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Vacuoles, E1-enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome is caused by mutations in the UBA1 gene in myeloid precursors, leading to systemic inflammatory manifestations. We present the case of a 75-year-old man presenting with fever, panniculitis, and macrocytic anemia testing repeatedly negative for UBA1 mutations in peripheral blood samples, but ultimately found positive on bone marrow mononuclear cell DNA. The man has been successfully treated with prednisone and methotrexate. [ABSTRACT FROM AUTHOR]

El síndrome de VEXAS (Vacuolas, enzima E1, ligado al X, Autoinflamatorio, Somático) es un síndrome autoinflamatorio de inicio en la edad adulta que se caracteriza por mutaciones somáticas en el gen UBA1 y se considera el prototipo de enfermedad hematoinflamatoria. Los pacientes con síndrome de VEXAS exhiben manifestaciones inflamatorias y hematológicas que pueden conducir a diagnósticos clínicos como policondritis recidivante, poliarteritis nodosa, síndrome de Sweet y síndrome mielodisplásico. El diagnóstico requiere la evaluación de la médula ósea en búsqueda de vacuolas citoplásmicas en precursores mieloides y eritroides. Sin embargo, la confirmación genética de las mutaciones en UBA1 es necesaria. El tratamiento es un desafío y a menudo incluye glucocorticoides e inmunosupresores, con respuestas variables. Las terapias hipometilantes y el trasplante alogénico de células progenitoras hematopoyéticas se consideran terapias prometedoras. El pronóstico es influido por factores genéticos y clínicos. El objetivo de esta revisión es proporcionar una visión general sobre la patogénesis, la presentación clínica, el tratamiento y el pronóstico del síndrome de VEXAS para la comunidad médica latinoamericana. VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is an adult-onset autoinflammatory syndrome characterized by somatic mutations in the UBA1 gene and is considered the prototype of hematoinflammatory diseases. Patients with VEXAS syndrome exhibit inflammatory and hematological manifestations that can lead to clinical diagnoses such as relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, and myelodysplastic syndrome. Diagnosis requires bone marrow evaluation to identify cytoplasmic vacuoles in myeloid and erythroid precursors. However, genetic confirmation of mutations in UBA1 is necessary. Treatment is challenging and often involves glucocorticoids and immunosuppressants with variable responses. Hypomethylating agents and allogenic haemopoietic stem cell transplant are considered promising therapies. Prognosis is influenced by genetic and clinical factors. The aim of this review is to provide an overview of the pathogenesis, clinical presentation, treatment, and prognosis of VEXAS syndrome for the Latin American medical community. [ABSTRACT FROM AUTHOR]

Abstract Background Respiratory conditions, such as asthma, are infrequently associated with auto-inflammatory diseases. We describe five patients with uncontrolled respiratory symptoms that were seen at St. Joesph’s Healthcare in Hamilton for severe asthma management diagnosed with rare autoinflammatory conditions using genetic molecular analysis. Case presentation Five patients are included in this case series. Gene mutations associated with familial Mediterranean fever, Yao syndrome, Cryopyrin-associated periodic syndrome, and Majeed syndrome were considered to explain partly the patient’s clinical manifestation after comprehensive clinical, biochemical, hematological investigations ruled out other disorders such as parasitosis, Allergic Bronchopulmonary Fungosis, Eosinophilic Granulomatosis with Poly Angitis, IgG4 disease, and Hypereosinophilia syndrome. Conclusions Complex patients initially presenting with respiratory conditions in addition to unexplained autoinflammatory conditions are a diagnostic challenge. Genetic molecular testing provides healthcare practitioners with useful information that may diagnose underlying auto-inflammatory diseases in undifferentiated patients. Role of inflammasome-activation in asthma and eosinophilia needs further investigation.

Abstract Background Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disease caused by mutations in the ADA2 gene. DADA2 has a broad spectrum of clinical presentations. Apart from systemic manifestations, we can categorize most of the signs and symptoms of DADA2 into the three groups of vasculitis, hematologic abnormalities, and immunologic dysregulations. The most dominant vasculitis features are skin manifestations, mostly in the form of livedo racemosa/reticularis, and early onset ischemic or hemorrhagic strokes. Hypogammaglobulinemia that is found in many cases of DADA2 brings immunodeficiencies into the differential diagnosis. Cytopenia, pure red cell aplasia (PRCA), and bone marrow failure (BMF) are the hematologic abnormalities commonly found in DADA. Case presentation We introduce eleven patients with DADA2 diagnosis, including two brothers and sisters, one set of twin sisters, and one father and his daughter and son. Ten patients (91%) had consanguineous parents. All the patients manifested livedo racemose/reticularis. Ten patients (91%) reported febrile episodes, and seven (64%) had experienced strokes. Only one patient had hypertension. Two of the patients (11%) presented decreased immunoglobulin levels. One of the patients presented with PRCA. Except for the PRCA patient with G321E mutation, all of our patients delivered G47R mutation, the most common mutation in DADA2 patients. Except for one patient who unfortunately passed away before the diagnosis was made and proper treatment was initiated, the other patients’ symptoms are currently controlled; two of the patients presented with mild symptoms and are now being treated with colchicine, and the eight others responded well to anti-TNFs. The PRCA patient still suffers from hematologic abnormalities and is a candidate for a bone marrow transplant. Conclusions Considering the manifestations and the differential diagnoses, DADA2 is not merely a rheumatologic disease, and introducing this disease to hematologists, neurologists, and immunologists is mandatory to initiate prompt and proper treatment. The efficacy of anti-TNFs in resolving the symptoms of DADA2 patients have been proven, but not for those with hematologic manifestations. Similarly, they were effective in controlling the symptoms of our cohort of patients, except for the one patient with cytopenia.

Background: Respiratory conditions, such as asthma, are infrequently associated with auto-inflammatory diseases. We describe five patients with uncontrolled respiratory symptoms that were seen at St. Joesph's Healthcare in Hamilton for severe asthma management diagnosed with rare autoinflammatory conditions using genetic molecular analysis. Case presentation: Five patients are included in this case series. Gene mutations associated with familial Mediterranean fever, Yao syndrome, Cryopyrin-associated periodic syndrome, and Majeed syndrome were considered to explain partly the patient's clinical manifestation after comprehensive clinical, biochemical, hematological investigations ruled out other disorders such as parasitosis, Allergic Bronchopulmonary Fungosis, Eosinophilic Granulomatosis with Poly Angitis, IgG4 disease, and Hypereosinophilia syndrome. Conclusions: Complex patients initially presenting with respiratory conditions in addition to unexplained autoinflammatory conditions are a diagnostic challenge. Genetic molecular testing provides healthcare practitioners with useful information that may diagnose underlying auto-inflammatory diseases in undifferentiated patients. Role of inflammasome-activation in asthma and eosinophilia needs further investigation. [ABSTRACT FROM AUTHOR]

Background: Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disease caused by mutations in the ADA2 gene. DADA2 has a broad spectrum of clinical presentations. Apart from systemic manifestations, we can categorize most of the signs and symptoms of DADA2 into the three groups of vasculitis, hematologic abnormalities, and immunologic dysregulations. The most dominant vasculitis features are skin manifestations, mostly in the form of livedo racemosa/reticularis, and early onset ischemic or hemorrhagic strokes. Hypogammaglobulinemia that is found in many cases of DADA2 brings immunodeficiencies into the differential diagnosis. Cytopenia, pure red cell aplasia (PRCA), and bone marrow failure (BMF) are the hematologic abnormalities commonly found in DADA. Case presentation: We introduce eleven patients with DADA2 diagnosis, including two brothers and sisters, one set of twin sisters, and one father and his daughter and son. Ten patients (91%) had consanguineous parents. All the patients manifested livedo racemose/reticularis. Ten patients (91%) reported febrile episodes, and seven (64%) had experienced strokes. Only one patient had hypertension. Two of the patients (11%) presented decreased immunoglobulin levels. One of the patients presented with PRCA. Except for the PRCA patient with G321E mutation, all of our patients delivered G47R mutation, the most common mutation in DADA2 patients. Except for one patient who unfortunately passed away before the diagnosis was made and proper treatment was initiated, the other patients' symptoms are currently controlled; two of the patients presented with mild symptoms and are now being treated with colchicine, and the eight others responded well to anti-TNFs. The PRCA patient still suffers from hematologic abnormalities and is a candidate for a bone marrow transplant. Conclusions: Considering the manifestations and the differential diagnoses, DADA2 is not merely a rheumatologic disease, and introducing this disease to hematologists, neurologists, and immunologists is mandatory to initiate prompt and proper treatment. The efficacy of anti-TNFs in resolving the symptoms of DADA2 patients have been proven, but not for those with hematologic manifestations. Similarly, they were effective in controlling the symptoms of our cohort of patients, except for the one patient with cytopenia. [ABSTRACT FROM AUTHOR]

Background: VEXAS (vacuoles, E1 enzyme, X-linked, auto-inflammatory, somatic) syndrome is a newly described auto-inflammatory disease. Many cases feature pulmonary infiltrates or respiratory failure. This systematic review aimed to summarize respiratory manifestations in VEXAS syndrome described to date. Methods: Databases were searched for articles discussing VEXAS syndrome until May 2022. The research question was: What are the pulmonary manifestations in patients with VEXAS syndrome? The search was restricted to English language and those discussing clinical presentation of disease. Information on basic demographics, type and prevalence of pulmonary manifestations, co-existing disease associations and author conclusions on pulmonary involvement were extracted. The protocol was registered on the PROSPERO register of systematic reviews. Results: Initially, 219 articles were retrieved with 36 ultimately included (all case reports or series). A total of 269 patients with VEXAS were included, 98.6% male, mean age 66.8 years at disease onset. The most frequently described pulmonary manifestation was infiltrates (43.1%; n = 116), followed by pleural effusion (7.4%; n = 20) and idiopathic interstitial pneumonia (3.3%; n = 9). Other pulmonary manifestations were: nonspecific interstitial pneumonia (n = 1), bronchiolitis obliterans (n = 3), pulmonary vasculitis (n = 6), bronchiectasis (n = 1), alveolar haemorrhage (n = 1), pulmonary embolism (n = 4), bronchial stenosis (n = 1), and alveolitis (n = 1). Several patients had one or more co-existing autoimmune/inflammatory condition. It was not reported which patients had particular pulmonary manifestations. Conclusion: This is the first systematic review undertaken in VEXAS patients. Our results demonstrate that pulmonary involvement is common in this patient group. It is unclear if respiratory manifestations are part of the primary disease or a co-existing condition. Larger epidemiological analyses will aid further characterisation of pulmonary involvement and disease management. [ABSTRACT FROM AUTHOR]

In the previous part of the review clinical and diagnostic aspects of some non-infectious uveitis in patients with immunoinflammatory diseases were discussed. In this part we proceed the discussion of ocular manifestations of a number of other immunoinflammatory conditions. In addition to uveitis associated with spondyloarthropathies, rheumatoid arthritis, Still’s disease, juvenile idiopathic arthritis and systemic sarcoidosis described in the previous part, ocular manifestations are also common in systemic vasculitis, systemic lupus erythematosus, Vogt—Koyanagi—Harada syndrome. Despite the numerous diagnostic schemes and therapy algorithms developed to date, much in the pathogenesis of uveitis associated with immuno-inflammatory diseases remains unclear. The need to develop personalized and multidisciplinary approaches for the treatment and diagnosis of non-infectious uveitis in numerous systemic immunoinflammatory diseases remains relevant. In-depth understanding of etiopathogenetic mechanisms of immunoinflammatory processes will allow to develop new approaches in the treatment of patients with uveitis.

Yuqi Chu, Taoming Liu, Juan Bai, Hong Fang, Jianjun Qiao Department of Dermatology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaCorrespondence: Jianjun Qiao, Department of Dermatology, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, People’s Republic of China, Tel +86 13735542393, Email qiaojianjun@zju.edu.cnAbstract: Pyoderma gangrenosum (PG) is a rare autoinflammatory skin disorder, which is characterised by rapidly developing and tender cutaneous ulcers. The treatment of PG is challenging. Palmoplantar pustulosis (PPP) is also an autoinflammatory dermatosis with sterile pustules on the palms and/or the soles. We demonstrated a 68-year-old patient with coexisting autoinflammatory diseases including PG, 1-year history of plaque psoriasis and PPP, recovered after treatment with adalimumab. We also reviewed published reports of PG-associated autoinflammatory syndromes with adalimumab.Keywords: adalimumab, autoinflammatory syndrome, palmoplantar pustulosis, plaque psoriasis, pyoderma gangrenosum

Sweet syndrome is a neutrophilic dermatosis associated with multiple disorders. This retrospective case-series study of patients with Sweet syndrome in a tertiary hospital in Spain from 2001 to 2021, explores clinicopathological characteristics of Sweet syndrome and variables associated with malignancy, presence of autoinflammatory disorders and differences between histological subtypes. A total of 93 patients were identified: 30% idiopathic, 34% malignancy-associated, 29% reactive to infections or drug-associated, and 6% with an autoimmune/inflammatory condition. Acute myeloid leukaemia was the most common malignancy (16/93) followed by myelodysplastic syndrome (7/93). Patients with acute myeloid leukaemia presented isolated flares, marked cytopaenia and rapid response to treatment, whereas myelodysplastic syndrome followed a chronic-recurrent course. The most frequent associated medications and inflammatory disorders were filgrastim and hydroxyurea (n=2); and inflammatory bowel disease (n=4). In addition, 3 patients were diagnosed with VEXAS syndrome. Male sex (p=0.006), fever (p=0.034), increased erythrocyte sedimentation rate (p<0.001), anaemia (p<0.001), and thrombocytopaenia (p<0.001) were associated with malignancy. Histologically, patients were classified as classic (60%), histiocytoid (22.5%) or subcutaneous (15%), with pain (p=0.011) and nodules (p<0.001) being associated with subcutaneous-Sweet syndrome. Sweet syndrome in the context of cytopaenia should alert the presence of malignancy. An acquired autoinflammatory condition should be explored in relapsing Sweet syndrome with myelodysplastic syndrome. A minimum follow-up of 6 months is recommended. [ABSTRACT FROM AUTHOR]

Inherited disorders of the inflammasome pathway causes dysregulated inflammasome activation, which presents with inflammation and other clinical features linked to the defective protein. Eight mutations have been previously described in the NLRP1 inflammasome protein, causing different inflammatory skin disorders. Two of these mutations are associated with “autoinflammation with arthritis and dyskeratosis (AIADK),” a novel Mendelian auto-inflammatory disorder, in the 2017 International Union of Immunological Societies phenotypic classification for primary immunodeficiencies. We report a 22-year-old female, with recurrent generalized urticaria, periodic fever and pain abdomen, inflammatory polyarthritis, cutaneous lesions over the extremities, and persistently elevated inflammatory markers. On next-generation sequencing, a heterozygous missense mutation in exon 4 of the NLRP1 gene (chr17:G.5461839C>T) was detected, which results in the amino acid substitution of glutamine for arginine at codon 726 (c.2177G>A; p.Arg726Gln). A probable diagnosis of AIADK, possibly caused by this mutation was proposed, and patient responded well to colchicine.

Haploinsufficiency of suppressor of cytokine signaling 1 (SOCS1) is a recently discovered autoinflammatory disorder with significant rheumatologic, immunologic, and hematologic manifestations. Here we report a case of SOCS1 haploinsufficiency in a 5-year-old child with profound arthralgias and immune-mediated thrombocytopenia unmasked by SARS-CoV-2 infection. Her clinical manifestations were accompanied by excessive B cell activity, eosinophilia, and elevated IgE levels. Uniquely, this is the first report of SOCS1 haploinsufficiency in the setting of a chromosomal deletion resulting in complete loss of a single SOCS1 gene with additional clinical findings of bone marrow hypocellularity and radiologic evidence of severe enthesitis. Immunologic profiling showed a prominent interferon signature in the patient's peripheral blood mononuclear cells, which were also hypersensitive to stimulation by type I and type II interferons. The patient showed excellent clinical and functional laboratory response to tofacitinib, a Janus kinase inhibitor that disrupts interferon signaling. Our case highlights the need to utilize a multidisciplinary diagnostic approach and consider a comprehensive genetic evaluation for inborn errors of immunity in patients with an atypical immune-mediated thrombocytopenia phenotype. [ABSTRACT FROM AUTHOR]

The aim of this study was to analyze the clinical, laboratory and molecular genetic data of 26 patients (15 boys, 11 girls) diagnosed with mevalonate kinase deficiency syndrome (MKD).Subjects and methods. The age of MKD manifestation ranged from 0 to 30.0 months (M – 1.5 months). Clinical manifestations and their severity were extremely diverse: from symptoms resembling Marshall’s syndrome to severe systemic manifestations with respiratory failure, hepatosplenomegaly and pancytopenia.Results/Conclusion. All patients had homozygous/compound-heterozygous mutations in the MVK gene, including 10 newly described variants. In all 20 patients, who have been treated with IL-1 inhibitors long enough to assess the effect of the treatment, drastic improvement of the condition was noted, but only in 17/20 patients achieved full remission.

VEXAS is a newly recognised adult‐onset autoinflammatory syndrome resulting from a somatic mutation in the UBA1 gene. Herein, we present three cases of VEXAS syndrome in Sydney, Australia, that capture key clinical features and the refractory nature of the condition. They highlight the importance of multidisciplinary collaboration for early diagnosis and the need for new therapeutic options. [ABSTRACT FROM AUTHOR]

Inherited disorders of the inflammasome pathway causes dysregulated inflammasome activation, which presents with inflammation and other clinical features linked to the defective protein. Eight mutations have been previously described in the NLRP1 inflammasome protein, causing different inflammatory skin disorders. Two of these mutations are associated with "autoinflammation with arthritis and dyskeratosis (AIADK)," a novel Mendelian auto-inflammatory disorder, in the 2017 International Union of Immunological Societies phenotypic classification for primary immunodeficiencies. We report a 22-year-old female, with recurrent generalized urticaria, periodic fever and pain abdomen, inflammatory polyarthritis, cutaneous lesions over the extremities, and persistently elevated inflammatory markers. On next-generation sequencing, a heterozygous missense mutation in exon 4 of the NLRP1 gene (chr17:G.5461839C>T) was detected, which results in the amino acid substitution of glutamine for arginine at codon 726 (c.2177G>A; p.Arg726Gln). A probable diagnosis of AIADK, possibly caused by this mutation was proposed, and patient responded well to colchicine. [ABSTRACT FROM AUTHOR]

Pyoderma gangrenosum, acne, and hidradenitis suppurativa syndrome is a rare inflammatory disease characterized by pyoderma gangrenosum (PG), mild to severe facial acne, and hidradenitis suppurativa (HS). It only affects the skin and represents cutaneous characteristics of a spectrum of autoinflammation. Lack of pyogenic sterile arthritis (PA) distinguishes the pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH) syndrome from pyogenic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PA-PASH), pyoderma gangrenosum, acne, hidradenitis suppurtiva, and ankylosing spondylitis (PASS), and pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndromes. The exact etiology and pathogenesis of PASH syndrome remain unknown. Both PG and HS are contained in the spectrum of neutrophilic dermatitis, which is considered as an autoinflammatory syndrome. From a pathophysiological point of view, they show similar mechanisms, including neutrophil-rich cutaneous infiltration and overexpression of the interleukin-1 (IL-1) family. These findings provide guidance for these intractable diseases. In this review, we described a case of PASH syndrome in a patient who initially failed to respond to immunosuppressive treatment but responded to a combination of colchicine and thalidomide. We reviewed the relevant literature that focuses on PASH syndrome management.

Background: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is an autoinflammatory disease occurring in children. Although PFAPA is the most common periodic fever syndrome found in children, there are only a few studies defining the clinical characteristics and the efficacy of treatment strategies among Japanese children. This study aimed to clarify the demographic characteristics and clinical features of patients with PFAPA syndrome and to evaluate treatment efficacy. Methods: We retrospectively reviewed the clinical features of children with PFAPA who visited Saitama Children’s Medical Center between January and December 2019. We also evaluated treatment strategies and their efficacy; abortive treatment with corticosteroids, prophylaxis with cimetidine or colchicine, and surgical management with tonsillectomy. Results: A total of 100 Japanese children (61% male) with PFAPA were included. Median age of onset was 3 years, median duration of fever episodes was 5 days, and median interval between episodes was 4 weeks. The symptoms (frequencies) were pharyngitis (89%), exudate on tonsils (71%), cervical adenitis (50%), and aphthous stomatitis (49%). Approximately 37% of patients took prednisolone for aborting fever attacks, showing a 100% response; 93% were treated with cimetidine, showing an 79.6% response, and 18% were treated with colchicine, showing a 66.7% response. Only one patient underwent tonsillectomy. Conclusions: Among Japanese children with PFAPA, 28% of them were ≥5 years with a male predominance. Pharyngitis is the most frequent symptom associated with fever. Cimetidine is suitable for initial therapy because of its safety and efficacy. [ABSTRACT FROM AUTHOR]

Mutations in the gene encoding tRNA nucleotidyltransferase 1 (TRNT1) are associated with heterogeneous phenotypes and multisystem involvement of variable severity and progression. Immunodeficiency and inflammation are recurrent-associated features. The use of cytokine inhibitors in suppressing the inflammatory phenotype has been recently reported, with a 3-year follow-up for patients treated with Etanercept. We report on two unrelated patients sharing the same clinical condition, who had been referred to our Pediatric Rheumatology Unit because of recurrent fever associated with cutaneous lesions and increased levels of inflammatory markers since their first months of life. Whole exome sequencing allowed to identify compound heterozygosity for functionally relevant variants in TRNT1 as the only molecular event shared by the two patients. Both patients have been treated with Etanercept during 11 years, documenting normalization of inflammatory indexes and resolution of recurrent fever and associated symptoms. This is the longest follow-up assessment of Etanercept treatment in patients with TRNT1 mutations. Our findings confirm efficacy and safety of the treatment. Key Points • Mutations in TRNT1 have been associated with phenotypic heterogeneity. • We report on two patients with early-onset autoinflammatory syndrome. • Whole exome sequencing led to reveal compound heterozygosity for two variants in TRNT1 in both patients. • The patients were successfully treated with Etanercept for more than 10 years, the longest follow-up described in literature. [ABSTRACT FROM AUTHOR]

A case of a malignant peritoneal mesothelioma mimicking an autoinflammatory syndrome in a 12-year-old boy is reported. The patient initially presented with lymphadenopathy and weight loss but without abdominal pain. Three things confounded the initial diagnosis: a positive test result for a gene related to cryopyrin-associated periodic syndrome, a positive response to the autoinflammatory syndrome treatment, and a lymph node biopsy which showed "hyperplastic mesothelial cells in the lymph sinuses." His symptoms relapsed several years later, and a peritoneal biopsy confirmed the final diagnosis. Complete morphological, immunohistochemical, and molecular diagnoses are described. A translocation in the TERT gene involving the truncation of the promoter was found in the mesothelioma. The translocation has never been described in mesotheliomas and is of an unknown significance. [ABSTRACT FROM AUTHOR]

The proteasome is a multisubunit protease that degrades intracellular proteins into small peptides. Besides playing a pivotal role in many cellular processes indispensable for survival, it is involved in the production of peptides presented by major histocompatibility complex class I molecules. In addition to the standard proteasome shared in all eukaryotes, jawed vertebrates have two specialized forms of proteasome known as immunoproteasomes and thymoproteasomes. The immunoproteasome, which contains cytokine‐inducible catalytic subunits with distinct cleavage specificities, produces peptides presented by class I molecules more efficiently than the standard proteasome. The thymoproteasome, which contains a unique catalytic subunit β5t, is a tissue‐specific proteasome expressed exclusively in cortical thymic epithelial cells. It plays a critical role in CD8+ cytotoxic T cell development via positive selection. This review provides a brief overview on the structure and function of these specialized forms of proteasome and their involvement in human disease. [ABSTRACT FROM AUTHOR]

Koichiro Ohmura Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, JapanCorrespondence: Koichiro OhmuraDepartment of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, JapanTel +81 75 751 4380Fax +81 75 751 4338Email ohmurako@kuhp.kyoto-u.ac.jpAbstract: Nakajo–Nishimura syndrome (NNS) is a rare hereditary autoinflammatory disorder with lipodystrophy. This disease is caused by a homozygous mutation of PSMB8 gene, which encodes immunoproteasome subunit β5i. Phenotypes of NNS patients are periodic fever, pernio-like rash, nodular erythema-like eruptions, and lipomuscular dystrophy, especially in the upper body, leading to the characteristic long, clubbed fingers. NNS was considered to be endemic to the Kansai area of Japan, but patients with similar phenotypes and the mutation of PSMB8 gene were reported in other countries, and named Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome and joint contractures, muscular atrophy, microcytic anemia, and panniculitis-associated lipodystrophy (JMP) syndrome. These syndromes are now called proteasome-associated autoinflammatory syndromes (PRAASs), and their main pathophysiological mechanism seems to be interferonopathy. In this review, the history, characteristics, and the pathophysiological mechanism of PRAASs will be discussed, focusing mainly on NNS.Keywords: Nakajo-Nishimura syndrome, PSMB8, autoinflammatory syndrome, proteasome, lipodystrophy, interferonopathy

Objective: To make an accurate diagnosis of systemic autoinflammatory diseases (SAIDs), clinical and genetic analyses were performed in patients with unexplained fever. Methods: The clinical phenotype and genomic variants of 11 genes responsible for SAIDs were analyzed in 179 Japanese patients with unexplained fever. Genetic analysis was performed by next generation sequencing (NGS) on exons including exon-intron boundaries. Results: Three cases met the diagnostic criteria for SAIDs other than familial Mediterranean fever (FMF). Considering 176 patients with unexplained fever, 43 cases (24.0%) were clinically diagnosed as FMF. Gene variants were found in 53 cases (30.1%) when searching for variants in the 10 disease genes other than the MEFV gene. Among them, the most frequently-identified genes were NLRP3, NOD2, NLRP12, NLRC4, and PLCG2, which accounted for 14, 7, 17, 7, and 6 cases, respectively. These variants were less than 1% of healthy individuals or novel variants, but not regarded as pathogenic since the patients did not meet the diagnostic criteria of SAIDs caused by their identified variants clinically. Conclusion: Twenty four percent of Japanese patients with unexplained fever were clinically diagnosed as FMF in this study. Low frequency but not pathogenic variants in genes other than MEFV were identified in 30.1% of the cases. It is not clear how much these gene variants contribute to the inflammatory phenotypes; therefore, further analysis would uncover their autoinflammatory phenotypes that cause fever. [ABSTRACT FROM AUTHOR]

Autoinflammatory syndromes are disorders characterized by recurrent or chronic inflammation caused by the dysregulation of the innate immune system. Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome of overactivation of the immune system. We present a case of a 20-month-old boy who was referred to an oncology clinic because of HLH suspicion. In the preceding time, our patient suffered from a severe form of chickenpox with prolonged fever. Tests including myelogram, cerebrospinal fluid, and magnetic resonance (MR) of the brain gave a diagnosis of acute lymphoblastic leukemia from B lymphocyte precursors, without occupying the central nervous system. To exclude inherited HLH in our patient, next-generation sequencing was performed, which revealed a heterozygous missense mutation in exon 15 of the PSTPIP1 gene (c.1213C>T, R405C). No mutations of genes associated with familial HLH syndrome were found. Our patient may be evidence that autoinflammatory diseases caused by PSTPIP1 gene mutations are not limited to the classical pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) phenotype but may have a different clinical presentation, and the spectrum of the PSTPIP1-associated inflammatory diseases (PAID) syndrome is more extensive than previously thought. [ABSTRACT FROM AUTHOR]

Behcet's disease (BD) is a chronic inflammatory disease with multisystemic involvement. Its etiology is considered to involve complex environmental and genetic factors. Several susceptibility genes for BD, such as human leukocyte antigen (HLA)-A26, IL23R-IL12RB2, IL10 and ERAP1, in addition to the well-studied HLA-B51, were mainly identified by genome-wide association studies. A heterozygous mutation in TNFAIP3, which leads to A20 haploinsufficiency, was found to cause an early-onset autoinflammatory disease resembling BD in 2016. Several monogenic diseases associated with primary immunodeficiency disease and trisomy 8 have recently been reported to display BD-like phenotypes. Among the genes causing these diseases, TNFAIP3, NEMO, RELA, NFKB1 and TNFRSF1A are involved in the NF-κ B (nuclear factor κ light-chain enhancer of activated B cells) signaling pathway, indicating that this pathway plays an important role in the pathogenesis of BD. Because appropriate treatment may vary depending on the disease, analyzing the genetic background of patients with such diseases is expected to help elucidate the etiology of pediatric BD and assist with its treatment. Here, we summarize recently emerging knowledge about genetic predisposition to BD. [ABSTRACT FROM AUTHOR]

In the last decade, new scientific findings significantly improved our understanding of the molecular pathogenesis of autoinflammation and have resulted in the identification and definition of several pyoderma gangrenosum-associated autoinflammatory syndromes (PGAAIS) as new and distinct clinical entities. These different clinical entities include PAPA (pyogenic arthritis, pyoderma gangrenosum and acne conglobata), PASH (pyoderma gangrenosum, acne and suppurative hidradenitis), PAPASH (pyoderma gangrenosum, acne, suppurative hidradenitis and pyogenic arthritis), PsAPASH (pyoderma gangrenosum, acne, suppurative hidradenitis and psoriatic arthritis), PASS (pyoderma gangrenosum, acne conglobata, suppurative hidradenitis, and axial spondyloarthritis) and PAC (pyoderma gangrenosum, acne and ulcerative colitis), which can be distinguished by their clinical presentation and the presence or absence of mutations in several genes, such as the genes encoding proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1), nicastrin (NCSTN), Mediterranean fever (MEFV) and nucleotide-binding oligomerization domain-containing protein (NOD). In this systematic review, we summarize the present knowledge of this rapidly developing hot topic and provide a guide to enable the easy diagnosis of these syndromes in everyday clinical practice. Moreover, we report a rare case of PASS syndrome demonstrating successful treatment with adalimumab and another case of a previously unreported combination of symptoms, including psoriatic arthritis, pyoderma gangrenosum, suppurative hidradenitis and Crohn’s disease (newly coined PsAPSC), as examples. Because of the identification of similar genetic and pathogenic mechanisms of PGAAIS, we think the wide variety of seemingly different syndromes may represent distinct phenotypes of one disease.

Behçet's disease (BD) is a heterogeneous multi‐organ disorder in search of a unified pathophysiological theory and classification. The disease frequently has overlapping features resembling other disease clusters, such as vasculitides, spondyloarthritides and thrombophilias with similar genetic risk variants, namely HLA‐B*51, ERAP1, IL‐10, IL‐23R. Many of the BD manifestations, such as unprovoked recurrent episodes of inflammation and increased expression of IL‐1, IL‐6 and TNFα, overlap with those of the hereditary monogenic autoinflammatory syndromes, positioning BD at the crossroads between autoimmune and autoinflammatory syndromes. BD‐like disease associates with various inborn errors of immunity, including familial Mediterranean fever, conditions related to dysregulated NF‐κB activation (eg TNFAIP3, NFKB1, OTULIN, RELA, IKBKG) and either constitutional trisomy 8 or acquired trisomy 8 in myelodysplastic syndromes. We review here the recent advances in the immunopathology of BD, BD‐like diseases and the NF‐κB pathway suggesting new elements in the elusive BD etiopathogenesis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Inflammasomes are a specialized group of intracellular sensors that are key components of the host innate immune system. Autoinflammatory diseases are disorders of the innate immune system that are characterized by recurrent inflammation and serious complications. Dysregulation of the inflammasome is associated with the onset and progression of several autoinflammatory and autoimmune diseases, including cryopyrin‐associated periodic fever syndrome, familial Mediterranean fever, rheumatoid arthritis, and systemic lupus erythematosus. In this review, we discuss the involvement of various inflammasome components in the regulation of autoinflammatory disorders and describe the manifestations of these autoinflammatory diseases caused by inflammasome activation. [ABSTRACT FROM AUTHOR]

Abstract Background Chronic Non-Bacterial Osteomyelitis (CNO) is an inflammatory disorder that primarily affects children. Although underestimated, its incidence is rare. For these reasons, no diagnostic and no therapeutic guidelines exist. The manuscript wants to give some suggestions on how to deal with these patients in the every-day clinical practice. Main body CNO is characterized by insidious onset of bone pain with local swelling. Systemic symptoms such as fever, skin involvement and arthritis may be sometimes present. Radiological findings are suggestive for osteomyelitis, in particular if multiple sites are involved. CNO predominantly affects metaphyses of long bones, but clavicle and mandible, even if rare localizations of the disease, are very consistent with CNO diagnosis. CNO pathogenesis is still unknown, but recent findings highlighted the crucial role of cytokines such as IL-1β and IL-10 in disease pathogenesis. Moreover, the presence of non-bacterial osteomyelitis among autoinflammatory syndromes suggests that CNO could be considered an autoinflammatory disease itself. Differential diagnosis includes infections, malignancies, benign bone tumors, metabolic disorders and other autoinflammatory disorders. Radiologic findings, either with Magnetic Resonance or with Computer Scan, may be very suggestive. For this reason in patients in good clinical conditions, with multifocal localization and very consistent radiological findings bone biopsy could be avoided. Non-Steroidal Anti-Inflammatory Drugs are the first-choice treatment. Corticosteroids, methotrexate, bisphosphonates, TNFα-inhibitors and IL-1 blockers have also been used with some benefit; but the choice of the second line treatment depends on bone lesions localizations, presence of systemic features and patients’ clinical conditions. Conclusion CNO may be difficult to identify and no consensus exist on diagnosis and treatment. Multifocal bone lesions with characteristic radiological findings are very suggestive of CNO. No data exist on best treatment option after Non-Steroidal Anti-Inflammatory Drugs failure.

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.

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.

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. [ABSTRACT FROM AUTHOR]

Neurologic complications of chronic infantile neurologic, cutaneous and articular syndrome (CINCA) are well-known, whereas there are scarce data regarding neurologic features of milder cryopyrin-associated periodic syndrome (CAPS) phenotypes. We aimed to review the neurologic features in detail and summarize the other CAPS-related manifestations in 12 children. All children with CAPS that have been followed-up from pediatric rheumatology outpatient clinic, were enrolled to the study. In addition to the neurologic examination, magnetic resonance imaging (MRI) of brain, electroencephalography, eye examination, hearing test and intellectual assessment were done. Demographic, clinical features, genetic analysis and laboratory tests were noted from patient records and hospital database. The median age of the subjects was 7 years (range 2–19 years), with a female-to-male ratio 2/1. The phenotype was consistent with familial cold autoinflammatory syndrome in 7 patients, Muckle–Wells syndrome in 3 patients and chronic infantile neurologic, cutaneous and articular syndrome in 2 patients. Most frequently noted neurologic clinical manifestation during the entire disease course was headache (n = 4/12) followed by seizures (n = 3/12), papilledema (n = 3/12), intellectual disability (n = 2/12), aseptic meningitis (n = 2/12), hearing loss (n = 2/12) and optic atrophy (n = 1/12). MRI of the brain revealed abnormal lesions in two patients. Uveitis or conjunctivitis were seen in two children. Overall, neurological involvement was detected in 6/12 of our cohort, of which half (n = 3) was in severe form. Half of the children with CAPS exhibited neurologic manifestations with varying degrees of severity. Increased understanding and awareness of this rare but treatable syndrome among neurologists is essential. If remains untreated and unrecognized, this autoinflammatory syndrome could lead to significant morbidity and mortality. Besides complete resolution of systemic symptoms, anti-interleukin-1 treatment may also prevent progression of neurologic findings when initiated in the early stage of the disease. • CAPS is an autoinflammatory syndrome with frequent neurological manifestations. • Management of this multisystemic disease requires a team approach. • Delayed diagnosis leads to significant morbidity and mortality. • Increased awareness of this rare but treatable IL1-associated disease is essential. [ABSTRACT FROM AUTHOR]

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The article presents a case of a successful canakinumab application (preparation of monoclonal antibodies to 1 interleukin) for undifferentiated autoinflammatory syndrome in a patient with refractoriness to oral glucocorticosteroids and genetically engineered biological drugs with a different action mechanisms. After 8 weeks of canakinumab therapy, systemic manifestations were cropped, and laboratory parameters of the disease activity were normalized. During the entire care period (12 months), neither serious adverse events nor increased incidence of acute respiratory infections have been reported.