A comparison of three treatment strategies in recent onset non-systemic Juvenile Idiopathic Arthritis: Initial 3-months results of the BeSt for Kids-study

Background: Combination therapy with prednisone or etanercept may induce earlier and/or more improvement in disease activity in Disease Modifying Anti Rheumatic Drug (DMARD) naïve non-systemic Juvenile Idiopathic Arthritis (JIA) patients. Here we present three months clinical outcome of initial treatments of the BeSt-for-Kids study. Methods: Included patients were randomized to either: 1. initial DMARD-monotherapy (sulfasalazine (SSZ) or methotrexate (MTX)), 2. Initial MTX / prednisolone-bridging, 3. Initial combination MTX/etanercept. Percentage inactive disease, adjusted (a) ACR Pedi30, 50 and 70 and JADAS after 6 and 12 weeks of treatment (intention to treat analysis) and side effects are reported. Results: 94 patients (67% girls, 32 (arm 1), 32 (arm 2) and 30 (arm 3) with median (InterQuartileRange) age of 9.1 (4.7-12.9) years were included. 38% were ANA positive, 10 had oligo-articular disease, 68 polyarticular JIA and 16 psoriatic arthritis. Baseline median (IQR) ACRpedi-scores: VAS physician 49 (40-58) mm, VAS patient 54 (37-70) mm, ESR 6.5 (2-14.8)mm/hr, active joint count 8 (5-12), limited joint count 3 (1-5), CHAQ score 0.88 (0.63-1.5). In arm 1, 17 started with MTX, 15 with SSZ. After 3 months, aACR Pedi 50 was reached by 10/32 (31%), 12/32(38%) and 16/30 (53%) (p = 0.19) and aACR Pedi 70 was reached by 8/32 (25%), 6/32(19%) and 14/30(47%) in arms 1-3 (p = 0.04). Toxicity was similar. Few serious adverse events were reported. Conclusion: After 3 months of treatment in a randomized trial, patients with recent-onset JIA achieved significantly more clinical improvement (aACRPedi70) on initial combination therapy with MTX / etanercept than on initial MTX or SSZ monotherapy. Trial registration:NTR1574. Registered 3 December 2008

Significant pain decrease in children with non-systemic Juvenile Idiopathic Arthritis treated to target:results over 24 months of follow up

Background: The aim of this study was to compare pain-scores in three targeted treatment-strategies in JIA-patients and to identify characteristics predicting persistent pain. Methods: In the BeSt-for-Kids-study 92 DMARD-naïve JIA-patients were randomized in 3 treatment-strategies: 1) initial sequential DMARD-monotherapy 2) initial methotrexate (MTX)/prednisolone-bridging or 3) initial MTX/etanercept. Potential differences in VAS pain scores (0-100 mm) over time between treatment-strategies were compared using linear mixed models with visits clustered within patients. A multivariable model was used to assess the ability of baseline characteristics to predict the chance of high pain-scores during follow-up. Results: Pain-scores over time reduced from mean 55.3 (SD 21.7) to 19.5 (SD 25.3) mm after 24 months. On average, pain-scores decreased significantly with β -1.37 mm (95% CI -1.726; -1.022) per month. No significant difference was found between treatment-strategies (interaction term treatment arm*time (months) β (95% CI) arm 1: 0.13 (-0.36; 0.62) and arm 2: 0.37 (-0.12; 0.86) compared to arm 3). Correction for sex and symptom duration yielded similar results. Several baseline characteristics were predictive for pain over time. Higher VAS pain [β 0.44 (95% CI 0.25; 0.65)] and higher active joint count [0.77 (0.19; 1.34)] were predictive of higher pain over time, whereas, low VAS physician [-0.34 (-0.55; -0.06)], CHQ Physical [-0.42 (-0.72; -0.11)] and Psychosocial summary Score [-0.42 (-0.77; -0.06)] were predictive of lower pain. Conclusions: Treatment-to-target seems effective in pain-reduction in non-systemic JIA-patients irrespective of initial treatment-strategy. Several baseline-predictors for pain over time were found, which could help to identify patients with a high risk for development of chronic pain. Trial registration: Dutch Trial Registry number 1574.</p

Increasing the etanercept dose in a treat-to-target approach in juvenile idiopathic arthritis:does it help to reach the target? A post-hoc analysis of the BeSt for Kids randomised clinical trial

Background: Etanercept has been studied in doses up to 0.8 mg/kg/week (max 50 mg/week) in juvenile idiopathic arthritis (JIA) patients. In clinical practice higher doses are used off-label, but evidence regarding the relation with outcomes is lacking. We describe the clinical course of JIA-patients receiving high-dose etanercept (1.6 mg/kg/week; max 50 mg/week) in the BeSt for Kids trial. Methods: 92 patients with oligoarticular JIA, RF-negative polyarticular JIA or juvenile psoriatic arthritis were randomised across three treat-to-target arms: (1) sequential DMARD-monotherapy (sulfasalazine or methotrexate (MTX)), (2) combination-therapy MTX + 6 weeks prednisolone and (3) combination therapy MTX + etanercept. In any treatment-arm, patients could eventually escalate to high-dose etanercept alongside MTX 10mg/m2/week. Results: 32 patients received high-dose etanercept (69% female, median age 6 years (IQR 4–10), median 10 months (7–16) from baseline). Median follow-up was 24.6 months. Most clinical parameters improved within 3 months after dose-increase: median JADAS10 from 7.2 to 2.8 (p = 0.008), VAS-physician from 12 to 4 (p = 0.022), VAS-patient/parent from 38.5 to 13 (p = 0.003), number of active joints from 2 to 0.5 (p = 0.12) and VAS-pain from 35.5 to 15 (p = 0.030). Functional impairments (CHAQ-score) improved more gradually and ESR remained stable. A comparable pattern was observed in 11 patients (73% girls, median age 8 (IQR 6–9)) who did not receive high-dose etanercept despite eligibility (comparison group). In both groups, 56% reached inactive disease at 6 months. No severe adverse events (SAEs) occurred after etanercept dose-increase. In the comparison group, 2 SAEs consisting of hospital admission occurred. Rates of non-severe AEs per subsequent patient year follow-up were 2.27 in the high-dose and 1.43 in the comparison group. Conclusions: Escalation to high-dose etanercept in JIA-patients who were treated to target was generally followed by meaningful clinical improvement. However, similar improvements were observed in a smaller comparison group who did not escalate to high-dose etanercept. No SAEs were seen after escalation to high-dose etanercept. The division into the high-dose and comparison groups was not randomised, which is a potential source of bias. We advocate larger, randomised studies of high versus regular dose etanercept to provide high level evidence on efficacy and safety. Trial registration: Dutch Trial Register; NTR1574; 3 December 2008; https://onderzoekmetmensen.nl/en/trial/26585.</p

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The 'omics' approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n = 20) and confirmed viral infection (n = 20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group. A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection ar

6022 Study on Regional Management Structure Focused on Cooperation Between NPO-Kanakura-School and Kanakura-Village : In the case of District Kanakura, Machino-machi, Wajima-shi

textabstractObjective. To evaluate response in patients with juvenile idiopathic arthritis (JIA) who failed to meet response criteria after 3 months of etanercept treatment. Methods. This was a prospective ongoing multicenter observational study of all Dutch patients with JIA using etanercept. Response according to American College of Rheumatology Pediatric 30 criteria was assessed at study start and at 3 and 15 months. Results. In total we studied 179 patients of median age 5.8 years at disease onset; 70% were female. Thirty-four patients did not respond after 3 months, of which 20 continued etanercept and 11 achieved response thereafter. Conclusion. The delayed clinically relevant response in a substantial proportion of patients who initially did not respond justifies the consideration of continuing therapy to at least 6 months. The Journal of Rheumatology Copyrigh

Long-term quality of life and functional outcome of patients with juvenile idiopathic arthritis in the biologic era: a longitudinal follow-up study in the Dutch Arthritis and Biologicals in Children Register

To carry out a longitudinal investigation of functional outcome, health-related quality of life (HRQoL) and treatment strategies in JIA patients who started etanercept >5 years ago. We approached patients whose HRQoL changes were described previously in a subanalysis of the Dutch Arthritis and Biologicals in Children register. Recent disease status, co-morbidities and structural damage were retrieved. Disability and HRQoL were assessed by (Childhood) HAQ [(C)HAQ], Child Health Questionnaire, Short Form 36 and Health Utilities Index Mark 3. Changes over time were analysed with linear mixed models. Forty-three patients (81% response) started etanercept a median 8.5 years ago. At the time of this long-term analysis, median age was 22 years (interquartile range: 18-24 years). HRQoL outcome was similar to HRQoL 15-27 months after the initiation of etanercept; 42% had a (C)HAQ of 0.00 and 67% had achieved inactive disease. Patients reported increasing levels of bodily pain compared with earlier measurements. Unemployment (12%) was comparable to the general population; educational level was higher. Use of biologic agents was as follows: 40% etanercept; 40% other biologic agents; and 20% none. Joint surgery occurred in 14% of patients. At a median 8.5 years after the commencement of etanercept treatment, JIA patients maintain most of the acquired improvement in HRQoL. Although disability and disease activity are low, chronic pain remains an issue. Persistence and possible deterioration of radiological damage emphasize the importance of early treatment. The fact that 20% of patients do not use any anti-rheumatic medication shows that clinical remission of medication might be an achievable goa

Concise report Long-term quality of life and functional outcome of patients with juvenile idiopathic arthritis in the biologic era: a longitudinal follow-up study in the Dutch Arthritis and Biologicals in Children Register

Abstract Objective. To carry out a longitudinal investigation of functional outcome, health-related quality of life (HRQoL) and treatment strategies in JIA patients who started etanercept &gt;5 years ago. Methods. We approached patients whose HRQoL changes were described previously in a subanalysis of the Dutch Arthritis and Biologicals in Children register. Recent disease status, co-morbidities and structural damage were retrieved. Disability and HRQoL were assessed by (Childhood) HAQ [(C)HAQ], Child Health Questionnaire, Short Form 36 and Health Utilities Index Mark 3. Changes over time were analysed with linear mixed models

Delayed Clinical Response in Patients with Juvenile Idiopathic Arthritis Treated with Etanercept

textabstractObjective. To evaluate response in patients with juvenile idiopathic arthritis (JIA) who failed to meet response criteria after 3 months of etanercept treatment. Methods. This was a prospective ongoing multicenter observational study of all Dutch patients with JIA using etanercept. Response according to American College of Rheumatology Pediatric 30 criteria was assessed at study start and at 3 and 15 months. Results. In total we studied 179 patients of median age 5.8 years at disease onset; 70% were female. Thirty-four patients did not respond after 3 months, of which 20 continued etanercept and 11 achieved response thereafter. Conclusion. The delayed clinically relevant response in a substantial proportion of patients who initially did not respond justifies the consideration of continuing therapy to at least 6 months. The Journal of Rheumatology Copyrigh

Loss of ADAM17 is associated with severe multiorgan dysfunction

ADAM metallopeptidase domain 17 (ADAM17) is responsible for processing large numbers of proteins. Recently, 1 family involving 2 patients with a homozygous mutation in ADAM17 were described, presenting with skin lesions and diarrhea. In this report, we describe a second family confirming the existence of this syndrome. The proband presented with severe diarrhea, skin rash, and recurrent sepsis, eventually leading to her death at the age of 10 months. We performed exome sequencing and detailed pathological and immunological investigations. We identified a novel homozygous frameshift mutation in ADAM17 (NM_003183.4:c.308dupA) leading to a premature stop codon. CD4(+) and CD8(+) T-cell stimulation assays showed severely diminished tumor necrosis factor-α and interleukin-2 production. Skin biopsies indicated a focal neutrophilic infiltrate and spongiotic dermatitis. Interestingly, the patient developed unexplained systolic hypertension and nonspecific hepatitis with apoptosis. This report provides evidence for an important role of ADAM17 in human immunological response and underscores its multiorgan involvement