbidity indices were associated with each outcome, and differences in their performance were moderate. The RDCI and FCI performed better on clinical outcomes: modified HAQ and HAQ, hospitalization, physical and mental component summary, and SF6D. Any non-RA related HRU was best predicted by RDCI followed by CDI. CONCLUSION: An algorithm is now available to compute three commonly used comorbidity indices from MedDRA classification. Indices performed comparably well in predicting a variety of outcomes, with the CDI performing slightly worse when predicting outcomes reflecting functioning and health.

Risk of cardiac rhythm disturbances and aortic regurgitation in different spondyloarthritis subtypes in comparison with general population: a register-based study from Sweden.

OBJECTIVES: To describe the incidence of atrioventricular (AV) block II-III, atrial fibrillation (AF), pacemaker implantation (PM) and aortic regurgitation in patients with ankylosing spondylitis (AS), undifferentiated spondyloarthritis (uSpA) and psoriatic arthritis (PsA) compared with the general population (GP) and with each other. METHODS: A prospective nationwide study with cohorts of patients with AS (n=6448), PsA (n=16 063) and uSpA (n=5190) and a GP (n=2 66 435) cohort, identified in 2001-2009 in the Swedish National Patient and Population registers. Follow-up began on 1 January 2006 and ended at event, death, emigration or 31 December 2012. Age-standardised and sex-standardised incidence rates and hazard ratios (HRs) were calculated. RESULTS: The highest incidence rates were noted for AF (5.5-7.4 events per 1000 person-years), followed by PM (1.0-2.0 events per 1000 person-years). HRs for AV block, AF, PM and aortic regurgitation were significantly increased in AS (HRs 2.3, 1.3, 2.1 and 1.9), uSpA (HRs 2.9, 1.3, 1.9 and 2.0) and PsA (HRs 1.5, 1.5, 1.6 and 1.8) compared with the GP cohort. The highest HRs were seen for AV block in male uSpA (HR 4.2) and AS (HR 2.5) compared with GP. Compared with PsA, significantly increased HRs were noted for PM (HR 1.5) in AS and for AV block (HR 1.8) in uSpA. CONCLUSIONS: Patients with SpA are at increased risk of aortic regurgitation, cardiac rhythm disturbances and, as a probable consequence, also PM. Particularly for AF, the most common arrhythmia, increased caution is warranted, whereas AV block should be looked for especially in men with AS or uSpA.

Self-Reported Symptoms and Pesticide Use among Farm Workers in Arusha, Northern Tanzania: A Cross Sectional Study.

The objective of the study was to describe self-reported health symptoms, the use of personal protective gear and clothing and poor safety procedures when applying pesticides among farm workers. A total of 128 adult farm workers were interviewed using a structured questionnaire during the farming season. The commonly used pesticides included profenofos, mancozeb, chlorpyrifos, cypermethrin, deltamethrin, permethrin, lambda-cyhalothrin, endosulfan and carbosulfan. The majority (>90%) of farm workers used no personal protective clothing while handling pesticides. More than one-third of farm workers ate and drank without washing their hands following pesticide handling, while a smaller number smoked or chewed gum. Wearing special boots during pesticide application was found to reduce the risk of skin rash (OR = 0.2, 95% CI: 0.06-0.66), whereas smoking when applying pesticides increased the risk of chest pain occurrence (OR = 4.0, 95% CI: 1.14-15.43), as well as forgetfulness (OR = 4.0, 95% CI: 1.30-14.02). Chewing gum and eating when applying pesticides was associated with diarrhoea (OR = 11.0, 95% CI: 1.80-6.84 and OR = 7.0, 95% CI: 1.27-3.67 respectively). The increased self-reported prevalence of post-exposure adverse health effects among farm workers was associated with poor use of personal protective clothing and poor safety practices during pesticide use and handling. These data indicate the need for improved availability and use of protective equipment, and training in crop and pest management practices to prevent risky behavioursand for safer and sustainable vegetable production.

Role of erosions typical of rheumatoid arthritis in the 2010 ACR/EULAR rheumatoid arthritis classification criteria: results from a very early arthritis cohort.

OBJECTIVE: To determine how the European League Against Rheumatism (EULAR) definition of erosive disease (erosion criterion) contributes to the number of patients classified as rheumatoid arthritis (RA) according to the 2010 American College of Rheumatology/EULAR RA classification criteria (2010 RA criteria) in an early arthritis cohort. METHODS: Patients from the observational study Norwegian Very Early Arthritis Clinic with joint swelling ≤16 weeks, a clinical diagnosis of RA or undifferentiated arthritis, and radiographs of hands and feet were included. Erosive disease was defined according to the EULAR definition accompanying the 2010 RA criteria. We calculated the additional number of patients being classified as RA based on the erosion criteria at baseline and during follow-up. RESULTS: Of the 289 included patients, 120 (41.5%) fulfilled the 2010 RA criteria, whereas 15 (5.2%) fulfilled only the erosion criterion at baseline. 118 patients had radiographic follow-up at 2 years, of whom 6.8% fulfilled the 2010 RA criteria and only one patient fulfilled solely the erosion criterion during follow-up. CONCLUSION: Few patients with early arthritis were classified as RA based on solely the erosion criteria, and of those who did almost all did so at baseline.

Do depression and anxiety reduce the likelihood of remission in rheumatoid arthritis and psoriatic arthritis? Data from the prospective multicentre NOR-DMARD study.

OBJECTIVE: To investigate the predictive value of baseline depression/anxiety on the likelihood of achieving joint remission in rheumatoid arthritis (RA) and psoriatic arthritis (PsA) as well as the associations between baseline depression/anxiety and the components of the remission criteria at follow-up. METHODS: We included 1326 patients with RA and 728 patients with PsA from the prospective observational NOR-DMARD study starting first-time tumour necrosis factor inhibitors or methotrexate. The predictive value of depression/anxiety on remission was explored in prespecified logistic regression models and the associations between baseline depression/anxiety and the components of the remission criteria in prespecified multiple linear regression models. RESULTS: Baseline depression/anxiety according to EuroQoL-5D-3L, Short Form-36 (SF-36) Mental Health subscale ≤56 and SF-36 Mental Component Summary ≤38 negatively predicted 28-joint Disease Activity Score <2.6, Simplified Disease Activity Index ≤3.3, Clinical Disease Activity Index ≤2.8, ACR/EULAR Boolean and Disease Activity Index for Psoriatic Arthritis ≤4 remission after 3 and 6 months treatment in RA (p≤0.008) and partly in PsA (p from 0.001 to 0.73). Baseline depression/anxiety was associated with increased patient's and evaluator's global assessment, tender joint count and joint pain in RA at follow-up, but not with swollen joint count and acute phase reactants. CONCLUSION: Depression and anxiety may reduce likelihood of joint remission based on composite scores in RA and PsA and should be taken into account in individual patients when making a shared decision on a treatment target.

Relationships between POPs, biometrics and circulating steroids in male polar bears (Ursus maritimus) from Svalbard.

The aim of this study was to determine the effects of persistent organic pollutants (POPs) and biometric variables on circulating levels of steroid hormones (androgens, estrogens and progestagens) in male polar bears (Ursus maritimus) from Svalbard, Norway (n = 23). Levels of pregnenolone (PRE), progesterone (PRO), androstenedione (AN), dehydroepiandrosterone (DHEA), testosterone (TS), dihydrotestosterone (DHT), estrone (E1), 17α-estradiol (αE2) and 17ß-estradiol (ßE2) were quantified in polar bear serum by gas chromatography tandem mass spectrometry (GC-MS/MS), while POPs were measured in plasma. Subsequently, associations between hormone concentrations (9 steroids), POPs (21 polychlorinated biphenyls (PCBs), 8 OH-PCBs, 8 organochlorine pesticides (OCPs) and OCP metabolites, and 2 polybrominated diphenyl ethers (PBDEs)) and biological variables (age, head length, body mass, girth, body condition index), capture date, location (latitude and longitude), lipid content and cholesterol levels were examined using principal component analysis (PCA) and orthogonal projections to latent structures (OPLS) modelling. Average concentrations of androgens, estrogens and progestagens were in the range of 0.57-83.7 (0.57-12.4 for subadults, 1.02-83.7 for adults), 0.09-2.69 and 0.57-2.44 nmol/L, respectively. The steroid profiles suggest that sex steroids were mainly synthesized through the Δ-4 pathway in male polar bears. The ratio between androgens and estrogens significantly depended on sexual maturity with androgen/estrogen ratios being approximately 60 times higher in adult males than in subadult males. PCA plots and OPLS models indicated that TS was positively related to biometrics, such as body condition index in male polar bears. A negative relationship was also observed between POPs and DHT. Consequently, POPs and body condition may potentially affect the endocrinological function of steroids, including development of reproductive tissues and sex organs and the general condition of male polar bears.

Are ankylosing spondylitis, psoriatic arthritis and undifferentiated spondyloarthritis associated with an increased risk of cardiovascular events? A prospective nationwide population-based cohort study.

BACKGROUND: To investigate the risk of first-time acute coronary syndrome (ACS), stroke and venous thromboembolism (VTE) in patients with ankylosing spondylitis (AS), psoriatic arthritis (PsA) and undifferentiated spondyloarthritis (uSpA), compared to each other and to the general population (GP). METHODS: This is a prospective nationwide cohort study. Cohorts with AS (n = 6448), PsA (n = 16,063) and uSpA (n = 5190) patients and a GP (n = 266,435) cohort, were identified 2001-2009 in the Swedish National Patient and Population registers. The follow-up began 1 January 2006, or 6 months after the first registered spondyloarthritis (SpA) diagnosis thereafter, and ended at ACS/stroke/VTE event, death, emigration or 31 December 2012. Crude and age- and sex-standardized incidence rates (SIRs) and hazard ratios (HRs) were calculated for incident ACS, stroke or VTE, respectively. RESULTS: Standardized to the GP cohort, SIRs for ACS were 4.3, 5.4 and 4.7 events per 1000 person-years at risk in the AS, PsA and uSpA cohort, respectively, compared to 3.2 in the GP cohort. SIRs for stroke were 5.4, 5.9 and 5.7 events per 1000 person-years at risk in the AS, PsA and uSpA cohort compared to 4.7 in the GP cohort. Corresponding SIRs for VTE were 3.6, 3.2 and 3.5 events per 1000 person-years at risk compared to 2.2 in the GP cohort. Age-and sex-adjusted HRs (95% CI) for ACS events were significantly increased in AS (1.54 (1.31-1.82)), PsA (1.76 (1.59-1.95)) and uSpA (1.36 (1.05-1.76)) compared to GP. Age-adjusted HRs for ACS was significantly decreased in female AS patients (0.59 (0.37-0.97)) compared to female PsA patients. Age-and sex-adjusted HRs for stroke events were significantly increased in AS (1.25 (1.06-1.48)) and PsA (1.34 (1.22-1.48)), and nonsignificantly increased in uSpA (1.16 (0.91-1.47)) compared to GP. For VTE the age-and sex-adjusted HRs for AS, PsA and uSpA were equally and significantly increased with about 50% compared to GP. CONCLUSIONS: Patients with AS, PsA and uSpA are at increased risk for ACS and stroke events, which emphasizes the importance of identification of and intervention against cardiovascular risk factors in SpA patients. Increased alertness for VTE is warranted in patients with SpA.

Tumour necrosis factor inhibitor treatment and occurrence of anterior uveitis in ankylosing spondylitis: results from the Swedish biologics register.

OBJECTIVES: Tumour necrosis factor-α inhibitor (TNFi) treatment has been shown to reduce the rates of anterior uveitis (AU) in patients with ankylosing spondylitis (AS). Our objective was to compare the effect of adalimumab (ADA), etanercept (ETN) and infliximab (IFX) on AU occurrence in AS, using real-world data. METHODS: Patients with AS starting ADA, ETN or IFX as their first TNFi from January 2003 to December 2010 were extracted from the Swedish Rheumatology Quality Register. AU rates, based on visits to an ophthalmologist with International Classification of Diseases 10 codes for AU, were obtained by linkage to the Swedish National Patient Register. For each TNFi, AU rates 2 years before TNFi start and for the first 2 years on TNFi treatment were compared. In the subgroup of patients who were AU-free during the 2 years before TNFi start, we also compared the risk of a first AU event. RESULTS: 1365 patients with AS were included (406 ADA, 354 ETN, 605 IFX). Compared with pretreatment rates, we noted a reduction in overall AU rates for ADA and IFX, and an increase for ETN. The adjusted HRs for AU in 1127 patients who were free of AU in the last 2 years before TNFi start were significantly higher for ETN versus ADA (HR: 3.86 95% CI 1.85 to 8.06) and ETN versus IFX (HR: 1.99, 95% CI 1.23 to 3.22), while the HR for IFX versus ADA was not statistically significant. CONCLUSIONS: The results suggest differences in effect on AU risk between ADA, ETN and IFX, with a clear advantage for ADA/IFX over ETN.

Disease Characteristics and Rheumatoid Arthritis Development in Patients with Early Undifferentiated Arthritis: A 2-year Followup Study.

OBJECTIVE: To examine the 2-year disease course in patients with undifferentiated arthritis (UA) focusing on fulfillment of the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) rheumatoid arthritis (RA) classification criteria. METHODS: Data were provided by the Norwegian Very Early Arthritis Clinic study, which included patients presenting with ≥ 1 swollen joint of ≤ 16 weeks' duration. UA was defined as patients not fulfilling the 2010 ACR/EULAR RA criteria and who did not have a clinical diagnosis other than RA at baseline. The main outcome was fulfillment of the 2010 RA criteria. Secondary outcomes were disease-modifying antirheumatic drug (DMARD) use, resolution of synovitis without use of DMARD during followup, and final clinical diagnosis. RESULTS: We included 477 patients with UA of whom 47 fulfilled the 2010 ACR/EULAR RA criteria during followup (UA-RA) and 430 did not (UA-non-RA). Of the UA-RA patients, 70% fulfilled the criteria within the first 6 months. UA-RA patients were older, more often positive for rheumatoid factor and anticitrullinated protein antibodies, female, and ever smokers, and they more often presented with polyarticular arthritis, small joint involvement, and a swollen shoulder joint. During followup, 53% of UA-RA patients vs 13% of UA-non-RA patients used DMARD (p < 0.001). Overall, 71% of patients with UA achieved absence of clinical synovitis at final followup without use of DMARD. The most frequent final clinical diagnosis was UA (61%). CONCLUSION: Only 9.8% of patients with UA fulfilled the 2010 RA criteria during 2-year followup. Small joint involvement and swollen shoulder joint were among the factors associated with RA development. In two-thirds of patients with UA, the arthritis resolved without use of DMARD.