BackgroundThe interleukin-1 (IL-1) mediated systemic autoinflammatory diseases, including the cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD) and deficiency of the IL-1 receptor antagonist (DIRA), belong to a group of rare immunodysregulatory diseases that primarily present in early childhood with variable multiorgan involvement. When untreated, patients with severe clinical phenotypes have a poor prognosis, and diagnosis and management of these patients can be challenging. However, approved treatments targeting the proinflammatory cytokine IL-1 have been life changing and have significantly improved patient outcomes.ObjectiveTo establish evidence-based recommendations for diagnosis, treatment and monitoring of patients with IL-1 mediated autoinflammatory diseases to standardise their management.MethodsA multinational, multidisciplinary task force consisting of physician experts, including rheumatologists, patients or caregivers and allied healthcare professionals, was established. Evidence synthesis, including systematic literature review and expert consensus (Delphi) via surveys, was conducted. Consensus methodology was used to formulate and vote on statements to guide optimal patient care.ResultsThe task force devised five overarching principles, 14 statements related to diagnosis, 10 on therapy, and nine focused on long-term monitoring that were evidence and/or consensus-based for patients with IL-1 mediated diseases. An outline was developed for disease-specific monitoring of inflammation-induced organ damage progression and reported treatments of CAPS, TRAPS, MKD and DIRA.ConclusionThe 2021 EULAR/American College of Rheumatology points to consider represent state-of-the-art knowledge based on published data and expert opinion to guide diagnostic evaluation, treatment and monitoring of patients with CAPS, TRAPS, MKD and DIRA, and to standardise and improve care, quality of life and disease outcomes.

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Objectives FMF is the most common periodic fever syndrome, characterized by recurrent episodes of fever and serosal inflammation accompanied with high acute phase reactants. The analysis of possible comorbidities is important to understand the impact of these conditions on clinical care and whether they share a common aetiological pathway. In this study, we aimed to evaluate the comorbidities associated with FMF patients in a large genetically diagnosed cohort. Methods We retrospectively evaluated the medical and genetic records of FMF patients who were followed up by rheumatologists in Hacettepe University for 15 years. The FMF patients who had homozygous or compound heterozygous mutations were included in the study. Comorbidities associated with FMF were divided into three groups: (i) comorbidities directly related to FMF, (ii) comorbidities due to increased innate inflammation, and (iii) comorbidities that were regarded as being incidental. Results A total of 2000 patients with a diagnosis of FMF were enrolled in the study. Among them 636 were children (31.8%) and M694V was the most common mutation in patients with associated inflammatory conditions. The frequency of AS, Iga Vasculitis (Henoch–Schönlein purpura), juvenile idiopathic arthritis, polyarteritis nodosa, multiple sclerosis and Behçet’s disease were increased in patients with FMF when compared with those in the literature. Conclusion This study represents the largest genetically confirmed cohort and compares the frequencies with existing national and international figures for each disease. The increased innate immune system inflammation seen in FMF may be considered as a susceptibility factor since it predisposes to certain inflammatory conditions.

Background: Hypersensitivity reactions (HSR) to biologic drugs (BD) may limit their use in children with rheumatic diseases. We aimed to analyze the incidence and clinical characteristics of immediate type I (IgE/non-IgE) hypersensitivity reactions to BD and the risk factors for these reactions.Methods: Children with rheumatic diseases using BD who were evaluated in the pediatric allergy department for possible drug hypersensitivity reaction (DHR) due to BD or any other drug were included in the study. Results: One hundred and twenty-eight children (49.2% boys; 14.6 years [9.9-16.9 years] with juvenile idiopathic arthritis [58%], familial Mediterranean fever [14%], vasculitis [14%], and other diseases [14%]) had used eight different BD with 32 494 infusions/injections. Fifteen patients were evaluated for DHR [injection-site reactions [n = 4], adverse events [n = 2], drug hypersensitivity other than BD [n = 3],and immediate BD hypersensitivity [n = 6]). The incidence of immediate BD HSR was 4.7%, with a clinical presentation of anaphylaxis in 3.9% (tocilizumab [n = 3], rituximab [n = 2], positive skin test with culprit BD [n = 3]). Among patients with BD HSR, the median follow-up was longer (84.5 vs 54 months, P = .048), and renal (33.3% vs 4.1%, P = .002), hematologic involvement (16.7% vs 0, P < .001), and active disease (83.3% vs 13.9%, P < .001) were more common. Logistic regression analysis revealed that renal involvement, more than 14 hospitalizations per lifetime, and more than two different BD used were associated with BD hypersensitivity. Conclusion:The frequency of severe immediate HSR due to BD was shown to be 3.9% in children with rheumatic diseases. Children with active rheumatic disease and who have exposure to multiple BD should be monitored for BD HSR, particularly during intravenous BD infusions. K E Y W O R D Sbiologic drugs, children, hypersensitivity, rheumatic diseases

In order to evaluate the genetic epidemiology of deafness in Turkey, we first analyzed the pedigree data obtained from 2,169 families whose children were students of the schools for hearing loss/deafness in 31 cities of Turkey. Single major locus segregation analysis was performed after families were grouped according to hearing status of the parents. The results showed that sporadic phenocopies, autosomal dominant, and autosomal recessive transmission account for 18.2%, 4.9%, and 76.9% of the cases respectively, after exclusion of probands with unequivocal evidence for environmental etiologies. The high frequency of autosomal recessive transmission of this study differs from those of previous ones in Western populations. We subsequently analyzed the data from a subset of 574 unrelated families that were evaluated clinically, including mutation analysis of the GJB2 gene in 406 probands. Biallelic mutations were detected in 22.4% of all probands. They were present in 68.8% of probands whose parents were both deaf, yet in only 9.3% when both parents were hearing and consanguineous without a family history of deafness. Our study shows that GJB2 is the major gene for deafness in Turkey and was amplified in deaf by deaf matings, since assortative mating preferentially affects common genes. Deafness in the remaining families appears to result from mutations at many loci that are less frequent causes of deafness, because consanguinity has a proportionally greater effect on rare genes. Conclusions of this study may be relevant to other populations where consanguineous or assortative mating is present with various frequencies.

Background The interleukin‐1 (IL‐1) mediated systemic autoinflammatory diseases, including the cryopyrin‐ associated periodic syndromes (CAPS), tumour necrosis factor receptor‐associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD) and deficiency of the IL‐1 receptor antagonist (DIRA), belong to a group of rare immunodysregulatory diseases that primarily present in early childhood with variable multiorgan involvement. When untreated, patients with severe clinical phenotypes have a poor prognosis, and diagnosis and management of these patients can be challenging. However, approved treatments targeting the proinflammatory cytokine IL‐1 have been life changing and have significantly improved patient outcomes. Objective To establish evidence‐based recommendations for diagnosis, treatment and monitoring of patients with IL‐1 mediated autoinflammatory diseases to standardise their management. Methods A multinational, multidisciplinary task force consisting of physician experts, including rheumatologists, patients or caregivers and allied healthcare professionals, was established. Evidence synthesis, including systematic literature review and expert consensus (Delphi) via surveys, was conducted. Consensus methodology was used to formulate and vote on statements to guide optimal patient care. Results The task force devised five overarching principles, 14 statements related to diagnosis, 10 on therapy, and nine focused on long‐term monitoring that were evidence and/or consensus‐based for patients with IL‐1 mediated diseases. An outline was developed for disease‐specific monitoring of inflammation‐induced organ damage progression and reported treatments of CAPS, TRAPS, MKD and DIRA. Conclusion The 2021 EULAR/American College of Rheumatology points to consider represent state‐of‐the‐art knowledge based on published data and expert opinion to guide diagnostic evaluation, treatment and monitoring of patients with CAPS, TRAPS, MKD and DIRA, and to standardise and improve care, quality of life and disease outcomes.

To our knowledge, this is the first study comparing characteristics of adult and childhood onset PAN. Our results have suggested that juvenile PAN had a more benign course (with less renal and neurologic involvement, shorter duration of induction treatment) than adult onset PAN.

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease in the world. The disease characteristics may vary in different age groups. In this study, we aimed to compare disease characteristics and treatment compliance according to the age of pediatric FMF patients. This is a single-center, cross-sectional study. Between August and October 2016, patients who were diagnosed with FMF, participated to the study. 378 pediatric FMF patients were enrolled in the study. Among those, age at symptom onset was ≤ 5 years in 69%, 6-11 years in 26% and ≥ 12 years in 5%. Patients older than 12 years old at symptom onset, had significantly less frequent fever attacks than the patients from other age groups. Patients younger than 5 years old at symptom onset had significantly higher international severity scoring system for FMF (ISSF) than other patients. And M694V homozygosity was significantly more frequent in patients with younger age at symptom onset. Patients younger than 5 years old were using their drugs more regularly than the other age groups (p = 0.002). Drug compliance was 90.5% in patients ≤ 5 years, 64.4% in patients 6-11 years, 58.3% in patients ≥ 12 years. The disease characteristics of FMF may differ between patients with different age at symptom onset. Younger age at disease onset seems to be related with more severe course; thus these patients should be followed-up more closely. In addition, treatment compliance which is critical for prevention of amyloidosis in FMF should be questioned especially in adolescent patients.