Bullous Diseases in Children: A Review of Clinical Features and Treatment Options Abstract Bullous diseases are uncommon in children; however, as they have the potential to affect quality of life, occasionally have long-term side effects in the setting of scarring processes, and carry a rare risk of underlying malignancy [e.g., with paraneoplastic pemphigus (PNP)], knowledge of their clinical presentation and treatment options is essential. Given the rarity of these conditions, our current state of knowledge is largely derived from case reports and case series, with a paucity of evidence-based recommendations. In this review, we discuss the clinical presentation of and treatment options for linear immunoglobulin A disease, dermatitis herpetiformis, pemphigus vulgaris, pemphigus foliaceus, PNP, bullous pemphigoid, mucus membrane pemphigoid, epidermolysis bullosa acquisita, and inherited epidermolysis bullosa. In general, when these conditions, except for PNP, occur in childhood, they have a better prognosis than when they occur in adults. Clinical, histopathological, and immunologic features frequently overlap, but distinct differences have also been reported, most commonly in clinical presentation. Treatment is often similar to that in adults, although specific considerations are necessary for a pediatric population.

Oral Lorazepam is not Superior to Placebo for Lowering Stress in Children Before Digestive Endoscopy: A Double-Blind, Randomized, Controlled Trial Abstract Background Digestive endoscopies must be performed within a safe and comfortable environment. We have previously shown that the quality of intravenous sedation is influenced by preoperative stress. Aim Our primary objective was to compare the effects of oral lorazepam and placebo on the salivary cortisol response of children undergoing a digestive endoscopy. Secondary objectives were the assessment of procedural pain and comfort as well as the occurrence of adverse events. Methods Participants were randomized and received either lorazepam, placebo, or no premedication. Saliva was collected upon arrival at the hospital and 1 h following randomization. The sedation protocol included midazolam and fentanyl ± ketamine. Procedural pain was evaluated with the Nurse Assessed Patient Comfort Score (NAPCOMS). Patients completed a postoperative questionnaire. The primary outcome was defined as the proportion of children having a cortisol decrease ≥ 15 nmol/L. Results 101 participants (54 females) were included. The rate of children having a cortisol decrease ≥ 15 nmol/L was 27.3%, 35.3%, and 19.4% for lorazepam, placebo, and no premedication, respectively (p = 0.356). The median (IQR) NAPCOMS pain score was 3.0 (0–6) for lorazepam, 4.4 (0–6) for placebo, and 3.4 (3–4) for no premedication (p = 0.428). With lorazepam, 75.9% of children reported experiencing a comfortable procedure, compared with 41.9% taking placebo and 34.5% with no premedication (p = 0.013). Transient tachycardia was the most frequent intraoperative adverse event, particularly with lorazepam (62.5%, p = 0.029). Conclusions Oral lorazepam had no effect on patients’ preoperative stress, as measured by salivary cortisol, but was associated with a higher rate of comfortable procedures. Clinical Trial Registration Clinicaltrials.gov, Identifier NCT03180632.

Canakinumab in Children with Familial Mediterranean Fever: A Single-Center, Retrospective Analysis Abstract Introduction Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by interleukin (IL)-1 overproduction. Colchicine is the mainstay drug in the treatment of FMF; however, a minority of patients do not respond despite the highest tolerated doses. We aimed to share our experience with canakinumab, a human monoclonal antibody against IL-1β, in pediatric FMF patients. Methods This historical, single-cohort study retrospectively evaluated the disease characteristics, indications, and treatment responses of 14 pediatric FMF patients treated with canakinumab in our pediatric rheumatology department. Results The median age at onset and diagnosis of 14 FMF patients (9 females, 5 males), were 3.5 (range 0.5–10) years and 6 (range 3–16) years, respectively. Indications for canakinumab treatment were renal amyloidosis (n = 1), colchicine resistance (n = 11), and persistent arthritis (n = 2). Only two (14.3%) patients had colchicine intolerance. Complete response was obtained in 10/14 (71.5%) among all patients and 10/12 (86%) in patients with typical phenotype. The patient with chronic oligoarthritis had a complete response, whereas the patient with rheumatoid factor (RF)-positive polyarthritis demonstrated an initial partial response to canakinumab treatment. We found that attack frequency, proteinuria, and acute phase reactants, including erythrocyte sedimentation rate and C-reactive protein, were significantly decreased after canakinumab treatment in children with FMF. Conclusion Canakinumab may be an effective treatment option for pediatric FMF patients with colchicine resistance, renal amyloidosis, and chronic oligoarthritis. Further studies are needed to clarify the efficacy of canakinumab in patients with a second disease, RF-positive polyarticular juvenile idiopathic arthritis.

Drug Dose Selection in Pediatric Obesity: Available Information for the Most Commonly Prescribed Drugs to Children Abstract Obesity rates continue to rise in children, and little guidance exists regarding the need for adjustment away from total body weight-based doses for those prescribing drugs to this population of children. A majority of drugs prescribed to children with obesity result in either sub-therapeutic or supra-therapeutic concentrations, placing these children at risk for treatment failure and drug toxicities. In this review, we highlight available obesity-specific pharmacokinetic and dosing information for the most frequently prescribed drugs to children in the inpatient and outpatient clinical settings. We also comment on available dosing recommendations for drugs prescribed to treat common pediatric obesity-related comorbidities. This review highlights that there is no safe or proven ‘rule of thumb,’ for dosing drugs for children with obesity, and a striking lack of pharmacokinetic data to support the creation of dosing guidelines for children with obesity for the most commonly prescribed drugs. It is important that those prescribing for children with obesity are aware of these gaps in knowledge and of potential drug treatment failure or adverse events related to drug toxicity as a result of these knowledge gaps. Until more data are available, we recommend close monitoring of drug response and adverse events in children with obesity receiving commonly prescribed drugs.

Good Pharmacovigilance Practice in Paediatrics: An Overview of the Updated European Medicines Agency Guidelines

Drug-Induced Urolithiasis in Pediatric Patients Abstract Drug-induced nephrolithiasis is a rare condition in children. The involved drugs may be divided into two different categories according to the mechanism involved in calculi formation. The first one includes poorly soluble drugs that favor the crystallization and calculi formation. The second category includes drugs that enhance calculi formation through their metabolic effects. The diagnosis of these specific calculi depends on a detailed medical history, associated comorbidities and the patient’s history of drug consumption. There are several risk factors associated with drug-induced stones, such as high dose of consumed drugs and long duration of treatment. Moreover, there are some specific risk factors, including urinary pH and the amount of fluid consumed by children. There are limited data regarding pediatric lithogenic drugs, and hence, our aim was to perform a comprehensive review of the literature to summarize these drugs and identify the possible mechanisms involved in calculi formation and discuss the management and preventive measures for these calculi.

Triclofos Sodium for Pediatric Sedation in Non-Painful Neurodiagnostic Studies Abstract Aim Triclofos sodium (TFS) has been used for many years in children as a sedative for painless medical procedures. It is physiologically and pharmacologically similar to chloral hydrate, which has been censured for use in children with neurocognitive disorders. The aim of this study was to investigate the safety and efficacy of TFS sedation in a pediatric population with a high rate of neurocognitive disability. Methods The database of the neurodiagnostic institute of a tertiary academic pediatric medical center was retrospectively reviewed for all children who underwent sedation with TFS in 2014. Data were collected on demographics, comorbidities, neurologic symptoms, sedation-related variables, and outcome. Results The study population consisted of 869 children (58.2% male) of median age 25 months (range 5–200 months); 364 (41.2%) had neurocognitive diagnoses, mainly seizures/epilepsy, hypotonia, or developmental delay. TFS was used for routine electroencephalography in 486 (53.8%) patients and audiometry in 401 (46.2%). Mean (± SD) dose of TFS was 50.2 ± 4.9 mg/kg. Median time to sedation was 45 min (range 5–245), and median duration of sedation was 35 min (range 5–190). Adequate sedation depth was achieved in 769 cases (88.5%). Rates of sedation-related adverse events were low: apnea, 0; desaturation ≤ 90%, 0.2% (two patients); and emesis, 0.35% (three patients). None of the children had hemodynamic instability or signs of poor perfusion. There was no association between desaturations and the presence of hypotonia or developmental delay. Conclusion TFS, when administered in a controlled and monitored environment, may be safe for use in children, including those with underlying neurocognitive disorders.

DTaP-IPV-HepB-Hib Vaccine (Hexyon ® ): An Updated Review of its Use in Primary and Booster Vaccination Abstract Hexyon® is a fully-liquid, ready-to-use, hexavalent vaccine approved in the EU since 2013 for primary and booster vaccination in infants and toddlers from age 6 weeks against diphtheria, tetanus, pertussis, hepatitis B (HB), poliomyelitis, and invasive diseases caused by Haemophilus influenzae type b (Hib). While the source of HB antigen in Hexyon® is different from other vaccines, the rest of its valences have been extensively used in other approved vaccines. Hexyon® is highly immunogenic for all its component toxoids/antigens when used as primary and booster vaccine in infants and toddlers, irrespective of vaccination schedule. It provides durable protection against hepatitis B. Hexyon® can be used for a mixed primary series of hexavalent-pentavalent-hexavalent vaccines or as a booster in infants primed with Infanrix hexa™ or pentavalent (whole-cell or acellular pertussis) vaccines. Coadministration of Hexyon® with other common childhood vaccines did not affect immune response to any vaccines. Hexyon® has a good reactogenicity/safety profile. The immunogenicity and safety profile of Hexyon® was similar to that of several approved vaccines, including Infanrix hexa™. However, Hexyon® offers the convenience of full-liquid, ready-to-use formulation, which may minimize vaccination errors and preparation time. Thus, Hexyon® is a convenient, useful option for vaccination against childhood diseases caused by six major pathogens.

Annual European Congress of Rheumatology

Safety and Tolerability of Adjunctive Brivaracetam in Pediatric Patients < 16 Years with Epilepsy: An Open-Label Trial Abstract Objective This trial evaluated the short-term safety and tolerability, steady-state pharmacokinetics, and preliminary efficacy of brivaracetam oral solution in children aged 1 month to < 16 years with epilepsy. Methods This was a phase IIa, open-label, single-arm, fixed three-step dose escalation trial of 3-weeks duration (N01263; NCT00422422). Patients were taking one to three concomitant antiepileptic drugs. Brivaracetam oral solution dosage, in two divided daily doses, was increased each week: approximately 0.8, 1.6, and 3.2 mg/kg/day for patients aged ≥ 8 years, and 1.0, 2.0, and 4.0 mg/kg/day for patients aged < 8 years. Results Of the 100 patients enrolled, 90 (90.0%) completed the trial. The safety population comprised 99 patients. Treatment-emergent adverse events (TEAEs) considered drug related by the investigator were reported by 32/99 (32.3%) patients, most commonly (≥ 5%) somnolence (7.1%) and decreased appetite (6.1%). TEAEs were reported by 66/99 (66.7%) patients, most commonly (≥ 5%) convulsion, irritability, pyrexia, somnolence, and decreased appetite. In patients with a history of focal seizures with or without secondary generalization and no primary generalized seizures aged 4 to < 16 years (n = 34), drug-related TEAEs and TEAE incidences were 47.1% and 67.6%, respectively. Steady-state trough brivaracetam and brivaracetam metabolite plasma concentrations increased proportionally with dose. The ≥ 50% responder rates (all seizure types) were 21.3% (all patients, n = 80) and 36.4% (patients with focal seizures, aged 4 to < 16 years, n = 22). Conclusions This open-label trial in pediatric patients with epilepsy provides preliminary information that short-term, adjunctive brivaracetam treatment is well tolerated and effective. Plasma concentrations of brivaracetam and metabolites increased with increasing dose.