Canakinumab for Treatment of Adult-Onset Still's Disease to Achieve Reduction of Arthritic Manifestation (CONSIDER): phase II, randomised, double-blind, placebo-controlled, multicentre, investigator-initiated trial

Background: Inhibition of interleukin (IL)-1 represents a promising treatment option in adult-onset Still's disease (AOSD). Objective: To investigate the efficacy and safety of canakinumab in patients with AOSD and active joint involvement by means of a multicentre, double-blind, randomised, placebo-controlled trial. Methods Patients with AOSD and active joint involvement (tender and swollen joint counts of >= 4 each) were treated with canakinumab (4 mg/kg, maximum 300 mg subcutaneous every 4 weeks) or placebo. The primary endpoint was the proportion of patients with a clinically relevant reduction in disease activity at week 12 as determined by the change in disease activity score (Delta DAS28>1.2). Results At enrolment, patients had high active disease with a mean DAS28(ESR) of 5.4 in the canakinumab and 5.3 in the placebo group, respectively. In the intention-to-treat analysis, 12 patients (67%) in the canakinumab group and 7 patients (41%) in the placebo group fulfilled the primary outcome criterion (p=0.18). In the per-protocol analysis, significantly higher American College of Rheumatology (ACR) 30% (61% vs 20%, p=0.033), ACR 50% (50% vs 6.7%, p=0.009) and ACR 70% (28% vs 0%, p=0.049) response rates were observed in the canakinumab group compared with the placebo group. Two patients in the canakinumab group experienced a serious adverse event. Conclusion Although the study was terminated prematurely and the primary endpoint was not achieved, treatment with canakinumab led to an improvement of several outcome measures in AOSD. The overall safety findings were consistent with the known profile of canakinumab. Thus, our data support indication for IL-1 inhibition with canakinumab in AOSD

Impacts of maternal vitamin D deficiency on cardiac development and metabolism of the offspring

L’environnement in utero, dont le statut en vitamine D, est un facteur crucial pour assurer le développement normal du fœtus, mais il participe également à la susceptibilité à développer des maladies métaboliques et cardiaques tout au long de la vie. Cette thèse a pour objectif d’étudier les interactions existantes entre la carence maternelle en vitamine D (VDD) et la programmation du devenir cardio-métabolique de la descendance. D’abord, chez la descendance juvénile, l’homéostasie énergétique et le poids de la descendance issue de mères VDD étaient altérés de manière sexe-dépendant. A l’âge adulte, une alimentation obésogène combinée à la VDD maternelle, altérait l’homéostasie glucidique et l’adiposité de la descendance mâle mais pas des femelles. De telles phénotypes été associés à des profils transcriptomiques différentiels dans le tissu adipeux, qui pourraient être associés à une modulation différentielle des taux circulants d’estradiol chez les femelles. La VDD maternelle module donc le devenir métabolique de la descendance, dans des proportions amplifiées, lorsque celle-ci est exposée à une alimentation obésogène au cours de sa vie. Ensuite, nous avons étudié l’impact de la VDD maternelle sur le devenir cardiaque de la descendance. Chez les embryons, la VDD maternelle induisait une hypertrophie ventriculaire gauche, modulait leur transcriptome cardiaque et de telles modifications semblait être liées à une modulation de la structure chromatinienne. La morphologie et le fonctionnement du cœur, étaient également altérés chez la descendance adulte. La VDD maternelle altère donc le développement cardiaque du fœtus et induit des altérations jusqu’à l’âge adulte.In utero environment, including vitamin D status, is crucial to ensure normal development of the foetus and to prevent any metabolic and cardiac diseases throughout the whole life. The aim of this thesis is to highlight the interactions existing between maternal vitamin D deficiency (VDD) and the potential programming of cardio-metabolic fate of the offspring. First, for the juvenile offspring, the energetic homeostasis and the weight of the offspring from deficient mother were sex-dependently altered. In adulthood, an obesogenic diet combined with maternal VDD, disrupted glucose homeostasis and adiposity in male offspring but not in females. Such phenotypes were associated to different transcriptomic profiles in adipose tissue, that could be related to differential modulation of circulating levels of estradiol in females. The maternal VDD modulates metabolic fate of the offspring, in exacerbated proportions, when the offspring was exposed to obesogenic diet during adulthood. Then, we studied the impact of maternal VDD on the cardiac fate of offspring. In embryos maternal VDD induced left ventricular hypertrophy, modulated their cardiac transcriptome and such modifications seemed to be related to the modulation of chromatin structure. Also, the morphology and cardiac function were altered in the adult offspring. Maternal VDD impairs the cardiac development of the foetus and programs cardiac outcomes in adulthood

Maternal Vitamin D Deficiency in Mice Increases White Adipose Tissue Inflammation in Offspring

Vitamin D is acknowledged to play an important biological and metabolic role in adipose tissue, which is also the main storage site for this vitamin. Its anti-inflammatory effect in adipocytes and adipose tissue has notably been highlighted in adult mice. This vitamin is also crucial during fetal development since maternal vitamin D deficiency is suspected to program future metabolic disorders. Based on these observations, the aim of this study was to evaluate the consequences of maternal vitamin D deficiency (VDD) on white adipose tissue inflammation in adult offspring fed with normal or obesogenic diet (high-fat diet). White adipose tissue morphology, RNA and miRNA expression profiles, and signaling pathways were studied in adult males and females. In males, a HF diet coupled with maternal VDD increased expression of RNA and miRNA linked to inflammation leading to over-representation of inflammatory pathways. Interestingly, genomic and epigenetic profiles were associated with activation of the NF-kB signaling pathway and adiposity index. In females, no major modulation of inflammatory pathways was observed under VDD, contrarily to males. We concluded that maternal VDD coupled with HF diet activated inflammatory pathway in adipose tissue of the offspring, in a sex-dependent manner. Such activation is strongly related to activation of NF-kB signaling and increased adiposity only in males

Prenatal maternal vitamin D deficiency sex‐dependently programs adipose tissue metabolism and energy homeostasis in offspring

International audienceIn utero environment is crucial to ensure normal development of the fetus and to program metabolic health throughout the life. Beside macronutrients, the role of micronutrients, including vitamin D, begins to be explore. The aim of this study was to decipher the impact of maternal vitamin D deficiency (VDD), in normal and high‐fat (HF) diet context, on adipose tissue metabolism and energy homeostasis in offspring, considering sex‐specific responses. Body weight, energy expenditure, and spontaneous activity was differential impacted in juvenile male and female offspring born from VDD mice. In adulthood, a HF diet combined with maternal VDD disrupted glucose homeostasis and adiposity in male offspring but not in females. Such phenotypes were associated to different transcriptomic profiles in adipose tissue, which could be related to differential modulation of plasma 17β‐estradiol concentrations. Thus, maternal VDD sex‐dependently modulated metabolic fate of the offspring, especially when associated with HF diet in adulthood

Maternal Vitamin D Deficiency in Mice Sex‐Dependently Affects Hepatic Lipid Accumulation in Offspring

International audienceScope Vitamin D deficiency (VDD) is becoming a global issue and low 25‐hydroxyvitamin D (25(OH)D) plasma levels have been linked to hepatic steatosis in adulthood. Nevertheless, the impact of maternal VDD on lipid metabolism and hepatic steatosis remains poorly documented, especially under obesogenic condition. The goal of this study is to assess the effects of maternal VDD on hepatic lipid accumulation in adult offspring fed a normal or obesogenic diet. Methods and results Several approaches are implemented including histology and lipidomics on the liver in both males and females. No major impact of high‐fat (HF) or VDD is observed at histological level in both males and females. Nevertheless, in males born from VDD mice and fed an HF diet, an increase of total lipids and modulation of the relative lipid species distribution characterized by a decrease of triglycerides and increase of phospholipids is observed. In female no major lipid profile is noticed. Conclusion Maternal VDD combined with a HF diet in male may predispose to hepatic hypertrophia, with a specific lipid profile. Such observations reinforce our knowledge of the impact of maternal VDD on hepatic programming in the offspring

Pregnancy outcomes in DMARD-exposed patients with juvenile idiopathic arthritis-results from a JIA biologic registry

Objectives. To investigate the courses and outcomes of pregnancies involving JIA patients who were exposed to DMARDs. Methods. In the Juvenile arthritis MTX/Biologics long-term Observation study, pregnant patients or male patients with pregnant partners were identified. Standardized patient interviews were conducted, and the course and outcome of pregnancy were assessed. Prospectively collected physician- and patient-reported data were also considered in the analysis. Results. The study sample included 152 pregnancies in 98 women with JIA and 39 pregnancies involving 21 male patients as partners. The majority of patients had polyarticular-onset/-course JIA (61%). The average age of patients at first pregnancy was 24.1 (4.5) years, and their mean disease duration was 13.8 (5.9) years. Patients had been exposed to DMARDs for 9.5 (5.6) years, and 90% of these patients had received biologics before. Half of the pregnancies occurred during DMARD exposure, mostly with etanercept. Significant differences in pregnancy outcomes between DMARD-exposed and -unexposed pregnancies were not observed. Spontaneous abortion (13.1%) and congenital anomaly (3.6%) rates were not suggestive of increased risk compared with expected background rates. However, the rates of premature birth (12.3%) and caesarean section (37.7%) were slightly above those in the German birthing population. The disease activity of female patients remained relatively stable in pregnancy, with mean cJADAS-10 scores of 5.3, 7.1 and 5.6 in each trimester, respectively. Conclusion. Young adults with JIA often become pregnant or become fathers of children while still being treated with DMARDs. Data suggest no increased risk of major adverse pregnancy outcomes

Botanic Origin of Propolis Extract Powder Drives Contrasted Impact on Diabesity in High-Fat-Fed Mice

International audiencePropolis extracts are considered as nutraceutical products with potentialities towards obesity and comorbidities management. Nevertheless, propolis extracts composition is highly variable and depends on the botanic origin of plants used by the bees to produce propolis. This study aims to evaluate the differential effect of poplar propolis extract powder (PPEP), Baccharis propolis extract powder (BPEP), and/ or Dalbergia propolis extract powder (DPEP) on obesity and glucose homeostasis in high-fat-fed mice. PPEP supplementation reduced high-fat (HF)-mediated body weight gain, adiposity index, and improved glucose homeostasis in male C57Bl/6J mice that were submitted to a high-fat diet for 12 weeks, whereas BPEP, DPEP, or a mix of the three PEPs did not modify those parameters. Adipose tissue (AT) gene expression profiling highlighted an induction of mRNA related to lipid catabolism and an inhibition of mRNA coding for inflammatory markers. Several Nrf2 target genes, coding for antioxidant enzymes, were induced in AT under PPEP effect, but not by other PEP. Interestingly, representative PPEP polyphenols mediated the induction of Nrf2 target genes cell-autonomously in adipocytes, suggesting that this induction may be related to the specific polyphenol content of PPEP. Whereas PPEP supplementation has demonstrated a clear potential to blunt the onset of obesity and associated comorbidities, other PEPs (from Baccharis and Dalbergia) were inefficient to support their role in preventive nutrition

Time of Disease-Modifying Antirheumatic Drug Start in Juvenile Idiopathic Arthritis and the Likelihood of a Drug-Free Remission in Young Adulthood

Objective To study juvenile idiopathic arthritis (JIA) long-term outcomes in relation to the time of initiation of biologic disease-modifying antirheumatic drug (bDMARD). Methods Outcomes of JIA patients prospectively followed by the Biologika in der Kinderrheumatologie (BiKeR) and Juvenile Arthritis Methotrexate/Biologics Long-Term Observation (JuMBO) registers were analyzed with regard to drug-free remission and inactive disease, functional status and quality of life, and surgery. To analyze the influence of early bDMARD therapy on outcomes, patients were assigned to 3 groups based on the time from symptom onset to bDMARD start (G1: 2 to 5 years). Propensity score-adjusted outcome differences were analyzed by multinomial logistic regression analyses among the groups. Results A total of 701 JIA patients were observed for mean +/- SD 9.1 +/- 3.7 years. At the last follow-up (disease duration mean +/- SD 14.3 +/- 6.1 years), 11.7% of patients were in drug-free remission, and 40.0% had inactive disease. More than half of the patients reported no functional limitation, while 5% had undergone arthroplasty, and 3% had eye surgery. At the 10-year time point, patients in G1 (n = 108) were significantly more likely to be in drug-free remission than those patients who began treatment later (G2, n = 199; G3, n = 259), with 18.5%, 10.1%, and 4.9%, respectively. Patients in G1 had significantly lower disease activity (clinical Juvenile Arthritis Disease Activity Score in 10 joints = 4.9), a better overall well-being (18.2% patient global assessment score = 0), and higher functional status (59.2% Health Assessment Questionnaire score = 0), compared to patients in G3 (7.1, 8.4%, and 43.7%, respectively). G1 patients required arthroplasty significantly less frequently than G3 patients and had significantly lower disease activity over time than patients in both G2 and G3. Conclusion Early DMARD treatment is associated with better disease control and outcomes, which supports the concept of a window of opportunity for JIA

Medication burden in young adults with juvenile idiopathic arthritis: data from a multicentre observational study

Objective To assess the medication and disease burden of young adults with juvenile idiopathic arthritis (JIA). Methods Young adults with JIA prospectively followed in the Juvenile Arthritis Methotrexate/Biologics long-term Observation reported on their health status and medication use. All medications taken (disease-modifying antirheumatic drugs (DMARDs)/prescription/over-the-counter drugs, but excluding most local therapies) classified according to the Anatomical Therapeutic Chemical Classification System were included in this analysis. Medication use at last follow-up was evaluated by sex, JIA category and time from symptom onset to the first biological DMARD (bDMARD) start. Results A total of 1306 young adults (68% female) with JIA and a mean disease duration of 13.6 +/- 6 years were included in the study. Patients reported using on average 2.4 +/- 2.1 medicines and 1.5 +/- 1.7 non-DMARD medicines, respectively, at the last follow-up. Almost a quarter of the patients reported polypharmacy. The higher the number of medications used was, the higher the disease activity, pain and fatigue, and the lower the quality of life of patients. Medication usage differed significantly between sexes and JIA categories, being highest in patients with rheumatoid factor-positive polyarthritis and systemic JIA. The number of medications used was significantly associated with the time from symptom onset to bDMARD start. Patients taking opioids or antidepressants had a particularly high disease burden and had received bDMARDs an average of 2 years later than patients not taking these medications. Conclusion Medication use in adults with JIA varies depending on sex, JIA category, and the time between symptom onset and initiation of treatment with bDMARD

Outcome of adult patients with JIA treated with the biosimilar Benepali (R): results of the biologic register JuMBO

Background: To analyze therapy adherence, safety, and outcome in adult patients with juvenile idiopathic arthritis (JIA) treated with the etanercept biosimilar Benepali (R) (Biogen Inc, Cambridge, USA). Methods: Data from the prospective registry, JuMBO (Juvenile arthritis MTX/Biologics long-term Observation), were used for the analysis. JuMBO is a long-term observational cohort study. It follows adult patients with JIA who were formerly included in the national JIA biologic register (BiKeR Registry). Both registries provide individual trajectories of clinical data and outcomes from childhood to adulthood in JIA patients treated with disease-modifying anti-rheumatic drugs (DMARDs). Results: Eighty-three patients from the German JuMBO registry were treated with Benepali (R). Of these, 74% had switched from Enbrel (R) (Pfizer Inc., NYC, USA) the originator of etanercept to Benepali (R) for cost reasons. Therapy survival of patients treated with Benepali (R) in comparison to Enbrel (R) in patients matched by significant parameters was comparable. Adverse events (AE) were reported in 25.3% and serious adverse events (SAE) in 9.6% of patients. Physicians rated no SAE causative related to Benepali (R). The majority of SAEs were surgical/medical procedures and there was only one infection. All efficacy parameters (cJADAS-10, Physician Global Assessment, number of joints with active arthritis, patients' overall well-being, pain, and HAQ) demonstrated improvement over 24 months (p-values were not significant). 9.6% of patients permanently discontinued Benepali (R) because of an AE. Conclusions: Tolerability and effectiveness of the biosimilar Benepali (R) were satisfactory and therapy survival was comparable to the originator. Further data on therapy with biologics and biosimilars such as Benepali (R) must be collected by registries such as BiKeR and JuMBO in order to optimize therapy and patient outcomes and to reduce costs in the health system in the long term