BackgroundJuvenile idiopathic arthritis (JIA) is a rare disease that is not widely known by paediatricians and general practitioner (GP) leading to diagnostic error and delayed care provision. We aimed to analyse patient’s journey and time to diagnosis of JIA (delay from the first symptom to the diagnosis of JIA).We performed a retrospective cohort study of 67 patients diagnosed with JIA and seen in the paediatric rheumatology department of the Kremlin Bicêtre Hospital, between July 2002 and January 2015. Patients were selected for analysis in order to represent an equal distribution of five JIA subtypes: oligoarticular onset (21), polyarticular onset (13), enthesitis-related arthritis (17), and systemic onset (16).ResultsSixty-seven patients were finally analysed (42 girls). Before JIA diagnosis was made, patients had visited a mean of three physicians (3.6 ± 1.4 (mean; SD)). Emergency room physicians (52%) were the first patient’s referral before GP (42%). Paediatric rheumatologists were mostly seen as third referral (52% versus 3% at first referral). Reactive arthritis (34%) and septic arthritis (24%) represented both the most common initial diagnosis. JIA was suspected after an average median time delay of 3 months (0.26–81.2) except for 25 patients (37%): SJIA (n = 9), ERA (n = 7), OAJIA (3) and POJIA (n = 6) for whom diagnosis was suspected straightaway. In most cases (88%), JIA was established by paediatric rheumatologists.Surprisingly, the median total time to diagnosis in our population was rather short (3 months). Paediatric rheumatologist played a major role in making the diagnosis but the journey to reach them was long and complex with multiple referrals. These results reinforce the necessity of improving GP and emergency physician’s awareness and education on paediatric rheumatic diseases as the importance of a strong network in paediatric rheumatology to improve patient’s level of care.ConclusionWe highlighted the complex patient’s journey to diagnosis in children with JIA and made assumptions that reference center might reduce time to diagnosis although not statically proven. Further analysis with a larger number of patients might be needed to better investigate this probability.

IntroductionPulmonary alveolar proteinosis related to mutations in the methionine tRNA synthetase (MARS1) gene is a severe, early-onset disease that results in death before the age of 2 years in one-third of patients. It is associated with a liver disease, growth failure and systemic inflammation. As methionine supplementation in yeast models restored normal enzymatic activity of the synthetase, we studied the tolerance, safety and efficacy of daily oral methionine supplementation in patients with severe and early disease.MethodsFour patients received methionine supplementation and were followed for respiratory, hepatic, growth, and inflammation-related outcomes. Their course was compared to those of historical controls. Reactive oxygen species (ROS) production by patient monocytes before and after methionine supplementation was also studied.ResultsMethionine supplementation was associated with respiratory improvement, clearance of the extracellular lipoproteinaceous material, and discontinuation of whole-lung lavage in all patients. The three patients who required oxygen or non-invasive ventilation could be weaned off within 60 days. Liver dysfunction, inflammation, and growth delay also improved or resolved. At a cellular level, methionine supplementation normalised the production of reactive oxygen species by peripheral monocytes.ConclusionMethionine supplementation was associated with important improvements in children with pulmonary alveolar proteinosis related to mutations in the MARS1 gene. This study paves the way for similar strategies for other tRNA synthetase deficiencies.

The biological diagnosis of cystic fibrosis (CF) is based on a sweat chloride (Cl − ) concentration (SCC) ⩾60 mmol•L −1 and/or the identification of two allelic CF-causing variants [1]. Diagnosis of CF can be challenging in subjects with intermediate SCC between 30 and 59 mmol•L −1 and only one CF-causing variant detected. A proportion of these individuals with a query diagnosis for CF (Q) are simple carriers but a subset carries two variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, some of which are of unknown significance. This includes patients referred for symptoms evocative of CF and infants with an inconclusive diagnosis after newborn screening. In such cases, diagnostic algorithms recommend performing CFTR functional investigations, such as trans-epithelial nasal potential difference (NPD) measurement and intestinal current measurement (ICM) in rectal biopsies [1]. However, these tests, which require expensive equipment, are only performed in a few expert laboratories [2,3]. The beta-adrenergic (β-adr) sweat secretion test (SST), which evaluates the specific CFTR activity in the sweat gland acinus, might be an alternative test for CFTR functional exploration [4]. We investigated β-adr SST measured by evaporimetry in a cohort of Q-patients in comparison to NPD and ICM. The diagnosis performance of the test was related to final patient classification after extensive genetic screening of the CFTR gene.We enrolled 24 symptomatic Q-patients with borderline SCC including 14 children (mean±SEM 12.5±1.1 years old) and 10 adults (41.9±5.7 years old), age range of 4.0 to 66.4 years old (figure 1a). Written informed consent was collected for all patients (IRB, Clinical trial number RCB2016-A01923-48, 2018).The β-adr SST was performed using evaporimeter probes (CyberDerm, PA, USA) as we previously published [5]. Maximal β-adr sweat rate was normalised to the maximal cholinergically stimulated sweat rate by calculating the ratio of β-adr peak to carbachol peak (β-adr ratio). Tracings were considered if: 1) sweat rate was stable at the reference probe during the whole test; 2) carbachol peak was >30 g water loss•m −2 •h −1 ; and 3) atropine injection completely inhibited the cholinergic response. The discrimination threshold for CF was calculated by receiver operating characteristic curve ⩽4.5 g water loss•m −2 •h −1 for β-adr peak and 0.08 for β-adr ratio, based on our reference population composed of adolescents or young adults (31 healthy controls, 20 with CF and four heterozygotes).CFTR activity in the nasal epithelium was assessed by the sum of the changes in NPD after perfusion with the low Cl − solution and isoproterenol (Δtotal Cl − response, ΔTCR) and in the intestinal mucosa by the change in short circuit current (IsC) after addition of forskolin (Δforskolin) [2,3].Search for frequent CF-causing variants was followed, when necessary, by extensive analysis of all coding regions using next generation sequencing [6]. The CFTR variants were classified as follows: CF-causing; variants...

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