Sustainability of biologic treatment in paediatric patients with Crohn's disease: population-based registry analysis.

BACKGROUND: We aimed to evaluate the predictors of sustainability of biologic drugs for paediatric patients with Crohn's disease (CD). METHODS: The Czech National Prospective Registry of Biologic and Targeted Therapy of Inflammatory Bowel Disease (CREdIT) was used to identify the biologic treatment courses in paediatric patients with CD. Mixed-effects Cox models and propensity score analyses were employed to evaluate predictors of treatment sustainability. RESULTS: Among the 558 observations of 473 patients, 264 were treated with adalimumab (47%), 240 with infliximab (43%), 41 with ustekinumab (7%), and 13 with vedolizumab (2%). Multivariable analysis revealed higher discontinuation risk with infliximab compared to adalimumab (HR = 0.600, 95%CI 0.389-0.926), both overall and in first-line treatment (HR = 0.302, 95%CI 0.103-0.890). Infliximab versus adalimumab was associated with shorter time to escalation (HR = 0.094, 95%CI 0.043-0.203). Propensity-score analysis demonstrated lower sustainability of infliximab (HR = 0.563, 95%CI 1.159-2.725). The time since diagnosis to treatment initiation (HR = 0.852, 95%CI 0.781-0.926) was the most important predictor. Baseline immunosuppressive therapy prolonged sustainability with infliximab (HR = 2.899, 95%CI 1.311-6.410). CONCLUSIONS: Given the results suggesting shorter sustainability, the need for earlier intensification and thus higher drug exposure, and the greater need for immunosuppression with infliximab than with adalimumab, the choice of these drugs cannot be considered completely equitable. IMPACT: Our study identified predictors of sustainability of biologic treatment in paediatric patients with Crohn's disease, including adalimumab (versus infliximab), early initiation of biologic treatment, and normalised baseline haemoglobin levels. Infliximab treatment was associated with earlier intensification, higher drug exposure, and a greater need for immunosuppression. Parents and patients should be fully informed of the disadvantages of intravenous infliximab versus adalimumab during the decision-making process. This study emphasises the importance of not delaying the initiation of biologic therapy in paediatric patients with Crohn's disease.

Age Dependent Progression of Multiple Epiphyseal Dysplasia and Pseudoachondroplasia Due to Heterozygous Mutations in COMP Gene.

Dominantly inherited mutations in COMP gene encoding cartilage oligomeric matrix protein may cause two dwarfing skeletal dysplasias, milder multiple epiphyseal dysplasia (MED) and more severe pseudoachondroplasia (PSACH). We studied the phenotype and X-rays of 11 patients from 5 unrelated families with different COMP mutations. Whole exome and/or Sangers sequencing were used for molecular analyses. Four to ten X-ray images of hands hips, knees or spine were available for each patient for retrospective analyses. Eight patients with MED have mutation c.1220G>A and 3 children with PSACH mutations c.1359C>A, c.1336G>A, or the novel mutation c.1126G>T in COMP. Progressive failure in growth developed in all patients from early childhood and resulted in short stature < 3rd percentile in 7 patients and very short stature < 1st percentile in four. Most patients had joint pain since childhood, severe stiffness in shoulders and elbows but increased mobility in wrists. Six children had bowlegs and two had knock knees. In all patients, X-rays of hands, hips and knees showed progressive, age-dependent skeletal involvement more pronounced in the epiphyses of long rather than short tubular bones. Anterior elongation and biconvex configuration of vertebral bodies were more conspicuous for kids. Six children had correction of knees and two adults had hip replacement. Skeletal and joint impairment in patients with MED and PSACH due to COMP mutation start in early childhood. Although the clinical severity is mutation and age dependent, many symptoms represent a continuous phenotypic spectrum between both diseases. Most patients may benefit from orthopaedic surgeries.

X-linked adrenoleukodystrophy: phenotype-genotype correlation in hemizygous males and heterozygous females with ABCD1 mutations.

OBJECTIVES: X-linked adrenoleukodystrophy (X-ALD) causes cerebral adrenoleukodystrophy (cALD), myelopathy and/or adrenal insufficiency in males, and myelopathy/peripheral neuropathy in females. These distinct phenotypes are scarcely linked to a specific mutations. The objective herein was to find a link between the phenotype with the genotype mutation, serum very long-chain fatty acids (VLCFA), and the diet with Lorenzo´s and GTO oils in hemizygous males and heterozygous females. METHODS: A retrospective study design with follow-up of 45 hemizygous males and 50 heterozygous females carrying mutations in ABCD1 from 35 unrelated families with X-ALD. Mutation analysis was performed by Sanger sequencing of PCR and/or RT-PCR and the severity of missense mutations was evaluated using GERP++ score and CADD score. RESULTS: Twenty-five described and eight novel ABCD1 mutations were identified. Fifteen males and 23 females had severe mutations while 30 males and 27 females had less detrimental ones. cALD developed in 25 males (56%) including nine boys with severe mutations, 10 boys with less detrimental mutations and 6 adults with adrenomyelopathy. Myelopathy and/or adrenal insufficiency developed in 14 males (31%), six were asymptomatic. Adrenal insufficiency developed in two of five boys treated with hematopoietic stem cell transplantation (HSCT). Myelopathy/peripheral neuropathy developed in 26% of females. No correlation was found between the disease severity and the genotype, GERP++ and CADD scores, presence/absence of aberrant ALDP protein or X-inactivation. VLCFA were higher in males than heterozygous females and decreased during Lorenzo´s and GTO oils diet without a clear clinical impact on the disease. CONCLUSION: The prognosis was unfavourable in most males and significant part of females. Therapy with early HSCT is effective. Thus, the need for early diagnosis with the neonatal screening is crucial.

Scintigraphy with 99mTc-HMPAO labeled leukocytes is still an accurate and convenient tool to rule out suspected inflammatory bowel disease in children.

BACKGROUND: Abdominal pain is a common complaint in children and its differential diagnosis includes inflammatory bowel disease (IBD). The aim of the study was to assess the diagnostic accuracy of scintigraphy with 99mTechnetium Hexamethylpropyleneamine Oxime (99mTc-HMPAO) labeled leukocytes in children with suspected IBD. MATERIAL AND METHODS: Eighty-five children (age 12.4 ± 4.3 years, 47% boys) with suspected IBD based on clinical presentation, laboratory and ultrasound findings underwent scintigraphy with 99mTc-HMPAO labeled leukocytes. Abdominal scintigrams were acquired 40 min and 90 min post injection, and whole body scintigrams at 180 min. Scintigraphy was evaluated by two specialists in nuclear medicine. The results were compared with the final diagnosis established by endoscopy, histology, other imaging methods, and follow-up evaluated by an expert in pediatric gastroenterology. RESULTS: Scintigraphy results corresponded with the final diagnosis in 78 (91%) patients resulting in a sensitivity of 89% (95%CI 72 to 98%), specificity of 91% (95% CI 82 to 98%), and accuracy of 91% (95% CI 83 to 96%). The interobserver agreement was 0.82 (95% CI 0.75 to 0.88) and the radiation dose estimate was 4.2 ± 1.5 mSv. In 28 children (25 positives and 3 negatives on scintigraphy), the diagnosis of IBD was established by endoscopy, histology, MR enterography, or fluoroscopy. Five positive findings on scintigraphy were not confirmed by other methods or during follow-up. CONCLUSION: Scintigraphy with 99mTc-HMPAO labeled leukocytes in children with suspected IBD has high accuracy and offers a non-invasive option for detecting the presence of gastrointestinal inflammation. Scintigraphy is a powerful non-invasive decision-making tool in the management of suspected IBD that may spare a greater proportion of children of more invasive and demanding examinations.

Ultra-low-dose CT Imaging of the Thorax: Decreasing the Radiation Dose by One Order of Magnitude.

Computed tomography (CT) is an indispensable tool for imaging of the thorax and there is virtually no alternative without associated radiation burden. The authors demonstrate ultra-low-dose CT of the thorax in three interesting cases. In an 18-y-old girl with rheumatoid arthritis, CT of the thorax identified alveolitis in the posterior costophrenic angles (radiation dose = 0.2 mSv). Its resolution was demonstrated on a follow-up scan (4.2 mSv) performed elsewhere. In an 11-y-old girl, CT (0.1 mSv) showed changes of the right collar bone consistent with chronic recurrent multifocal osteomyelitis. CT (0.1 mSv) of a 9-y-old girl with mucopolysaccharidosis revealed altogether three hamartomas, peribronchial infiltrate, and spine deformity. In some indications, the radiation dose from CT of the thorax can approach that of several plain radiographs. This may help the pediatrician in deciding whether "gentle" ultra-low-dose CT instead of observation or follow-up radiographs will alleviate the uncertainty of the diagnosis with little harm to the child.