E148Q variant: a familial Mediterranean fever-causing mutation or a sequence variant?

Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease, linked to mutations in the MEFV gene. The p.E148Q variant, found on exon 2, has an uncertain role in FMF, with debates on whether it is a benign polymorphism or a pathogenic mutation. This study aimed to assess the clinical characteristics and severity of FMF in patients homozygous for the p.E148Q variant and to evaluate the impact of the p.V726A variant in these patients. This retrospective cohort study analyzed data from electronic medical records at Carmel Medical Center, Israel. Patients who underwent genetic testing for FMF from November 2004 to December 2019 and had p.E148Q/p.E148Q or p.E148Q/p.E148Q + p.V726A variants were included. Disease severity was assessed using the Tel Hashomer Key to Severity Score. Statistical analyses compared clinical characteristics and severity between genotype groups. The study included 61 FMF patients, with 24 (39%) having p.E148Q/p.E148Q and 37 (61%) having p.E148Q/p.E148Q + p.V726A variants. The majority (72%) were Druze. Most patients (65.5%) exhibited mild disease, while 31.1% had moderate disease, with no cases of severe disease. Colchicine treatment significantly reduced CRP levels in all patients. CONCLUSION: These findings suggest that the p.E148Q variant, whether alone or with p.V726A, generally results in mild to moderate FMF severity, supporting its pathogenic role in particular ethnicity. These results contribute to understanding the clinical significance of the p.E148Q variant and considering the patient's need for Colchicine treatment. WHAT IS KNOWN: • The role of the p.E148Q variant in FMF is debated, with questions about whether it is a benign polymorphism or a pathogenic mutation. • The prevalence of MEFV variants can vary significantly among different ethnic groups. WHAT IS NEW: • The p.E148Q variant has clinical significance in particular ethnicities, as supported by a significant reduction in CRP levels following colchicine treatment. • The p.E148Q variant, whether alone or with p.V726A, generally results in mild to moderate FMF severity.

Infantile Takayasu: clinical features and long-term outcome.

OBJECTIVES: Takayasu arteritis (TAK) is a large-vessel vasculitis rarely reported in children and infants. Most articles on paediatric TAK have not focused on infants. We present the largest case series of infantile TAK, aiming to identify its demographic and clinical characteristics and compare them with existing data on older children. METHODS: We conducted an international multicentre retrospective cohort study. Epidemiological and clinical data were collected from patients' charts from six rheumatology centres. All patients met both the EULAR/PReS 2008 criteria and the 1990 ACR/EULAR criteria and were diagnosed with TAK at age <5 years. RESULTS: Twelve patients were included (50% female). Median age of symptom onset was 11 months, with a diagnostic delay of 4 months. The most common symptoms at presentation were hypertension, blood pressure differences between limbs, and fever. The most commonly involved arteries were the abdominal aorta and renal artery. Medications included steroids, conventional and biologic DMARDs, and other immunosuppressive therapies. Half of the patients received biologic agents, of which infliximab had the highest complete remission rate (40%). Other medications resulting in complete remission were CYC (40%) and MTX (38%). Invasive procedures were required for 58% of patients. The most common complications were cardiac (50%), stroke (42%), and serious infections (33%). No patients died. CONCLUSION: This study presents the largest series of infantile TAK. Compared with other reported series on older children, infants with TAK have more severe disease and were more likely to receive biologic agents, develop complications, and require invasive interventions.

Oxygenation Instability Assessed by Oxygen Saturation Histograms during Supine vs Prone Position in Very Low Birthweight Infants Receiving Noninvasive Respiratory Support.

OBJECTIVE: To evaluate the effect of prone vs supine position on the oxygenation instability among very low birth weight (VLBW) infants receiving noninvasive respiratory support, as assessed by the average oxygen saturation (SpO2) histograms. STUDY DESIGN: Sixty-nine histograms from 23 VLBW infants were studied prospectively. Each infant was studied during 3 consecutive 3-hour periods of alternating positions; 12 infants started the study while prone and 11 infants started supine, by random order. Histogram classification system was used to quantify oxygenation stability and time spent in different SpO2 ranges. RESULTS: The fraction of inspired oxygen values were similar in both positions. Unstable histograms were more common in supine vs prone position (20/34 [59%] vs 10/35 [29%]; P = .02, respectively). Analyzing oxygenation stability as per position change revealed that a change from prone to supine increased oxygenation instability, and supine to prone decreased instability (P = .02). In the supine vs prone position, percent of time spent in SpO2 ≤80% and <90% was higher (5.0 ± 4.2 vs 2.4 ± 3.4 [P < .001] and 24.1 ± 13.7 vs 13.2 ± 10.0 [P < .001], respectively), and percent of time in SpO2 >94% was lower (39.7 ± 26.0 vs 52.4 ± 23.4 [P = .04]). CONCLUSIONS: Prone positioning decreased oxygenation instability and resulted in higher oxygenation among VLBW premature infants on noninvasive respiratory support. SpO2 histograms allow easy bedside assessment of oxygenation instability, and quantification of the time spent at different SpO2 ranges.

CPM Test-Retest Reliability: "Standard" vs "Single Test-Stimulus" Protocols.

OBJECTIVES: Assessment of pain inhibitory mechanisms using conditioned pain modulation (CPM) is relevant clinically in prediction of pain and analgesic efficacy. Our objective is to provide necessary estimates of intersession CPM reliability, to enable transformation of the CPM paradigm into a clinical tool. DESIGN: Two cohorts of young healthy subjects (N = 65) participated in two dual-session studies. In Study I, a Bath-Thermode CPM protocol was used, with hot water immersion and contact heat as conditioning- and test-stimuli, respectively, in a classical parallel CPM design introducing test-stimulus first, and then the conditioning- and repeated test-stimuli in parallel. Study II consisted of two CPM protocols: 1) Two-Thermodes, one for each of the stimuli, in the same parallel design as above, and 2) single test-stimulus (STS) protocol with a single administration of a contact heat test-stimulus, partially overlapped in time by a remote shorter contact heat as conditioning stimulus. Test-retest reliability was assessed within 3-7 days. RESULTS: The STS-CPM had superior reliability intraclass correlation (ICC2 ,: 1 = 0.59) over Bath-Thermode (ICC2 ,: 1 = 0.34) or Two-Thermodes (ICC2 ,: 1 = 0.21) protocols. The hand immersion conditioning pain had higher reliability than thermode pain (ICC2 ,: 1 = 0.76 vs ICC2 ,: 1 = 0.16). Conditioned test-stimulus pain scores were of good (ICC2 ,: 1 = 0.62) or fair (ICC2 ,: 1 = 0.43) reliability for the Bath-Thermode and the STS, respectively, but not for the Two-Thermodes protocol (ICC2 ,: 1 = 0.20). CONCLUSIONS: The newly developed STS-CPM paradigm was more reliable than other CPM protocols tested here, and should be further investigated for its clinical relevance. It appears that large contact size of the conditioning-stimulus and use of single rather than dual test-stimulus pain contribute to augmentation of CPM reliability.

An "On Demand" canakinumab regimen for treating children with Colchicine-Resistant familial Mediterranean fever - A multicentre study.

OBJECTIVES: Canakinumab, a human monoclonal antibody targeted at interleukin-1 beta, has demonstrated safety and efficacy in preventing familial Mediterranean fever (FMF) attacks among individuals with colchicine-resistant (crFMF). The manufacturer orders prescribe monthly subcutaneous injections. However, a subset of our patients is treated with an "canakinumab on demand " (COD) strategy, with wider intervals between drug administrations. Therefore, we aimed to compare disease activity and drug safety between COD and "canakinumab fixed frequency" (CFF) policies. METHODS: This retrospective study collected data from three Israeli paediatric rheumatology centres, of children with crFMF who were treated with canakinumab. Epidemiological and clinical parameters, cumulative drug dosages, and adverse events were compared between children treated by both policies. RESULTS: Twenty-five (49 %) children were treated according to COD policy and 26 according to CFF policy. Demographic parameters and most of the disease features did not differ significantly between the groups. Both groups showed significant reduction in attacks after canakinumab introduction. The median number (interquartile range) of attacks per month did not differ significantly between the COD and CFF groups (0.33 (0.08, 0.58) and 0.13 (0, 0.5), respectively, p = 0.485 (even though, per definition, COD patients presumably had an attack before receiving the second canakinumab dose). The mean monthly dose was lower for the COD than the CFF group (1.13 ± 1.13 vs. 3.16 ± 1.46 mg/kg, p < 0.001). Adverse events were similar between the groups. CONCLUSION: For individuals with crFMF, COD compared to CFF policy can achieve similar efficacy and safety, with a lower accumulated canakinumab dose, rendering it less immunosuppressive and less expensive.

Longitudinal safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine in children aged 4-11 years with juvenile-onset autoimmune inflammatory rheumatic diseases: A prospective multicenter study.

This prospective, longitudinal, multicenter study assessed the safety and efficacy of the Pfizer-BioNTech BNT162b2 mRNA COVID-19 vaccine among children 4-11 years-old with autoimmune inflammatory rheumatologic disease (AIIRD), compared to healthy controls. The study was conducted from 11/2021-12/2022 at 4 tertiary pediatric rheumatology units in Israel. Participants received at least 2 vaccine doses. Safety analysis included adverse events and disease activity measures. Efficacy was assessed by COVID-19 infection rates. Immunogenicity was evaluated in a subset of participants using anti- receptor binding domain antibody titers. Thirty-one children with AIIRD and 45 immunocompetent controls with similar baseline characteristics were included. Safety profile was favorable, with mild or no adverse events reported. The adverse event rates were similar in the AIIRD and control groups after the first (27 (60 %) vs. 14 (45.2 %), p = 0.2977) and the second vaccine doses (22 (49.0 %) vs. 18 (58.1 %), p = 0.5799), respectively. AIIRD activity remained stable and low after vaccination. Breakthrough COVID-19 infection rates were similar between groups, with 15 (48.4 %) in the AIIRD vs. 25 (55.6 %) in the control group (p = 0.7029). All reported COVID-19 infections in the AIIRD group and 18 (72 %) in the control group were symptomatic (p = 0.033), although symptoms were generally mild, with no severe disease. The safety of the BNT162b2 COVID-19 vaccine was excellent in children ages 4-11 years with AIIRD and healthy controls. Efficacy between groups was similar.

Safety and Immunogenicity Following the Second and Third Doses of the BNT162b2 mRNA COVID-19 Vaccine in Adolescents with Juvenile-Onset Autoimmune Inflammatory Rheumatic Diseases: A Prospective Multicentre Study.

BACKGROUND: To explore the long-term safety and dynamics of the immune response induced by the second and third doses of the BNT162b2 mRNA COVID-19 vaccine in adolescents with juvenile-onset autoimmune inflammatory rheumatic diseases (AIIRDs) compared with healthy controls. METHODS: This international prospective study included adolescents with AIIRDs and controls vaccinated with two (AIIRDs n = 124; controls n = 80) or three (AIIRDs n = 64; controls n = 30) doses of the BNT162b2 vaccine, evaluated for vaccine side-effects, disease activity, COVID-19 breakthrough infection rates and severity, and anti-spike S1/S2 IgG antibody titers in a sample from both groups. RESULTS: The vaccination safety profile was favorable, with most patients reporting mild or no side-effects. The rheumatic disease remained stable at 98% and 100% after the second and third doses, respectively. The two-dose vaccine induced comparable seropositivity rates among patients (91%) and controls (100%), (p = 0.55), which declined within 6 months to 87% and 100%, respectively (p = 0.3) and increased to 100% in both groups after the third vaccine dose. The overall post-vaccination COVID-19 infection rate was comparable between patients and controls, 47.6% (n = 59) and 35% (n = 28), respectively; p = 0.5278, with most infections occurring during the Omicron surge. In relation to the last vaccination, time-to-COVID-19 infection was similar between patients and controls, at a median of 5.5 vs. 5.2 months, respectively (log-rank p = 0.1555). CONCLUSION: The safety profile of three doses of the BNT162b2 mRNA vaccine was excellent, with adequate humoral response and similar efficacy among patients and controls. These results support the recommendation for vaccinating adolescents with juvenile-onset AIIRDs against COVID-19.

Adherence of caregivers of children to advice provided by a National Poison Information Center.

INTRODUCTION: Most calls to poison information centers are from the public, pertaining to young children, and due to minor or nontoxic exposures. Rational poison center consultations can prevent unnecessary visits to emergency departments (EDs), callers' adherence to such advice is required. OBJECTIVES: Estimate adherence of callers from the public to the poison center concerning exposures of young children to the advice provided by the clinical toxicologist, estimate the number of unnecessary ED visits of these children prevented by poison center consultations. METHODS: Prospective, phone-survey cohort study. Calls from the public concerning children under 6 years old were recorded and collected, telephone follow-up was performed within two weeks. Data collected included: demographics, exposure, severity, triage advised, adherence to the advice, reasons for nonadherence, and what the caller would have done had the poison center been unavailable. The study was conducted over 3 months representing different seasons and holidays times during a 1-year period. RESULTS: 1762 callers completed the telephone follow-up; 1443 (81.9%) cases were asymptomatic at the time of call; 1452 (82.3%) were advised to remain at home, 175 (9.9%) and 137 (7.8%) were referred to community clinics and EDs, respectively; 1648 (93.5%) of callers adhered to the advice provided; highest adherence rate was among callers advised to stay home (98.3%, 1427), and 78.9% (108) and 62.1% (109) among callers referred to EDs and community clinics, respectively. Among callers advised to stay home, 491 stated that they would have referred themselves to the ED had the poison center been unavailable, an annual estimate of 4309 cases. The main parameter predicting nonadherence was calls made during night shift. CONCLUSIONS: The high adherence of callers to the poison center consultation suggests it plays an important role in preventing unnecessary ED visits of young children due to poison exposures, and may substantially reduce ED load and costs.