Objective: In this study, we aimed to evaluate other interleukin-1b-mediated monogenic autoinflam- matory diseases (AIDs) (tumor necrosis factor receptor-1-associated periodic syndrome, hyperimmuno- globulin D syndrome, cryopyrin-associated periodic syndrome (CAPS), pyogenic arthritis, pyoderma gangrenosum, and acne syndrome) by the next-generation sequencing method (NGS) in cases with clinical Familial Mediterranean Fever symptoms, and no variant detected in the MEFV gene. Methods: The cases included in this study and their parents were interviewed and filled in a survey form. The targeted genetic panel for interleukin-1b-mediated AIDs covering four genes (MVK, NLRP3,TNFRSF1A, and PSTPIP1) was studied for cases with a negative result from the MEFV gene analysis. The genetic analysis was conducted using the targeted NGS method. Results: Variants were found in 16 out of the 40 patients in the study sample. These variants were pri- orly reported in variant databases, and three of them were identified as definitely pathogenic (V377I of the MVK gene, C52Y of the TNFRSF1A gene, and I313V of the NLRP3 gene), four as a variant of uncer- tain significance (VUS) (R92Q of the TNFRSF1A, A372V of the PSTPIP1, and V198M and Q703K of the NLRP3), and one as benign polymorphism (S52N of the MVK gene). The median age of onset among variant-positive cases was 10.5 (3.5-18) years. The most common clinical findings in the variant-positive group were arthralgia, fever, and abdominal pain. While three out of 40 patients met the classification criteria before genetic analysis, only one patient was diagnosed with CAPS as a result of genetic analy- sis, and other patients were considered as nonspecific phenotype. Conclusion: The use of NGS gene panels seems beneficial in diseases with heterogeneous clinical manifestations such as systemic AIDs. Although the number of variants detected is high, clinical diag- nosis rates remain low. The genotype–phenotype relationship in these diseases is still unclear.

In the last 20 years the clarification of monogenic periodic febrile diseases has led to the independent concept of autoinflammation. In this heterogeneous group polygenic complex diseases are also now included. The spectrum of symptoms is continuously growing. The main difference to autoimmunity is an excessive activation of the innate immune system without formation of autoantibodies or antigen-specific T‑cells. The cardinal symptom is recurrent fever episodes accompanied by signs of inflammation, which in the periodic manifestations alternate with intervals of general well-being. The classical monogenic diseases are also known as hereditary recurrent fever (HRF). Examples are familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), tumor necrosis factor receptor 1‑associated periodic syndrome (TRAPS), adenosine deaminase 2 (ADA2) deficiency and mevalonate kinase deficiency (MKD, hyper-IgD syndrome). The polygenic diseases are also known as nonhereditary fever syndromes. These include adult-onset Still's disease (AoSD), Adamantiades-Behçet disease, the PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) and gouty arthritis. All autoinflammatory fever syndromes are accompanied by a long-term risk of development of amyloid A amyloidosis, depending on the individual severity and treatment success. In some diseases severe complications can sometimes occur. In den letzten 20 Jahren hat die Aufklärung von monogenetisch verursachten periodischen Fiebererkrankungen zum eigenständigen Konzept der Autoinflammation geführt. In diese heterogene Gruppe werden inzwischen auch polygenetisch verursachte, komplexe Erkrankungen eingruppiert. Das Spektrum der Krankheitsbilder wächst kontinuierlich. Hauptunterschied zur Autoimmunität ist eine übermäßige Aktivierung des angeborenen Immunsystems ohne Autoantikörperbildung oder antigenspezifische T‑Zellen. Als Kardinalsymptom treten rezidivierende Fieberschübe, begleitet von Entzündungszeichen, auf; diese wechseln sich bei den periodischen Krankheitsbildern mit Intervallen allgemeinen Wohlbefindens ab. Die klassischen monogenetischen Erkrankungen werden auch als hereditäres rezidivierendes Fieber (HRF) bezeichnet. Beispiele sind das familiäre Mittelmeerfieber (FMF), das Cryopyrin-assoziierte periodische Syndrom (CAPS), das Tumor-Nekrose-Faktor-Rezeptor-1-assoziierte periodische Syndrom (TRAPS), die Adenosindesaminase(ADA2)-Defizienz und die Mevalonatkinasedefizienz (MKD; Hyper-IgD-Syndrom). Die polygenetischen Erkrankungen werden auch als nichthereditäre Fiebersyndrome bezeichnet. Hierzu zählen die adulte Form der Still-Erkrankung („adult-onset Still’s disease“, AoSD), die Adamantiades-Behçet-Erkrankung, das PFAPA-Syndrom (periodisches Fieber, aphthöse Stomatitis, Pharyngitis und zervikale Adenitis) und die Gichtarthritis. Alle autoinflammatorischen Fiebersyndrome gehen mit einem von individuellem Schweregrad und Therapieerfolg abhängigen Langzeitrisiko für die Entwicklung einer Amyloid-A-Amyloidose einher. Bei einigen Erkrankungen können z. T. schwere Komplikationen auftreten.

Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is a rare hereditary systemic autoinflammatory disease (SAID). Treatment is based on corticosteroids, but often requires the addition of a biologic drug (anti-TNF agent, IL-1 receptor antagonist, etc) to achieve symptom control. The addition of the second drug is not clearly defined and must take into account the characteristics and preferences of the patient. We describe a patient with TRAPS and an allergic reaction to anakinra which was difficult to manage clinically while alternative treatment was being identified. Treatment of tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) often requires adding a biologic drug to corticosteroids to achieve the best efficacy.Currently, IL-1 receptor antagonists are considered the first line of treatment in TRAPS.The most frequent adverse effect of anakinra is a reaction at the injection site.Canakinumab has shown better response compared to placebo in the treatment of TRAPS.

Tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS) is a very rare, hereditary, auto-inflammatory disorder caused by a genetic mutation within the tumor necrosis factor receptor superfamily member one-A (TNFRSF1A) gene, resulting in unregulated, systemic inflammation. We will present a patient who suffered through years of multiple medical problems of unknown etiology and will describe the process leading to the diagnosis of TRAPS. It is important to consider this syndrome as a rare but probable diagnosis in patients who lack a unifying explanation for multiple inflammatory symptoms.

To investigate frequency and phenotype of TNFRSF1A and MEFV mutations in childhood-onset multiple sclerosis (MS). Twenty-nine clinically well characterized patients were investigated for mutations in exons 2, 3, 4, and 6 of the TNFRSF1A gene and in exons 2, 3, 9, 10 of the MEFV gene. Standardized morbidity ratio (SMR) was used to assess whether the number of observed mutations was higher than expected. Eleven out of 29 patients tested positive for mutations. Heterozygosity for the TNFRSF1A R92Q (rs4149584) variant was found in 6/11 mutation-positive patients. The SMR for R92Q in our pediatric MS population was 4.6 (95% CI 1.7-10.0), 7.0 (95% CI 2.6-15.2), and 13.6 (95% CI 5.0-29.7), depending on reference population. Six patients carried at least one heterozygous MEFV mutation with SMRs of 21.4 (95% CI 7.9-46.6) and 14.6 (95% CI 5.4-31.9). Clinical characteristics of childhood MS patients with or without mutations did not differ significantly. Conclusion One third of our childhood MS patients had a heterozygous mutation in the TNFRSF1A and/or MEFV gene. This proportion by far exceeds the number of mutations expected and was higher than in adult MS patients, suggesting that these mutations might contribute to the pathogenesis of childhood MS.