Colchicine treatment can be discontinued in a selected group of pediatric FMF patients.

OBJECTIVES: Familial Mediterranean Fever (FMF) patients are required to adhere to a life-long treatment with colchicine, primarily for preventing amyloidosis. As some patients may be asymptomatic for long periods of time, it remains unclear whether it is possible to discontinue colchicine treatment in a selective group of patients. We aimed to identify predictive characteristics for a successful cessation of colchicine therapy. METHODS: Out of 646 FMF pediatric patients followed in our referral FMF clinic, colchicine treatment was discontinued in 51 patients. In this study we compared the genetic, demographic, and clinical characteristics between patients for whom a successful cessation of therapy was made (Group 1; n = 21) and patients for whom cessation of therapy was deemed a failure (Group 2; n = 30) and consequently had to resume colchicine therapy. RESULTS: Patients for whom a successful cessation of therapy was achieved had no biallelic pathogenic MEFV mutations, were less likely to have "severe attacks" (two or more FMF characteristic symptoms) (24% vs 80%; P = 0.000067) and did not require higher than 1 mg/day of colchicine, prior to the drug cessation. Remission duration under colchicine treatment was significantly higher in group 1 compared with group 2 (4.36 years ±2.12 vs 2.53 years ±2; P = 0.0036). CONCLUSION: This study supports the concept of colchicine free remission in a minority of FMF patients (3%). Holding treatment, under close monitoring, may be reasonable when selecting the appropriate patients.

Acceptance Rates of COVID-19 Vaccine Highlight the Need for Targeted Public Health Interventions.

We aimed to examine rates of COVID-19 vaccination to elucidate the need for targeted public health interventions. We retrospectively reviewed the electronic medical files of all adults registered in a central district in Israel from 1 January 2021 to 31 March 2022. The population was characterized by vaccination status against COVID-19 and the number of doses received. Univariate and multivariable analyses were used to identify predictors of low vaccination rates that required targeted interventions. Of the 246,543 subjects included in the study, 207,911 (84.3%) were vaccinated. The minority groups of ultra-Orthodox Jews and Arabs had lower vaccination rates than the non-ultra-Orthodox Jews (68.7%, 80.5% and 87.7%, respectively, p < 0.001). Adults of low socioeconomic status (SES) had lower vaccination rates compared to those of high SES (74.4% vs. 90.8%, p < 0.001). Adults aged 20−59 years had a lower vaccination rate than those ≥60 years (80.0% vs. 92.1%, p < 0.0001). Multivariate analysis identified five independent variables that were significantly (p < 0.001) associated with low vaccination rates: minority groups of the ultra-Orthodox sector and Arab population, and underlying conditions of asthma, smoking and diabetes mellitus (odds ratios: 0.484, 0.453, 0.843, 0.901 and 0.929, respectively). Specific targeted public health interventions towards these subpopulations with significantly lower rates of vaccination are suggested.

How to increase COVID-19 vaccine uptake among children? determinants associated with vaccine compliance.

Objective: Three aims: to elucidate determinants associated with COVID-19 vaccine uptake in children and the association with parental vaccination; to compare rates of PCR-positive SARS-CoV-2 results between vaccinated and unvaccinated children; to estimate the rate of parental COVID-19 vaccination and its association with the vaccination rate of their children. Methods: We performed a retrospective chart review of all children aged 5-11 years registered at a central district in Israel from November 21st, 2021 to April 30th, 2022, and characterized COVID-19 vaccinated vs. unvaccinated individuals. Data retrieved from the electronic medical files included: demographics [age, gender, sector, socioeconomic status (SES)]; COVID-19 vaccination (first and second doses) and influenza vaccination status; co-morbidities; and parental vaccinations for COVID-19. We divided the population into three distinct demographic groups: non-ultra-orthodox Jews (43,889 children), ultra-orthodox Jews (13,858 children), and Arabs (4,029 children). Results: Of the 61,776 children included in the study, 20,355 (32.9%) received at least one dose of the COVID-19 vaccine. Vaccination rates were similar amongst males and females and were higher in children aged 9-11 years compared to children aged 5-6 years. Multivariate analysis identified five independent determinants that were significantly (p < 0.001) associated with low vaccination rates: Arab and ultra-orthodox sectors (odds ratios: 0.235 and 0.617, respectively); children aged 5-8 years; children of low SES; and children who had not received previous seasonal influenza vaccination. Relatively high vaccination rates were noted amongst children with the following medical co-morbidities: treatment with biological agents (42.9%); solid tumor transplantation (42.9%); type 1 diabetes mellitus (38.5%), asthma (38.2%), and attention deficit and hyperactivity disorder (ADHD) (37.6%). Regarding the uptake of two vaccine doses among children with co-morbidities, it was highest in those with type 1 diabetes mellitus, heart failure, treatment with biological agents, asthma and obesity. Conclusion: This study highlights several pediatric sub-populations with low and high vaccine uptake. It is essential to focus on determinants associated with low vaccination rates.

Whole exome sequencing in childhood-onset lupus frequently detects single gene etiologies.

BACKGROUND: Systemic lupus erythematosus (SLE) comprise a diverse range of clinical manifestations. To date, more than 30 single gene causes of lupus/lupus like syndromes in humans have been identified. In the clinical setting, identifying the underlying molecular diagnosis is challenging due to phenotypic and genetic heterogeneity. METHODS: We employed whole exome sequencing (WES) in patients presenting with childhood-onset lupus with severe and/or atypical presentations to identify cases that are explained by a single-gene (monogenic) cause. RESULTS: From January 2015 to June 2018 15 new cases of childhood-onset SLE were diagnosed in Edmond and Lily Safra Children's Hospital. By WES we identified causative mutations in four subjects in five different genes: C1QC, SLC7A7, MAN2B1, PTEN and STAT1. No molecular diagnoses were established on clinical grounds prior to genetic testing. CONCLUSIONS: We identified a significant fraction of monogenic SLE etiologies using WES and confirm the genetic locus heterogeneity in childhood-onset lupus. These results highlight the importance of establishing a genetic diagnosis for children with severe or atypical lupus by providing accurate and early etiology-based diagnoses and improving subsequent clinical management.

Characteristics of congenital hepatic fibrosis in a large cohort of patients with autosomal recessive polycystic kidney disease.

BACKGROUND & AIMS: Autosomal recessive polycystic kidney disease (ARPKD), the most common ciliopathy of childhood, is characterized by congenital hepatic fibrosis and progressive cystic degeneration of kidneys. We aimed to describe congenital hepatic fibrosis in patients with ARPKD, confirmed by detection of mutations in PKHD1. METHODS: Patients with ARPKD and congenital hepatic fibrosis were evaluated at the National Institutes of Health from 2003 to 2009. We analyzed clinical, molecular, and imaging data from 73 patients (age, 1-56 years; average, 12.7 ± 13.1 years) with kidney and liver involvement (based on clinical, imaging, or biopsy analyses) and mutations in PKHD1. RESULTS: Initial symptoms were liver related in 26% of patients, and others presented with kidney disease. One patient underwent liver and kidney transplantation, and 10 others received kidney transplants. Four presented with cholangitis and one with variceal bleeding. Sixty-nine percent of patients had enlarged left lobes on magnetic resonance imaging, 92% had increased liver echogenicity on ultrasonography, and 65% had splenomegaly. Splenomegaly started early in life; 60% of children younger than 5 years had enlarged spleens. Spleen volume had an inverse correlation with platelet count and prothrombin time but not with serum albumin level. Platelet count was the best predictor of spleen volume (area under the curve of 0.88905), and spleen length corrected for patient's height correlated inversely with platelet count (R(2) = 0.42, P < .0001). Spleen volume did not correlate with renal function or type of PKHD1 mutation. Twenty-two of 31 patients who underwent endoscopy were found to have varices. Five had variceal bleeding, and 2 had portosystemic shunts. Forty-percent had Caroli syndrome, and 30% had an isolated dilated common bile duct. CONCLUSIONS: Platelet count is the best predictor of the severity of portal hypertension, which has early onset but is underdiagnosed in patients with ARPKD. Seventy percent of patients with ARPKD have biliary abnormalities. Kidney and liver disease are independent, and variability in severity is not explainable by type of PKHD1 mutation; ClinicalTrials.gov number, NCT00068224.

Cellular interactions of synovial fluid γδ T cells in juvenile idiopathic arthritis.

The pathogenesis of juvenile idiopathic arthritis (JIA) is thought to involve multiple components of the cellular immune system, including subsets of γδ T cells. In this study, we conducted experiments to define the functional roles of one of the major synovial fluid (SF) T cell subsets, Vγ9(+)Vδ2(+) (Vγ9(+)) T cells, in JIA. We found that as opposed to CD4(+) T cells, equally high percentages (∼35%) of Vγ9(+) T cells in SF and peripheral blood (PB) produced TNF-α and IFN-γ. Furthermore, stimulation with isopentenyl pyrophosphate (IPP), a metabolite in the mevalonate pathway, which is a specific potent Ag for Vγ9Jγ1.2(+) T cells, similarly amplified cytokine secretion by SF and PB Vγ9(+) T cells. Significantly, the SF subset expressed higher levels of CD69 in situ, suggesting their recent activation. Furthermore, 24-h coculturing with SF-derived fibroblasts enhanced CD69 on the SF > PB Vγ9(+) T cells, a phenomenon strongly augmented by zoledronate, a farnesyl pyrophosphate synthase inhibitor that increases endogenous intracellular IPP. Importantly, although Vγ9(+) T cell proliferation in response to IPP was significantly lower in SF than PBMC cultures, it could be enhanced by depleting SF CD4(+)CD25(+)FOXP3(+) cells (regulatory T cells). Furthermore, coculture with the Vγ9(+) T cells in medium containing zoledronate or IPP strongly increased SF-derived fibroblasts' apoptosis. The findings that IPP-responsive proinflammatory synovial Vγ9(+) T cells for which proliferation is partly controlled by regulatory T cells can recognize and become activated by SF fibroblasts and then induce their apoptosis suggest their crucial role in the pathogenesis and control of synovial inflammation.

Hepatorenal findings in obligate heterozygotes for autosomal recessive polycystic kidney disease.

Autosomal recessive polycystic kidney disease (ARPKD), characterized by progressive cystic degeneration of the kidneys and congenital hepatic fibrosis (CHF), is the most common childhood onset ciliopathy, with an estimated frequency of 1 in 20,000 births. It is caused by mutations in PKHD1. The carrier frequency for ARPKD in the general population is estimated at 1 in 70. Given the recessive inheritance pattern, individuals who are heterozygous for PKHD1 mutations are not expected to have clinical findings. We performed ultrasound (USG) evaluations on 110 parents from 64 independent ARPKD families and identified increased medullary echogenicity in 6 (5.5%) and multiple small liver cysts in 10 parents (9%). All ARPKD parents with these abnormal imaging findings were asymptomatic; kidney and liver function tests were unremarkable. Complete sequencing of PKHD1 in the 16 ARPKD parents with abnormal imaging confirmed the mutation transmitted to the proband, but did not reveal any other pathogenic variants. Our data suggest that carrier status for ARPKD is a predisposition to polycystic liver disease and renal involvement associated with increased medullary echogenicity on USG. Whether some of these individuals become symptomatic as they age remains to be determined.