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Human C2orf69 is an evolutionarily conserved gene whose function is unknown. Here, we report eight unrelated families from which 20 children presented with a fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. C2ORF69 bears homology to esterase enzymes, and orthologs can be found in most eukaryotic genomes, including that of unicellular phytoplankton. We found that endogenous C2ORF69 (1) is loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. We show that CRISPR-Cas9-mediated inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures, which is preceded by persistent brain inflammation. Collectively, our results delineate an autoinflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems.

The co-existence of an autoinflammatory syndrome with a demyelinating disorder is a very rare occurrence raising the question whether there is a pathophysiological connection between them. We describe the case of a man with symptoms of cryopyrin-associated periodic syndrome (CAPS) since infancy who later developed multiple sclerosis (MS). As CAPS was genetically confirmed, the inhibition of interleukin-1 (IL-1) with anakinra led to a swift resolution of the CAPS symptoms and also, in combination with teriflunomide, to a clinical and imaging improvement of MS. In vitro studies showed that, upon a CAPS flare, the patient's peripheral neutrophils released neutrophil extracellular traps (NETs) decorated with IL-1β, while NET release was markedly decreased following anakinra-induced remission of CAPS. Taking into account the growing evidence on the involvement of IL-1β in experimental models of MS, this rare patient case suggests that the role of neutrophils/NETs and IL-1β in MS should be further studied.

The term proteasome-associated autoinflammatory syndrome (PRAAS) has been proposed to encompass a group of disorders caused by autosomal recessive mutations in the inducible proteasome subunit β ty...

Background Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory syndrome characterized by recurrent serositis or arthritis attacks and, in some patients, chronic subclinical inflammation that predisposes to secondary amyloidosis. Colchicine is the gold standard of treatment, which reduces attack frequency and amyloidosis risk. However, up to 5% of patients are considered resistant or inadequately respond to colchicine, and some others cannot tolerate the side effects of effective doses of colchicine (colchicine intolerant). Methods We examine how the definition of colchicine resistance has evolved along with various characteristics of colchicine that may help explain unresponsiveness to the drug. Results Key factors in assessing colchicine resistance include attack frequency and severity, levels of acute phase reactants, colchicine dosage and composition, and treatment compliance. Promising clinical results have been obtained with biologics targeting interleukin-1 in colchicine-resistant or -intolerant patients with FMF. Conclusions These results underscore the need to identify patients who are not optimally managed with colchicine and who might therefore benefit from additional biologic therapies.

Adult-onset Still disease (AOSD) is a rare autoinflammatory syndrome characterized by recurring fevers, arthralgia, and consistent laboratory abnormalities that include leukocytosis and hyperferritinemia. Skin findings accompany the disease in nearly 90% of the cases. Early reports described evanescent, pruritic, salmon-pink or urticarial lesions, referred to as the typical eruption of AOSD. Histopathologic findings consist of superficial perivascular dermatitis with varying number of interstitial neutrophils. Later reports described a more persistent rash that tended to be photodistributed, hyperpigmented, often in a linear configuration, sometimes in a rippled pattern, referred to as the atypical eruption of AOSD. The presence of individual necrotic keratinocytes in the upper spinous layer has been the consistent histopathologic finding. The persistent rash may not represent an atypical presentation of AOSD as recent reports indicate a high prevalence of the rash. Emerging data also suggest that patients with persistent eruption have a worse prognosis. The recognition of the clinical and histopathological findings of skin eruptions of AOSD may facilitate an earlier diagnosis, potentially improving disease outcome. Herein, clinical and histopathological features of cutaneous manifestation of AOSD in 2 Asian women are highlighted accompanied by a relevant review of the disease.

Autoinflammatory syndromes are characterized by recurrent episodes of sterile inflammation in the absence of circulating autoantibodies or autoreactive T cells. PASH syndrome is a recently identified hereditary autoinflammatory syndrome consisting of multiple neutrophilic dermatoses including pyoderma gangrenosum (PG), acne, and hidradenitis suppurativa (HS). The triad of PG, acne, and HS occurs in extremely rare instances. To our knowledge, the clinical tetrad of PG, acne, HS, and vasculitis has not been reported.

Background Nakajo-Nishimura syndrome (NNS) is an autosomal recessive heredity disorder, one of a spectrum of autoinflammatory diseases named proteasome-associated autoinflammatory syndrome (PRAAS) caused by mutations of PSMB8 gene. NNS is characterized by pernio-like skin rashes, intermittent fever, and long clubbed fingers and toes with joint contractures, partially with progressive lipomuscular atrophy, emaciation, hepatosplenomegaly and basal ganglion calcification. Case presentation We presented a sporadic case of NNS with compound heterozygous mutations in the PSMB8 gene. The 4-year-old boy was affected by progressive erythematous plaques on his nose and gradually involved hands and feet later with characteristic appearance of long clubbed fingers. The repetitive periodic intermittent fever was recorded. By gene sequencing, novel compound heterozygous mutations c.373C > T (p.R125C) and c.355G > A (p.D119N) in the PSMB8 gene were found. The patient responded well to low dosage of oral methylprednisolone. Conclusions We reported novel compound heterozygous mutations in PSMB8 in a sporadic Chinese NNS patient.

Autoinflammatory disorders were first recognized nearly two decades ago as unique historical and physical features caused by dysregulation in the innate immune system. Since then, the application of the next-generation sequencing techniques have led to the identification of new monogenic disorders and help to understand the molecular link between disease-causing mutations and inflammation. Most of the newly identified syndromes are characterized by fever episodes and systemic inflammation. Specifically, pediatric rheumatologists are likely to be asked to evaluate patients with periodic or nonperiodic fever syndromes. It is important that they should be aware of the clinical, laboratory characteristics and treatment modalities of these rare autoinflammatory disorders. In this chapter, we review some of these monogenic autoinflammatory diseases, including Behcet-like autoinflammatory syndrome (AISBL), otulipenia, DIRA (deficiency of interleukin 1 receptor antagonist), and DITRA (deficiency of interleukin-36 receptor antagonist). We describe clinical features of these syndromes and further examine their molecular mechanisms and therapeutic options.

Tumor necrosis factor receptor periodic fever syndrome (TRAPS) is a hereditary fever syndrome characterized by prolonged fever episodes, myalgia and arthralgia, abdominal pain, characteristic skin rashes, and periorbital edema. It is an autosomal dominant disease caused by mutations in the tumor necrosis factor receptor superfamily 1A (TNFRSF1A) gene that encodes for the TNF receptor 1. It was originally thought to be predominantly in Western European countries, but cases from all around the world have now been reported. More than 140 different disease-causing mutations have been found in TRAPS, most of which are single-nucleotide missense mutations occurring within exons 2–4. TRAPS cases are at increased risk of developing AA amyloidosis, so early diagnosis and treatment are crucial to prevent the development of life-threatening complications. The advent of biological drugs has revolutionized the management of autoinflammatory syndromes, and general treatment goals now include elimination of active disease and prevention of long-term complications. Despite the great improvement in prognosis over the last years, there are still severe cases that are not completely controlled by current therapeutic regimes. Targeting candidate immune pathways that may be contributing to disease pathogenesis is an active area of research.

Autoinflammatory disease can result from monogenic errors of immunity. We describe herein the first example of a patient with early-onset widespread autoinflammation resulting from a mosaic, heterozygous, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of over twenty-five cytokines. By first-of-its-kind custom single-cell RNA sequencing, we examine mosaicism with single cell resolution. We uncover that JAK1 transcription is predominantly restricted to a single allele across different immune cells, introducing the concept of a mutational “transcriptotype” that differs from the genotype. Functionally, the S703I mutation not only increased JAK1 kinase activity, but also resulted in transactivation of partnering JAKs, independently of its catalytic domain. Further, S703I JAK1 was not solely hypermorphic for cytokine signaling, but neomorphic as well, as it enabled downstream signaling cascades not canonically mediated by JAK1. Given these results, the patient was treated with tofacitinib, a JAK inhibitor, which led to rapid resolution of her clinical disease. Together, these findings represent an unprecedented degree of personalized medicine with the concurrent discovery of fundamental biological principles.

BackgroundAutoinflammatory diseases (AID) result from dysregulation of the first lines of innate immune responses. Recently, development of high throughput genome sequencing technology led to the rapid emergence of important knowledge in the genetic field. About 20 genes have been identified so far in monogenic forms of distinct AID. However, 70-90 % of patients with AID remain without genetic diagnosis.ObjectiveWe report the identification and characterization of a mutation in the C-terminal region of the Rho GTPase Cdc42 in a patient presenting a severe autoinflammatory phenotype.MethodsWe have analyzed the consequences of the mutation on the subcellular localization of the Cdc42 protein using imaging techniques. Molecular studies were performed using proteomic and biochemical experiments to provide mechanistic bases of the observed defects. Functional assays were also conducted using flow cytometry and cytokine production measurements.ResultsWe show that mutant Cdc42 is trapped in the Golgi apparatus due to the aberrant addition of a palmitate that both enhances the interaction of mutant Cdc42 with Golgi membranes and inhibit its extraction by GDP dissociation inhibitor (GDI), thus impairing its cytosol/membrane shuttling. At the functional level, mutant Cdc42 fails to sustain actin filaments polymerization and induces an exacerbated profile of pro-inflammatory cytokine production due to increased NF-κB activation.ConclusionsOur study now provides a molecular explanation for mutations that have been identified recently in our AID patient and others in the C-terminal part of Cdc42. Mutations located in this region of Cdc42 impair the intracellular localization of Cdc42, preventing its interaction with the plasma membrane. Thus, our results definitively link mutations in the CDC42 gene to a complex immune-hemato-autoinflammatory phenotype in humans.

International audience; The spectrum of factors known to mediate autoinflammation has broadened recently to include not only interleukin-1 (IL-1) and interferon, but also abnormalities that impair NF-κB pathway negative regulation. The NF-κB pathway is activated upon contact of a ligand with tumor necrosis factor receptor 1 (TNFR1) and plays a pivotal role in triggering the inflammatory process by producing major cytokines such as IL-1, IL-6, and TNF. Negative regulation of the NF-κB pathway, which is essential to stop the inflammatory process, depends on the level of ubiquitination of the proteins associated with TNFR1 and of other intermediate compounds. A20 and otulin are proteins that influence the level of ubiquitination, and a deficiency in either can result in NF-κB activation with overproduction of pro-inflammatory cytokines. Similar to Behçet's disease, A20 haploinsufficiency manifests as oral and genital ulcers and, more rarely, as uveitis. However, transmission is dominant, symptom onset occurs at a younger age, and severe gastrointestinal involvement is at the forefront of the clinical picture. Clinical presentations are extremely diverse. Over their lifetime, affected patients simultaneously or sequentially experience autoinflammatory and autoimmune manifestations. Mild immune deficiency predominantly affecting humoral responses is less common. Otulin deficiency results in systemic inflammatory manifestations at a very young age, with panniculitis, lipodystrophy, and inflammatory bowel disease. The main differential diagnosis is proteasome-associated autoinflammatory syndrome. The treatment of A20 haploinsufficiency and otulin deficiency is challenging and remains unstandardized. The symptoms respond to high-dose glucocorticoid therapy. TNF antagonists and IL-1 antagonists have shown some measure of efficacy.

Histiocytosis-lymphadenopathy plus syndrome (H syndrome) is caused by mutations in the SLC29A3 gene that result in histiocytic infiltration of numerous organs. Patients suffering from this disorder can be easily mistaken for similar conditions such as Muckle–Wells syndrome. We present a 9.5-year-old boy, who is the offspring of a consanguineous marriage. He suffered from sensorineural hearing loss, dark hyperpigmented indurated dry areas on the medial thighs sparing the knees with hypertrichosis on the affected areas, and areas of hypopigmentation on the abdomen. The patient displayed mild dysmorphism including frontal bossing, synophrys, bilateral proptosis (with normal thyroid function), thick eyebrows, flat nose, long philtrum, and pectus excavatum. Formal intelligence testing showed that he was a slow learner. Laboratory findings included elevated serum amyloid-A, erythrocyte sedimentation rate, and total proteins in urine tests. Complete blood count showed mild microcytic hypochromic anemia. The molecular analysis was crucial to confirm the provisional clinical diagnosis. H syndrome is a rare autoinflammatory syndrome with pleiotropic manifestations that affect many organs and can be mistaken for other conditions. Our patient's description may expand the phenotype of H syndrome, as areas of hypopigmentation were observed on the abdomen. Molecular analysis of SLC29A3-related diseases is essential to highlight the variability and increase the awareness of H syndrome aiming for early diagnosis and proper treatment.

Genetic testing has become an important tool in diagnosing monogenic disorders, particularly after the widespread availability of next-generation sequencing technologies in commercial laboratories. In rheumatology, hereditary diseases often present early in childhood, but adult-onset genetic disorders are also seen. The monogenic autoinflammatory syndromes (MAIS) and heritable disorders of connective tissue (HDCT) are two heterogeneous groups of conditions that are seen in rheumatology practice and largely depend on genetic testing for an accurate diagnosis. MAIS are a group of diseases characterized by recurrent and spontaneous episodes of inflammation, including fever, arthritis, and serositis, with long-term serious complications such as AA amyloidosis if untreated. HDCT are a heterogeneous group of diseases characterized by defects in several extracellular matrix elements, producing clinically obvious changes in the skeleton, skin, ligaments, tendons, and other soft tissues. This chapter presents an overview of terminology in clinical genetics, the regulations and advantages of genetic testing in rheumatology, and a review of the most common MAIS and HDCT.

Introduction Autoinflammatory diseases are an emerging group, characterised by recurrent inflammatory episodes due to dysregulated innate immunity. Common features include fevers, rash, arthralgia, lymphadenopathy and systemic symptoms. Castleman’s disease is a rare lymphoproliferative disease, associated with the overproduction of interleukin-6 (IL-6). Its two main variants: unicentric and multicentric differ in aetiology and clinical outcomes. The cytokine storm driven by IL-6 can mimic autoinflammatory disease. We present the case of an acquired autoinflammatory syndrome in a 33-year-old male with the clinical phenotype of Castleman’s but no culprit lymph node detected radiologically. Symptoms dramatically improved with yocilizumab, an IL-6 blocker. Case description A 33-year-old Caucasian man was referred to rheumatology at his local District General Hospital with flitting joint pains, fevers, night sweats and weight loss for eighteen months. He had associated fatigue, myalgia, sore throat and an intermittent maculopapular rash. There were no specific symptoms of infection, malignancy or underlying connective tissue disease. No risk factors for blood-borne viruses were identified. Past medical history included hearing difficulties in childhood, and maternal family history of Crohn’s disease. Currently he was unemployed, having previously worked in a concrete factory. There was a 30 pack-year smoking history with moderate alcohol intake. Physical examination revealed a faint maculopapular rash over his right forearm but was otherwise normal. Full blood count showed an improved microcytic anaemia with recent haemoglobin 132 g/L, raised white cell count up to 33 x 109/L (predominant neutrophilia) and mild thrombocytosis up to 480 x 109/L. Inflammatory were persistently elevated with CRP 124 mg/L and ESR 67 mm/hr. Renal, liver and thyroid functions were all normal as well as creatine kinase. Iron studies suggested iron-deficiency with negative anti-endomysial antibodies. Serum ferritin peaked at 1028 during µg/L during flares, with normal triglycerides. A full autoimmune screen was negative. Immunoglobulins showed a polyclonal rise only. HIV and Hepatitis screens were negative. CT chest, abdomen and pelvis and subsequent PET-CT scan were unremarkable. A bone marrow biopsy showed reactive changes only. A trial of low-dose prednisolone provided dramatic symptomatic improvement but symptoms flared on weaning to 10mg daily. Both steroid-sparing agents azathioprine and methotrexate were not tolerated. After further investigations by the National Amyloidosis Centre, he was commenced on weekly tocilizumab 162mg subcutaneous injections after a successful individual funding request. This provided an excellent clinical response which has been sustained for over two years. Discussion This case was difficult given the wide differential diagnoses. It was important to rule out infection, malignancy and autoimmune disease which were commoner causes of recurrent fevers and systemic symptoms. The long duration of symptoms, negative blood cultures and unremarkable CT imaging were against deep-seated infection. He was low risk for tuberculosis, zoonosis and tropical infections. No solid tumours or lymph nodes were seen on imaging but the PET-CT noted non-specific bone marrow changes. Bone marrow biopsy showed increased granulopoiesis without features of malignancy, and JAK-2 mutation was negative. Lactate dehydrogenase was normal with negative haemolysis screen. Upper and lower gastrointestinal endoscopies to investigate his iron-deficiency anaemia were normal. A full autoimmune screen was normal including anti-nuclear antibody, extractible nuclear antigen, rheumatoid factor, anti-cyclic citrullinated peptide antibody, complement C3 and C4 and anti-double-stranded DNA antibody. As no malignancy was found, prednisolone 40mg daily was trialled with fortnightly tapering. This produced a marked improvement in symptoms and inflammatory markers. However there were frequent flares on tapering the dose. He was therefore referred to the National Amyloidosis Centre at the Royal Free Hospital in London for an expert opinion. A genetic screen was negative for NLPR3 (CAPS gene), LRP12, TRAPS gene and the mevalonate kinase gene. Serum amyloid A (SAA) was very high 591 m/l ( Key learning points Autoinflammatory diseases are rare but treatable causes of fever syndromes. Extensive investigations are needed to exclude mimics such as infection, malignancy (especially haematological) and autoimmune conditions. Genetic testing can reveal the diagnosis for monogenic types such as familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS) and tumour necrosis factor receptor-associated periodic syndrome (TRAPS). Castleman’s disease can be caused by a single lymph node (unicentric) or diffuse lymph nodes (multicentric). The unicentric type is less associated with systemic symptoms compared to multicentric, except for its rarer plasmacytosis variant. Consider HIV and human herpes virus-8 infection in the multicentric type. IL-6 blockade is extremely effective in Castleman’s but optimum duration of therapy remains unclear. Surgical resection of the solitary lymph node in unicentric Castleman’s has a good prognosis. Serum amyloid A can be a useful marker of disease activity in autoinflammatory disease compared with CRP. Conflict of interest The authors declare no conflicts of interest.

Hidradenitis suppurativa (HS) is a chronic inflammatory disorder characterized by painful nodules, sinus tracts, and scars occurring predominantly in intertriginous regions. The prevalence of HS is currently 0.053–4%, with a predominance in African-American women and has been linked to low socioeconomic status. The majority of the reported literature is retrospective, population based, epidemiologic studies. In this regard, there is a need to establish a repository of biospecimens, which represent appropriate gender and racial demographics amongst HS patients. These efforts will diminish knowledge gaps in understanding the disease pathophysiology. Hence, we sought to outline a step-by-step protocol detailing how we established our HS biobank to facilitate the formation of other HS tissue banks. Equipping researchers with carefully detailed processes for collection of HS specimens would accelerate the accumulation of well-organized human biological material. Over time, the scientific community will have access to a broad range of HS tissue biospecimens, ultimately leading to more rigorous basic and translational research. Moreover, an improved understanding of the pathophysiology is necessary for the discovery of novel therapies for this debilitating disease. We aim to provide high impact translational research methodology for cutaneous biology research and foster multidisciplinary collaboration and advancement of our understanding of cutaneous diseases.

Cryopyrin-associated periodic fever syndrome (CAPS) represents an increasingly recognized disease group entity, with varied presentations. CAPS includes 3 clinical entities, namely, familial cold-induced autoinflammatory syndrome (FCAS; MIM #120100), Muckle-Wells syndrome (MWS; MIM #191900) and chronic inflammatory neurologic cutaneous and articular syndrome (CINCA; MIM #607115); which share several overlapping clinical features. These patients often present with early-onset episodes of fever and rash, and variable systemic signs and symptoms, making it a great mimicker of other systemic autoimmune diseases. The episodes are transient and related to exposure to cold temperature and worsen in the winter season. We hereby present a case presenting with recurrent seasonal fever and rash, diagnosed as FCAS/ MWS overlap based on clinical signs and symptoms and positive testing for NLRP3 gene mutation. We also discuss the clinical presentation and complications of CAPS, chiefly FCAS and MWS, along with the previously described pediatric cases of CAPS. We tried to review the complexities of management of such patients, including the genetic diagnosis and the role of biological therapy. Based on the review of the literature, given the evident broad spectrum of symptoms and signs, use of next-generation sequencing can help in prompt diagnosis and early initiation of biological agents, which may play a great role in reducing the complications that these patients may experience in the long run.

Background: Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) is an autosomal dominant autoinflammatory disase, associated with the mutation of tumor necrosis receptor superfamily member 1A (TNFRSF1A) gene, located on chromosome12p13. TRAPS is usually diagnosed during pediatric age. However, adult-onset disease or diagnosis during adulthood has been occasionally described. Moreover, TRAPS has been hardly reported in the Chinese population. Herein, we aimed to characterize the clinical and genetic features of Chinese adult patients with TRAPS. Objectives: Adult patients (≥16 years) suspected monogenic autoinflammatory diseases during the period April 2015 to October 2018, at the adult autoinflammatory disease center, Department of Rheumatology, Peking Union Medical College Hospital (PUMCH). Methods: Clinical data were evaluated. Gene sequencing was performed in each patient to support the diagnosis and exclude other monogenic autoinflammatory diseases. Finally we compared the data with those from Japan and Europe. Results: During the study period, 8 patients with TRAPS were diagnosed and follow-up. The ratio of male to female was 3: 1. The median age of disease onset was 4 (0.5–38.5), and adult-onset was observed in 2 (25%) patients. The median time of diagnosis delay was 17.8 (1.5-50.5) years. There were seven Chinese Han and one Manchu patients. One patient had a family history of TRAPS. The most frequent symptom was fever (8, 100%). The attacks of 5 (62.5%) patients lasted more than 1 week, and the intervals of 7 (87.5%) patients were longer than 2 weeks. Skin involvement occurred in 6 (75%) patients, with maculopapular mentioned in 6 and erythema annulare presented in 3. Four (50%) patients had arthralgia, while one had polyarthritis. 4 (50%) patients complained respectively of myalgia or headache. 4 (50%) patients experienced abdominal pain and one (12.5%) had vomiting. One (12.5%) patient had periorbital edema, while 3 (37.5%) had conjunctivitis. Up to 5 (62.5%) patients got nonspecific pharyngitis. No patient suffered from chest pain or amyloidosis. Eight gene variants were detected in TNFRSF1A gene. Heterozygous gene variants were found in 7 Chinese Han patients, and homozygous (c.769-23, T>C) happened to the Manchu patient. The variants included C58 (exon 2), G65E (exon 3), F89L (exon 3), C99G (exon 3), V202G (exon 6), c.769-23T>C (IVS8), S290I (exon 9) and m.1735A>G (non-coding region). NSAIDs were given to 2 patients, glucocorticoid or immunosuppressive agents given to 3 patients respectively, and etanercept to 5 patients. A complete response was found in all the 5 patients received etanercept. The effectiveness of other drugs were 50% in NSAIDs, 66.7% in glucocorticoid and immunosuppressive agents. Conclusion: This is the first and largest case series of TRAPS in Chinese adult patients. It highlights the importance of screening TNFRSF1A gene in patients with unexplained periodic fever syndrome. Four novel TNFRSF1A variants, S290I, F89L, V202G and m.1735A>G in non-coding region, have been identified. The atypical clinical manifestations of our patients compared to those from Europe might be related to their low-penetrance TNFRSF1A variants. Further studies are needed to explore the more accurate phenotypes and genotypes of the Chinese patients with TRAPS. References: [1] Lachmann HJ, et al. The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry. Ann Rheum Dis2014, 73: 2160-2167. [2] Ueda N, et al. Clinical and Genetic Features of Patients With TNFRSF1A Variants in Japan: Findings of a Nationwide Survey. Arthritis Rheumatol 2016, 68: 2760-2771. Disclosure of Interests: None declared

Background Tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is one of the best known monogenic auto-inflammatory disorder resulting from an autosomal dominant variation in the TNF super family receptor 1A (TNFRSF1A) gene. Objectives To define best treatment approach in patients with TRAPS and effect on long-term outcomes. Methods We reviewed all data on patients with TNFRSF1A variants enrolled in the Eurofever/EUROTRAPS international registry. Results Data on 290 patients were available. Patients with R92Q, P46L or intronic variants (49%) displayed milder disease than 147 patients with mutations affecting other coding regions, with less frequent abdominal pain and skin rashes (P 90% complete response), while Etanercept was less effectively used and discontinued in 72% of patients. No patients on anti-IL1β treatment developed amyloidosis and 10 patients with amyloidosis have been successfully treated with anti IL-1 agents with preservation of native renal function in 7 and excellent long-term transplant function in 2. Nine women had a history of failure to conceive and seven had successful pregnancies without fertility treatment following complete disease control with anti-IL1β drugs. Long term safety profiles for anti IL-1 agents were excellent even in the presence of comorbidity. Conclusion Anti-IL1β drugs are the best maintenance treatment in TRAPS with potential to reverse the most serious disease complications of AA amyloidosis and infertility. The diagnosis of TRAPS should be considered very carefully in patients carrying R92Q, P46L or intronic TNFRSF1A variants. References [1] Lachmann HJ, Papa R, Gerhold K, Obici L, Touitou I, Cantarini L, et al. The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry. Annals of the rheumatic diseases. 2014;73(12):2160-7. [2] Papa R, Doglio M, Lachmann HJ, Ozen S, Frenkel J, Simon A, et al. A web-based collection of genotype-phenotype associations in hereditary recurrent fevers from the Eurofever registry. Orphanet Journal of Rare Diseases. 2017;12(1):16. [3] Papa R, Lachmann HJ. Secondary, AA, Amyloidosis. Rheum Dis Clin North Am. 2018;44(4):585–603. Acknowledgement The presenting author would like to thank the European Federation of Immunology (EFIS) for the short term fellowship bursary. Disclosure of Interests Riccardo Papa: None declared, Thirusha Lane: None declared, Taryn Youngstein: None declared, Tamer Rezk: None declared, Charalampia Papadopoulou: None declared, Nicolino Ruperto Grant/research support from: The Gaslini Hospital, where NR works as full-time public employee, has received contributions (> 10.000 USD each) from the following industries in the last 3 years: BMS, Eli-Lilly, GlaxoSmithKline, F Hoffmann-La Roche, Janssen, Novartis, Pfizer, Sobi. This funding has been reinvested for the research activities of the hospital in a fully independent manner, without any commitment with third parties., Consultant for: Received honoraria for consultancies or speaker bureaus (

Background Autoinflammatory diseases (AID) are a group of hereditary diseases characterised by inflammation periods accompanied with clinical findings such as fever, skin rash, lymphadenopathy, abdominal pain, musculoskeletal symptoms, and with sign of inflammation in the blood. Each disease has own typical clinical findings and they are associated with mutations in specific genes such as in MEFV gene in familial Mediterranean fever (FMF), MVK gene in hyperimmunglobulin D syndrome (HIDS), TNFRSF1A gene in tumor necrosis factor-alpha receptor associated periodic fever syndrome (TRAPS) and NLRP3 gene in cryopyrin associated periodic fever syndrome (CAPS) (1,2). Also in some patients with periodic fever syndrome (PFS), clinical signs of these diseases can be seen but no mutation can be detected in the related genes (3,4). There are also patients exhibit the incomplete phenotype of a disease or overlap signs of more than one AID. The diagnosis of these undifferentiated patients have difficult and may not be possible by a single target gene analysis (5). Screening of the periodic fever syndrome (PFS) panel including various AID genes may be beneficial to define the atypical cases. Molecular genetics has an important role for lead to diagnosis in these patients. Objectives The aim of this study was to investigate the genotypic diagnosis in patients with non-characteristic PFS findings for any AID. Methods This is a prospective study and conducted between June 2016 and December 2018. Next-generation sequencing (NGS) analysis was performed by using “Fever and AutoInflammatory Syndrome panel: Panel by Sophia Genetics” including 8 genes (MEFV, MVK, NLRP3, NLRP12, TNFRSF1A, TNFRSF11A, LPIN2 and PSTPIP1) in 30 patients with undifferentiated PFS. Clinical features and genetic results were evaluated together and final diagnoses were determined. Results Thirty patients included in the study did not have typical clinical features for any of the eight monogenic diseases in the PFS panel. In the result of the genetic screening; disease-causing mutation was found in MEFV gene in 12 patient, in NLRP3 gene in four patient, in NLRP12 gene in two patient and in MVK gene in one patient. Also, genetic variants of uncertain significance (VUS) in different genes were shown in five patient. No mutation was detected in remaining six patient. The final diagnosis was made by both phenotypic and genotypic data. 12 patients were diagnosed with FMF, four were FCAS, two were FCAS2, one was TRAPS and one was HIDS. Patients with negative genetic screening or had mutation as VUS, were followed as undifferentiated PFS. Conclusion Autoinflammatory diseases may not always be appear with typical clinical findings of related disease. In such patients, target gene sequencing and detection of underlying disease can be challenging. Our study has shown that the NGS analysis may help to determined the diagnosis in patients with non-characteristic PFS findings for any AID. References [1] Federici S, et al, An International Delphi Survey for the Definition of New Classification Criteria for Familial Mediterranean Fever, Mevalonate Kinase Deficiency, TNF Receptor-associated Periodic Fever Syndromes, and Cryopyrin-associated Periodic Syndrome. J Rheumatol. 2018Nov1. Disclosure of Interests None declared

Background: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a disease that is included within of hereditary syndromes of periodic fever. It presents an autosomal dominant pattern of inheritance. It’s due to mutations of TNFRSF1A gene. It is usually present in childhood although it can also appear in adulthood and it tends to cause high levels of acute phase reactants, fever, musculoskeletal symptoms (myalgias, arthralgias, arthritis), rash, abdominal pain, etc Objectives: To describe the clinical characteristics and genetic variants of patients diagnosed with TRAPS syndrome in a cohort of patients with autoinflammatory syndromes with follow-up in a tertiary hospital from 2013 to the present Methods: Retrospective descriptive study of adult patients diagnosed with autoinflammatory syndrome since 2013 (year of introduction of genetic tests in the hospital laboratory) until now. The data was obtained from the review of medical records. All patients with mutations in TNRFSF1A gene and clinically compatible with this diagnosis were reviewed Results: Of a total of 44 adult patients diagnosed with hereditary syndromes of periodic fever (FMF, TRAPS, cryopyrinopathies, HIDS) and compatible genetic mutations (excluding polymorphisms), 13 (29.5%) presented mutations in the TNFRSF1A gene. Of those 13 patients, 9 (69.2%) were women. The most frequent mutations were the mutation in heterozygosis in exon 4 (p.R92Q) with 12 cases (92.3%) and one case (7.6%) with mutation in heterozygosis in exon 3 (p.P46L). The mean age at diagnosis was 27.92 years (IR 12-55 years). 5 patients showed simultaneous genetic variants in other genes related to autoinflammatory syndromes. Signs and/or symptoms were myalgia and elevation of acute-phase reactants with 12 patients (86%) followed by fever and joint symptoms (arthralgias and/or arthritis) with 11 patients (79%) were the most frequent. 2 patients (14%) had conjunctivitis. 9 patients (64%) presented cutaneous involvement. 2 cases (14%) presented lymphadenopathy. Regarding treatment, 5 patients (36%) had received treatment with biological therapy (anti-IL-1 or anti-TNF) and another 5 patients (36%) had used colchicine. The corticoids were used in 6 patients (43%) Conclusion: The TRAPS syndrome is a clinical entity to consider when making a differential diagnosis in patients with suspected autoinflammatory syndrome, that present fever, acute phase reactants elevation, arthromyalgia and its confirmation diagnosis is with genetic test Disclosure of Interests: None declared

Autoinflammatory disease is an ‘inborn error of immunity’, resulting in systemic inflammation. Cryopyrin-associated periodic syndrome (CAPS) is a prototypical autoinflammatory disease caused by gain-of-function mutations in the NLRP3 (NLR family pyrin domain containing 3) gene; these mutations activate the NLRP3 inflammasome, resulting in overproduction of IL-1β. The first case of CAPS caused by somatic NLRP3 mosaicism was reported in 2005 after identification of variant small peaks by Sanger sequencing. An international collaborative study revealed that the majority of mutation-negative CAPS cases are due to low-level NLRP3 mosaicism, suggesting that central nervous system involvement in somatic mosaicism patients is milder than in genotype-matched heterozygous patients. Recent advances in next-generation sequencing have expanded the number of NLRP3 somatic mosaicism cases and identified a new entity called ‘late-onset CAPS with myeloid-specific NLRP3 mosaicism’; however, no mosaic-specific clinical features have been identified/confirmed yet. With respect to NLRP3 mosaicism in CAPS, a prospective longitudinal study on the variant genotype, its allele frequency and its tissue distribution (along with a comprehensive clinical phenotype) would provide better understanding of NLRP3 mosaicism, resulting in more appropriate patient care and genetic counseling.

Palindromic rheumatism (PR) is a type of acute arthritis or periarthritis characterized by recurrence, paroxysmal, or intermittent disease attacks and occasionally progresses to other types of rheumatic disease. PR patients who are anti-citrullinated protein antibodies (ACPA)-negative have a high prevalence of MEFV gene polymorphisms, and intermittent hydrarthrosis (IH) is also associated with MEFV polymorphisms. The purpose of this study was to evaluate the clinical characteristics of and autoinflammatory syndrome-associated gene polymorphisms in patients with PR and IH and to identify predictive factors for developing other rheumatic diseases.Six PR patients (four females; median age at disease onset, 20.0 years; median age at evaluation, 47.0 years) were retrospectively evaluated for clinical features and polymorphisms in genes responsible for autoinflammatory diseases.All six patients fulfilled the diagnostic criteria for PR and showed clinical feature of IH. Two presented with recurrent fever. All six patients were negative for rheumatoid factor and ACPA and had normal articular X-ray findings. Among the six patients, MEFV gene polymorphisms known to cause FMF were identified in four, CIAS1 mutation was observed in one, and TNFRSFIA mutation was observed in one. Colchicine was effective in three patients with MEFV polymorphisms. The other five patients continued to experience PR, although three patients achieved remission with medication.PR presenting with IH might be associated with gene polymorphisms responsible for autoinflammatory diseases; colchicine appears to be effective in these patients.Key Point• Palindromic rheumatism with intermittent hydrarthrosis might be associated with gene polymorphisms responsible for autoinflammatory diseases.

Introduction: Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) is an autoinflammatory syndrome. Up to now no case of PASH syndrome has been reported from Iran and we report the first case in this paper. Case Presentation: In case report, we report a 44-year-old Iranian female with PASH syndrome. Her skin manifestation was first suppurative hidradenitis when she was 16 years old, then acne 20 years ago and now PG. In addition, she had history of a mass in pituitary diagnosed as prolactinoma, hormonal problems like hypothyroidism, abnormal menstrual cycles and obesity that were not reported in previous cases of PASH. It should be noted that no sign of remission and recurrence was seen in this case after 2 years. Conclusions: Further studies are being performed on the reported patient to achieve a better presentation of this disease and report the case in further papers especially with focus on laboratory and therapeutic information.

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.

An otherwise healthy male child of 9 years presented with paroxysmal fever and diffuse abdominal pain along with loss of appetite and nausea lasting for 3-4days every 4-6 weeks for last 2 years. He also has stretchable skin and hypermobile joint which he inherited from his mother who never suffered any paroxysmal attack of the kind. Work up for acute intermittent porphyria, lead poisoning and familial mediterranean fever was negative. A novel harmful sequence change in NLRP12 gene was detected and a diagnosis of NLRP12 associated autoinflammatory syndrome was made. This sequence change with disease has not yet been reported in the literature and is the first such case of NLRP12 related autoinflammatory syndrome from India.

The deubiquitinase OTULIN removes methionine‐1 (M1)‐linked polyubiquitin signals conjugated by the linear ubiquitin chain assembly complex (LUBAC) and is critical for preventing TNF‐driven inflammation in OTULIN‐related autoinflammatory syndrome (ORAS). Five ORAS patients have been reported, but how dysregulated M1‐linked polyubiquitin signalling causes their symptoms is unclear. Here, we report a new case of ORAS in which an OTULIN‐Gly281Arg mutation leads to reduced activity and stabilityinvitroand in cells. In contrast to OTULIN‐deficient monocytes, in which TNF signalling and NF‐κB activation are increased, loss of OTULIN in patient‐derived fibroblasts leads to a reduction in LUBAC levels and an impaired response to TNF. Interestingly, both patient‐derived fibroblasts and OTULIN‐deficient monocytes are sensitised to certain types of TNF‐induced death, and apoptotic cells are evident in ORAS patient skin lesions. Remarkably, haematopoietic stem cell transplantation leads to complete resolution of inflammatory symptoms, including fevers, panniculitis and diarrhoea. Therefore, haematopoietic cells are necessary for clinical manifestation of ORAS. Together, our data suggest that ORAS pathogenesis involves hyper‐inflammatory immune cells and TNF‐induced death of both leukocytes and non‐haematopoietic cells.

Autoinflammatory syndromes are a group of disorders characterized by recurring episodes of inflammation as a result of specific defects in the innate immune system. Patients with autoinflammatory disease present with recurrent outbreaks of chronic systemic inflammation that are mediated by innate immune cells, for the most part. A number of these diseases arise from defects in the tumour necrosis factor receptor (TNFR) signalling pathway leading to elevated levels of inflammatory cytokines. Elucidation of the molecular mechanisms of these recently defined autoinflammatory diseases has led to a greater understanding of the mechanisms of action of key molecules involved in TNFR signalling, particularly those involved in ubiquitination, as found in haploinsufficiency of A20 (HA20), otulipenia/OTULIN-related autoinflammatory syndrome (ORAS) and linear ubiquitin chain assembly complex (LUBAC) deficiency. In this review, we also address other TNFR signalling disorders such as TNFR-associated periodic syndrome (TRAPS), RELA haploinsufficiency, RIPK1-associated immunodeficiency and autoinflammation, X-linked ectodermal dysplasia and immunodeficiency (X-EDA-ID) and we review the most recent advances surrounding these diseases and therapeutic approaches currently used to target these diseases. Finally, we explore therapeutic advances in TNF-related immune-based therapies and explore new approaches to target disease-specific modulation of autoinflammatory diseases.

Familial Mediterranean Fever (FMF) is an inherited autoinflammatory syndrome caused by mutations in the MEFV gene. MEFV variants are still in large part classified as variant of uncertain significance (VOUS), or with classification unresolved, posing significant challenges in the clinical diagnosis of Familial Mediterranean Fever (FMF). REVEL is a recently developed variant metapredictor tool. To reduce the number of MEFV variants with ambiguous classification we extracted the REVEL score for all missense variants reported at the locus specific database INFEVERS, and analyzed its correlation with expert-based classification and localization in the MEFV-encoded pyrin protein functional domains.The data set of 216 missense variants was divided in four classification categories (BENIGN, VOUS, PATHOGENIC and UNRESOLVED). MEFV variants were plotted onto the pyrin protein, the distribution of REVEL scores in each category was computed and means, confidence intervals, and area under the receiver operating curve were calculated.We observed a non-random distribution of pathogenic variants along the functional domains of the pyrin protein. The REVEL scores demonstrated a good correlation with the consensus classification of the International Study Group for Systemic Autoinflammatory Diseases (INSAID). Sensitivity, specificity, and accuracy were calculated for different cutoff values of REVEL scores and a gene-specific threshold was computed with confidence boundary limits. A REVEL score of 0.298 was the best performing cut-off to reclassify 96 MEFV gene variants previously of uncertain significance or unsolved thus reducing their proportion from 61.6% to 17.6%.In conclusion, the combination of available expert information with highly sensitive predictor tools yields to more accurate interpretation of clinical consequences of MEFV gene variants. This approach should bring to a better genetic counseling and patient management.Author summaryWe aimed to refine MEFV gene variants classification using the metapredictor REVEL. We demonstrate that a gene-specific threshold is effective for accurate variants’ classification. Using this threshold, we reduced significantly the proportion of MEFV variants with an ambiguous classification. The proposed classification could represent a useful resource for variant interpretation in the context of FMF diagnosis.

We report a clinical case of adult-onset Still’s disease. In addition to the imaging features of the case, the following aspects are also briefly described: clinical presentation (prolonged fever associated with migratory polyarthritis and skin rash), treatment performed (resort to anti-inflammatory and corticoid), and clinical evolution of the patient after having performed the adult-onset. The treatment was found to be appropriate as the patient presented a favourable clinical evolution. LEARNING POINTS Skin manifestations are associated with systemic diseases. Persistent febrile syndromes typically occur in young age. Adult-onset Still’s disease is generally considered as a diagnosis of exclusion, as it presents with a combination of non-specific symptoms. Keywords: Adult-onset Still’s disease, skin rash, fever of unknown origin INTRODUCTION First described in 1971, adult-onset Still’s disease (AOSD) is a rare multisystem disorder considered as a complex autoinflammatory syndrome characterised by quotidian fevers, arthritis and an evanescent rash[1,2]. The aetiology of AOSD is unknown. Both genetic factors and a variety of infectious triggers have been suggested as important, but there has been no conclusive evidence to date[1,2].

European Journal of Case Reports in Internal Medicine © EFIM 2019, Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) is a new entity in which exposure to an adjuvant triggers an aberrant autoimmune response. Metallosis is a rare condition characterized by the deposition and build-up of metal debris in the soft tissues of the body associated with metal-on-metal (MOM) prosthetic devices. It can present with local/systemic symptoms and signs due to a chronic inflammatory host response. The authors present the case of a 51-year-old woman with a 6-month history of systemic complaints due to intoxication with metal ions from hip metallosis. This case highlights the importance of follow-up and continuous monitoring of patients with a hip prosthesis. As this is a rare condition, a patient presenting with unspecific symptoms such as ASIA syndrome induced by metallosis requires a high level of clinical suspicion as the removal of the adjuvant can resolve the condition. Learning points: Asia syndrome is a new entity in which exposure to an adjuvant triggers an aberrant autoimmune response.Metallosis is an uncommon condition with local and systemic presentation.A high level of suspicion and close monitoring is needed in patients with vague systemic complaints.

International audience; Certain types of vasculitis occur more frequently and present differently in patients with familial Mediterranean fever (FMF). We assessed the characteristics of patients with FMF and systemic vasculitis through a systematic review of the literature. Medline was searched by two independent investigators until December 2017. We screened 310 articles and selected 58 of them (IgA vasculitis n = 12, polyarteritis nodosa (PAN) n = 25, Behçet's disease (BD) n = 7, other vasculitis n = 14). Clinical case reports were available for 167 patients (IgA vasculitis n = 46, PAN n = 61, BD n = 46, other vasculitis n = 14), and unavailable for 45 patients (IgA vasculitis n = 38, PAN n = 7). IgA vasculitis was the most common vasculitis in FMF patients with a prevalence of 2.7-7%, followed by PAN with a prevalence of 0.9-1.4%. Characteristics of FMF did not differ between patients with and without vasculitis. Patients with FMF and IgA vasculitis displayed more intussusception (8.7%) and possibly less IgA deposits on histological analysis than patients with IgA vasculitis alone. Patients with FMF and PAN had a younger age at vasculitis onset (mean age = 17.9 years), as well as more perirenal hematomas (49%) and CNS involvement (31%) than patients with PAN alone. Glomerular involvement was noted in 33% of patients diagnosed with PAN, suggesting an alternative diagnosis. Sequencing of the MEFV gene confirmed the presence of two pathogenic variants in 73% of FMF patients with IgA vasculitis or PAN. The majority of patients with BD were from one case series, and presented more skin, gastrointestinal, and CNS involvement than patients with isolated BD. In conclusion, FMF, particularly when supported by two pathogenic MEFV mutations, could predispose to IgA vasculitis, or a PAN-like vasculitis with more perirenal bleeding and CNS involvement.

In this chapter, we present the clinical approach to patients with a suspected autoinflammatory syndrome. We describe a systematic approach to the history, physical examination, system involvement and laboratory testing and offer an algorithm on investigative pathways for these patients. We discuss the various diagnostic criteria currently used for specific autoinflammatory diseases. Finally, we propose an approach, including empiric treatment and management, to the many patients with suspected autoinflammatory syndromes who remain undiagnosed, despite a comprehensive work-up, including genetic testing.

Mixed phenotype in a case of an undefined autoinflammatory syndrome

The induction and action of type I interferon (IFN) is of fundamental importance in human immune defenses toward microbial pathogens, particularly viruses. Basic discoveries within the molecular and cellular signaling pathways regulating type I IFN induction and downstream actions have shown the essential role of the IFN regulatory factor (IRF) and the signal transducer and activator of transcription (STAT) families, respectively. However, the exact biological and immunological functions of these factors have been most clearly revealed through the study of inborn errors of immunity and the resultant infectious phenotypes in humans. The spectrum of human inborn errors of immunity caused by mutations in IRFs and STATs has proven very diverse. These diseases encompass herpes simplex encephalitis (HSE) and severe influenza in IRF3- and IRF7/IRF9 deficiency, respectively. They also include Mendelian susceptibility to mycobacterial infection (MSMD) in STAT1 deficiency, through disseminated measles infection associated with STAT2 deficiency, and finally staphylococcal abscesses and chronic mucocutaneous candidiasis (CMC) classically described with Hyper-IgE syndrome (HIES) in the case of STAT3 deficiency. More recently, increasing focus has been on aspects of autoimmunity and autoinflammation playing an important part in many primary immunodeficiency diseases (PID)s, as exemplified by STAT1 gain-of-function causing CMC and autoimmune thyroiditis, as well as a recently described autoinflammatory syndrome with hypogammaglobulinemia and lymphoproliferation as a result of STAT3 gain-of-function. Here I review the infectious, inflammatory, and autoimmune disorders arising from mutations in IRF and STAT transcription factors in humans, highlightning the underlying molecular mechanisms and immunopathogenesis as well as the clinical/therapeutic perspectives of these new insights.

Deficiency of adenosine deaminase type 2 (DADA2) is a recently discovered, pathogenetically complex autoinflammatory syndrome with features of autoinflammation, immunodeficiency, and autoimmunity. The disease is highly variable in regard to age at onset, disease severity, and organ involvement but typically presents as a childhood-onset vasculopathy resembling polyarteritis nodosa (PAN). Patients with DADA2 characteristically present with livedo racemosa, purpura, leg ulcers, Raynaud’s phenomenon, and digital necrosis and in more severe cases with peripheral neuropathy, and early-onset hemorrhagic and ischemic strokes. Other symptoms include subcutaneous nodules, recurrent fevers, hepatosplenomegaly, ophthalmologic manifestations, hypertension, musculoskeletal symptoms, marrow failure, and hypogammaglobulinemia. Evaluation of ADA2 enzymatic activity and genetic analysis for CECR1 gene mutations may aid in the diagnosis. Treatment for DADA2 is not yet well established and should be based on the individual presentation and severity of the disease.

The TNF receptor-associated autoinflammatory syndrome (TRAPS, MIM 142680), formerly known as familial Hibernian fever [1], is a rare dominantly inherited disorder, caused by mutations in the p55 TNF receptor (or TNFR1), encoded by the TNF superfamily receptor 1A (TNFRSF1A) gene [2]. The disease was originally identified in families of Northern European ancestry but has been described in almost all ethnic groups, including those living in Mediterranean countries and Asia. Fever is often prolonged and can be accompanied by serositis, arthritis, a skin rash with underlying fasciitis and periorbital oedema.

Autoinflammatory diseases (AID) are diseases of the innate immune system, characterized by recurrent episodes of localized or systemic inflammation. Vasculitis may accompany AID. The causes of the association of vasculitis with monogenic AID are still debated. Among the monogenic AID, Familial Mediterranean Fever (FMF) is the most common. IgA-related vasculitis (IgAV) and Polyarteritis Nodosa (PAN) involving small and/or medium-sized vessels have an increased frequency among FMF patients. There are also case reports revealing vasculitic features in Cryopyrin-Associated Periodic Fever Syndrome (CAPS), Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS), Mevalonate Kinase Deficiency (MKD), also known as Hyper IgD syndrome (HIDS), Deficiency of IL-1 Receptor Antagonist (DIRA) and Pyogenic Arthritis, Pyoderma gangrenosum, and Acne (PAPA) patients. Central nervous system vasculitis and vasculopathy have been reported in DIRA and PAPA patients whereas small vessel involvement affecting skin has been reported in CAPS, TRAPS, and MKD patients. Alternatively, vasculitis can also be a leading feature especially in the recently defined monogenic AID (Otulipenia, Deficiency of Adenosine Deaminase 2-DADA2, Haploinsufficiency of A20) and interferonopathies (STING-associated vasculopathy with onset in infancy-SAVI). DADA2 often presents as a PAN-like disease. In otulipenia, patients have painful subcutaneous nodules caused by septal panniculitis with small and medium vessel vasculitis. Haploinsufficiency of A20 (also called Familial Behcet-like Autoinflammatory Syndrome) results in a phenotype very similar to the variable vessel vasculitis of Behcet's disease with recurrent oral-genital ulcers, in addition to, skin rash, uveitis, and polyarthritis. SAVI is an autoinflammatory vasculopathy with increased Interferon (IFN) signature, causing severe skin lesions resulting in ulceration, necrosis, and in some cases, amputation. Behcet's Disease (BD) is a multifactorial polygenic AID characterized by recurrent attacks of oral-genital ulcers, skin lesions, uveitis and a unique vasculitis affecting both arteries and veins of all sizes. Many clinical features overlap with other autoinflammatory diseases and overexpression of proinflammatory cytokines is an important feature of the disease.

Introduction Haploinsufficiency of A20 (HA20) is a novel genetic disease presented by Zhou et al in 2016. A20 is a protein encoded by TNFAIP3. Loss-of-function mutation in TNFAIP3 will trigger a new autoinflammatory disease: HA20. HA20-affected patients may develop a wide range of clinical manifestations, such as Behcet disease, rheumatoid arthritis, rheumatic fever, juvenile idiopathic arthritis, and systemic lupus erythematosus. HA20 is rarely reported, thus remaining far from thoroughly understood. Sixty-one cases of HA20 have been reported worldwide, among which 29 cases were diagnosed with Behcet disease ultimately. Moreover, 3 cases have been reported in China, which was the first report of HA20 characterized by Behcet disease. A comprehensive understanding of the pathogenic genes of HA20 could help us apply targeted therapy as soon as possible to improve patients' survival rates. Patient concerns A 2-year-old 3-month-old child was presented to our hospital with recurrent infectious enteritis and stomatitis. Diagnosis Genetic mutations were detected immediately, and a novel pathogenic mutation was found in TNFAIP3. A heterozygous mutation (c.436-437deTC) located at TNFAIP3 was confirmed. The present research indicated that the TNFAIP3 mutation of c.436-437deTC (p.L147Qfs∗7) accounted for familial Behcet-like autoinflammatory syndrome in the child suffering from HA20, while no variation in this locus was found in her parents. Interventions Symptomatic treatments including oral administration of prednisone (12.5 mg/d) and iron supplement were performed, and repeated infection was no longer observed in the child. Pain and activity limitation was found in the knee joints. The treatment regimen was adjusted to oral prednisone (12.5 mg/dose, 2 doses/d) and subcutaneous injection of rhTNFR:Fc (12.5 mg/week).Outcomes: At the last follow-up, the limbs' activities were normal, the inflammatory indicators were reduced or within the normal range. The prednisone dose was reduced to 7.5 mg/d, while the dose of rhTNFR:Fc was not changed. Conclusion We have identified a novel pathogenic HA20 mutation. In this article, 1 case was analyzed in-depth in terms of clinical manifestations of the patient and new sources of such a novel disease, which might improve our understanding of this disease.

In this review we give an overview of the NAIP/NLRC4 activation mechanism as well as the described roles of this inflammasome, with a focus on in vivo infection and pathology. After ligand recognition by NAIP sensor proteins the NAIP/NLRC4 inflammasome forms through oligomerization with the NLRC4 adaptor to activate Caspase-1. The activating ligands are intracellular bacterial flagellin or type-3 secretion system components, delivered by pathogens. In vivo experiments indicate a role in macrophages during lung, spleen and liver infection and systemic sepsis like conditions, as well as in intestinal epithelial cells. Upon NAIP/NLRC4 activation in the intestine, epithelial cell extrusion is triggered in addition to the canonical inflammasome outcomes of cytokine cleavage and pyroptosis. Human patients with auto-activating mutations in NLRC4 present with an autoinflammatory syndrome including enterocolitis. Although one of the better understood inflammasomes in terms of mechanism, tissue specific functions of NAIP/NLRC4 are only beginning to be understood.