Neurodevelopmental and other phenotypes recurrently associated with heterozygous BAZ2B loss-of-function variants.

The bromodomain adjacent to zinc finger 2B (BAZ2B) gene encodes a chromatin remodeling protein that has been shown to perform a variety of regulatory functions. It has been proposed that loss of BAZ2B function is associated with neurodevelopmental phenotypes, and some recurrent structural birth defects and dysmorphic features have been documented among individuals carrying heterozygous loss-of-function BAZ2B variants. However, additional evidence is needed to confirm that these phenotypes are attributable to BAZ2B deficiency. Here, we report 10 unrelated individuals with heterozygous deletions, stop-gain, frameshift, missense, splice junction, indel, and start-loss variants affecting BAZ2B. These included a paternal intragenic deletion and a maternal frameshift variant that were inherited from mildly affected or asymptomatic parents. The analysis of molecular and clinical data from this cohort, and that of individuals previously reported, suggests that BAZ2B haploinsufficiency causes an autosomal dominant neurodevelopmental syndrome that is incompletely penetrant. The phenotypes most commonly seen in association with loss of BAZ2B function include developmental delay, intellectual disability, autism spectrum disorder, speech delay-with some affected individuals being non-verbal-behavioral abnormalities, seizures, vision-related issues, congenital heart defects, poor fetal growth, and an indistinct pattern of dysmorphic features in which epicanthal folds and small ears are particularly common.

Treat to target (drug-free) inactive disease in DMARD-naive juvenile idiopathic arthritis: 24-month clinical outcomes of a three-armed randomised trial.

QUESTION: Which is the best strategy to achieve (drug-free) inactive disease in juvenile idiopathic arthritis (JIA)? METHODS: In a randomised, single-blinded, study in disease-modifying anti-rheumatic drug (DMARD)-naive patients with JIA, three treatment-strategies were compared: (1) sequential DMARD-monotherapy (sulfasalazine or methotrexate (MTX)), (2) combination therapy MTX + 6 weeks prednisolone and (3) combination therapy MTX +etanercept. Treatment-to-target entailed 3-monthly DMARD/biological adjustments in case of persistent disease activity, with drug tapering to nil in case of inactive disease.After 24 months, primary outcomes were time-to-inactive-disease and time-to-flare after DMARD discontinuation. Secondary outcomes were adapted ACRPedi30/50/70/90 scores, functional ability and adverse events. RESULTS: 94 children (67 % girls) aged median (IQR) 9.1 (4.6-12.9) years were enrolled: 32 in arms 1 and 2, 30 in arm 3. At baseline visual analogue scale (VAS) physician was mean 49 (SD 16) mm, VAS patient 53 (22) mm, erythrocyte sedimentation rate 12.8 (14.7), active joints median 8 (5-12), limited joints 2.5 (1-4.8) and Childhood Health Assessment Questionnaire score mean 1.0 (0.6).After 24 months, 71% (arm 1), 70% (arm 2) and 72% (arm 3) of patients had inactive disease and 45% (arm 1), 31% (arm 2) and 41% (arm 3) had drug-free inactive disease. Time-to-inactive-disease was median 9.0 (5.3-15.0) months in arm 1, 9.0 (6.0-12.8) months in arm 2 and 9.0 (6.0-12.0) months in arm 3 (p=0.30). Time-to-flare was not significantly different (overall 3.0 (3.0-6.8) months, p=0.7). Adapted ACR pedi-scores were comparably high between arms. Adverse events were similar. CONCLUSION: Regardless of initial specific treatments, after 24 months of treatment-to-target aimed at drug-free inactive disease, 71% of recent-onset patients with JIA had inactive disease (median onset 9 months) and 39% were drug free. Tightly controlled treatment-to-target is feasible. TRIAL REGISTRATION NUMBER: 1574.

Trends in prescription of biological agents and outcomes of juvenile idiopathic arthritis: results of the Dutch national Arthritis and Biologics in Children Register.

BACKGROUND: Treatment of juvenile idiopathic arthritis (JIA) has changed dramatically since the introduction of biological agents in 1999. OBJECTIVE: To evaluate trends in prescription patterns of biological agents and the subsequent outcome of JIA. METHODS: The Arthritis and Biologics in Children register (multicentre prospective observational study) aimed to include all consecutive patients with JIA in the Netherlands who had started biological agents since 1999. Patients were divided according to year of introduction of first biological agent. Patient characteristics at introduction of the first biological agent and its effectiveness were analysed over 12 years. RESULTS: 335 patients with non-systemic JIA and 86 patients with systemic JIA started a biological agent between 1999 and 2010. Etanercept remained the most often prescribed biological agent for non-systemic JIA; anakinra became first choice for systemic JIA. The use of systemic glucocorticoids and synthetic disease-modifying antirheumatic drugs before biological agents decreased. During these 12 years of observation, biological agents were prescribed earlier in the disease course and to patients with lower baseline JADAS (Juvenile Arthritis Disease Activity Score) disease activity. All baseline disease activity parameters were lowered in patients with non-systemic JIA. In systemic JIA, prescription patterns changed towards very early introduction of biological agents (median 0.4 years of disease duration) in patients with a low number of joints with active arthritis and high erythrocyte sedimentation rates. These changes for both systemic and non-systemic JIA resulted in more patients with inactive disease after 3 and 15 months of treatment. CONCLUSIONS: Biological agents are increasingly prescribed, earlier in the disease and in patients with JIA with lower disease activity. These changes are accompanied by better short-term disease outcomes.

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.

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 >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. RESULTS: 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. CONCLUSION: 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 goal.

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 .

Effectiveness and safety of a second and third biological agent after failing etanercept in juvenile idiopathic arthritis: results from the Dutch National ABC Register.

OBJECTIVE: To evaluate the effectiveness and safety of switching to a second or third biological agent in juvenile idiopathic arthritis (JIA) after etanercept failure. METHODS: The Arthritis and Biologicals in Children Register aims to include all Dutch JIA patients who have used biological agents. Data on the disease course were used to estimate drug survival with Kaplan-Meier and calculate adverse event (AE) rates. RESULTS: Of 307 biologically naive JIA patients who started etanercept, 80 (26%) switched to a second and 22 (7%) to a third biological agent. During 1030 patient-years of follow-up after the introduction of etanercept, 49 switches to adalimumab, 28 infliximab, 17 anakinra, four abatacept and four trial drugs were evaluated. 84% (95% CI 80% to 88%) of patients who started etanercept as a first biological agent were, after 12 months, still on the drug, compared with 47% (95% CI 35% to 60%) who started a second and 51% (95% CI 26% to 76%) who started a third biological agent. Patients who switched because of primary ineffectiveness continued the second agent less often (32%, 95% CI 12% to 53%). After etanercept failure, drug continuation of adalimumab was similar to infliximab for patients with non-systemic JIA; anakinra was superior to a second TNF-blocker for systemic JIA. AE rates within first 12 months after initiation were comparable for each course and each biological agent. CONCLUSIONS: Switching to another biological agent is common, especially for systemic JIA patients. A second (and third) agent was less effective than the first. The choice of second biological agent by the physician mainly depends on availability and JIA category.

Tumour necrosis factor-blocking agents in persistent oligoarticular juvenile idiopathic arthritis: results from the Dutch Arthritis and Biologicals in Children Register.

OBJECTIVE: Because TNF inhibitors are not approved for persistent oligoarticular JIA (oJIA), although they are used off-label, we evaluated their effectiveness in patients in this category. METHODS: Persistent oJIA patients were selected from the Dutch Arthritis and Biologicals in Children (ABC) register, an ongoing multicentre prospective study that aims to include all Dutch children with JIA using biologic agents. Response was assessed by the JIA core-set disease activity variables and modified Wallace criteria for inactive disease. RESULTS: Until February 2011, 16 persistent oJIA patients (68.8% females) had been included in the register. Median age of onset was 8.4 years [interquartile range (IQR) 2.1-13.5 years]; history of uveitis in 18.8%; ANA-positive 56.3%. All had previously used MTX, and 81.3% had used IA CSs. Median follow-up after the introduction of biologic treatment was 13.7 months (IQR 8.3-16.7 months). Fourteen patients started etanercept and two patients who had active arthritis as well as uveitis started adalimumab. Although patients with persistent oJIA had few affected joints [median of two active joints at the start of biologic (IQR 1-3)], the patient/parent assessments of pain [median visual analogue score (VAS) 51 (IQR 1-64)] and well-being [median VAS 44 (IQR 6-66)] were high. Additionally, their physician evaluated the disease activity as moderately high [median VAS 36 (IQR 4-65)]. After 3 months this decreased to 0 (IQR 0-30) and 63% achieved inactive disease. After 15 months the disease was inactive in 9/10 observed patients. TNF inhibitors were tolerated well. CONCLUSION: TNF blocking agents seem an effective and justifiable option in persistent oJIA when treatment with IA CS injections and MTX has failed.

Treatment choices of paediatric rheumatologists for juvenile idiopathic arthritis: etanercept or adalimumab?

OBJECTIVES: To evaluate differences in baseline characteristics between etanercept- and adalimumab-treated JIA patients and to reveal factors that influence the choice between these TNF inhibitors, which are considered equally effective in the recent ACR recommendations for JIA treatment. METHODS: Biologic-naïve JIA patients with active arthritis who started treatment with adalimumab or etanercept between March 2008 and December 2011 were selected from the Dutch Arthritis and Biologicals in Children register. Baseline characteristics were compared. Focus group interviews with paediatric rheumatologists were performed to evaluate factors determining treatment choices. RESULTS: A total of 193 patients started treatment with etanercept and 21 with adalimumab. Adalimumab-treated patients had longer disease duration prior to the start of biologics (median 5.7 vs 2.0 years) and more often a history of uveitis (71% vs 4%). Etanercept-treated patients had more disability at baseline (median Childhood Health Assessment Questionnaire score 1.1 vs 0.4) and more active arthritis (median number of active joints 6 vs 4). The presence of uveitis was the most important factor directing the choice towards adalimumab. Factors specific for the paediatric population-such as painful adalimumab injections-as well as the physician's familiarity with the drug accounted for the preference for etanercept. CONCLUSION: Although the two TNF inhibitors are considered equally effective, in daily practice etanercept is most often prescribed; adalimumab is mainly preferred when uveitis is present. In choosing the most suitable biologic treatment, paediatric rheumatologists take into account drug and patient factors, considering newly published data and cautiously implementing this into daily care.

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 ß -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) ß (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 [ß 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.

Tumour necrosis factor (TNF)-blocking agents in juvenile psoriatic arthritis: are they effective?

OBJECTIVES: To evaluate the effectiveness of tumour necrosis factor (TNF) blockers in juvenile psoriatic arthritis (JPsA). METHODS: The study was a prospective ongoing multicentre, observational study of all Dutch juvenile idiopathic arthritis (JIA) patients using biologicals. The response of arthritis was assessed by American College of Rheumatology (ACR) paediatric response and Wallace inactive disease criteria. The response of psoriatic skin lesions was scored by a 5-point scale. RESULTS: Eighteen JPsA patients (72% female, median age onset 11.1 (range 3.3-14.6) years, 50% psoriatic skin lesions, 39% nail pitting, 22% dactylitis) were studied. The median follow-up time since starting anti-TNFα was 26 (range 3-62) months. Seventeen patients started on etanercept and one started on adalimumab. After 3 months of treatment 83% of the patients achieved ACR30 response, increasing to 100% after 15 months. Inactive disease reached in 67% after 39 months. There was no discontinuation because of inefficacy. Six patients discontinued treatment after a good clinical response. However, five patients flared and restarted treatment, all with a good response. During treatment four patients (two JPsA and two JIA patients with other subtypes) developed de novo psoriasis. In four of the nine patients the pre-existing psoriatic skin lesions improved. CONCLUSION: Anti-TNFα therapy in JPsA seems effective in treating arthritis. However, in most patients the arthritis flared up after treatment discontinuation, emphasising the need to investigate optimal therapy duration. The psoriatic skin lesions did not respond well and four patients developed de novo psoriasis.

An analysis of the costs and treatment success of etanercept in juvenile idiopathic arthritis: results from the Dutch Arthritis and Biologicals in Children register.

OBJECTIVE: To analyse and report the costs and effects of etanercept therapy in patients with JIA. METHODS: Forty-nine JIA patients were evaluated by means of the JIA core set at the start of etanercept and after 3, 15 and 27 months of therapy. At the same time-points, parents of the patients were asked to complete the Health Utility Index Mark 3 (HUI3). Direct medical costs were collected for 1 year before and 27 months after the start of etanercept and compared with gain in utility. RESULTS: Mean total direct medical costs after the start of etanercept were on average 12 478 euros per patient-year compared with 3720 euros before start. The cost analysis showed that three-quarters of total direct medical costs were from etanercept itself. Other direct medical costs, such as costs concerning hospitalization and concomitant medication, decreased compared with the costs in the period before start of etanercept. Especially a great reduction of consultations at the outpatient clinic was seen. Utility was 0.53 before start of etanercept, according to the multi-attribute utility function of the HUI3 on a scale from 0 (dead) to 1 (perfect health). After 27 months, utility was 0.78. In accordance, also all JIA core set response variables improved significantly over 27 months of etanercept treatment. CONCLUSIONS: Although costs of etanercept therapy are substantial, the gain in utility is even more impressive. Considering that these JIA patients were previously refractory to conventional treatment including MTX, and were at risk of long-time disability and pain, costs are justifiable.

Factors associated with treatment response to etanercept in juvenile idiopathic arthritis.

CONTEXT: Since the introduction of biologic therapies, the pharmacological treatment approach for juvenile idiopathic arthritis (JIA) has changed substantially, with achievement of inactive disease as a realistic goal. OBJECTIVE: To determine the response to therapy after initiation of etanercept therapy among patients with JIA and to examine the association between baseline factors and response to etanercept treatment. DESIGN, SETTING, AND PATIENTS: The Arthritis and Biologicals in Children Register, an ongoing prospective observational study since 1999, includes all Dutch JIA patients who used biologic agents. All biologically naive patients who started etanercept before October 2009 were included, with follow-up data to January 2011. Among the 262 patients, 185 (71%) were female, 46 (18%) had systemic-onset, and the median age at initiation of etanercept treatment was 12.4 years. MAIN OUTCOME MEASURES: Excellent response (inactive disease or discontinuation earlier due to disease remission), intermediate response (more than 50% improvement from baseline, but no inactive disease), and poor response (less than 50% improvement from baseline or discontinuation earlier due to ineffectiveness or intolerance) evaluated 15 months after initiation of etanercept. RESULTS: At 15 months after treatment initiation, 85 patients (32%) were considered excellent responders; 92 (36%), intermediate responders; and 85 (32%), poor responders. Compared with an intermediate or poor response, an excellent response was associated with lower baseline disability score (range, 0-3 points, with 0 being the best score; adjusted odds ratio [OR] per point increase, 0.49; 95% CI, 0.33-0.74); fewer disease-modifying antirheumatic drugs (DMARD) (including methotrexate) used before initiating etanercept (adjusted OR per DMARD used, 0.64; 95% CI, 0.43-0.95), and younger age at onset (adjusted OR per year increase, 0.92; 95% CI, 0.84-0.99). Compared with an intermediate or excellent response, a poor response was associated with systemic JIA (adjusted OR systemic vs nonsystemic categories, 2.92; 95% CI, 1.26-6.80), and female sex (adjusted OR female vs male, 2.16; 95% CI, 1.12-4.18). Within the first 15 months of etanercept treatment, 119 patients experienced 1 or more infectious, noninfectious, or serious adverse events, including 37 among those with an excellent response, 36 with an intermediate response, and 46 with a poor response. Within the first 15 months of treatment, 61 patients discontinued etanercept treatment, including 4 with an excellent response, 0 with an intermediate response, and 57 with a poor response. In a secondary analysis of 262 patients with a median follow-up of 35.6 months after initiation of etanercept, a range of 37% to 49% of patients reached inactive disease. The mean adherence to etanercept was 49.2 months (95% CI, 46.4-52.0) for patients with an excellent response after 15 months, 47.5 months (95% CI, 44.9-50.1) for patients with an intermediate response, and 17.4 months (95% CI, 13.6-21.2) for patients with a poor response. CONCLUSIONS: Among patients with JIA who initiated treatment with etanercept, one-third achieved an excellent response, one-third an intermediate response, and one-third a poor response to therapy. Achievement of an excellent response was associated with low baseline disability scores, DMARDs used before initiating etanercept, and younger age at onset of JIA. Achievement of a poor treatment response was associated with systemic JIA and female sex.

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.

Tumor necrosis factor-blocking agents for children with enthesitis-related arthritis--data from the dutch arthritis and biologicals in children register, 1999-2010.

OBJECTIVE: To evaluate the effectiveness and safety of biological agents in children with enthesitis-related arthritis (ERA). METHODS: All patients with ERA in whom a biological agent was initiated between 1999 and 2010 were selected from the Dutch Arthritis and Biologicals in Children (ABC) register. In this ongoing multicenter observational register, data on the course of the disease and medication use are retrieved prospectively at the start of the biological agent, after 3 months, and yearly thereafter. Inactive disease was assessed in accordance with the Wallace criteria. RESULTS: Twenty-two patients with ERA started taking 1 or more biological agents: 20 took etanercept, 2 took adalimumab (1 switched from etanercept to adalimumab), and 2 took infliximab (1 switched from etanercept to infliximab). Characteristics: 77% were male, 77% had enthesitis, 68% were HLA-B27-positive. The median age of onset was 10.4 (IQR 9.4-12.0) years; median followup from the start of the biological agent was 1.2 (IQR 0.5-2.4) years. Intention-to-treat analysis shows that inactive disease was achieved in 7 of 22 patients (32%) after 3 months, 5 of 13 patients (38%) after 15 months, and 5 of 8 patients (63%) after 27 months of treatment. Two patients discontinued etanercept because of ineffectiveness, and switched to adalimumab (inactive disease achieved) or infliximab (decline in joints with arthritis after 3 months of treatment). One patient discontinued etanercept because of remission, but had flare and restarted treatment, with good clinical response. No serious adverse events occurred. CONCLUSION: Tumor necrosis factor (TNF)-blocking agents seem effective and safe for patients with ERA that was previously unresponsive to 1 or more DMARD. However, a sustained disease-free state could not be achieved, and none discontinued TNF-blocking agents successfully.

[Serious gastrointestinal complications due to accidental ingestion of magnetic toy parts]. / Ernstige gastro-intestinale complicaties door inslikken van magnetisch speelgoed.

A 3-year-old boy presented at the emergency room with abdominal pain, nausea and non-bilious vomiting. Physical examination revealed moderate symptoms of dehydration, a tender and slightly extended but soft abdomen and active peristalsis. With the working diagnosis of viral gastroenteritis the boy was admitted to the hospital for rehydration therapy by nasogastric tube. After a few days an abdominal X-ray was taken because of bilious vomiting and persistent absence of defecation. Connected foreign bodies were seen in the small intestine. These appeared to be 3 magnetic toy parts. Laparotomy showed that all symptoms were due to a volvulus of the small intestine around a fistula caused by entrapment of the intestinal wall between attracted magnets. Magnetic construction toys can be bought in toy stores in the Netherlands. Vigilance should be exercised with magnetic toys, because ingestion of multiple magnets can cause potentially life-threatening bowel complications.

Delayed clinical response in patients with juvenile idiopathic arthritis treated with etanercept.

OBJECTIVE: 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.