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Methotrexate is one of the cornerstones of rheumatoid arthritis (RA) therapy. Genetic factors or single nucleotide polymorphisms (SNPs) are responsible for 15%–30% of the variation in drug response. Identification of clinically effective SNP biomarkers for predicting methotrexate (MTX) sensitivity has been a challenge. The aim of this study was to explore the association between the disease related outcome of MTX treatment and 23 SNPs in 8 genes of the MTX pathway, as well as one pro-inflammatory related gene in RA patients naïve to MTX. Categorical outcomes such as Disease Activity Score (DAS)-based European Alliance of Associations for Rheumatology (EULAR) non-response at 4 months, The American College of Rheumatology and EULAR (ACR/EULAR) non-remission at 6 months, and failure to sustain MTX monotherapy from 12 to 24 months were assessed, together with continuous outcomes of disease activity, joint pain and fatigue. We found that the SNPs rs1801394 in the MTRR gene, rs408626 in DHFR gene, and rs2259571 in AIF-1 gene were significantly associated with disease activity relevant continuous outcomes. Additionally, SNP rs1801133 in the MTHFR gene was identified to be associated with improved fatigue. Moreover, associations with p values at uncorrected significance level were found in SNPs and different categorical outcomes: 1) rs1476413 in the MTHFR gene and rs3784864 in ABCC1 gene are associated with ACR/EULAR non-remission; 2) rs1801133 in the MTHFR gene is associated with EULAR response; 3) rs246240 in the ABCC1 gene, rs2259571 in the AIF-1 gene, rs2274808 in the SLC19A1 gene and rs1476413 in the MTHFR gene are associated with failure to MTX monotherapy after 12–24 months. The results suggest that SNPs in genes associated with MTX activity may be used to predict MTX relevant-clinical outcomes in patients with RA.

Objective To investigate the impact of baseline and time‐varying factors on the risk of serious adverse events (SAEs) in patients during long‐term certolizumab pegol (CZP) treatment. Methods Safety data were pooled across 34 CZP clinical trials in rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), psoriatic arthritis (PsA), and plaque psoriasis (PSO). Cox proportional hazards modeling was used to investigate the association of baseline patient characteristics with risk of serious infectious events (SIEs), malignancies, and major adverse cardiac events (MACEs). Cox modeling for recurrent events assessed the impact of time‐varying body mass index (BMI), systemic corticosteroid (CS) use, and disease activity on SIE risk in RA and SAE risk in PSO. Results Data were pooled from 8747 CZP‐treated patients across indications. Cox models reported a 44% increase in SIE risk associated with a baseline BMI of 35 kg/m2 or more versus a baseline BMI of 18.5 kg/m2 to less than 25 kg/m2. Baseline systemic CS use, age of 65 years or more, and disease duration of 10 years or longer also increased SIE risk. Older age was the only identified risk factor for malignancies. The risk of MACEs increased 107% for BMI of 35 kg/m2 or more versus BMI of 18.5 kg/m2 to less than 25 kg/m2 and increased 51% for men versus women. Higher disease activity, older age, systemic CS use, BMI of 35 kg/m2 or more, and baseline comorbidities were SIE risk factors in RA. Age and systemic CS use were risk factors for SAEs in PSO. Conclusion Age, BMI, systemic CS use, and disease activity were identified as SIE risk factors in CZP‐treated patients. Risk of malignancies was greater in older patients, whereas obesity and male sex were MACE risk factors.

Anti‐tumor necrosis factor (anti‐TNF) drugs are often prescribed for the treatment of rheumatoid arthritis (RA) and other immune‐mediated inflammatory diseases. Although this treatment has been shown to be effective in many patients, up to 40% of patients do not achieve disease control. Drug concentration in plasma may be a factor affecting the observed variability in therapeutic response. In this study, we aimed to identify the plasma concentrations of the anti‐TNF certolizumab pegol (CZP), associated with improvement in disease activity in patients with RA. Data were pooled from three randomized, controlled clinical trials with a combined total of 1,935 patients analyzed. Clinical outcomes of low disease activity (LDA) and remission were defined as Disease Activity Score in 28 joints with C‐reactive protein (DAS28(CRP)) ≤ 2.7 and < 2.3, respectively. Quartile analysis results indicated that there may be an exposure‒response relationship between CZP concentration and LDA/remission outcomes at weeks 12 and 24; the association was strongest for LDA (P

Abstract Background In younger individuals, low absolute risk of cardiovascular disease (CVD) may conceal an increased risk age and relative risk of CVD. Calculation of risk age is proposed as an adjuvant to absolute CVD risk estimation in European guidelines. We aimed to compare the discriminative ability of available risk age models in prediction of CVD in rheumatoid arthritis (RA). Secondly, we also evaluated the performance of risk age models in subgroups based on RA disease characteristics. Methods RA patients aged 30–70 years were included from an international consortium named A Trans-Atlantic Cardiovascular Consortium for Rheumatoid Arthritis (ATACC-RA). Prior CVD and diabetes mellitus were exclusion criteria. The discriminatory ability of specific risk age models was evaluated using c-statistics and their standard errors after calculating time until fatal or non-fatal CVD or last follow-up. Results A total of 1974 patients were included in the main analyses, and 144 events were observed during follow-up, the median follow-up being 5.0 years. The risk age models gave highly correlated results, demonstrating R 2 values ranging from 0.87 to 0.97. However, risk age estimations differed > 5 years in 15–32% of patients. C-statistics ranged 0.68–0.72 with standard errors of approximately 0.03. Despite certain RA characteristics being associated with low c-indices, standard errors were high. Restricting analysis to European RA patients yielded similar results. Conclusions The cardiovascular risk age and vascular age models have comparable performance in predicting CVD in RA patients. The influence of RA disease characteristics on the predictive ability of these prediction models remains inconclusive.

Objective: To examine whether psychological symptoms and cognitive patterns are associated with self-reported pain and pain sensitization in people with hand osteoarthritis (OA). Design: In the Nor-Hand study (n ​= ​300), people with hand OA self-reported psychological symptoms (Hospital Anxiety and Depression Scale), cognitive patterns (Pain catastrophizing Scale and Arthritis Self-Efficacy Scale) as well as their pain severity in hands, overall pain and multi-joint pain. Central pain sensitization was measured clinically by temporal summation and pressure pain threshold tests. We examined whether psychological symptoms and cognitive patterns were cross-sectionally associated with pain using linear regression. Beta coefficients (β) per one standard deviation of the independent variable were presented. Stratified analyses were performed in cases of significant interactions (p ​

Abstract Background Ultrasound (US) is a sensitive method for detecting joint/tendon inflammation in patients with rheumatoid arthritis (RA). Subclinical inflammation is often found in patients with RA in composite score remission. The purpose of the present study was to explore whether US of only the hands is sufficient to identify subclinical inflammation in patients with established RA in clinical remission. Methods A total of 209 patients with established RA (81% women, mean [SD] age 53.3 (13.2) years, disease duration 10.0 [8.8] years) were examined when initiating biologic disease-modifying anti-rheumatic drugs (bDMARDs) and after 6 months (184 patients) and 12 months (152 patients) of follow-up. They were assessed by US (greyscale [GS] and power Doppler [PD] of 36 joints and 4 tendons, scored 0–3) as well as clinical and laboratory examinations, and different disease activity composite scores were calculated. The presence of US synovitis (GS score ≥ 2, PD score ≥ 1 [PD1] and score ≥ 2 [PD2]) in composite score remission was explored. Results Remission at 6 and 12 months was achieved in 74 and 59 patients, respectively, for Disease Activity Score based on 28 joints (DAS28); in 37 and 38 patients, respectively, for Clinical Disease Activity Index; in 42 and 42 patients, respectively, for Simplified Disease Activity Index; and in 38 and 35 patients, respectively, for Boolean remission. The percentages of patients in DAS28 remission at 6 months with synovitis in hands/other regions were 73.0%/64.9% for GS, 64.9%/41.9% for PD1 and 32.4%/20.3% for PD2; at 12 months, the corresponding percentages were 61.0%/64.4% for GS, 62.7%/39.0% for PD1 and 44.1%/15.3% for PD2, respectively. PD activity was more often present in the hands (p

Abstract Background Patients with inflammatory joint diseases (IJD) have increased risk of cardiovascular disease (CVD). Our aim was to compare CVD risk profiles in patients with IJD, including rheumatoid arthritis (RA), axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) and evaluate the future risk of CVD. Methods The prevalence and numbers of major CVD risk factors (CVD-RFs) (hypertension, elevated cholesterol, obesity, smoking, and diabetes mellitus) were estimated in patients with RA, axSpA and PsA. Relative and absolute risk of CVD according to Systematic Coronary Risk Evaluation (SCORE) was calculated. Results In total, 3791 patients were included. CVD was present in 274 patients (7.2%). Of those without established CVD; hypertension and elevated cholesterol were the most frequent CVD-RFs, occurring in 49.8% and 32.8% of patients. Patients with PsA were more often hypertensive and obese. Overall, 73.6% of patients had a minimum of one CVD-RF, which increased from 53.2% among patients aged 30 to

Three biosimilar products are now licensed for the treatment of rheumatic diseases in Europe. The European Medicines Agency (EMA) requires that similarity between a biosimilar and its reference product is demonstrated using a rigorous, stepwise process that includes extensive physicochemical and biological analytical testing, non-clinical pharmacology, clinical evaluations, and pharmacovigilance plans. Each step is highly sensitive to any differences between products and progressively reduces any uncertainty over similarity; all steps must be satisfied to demonstrate biosimilarity. The US Food and Drug Administration (FDA) requires a similar stringent biosimilar development process. The etanercept biosimilar SB4 (Benepali®), recently approved for the treatment of rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis (ankylosing spondylitis, non-radiographic axial spondyloarthritis), and plaque psoriasis, is herein used to demonstrate the detailed analytical characterisation and clinical testing that are required by the EMA before biosimilars are approved for use. A comprehensive characterisation study involving >55 physiochemical and >25 biological assays demonstrated that SB4 has highly similar structural, physicochemical, and biological quality attributes to reference etanercept. A Phase I study demonstrated pharmacokinetic equivalence between SB4 and reference etanercept in healthy male subjects. Furthermore, a Phase III, randomised, controlled trial performed in patients with moderate-to-severe rheumatoid arthritis despite treatment with methotrexate (MTX) showed that SB4 was equivalent to etanercept in terms of efficacy, safety, and immunogenicity. In conclusion, the biosimilar development process performed according to EMA or FDA guidelines is highly rigorous and comprehensive. Biosimilars such as SB4 are now available in clinical practice and are likely to improve access, reduce costs, and ultimately, improve health outcomes.