Epidemiological and clinical features of pediatric-onset multiple sclerosis: A population-based study in Isfahan, Iran, between 1997-2020

Background: Pediatric-onset multiple sclerosis (POMS) is an autoimmune demyelinating disorder of the central nervous system (CNS), affecting individuals younger than 18 years of age. We sought to characterize the epidemiological and clinical features of patients with POMS in Isfahan, Iran, from April 1997 to March 2020. Methods: The medical records of patients with POMS in the databases of Isfahan Department of Public Health and Isfahan Multiple Sclerosis Society (IMSS) were retrospectively reviewed. The 2006 and 2016 Isfahan Province population censuses were used as reference values for assessing the temporal trend of POMS. Results: From April 1997 to March 2020, 509 individuals under18 years of age were diagnosed with POMS in Isfahan. 404 of these patients (79.4%) were girls, and 105 patients (20.6%) were boys (a female to male ratio of 3.85:1). Most of the patients (83%) were monosymptomatic at onset, with optic neuritis and brainstem-cerebellar disorders being the most frequent initial presentations. Mean ± standard deviation (SD) of age at disease diagnosis was 15.8 ± 2.5 years (ranging from 3 to 18, mode = 18).From April 2019 to March 2020, the crude prevalence and the crude incidence rate of the POMS were 5.42 per 100000 and 1.86 per 100000, respectively. Poisson regression analysis revealed a 3.4% increase in the incidence rate of POMS from April 1997 to March 2020 [relative rate:1.034, 95% confidence interval (CI): 1.021-1.048]. Conclusion: The female to male ratio in our cohort was significantly higher than any other studies conducted previously. The high female to male ratio and increasing incidence of the disease suggest increasing regionalization of care.

Gene–environment interactions increase the risk of pediatric-onset multiple sclerosis associated with ozone pollution

Background: We previously reported a relationship between air pollutants and increased risk of pediatric-onset multiple sclerosis (POMS). Ozone is an air pollutant that may play a role in multiple sclerosis (MS) pathoetiology. CD86 is the only non-HLA gene associated with POMS for which expression on antigen-presenting cells (APCs) is changed in response to ozone exposure. Objectives: To examine the association between county-level ozone and POMS, and the interactions between ozone pollution, CD86, and HLA- DRB1*15, the strongest genetic variant associated with POMS. Methods: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. County-level-modeled ozone data were acquired from the CDC’s Environmental Tracking Network. Participants were assigned ozone values based on county of residence. Values were categorized into tertiles based on healthy controls. The association between ozone tertiles and having MS was assessed by logistic regression. Interactions between tertiles of ozone level and the GG genotype of the rs928264 (G/A) single nucleotide polymorphism (SNP) within CD86, and the presence of DRB1*15:01 ( DRB1*15) on odds of POMS were evaluated. Models were adjusted for age, sex, genetic ancestry, and mother’s education. Additive interaction was estimated using relative excess risk due to interaction (RERI) and attributable proportions (APs) of disease were calculated. Results: A total of 334 POMS cases and 565 controls contributed to the analyses. County-level ozone was associated with increased odds of POMS (odds ratio 2.47, 95% confidence interval (CI): 1.69–3.59 and 1.95, 95% CI: 1.32–2.88 for the upper two tertiles, respectively, compared with the lowest tertile). There was a significant additive interaction between high ozone tertiles and presence of DRB1*15, with a RERI of 2.21 (95% CI: 0.83–3.59) and an AP of 0.56 (95% CI: 0.33–0.79). Additive interaction between high ozone tertiles and the CD86 GG genotype was present, with a RERI of 1.60 (95% CI: 0.14–3.06) and an AP of 0.37 (95% CI: 0.001–0.75) compared to the lowest ozone tertile. AP results indicated that approximately half of the POMS risk in subjects can be attributed to the possible interaction between higher county-level ozone carrying either DRB1*15 or the CD86 GG genotype. Conclusions: In addition to the association between high county-level ozone and POMS, we report evidence for additive interactions between higher county-level ozone and DRB1*15 and the CD86 GG genotype. Identifying gene–environment interactions may provide mechanistic insight of biological processes at play in MS susceptibility. Our work suggests a possible role of APCs for county-level ozone-induced POMS risk.

Metagenomic Analysis of the Pediatric-Onset Multiple Sclerosis Gut Microbiome

Background and Objectives:Little is known of the functional potential of the gut microbiome in pediatric-onset multiple sclerosis (MS). We performed metagenomic analyses using stool samples from individuals with pediatric-onset MS and unaffected controls.Methods:Persons ≤21 years old enrolled in the Canadian Pediatric Demyelinating Disease Network providing a stool sample were eligible. Twenty MS patients (McDonald criteria) with symptom onset <18 years were matched to 20 controls by sex, age (±3 years), stool consistency, and race. Microbial taxonomy and functional potentials were estimated from stool sample-derived metagenomic reads and compared by disease status (MS vs controls) and disease-modifying drug (DMD) exposure using alpha-diversity, relative abundance, and prevalence using Wilcoxon rank-sum, ALDEx2 and Fisher’s exact tests, respectively.Results:Individuals with MS were aged 13.6 years (mean) at symptom onset and 8 were DMD naïve. Mean ages at stool sample were 16.1 and 15.4 years for MS and control participants, respectively; 80% were girls. Alpha-diversity of enzymes and proteins did not differ by disease or DMD status (p>0.20), but metabolic pathways, gene annotations and microbial taxonomy did. Individuals with MS (vs controls) exhibited higher methanogenesis prevalence (odds ratio=10, p=0.044), and Methanobrevibacter abundance (log2 fold-change[LFC]=1.7, p=0.0014), but lower homolactic fermentation abundance (LFC=-0.48, p=0.039). Differences by DMD status included lower phosphate butyryltransferase for DMD-naïve vs exposed MS patients (LFC=-1.0, p=0.033).Discussion:The gut microbiome’s functional potential and taxonomy differed between individuals with pediatric-onset MS versus controls, including higher prevalence of a methane-producing pathway from Archaea and depletion of the lactate fermentation pathway. DMD exposure was associated with butyrate-producing enzyme enrichment. Together these findings indicate that the gut microbiome of individuals with MS may have a disturbed functional potential.

Impact of Diagnostic Delay on Disease Course in Pediatric Versus Adult-onset Patients with Ulcerative Colitis: Data from the Swiss IBD Cohort

Introduction: Given the lack of data we aimed to assess the impact of the length of diagnostic delay on natural history of ulcerative colitis in pediatric (diagnosed <18 years) and adult patients (diagnosed ≥18 years). Methods: Data from the Swiss Inflammatory Bowel Disease cohort study were analyzed. Diagnostic delay was defined as interval between the first appearance of UC-related symptoms until diagnosis. Logistic regression modeling evaluated the appearance of the following complications in the long term according to the length of diagnostic delay: colonic dysplasia, colorectal cancer, UC-related hospitalization, colectomy, and extra-intestinal manifestations (EIM). Results: A total of 184 pediatric and 846 adult patients were included. Median diagnostic delay was 4 [IQR 2-7.5] months for the pediatric-onset group and 3 [IQR 2-10] months for the adult-onset group (P=0.873). In both, pediatric and adult-onset groups, length of diagnostic delay at UC diagnosis was not associated with colectomy, UC-related hospitalization, colon dysplasia, and colorectal cancer. EIM were significantly more prevalent at UC diagnosis in the adult-onset group with long diagnostic delay compared to the adult-onset group with short diagnostic delay (p = 0.022). In the long term, length of diagnostic delay was associated in the adult onset group with colorectal dysplasia (p=0.023), EIMs (p<0.001) and more specifically arthritis/arthralgias (p<0.001) and ankylosing spondylitis/sacroiliitis (p<0.001). In the pediatric-onset UC group, length of diagnostic delay in the long term was associated with arthritis/arthralgias (p=0.017); however, it was not predictive for colectomy and UC-related hospitalization. Conclusions: As colorectal cancer and EIMs are associated with considerable morbidity and costs, every effort should be made to reduce diagnostic delay in UC patients.