Response to: 'Correspondence on 'EULAR definition of difficult-to-treat rheumatoid arthritis'' by Novella-Navarro et al

Pathophysiology and treatment of rheumatic disease

Characteristics of difficult-to-treat rheumatoid arthritis: results of an international survey

Objectives: Patients with difficult-to-treat rheumatoid arthritis (RA) remain symptomatic despite treatment according to current European League Against Rheumatism (EULAR) management recommendations. These focus on early phases of the disease and pharmacological management. We aimed to identify characteristics of difficult-to-treat RA and issues to be addressed in its workup and management that are not covered by current management recommendations. Methods: An international survey was conducted among rheumatologists with multiple-choice questions on disease characteristics of difficult-to-treat RA. Using open questions, additional items to be addressed and items missing in current management recommendations were identified. Results: 410 respondents completed the survey: 50% selected disease activity score assessing 28 joints >3.2 OR presence of signs suggestive of active disease as characteristics of difficult-to-treat RA; 42% selected fatigue; 48% selected failure to ≥2 conventional synthetic disease-modifying antirheumatic drugs (DMARDs) AND ≥2 biological/targeted synthetic DMARDs; 89% selected inability to taper glucocorticoids below 5 mg or 10 mg prednisone equivalent daily. Interfering comorbidities, extra-articular manifestations and polypharmacy were identified as important issues missing in current management recommendations. Conclusions: There is wide variation in concepts of difficult-to-treat RA. Several important issues regarding these patients are not addressed by current EULAR recommendations

EULAR definition of difficult-to-treat rheumatoid arthritis

Background: Despite treatment according to the current management recommendations, a significant proportion of patients with rheumatoid arthritis (RA) remain symptomatic. These patients can be considered to have ‘difficult-to-treat RA’. However, uniform terminology and an appropriate definition are lacking. Objective: The Task Force in charge of the „Development of EULAR recommendations for the comprehensive management of difficult-to-treat rheumatoid arthritis” aims to create recommendations for this underserved patient group. Herein, we present the definition of difficult-to treat RA, as the first step. Methods: The Steering Committee drafted a definition with suggested terminology based on an international survey among rheumatologists. This was discussed and amended by the Task Force, including rheumatologists, nurses, health professionals and patients, at a face-to-face meeting until sufficient agreement was reached (assessed through voting). Results: The following three criteria were agreed by all Task Force members as mandatory elements of the definition of difficult-to-treat RA: 1) Treatment according to EULAR rec-ommendation and failure of ≥2 b/tsDMARDs (with different mechanisms of action) after failing csDMARD therapy (unless contraindicated); 2) presence of at least one of the follow-ing: at least moderate disease activity; signs and/or symptoms suggestive of active disease; inability to taper glucocorticoid treatment; rapid radiographic progression; RA symptoms that are causing a reduction in quality of life; 3) the management of signs and/or symptoms is perceived as problematic by the rheumatologist and/or the patient. Conclusions: The proposed EULAR definition for difficult-to-treat RA can be used in clinical practice, clinical trials and can form a basis for future research

EULAR points to consider for the management of difficult-to-treat rheumatoid arthritis

Objective: To develop evidence-based European Alliance of Associations for Rheumatology (EULAR) points to consider (PtCs) for the management of difficult-to-treat rheumatoid arthritis (D2T RA). Methods: A EULAR Task Force was established comprising 34 individuals: 26 rheumatologists, patient partners and rheumatology experienced health professionals. Two systematic literature reviews addressed clinical questions around diagnostic challenges, and pharmacological and non-pharmacological therapeutic strategies in D2T RA. PtCs were formulated based on the identified evidence and expert opinion. Strength of recommendations (SoR, scale A-D: A typically consistent level 1 studies, D level 5 evidence or inconsistent studies) and level of agreement (LoA, scale 0-10: 0 completely disagree, 10 completely agree) of the PtCs were determined by the Task Force members. Results: Two overarching principles and eleven PtCs were defined concerning diagnostic confirmation of RA, evaluation of inflammatory disease activity, pharmacological and nonpharmacological interventions, treatment adherence, functional disability, pain, fatigue, goal setting and self-efficacy and the impact of comorbidities. The SoR varied from level C to D. The mean LoA with the overarching principles and PtCs was generally high (8.4-9.6). Conclusions: These points to consider for D2T RA can serve as a clinical roadmap to support healthcare professionals and patients to deliver holistic management and more personalised pharmacological and non-pharmacological therapeutic strategies. High-quality evidence was scarce. A research agenda was created to guide future research

Steroid-sparing agents in giant cell arteritis

Background: Giant cell arteritis is the commonest form of medium-to-large vessel vasculitis, requiring long-term corticosteroid therapy. The short- and long-term side effects of corticosteroids are many, including weight gain, psychological effects, osteoporosis, cardiometabolic complications, and infections. Materials and Methods: Various agents used in place of or in combination with corticosteroids to reduce corticosteroid-related side effects were reviewed. However, considerable variation in practice was identified giving unclear guidance. This review included the most recent evidence on methotrexate, mycophenolate mofetil, azathioprine, cyclophosphamide, abatacept, and tocilizumab Results and Discussion: Also discussed are encouraging results with tocilizumab in GCA patients. Amongst the agents available for steroid-sparing effects, tocilizumab demonstrated the most robust data and is consequently recommended as the agent of choice for steroid-sparing, for remission induction, remission maintenance, and treating relapsing and refractory cases of GCA.Published versio

Identification of common genetic risk variants for autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.Peer reviewe

Genome-wide by Environment Interaction Studies of Depressive Symptoms and Psychosocial Stress in UK Biobank and Generation Scotland

Stress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by environment interaction studies (GWEIS) of depressive symptoms and stressful life events (SLE) in two UK population-based cohorts (Generation Scotland and UK Biobank). No SNP was individually significant in either GWAS, but gene-based tests identified six genes associated with depressive symptoms in UK Biobank (DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU; p < 2.77 x 10(-6)). Two SNPs with genome-wide significant GxE effects were identified by GWEIS in Generation Scotland: rs12789145 (53-kb downstream PIWIL4; p = 4.95 x 10(-9); total SLE) and rs17070072 (intronic to ZCCHC2; p = 1.46 x 10(-8); dependent SLE). A third locus upstream CYLC2 (rs12000047 and rs12005200, p < 2.00 x 10(-8); dependent SLE) when the joint effect of the SNP main and GxE effects was considered. GWEIS gene-based tests identified: MTNR1B with GxE effect with dependent SLE in Generation Scotland; and PHF2 with the joint effect in UK Biobank (p < 2.77 x 10(-6)). Polygenic risk scores (PRSs) analyses incorporating GxE effects improved the prediction of depressive symptom scores, when using weights derived from either the UK Biobank GWAS of depressive symptoms (p = 0.01) or the PGC GWAS of major depressive disorder (p = 5.91 x 10(-3)). Using an independent sample, PRS derived using GWEIS GxE effects provided evidence of shared aetiologies between depressive symptoms and schizotypal personality, heart disease and COPD. Further such studies are required and may result in improved treatments for depression and other stress-related conditions

Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns

Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk

Towards safer use of glucocorticoids. Studies in patients with rheumatic diseases

Glucocorticoids are highly effective in many inflammatory rheumatic diseases because of their ability to inhibit the disease process at the local and systemic level. Thereby, they are capable of relieving symptoms and inhibiting the progression of the disease and –in early rheumatoid arthritis– also of joint damage. After the trials in rheumatoid arthritis patients who received additional treatment of 7.5 to 10 milligram prednisone daily or placebo, further progression of radiological joint damage was not significantly different for the different treatment groups according to the author’s group meta-analysis on the individual patient level. Nevertheless, the gain acquired during the treatment with glucocorticoids was preserved even 3-4 years after stopping of these trials, supporting the strategy of early intensive treatment. These findings clearly corroborate that treatment with disease-modifying antirheumatic drugs (DMARDs) combined with glucocorticoids is more effective compared to treatment with DMARDs only in early rheumatoid arthritis. At the joint level, it remains hard to predict the clinical response to intra-articular injection of glucocorticoids. Numbers of glucocorticoid receptor positive cells and other steroid hormone receptor positive cells in synovial tissue of the inflamed joint decreased after glucocorticoid injection, but were not predictive of the clinical effect. However, down regulation of estrogen receptor αpositive cells and clinical outcome were associated, indicating an involvement of these receptors in the inflammatory process. Efficacy of glucocorticoids clearly outweighs toxicity if glucocorticoids are used in dosages up to 10 milligram prednisone daily in early rheumatoid arthritis. Few adverse effects are encountered in randomized controlled trials. Both the inflammatory process itself as glucocorticoid therapy are thought to induce negative changes in glucose metabolism and bone. However, during adequate prophylactic medication for osteoporosis in early rheumatoid arthritis patients on methotrexate and 10 mg prednisone daily, even a slight increase instead of decrease of bone mineral density was observed by the author during the first year of treatment. This can be explained by the inhibition of bone loss inducing disease activity by the medication including glucocorticoids, next to the positive effects of the prophylactic medication for osteoporosis. Moreover, author’s group findings were that low dose glucocorticoid therapy for multiple years did not impair glucose metabolism and did not negatively influence physical activity levels. Low dose glucocorticoid therapy thus does not increase cardiovascular risk via these pathways. The author’s group also developed guidelines for the use of glucocorticoids and concluded that optimal choices regarding the use of glucocorticoids in rheumatic diseases are patient specific. The underlying disease, the presence of comorbidity, the response to initial treatment, the dosages used and the development of adverse effects should guide treatment decisions. Monitoring for adverse effect should also be patient tailored: specific aspects of individual patients may warrant a higher frequency of monitoring or a more comprehensive set of adverse effects to monitor. Continuously balancing the benefits and risks of glucocorticoid therapy is recommended. In all, based on these studies, one could conclude that the benefit of especially low dose glucocorticoids, if used adequately to treat an inflammatory rheumatic condition, clearly outweighs the ris

Glucose tolerance, insulin sensitivity and beta-cell function in patients with rheumatoid arthritis treated with or without low-to-medium dose glucocorticoids

To compare glucose tolerance and parameters of insulin sensitivity and β-cell function between chronic glucocorticoid (GC)-using and GC-naive patients with rheumatoid arthritis (RA). Frequently sampled 75 g oral glucose tolerance tests were performed in 58 chronic GC-using and 82 GC-naive patients with RA with established disease, with no known type 2 diabetes mellitus (T2DM), and 50 control subjects of comparable age with normal glucose tolerance. The associations between cumulative GC dose and disease characteristics and glucose tolerance state, insulin sensitivity and β-cell function were tested using multivariate linear and logistic regression models, correcting for patient characteristics. Glucose tolerance state, insulin sensitivity and β-cell function did not differ between the two RA populations; de novo T2DM was detected in 11% and impaired glucose metabolism in 35% of patients with RA. In patients with RA, cumulative GC dose was associated with T2DM, which seemed mostly driven by the effects of cumulative GC dose on insulin resistance; however, the association decreased when corrected for current disease activity. Patients with RA had decreased insulin sensitivity and impaired β-cell function compared with controls, and multivariate regression analyses showed a negative association between the presence of RA and insulin sensitivity. GC-using and GC-naive patients with RA had comparable metabolic parameters, and had decreased insulin sensitivity and β-cell function as compared with healthy controls. Although cumulative GC dose was shown to have a negative impact on glucose tolerance state and insulin sensitivity, confounding by indication remains the main challenge in this cross-sectional analysi