Hidradenitis Suppurativa-Related Autoinflammatory Syndromes: An Updated Review on the Clinics, Genetics, and Treatment of Pyoderma gangrenosum, Acne and Suppurative Hidradenitis (PASH), Pyogenic Arthritis, Pyoderma gangrenosum, Acne and Suppurative Hidradenitis (PAPASH), Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis (SAPHO), and Rarer Forms.

Hidradenitis suppurativa (HS) is an autoinflammatory skin disorder of the terminal hair follicle, which can present in sporadic, familial, or syndromic form. A classification has been proposed for the latter, distinguishing cases associated with a known genetic condition, with follicular keratinization disorders or with autoinflammatory diseases. This review focuses on the clinical and genetic features of those entities (ie, pyoderma gangrenosum [PG], acne and HS; PG, acne, pyogenic arthritis and HS; psoriatic arthritis, PG, acne and HS; synovitis, acne, pustulosis, hyperostosis, osteitis; and so forth) for which the collective term HS-related autoinflammatory syndromes is proposed.

Genetic mutations in pyoderma gangrenosum, hidradenitis suppurativa, and associated autoinflammatory syndromes: Insights into pathogenic mechanisms and shared pathways.

Pyoderma gangrenosum (PG), hidradenitis suppurativa (HS), and the associated autoinflammatory syndromes, including pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome, PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH) syndrome, and pyogenic arthritis, pyoderma gangrenosum, acne, and suppurative hidradenitis (PAPASH) syndrome are dermatological conditions characterized by chronic inflammation and tissue damage. Recent advances in genetic research have identified specific mutations associated with these disorders, shedding light on their underlying pathogenic mechanisms. This review aims to summarize the current knowledge of identified mutations and presumed pathophysiology in PG, HS, and the associated autoinflammatory syndromes.

Tissue factor binds to and inhibits interferon-α receptor 1 signaling.

Tissue factor (TF), which is a member of the cytokine receptor family, promotes coagulation and coagulation-dependent inflammation. TF also exerts protective effects through unknown mechanisms. Here, we showed that TF bound to interferon-α receptor 1 (IFNAR1) and antagonized its signaling, preventing spontaneous sterile inflammation and maintaining immune homeostasis. Structural modeling and direct binding studies revealed binding of the TF C-terminal fibronectin III domain to IFNAR1, which restricted the expression of interferon-stimulated genes (ISGs). Podocyte-specific loss of TF in mice (PodΔF3) resulted in sterile renal inflammation, characterized by JAK/STAT signaling, proinflammatory cytokine expression, disrupted immune homeostasis, and glomerulopathy. Inhibiting IFNAR1 signaling or loss of Ifnar1 expression in podocytes attenuated these effects in PodΔF3 mice. As a heteromer, TF and IFNAR1 were both inactive, while dissociation of the TF-IFNAR1 heteromer promoted TF activity and IFNAR1 signaling. These data suggest that the TF-IFNAR1 heteromer is a molecular switch that controls thrombo-inflammation.

Recent Insights in Pyrin Inflammasome Activation: Identifying Potential Novel Therapeutic Approaches in Pyrin-Associated Autoinflammatory Syndromes.

Pyrin is a cytosolic protein encoded by the MEFV gene, predominantly expressed in innate immune cells. Upon activation, it forms an inflammasome, a multimolecular complex that enables the activation and secretion of IL-1ß and IL-18. In addition, the Pyrin inflammasome activates Gasdermin D leading to pyroptosis, a highly pro-inflammatory cell death. Four autoinflammatory syndromes are associated with Pyrin inflammasome dysregulation: familial Mediterranean fever, hyper IgD syndrome/mevalonate kinase deficiency, pyrin-associated autoinflammation with neutrophilic dermatosis, and pyogenic arthritis, pyoderma gangrenosum, and acne syndrome. In this review, we discuss recent advances in understanding the molecular mechanisms regulating the two-step model of Pyrin inflammasome activation. Based on these insights, we discuss current pharmacological options and identify a series of existing molecules with therapeutic potential for the treatment of pyrin-associated autoinflammatory syndromes.

Case report: De novo SAMD9L truncation causes neonatal-onset autoinflammatory syndrome which was successfully treated with hematopoietic stem cell transplantation.

During recent years, the identification of monogenic mutations that cause sterile inflammation has expanded the spectrum of autoinflammatory diseases, clinical disorders characterized by uncontrolled systemic and organ-specific inflammation that, in some cases, can mirror infectious conditions. Early studies support the concept of innate immune dysregulation with a predominance of myeloid effector cell dysregulation, particularly neutrophils and macrophages, in causing tissue inflammation. However, recent discoveries have shown a complex overlap of features of autoinflammation and/or immunodeficiency contributing to severe disease phenotypes. Here, we describe the first Argentine patient with a newly described frameshift mutation in SAMD9L c.2666delT/p.F889Sfs*2 presenting with a complex phenotypic overlap of CANDLE-like features and severe infection-induced cytopenia and immunodeficiency. The patient underwent a fully matched unrelated HSCT and has since been in inflammatory remission 5 years post-HSCT.

A novel frameshift variant in the ADA2 gene of a patient with a neurological phenotype: a case report.

BACKGROUND: Adenosine deaminase 2 (ADA2) deficiency is an inherited autoinflammatory syndrome caused by a defect in the ADA2 gene. Most common manifestations include peripheral vasculopathy, early-onset stroke, immunodeficiency, and haematological manifestations. Patients with pathogenic variants that are more detrimental to ADA2's enzymatic function (e.g. frameshift) have been reported to be prone to developing hematological phenotype. We report here the case of a 13-year-old Caucasian girl with a novel frameshift variant in the ADA2 gene and a clinical phenotype of early-onset stroke. CASE PRESENTATION: The patient was admitted to hospital with complaints of weakness in her right arm, unilateral facial weakness and speech problems. Her initial laboratory workup was normal; however, magnetic resonance imaging of her brain confirmed acute/subacute ischaemic changes in the posterior limb of the left-sided internal capsule and in the apical part of the thalamus. She also had manifestations of immunodeficiency - recurrent skin infections and otitis, chronic Molluscum contagiosum infection in anamnesis and B cell deficiency with a low level of serum IgA. The patient's DNA was analysed and two pathogenic variants were identified in the ADA2 gene, confirming a diagnosis of adenosine deaminase 2 (ADA2) deficiency. While one of the variants (c.506G > A (p.Arg169Gln)) has been reported previously, the other one is a novel frameshift variant, namely, c.464del (p.Pro155Hisfs*29). The patient received stroke rehabilitation, which significantly improved her functional state. Tumour necrosis factor inhibitor and methotrexate treatment was commenced, and the patient has remained stable with no further ischaemic events. CONCLUSIONS: Although rare, ADA2 deficiency should be considered in patients with early-onset stroke, especially with concomitant manifestations of inflammatory features or immunodeficiency. This case report extends the genotypic spectrum of ADA2 deficiency.

Differential Diagnosis of Urticarial Lesions.

Urticaria is a mast cell-dependent disease, characterized by the presence of wheals, angioedema, or both in the absence of systemic symptoms. It is a common disease worldwide, with an important health burden especially in chronic situations, that last more than 6 weeks. Although urticaria is usually a straightforward diagnosis, some diseases presenting with urticarial lesions must be excluded, particularly urticarial vasculitis and auto-inflammatory syndromes. In these settings additional atypical features are often present (long-lasting lesions, bruising, fever, malaise, arthralgia), allowing the clinician to suspect a diagnosis other than urticaria. The authors propose an approach based on these atypical features, the presence or absence of systemic symptoms and on skin histopathology as well as some blood parameters.

Coronavirus disease 2019 vaccination uptake and hesitancy among Polish patients with inborn errors of immunity, autoinflammatory syndromes, and rheumatic diseases: A multicenter survey.

Data regarding the willingness of patients affected by inborn errors of immunity to accept vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are limited. Therefore, this study assessed SARS-CoV-2 vaccination coverage and hesitancy in immunodeficient patients by surveying adults with primary immune deficiencies and autoinflammatory and rheumatic diseases on biologic therapy. The study was conducted from September 20, 2021, to January 22, 2022, when the primary coronavirus disease 2019 (COVID-19) vaccinations were available to all adults in Poland. We included 207 participants consecutively recruited from five referral centers (57% female; median age: 42.6 [range: 18-76, standard deviation ± 14.70] years). Overall, 55% (n = 114), 17% (n = 36), and 28% (n = 57) of the patients had primary immune deficiencies, autoinflammatory diseases, and rheumatic diseases, respectively. Among the entire cohort, 168 patients (81%) were vaccinated, and 82% were willing to receive a booster dose. Patients with autoinflammatory diseases had the highest vaccination rate (94.4%). A strong conviction that it was the correct decision (72%), fear of getting COVID-19 (38%), and expert opinions (34%) influenced the decision to vaccinate. Among the unvaccinated patients, 33.3% had primary or vocational education (p <0.001). Furthermore, only 33% believed they were at risk of a severe course of COVID-19 (p = 0.014), and 10% believed in vaccine efficacy (p <0.001). They also doubted the safety of the vaccine (p <0.001) and feared a post-vaccination flare of their disease (p <0.001). Half of the unvaccinated respondents declared that they would consider changing their decision. Vaccination coverage in immunodeficient patients was higher than in the general Polish population. However, the hesitant patients doubted the vaccine's safety, feared a post-vaccination disease flare, and had primary or vocational education. Therefore, vaccination promotion activities should stress personal safety and the low risk of disease flares due to vaccination. Furthermore, all evidence must be communicated in patient-friendly terms.

Generalized pustular psoriasis is a disease distinct from psoriasis vulgaris: evidence and expert opinion.

INTRODUCTION: Generalized pustular psoriasis (GPP) is a rare, severe, clinically heterogeneous disease characterized by flares of widespread, noninfectious, macroscopically visible pustules that occur with or without systemic inflammation, and are associated with significant morbidity and mortality. Historically, GPP has been classified as a variant of psoriasis vulgaris (PV, or plaque psoriasis); however, accumulating evidence indicates that these are distinct conditions, requiring different treatment approaches. AREAS COVERED: In this perspective article we review evidence that supports the classification of GPP as distinct from PV. EXPERT OPINION: The histopathologic and clinical appearance of GPP is distinct from that of PV and fundamental differences exist between the two conditions in terms of genetic causes and expression-related mechanisms of disease development. GPP results from dysregulation of the innate immune system, with disruption of the interleukin (IL)-36 inflammatory pathway, induction of inflammatory keratinocyte responses, and recruitment of neutrophils. PV is driven by the adaptive immune system, with a key role played by IL-17. Considering GPP as a separate disease will enable greater focus on its specific pathogenesis and the needs of patients. Many treatments for PV have insufficient efficacy in GPP and a therapeutic approach developed specifically for GPP might lead to better patient outcomes.

Generalized pustular psoriasis (GPP) is a rare disease. During episodes of worsening disease, the immune system attacks the skin. This causes large areas of skin to become red and painful, pus-filled blisters suddenly form. Some people with GPP have a history of another, more common, skin condition called psoriasis vulgaris (PV). People with PV develop patches of scaly, itchy skin. In the past, GPP was classed as a type of PV and treated with the same medicines. However, these medicines do not work well in GPP. Researchers now understand more about what causes GPP and how it differs from PV. GPP can cause medical problems throughout the body, leading to life-threatening complications. This means that people with GPP often need urgent medical treatment in hospitals. People with PV are mostly treated outside of hospitals. Any other medical problems are not usually due to PV itself. Researchers have found several genes that are altered in people with GPP and PV, and they differ between the two diseases. For example, changes in a gene called IL36RN are common in GPP but are not seen in PV. The skin of people with these two diseases also looks different under a microscope. Knowing more about GPP and how it differs from PV will help people with GPP to be diagnosed more quickly. It will also help researchers to develop new medicines specifically for GPP, so people can receive better treatment in the future.

The Added Value of a Multidisciplinary Clinic for Systemic Autoinflammatory Diseases.

Background: Systemic autoinflammatory diseases (SAID) are characterized by inappropriate activation of the innate immune system and include not only monogenic periodic fever syndromes but also multifactorial conditions. As SAID are rare and represent a diagnostic challenge, a multidisciplinary approach is important to ensure successful diagnosis and adequate follow-up of these patients. Objective: To describe the organization of our multidisciplinary SAID clinic and to characterize our clinical experience, highlighting the benefits of multidisciplinary team management. Methods: Our SAID clinic takes place monthly and is managed by pediatric rheumatologists closely collaborating with pediatricians specialized in infectious diseases and immunodeficiencies and one medical geneticist. Patients' data are systematically incorporated in the Rheumatic Diseases Portuguese Register (Reuma.pt). Biological samples are stored in a biobank. We describe our clinical experience based on SAID patients registered into Reuma.pt/SAID between July 2011 and June 2020. Results: We have registered 176 patients, with a median age of disease onset of 3.1 ± 4.4 years and median age at disease diagnosis of 4.7 ± 4.0 years. Most patients were diagnosed with periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome (PFAPA) (n=133), 20 with undefined SAID (uSAID) and 13 with monogenic SAID, including familial Mediterranean fever (FMF) (n=5), tumor necrosis factor receptor-associated periodic syndrome (TRAPS) (n=1), cryopyrin-associated periodic disease (CAPS) (n=1), and hyperimmunoglobulin D syndrome/mevalonate kinase deficiency (HIDS/MKD) (n=2). A genetic test was performed in 31 patients (18%), and in 26% of these a mutation responsible for the phenotype was found. Thirty-four patients (19%) achieved remission. Conclusion: FMF was the most common monogenic SAID and the percentage of patients with an identified causal mutation was low. A structured electronic clinical record coupled with a biobank and a multidisciplinary approach are crucial to ensure successful diagnosis and adequate follow-up of these patients.

The challenge of early diagnosis of autoimmune lymphoproliferative syndrome in children with suspected autoinflammatory/autoimmune disorders.

OBJECTIVES: To test the usefulness of an extended panel of lymphocyte subsets in combination with Oliveira's diagnostic criteria for the identification of autoimmune lymphoproliferative syndrome (ALPS) in children referred to a paediatric rheumatology centre. METHODS: Patients referred from 2015 to 2018 to our rheumatology unit for an autoimmune or autoinflammatory condition were retrospectively analysed. Oliveira's required criteria [chronic lymphoproliferation and elevated double-negative T (DNT)] were applied as first screening. Flow cytometry study included double-negative CD4-CD8-TCRαß+ T lymphocytes (DNT), CD25+CD3+, HLA-DR+CD3+ T cells, B220+ T cells and CD27+ B cells. Data were analysed with a univariate logistic regression analysis, followed by a multivariate analysis. Sensitivity and specificity of the Oliveira's required criteria were calculated. RESULTS: A total of 264 patients were included in the study and classified as: (i) autoimmune diseases (n = 26); (ii) juvenile idiopathic arthritis (JIA) (35); (iii) monogenic systemic autoinflammatory disease (27); (iv) periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (100); (v) systemic undefined recurrent fever (45); (vi) undetermined-systemic autoinflammatory disease (14); or (vii) ALPS (17). Oliveira's required criteria displayed a sensitivity of 100% and specificity of 79%. When compared with other diseases the TCRαß+B220+ lymphocytes were significantly increased in ALPS patients. The multivariate analysis revealed five clinical/laboratory parameters positively associated to ALPS: splenomegaly, female gender, arthralgia, elevated DNT and TCRαß+B220+ lymphocytes. CONCLUSIONS: Oliveira's required criteria are useful for the early suspicion of ALPS. TCRαß+B220+ lymphocytes should be added in the diagnostic work-up of patients referred to the paediatric rheumatology unit for a suspected autoimmune or autoinflammatory condition, providing a relevant support in the early diagnosis of ALPS.

Expanding spectrum of DADA2: a review of phenotypes, genetics, pathogenesis and treatment.

Deficiency of adenosine deaminase 2 (DADA2) is a monogenic disease caused by biallelic mutations in ADA2 gene (previously CECR1). The aim of this review was to describe the clinical phenotypes, genetics, pathogenesis and treatment of DADA2. ADA2 is highly expressed on myeloid cells and deficiency leads to polarisation of macrophages to an M1 inflammatory type and activation of neutrophils. The pathogenesis of immunological and haematological manifestations is less clear. The spectrum of clinical presentations varies widely from asymptomatic individual to severe vasculitis, several autoinflammatory, immunological and haematological manifestations. Initially considered a childhood disease, the first presentation is now being reported well into adulthood. Vasculitis closely resembles polyarteritis nodosa. Livedoid reticularis/racemosa like skin rash and central nervous system involvement in the form of ischemic or haemorrhagic stroke are dominant manifestations. Immunological manifestations include hypogammaglobulinemia and recurrent infections. Lymphopenia is the most common haematological manifestation; pure red cell aplasia and bone marrow failure has been reported in severe cases. The disease is extremely heterogeneous with variable severity noted in patients with the same mutation and even within family members. Tumour necrosis factor inhibitors are currently the treatment of choice for vasculitic and inflammatory manifestations and also prevent strokes. Haematopoietic stem cell transplantation is a curative option for severe haematological manifestations like pure red cell aplasia, bone marrow failure and immunodeficiency. Further research is required to understand pathogenesis and all clinical aspects of this disease to enable early diagnosis and prompt treatment. Key Points • Deficiency of adenosine deaminase 2 (DADA2) is a monogenic disease caused by biallelic mutations in ADA2 gene. • The clinical features include vasculitis resembling polyarteritis nodosa, autoinflammation, haematological manifestations and immunodeficiency. • The severity varies widely from mild to fatal even in patients within a family and with the same mutation. • The treatment of choice for inflammatory and vasculitic disease is tumour necrosis factor α blockers. Bone marrow transplant may be considered for severe haematological disease.

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.

[Autoinflammatory skin diseases : Diagnosis and therapy]. / Autoinflammatorische Dermatosen : Diagnostik und Therapie.

Autoinflammatory syndromes are characterized by an exaggerated activation of the innate immune system and frequently present with skin symptoms. In contrast to autoimmune disorders no specific autoantibodies or autoreactive immune cells are detected. Thus, the diagnosis is usually difficult and can only be made by a careful interpretation of anamnestic, clinical and laboratory parameters. In some hereditary autoimmune syndromes specific genetic mutations are described and can be helpful for the diagnosis. For treatment of these disorders both classic immunomodulatory drugs and specific cytokine inhibitors are used, mainly directed against interleukin­1. Long-term therapy is generally required.

Mevalonic aciduria: Does stem cell transplant fully cure disease?

MA is a rare, autosomal recessive disorder characterized by episodes of inflammation and periodic fevers. In its most severe form, it can result in facial dysmorphism, growth inhibition, ataxia, liver dysfunction, intellectual disability, and at times can be fatal. A number of case reports exist stating that SCT is curative in these patients. We present the case of a patient diagnosed with MA at birth, who underwent SCT at the age of 14 months with intent to cure. She achieved complete engraftment and urine mevalonate became undetectable. However, 18 months following transplant, she developed frequent episodes of fevers, rashes, arthritis, and a rising urinary mevalonate. She was subsequently diagnosed with relapse. She now requires treatment with steroids and canakinumab to manage her disease. This case is the first report of disease relapse following transplant for MA. It runs contrary to prior reports that SCT is fully curative of MA and suggests that transplant may instead provide a means of decreasing disease severity without entirely eradicating the condition.

Induced pluripotent stem cells representing Nakajo-Nishimura syndrome.

Nakajo-Nishimura syndrome is a proteasome-associated autoinflammatory syndrome with a distinct homozygous mutation in the PSMB8 gene encoding an inducible ß5i subunit of the immunoproteasome. Although it is considered that immunoproteasome dysfunction causes cellular stress and contributes to the production of inflammatory cytokines and chemokines, its detailed mechanism is still unknown. On the other hand, hereditary autoinflammatory diseases are considered as a good target for the analyses using induced pluripotent stem cells, whose differentiation systems to the innate immune cells such as neutrophils and monocytes have been established. Therefore, to elucidate the pathogenesis of Nakajo-Nishimura syndrome, we attempted in vitro disease modeling using patient-derived induced pluripotent stem cells. For analyses, isogenic control cells in which the responsible mutation was repaired and another pair of healthy embryonic stem cells and isogenic mutant cells in which the same mutation was introduced had also been prepared with genetic engineering. By comparing a pair of isogenic cells with the wild-type and the mutant PSMB8 gene after differentiation into monocytes and immortalization to synchronize their differentiation stages, the reduction of immunoproteasome enzyme activity and increased cytokine and chemokine production in the mutant cells without stimulation or with interferon-γ plus tumor necrosis factor-α stimulation were observed, and therefore, the autoinflammatory phenotype was successfully reproduced. Decreased cytokine production was observed by the addition of antioxidants as well as inhibitors for Janus kinase and p38-mitogen-activated protein kinase. At the same time, the increased production of reactive oxygen species and phosphorylation of both signal transducers and activator of transcription 1 and p38-mitogen-activated protein kinase were detected without stimulation. Notably, an antioxidant specifically decreased the constitutive phosphorylation of signal transducers and activator of transcription 1. These results indicate the usefulness of a disease modeling using pluripotent stem cell-derived cells in clarification of the pathomechanism and discovery of new therapeutic drugs for Nakajo-Nishimura syndrome and related proteasome-associated autoinflammatory syndromes.

Genetics of Inflammasomes.

Mutations in inflammasome genes are responsible for rare monogenic and polygenic autoinflammatory diseases. On the other side, genetic polymorphisms in the same molecules contribute to the development of common multifactorial diseases (i.e., autoimmune diseases, cardiovascular pathologies, cancer). In this chapter we depicted the current knowledge about inflammasome genetics.

Evidence for genetic overlap between adult onset Still's disease and hereditary periodic fever syndromes.

OBJECTIVE: Adult onset Still's disease (AOSD) is a severe, autoimmune disease that can be challenging to treat with conventional therapeutics and biologicals in a considerable number of cases. Therefore, there is a high need to understand its pathogenesis better. As major clinical symptoms overlap between AOSD and hereditary periodic fever syndromes (HPFS), we analysed four known HPFS genes in AOSD. METHODS: We performed Sanger sequencing and quantitative analysis of all coding regions of MEFV, TNFRSF1A, MVK and NLRP3 in 40 AOSD patients. All rare coding variants (n = 6) were evaluated for several aspects to classify them as benign to pathogenic variants. Statistical analysis was performed to analyse whether variants classified as (likely) pathogenic were associated with AOSD. RESULTS: We identified three rare variants in MEFV, one previously not described. Association to the three likely pathogenic MEFV variants was significant (p c = 2.34E- 03), and two of the three carriers had a severe course of disease. We observed strong evidence for significant association to mutations in TNFRSF1A (p c = 2.40E- 04), as 5% of patients (2/40) carried a (likely) pathogenic variant in this gene. Both of them received a biological for treatment. CONCLUSION: Our results indicate TNFRSF1A as a relevant gene in AOSD, especially in patients with a more challenging course of disease, while causal variants remain to be identified in the majority of patients.