RESUMO
Systemic autoinflammatory diseases (SAIDs) arise from dysregulated innate immune system activity, which leads to systemic inflammation. These disorders, encompassing a diverse array of genetic defects classified as inborn errors of immunity, are significant diagnostic challenges due to their genetic heterogeneity and varied clinical presentations. Although recent advances in genetic sequencing have facilitated pathogenic gene discovery, approximately 40% of SAIDs patients lack molecular diagnoses. SAIDs have distinct clinical phenotypes, and targeted therapeutic approaches are needed. This review aims to underscore the complexity and clinical significance of SAIDs, focusing on prototypical disorders grouped according to their pathophysiology as follows: (i) inflammasomopathies, characterized by excessive activation of inflammasomes, which induces notable IL-1ß release; (ii) relopathies, which are monogenic disorders characterized by dysregulation within the NF-κB signaling pathway; (iii) IL-18/IL-36 signaling pathway defect-induced SAIDs, autoinflammatory conditions defined by a dysregulated balance of IL-18/IL-36 cytokine signaling, leading to uncontrolled inflammation and tissue damage, mainly in the skin; (iv) type I interferonopathies, a diverse group of disorders characterized by uncontrolled production of type I interferons (IFNs), notably interferon α, ß, and ε; (v) anti-inflammatory signaling pathway impairment-induced SAIDs, a spectrum of conditions characterized by IL-10 and TGFß anti-inflammatory pathway disruption; and (vi) miscellaneous and polygenic SAIDs. The latter group includes VEXAS syndrome, chronic recurrent multifocal osteomyelitis/chronic nonbacterial osteomyelitis, Schnitzler syndrome, and Still's disease, among others, illustrating the heterogeneity of SAIDs and the difficulty in creating a comprehensive classification. Therapeutic strategies involving targeted agents, such as JAK inhibitors, IL-1 blockers, and TNF inhibitors, are tailored to the specific disease phenotypes.
Assuntos
Doenças Hereditárias Autoinflamatórias , Humanos , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Doenças Hereditárias Autoinflamatórias/diagnóstico , Inflamassomos/genética , Inflamação/genética , Transdução de Sinais , Interleucina-18/genética , Interleucina-1beta/genética , Interleucina-1beta/antagonistas & inibidores , NF-kappa B , Anemia Diseritropoética Congênita/genética , Anemia Diseritropoética Congênita/terapia , Anemia Diseritropoética Congênita/diagnóstico , Síndrome de Schnitzler/genética , Síndrome de Schnitzler/tratamento farmacológico , Síndrome de Schnitzler/diagnóstico , Osteomielite/genética , Osteomielite/tratamento farmacológico , Osteomielite/imunologia , Deficiência de Mevalonato Quinase/genética , Deficiência de Mevalonato Quinase/tratamento farmacológico , Deficiência de Mevalonato Quinase/diagnóstico , Síndromes de ImunodeficiênciaRESUMO
Cytokine Storm is a complex and heterogeneous state of life-threatening systemic inflammation and immunopathology. Autoinflammation is a mechanistic category of immune dysregulation wherein immunopathology originates due to poor regulation of innate immunity. The growing family of monogenic Systemic Autoinflammatory Diseases (SAIDs) has been a wellspring for pathogenic insights and proof-of-principle targeted therapeutic interventions. There is surprisingly little overlap between SAID and Cytokine Storm Syndromes, and there is a great deal to be inferred from those SAID that do, and do not, consistently lead to Cytokine Storm. This chapter will summarize how illustrations of the autoinflammatory paradigm have advanced the understanding of human inflammation, including the role of autoinflammation in familial HLH. Next, it will draw from monogenic SAID, both those with strong associations with cytokine storm and those without, to illustrate how the cytokine IL-18 links innate immune dysregulation and cytokine storm.
Assuntos
Síndrome da Liberação de Citocina , Imunidade Inata , Humanos , Síndrome da Liberação de Citocina/imunologia , Interleucina-18/imunologia , Interleucina-18/genética , Inflamação/imunologia , Doenças Hereditárias Autoinflamatórias/imunologia , Doenças Hereditárias Autoinflamatórias/genética , Animais , Citocinas/imunologia , Citocinas/metabolismoRESUMO
Advances in DNA sequencing technologies, especially next-generation sequencing (NGS), which is the basis for whole-exome sequencing (WES) and whole-genome sequencing (WGS), have profoundly transformed immune-mediated rheumatic disease diagnosis. Recently, substantial cost reductions have facilitated access to these diagnostic tools, expanded the capacity of molecular diagnostics and enabled the pursuit of precision medicine in rheumatology. Understanding the fundamental principles of genetics and diversity in genetic variant classification is a crucial milestone in rheumatology. However, despite the growing availability of DNA sequencing platforms, a significant number of autoinflammatory diseases (AIDs), neuromuscular disorders, hereditary collagen diseases, and monogenic bone diseases remain unsolved, and variants of uncertain significance (VUS) pose a formidable challenge to addressing these unmet needs in the coming decades. This article aims to provide an overview of the clinical indications and interpretation of comprehensive genetic testing in the medical field, addressing the related complexities and implications.
Assuntos
Testes Genéticos , Doenças Reumáticas , Humanos , Testes Genéticos/métodos , Doenças Reumáticas/genética , Doenças Reumáticas/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Reumatologia , Sequenciamento do Exoma , Doenças Neuromusculares/genética , Doenças Neuromusculares/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/diagnóstico , ReumatologistasRESUMO
Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a rare disease first reported in 2020, most commonly seen in men aged 56-75 years old. Common clinical features include skin lesions (83.5%), fever (63.6%), relapsing chondritis (36.4%), venous thrombosis (34.7%) and lymph node enlargement (33.9%). The patient is a man in his 40s who presented with testicular and lower extremity pain, followed by a rash and bicytopenia. He was initiated on corticosteroids and sulfasalazine. He was found to have mediastinal lymphadenopathy and underwent an endobronchial ultrasound and transbronchial needle aspiration followed by a video-assisted thoracic surgery biopsy which were unrevealing. Eventually, an ubiquitin-like modifier activating enzyme (UBA-1) gene analysis was performed that was consistent with VEXAS syndrome. Patients with VEXAS syndrome usually present with a red or violaceous rash and dyspnoea. Laboratory abnormalities include anaemia, elevated mean corpuscular volume, thrombocytopenia and elevated inflammatory markers. Diagnosis is based on the genetic mutation and associated symptoms. The treatment includes steroids and Janus kinase (JAK) inhibitors, specifically ruxolitinib.
Assuntos
Linfadenopatia , Humanos , Masculino , Linfadenopatia/etiologia , Adulto , Enzimas Ativadoras de Ubiquitina/genética , Doenças do Mediastino/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Diagnóstico Diferencial , Síndrome , Nitrilas , Pirazóis , PirimidinasRESUMO
Blau syndrome (BS) is a rare autoinflammatory granulomatosis characterized by granulomatous arthritis, uveitis, and dermatitis. Ocular complications are particularly severe in BS, significantly contributing to morbidity. This study aims to identify potential biomarkers for BS ocular degeneration through proteomic profiling of tear samples from affected patients. Seven subjects from the same family, including four carriers of the BS-associated NOD2 mutation (p.E383K), were recruited alongside healthy controls. Tear samples were collected using Schirmer strips and analyzed via mass spectrometry. A total of 387 proteins were identified, with significant differences in protein expression between BS patients, healthy familial subjects, and healthy controls. Key findings include the overexpression of alpha-2-macroglobulin (A2M) and immunoglobulin heavy constant gamma 4 (IGHG4) in BS patients. Bioinformatic analysis revealed that differentially expressed proteins are involved in acute-phase response, extracellular exosome formation, and protein binding. Notably, neutrophils' azurophilic granule components, as azurocidin (AZU1), myeloperoxidases (MPO), and defensins (DEFA3), were highly expressed in the most severely affected subject, suggesting a potential role of neutrophils in BS ocular severity. These proteins might be promising biomarkers for ocular involvement in BS, facilitating early detection and tailored treatment strategies.
Assuntos
Artrite , Biomarcadores , Proteômica , Sarcoidose , Sinovite , Lágrimas , Uveíte , Humanos , Lágrimas/metabolismo , Biomarcadores/metabolismo , Uveíte/metabolismo , Uveíte/genética , Uveíte/diagnóstico , Feminino , Masculino , Artrite/genética , Artrite/metabolismo , Sinovite/metabolismo , Sinovite/genética , Sarcoidose/genética , Sarcoidose/metabolismo , Adulto , Proteômica/métodos , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Adaptadora de Sinalização NOD2/metabolismo , Pessoa de Meia-Idade , Mutação , Proteoma/metabolismo , Doenças Hereditárias AutoinflamatóriasRESUMO
Blau syndrome is an autosomal dominant chronic inflammatory disease, which may begin with skin manifestations in the first months of life, alerting physicians to the diagnosis. This case reports a patient diagnosed jointly by pediatric dermatology and rheumatology consultants at two years of age.
Assuntos
Artrite , Sarcoidose , Sinovite , Uveíte , Humanos , Sinovite/genética , Sinovite/diagnóstico , Uveíte/diagnóstico , Sarcoidose/diagnóstico , Sarcoidose/patologia , Artrite/diagnóstico , Pré-Escolar , Masculino , Feminino , Artrite Infecciosa/diagnóstico , Doenças Hereditárias AutoinflamatóriasRESUMO
This case report presents the diagnostic journey of a man in his mid-70s who experienced shortness of breath, cough, recurrent episodes of fever, weight loss, pruritic erythroderma, uveitis and macrocytic anaemia. The initial diagnosis of cryptogenic organising pneumonia was made based on antibiotic refractory infiltrates seen in the lung CT scan. The patient initially responded favourably to immunosuppression but experienced a recurrence of symptoms when the corticosteroid dose was tapered. Despite ongoing systemic inflammation and refractory symptoms, it took nearly a year to establish the diagnosis of VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic) syndrome. This case highlights the challenges in diagnosing and managing VEXAS syndrome due to its recent discovery and limited awareness in the medical community, as well as the need to consider this syndrome as a rare differential diagnosis of therapy-refractory pulmonary infiltrates.
Assuntos
Tomografia Computadorizada por Raios X , Humanos , Masculino , Diagnóstico Diferencial , Idoso , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Tosse/etiologia , Dispneia/etiologia , Uveíte/diagnóstico , Uveíte/tratamento farmacológico , Febre/etiologia , Pulmão/diagnóstico por imagem , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Doenças Hereditárias Autoinflamatórias/complicações , Síndrome , Dermatite Esfoliativa/diagnóstico , Dermatite Esfoliativa/etiologia , Pneumonia em Organização Criptogênica/diagnóstico , Pneumonia em Organização Criptogênica/tratamento farmacológicoRESUMO
Systemic autoinflammatory diseases (SAID) are a growing family of disorders of the innate immune system. Over the years, there have been changes in the definition, classification and nomenclature of SAID as new syndromes and pathophysiologic mechanisms continue to be described. Recognizing the clinical manifestations of SAID is important for their early diagnosis and management. The field continues to advance with potential new therapies underway.
Assuntos
Doenças Hereditárias Autoinflamatórias , Humanos , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/classificação , Doenças Hereditárias Autoinflamatórias/terapia , Doenças Hereditárias Autoinflamatórias/imunologia , Criança , Imunidade InataRESUMO
Nucleotide-binding leucine-rich repeat-containing receptor 12-associated autoinflammatory disease (NLRP12-AID) is a rare autosomal dominant disorder. In this study, we reported a case of this rare disease with a novel NLRP12 mutation (A218V, rs749659859). The patient displayed typical symptoms, including recurrent fever, arthralgia, and skin allergies. Elevated serum IgE, decreased apolipoprotein A1, high-density lipoprotein cholesterol, and fluctuating levels of various leukocyte subtypes, procalcitonin, IL6, creatine kinase, and 25-hydroxyvitamin D were also detected. Inflammatory lesions were observed in multiple organs using 18F-FDG PET/CT. By mining single-cell transcriptome data, we identified relatively high expression of NLRP12 in monocytes compared to other human peripheral blood mononuclear cells. NLRP12-positive monocytes exhibited reduced expression of IL18, CCL3, and TNFA compared to NLRP12-negative monocytes. Structural analyses suggested that the A218V mutation, along with A218T and F402L, may reduce the ATP-binding affinity of the NLRP12 protein. These findings may provide new insights into the mechanisms of NLRP12-AID, and suggest the potential ATP-based therapy for further investigation.
Assuntos
Biologia Computacional , Doenças Hereditárias Autoinflamatórias , Mutação , Humanos , Biologia Computacional/métodos , Doenças Hereditárias Autoinflamatórias/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Monócitos/imunologia , Monócitos/metabolismo , Feminino , AdultoRESUMO
Importance: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly defined genetic disease with an estimated prevalence of 1 in 4269 men older than 50 years and is marked by systemic inflammation, progressive bone marrow failure, and inflammatory cutaneous manifestations. Objective: To define the spectrum of cutaneous manifestations in VEXAS syndrome and the association of these findings with clinical, genetic, and histological features. Design, Setting, and Participants: This observational cohort study included data from 112 patients who were diagnosed with VEXAS-defining genetic variants in UBA1 between 2019 and 2023. Data were collected from medical record review or from patients with VEXAS directly evaluated at the National Institutes of Health in Bethesda, Maryland. Main Outcomes and Measures: To define the spectrum of cutaneous manifestations in VEXAS in association with genetic, histological, and other clinical findings. A secondary outcome was cutaneous response to treatment in VEXAS. Results: Among the 112 patients (median [range] age, 69 [39-79] years; 111 [99%] male), skin involvement was common (93 [83%]), and the most frequent presenting feature of disease (68 [61%]). Of 64 histopathologic reports available from 60 patients, predominant skin histopathologic findings were leukocytoclastic vasculitis (23 [36%]), neutrophilic dermatosis (22 [34%]), and perivascular dermatitis (19 [30%]). Distinct pathogenic genetic variants were associated with specific cutaneous manifestations. The p.Met41Leu variant was most frequently associated with neutrophilic dermal infiltrates (14 of 17 patients [82%]), often resembling histiocytoid Sweet syndrome. In contrast, the p.Met41Val variant was associated with vasculitic lesions (11 of 20 patients [55%]) with a mixed leukocytic infiltrate (17 of 20 patients [85%]). Oral prednisone improved skin manifestations in 67 of 73 patients (92%). Patients with VEXAS treated with anakinra frequently developed severe injection-site reactions (12 of 16 [75%]), including ulceration (2 of 12 [17%]) and abscess formation (1 of 12 [8%]). Conclusions and Relevance: Results of this cohort study show that skin manifestations are a common and early manifestation of VEXAS syndrome. Genetic evaluation for VEXAS should be considered in older male patients with cutaneous vasculitis, neutrophilic dermatoses, or chondritis. Awareness of VEXAS among dermatologists is critical to facilitate early diagnosis.
Assuntos
Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Adulto , Estudos de Coortes , Pele/patologia , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/diagnóstico , Mutação , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Enzimas Ativadoras de UbiquitinaRESUMO
The aim of this study was to describe the clinical and molecular genetic findings in seven individuals from three unrelated families with Blau syndrome. A complex ophthalmic and general health examination including diagnostic imaging was performed. The NOD2 mutational hot spot located in exon 4 was Sanger sequenced in all three probands. Two individuals also underwent autoinflammatory disorder gene panel screening, and in one subject, exome sequencing was performed. Blau syndrome presenting as uveitis, skin rush or arthritis was diagnosed in four cases from three families. In two individuals from one family, only camptodactyly was noted, while another member had camptodactyly in combination with non-active uveitis and angioid streaks. One proband developed two attacks of meningoencephalitis attributed to presumed neurosarcoidosis, which is a rare finding in Blau syndrome. The probands from families 1 and 2 carried pathogenic variants in NOD2 (NM_022162.3): c.1001G>A p.(Arg334Gln) and c.1000C>T p.(Arg334Trp), respectively. In family 3, two variants of unknown significance in a heterozygous state were found: c.1412G>T p.(Arg471Leu) in NOD2 and c.928C>T p.(Arg310*) in NLRC4 (NM_001199139.1). In conclusion, Blau syndrome is a phenotypically highly variable, and there is a need to raise awareness about all clinical manifestations, including neurosarcoidosis. Variants of unknown significance pose a significant challenge regarding their contribution to etiopathogenesis of autoinflammatory diseases.
Assuntos
Artrite , Mutação , Proteína Adaptadora de Sinalização NOD2 , Linhagem , Sarcoidose , Sinovite , Uveíte , Humanos , Artrite/genética , Artrite/diagnóstico , Artropatia Neurogênica/genética , Artropatia Neurogênica/diagnóstico , Doenças do Sistema Nervoso Central , Sequenciamento do Exoma , Doenças Hereditárias Autoinflamatórias , Linfedema/genética , Linfedema/diagnóstico , Proteína Adaptadora de Sinalização NOD2/genética , Sarcoidose/genética , Sarcoidose/diagnóstico , Sinovite/genética , Sinovite/diagnóstico , Uveíte/genética , Uveíte/diagnósticoRESUMO
Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a recently characterized disease associated with somatic mutations in the UBA1 gene, which cause dysregulation of ubiquitin-mediated processes. This case describes a 71-year-old male patient with VEXAS syndrome who presented with refractory lung inflammation with a pattern similar to computed tomography hypersensitivity pneumonitis, a novel finding in VEXAS syndrome. The presented clinical case highlights the protean involvement of the lung in VEXAS syndrome and emphasizes the importance of considering interstitial lung disease in the differential diagnosis.
Assuntos
Alveolite Alérgica Extrínseca , Enzimas Ativadoras de Ubiquitina , Humanos , Masculino , Idoso , Alveolite Alérgica Extrínseca/genética , Alveolite Alérgica Extrínseca/diagnóstico , Enzimas Ativadoras de Ubiquitina/genética , Síndrome , Vacúolos , Diagnóstico Diferencial , Tomografia Computadorizada por Raios X , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/complicações , Mutação , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Pulmão/patologiaRESUMO
A girl in the early adolescent age group presented with multisystem manifestations in the form of periodic fever, recurrent abdominal pain, hypertension, seizure, skin lesions over the chest and gangrene over the left ring and middle fingertips. Her condition had remained undiagnosed for 11 years. On evaluation, she had features of polyarteritis nodosa (PAN) (multiple aneurysms, symmetric sensorimotor peripheral neuropathy, superficial ulcers, digital necrosis, myalgia, hypertension and proteinuria). As childhood PAN is a phenocopy of adenosine deaminase 2 with a different management strategy, whole-exome sequencing was performed, which revealed a pathogenic variant in ADA2 gene. The child was treated with TNF alpha inhibitors and showed improvement in the Paediatric Vasculitis Activity Score. The paper highlights the gratifying consequences of correct diagnosis with disease-specific therapy that ended the diagnostic odyssey, providing relief to the patient from debilitating symptoms and to the family from the financial burden of continued out-of-pocket health expenditure.
Assuntos
Adenosina Desaminase , Poliarterite Nodosa , Humanos , Poliarterite Nodosa/diagnóstico , Poliarterite Nodosa/tratamento farmacológico , Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Feminino , Diagnóstico Diferencial , Adolescente , Sequenciamento do Exoma , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Criança , Peptídeos e Proteínas de Sinalização IntercelularRESUMO
OBJECTIVES: The study is aimed to evaluate the impact of safety events in the Eurofever registry for Autoinflammatory diseases. METHODS: This was a retrospective and longitudinal observational multicentre study. Data were retrieved from the international registry Eurofever, starting patients' enrolment since 2009. All moderate, severe, or very severe AEs reported by treating physician in Eurofever were analyzed regardless of a possible suspected causal relationship to any therapies and according to the latest release of the Medical Dictionary for Regulatory Activities. RESULTS: Complete information on safety were available in 2464 patients enrolled in the registry. In 1499 of them retrospective data encompassing the period from disease onset to enrolment were available, whereas 965 consecutive patients entered in the longitudinal part of the study. A total of 479 AEs have been reported in 275 patients. Eighty-two AEs were reported as serious and 99 were drug-related according to the physicians. Infections or infestations (94; 19.6%), gastrointestinal disorders (66; 13.8%), nervous system disorders (41; 8.6%) and systemic disorders or administration site reactions (35; 7.3%) were the most frequent reported events. The highest absolute number of drug-related AEs were related to biologic DMARDs (40/99 reports, 40,4%) and colchicine (31/99 reports, 31.3%). CONCLUSIONS: Present study shows the importance of a longitudinal and homogeneous registration of the AEs in rare conditions, with a particular focus on the safety profile of the treatments used in these conditions.
Assuntos
Sistema de Registros , Humanos , Feminino , Masculino , Adulto , Estudos Retrospectivos , Adolescente , Estudos Longitudinais , Adulto Jovem , Pessoa de Meia-Idade , Criança , Pré-Escolar , Idoso , Doenças Hereditárias Autoinflamatórias/epidemiologia , Lactente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Europa (Continente)/epidemiologia , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricosRESUMO
Deficiency of Adenosine Deaminase 2 (DADA2) patients presenting with primary immunodeficiency are at risk of uncontrolled EBV infection and secondary malignancies including EBV-related lymphoproliferative disorders (LPD). This paper describes the first case of EBV related diffuse large B-cell lymphoma in a patient with DADA2 and uncontrolled EBV infection. Consideration should be given to monitoring for EBV viraemia and to preventative EBV specific therapy in DADA2 and patients with at risk primary immunodeficiencies. A type I interferon (IFN) gene signature is associated with DADA2 though its association with immune dysregulation is unclear.
Assuntos
Adenosina Desaminase , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/etiologia , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/genética , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico , Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Feminino , Doenças Hereditárias AutoinflamatóriasRESUMO
BACKGROUND: Systemic autoinflammatory disorders (SAIDs) represent a growing spectrum of diseases characterized by dysregulation of the innate immune system. The most common pediatric autoinflammatory fever syndrome, Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA), has well defined clinical diagnostic criteria, but there is a subset of patients who do not meet these criteria and are classified as undefined autoinflammatory diseases (uAID). This project, endorsed by PRES, supported by the EMERGE fellowship program, aimed to analyze the evolution of symptoms in recurrent fevers without molecular diagnosis in the context of undifferentiated AIDs, focusing on PFAPA and syndrome of undifferentiated recurrent fever (SURF), using data from European AID registries. METHODS: Data of patients with PFAPA, SURF and uSAID were collected from 3 registries including detailed epidemiological, demographic and clinical data, results of the genetic testing and additional laboratory investigations with retrospective application of the modified Marshall and PRINTO/Eurofever classification criteria on the cohort of PFAPA patients and preliminary SURF criteria on uSAID/SURF patients. RESULTS: Clinical presentation of PFAPA is variable and some patients did not fit the conventional PFAPA criteria and exhibit different symptoms. Some patients did not meet the criteria for either PFAPA or SURF, highlighting the heterogeneity within these groups. The study also explored potential overlaps between PFAPA and SURF/uAID, revealing that some patients exhibited symptoms characteristic of both conditions, emphasizing the need for more precise classification criteria. CONCLUSIONS: Patients with recurrent fevers without molecular diagnoses represent a clinically heterogeneous group. Improved classification criteria are needed for both PFAPA and SURF/uAID to accurately identify and manage these patients, ultimately improving clinical outcomes.