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.

Loss of function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling.

Histiocytoses are inflammatory myeloid neoplasms often driven by somatic activating mutations in mitogen-activated protein kinase (MAPK) cascade genes. H syndrome is an inflammatory genetic disorder caused by germ line loss-of-function mutations in SLC29A3, encoding the lysosomal equilibrative nucleoside transporter 3 (ENT3). Patients with H syndrome are predisposed to develop histiocytosis, yet the mechanism is unclear. Here, through phenotypic, molecular, and functional analysis of primary cells from a cohort of patients with H syndrome, we reveal the molecular pathway leading to histiocytosis and inflammation in this genetic disorder. We show that loss of function of ENT3 activates nucleoside-sensing toll-like receptors (TLR) and downstream MAPK signaling, inducing cytokine secretion and inflammation. Importantly, MEK inhibitor therapy led to resolution of histiocytosis and inflammation in a patient with H syndrome. These results demonstrate a yet-unrecognized link between a defect in a lysosomal transporter and pathological activation of MAPK signaling, establishing a novel pathway leading to histiocytosis and inflammation.

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.

Effect of interleukin-1 antagonist on growth of children with colchicine resistant or intolerant FMF.

INTRODUCTION: Familial Mediterranean Fever (FMF) is the most common monogentic autoinflammatory disease. FMF results from mutations in MEFV, which lead to a pro-inflammatory state and increased production of Interleukin 1 beta subunit (IL-1b) by myeloid cells. Despite the overall positive results obtained with anti-IL-1 agents in FMF patients, little is known about the long-term growth impact of these drugs in the pediatric population. OBJECTIVES: To assess the long-term body weight and height trajectories in children with FMF treated with anti-IL-1 agents. METHODS: We conducted a retrospective analysis of 646 pediatric FMF patients followed in our center, of whom 22 were treated with either anakinra (36.3%) and/or canakinumab (90.9%). Patients were assessed for demographic, clinical and genetic characteristics and were followed for a mean of 3.05 ± 1.75 years. Data of height and weight percentiles were recorded before and after treatment. RESULTS: The most common indication for IL-1 blockers treatment was colchicine resistance (66.6%). Ninety percent of those patients had a moderate or severe disease according to the Pras score and had higher proportion of M694V homozygosity compared with patients who did not require anti IL-1 agents (95.2% vs. 30.5%, p < 0.001). Overall, anakinra and canakinumab resulted in a complete response in 80% of patients and exhibited low rates of adverse effects. We found a significant increase in height and body weight percentiles following treatment (19.6 ± 16% vs. 30.8 ± 23%, p = 0.007, and 29.5 ± 30% vs. 39.1 ± 36%, p = 0.043, respectively). CONCLUSION: Treatment with anti-IL-1 agents in children with FMF is effective and safe and may potentiate long-term growth.

Obstacles in Early Diagnosis of Children With Juvenile Idiopathic Arthritis: A Nationwide Israeli Retrospective Study.

OBJECTIVE: Characterization of the stages that patients with juvenile idiopathic arthritis (JIA) pass until they are diagnosed, and analysis of the different causes that lead to a delay in JIA diagnosis in Israel. METHODS: This is a retrospective cohort study conducted in 8 pediatric rheumatology centers in Israel. All patients diagnosed with JIA between October 2017 and October 2019 were included in the study. Demographic, clinical, and data regarding the referring physicians were collected from hospital and community medical charts. RESULTS: Of 207 patients included in the study, 201 cases were analyzed, 71.1% of the population were female. Patients, on average, were evaluated during the diagnostic process by 3.1 different physicians. In most cases, they initially met with a pediatrician in the community setting (61.2%), and later, most commonly referred to a rheumatologist by the community pediatrician (27.9%). The median time until diagnosis was 56.0 days (range: 1.0-2451.0 days). Patients diagnosed with polyarticular and spondyloarthritis/enthesitis-related arthritis (SpA/ERA) JIA subtypes had the longest period until diagnosis (median: 115.5 and 112.0 days, respectively). Younger age correlated with a quicker diagnosis, and females were diagnosed earlier compared to males. Fever at presentation significantly shortened the time to diagnosis (P < 0.01), whereas involvement of the small joints/sacroiliac joints significantly lengthened the time (P < 0.05). CONCLUSION: This is the first nationwide multicenter study that analyzes obstacles in the diagnosis of JIA in Israel. Raising awareness about JIA, especially for patients with SpA/ERA, is crucial in order to avoid delays in diagnosis and treatment.

Poststreptococcal Myalgia and Protracted Febrile Myalgia Syndrome: Similar Yet Different.

We compare cases of familial Mediterranean fever-related protracted febrile myalgia and poststreptococcal myalgia, both rare disorders presenting with fever, myalgia, and inflammatory biomarkers. Although clinical symptoms may be undistinguishable, steroids are usually required in protracted febrile myalgia syndrome and poststreptococcal myalgia most often respond to nonsteroidal anti-inflammatory drugs. Awareness of poststreptococcal myalgia and preceding history may prevent unnecessary tests or overtreatment.

Validation of the psoriasis epidemiology screening tool (PEST) and the new early arthritis for psoriatic patients (EARP) in pediatric population: pilot study.

OBJECTIVE: Juvenile psoriatic arthritis (JPsA) is a severe inflammatory arthritis, which is associated with psoriasis in most cases. While there are few validated screening tools for diagnosis of arthritis for adult patients with psoriasis, those screening tools were never evaluated in children. The aims of this study were to evaluate two screening tools among pediatric patients with psoriasis. METHODS: Thirty-nine patients with the diagnosis of psoriasis completed two screening questionnaires: The Psoriasis Epidemiology Screening Tool (PEST) questionnaire and the new Early Arthritis for Psoriatic Patients (EARP) questionnaire. All patients were evaluated by a rheumatologist for the diagnosis of JPsA, and the accuracy of the two questionnaires was compared. RESULTS: The 4/39 (10.1%) patients diagnosed with JPsA had a PEST questionnaire score of ≥ 3, compared to a median PEST score of the patients without the diagnosis of JPsA of 0 (0-2). Thus, both the sensitivity and specificity of the PEST in diagnosing JPsA were 100%. For the EARP questionnaire, 8/39 patients had a screening questionnaire score of ≥ 3, suggestive of JPsA, four were true positive, and four false positive. Thus, the sensitivity and specificity of EARP in diagnosing JPsA were 100% and 89%, respectively. CONCLUSION: Both the PEST and EARP questionnaires were easy to use and had high sensitivity for the diagnosis of JPsA in the pediatric population with psoriasis. The PEST questionnaire had a higher specificity than the EARP. KEY POINTS: • EARP and PEST are good screening tools for diagnosis of arthritis in pediatric population with psoriasis.

Magnetic resonance findings may aid in diagnosis of protracted febrile myalgia syndrome: a retrospective, multicenter study.

BACKGROUND: Protracted febrile myalgia syndrome (PFMS) is a rare complication of Familial Mediterranean fever (FMF). The diagnosis is based on clinical symptoms and is often challenging, especially when PFMS is the initial manifestation of FMF. The aim of this report was to describe the magnetic resonance imaging (MRI) findings in pediatric patients with PFMS. RESULTS: There were three girls and two boys ranging in age from 6 months to 16 years, all of Mediterranean ancestry. Three had high-grade fever, and all had elevated inflammatory markers. MRI of the extremities yielded findings suggestive of myositis, which together with the clinical picture, normal CPK levels, and supporting family history of FMF, suggested the diagnosis of PFMS. Out of most common MEFV mutations tested, one patient was homozygous for M694V mutation, three were heterozygous for M694V mutation, and one was compound heterozygous for the M694V and V726A mutations. CONCLUSIONS: MRI may serve as an auxiliary diagnostic tool in PFMS.

Clinical significance of E148Q heterozygous variant in paediatric familial Mediterranean fever.

OBJECTIVES: FMF results from mutations in the Mediterranean fever (MEFV) gene. The p. E148Q protein alternation is one of the most frequent in the MEFV gene, yet the exact E148Q genotype-phenotype correlation remains unclear. The aim of this study was to examine clinical significance of heterozygous E148Q variant in a paediatric FMF cohort. METHODS: We compared the clinical manifestations and disease severity score of four genetic subgroups: (group 1) patients harbouring a single heterozygous p. E148Q variant (n = 6); (group 2) patients harbouring a single p. M694V heterozygous variant (n = 88); (group 3) patients harbouring compound heterozygous p. M694V and p. E148Q variants (n = 36); and (group 4) homozygotes for p. M694V variant (n = 160). RESULTS: Of 646 FMF children from our centre, only 1% (six patients) of our genetically characterized FMF cohort had a single E148Q variant, most presenting with recurrent fevers and abdominal pain. None of the participants was found to harbour homozygous E148Q. Overall, M694V/E148Q compound heterozygosity did not exhibit a more severe phenotype compared with patients with a single M694V variant. The former group were less likely to have abdominal pain and exertional leg pain (P < 0.004 and P < 0.001, respectively) and more likely to have chest pain (P < 0.01). Both subgroups showed milder clinical phenotype compared with patients with M694V homozygosity. CONCLUSION: Our findings demonstrate that a single heterozygous E148Q variant is unlikely to cause FMF in children and that E148Q/M694V is clinically indistinguishable from a single M694V variant. Thus, E148Q heterozygosity does not result in clinically meaningful phenotype in children.

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.