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
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
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
Autoinflammatory diseases are characterized by inflammatory manifestations in various organ systems, whereby recurrent febrile episodes, musculoskeletal complaints, gastrointestinal and cutaneous symptoms frequently occur accompanied by serological signs of inflammation. Autoinflammatory diseases include rare monogenic entities and multifactorial or polygenic diseases, which can manifest as a variety of symptoms in the course of time. Examples of monogenic autoinflammatory diseases are familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) and the recently described VEXAS (vacuoles, E1 enzyme, Xlinked, autoinflammatory and somatic) syndrome. For non-monogenically determined autoinflammatory diseases, the most important representatives in adulthood are adult-onset Still's disease (AOSD) and the Schnitzler syndrome, in which a polygenic susceptibility and epigenetic factors are more likely to play a role.
Assuntos
Doenças Hereditárias Autoinflamatórias , Humanos , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/diagnóstico , Adulto , Síndrome , Febre de Causa Desconhecida/etiologia , Febre de Causa Desconhecida/genéticaAssuntos
Doenças Autoimunes , DNA , Interleucina-1beta , Humanos , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Interleucina-1beta/sangue , Doenças Transmissíveis/diagnóstico , Doenças Transmissíveis/imunologia , Feminino , Diagnóstico Diferencial , Masculino , Adulto , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/imunologia , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Monogenic autoinflammatory disorders result in a diverse range of neurological symptoms in adults, often leading to diagnostic delays. Despite the significance of early detection for effective treatment, the neurological manifestations of these disorders remain inadequately recognized. METHODS: We conducted a systematic review searching Pubmed, Embase and Scopus for case reports and case series related to neurological manifestations in adult-onset monogenic autoinflammatory diseases. Selection criteria focused on the four most relevant adult-onset autoinflammatory diseases-deficiency of deaminase 2 (DADA2), tumor necrosis factor receptor associated periodic fever syndrome (TRAPS), cryopyrin associated periodic fever syndrome (CAPS), and familial mediterranean fever (FMF). We extracted clinical, laboratory and radiological features to propose the most common neurological phenotypes. RESULTS: From 276 records, 28 articles were included. The median patient age was 38, with neurological symptoms appearing after a median disease duration of 5 years. Headaches, cranial nerve dysfunction, seizures, and focal neurological deficits were prevalent. Predominant phenotypes included stroke for DADA2 patients, demyelinating lesions and meningitis for FMF, and meningitis for CAPS. TRAPS had insufficient data for adequate phenotype characterization. CONCLUSION: Neurologists should be proactive in diagnosing monogenic autoinflammatory diseases in young adults showcasing clinical and laboratory indications of inflammation, especially when symptoms align with recurrent or chronic meningitis, small vessel disease strokes, and demyelinating lesions.
Assuntos
Síndromes Periódicas Associadas à Criopirina , Febre Familiar do Mediterrâneo , Doenças Hereditárias Autoinflamatórias , Meningite , Adulto Jovem , Humanos , Adulto , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Neurologistas , Adenosina Desaminase/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Febre Familiar do Mediterrâneo/genética , Síndromes Periódicas Associadas à Criopirina/genética , Febre , FenótipoRESUMO
OTULIN-related autoinflammatory syndrome (ORAS), a severe autoinflammatory disease, is caused by biallelic pathogenic variants of OTULIN, a linear ubiquitin-specific deubiquitinating enzyme. Loss of OTULIN attenuates linear ubiquitination by inhibiting the linear ubiquitin chain assembly complex (LUBAC). Here, we report a patient who harbors two rare heterozygous variants of OTULIN (p.P152L and p.R306Q). We demonstrated accumulation of linear ubiquitin chains upon TNF stimulation and augmented TNF-induced cell death in mesenchymal stem cells differentiated from patient-derived iPS cells, which confirms that the patient has ORAS. However, although the de novo p.R306Q variant exhibits attenuated deubiquitination activity without reducing the amount of OTULIN, the deubiquitination activity of the p.P152L variant inherited from the mother was equivalent to that of the wild-type. Patient-derived MSCs in which the p.P152L variant was replaced with wild-type also exhibited augmented TNF-induced cell death and accumulation of linear chains. The finding that ORAS can be caused by a dominant-negative p.R306Q variant of OTULIN furthers our understanding of disease pathogenesis.
Assuntos
Ubiquitinação , Feminino , Humanos , Endopeptidases/genética , Endopeptidases/metabolismo , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/patologia , Doenças Hereditárias Autoinflamatórias/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Mutação , Linhagem , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/genética , Ubiquitina/metabolismo , Recém-NascidoRESUMO
Undiagnosed monogenic diseases represent a challenging group of human conditions highly suspicious to have a genetic origin, but without conclusive evidences about it. We identified two brothers born prematurely from a non-consanguineous healthy couple, with a neonatal-onset, chronic disease characterized by severe skin and bone inflammatory manifestations and a fatal outcome in infancy. We conducted DNA and mRNA analyses in the patients' healthy relatives to identify the genetic cause of the patients' disease. DNA analyses were performed by both Sanger and next-generation sequencing, which identified two novel heterozygous IL1RN variants: the intronic c.318 + 2T>G variant in the father and a ≈2,600-bp intragenic deletion in the mother. IL1RN mRNA production was markedly decreased in both progenitors when compared with healthy subjects. The mRNA sequencing performed in each parent identified two novel, truncated IL1RN transcripts. Additional experiments revealed a perfect intrafamilial phenotype-genotype segregation following an autosomal recessive inheritance pattern. The evidences shown here supported for the presence of two novel loss-of-function (LoF) IL1RN pathogenic variants in the analyzed family. Biallelic LoF variants at the IL1RN gene cause the deficiency of interleukin-1 receptor antagonist (DIRA), a monogenic autoinflammatory disease with marked similarities with the patients described here. Despite the non-availability of the patients' samples representing the main limitation of this study, the collected evidences strongly suggest that the patients described here suffered from a lethal form of DIRA likely due to a compound heterozygous genotype at IL1RN, thus providing a reliable genetic diagnosis based on the integration of old medical information with currently obtained genetic data.
Assuntos
Heterozigoto , Proteína Antagonista do Receptor de Interleucina 1 , Mutação , Linhagem , Feminino , Humanos , Recém-Nascido , Masculino , Evolução Fatal , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/diagnóstico , Proteína Antagonista do Receptor de Interleucina 1/genética , FenótipoRESUMO
The number of human inborn errors of immunity has now gone beyond 430. The responsible gene variants themselves are apparently the cause for the disorders, but the underlying molecular or cellular mechanisms for the pathogenesis are often unclear. In order to clarify the pathogenesis, the mutant mice carrying the gene variants are apparently useful and important. Extensive analysis of those mice should contribute to the clarification of novel immunoregulatory mechanisms or development of novel therapeutic maneuvers critical not only for the rare monogenic diseases themselves but also for related common polygenic diseases. We have recently generated novel model mice in which complicated manifestations of human inborn errors of immunity affecting degradation or transport of intracellular proteins were recapitulated. Here, we review outline of these disorders, mainly based on the phenotype of the mutant mice we have generated.
Assuntos
Doenças Hereditárias Autoinflamatórias , Humanos , Animais , Camundongos , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/terapia , Citocinas/genética , Fenótipo , SíndromeRESUMO
VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic mutation) syndrome is a novel autoinflammatory, late-onset, disorder first identified in 2020. It is caused by mutations in the UBA1 gene. The most prominent clinical features reported by VEXAS patients are cutaneous and haematological, having characteristic skin features reported as the initial presenting findings of the disease. VEXAS is a severe and treatment-resistant condition with high morbidity and mortality rates. Here, we examine all case reports and case series of VEXAS syndrome through March 2023 focusing on those presenting cutaneous manifestations. We discuss these manifestations and their reported treatment strategies. In many cases, it might be first suspected and diagnosed by dermatologists, highlighting their vital role in initiating timely multidisciplinary care.
Assuntos
Doenças Hereditárias Autoinflamatórias , Síndromes Mielodisplásicas , Dermatopatias Genéticas , Humanos , Mutação , Pele , Síndrome , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/terapiaRESUMO
Tumor necrosis factor receptor-associated periodic syndrome (TRAPS, OMIM: #142680) is a rare autoinflammatory disease (AID) with recurrent febrile episodes. To our knowledge, we report herein the first case of a patient with TRAPS in South Korea whose symptoms included fever, arthralgia, abdominal pain, rash, myalgia, cough, and lymphadenopathy. A pathogenic de novo mutation, c.175T>C (p.Cys59Arg), in the tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) gene, was confirmed by gene sequencing. The patient has been with tocilizumab (an interleukin-6 inhibitor); tocilizumab administration every other week has completely alleviated the patient's symptoms. Our report further expands the clinical spectrum of patients with TRAPS and reaffirms the use of tocilizumab as a viable alternative treatment option for those patients who are unsatisfactorily responsive to other commonly used biologics, such as canakinumab, anakinra, infliximab, and etanercept. Furthermore, our report may aid in increasing awareness about the existence of mutation-confirmed TRAPS in South Korea in addition to emphasizing the importance of actively pursuing genetic testing to correctly diagnose rare AID.
Assuntos
Febre , Doenças Hereditárias Autoinflamatórias , Humanos , Febre/complicações , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Doenças Hereditárias Autoinflamatórias/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/uso terapêutico , Mutação , Etanercepte/uso terapêuticoRESUMO
BACKGROUND: VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is a hematoinflammatory disease that typically affects adults. It results from a somatic mutation of the E1 ubiquitin conjugating enzyme encoded by the UBA1 gene. VEXAS is frequently accompanied by myelodysplastic syndrome (MDS). The purpose of this study is to describe the ocular and orbital manifestations of VEXAS patients in a case series in our medical centre. METHODS: A retrospective chart review was performed for all patients who were diagnosed with VEXAS syndrome in a tertiary medical centre over two years. RESULTS: Eight patients were identified with VEXAS. In six patients, the diagnosis was confirmed by genomic sequencing. Two patients were identified based on their phenotype. All patients were males. The mean age at diagnosis was 78.7 years. In two patients, the ocular manifestation was the presenting symptom for VEXAS. Seven patients (87.5%) had history of MDS. Systemic inflammation manifestations include: skin rash (n = 5), recurrent fevers (n = 2), relapsing polychondritis (n = 2), pleuritis and pleural effusion (n = 2), poly arteritis nodosa- PAN (n = 1) and thrombophlebitis (n = 1). Seven (87%) patients were presented with periorbital oedema. Three patients showed orbital inflammation. Dacryoadenitis was observed in two patients, and extraocular muscle (EOM) myositis was detected in two patients. Four patients demonstrated ocular inflammation such as: episcleritis, scleritis and anterior uveitis. CONCLUSION: ocular manifestations in VEXAS include orbital inflammation, dacryoadenitis, myositis, uveitis, scleritis, episcleritis and periorbital oedema. We recommend that in old male patients, with history of haematological disorder, presenting with ocular symptom, VEXAS investigation should be taken into consideration.