Joke Dehoorne

The effect of botulinum-A toxin in incontinent children with therapy resistant overactive detrusor.

PURPOSE We determined the effect of detrusor injection of botulinum-A toxin in a cohort of children with therapy resistant non-neurogenic detrusor overactivity. This prospective study included therapy resistant children with overactive bladder. MATERIAL AND METHODS During the study period of 19 months 10 boys and 11 girls were included. All patients showed decreased bladder capacity for age, urge and urge incontinence. Main treatment duration before inclusion was 45 months. A dose of 100 U botulinum-A toxin (Botox) was injected in the detrusor. RESULTS Side effects were evaluated in all 21 included patients. The side effects reported were 10-day temporary urinary retention in 1 girl and signs of vesicoureteral reflux with flank pain during voiding in 1 boy, which disappeared spontaneously after 2 weeks. No further examinations were done since the boy refused. Two girls experienced 1 episode each of symptomatic lower urinary tract infection. Eight girls and 7 boys with a minimum followup of 6 months represent the study group for long-term evaluation. In this study group after 1 injection 9 patients showed full response (no more urge and dry during the day) with a mean increase in bladder capacity from 167 to 271 ml (p <0.001). Three patients showed a partial response (50% decrease in urge and incontinence) and 3 remained unchanged. Eight of the 9 full responders were still cured after 12 months, while 1 of the initially successfully treated patients had relapse after 8 months. The 3 partial responders and the patient with relapse underwent a second injection with a full response in the former full responder and in 1 partial responder. CONCLUSIONS Botulinum-A toxin injection in children with non-neurogenic overactive detrusor is an excellent treatment adjunct, leading to long-term results in 70% after 1 injection.

Efficacy and safety of open-label etanercept on extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis and psoriatic arthritis: part 1 (week 12) of the CLIPPER study

Objective To investigate the efficacy and safety of etanercept (ETN) in paediatric subjects with extended oligoarticular juvenile idiopathic arthritis (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA). Methods CLIPPER is an ongoing, Phase 3b, open-label, multicentre study; the 12-week (Part 1) data are reported here. Subjects with eoJIA (2–17 years), ERA (12–17 years), or PsA (12–17 years) received ETN 0.8 mg/kg once weekly (maximum 50 mg). Primary endpoint was the percentage of subjects achieving JIA American College of Rheumatology (ACR) 30 criteria at week 12; secondary outcomes included JIA ACR 50/70/90 and inactive disease. Results 122/127 (96.1%) subjects completed the study (mean age 11.7 years). JIA ACR 30 (95% CI) was achieved by 88.6% (81.6% to 93.6%) of subjects overall; 89.7% (78.8% to 96.1%) with eoJIA, 83.3% (67.2% to 93.6%) with ERA and 93.1% (77.2% to 99.2%) with PsA. For eoJIA, ERA, or PsA categories, the ORs of ETN vs the historical placebo data were 26.2, 15.1 and 40.7, respectively. Overall JIA ACR 50, 70, 90 and inactive disease were achieved by 81.1, 61.5, 29.8 and 12.1%, respectively. Treatment-emergent adverse events (AEs), infections, and serious AEs, were reported in 45 (35.4%), 58 (45.7%), and 4 (3.1%), subjects, respectively. Serious AEs were one case each of abdominal pain, bronchopneumonia, gastroenteritis and pyelocystitis. One subject reported herpes zoster and another varicella. No differences in safety were observed across the JIA categories. Conclusions ETN treatment for 12 weeks was effective and well tolerated in paediatric subjects with eoJIA, ERA and PsA, with no unexpected safety findings.

Oral lyophylizate formulation of desmopressin: superior pharmacodynamics compared to tablet due to low food interaction.

PURPOSE Desmopressin is a standard treatment for monosymptomatic nocturnal enuresis. Different formulations are promoted as bioequivalent, although these claims are not supported by comparative pharmacodynamic data in children. Food interaction is known to influence the bioavailability of desmopressin. We compared the pharmacodynamics of the 2 most frequently used desmopressin formulations, tablet and lyophilizate, with a standardized meal, allowing extrapolation to clinical reality, where the interval between evening meal and medication intake is limited for school-age children. We hypothesized there would be a faster pharmacodynamic response, and greater concentrating and antidiuretic activity for the fast dissolving (melt) formulation compared to the tablet with simultaneous food intake. MATERIALS AND METHODS Two tests were performed on separate days in identical standardized conditions, starting with a 15 ml/kg water load. After achieving maximal diluting capacity a standardized meal was administered, followed by desmopressin tablet (t test) or melt (M-test). Diuresis rate and urinary osmolality were measured hourly. Paired data from 4 girls and 15 boys with a mean age of 12.1 years were obtained. RESULTS In the early response phase more than 25% of patients had a higher diuresis rate with tablet vs melt formulation, reaching statistical significance in the plateau phase (urine collected at hours 3 to 5, p <0.02) and in duration of action (urine collected at hours 5 to 8, p <0.005). For desmopressin melt smaller standard deviations in diuresis rate were remarkable. Concentrating capacity demonstrated no significant differences between formulations in the early response phase, in contrast to the plateau phase (p <0.036) and duration of action (p <0.001). CONCLUSIONS With meal combination desmopressin melt formulation has a superior pharmacodynamic profile to tablet, making it more suitable for the younger age group with a limited interval between meal and drug administration.

Solifenacin for Therapy Resistant Overactive Bladder

PURPOSE With the availability of the once daily oral antimuscarinic agent solifenacin (5 mg), we started to use it for therapy resistant overactive bladder. We evaluate side effects and efficacy. MATERIAL AND METHODS We reviewed the charts of children treated with solifenacin succinate between August 2005 and August 2008 for therapy resistant OAB. Incontinence was compared at study entry and study end. RESULTS During the study period 84 boys and 54 girls with a mean age of 9 years 2 months received solifenacin. Mean followup was 22.59 months. While on solifenacin, side effects were observed in 9 of 138 patients (6.5%). Efficacy evaluation included only 99 patients after 3 months of therapy. Mean voided volume after treatment was 253.5 ml, showing a significant 25% increase compared to the mean value before therapy (50.5 vs 203.0 ml, p <0.01). Of the patients 84 (85%) were considered responders, including 45 who were completely dry (full response) and 39 who had fewer nocturnal enuresis or diurnal incontinence symptoms (partial response). Of these 39 patients 17 became dry during the day, 1 became dry during the night and 21 had more than a 50% decrease in nocturnal enuresis and diurnal incontinence symptoms. In 15 patients the outcome was unchanged or worse (no response). CONCLUSION In this group of children with OAB we noted favorable results with solifenacin with few side effects. Despite the uncontrolled, retrospective study design the effect is attributable to solifenacin intake.

Elicitation of Expert Prior Opinion: Application to the MYPAN Trial in Childhood Polyarteritis Nodosa

Objectives Definitive sample sizes for clinical trials in rare diseases are usually infeasible. Bayesian methodology can be used to maximise what is learnt from clinical trials in these circumstances. We elicited expert prior opinion for a future Bayesian randomised controlled trial for a rare inflammatory paediatric disease, polyarteritis nodosa (MYPAN, Mycophenolate mofetil for polyarteritis nodosa). Methods A Bayesian prior elicitation meeting was convened. Opinion was sought on the probability that a patient in the MYPAN trial treated with cyclophosphamide would achieve disease remission within 6-months, and on the relative efficacies of mycophenolate mofetil and cyclophosphamide. Expert opinion was combined with previously unseen data from a recently completed randomised controlled trial in ANCA associated vasculitis. Results A pan-European group of fifteen experts participated in the elicitation meeting. Consensus expert prior opinion was that the most likely rates of disease remission within 6 months on cyclophosphamide or mycophenolate mofetil were 74% and 71%, respectively. This prior opinion will now be taken forward and will be modified to formulate a Bayesian posterior opinion once the MYPAN trial data from 40 patients randomised 1:1 to either CYC or MMF become available. Conclusions We suggest that the methodological template we propose could be applied to trial design for other rare diseases.

Complete factor i deficiency due to dysfunctional factor i with recurrent aseptic meningo-encephalitis

PurposeComplement regulators control the activated complement system. Defects in this homeostasis can result in tissue damage and autoimmune diseases with a heterogeneity in clinical presentation. Complement factor I (FI), a serine protease, is an important regulator of alternative pathway activation. We report a diagnostic work-up of a patient with relapsing inflammatory mediated meningo-encephalitis. Our work-up revealed a rare genetic factor I (FI) deficiency. So far, all cases of reported complete factor I deficiency have absent serum levels of FI. We present here a unique case of a complete factor I deficiency based on a functional FI defect.MethodsComplement assays and measurement of FI activity were performed in the patient, her family, factor H-deficient patients, a patient with C3-nephritic factor and 11 healthy controls. Genetic sequencing of the FI coding regions in the patient and her parents was performed.ResultsThe patient had absent alternative pathway activity with low levels of C3 and normal serum level of FI. The patient’s plasma FI did not degrade C3b, with normalisation of C3b degradation after adding purified FI. Mutation analysis of the complement factor I gene revealed two heterozygous mutations (I322T and D506V).ConclusionTo our knowledge, this paper describes a complete FI deficiency caused by a defect of FI activity for the first time. Normal FI concentration does not exclude a complete FI defect, additional functional analysis of FI is required in any patient with a defect of complement activation. Recurrent aseptic meningo-encephalitis is a rare clinical presentation of complete FI deficiency.

ASAS definition for sacroiliitis on MRI in SpA: applicable to children?

BackgroundThe Assessment of Spondyloarthritis International Society (ASAS) definition for a ‘positive’ Magnetic Resonance Imaging (MRI) for sacroiliitis is well studied and validated in adults, but studies about the value of this definition in children are lacking. The aim of this study is to evaluate whether the adult ASAS definition of a positive MRI of the sacroiliac joints can be applied to children with a clinical suspicion of Juvenile Spondyloarthritis (JSpA).MethodsTwo pediatric musculoskeletal radiologists blinded to clinical data independently retrospectively reviewed sacroiliac (SI) joint MRI in 109 children suspected of sacroiliitis. They recorded global impression (sacroiliitis yes/no) and whether the adult ASAS definition for sacroiliitis was met at each joint. This was compared to gold-standard clinical diagnosis of JSpA. Additionally, MRI were scored according to’adapted’ ASAS definitions including other features of sacroiliitis on MRI.ResultsJSpA was diagnosed clinically in 47/109 (43%) patients. On MRI, sacroiliitis was diagnosed by global assessment in 30/109 patients, of whom 14 also fulfilled ASAS criteria. No patients with negative global assessment for sacroiliitis fulfilled ASAS criteria. Sensitivity (SN) for JSpA was higher for global assessment (SN = 49%) than for ASAS definition (SN = 26%), but the ASAS definition was more specific (SP = 97% vs. 89%). Modifying adult ASAS criteria to allow bone marrow edema (BME) lesions seen on only one slice, synovitis or capsulitis, increased SN to 36%, 32% and 32% respectively, only slightly lowering SP. Including structural lesions increased SN to 28%, but lowered specificity to 95%.ConclusionThe adult ASAS definition for sacroiliitis has low sensitivity in children. A pediatric-specific definition of MRI-positive sacroiliitis including BME lesions visible on one slice only, synovitis and/or capsulitis may improve diagnostic utility, and increase relevance of MRI in pediatric rheumatology practice.

A novel IKAROS haploinsufficiency kindred with unexpectedly late and variable B-cell maturation defects

Delfien J. Bogaert, MD, PhDa,b,c,d,e, Hye Sun Kuehn, PhDf, Carolien Bonroy, MPharm, PhDd,g, Katherine R. Calvo, MD, PhDh, Joke Dehoorne, MD, PhDi, Arnaud V. Vanlander, MD, PhDj, Marieke De Bruyne, MSca,b,c,d, Urszula Cytlak, PhDk,l, Venetia Bigley, MD, PhDk,l, Frans De Baets, MD, PhDb,d, Elfride De Baere, MD, PhDc,d, Sergio D. Rosenzweig, MD, PhDf, Filomeen Haerynck, MD, PhD#a,b,d, and Melissa Dullaers, PhD#a,d,e,m aClinical Immunology Research Laboratory, Department of Pulmonary Medicine, Ghent University Hospital, Ghent, Belgium

An infant presenting with failure to thrive and hyperkalaemia owing to transient pseudohypoaldosteronism: case report

Abstract A 3-month-old boy presented with failure to thrive and a history of a prenatally detected unilateral hydroureteronephrosis which was confirmed after birth. His growth and developmental milestones had been normal during the first 2 months but in the third month his appetite was poor with reduced intake but no vomiting. At presentation, his temperature was normal, there was mild dehydration and there was weight loss (his weight had decreased by 270 g in the past month). Haemoglobin was 11.9 g/dL, total white cell count 20.2 × 109/L (7–15) [neutrophils 30% (39–75) and lymphocytes 61% (16–47)], platelets 702 × 109/L (150–450), BUN12.1 mmol/L (2.1–16.1), serum creatinine 35.4 μmol/L (15.0–37.1), sodium 126 mmol/L (135–144), potassium 6.8 mmol/L (3.6–4.8), chloride 88 mmol/L (98–106) and bicarbonate 14 mmol/L (19–24). Intravenous rehydration with sodium chloride 0.9% solution was commenced and he was transferred to the paediatric intensive care unit. A salt-wasting syndrome was suspected and a differential diagnosis included adrenal insufficiency, pseudohypoaldosteronism and congenital adrenal hyperplasia (owing to 21-hydroxylase deficiency). Urinalysis confirmed a urinary tract infection. Serum aldosterone was 3608 ng/dL (3.7–43.2), plasma renin activity > 38.9 pmol/L (<0.85), random cortisol 459 nmol/L (74–289), adrenocorticotropic hormone (ACTH) 6.01 pmol/L (1.32–6.60) and 17-hydroxyprogesterone 4.01 nmol/L (<3.2). Treatment of the urinary tract infection was followed by normalisation of serum electrolytes and other biochemical abnormalities, return of appetite and normal growth, which confirmed the diagnosis of transient pseudohypoaldosteronsim (TPHA). TPHA is discussed and insight provided to enable early recognition and adequate treatment of this rare clinical entity.

Diagnostic value of MRI of the sacroiliac joints in juvenile spondyloarthritis

Early diagnosis of spondyloarthritis (SpA) is becoming more important as new medical treatment options have become available to treat inflammation and delay progression of the disease. Increasingly, magnetic resonance imaging (MRI) of the sacroiliac joints is obtained for early detection of inflammatory changes, as it shows active inflammatory and structural lesions of sacroiliitis long before radiographic changes become evident. MRI of the sacroiliac joints in children is a useful tool for suspected juvenile spondyloarthritis (JSpA), even though it is not yet included in the current pediatric classification systems. Recognizing MRI features of pediatric sacroiliitis is a challenge. As most radiologists are not familiar with the normal MRI appearance of the pediatric sacroiliac joint, clear definitions are mandatory. Actually, the adult Assessment of Spondyloarthritis International Society (ASAS) definition for sacroiliitis needs some adaptations for children. A proposal for a possible pediatric-specific definition for active sacroiliitis on MRI is presented in this review. Furthermore, MRI without contrast administration is sufficient to identify bone marrow edema (BME), capsulitis, and retroarticular enthesitis as features of active sacroiliitis in JSpA. In selected cases, when high short tau inversion recovery (STIR) signal in the joint is the only finding, gadolinium-enhanced images may help to confirm the presence of synovitis. Lastly, we found a high correlation between pelvic enthesitis and sacroiliitis on MRI of the sacroiliac joints in children. As pelvic enthesitis indicates active inflammation, it may play a role in assessment of the inflammatory status. Therefore, it should be carefully sought and noted when examining MRI of the sacroiliac joints in children.