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.

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

Propolis 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.

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

In 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 17ß-estradiol concentrations. Thus, maternal VDD sex-dependently modulated metabolic fate of the offspring, especially when associated with HF diet in adulthood.

Poplar Propolis Ethanolic Extract Reduces Body Weight Gain and Glucose Metabolism Disruption in High-Fat Diet-Fed Mice.

SCOPE: Current evidence supports the beneficial effect of polyphenols on the management of obesity and associated comorbidities. This is the case for propolis, a polyphenol-rich substance produced by bees. The aim of the present study is to evaluate the effect of a poplar propolis ethanolic extract (PPEE) on obesity and glucose homeostasis, and to unveil its putative molecular mechanisms of action. METHODS AND RESULTS: Male high-fat (HF) diet-fed mice are administered PPEE for 12 weeks. PPEE supplementation reduces the HF-mediated adiposity index, adipocyte hypertrophy, and body weight gain. It also improves HOMA-IR and fasting glucose levels. Gene expression profiling of adipose tissue (AT) shows an induction of mRNA related to lipid catabolism and mitochondrial biogenesis and inhibition of mRNA coding for inflammatory markers. Interestingly, several Nrf2-target genes are induced in AT following administration of PPEE. The ability of PPEE to induce the expression of Nrf2-target genes is studied in adipocytes. PPEE is found to transactivate the Nrf2 response element and the Nrf2 DNA-binding, suggesting that part of the effect of PPEE can be mediated by Nrf2. CONCLUSION: PPEE supplementation may represent an interesting preventive strategy to tackle the onset of obesity and associated metabolic disorders.

Gene-Dose Effect of MEFV Gain-of-Function Mutations Determines ex vivo Neutrophil Activation in Familial Mediterranean Fever.

Familial Mediterranean fever (FMF) is caused by mutations within the Mediterranean fever (MEFV) gene. Disease severity depends on genotype and gene dose with most serious clinical courses observed in patients with M694V homozygosity. Neutrophils are thought to play an important role in the initiation and perpetuation of inflammatory processes in FMF, but little is known about the specific characteristics of these cells in FMF patients. To further characterize neutrophilic inflammatory responses in FMF and to delineate gene-dose effects on a cellular level, we analyzed cytokine production and activation levels of isolated neutrophils derived from patients and subjects with distinct MEFV genotypes, as well as healthy and disease controls. Serum levels of interleukin-18 (IL-18) (median 11,485 pg/ml), S100A12 (median 9,726 ng/ml), and caspase-1 (median 394 pg/ml) were significantly increased in patients with homozygous M694V mutations. Spontaneous release of S100A12, caspase-1, proteinase 3, and myeloperoxidase (MPO) was restricted to ex vivo cultured neutrophils derived from patients with two pathogenic MEFV mutations. IL-18 secretion was highest in patients with two mutations but also increased in neutrophils from healthy heterozygous MEFV mutation carriers, exhibiting an ex vivo gene-dose effect, which was formerly described by us in patients' serum. CD62L (l-selectin) was spontaneously shed from the surface of ex vivo cultured neutrophils [median of geometric mean fluorescence intensity (gMFI) after 5 h: 28.8% of the initial level]. While neutrophils derived from healthy heterozygous mutation carriers again showed a gene-dose effect (median gMFI: 67.1%), healthy and disease controls had significant lower shedding rates (median gMFI: 83.6 and 82.9%, respectively). Co-culture with colchicine and/or stimulation with adenosine triphosphate (ATP) and lipopolysaccharide (LPS) led to a significant increase in receptor shedding. Neutrophils were not prevented from spontaneous shedding by blocking IL-1 or the NLRP3 inflammasome. In summary, the data demonstrate that ex vivo cultured neutrophils derived from FMF patients display a unique phenotype with spontaneous release of high amounts of IL-18, S100A12, MPO, caspase-1, and proteinase 3 and spontaneous activation as demonstrated by the loss of CD62L. Neutrophilic activation seems to be independent from IL-1 activation and displays a gene-dose effect that may be responsible for genotype-dependent phenotypes.

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 years, G2: >2 to ≤5 years, and G3: >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.

Long-term outcome of patients with JIA treated with etanercept, results of the biologic register JuMBO.

OBJECTIVE: To assess the outcome of adult patients with JIA who received etanercept (ETA) during childhood. METHODS: JuMBO (Juvenile arthritis MTX/Biologics long-term Observation) is an ongoing prospective cohort study. It follows adult JIA patients who were formerly included in the national JIA biologic register. In JuMBO, clinical status, therapy and the occurrence of adverse events are documented every 6 months by physicians; additionally, patient-derived data are included [e.g. functional capacity and health-related quality of life (HRQoL)]. Here, data from the last available visit of patients were analysed. RESULTS: Until December 2010, 346 patients with a median age of 21 years were included in JuMBO. The majority of them had polyarthritis. Seventy-eight per cent of them were still on DMARDs, 45% on ETA. The disease was inactive in about one in five patients. A restricted functional capacity was reported by 51% of participants and fatigue by 76%. The patients judged their HRQoL to be lower than a reference group from the general population, but only with regard to physical health. HRQoL correlated with the patient's perceived fatigue. Most frequently observed comorbidities in the young adults with JIA were disease related and included uveitis, IBDs and psoriasis. During the observation period, 2.1 severe infections and 1.5 new-onset autoimmune events per 100 patient-years were reported in patients on ETA, respectively. CONCLUSION: The first data from the JuMBO register indicate an improved long-term outcome of patients with severe JIA treated in the biologic era and an acceptable safety profile of ETA.