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.

Risk factors for haemodynamic compromise in multisystem inflammatory syndrome in children: a multicentre retrospective study.

OBJECTIVES: To identify predictors of a severe clinical course of multisystem inflammatory syndrome in children (MIS-C), as defined by the need for inotropic support. METHODS: This retrospective study included patients diagnosed with MIS-C (according to the CDC definition) in nine Israeli and one US medical centre between July 2020 and March 2021. Univariate and multivariate regression models assessed odds ratio (OR) of demographic, clinical, laboratory and imaging variables during admission and hospitalization for severe disease. RESULTS: Of 100 patients, 61 (61%) were male; mean age 9.65 (4.48) years. Sixty-five patients were hypotensive, 44 required inotropic support. Eleven patients with MIS-C fulfilled Kawasaki disease diagnostic criteria; 87 had gastrointestinal symptoms on admission. Echocardiographic evaluation showed 10 patients with acute coronary ectasia or aneurysm, and 37 with left ventricular dysfunction. In a univariate model, left ventricular dysfunction was associated with severe disease [OR 4.178 (95% CI 1.760, 9.917)], while conjunctivitis [OR 0.403 (95% CI 0.173, 0.938)] and mucosal changes [OR 0.333 (95% CI 0.119, 0.931)] at admission were protective. Laboratory markers for a severe disease course were low values of haemoglobin, platelets, albumin and potassium; and high leukocytes, neutrophils, troponin and brain natriuretic peptide. In multivariate analysis, central nervous system involvement and fever >39.5°C were associated with severe disease. Mucosal involvement showed 6.2-fold lower risk for severe disease. Low haemoglobin and platelet count, and elevated C-reactive protein and troponin levels were identified as risk factors for severe disease. CONCLUSION: Key clinical and laboratory parameters of MIS-C were identified as risk factors for severe disease, predominantly during the disease course and not at the time of admission; and may prompt close monitoring, and earlier, more aggressive treatment decisions. Patients presenting with a Kawasaki-like phenotype were less likely to require inotropic support.

Performance of 2019 EULAR/ACR classification criteria for systemic lupus erythematosus in a paediatric population-a multicentre study.

OBJECTIVES: The European League Against Rheumatism and American College of Rheumatology 2019 (EULAR/ACR-19) criteria for the diagnosis of SLE were recently published, with the stated goal of maintaining the level of sensitivity and raising the level of specificity for classification of SLE in adults. The aim of this study is to examine their application to juvenile SLE (jSLE) patients. METHODS: In this multicentre study the charts of jSLE patients from three tertiary medical centres were reviewed and compared with patients with non-jSLE diagnosis. Paediatric rheumatologists, blinded to the original diagnosis, reviewed and diagnosed all cases. Paediatric patients' clinical and laboratory data were retrospectively extracted and then examined with regard to how they met the new and old criteria. RESULTS: Included were 225 patients (112 jSLE, 113 non-SLE). When applied to juvenile SLE classification, the sensitivity of the new EULAR/ACR-19 criteria was 0.96 (95% CI: 0.9, 0.99) and the specificity was 0.89 (95% CI: 0.82, 0.94). These were comparable to the SLICC criteria. The sensitivity of the EULAR/ACR-19 criteria improves over time and was 0.83 12 months following disease onset, reaching 0.96 after longer than 24 months. CONCLUSION: Among a cohort of jSLE patients, sensitivity of the new EULAR/ACR-19 criteria was found to be high and specificity may have improved slightly compared with the SLICC-12 criteria. We support the use of the new classification criteria for paediatric patients in future jSLE studies, but it should be noted that its specificity is lower than for adults.

Rituximab for refractory manifestations of the antiphospholipid syndrome: a multicentre Israeli experience.

OBJECTIVES: The clinical manifestations of the antiphospholipid syndrome (APS) are heterogeneous and related to anti-phospholipid antibodies (aPL). There is some evidence that B cells are involved in the pathogenesis of this condition. Thus the ability of rituximab (RTX) to deplete B cells makes it an appealing potential therapy for refractory antiphospholipid syndrome (APS). Real world data on RTX treatment of APS are still lacking. This study was conducted to report outcomes of RTX administration in the treatment of different aspects of APS. METHODS: This is a retrospective case series study on APS patients from 3 medical centres in Israel who were treated with RTX during 2010-2019 for refractory manifestations of APS including diffuse alveolar haemorrhage, recurrent thrombosis, cytopenia, neurological and skin manifestations. Medical records were reviewed regarding the clinical indication for RTX treatment, concomitant medications, RTX protocol, aPL status and response to treatment. Outcomes were defined as complete response if full resolution of the "indicated manifestation" was achieved and maintained for at least 12 months, partial response or no response. RESULTS: We identified 40 APS patients who were treated with RTX for refractory manifestations of this condition, of whom, 24 patients (60%) were female with a mean age of 40 years, and 31 patients (78%) were diagnosed with primary APS. A favourable response to RTX was documented in 32 patients (80%) including a complete response in 22 patients (55%). Response to RTX treatment was associated with a rituximab protocol of 375mg/m2 x 4 compared to a fixed dose of 1000 mg x2 (100% vs. 65%; p=0.01). Complete response was associated with a decrease in aPL titres within 4-6 months post treatment, whereas no significant change in aPL titres was observed in patients with partial or no response. CONCLUSIONS: Consistent with previous small case series, we report a good therapeutic response to RTX in patients with difficult to treat manifestations of APS. In this cohort, treatment protocols were associated with outcomes. Although further studies are required to verify our observations, our data support a plausible role for B cell depletion in refractory APS.

[NEW ONSET OF VALVULAR HEART DISEASE ALONG WITH ANCIENT PATHOLOGIC FINDING].

INTRODUCTION: Rheumatic fever (RF) is an autoinflammatory disease that is caused by the host response to an infection with group A ß-hemolytic streptococcus. In this case report we describe a 15 years old boy with Down syndrome who had unusual presentation of acute rheumatic fever with a fulminant multisystemic which included heart failure secondary to pancarditis and adult respiratory distress syndrome. The final diagnosis was confirmed after cardiac biopsy that was performed during valve replacement surgery and demonstrated Aschoff bodies - a pathognomonic finding in acute rheumatic fever.

Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome - Is It Related to Ethnicity? An Israeli Multicenter Cohort Study.

OBJECTIVES: To evaluate the ethnic distribution of Israeli patients with the syndrome of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA). STUDY DESIGN: The medical records of patients with PFAPA attending 2 pediatric tertiary medical centers in Israel from March 2014 to March 2019 were retrospectively reviewed. Patients with concomitant familial Mediterranean fever were excluded. Ethnicity was categorized as Mediterranean, non-Mediterranean, and multiethnic. Findings were compared with patients with asthma under treatment at the same medical centers during the same period. RESULTS: The cohort included 303 patients with PFAPA and 475 with asthma. Among the patients with PFAPA, 178 (58.7%) were of Mediterranean descent (Sephardic Jews or Israeli Arabs), 96 (33.0%) were multiethnic, and 17 (5.8%) were of non-Mediterranean descent (all Ashkenazi Jews). Patients with PFAPA had a significantly higher likelihood of being of Mediterranean descent than the patients with asthma (58.7% vs 35.8%; P < .0001). The Mediterranean PFAPA subgroup had a significantly earlier disease onset than the non-Mediterranean subgroup (2.75 ± 1.7 vs 3.78 ± 1.9 years, P < .04) and were younger at disease diagnosis (4.77 ± 2.3 vs 6.27 ± 2.9 years, P < .04). CONCLUSIONS: PFAPA was significantly more common in patients of Mediterranean than non-Mediterranean descent. Further studies are needed to determine the genetic background of these findings.

Small-fiber neuropathy associated with autoinflammatory syndromes in children and adolescents.

INTRODUCTION: Small-fiber neuropathy is rare in children. It has been associated with several autoimmune disorders, but there are no reports of an autoinflammatory etiology. METHODS: The data of four children/adolescents presenting with erythromelalgia and neuropathic pain from 2014 to 2019 were collected retrospectively from the electronic database of a pediatric medical center. RESULTS: Results of clinical and/or electrophysiological evaluation excluded large nerve fiber involvement. Skin biopsy results confirmed small-fiber neuropathy. According to genetic analysis, two patients were heterozygous and one was homozygous for mutations in the familial Mediterranean fever (MEFV) gene. Behcet disease was diagnosed in the fourth patient. Treatment with anti-interleukin-1 agents, intravenous immunoglobulin, and glucocorticoids was beneficial. DISCUSSION: The diagnosis of small-fiber neuropathy should be considered in children/adolescents presenting with erythromelalgia. A thorough investigation is required to reveal the underlying disorder. Clinicians should be alert to the peripheral neurological manifestations of autoinflammatory syndromes because effective treatments are available.

Safety and efficacy of intravenous Colchicine in children with Familial Mediterranean Fever.

Familial Mediterranean Fever (FMF), the most common monogenic inflammatory disease, is mainly treated by oral Colchicine. However, 5% of patients are considered non-responders and, therefore, candidates for biologic therapy. Intravenous (IV) Colchicine treatment has been shown to be effective and safe in adult patients. The objective of this study was to evaluate the safety of IV Colchicine for pediatric FMF patients in our hospital, refractory to oral Colchicine, by reviewing their medical records. Inclusion criteria were all patients with FMF who commenced treatment with IV Colchicine before the age of 18 years, and received at least 6 months of IV therapy. The patients completed questionnaires to assess the efficacy of the treatment. Between 2004 and 2017, 7 pediatric FMF patients receiving maximal oral Colchicine doses and deemed non-responders were treated with weekly IV Colchicine, including 38 cumulative patient years of follow-up data (a full blood count, renal and liver function tests). All patients were homozygous for the M694V genotype. Long-term follow-up showed normal laboratory results with no Colchicine-related hospital admissions or toxicity. Global health assessment and the number of disease-free days have significantly improved (P < 0.05). Prolonged IV Colchicine use is described in pediatric FMF patients for the first time, with an excellent safety profile in our population, and decrease in intensity and frequency of attacks. In the biological era, IV Colchicine, although not leading to complete remission, may be considered a second-line option in countries where anti-interleukin 1 blockers are not available, or as a third-line option in case of failure to respond to biologics.

Musculoskeletal Manifestations as Presenting Symptoms of Inflammatory Bowel Disease in Children and Adolescents.

A comparison of 23 children with inflammatory bowel disease presenting with musculoskeletal symptoms and 46 children with arthritis of other causes yielded significantly higher rates in the inflammatory bowel disease group of sacroiliitis, arthralgia, additive and recurrent arthritis, microcytic anemia, elevated inflammatory markers, and hypoalbuminemia. Clinical awareness of these findings could expedite diagnosis and treatment.

Familial Mediterranean Fever Is Commonly Diagnosed in Children in Israel with Periodic Fever Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome.

OBJECTIVES: To describe a cohort of pediatric patients diagnosed with periodic fever aphthous stomatitis, pharyngitis and adenitis (PFAPA) and familial Mediterranean fever (FMF) and compare them with children diagnosed solely with PFAPA (sPFAPA). STUDY DESIGN: Clinical, laboratory, and genetic data of all pediatric patients diagnosed with sPFAPA or PFAPA/FMF were retrospectively collected from 2 primary Israeli medical referral centers and compared. RESULTS: Of 270 patients with PFAPA, more than one-half were of Mediterranean ancestry. Among patients with PFAPA, 51 (18.9%) also were diagnosed with FMF (PFAPA/FMF). Genetic data on the 9 most common MEFV variants were available for 45 children (88%) in the PFAPA/FMF group. Two variants were found in 15 children (33.3 %), 1 variant was found 27 patients (60%), and 3 patients (6.6%) had no variants. Abdominal pain, myalgia, and arthralgia each were more commonly reported in the PFAPA/FMF group compared with the sPFAPA group (90% vs 49% [P < .0001]; 46% vs 23% [P = .02]; and 30% vs 17% [P = .049], respectively). Colchicine was more commonly prescribed for the PFAPA/FMF group compared with the sPFAPA group (82% vs 29%; P < .0001), but alleviation of PFAPA symptoms with colchicine was similar between groups (75% vs 63%; P = .23). CONCLUSION: We show a strong association between 2 common autoinflammatory syndromes, PFAPA and FMF, in patients from Mediterranean ancestry. Clinicians should be aware that presentation of 1 disease may clinically evolve into another. The association between PFAPA and FMF poses the question similar pathogenesis and genetic influence of the MEFV gene on PFAPA.

[WORLD YOUNG RHEUMATIC DISEASE DAY (WORD DAY): AN EXAMPLE OF CO-OPERATION BETWEEN DOCTORS AND PARENT ASSOCIATIONS FOR THE PURPOSE OF OPTIMAL PATIENT CARE].

INTRODUCTION: Pediatric rheumatic illnesses are not well known nor easily diagnosed, resulting in a long passage of time before diagnoses by a pediatric rheumatologist and the beginning of appropriate treatment. Early detection usually provides a better prognosis, whereas delay, misdiagnosis and subsequent mistreatment can aggravate damage and pain caused by the illness. To combat this problem, the European Society for Pediatric Rheumatologists, PReS and the European Parent/Patient Association ENCA, have jointly inaugurated WORD Day, "WOrld Young Rheumatic Disease Day" annually, on March 18th. The objectives of this day are to raise parental and professional awareness to these illnesses by giving parents and physicians necessary tools to recognize symptoms which require rheumatological attention. This day, as a joint cooperative venture of pediatric rheumatologists and parent associations, joins the progression towards increased cooperation between pediatric rheumatologist and parent associations. This cooperation, which asserts itself in many fields including research, educational activity and setting criteria for optimal care, is born of the belief that optimal patient care must take into account not only the medical knowledge that doctors have to offer, but also the attitudes and needs of the patients. Care formulated through this type of co-operation can significantly increase both the quality of care and patient compliance to treatment. This article describes the nature of this cooperation with an emphasis both on the structure of the cooperation utilized for the awareness day and its educational goals and tools.

The Hebrew version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR).

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Hebrew language. The reading comprehension of the questionnaire was tested in ten JIA parents and patients. Each participating centre was asked to collect demographic, clinical data, and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations, and construct validity (convergent and discriminant validity). A total of 116 JIA patients (17.2% systemic, 56% oligoarticular, 20.7% RF negative poly-arthritis, and 6.1% other categories) and 98 healthy children were enrolled in two centres. The JAMAR components discriminated well healthy subjects from JIA patients. All JAMAR components revealed good psychometric performances. In conclusion, the Hebrew version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and in clinical research.

Japanese scoring systems to predict resistance to intravenous immunoglobulin in Kawasaki disease were unreliable for Caucasian Israeli children.

AIM: This study assessed the validity of using established Japanese risk scoring methods to predict intravenous immunoglobulin (IVIG) resistance to Kawasaki disease in Israeli children. METHODS: We reviewed the medical records of 282 patients (70% male) with Kawasaki disease from six Israeli medical centres between 2004 and 2013. Their mean age was 2.5 years. The risk scores were calculated using the Kobayashi, Sano and Egami scoring methods and analysed to determine whether a higher risk score predicted IVIG resistance in this population. Factors that predicted a lack of response to the initial IVIG dose were identified. RESULTS: We found that 18% did not respond to the first IVIG dose. The three scoring methods were unable to reliably predict IVIG resistance, with sensitivities of 23%-32% and specificities of 67%-87%. Calculating a predictive score that was specific for this population was also unsuccessful. The factors that predicted a lacked of response to the first IVIG dose included low albumin, elevated total bilirubin and ethnicity. CONCLUSION: The established risk scoring methods created for Japanese populations with Kawasaki disease were not suitable for predicting IVIG resistance in Caucasian Israeli children, and we were unable to create a specific scoring method that was able to do this.

Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy.

BACKGROUND: Polyarteritis nodosa is a systemic necrotizing vasculitis with a pathogenesis that is poorly understood. We identified six families with multiple cases of systemic and cutaneous polyarteritis nodosa, consistent with autosomal recessive inheritance. In most cases, onset of the disease occurred during childhood. METHODS: We carried out exome sequencing in persons from multiply affected families of Georgian Jewish or German ancestry. We performed targeted sequencing in additional family members and in unrelated affected persons, 3 of Georgian Jewish ancestry and 14 of Turkish ancestry. Mutations were assessed by testing their effect on enzymatic activity in serum specimens from patients, analysis of protein structure, expression in mammalian cells, and biophysical analysis of purified protein. RESULTS: In all the families, vasculitis was caused by recessive mutations in CECR1, the gene encoding adenosine deaminase 2 (ADA2). All the Georgian Jewish patients were homozygous for a mutation encoding a Gly47Arg substitution, the German patients were compound heterozygous for Arg169Gln and Pro251Leu mutations, and one Turkish patient was compound heterozygous for Gly47Val and Trp264Ser mutations. In the endogamous Georgian Jewish population, the Gly47Arg carrier frequency was 0.102, which is consistent with the high prevalence of disease. The other mutations either were found in only one family member or patient or were extremely rare. ADA2 activity was significantly reduced in serum specimens from patients. Expression in human embryonic kidney 293T cells revealed low amounts of mutant secreted protein. CONCLUSIONS: Recessive loss-of-function mutations of ADA2, a growth factor that is the major extracellular adenosine deaminase, can cause polyarteritis nodosa vasculopathy with highly varied clinical expression. (Funded by the Shaare Zedek Medical Center and others.).

High-dose aspirin for Kawasaki disease: outdated myth or effective aid?

OBJECTIVES: To compare the efficacy and safety of intravenous immunoglobulin (IVIG) plus high-dose aspirin (HDA) vs. IVIG plus low-dose aspirin (LDA) for the treatment of Kawasaki disease, with an emphasis on coronary artery outcomes. METHODS: This study was a retrospective, medical record review of paediatric patients with Kawasaki disease comparing 6 centres that routinely used HAD for initial treatment and 2 that used LDA in 2004-2013. Treatment response and adverse events were compared. The primary outcome measure was the occurrence of coronary aneurysm at the subacute or convalescent stage. RESULTS: The cohort included 358 patients, of whom 315 were initially treated with adjunctive HDA and 43 with LDA. There were no demographic differences between the groups. Coronary aneurysms occurred in 10% (20/196) of the HDA group and 4% (1/24) of the LDA group (p=0.34). Equivalence tests indicate it is unlikely that the risk of coronary aneurysm in LDA exceeds HDA by more than 3.5%. There were no significant between-group differences in the need for glucocorticoid pulse therapy or disease recurrence. Coronary ectasia rate and hospitalisation time were significantly greater in the HDA group. Adverse events were similar in the two groups. CONCLUSIONS: We found no significant clinical benefit in using IVIG+HDA in Kawasaki disease compared to IVIG+LDA. The use of adjunctive HDA in this setting should be reconsidered.

[EOSINOPHILIC FASCIITIS (EF)].

INTRODUCTION: Eosinophilic fasciitis (EF) is a rare connective tissue disease characterized by erythema, edema and myalgia with induration and thickening of the skin and soft tissue, especially subcutaneous fascia. Laboratory findings usually show peripheral eosinophilia, and full-thickness wedge biopsy is essential to establish the diagnosis. Corticosteroids are effective and remain the standard therapy for EF, although some patients may improve spontaneously. In this article we report a case of a 17 years old male who has been diagnosed with EF 2 years after bone marrow transplantation and review the clinical manifestations, pathology, diagnosis, differential diagnosis, and treatment of EF.

Periodic fever, aphthous stomatitis, pharyngitis and cervical adenopathy syndrome is associated with activation of GM-CSF and burst-like expression of IL-8 in peripheral blood.

INTRODUCTION: Periodic fever, aphthous stomatitis, pharyngitis and cervical adenopathy (PFAPA) is an autoinflammatory syndrome characterized by periodic fever with aphthous stomatitis, cervical lymphadenopathy, myalgia, and abdominal pain. Peripheral blood concentrations of selected cytokines of PFAPA patients during and between febrile episodes were analyzed in a search for PFAPA-specific molecular signature. METHODS: 23 children with PFAPA (age 6.07 ± 2.94 years, range 5-9 years) and three control children with severe oropharyngeal infections (age 6.2 ± 7.95 years, range 1-17 years) participated in the study. Peripheral blood concentrations of IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IFN-γ, GM-CSF, TNF-α were measured using Luminex technology. RESULTS: PFAPA febrile episodes were characterized by detection of GM-CSF - 134.07 ± 315.5 pg/mL; significant (P < 0.001), compared to baseline and controls, elevation of concentrations of IL-8 (3193.7 ± 2508 pg/mL vs. 100.36 ± 119. pg/mL vs. 2.04 ± 4.08 pg/mL, respectively), IL-6 (1355.38 ± 2026.53 pg/mL vs. 28.8 ± 44.2 pg/mL and 27.13 ± 26.42 pg/mL, respectively). IL-1ß was detected only in febrile and afebrile PFAPA patients (922.8 ± 1639 pg/mL vs. 10.98 ± 19.4 pg/ml, P < 0.002, respectively), but not in controls. Peripheral blood concentration of TNFα did not differ significantly between study groups. IL-2, IL-4, IL-5, and IL-10 were negligible in all study subjects. DISCUSSION: PFAPA febrile episodes are characterized by activation of GM-CSF and IL-8 with Th1 skewing. We propose a molecular mechanism governing this phenomenon.

Discovery of a Novel Missense Variant in NLRP3 Causing Atypical Cryopyrin-Associated Periodic Syndromes With Hearing Loss as the Primary Presentation, Responsive to Anti-Interleukin-1 Therapy.

OBJECTIVE: Cryopyrin-associated periodic syndromes (CAPS), also known as NLRP3-associated autoinflammatory diseases, are a spectrum of rare autoinflammatory diseases caused by gain-of-function variants in the NLRP3 gene, resulting in inflammasome hyperactivation and dysregulated release of interleukin-1ß (IL-1ß). Many patients with CAPS develop progressive sensorineural hearing loss (SNHL) because of cochlear autoinflammation, which may be the sole manifestation in rare cases. This study was undertaken to establish the suspected diagnosis of CAPS in a family presenting with autosomal-dominant progressive/acute SNHL and a novel missense variant in the NLRP3 gene of unknown significance (NM_001079821.3:c.1784G>A p.Ser595Asn). METHODS: We conducted an ex vivo functional assessment of the NLRP3 inflammasome in heterozygous individuals (n = 10) and healthy family members (n = 5). RESULTS: The assay revealed hyperactivation of the inflammasome among heterozygous individuals, supporting the hypothesis that this missense variant is a pathogenic gain-of-function variant. Administration of IL-1 receptor antagonist resulted in a substantial clinical improvement among pediatric patients, who exhibited near resolution of hearing impairment within 1 to 3 months of treatment. CONCLUSION: Our findings highlight the crucial role of early diagnosis and treatment with an anti-IL-1 agent in reversing cochlear damage. Furthermore, our results suggest that high- and ultrahigh-frequency ranges need to be included in the auditory assessment to enable early detection of subclinical SNHL. Finally, incorporating functional inflammasome assessment as part of the clinical evaluation could establish the diagnosis in inconclusive cases.

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.