Uso de PCR digital para definir terapéuticas específicas y seguimiento en enfermedades autoinflamatorias / Use of digital PCR to define specific therapeutics and follow-up in autoinflammatory diseases

Las enfermedades autoinflamatorias (AIDs) son un grupo heterogéneo de desórdenes monogénicos o poligénicos, con características de disregulación inmune innata y/o adaptativa, cuyo mecanismo central es la autoinflamación pero también pueden presentarse con autoinmunidad e inmunodeficiencia. En estos últimos años el desarrollo de las tecnologías de secuenciación masiva han provocado una explosión en el descubrimiento de nuevos genes responsables de AIDs monogénicas. Esto remarca la importancia de implementar este tipo de estudios para llegar a un diagnóstico definitivo sobre todo en este grupo de patologías genéticamente muy diversas donde los fenotipos clínicos se solapan. Sin embargo, dada la presencia de variantes de significación incierta (VUS), los resultados pueden no ser concluyentes planteándose la necesidad de desarrollar pruebas funcionales para determinar la patogenicidad de dichas variantes genéticas. En nuestro grupo de trabajo estamos aplicando la PCR digital en gotas (ddPCR), una técnica cuantitativa de 3era generación altamente sensible, especifica y reproducible que no necesita de curvas de calibración, para desarrollar pruebas funcionales que permitan no sólo reclasificar variantes VUS para lograr diagnósticos definitivos sino también estudiar los mecanismos responsables de las principales AIDs que permitan una estratificación de las terapéuticas especificas a aplicar y de esta manera poder contribuir al diagnóstico, tratamiento y seguimiento de nuestros pacientes en forma personalizada. (AU)

Autoinflammatory diseases (AIDs) are a heterogeneous group of monogenic or polygenic disorders, with characteristics of inborn and/or adaptive immune dysregulation, whose central mechanism is autoinflammation but may also present with autoimmunity and immunodeficiency. In recent years the development of massive sequencing technologies has led to an exponential increase in the discovery of new genes responsible for monogenic AIDs. This emphasizes the importance of the implementation of this type of studies to make a definitive diagnosis, especially in this group of genetically very diverse diseases with overlapping clinical phenotypes. However, given the presence of variants of uncertain significance (VUS), the results may not be conclusive, raising the need to develop functional tests to determine the pathogenicity of these genetic variants. In our working group we are applying droplet digital PCR (ddPCR), a highly sensitive, specific and reproducible third generation quantitative technique that does not require calibration curves, to develop functional tests that allow not only to reclassify VUS variants to achieve definitive diagnoses but also to study the mechanisms responsible for the main AIDs that allow for the stratification of specific treatments to be used and thereby contribute to the individualized diagnosis, treatment, and follow-up of our patients (AU)

Hidradenitis supurativa: reporte de un caso / Hidradenitis suppurativa: a case report

Resumen La hidradenitis supurativa (HS) es una enfermedad dolorosa y crónica, que afecta en especial la unidad folículo-pilosebácea de la piel ubicada en ingle, axilas, región perianal, perineo, genitales y submamaria,regiones anatómicas donde se encuentran glándulas sudoríparas apocrinas. El curso clínico de la HS es heterogéneo pues varía desde formas muy graves con abscesos fluctuantes profundos y drenajes eventuales; concicatricesresiduales graves, hasta otra forma de enfermedad comparativamente leve caracterizada por la aparición de algunos nódulos inflamatorios,pústulas ypápulas,de manera recidivante. Comunicamos el caso de un niño de 12 añosde edad, con diagnóstico de hidradenitis supurativa,quien fue tratado con Adalimumab. Realizamos la revisión del estado de arte de esta patología, describimos sus características clínicas, criterios diagnósticos, diagnósticos diferenciales y los posibles tratamientos. Nuestra presentación, tiene por objeto relatar nuestra experiencia en el seguimiento del caso del paciente, y las vicisitudes diagnósticas al respecto, que variaron desde acné inflamatorio grave hasta finalmente arribar al diagnóstico de certeza de hidradenitis supurativa, basándonos en criterios clínicos y ecográficos.Consideramos de interés haber podido emplear el "agente biológico" inhibidordel factor de necrosis tumoral (FNT) que hemos mencionado, con excelente respuesta.

Abstract Hidradenitis suppurativa (HS) is a painful and chronic disease that particularlyaffects the follicle-pilosebaceous unit of the skin located in the groins, armpits, perianal region, perineum, genitals, and submammary glands, which areanatomical regions whereapocrine sweat glands are found. The clinical course of HS is heterogeneous as it varies from very severe forms with deep fluctuating abscesses and eventual drainage; with severe residual scars, to another form ofacomparatively mild condition characterized by the presence of some recurrent inflammatory nodules, pustules and papules as well. We report the case of a 12-year-old boy, diagnosed with hidradenitis suppurativa, who was treated with Adalimumab. We reviewed the state of the art of this pathology, described its clinical characteristics, diagnostic criteria, differential diagnoses and carried out possible treatments. The purpose of our presentation is to report our experience in monitoring the patient's case, along with the diagnostic vicissitudes in this regard, which ranged from severe inflammatory acne to finally arriving at a certain diagnosis of hidradenitis suppurativa, based on clinical and ultrasound criteria. We consider of interest the possibility of having been able to use the "biological agent" inhibitor of the tumor necrosis factor (TNF) that we have mentioned, with an excellent response.

A brazilian nationwide multicenter study on deficiency of deaminase-2 (DADA2)

Abstract Introduction The deficiency of ADA2 (DADA2) is a rare autoinflammatory disease provoked by mutations in the ADA2 gene inherited in a recessive fashion. Up to this moment there is no consensus for the treatment of DADA2 and anti-TNF is the therapy of choice for chronic management whereas bone marrow transplantation is considered for refractory or severe phenotypes. Data from Brazil is scarce and this multicentric study reports 18 patients with DADA2 from Brazil. Patients and methods This is a multicentric study proposed by the Center for Rare and Immunological Disorders of the Hospital 9 de Julho - DASA, São Paulo - Brazil. Patients of any age with a confirmed diagnosis of DADA2 were eligible for this project and data on clinical, laboratory, genetics and treatment were collected. Results Eighteen patients from 10 different centers are reported here. All patients had disease onset at the pediatric age (median of 5 years) and most of them from the state of São Paulo. Vasculopathy with recurrent stroke was the most common phenotype but atypical phenotypes compatible with ALPS-like and Common Variable Immunodeficiency (CVID) was also found. All patients carried pathogenic mutations in the ADA2 gene. Acute management of vasculitis was not satisfactory with steroids in many patients and all those who used anti-TNF had favorable responses. Conclusion The low number of patients diagnosed with DADA2 in Brazil reinforces the need for disease awareness for this condition. Moreover, the absence of guidelines for diagnosis and management is also necessary (t).

Progress of the Nod-like receptor family pyrin domain-containing protein 12 in autoinflammatory diseases / 中华实用儿科临床杂志

The Nod-like receptor family pyrin domain-containing protein 12(NLRP12), a newly discovered member of the Nod-like receptor family, is one of the important pattern recognition receptors.It recognizes a variety of pathogens, initiates downstream immune responses, and participates in the regulation of multiple inflammatory responses.NLRP12 is related to the occurrence and progression of inflammatory diseases.In this review, the structure and function of NLRP12 as well as NLRP12-associated autoinflammatory diseases were discussed, so as to provide new insights for the understanding, exploration and treatment of NLRP12-associated autoinflammatory diseases.

Multidisciplinary Treatment on a Case of ROSAH Syndrome / 罕见病研究

A 15-year-old female was referred to the hospital with intermittent fever, where multiple systemic abnormalities were found, such as splenomegaly, secondary hypersplenism, retinitis pigmentosa, and ectodermal dysplasia. Medical history revealed that she had suffered recurrent respiratory infections, blurred vision at night, and dysplasia of teeth and nail beds since childhood. Then she was suspected to be experiencing ROSAH syndrome, a rare disease newly recognized in recent years, which was finally confirmed by gene sequencing results. During a course of treatment with tumor necrosis factor inhibitors, recurrent fever with elevated inflammatory markers reappeared, and the child developed headaches. To guide the comprehensive treatment and improve the patient's quality of life, the multidisciplinary team in Peking Union Medical College Hospital discussed together and directed the following treatment.

Autoinflammatory Diseases: a Rapidly Advancing Field / 罕见病研究

Autoinflammatory diseases (AIDs) are a group of genetic disorders characterized by generalized inflammatory responses and multiorgan involvement primarily caused by dysregulated innate immunity. Since the introduction of this concept, AIDs has been a rapidly advancing research field including at least 56 diseases, deepening the understanding of the interaction between innate and adaptive immunity. Despite distinct features displayed by AIDs of different categories, genetic testing remains essential for highly suspected cases. The diagnosis of undifferentiated systemic autoinflammatory diseases, omics-powered precision stratification and targeted therapy for AIDs are promising research areas in the future. This article introduces the rapid progresses in AIDs concept, mechanism, and classification. We present a summary of the characteristic clinical phenotype, as well as the current diagnostic challenges and treatment experiences, in the hope of raising the awareness of these disorders.

Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome in children: a brief literature review / Síndrome da febre periódica, estomatite aftosa, faringite e adenite em crianças: uma breve revisão de literatura

ABSTRACT Objective: To describe clinical, diagnostic and therapeutic characteristics of the periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome. Data source: Literature review in the PubMed database by using specific descriptors to identify all articles published in the English language in the last three years; 38 articles were found. After performing selection of titles and abstract analysis, 13 out of the 38 articles were fully read. Relevant studies found in the references of the reviewed articles were also included. Data synthesis: The PFAPA syndrome (Periodic Fever, Aphthous Stomatitis, Pharyngitis and cervical Adenitis) is a medical condition grouped among the periodic fever syndromes. The etiology is uncertain, but possibly multifactorial, and its symptoms are accompanied by recurrent febrile episodes although weight and height development are preserved. It is a self-limiting disease of benign course with remission of two to three years without significant interference in the patient's overall development. Treatment consists of three pillars: interruption of febrile episodes, increase in the interval between episodes, and remission. Conclusions: Despite several attempts to establish more sensitive and specific criteria, the diagnosis of PFAPA syndrome is still clinical and reached by exclusion, based on the modified Marshall's criteria. The most common pharmacological options for treatment include prednisolone and betamethasone; colchicine may be used as prophylaxis, and surgical treatment with tonsillectomy can be considered in selected cases.

RESUMO Objetivo: Descrever as características clínicas, diagnósticas e de tratamento da síndrome de febre periódica, estomatite aftosa, faringite e adenite (PFAPA). Fontes de dados: Revisão de literatura na base de dados PubMed, feita por meio de descritores específicos para identificar todos os artigos publicados em língua inglesa nos últimos três anos. Dos 38 artigos encontrados, foram encaminhados para leitura integral 13 publicações após seleção de títulos e análise de abstract. Estudos relevantes encontrados nas referências dos artigos revisados também foram incluídos. Síntese dos dados: A PFAPA é traduzida do inglês periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis. Caracterizada por etiologia ainda incerta e possivelmente multifatorial, seus sintomas são acompanhados por episódios recorrentes de febre associados a um desenvolvimento pôndero-estatural preservado. É uma doença autolimitada de curso benigno, com remissão em dois a três anos, sem interferências significativas no desenvolvimento do paciente pediátrico. O tratamento consiste em três pilares: interrupção da crise febril, aumento do intervalo entre crises e remissão. Conclusões: Apesar de várias tentativas de estabelecer critérios atuais mais sensíveis e específicos, o diagnóstico da síndrome PFAPA ainda é clínico e de exclusão com base nos critérios de Marshall modificados. As opções farmacológicas mais utilizadas para o tratamento são a prednisolona e betametasona; colchicina pode ser utilizada como profilaxia e o tratamento cirúrgico com tonsilectomia pode ser considerado em casos selecionados.

O estado da arte das síndromes autoinflamatórias associadas à criopirina / The state of the art of cryopyrin-associated periodic syndromes

As síndromes autoinflamatórias associadas à criopirina (CAPS) compreendem um grupo espectral de doenças raras autoinflamatórias. Todas estas doenças estão relacionadas ao inflamassoma NLRP3, sendo que de 50-60% dos pacientes apresentam mutações ao longo do gene NLRP3. Clinicamente, febre recorrente associada à urticária neutrofílica e outros sintomas sistêmicos são o grande marco clínico, comum a todo o espectro. O bloqueio da interleucina-1 trouxe grande alívio ao tratamento destas desordens, mas variações na resposta clínica podem ser observadas, principalmente nos espectros mais graves. Neste trabalho os autores trazem uma revisão do estado da arte das doenças autoinflamatórias CAPS. Foi realizado levantamento de literatura e, ao final, 49 artigos restaram como base para construção do texto final. O trabalho traz de forma narrativa os principais pontos relacionados a imunofisiopatologia, manifestação clínica, diagnóstico, tratamento, complicações e novas armas diagnósticas, e terapia gênica.

Cryopyrin-associated periodic syndromes (CAPS) comprise a spectrum of rare autoinflammatory disorders. They are all related to the NLRP3 inflammasome, and 50-60% of the patients harbor mutations along the NLRP3 gene. Clinically, recurrent fever associated with neutrophilic urticaria and other systemic symptoms are a hallmark of all the disorders in the spectrum. Biologic drugs that can block interleukin-1 were a milestone for the treatment of such rare diseases, although variability in clinical response to this therapeutic intervention were observed, especially in those affected by severe phenotypes. In this paper, the authors provide a state-of-the-art review of CAPS. A literature search was performed and, finally, 49 articles remained for the construction of the final manuscript. The article presents a narrative review focused on the topics related to immune pathophysiology, clinical manifestations, diagnosis, treatment, complications and new therapeutic options, and gene therapy.

Atualizando e expandindo o universo de: "Uma nova classe de doenças ­ doenças autoinflamatórias" / Updating and expanding the universe of: "A new class of diseases ­ autoinflammatory disorders"

As síndromes autoinflamatórias são doenças raras, genéticas de envolvimento prioritário da imunidade inata. Avanços nas técnicas de sequenciamento genético permitiram dissecar os genes envolvidos nestas doenças, continuamente organizando o quebra-cabeça genético e fisiopatológico de tais desordens. Este artigo revisa os últimos achados genéticos com seus respectivos fenótipos, código OMIM e ORPHA. Além disso, sugere cautela na triagem clínica e na indicação de métodos restritivos de sequenciamentos genéticos.

Autoinflammatory diseases comprise a group of rare, genetic disorders with priority involvement of innate immunity. Advances in genetic sequencing techniques allowed genetic dissection of genes involved in these diseases, with continuous organization of the genetic and pathophysiologic puzzle of these disorders. This article reviews the most recent genetic findings linked to respective phenotypes and OMIM and ORPHA codes. Moreover, it suggests caution in clinical screening and genetic sequencing indication with restrictive genetic panels.

Síndrome de Hiper IgD: espectros clínicos, achados genéticos e condutas terapêuticas / Hyper-IgD syndrome: clinical spectrum, genetic findings, and therapeutic approaches

A deficiência de mevalonato quinase (MVK; MIM #142680; ORPHA #343) é uma doença genética, espectral, rara, associadas a mutações ao longo do gene MVK causando distúrbios na síntese do colesterol, que culminam em: inflamação sistêmica com febre, adenopatia, sintomas abdominais e outros achados clínicos. Enquanto no polo leve da doença os achados mais comuns são febres recorrentes com linfadenopatia, no polo mais grave adiciona-se o acometimento do sistema nervoso central (meningites assépticas, vasculites e atraso do desenvolvimento neuropsicomotor) e do sistema hematopoiético (síndrome de ativação macrofágica). Apesar de inúmeras terapêuticas, os bloqueadores da interleucina-1 ainda são os únicos medicamentos capazes de controlar a doença e de impedir a evolução para amiloidose. Os estudos atuais visam tentar novos tratamentos, como o transplante de células-tronco hematopoiéticas, ou mesmo a terapia gênica.

Mevalonate kinase deficiency (MVK; MIM #142680; ORPHA #343) is a rare spectral genetic disorder linked to mutations along the MVK gene leading to impaired cholesterol synthesis, clinically observed as systemic inflammation with fever, adenopathy, abdominal manifestations, and other clinical findings. While on mild forms recurrent fever with lymphadenopathy is commonly observed, severe forms add to that neurological (aseptic meningitis, vasculitis, and neuropsychomotor developmental delay) and hematopoietic involvement (macrophage activation syndrome). Despite of several therapeutic approaches, blocking interleukin-1 is the only effective method to control the disease and prevent the development of systemic amyloidosis. Ongoing studies aim to test new treatments, such as hematopoietic stem cell transplantation and gene therapy.

Autoinflammatory diseases accompanied by vasculitis / 中华皮肤科杂志

Autoinflammatory diseases are a group of inherited disorders characterized by dysregulation of the immune system,periodic fever and reccurrence of inflammation.The common rashes of autoinflammatory diseases include acne,pyoderma gangrenosum,erysipelas,urticaria,ichthyosis,pustulosis,while vasculitis is rare.This review summarizes autoinflammatory diseases accompanied by vasculitis.Familial Mediterranean fever mainly manifests as small-and medium-vessel vasculitis such as Henoch-Sch(o)nlein purpura and polyarteritis nodosa,while large-vessel vasculitis is common in Blau syndrome.Small-and medium-artery vasculitis can occur in patients with deficiency of adenosine deaminase 2 as well,so it should be differentiated from polyarteritis nodosa in clinical practice.Stimulator of interferon gene-associated vasculopathy with onset in infancy mainly presents as cutaneous small-vessel vasculitis and vasculopathy.

Clinical characteristics of autoinflammatory diseases: a retrospective analysis in a single centre over a 5-year period / 中国实用内科杂志

OBJECTIVE: This study is aimed to evaluate the features in patients with autoinflammatory diseases and to assess the applicability of the international clinical diagnostic criteria for autoinflammatory diseases in these patients. METHODS: We retrospectively reviewed clinical data patients with autoinflammatory diseases in Peking University First Hospital within 5 year.RESULTS: Totally 50 patients were included. Eighteen patients experienced their first attack before 18 years of age, and 32 patients were with adult onset. The median age at onset was 25.5 years(range 1-74); 35(70%) cases experienced recurrent episodes of fever;15(30%) cases had continuous fever. Inflammatory markers were elevated in most patients during fever attack, and reduced in period with no symptoms. All of patients had one or more sequence variants(SVs). MEFV gene mutations were the most common and all SVs were heterozygous.The most frequent genotype was E148 Q(23 patients 50%).Only 5 MEFV SVs cases(10.8%)were up to the familial Mediterranean fever(FMF) Tel Hashomer clinical criteria. Totlly 7 patients were diagnosed with single-gene hereditary autoinflammatory disease. CONCLUSION: Most patients in the study didn't show typical clinical features or typical gene mutations. The international diagnostic criteria of autoinflammatory diseases is not applicable to the patients in this study.

A report of clinical characteristics of 2 Chinese pedigrees with haploinsufficiency of A20 and literature review / 中华儿科杂志

Objective@#To summarize the clinical characteristics of patients with haploinsufficiency of A20 (HA20).@*Methods@#The clinical manifestations, laboratory examinations, treatment, outcome and genetic analysis of 4 cases with HA20 hospitalized in Peking Union Medical College Hospital were analysed.Further literature review was done after searching articles in PubMed and Wangfang databases with the key words "HA20" "A20 haploinsufficiency" "TNFAIP3" up to the date of September 2019.@*Results@#The 4 patients were a father and a daughter, as well as a mother and a daughter. Their phenotypes were quite variable, but all of them have been suffering from recurrent oral ulcer since childhood. Elevation of C-reactive protein (13-33 mg/L) and erythrocyte sedimentation rate (21-60 mm/1h) were found in these 4 patients, and there was positive antinuclear antibody in proband 1.The father in pedigree 1 and the 2 patients in pedigrees 2 have been diagnosed with Behçet disease and the proband 1 with undifferentiated connective tissue disease. The 2 patients in pedigree 1 have developed Hashimoto′s thyroiditis. After gene sequencing analysis, it was found that all the 4 patients have heterozygous nonsense mutations in TNFAIP3 gene, that is, c.811C>T, p.R271X in pedigree 1 and c.133C>T, p.R45X in pedigree 2.The diagnosis of HA20 was eventually established when sequencing results and their clinical manifestations were both compatible with this disease.A total of 21 articles were retrieved, all in English, with a total of 91 cases from 39 families (including the 4 cases reported in this paper). HA20 was reported more often in female (57, 64.8%). Most patients develop symptoms from childhood, but as many as 53.4% (47 cases) are not correctly diagnosed until adulthood. Oral ulcers, genital ulcers, periodic fever, gastrointestinal symptoms, rashes, and arthritis are the primary manifestations.Hashimoto′s thyroiditis is the most common autoimmune diseases that HA20 patients coexist with. Laboratory tests were characterized by significantly elevated inflammatory markers and low to moderate titers of autoantibodies in some patients.Most HA20 patients were reported to have nonsense mutations or shift mutations of TNFAIP3 gene, which leads to truncation of A20 protein, and only a small number of patients have missense mutation. In terms of treatment, anti-TNF treatment and anti-interleukin 1 is believed to be an effective and the most optimal therapy. The treatment effect is variable and requires long term observations.@*Conclusions@#The clinical phenotypes of HA20 are complex. For patients with both autoinflammatory and autoimmune characteristics, family history should be inquired in detail and gene sequencing should be performed if necessary.

Clinical and genetic analysis of 11 cases with periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome / 中华儿科杂志

Objective@#To investigate the clinical, inflammatory and genetic characteristics of cases with periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome.@*Methods@#Clinical and inflammatory manifestations and gene sequencing of 11 cases with PFAPA were retrospectively analyzed. Inflammatory markers including white blood cell (WBC) , C reactive protein (CRP) , and serum amyloid A (SAA) were compared between febrile period and intermittent period. Fifteen normal children were taken as healthy controls. The levels of plasma inflammatory cytokines including interleukin(IL)1β, IL-6, IL-17, tumor necrosis factor(TNF)-α, interferon (IFN)-γ, and granulocyte-colony stimulating factor(G-CSF) were compared between febrile period and intermittent period with paired-sample t test, and compared between febrile cases and healthy controls with independent t test.@*Results@#A total of 11 cases (7 females and 4 males) were included. The median onset age was 24 (3-60) months, and the median age of diagnosis was 69 (11-151) months. The median febrile duration was 4 (1-8) days, and the intermittent period lasted 1 to 8 weeks. All the cases had periodic fever and pharyngitis/tonsillitis, 7 of whom had combined lymphadenitis, and 5 of whom suffered from oral ulcers. Compared to intermittent-period-status,WBC ((14.7±4.1) ×109/L vs. (8.4±1.9) ×109/L, P<0.05), CRP((24.2±21.1) vs. (3.3±2.1)mg/L, P<0.05), SAA ((136.4±47.7) vs. (7.1±1.1)mg/L, P<0.05) were significantly elevated in febrile period. Compared to intermittent-period-status and healthy controls, plasma levels of IL-6 ((38±10) vs. (8±4) and (8±5)ng/L, t=6.514 and 6.830 respectively, P<0.05), IFN-γ ((132±43) vs.(49±21) and (53±21)ng/L, t=4.069 and 4.276 respectively, P<0.05), G-CSF ((403±12) vs. (175±90) and (121±49)ng/L, t=4.219 and 9.047 respectively, P<0.05) were significantly higher in febrile period, while no differences were found in levels of IL-1β, IL-17 and TNF-α. Gene sequencing found MEFV gene heterozygous variation in 8 cases.@*Conclusions@#PFAPA often manifests as periodic fever, pharyngitis, tonsillitis, aphthous stomatitis and adenitis. Gene sequencing analysis, detection of inflammation markers and cytokines could help with the diagnose of this disease.

Clinical characteristics of adult patients with autoinflammatory diseases presenting as recurrent fever of unknown origin / 中华全科医师杂志

Objective To analyze the clinical characteristics of adult patients with autoinflammatory diseases(AUID)presenting as recurrent fever of unknown origin(FUO).Methods The clinical and genetic features of 51 adult patients with recurrent FUO,who were suspected of monogenic AUID admitted in adult AUID center Department of Rheumatology,Peking Union Medical College Hospital from April 2015 to March 2017, were prospectively studied.The clinical phenotypes were compared between patients with pathogenic gene mutations and diagnosed as monogenic AUID(gene-positive group), and those without pathogenic gene mutations(gene-negative group).Results Among 51 patients,there were 26 patients with positive monogenic mutations(51.0%); in addition 6 patients were diagnosed as periodic fever-aphthous stomatitis-pharyngitis-adenitis(PFAPA)syndrome.Finally 32 patients(63.0%)were diagnosed as AUID, including 11 cases of familial Mediterranean fever(34.4%), 5 cases of cryopyrin-associated periodic syndrome(15.6%), 5 cases of NLRP12-autoinflammtory disease(15.6%), 2 cases of Blau syndrome (6.3%),2 cases of Yao syndrome(6.3%),1 case of tumor necrosis factor-receptor associated periodic syndrome(3.1%),and 6 cases of PFAPA syndrome(18.8%).Among 25 gene-negative patients except 6 cases of PFAPA syndrome, 9 were diagnosed as other diseases, and the diagnosis of AUID was not confirmed in 10 cases(40.0%).Compared with gene-negative group, gene-positive group had more common childhood-onset(30.8%vs.8.0%,P=0.041),longer disease duration(11.2 ±10.1 vs.6.1 ± 5.9,P=0.031),and more common abdominal pain/diarrhea(42.3% vs.12.0%, P=0.015).There were no significant differences in manifestations such as rash, arthralgia/arthritis, thoracic pain, eye inflammation and oral ulcers between two groups.One patient had family history of AUID, and finally diagnosed as Blau syndrome with NOD 2 gene mutation.Conclusion AUID is one of the main causes of adult patients with recurrent FUO.Childhood-onset, long disease duration, abdominal pain/diarrhea, and family history of AUID are more common in patients with AUID pathogenic gene variations.Recognizing these symptom patterns can provide the clues, leading to the initiation of gene testing for patients with recurrent FUO.Adults patients with recurrent FUO suspected of AUID should be referred to specialist physicians in adult AUID center.

Fiebres recurrentes / Recurrent fevers

Resumen: Las fiebres recurrentes corresponden a una proporción significativa pero menospreciada (18-42%) de las fiebres de origen desconocido. Un grupo de fiebres recurrentes, conocidas como enfermedades autoinflamatorias o síndromes hereditarios de fiebre periódica ocurren debido a una respuesta disregulada de la inmunidad innata, en donde ocurre una reacción autoinflamatoria que causa daño tisular. A diferencia de las enfermedades autoinmunitarias, las enfermedades autoinflamatorias no se asocian con autoanticuerpos específicos o complejos mayores de histocompatibilidad (CMHs), pero ocurren debido a la activación aberrante de las células de la inmunidad innata, como macrófagos y neutrófilos. Aunque la mayoría de los casos inicia durante la infancia, varios suelen ser diagnosticados años después de su inicio o comienzan durante la edad adulta, lo que justifica la necesidad de que el internista esté familiarizado con estas afecciones. En esta revisión discutimos la epidemiología, fisiopatología, manifestación clínica, diagnóstico y tratamiento de las principales enfermedades autoinflamatorias.

Abstract: Recurrent fevers make up a significant yet underappreciated proportion (18-42%) of fevers of unknown origin. A group of recurrent fevers, known as autoinflammatory diseases or hereditary periodic fever syndromes occur due to a deregulated response of innate immunity, whereby an autoinflammatory reaction occurs resulting in tissue damage. Unlike autoimmune diseases, the autoinflammatory diseases are not associated to specific autoantibodies or major histocompatibility complexes (MHCs), but rather result from an aberrant activation of innate immune cells such as macrophages and neutrophils. Although the majority of cases begin during childhood, several are often diagnosed years after their debut or begin during adult life, justifying the need for internists to be familiar with these diseases. In this review we discuss the epidemiology, pathophysiology, clinical presentation, diagnosis and management of the main autoinflammatory diseases.

Uma nova classe de doenças: doenças autoinflamatórias / A new class of diseases: autoinflammatory diseases

As doenças autoinflamatórias sistêmicas são um grupo de doenças raras recentemente descritas, mas que vêm ganhando espaço no cenário clínico. Caracterizam-se por alterações da imunidade inata, portanto sem a presença de linfócito T autorreator ou autoanticorpo, e que respondem ao bloqueio de uma única citocina. Esta revisão tem como objetivo analisar a base imunofisiológica destas doenças e descrever brevemente cada uma delas com suas características clínicas mais importantes.

Systemic autoinflammatory diseases are a group of rare diseases only recently described but rapidly growing in importance in the clinical setting. They are characterized by innate immunity impairment, i.e., absence of autoreactive T lymphocytes or autoantibodies, and respond to individual cytokine blockade. The objective of this review was to analyze the immunophysiological basis of these diseases and to briefly describe each of them along with their most relevant clinical characteristics.

Doenças autoinflamatórias em adultos: abordagem prática ao diagnóstico baseada em um caso clínico / Autoinflammatory diseases in adults: practical approaches to diagnosis based on a clinical case

As doenças autoinflamatórias são doenças inflamatórias raras cujo cerne imunológico baseia-se na imunidade inata. A maioria das doenças autoinflamatórias tem início na idade pediátrica, mas pouco se sabe sobre as doenças que se iniciam na vida adulta. O diagnóstico é feito por exclusão, e, quando possível, com auxílio de técnicas moleculares. Este artigo tem como objetivo relatar um caso de doença autoinflamatória de início na vida adulta e a partir dele estabelecer fluxograma de auxílio ao diagnóstico.

Autoinflammatory diseases are rare inflammatory conditions whose immunopathology relies essentially on innate immunity. The majority of autoinflammatory diseases have their onset in childhood, but little is known about diseases that initiate in adulthood. Diagnosis is made by exclusion and with the aid of molecular techniques whenever possible. This article describes a case of autoinflammatory disease that started in adulthood, and aims to propose a flowchart to aid in the diagnosis of these conditions.

Skin symptoms as diagnostic clue for autoinflammatory diseases

ABSTRACT Autoinflammatory disorders are immune-mediated diseases with increased production of inflammatory cytokines and absence of detectable autoantibodies. They course with recurrent episodes of systemic inflammation and fever is the most common symptom. Cutaneous manifestations are prevalent and important to diagnosis and early treatment of the syndromes. The purpose of this review is to emphasize to dermatologists the skin symptoms present in these syndromes in order to provide their early diagnosis.

Research progresses of the effective mechanism of pyroptosis and its related diseases / 医学研究生学报

Pyroptosis is a newly discovered form of programmed cell death, which has a close relationship with infectious diseases and spontaneous inflammatory disease and autoimmune disease.Gasdermin-D is the effector of pyroptosis.Inflammatory caspases cleave Gasdermin-D, break the structural autoinhibition and active the pore-forming activity of Gasdermin-D.Gasdermin-D-N domain is the active form of Gasdermin-D.Oligomerized Gasdermin-D-N domain forms membrane pores.Both pyroptosis and necroptosis can form pores.In this article, the progress of the research on pyroptosis, the involvement of Gasdermin-D in the molecular mechanism of pyroptosis, the distinguishment of pyroptosis from necroptosis and pyroptosis-related diseases are reviewed.