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Esgotamento Profissional , Medicina Interna , Resiliência Psicológica , Humanos , Medicina Interna/organização & administração , Medicina Interna/métodos , França/epidemiologia , Esgotamento Profissional/psicologia , Esgotamento Profissional/epidemiologia , Esgotamento Profissional/diagnósticoRESUMO
BACKGROUND: The objective was to assess the agreement between therapeutic proposals derived from basic critical care echocardiography performed by novice operators in ultrasonography after a limited training (residents) and by experts considered as reference. Secondary objectives were to assess the agreement between operators' answers to simple clinical questions and the concordance between basic two-dimensional measurements. METHODS: This observational, prospective, single-center study was conducted over a 3-year period in a medical-surgical intensive care unit. Adult patients with acute circulatory and/or respiratory failure requiring a transthoracic echocardiography (TTE) examination were studied. In each patient, a TTE was performed by a resident novice in ultrasonography after a short training program and by an expert, independently but within 1 h and in random order. Each operator addressed standardized simple clinical questions and subsequently proposed a therapeutic strategy based on a predefined algorithm. RESULTS: Residents performed an average of 33 TTE studies in 244 patients (156 men; age: 63 years [52-74]; SAPS2: 45 [34-59]; 182 (75%) mechanically ventilated). Agreement between the therapeutic proposals of residents and experienced operators was good-to-excellent. The concordance was excellent for suggesting fluid loading, inotrope or vasopressor support (all Kappa values > 0.80). Inter-observer agreement was only moderate when considering the indication of negative fluid balance (Kappa: 0.65; 95% CI 0.50-0.80), since residents proposed diuretics in 23 patients (9.5%) while their counterparts had the same suggestion in 35 patients (14.4%). Overall agreement of responses to simple clinical questions was also good-to-excellent. Intraclass correlation coefficient exceeded 0.75 for measurement of ventricular and inferior vena cava size. CONCLUSIONS: A limited training program aiming at acquiring the basic level in critical care echocardiography enables ICU residents novice in ultrasonography to propose therapeutic interventions with a good-to-excellent agreement with experienced operators.
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Granulomatous myositis is a clinical-pathological entity, which has been rarely reported, mostly described in sarcoidosis. Currently, no clear and simple prognostic factor has been identified to predict granulomatous myositis evolution. The clinical, anatomopathological, imaging, and biological characteristics of 26 patients with granulomatous myositis were retrospectively collected to describe clinical presentation and outcomes of this condition. Twenty-six patients with granulomatous myositis were included (14 males) with a median age of symptom onset of 65 years. 54 % of patients presented a severe form of the disease defined as a Rankin score ≥2 at last follow-up visit or a progressive form of the disease (no improvement under treatment). Etiology were sarcoidosis (n = 14), inclusion body myositis (n = 4), autoimmune disease (n = 1), hematological malignancy (n = 1), and idiopathic (n = 6). Distal deficit and amyotrophy were more frequent among those with a severe disease. Corticosteroids led to improvement in 75 % of cases, but 66 % of responders relapsed. Methotrexate appeared as a promising second line therapy with clinical improvement in 50 % of patients, and no relapse in responders. Granulomatous myositis is often a severe and difficult-to-treat disease in which patients frequently progress towards severe disability. The presence of muscle atrophy and distal weakness appears to be frequently associated with a severe form of the disease.
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Miosite , Humanos , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Miosite/patologia , Adulto , Sarcoidose/tratamento farmacológico , Sarcoidose/patologia , Metotrexato/uso terapêutico , Corticosteroides/uso terapêutico , Resultado do Tratamento , Granuloma/patologia , Idoso de 80 Anos ou maisRESUMO
OBJECTIVES: Vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease associated with somatic ubiquitin-like modifier-activating enzyme 1 (UBA1) mutations. We aimed to evaluate the efficacy and safety of targeted therapies. METHODS: Multicentre retrospective study including patients with genetically proven VEXAS syndrome who had received at least one targeted therapy. Complete response (CR) was defined by a clinical remission, C-reactive protein (CRP) ≤10 mg/L and a ≤10 mg/day of prednisone-equivalent therapy, and partial response (PR) was defined by a clinical remission and a 50% reduction in CRP levels and glucocorticoid dose. RESULTS: 110 patients (median age 71 (68-79) years) who received 194 targeted therapies were included: 78 (40%) received Janus kinase (JAK) inhibitors (JAKi), 51 (26%) interleukin (IL)-6 inhibitors, 33 (17%) IL-1 inhibitors, 20 (10%) tumour necrosis factor (TNFα) blockers and 12 (6%) other targeted therapies. At 3 months, the overall response (CR and PR) rate was 24% with JAKi, 32% with IL-6 inhibitors, 9% with anti-IL-1 and 0% with TNFα blockers or other targeted therapies. At 6 months, the overall response rate was 30% with JAKi and 26% with IL-6 inhibitors. Survival without treatment discontinuation was significantly longer with JAKi than with the other targeted therapies. Among patients who discontinued treatment, causes were primary failure, secondary failure, serious adverse event or death in 43%, 14%, 19% and 19%, respectively, with JAKi and 46%, 11%, 31% and 9%, respectively, with IL-6 inhibitors. CONCLUSIONS: This study shows the benefit of JAKi and IL-6 inhibitors, whereas other therapies have lower efficacy. These results need to be confirmed in prospective trials.
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NLRP3-associated autoinflammatory disease is a heterogenous group of monogenic conditions caused by NLRP3 gain-of-function mutations. The poor functional characterization of most NLRP3 variants hinders diagnosis despite efficient anti-IL-1 treatments. Additionally, while NLRP3 is controlled by priming and activation signals, gain-of-functions have only been investigated in response to priming. Here, we characterize 34 NLRP3 variants in vitro, evaluating their activity upon induction, priming, and/or activation signals, and their sensitivity to four inhibitors. We highlight the functional diversity of the gain-of-function mutants and describe four groups based on the signals governing their activation, correlating partly with the symptom severity. We identify a new group of NLRP3 mutants responding to the activation signal without priming, associated with frequent misdiagnoses. Our results identify key NLRP3 residues controlling inflammasome activity and sensitivity to inhibitors, and antagonistic mechanisms with broader efficacy for therapeutic strategies. They provide new insights into NLRP3 activation, an explanatory mechanism for NLRP3-AID heterogeneity, and original tools for NLRP3-AID diagnosis and drug development.
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Mutação com Ganho de Função , Proteína 3 que Contém Domínio de Pirina da Família NLR , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Mutação com Ganho de Função/genética , Inflamassomos/genética , Desenvolvimento de Medicamentos , SíndromeRESUMO
BACKGROUND/PURPOSE: To assess the efficacy and tolerance of hydroxychloroquine in sarcoidosis-associated uveitis. METHODS: Retrospective study on all patients with sarcoidosis-associated uveitis who were treated with hydroxychloroquine between 2003 and 2019 in a French university hospital. RESULTS: Twenty-seven patients with sarcoidosis-associated uveitis received hydroxychloroquine. The mean duration of treatment was 20.0 ± 10.9 months. At the end of the follow-up, hydroxychloroquine success was achieved in 15 (55.6%) patients. Four of them were also on oral corticosteroids, with a prednisone dose ≤5 mg/day. Under treatment, the median prednisone dose decreased from 20.0 (interquartile range (IQR), 7-25) to 5.0 (IQR, 3-6.5) mg/day (p = .02). The incidence rate of flare decreased from 204.6 to 63.8 per 100 person-years (p = .02). Hydroxychloroquine was discontinued in 12 (44.4%) patients during follow-up, including 8 (29.6%) for ineffectiveness, and three who experienced side effects. CONCLUSION: Hydroxychloroquine appears as an interesting option in sarcoidosis-associated uveitis.Abbreviations: AZA: Azathioprine; BAL: Bronchoalveolar Lavage; BCVA: Best-Corrected Visual Acuity; ENT: Ears, Nose and Throat; HCQ: Hydroxychloroquine; IOP: Intra-Ocular Pressure; IQR: interquartile range; MHC: Major Histocompatibility Complex; MMF: Mycophenolate Mofetil; MTX: Methotrexate; PMSI: Programme de Médicalisation du Système d'Information; SAU: Sarcoidosis-Associated Uveitis; SD: Standard Deviation; SUN: Standard Uveitis Nomenclature.
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Sarcoidose , Uveíte , Humanos , Imunossupressores/uso terapêutico , Prednisona/uso terapêutico , Hidroxicloroquina/uso terapêutico , Estudos Retrospectivos , Uveíte/complicações , Uveíte/diagnóstico , Uveíte/tratamento farmacológico , Metotrexato/uso terapêutico , Ácido Micofenólico/uso terapêutico , Ácido Micofenólico/efeitos adversos , Sarcoidose/complicações , Sarcoidose/diagnóstico , Sarcoidose/tratamento farmacológico , Resultado do TratamentoRESUMO
OBJECTIVE: FMF is the most common monogenic autoinflammatory disease associated with MEFV mutations. Disease phenotype and response to treatment vary from one patient to another, despite similar genotype, suggesting the role of environmental factors. The objective of this study was to analyse the gut microbiota of a large cohort of FMF patients in relation to disease characteristics. METHODS: The gut microbiotas of 119 FMF patients and 61 healthy controls were analysed using 16 s rRNA gene sequencing. Associations between bacterial taxa, clinical characteristics, and genotypes were evaluated using multivariable association with linear models (MaAslin2), adjusting on age, sex, genotype, presence of AA amyloidosis (n = 17), hepatopathy (n = 5), colchicine intake, colchicine resistance (n = 27), use of biotherapy (n = 10), CRP levels, and number of daily faeces. Bacterial network structures were also analysed. RESULTS: The gut microbiotas of FMF patients differ from those of controls in having increased pro-inflammatory bacteria, such as the Enterobacter, Klebsiella and Ruminococcus gnavus group. Disease characteristics and resistance to colchicine correlated with homozygous mutations and were associated with specific microbiota alteration. Colchicine treatment was associated with the expansion of anti-inflammatory taxa such as Faecalibacterium and Roseburia, while FMF severity was associated with expansion of the Ruminococcus gnavus group and Paracoccus. Colchicine-resistant patients exhibited an alteration of the bacterial network structure, with decreased intertaxa connectivity. CONCLUSION: The gut microbiota of FMF patients correlates with disease characteristics and severity, with an increase in pro-inflammatory taxa in the most severe patients. This suggests a specific role for the gut microbiota in shaping FMF outcomes and response to treatment.
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Clostridiales , Febre Familiar do Mediterrâneo , Microbioma Gastrointestinal , Humanos , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/genética , Febre Familiar do Mediterrâneo/complicações , Microbioma Gastrointestinal/genética , Genótipo , Colchicina/uso terapêutico , Fenótipo , Mutação , Pirina/genéticaRESUMO
Introduction: Severe Legionnaires' disease (LD) can lead to multi-organ failure or death in 10%-30% of patients. Although hyper-inflammation and immunoparalysis are well described in sepsis and are associated with high disease severity, little is known about the immune response in LD. This study aimed to evaluate the immune status of patients with LD and its association with disease severity. Methods: A total of 92 hospitalized LD patients were included; 19 plasmatic cytokines and pulmonary Legionella DNA load were measured in 84 patients on the day of inclusion (day 0, D0). Immune functional assays (IFAs) were performed from whole blood samples collected at D2 and stimulated with concanavalin A [conA, n = 19 patients and n = 21 healthy volunteers (HV)] or lipopolysaccharide (LPS, n = 14 patients and n = 9 HV). A total of 19 cytokines (conA stimulation) and TNF-α (LPS stimulation) were quantified from the supernatants. The Sequential Organ Failure Assessment (SOFA) severity score was recorded at D0 and the mechanical ventilation (MV) status was recorded at D0 and D8. Results: Among the 84 patients, a higher secretion of plasmatic MCP-1, MIP1-ß, IL-6, IL-8, IFN-γ, TNF-α, and IL-17 was observed in the patients with D0 and D8 MV. Multiparametric analysis showed that these seven cytokines were positively associated with the SOFA score. Upon conA stimulation, LD patients had a lower secretion capacity for 16 of the 19 quantified cytokines and a higher release of IL-18 and MCP-1 compared to HV. IL-18 secretion was higher in D0 and D8 MV patients. TNF-α secretion, measured after ex vivo LPS stimulation, was significantly reduced in LD patients and was associated with D8 MV status. Discussion: The present findings describe a hyper-inflammatory phase at the initial phase of Legionella pneumonia that is more pronounced in patients with severe LD. These patients also present an immunoparalysis for a large number of cytokines, except IL-18 whose secretion is increased. An assessment of the immune response may be relevant to identify patients eligible for future innovative host-directed therapies.
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Interleucina-18 , Doença dos Legionários , Humanos , Fator de Necrose Tumoral alfa , Lipopolissacarídeos , Doença dos Legionários/complicações , CitocinasRESUMO
PURPOSE: Determining uveitis etiology is a challenge. It is based primarily on demographic data and the characteristics of eye examination. It is not clear to what extent extraocular physical signs contribute to elucidating the etiology. This study aimed to establish the contribution of the clinical extra-ophthalmological features for the assessment of the underlying etiology of uveitis. METHODS: We retrospectively reviewed 1307 patients with uveitis referred to our tertiary center between 2003 and 2021. Uveitis was classified according to the Standardization of Uveitis Nomenclature. Clinical features were collected at diagnosis by internists before the etiological diagnosis was made. The main outcome description was the contribution of clinical features. RESULTS: Clinical extra-ophthalmological features contributed to the assessment of the underlying etiology of uveitis in 363 (27.8%) patients. The joint and the skin examinations were the most useful for etiological investigations, respectively in 12.3% and 11.8% of patients. Five etiologies of uveitis accounted for 80% of the cases: sarcoidosis, HLA-B27-related uveitis, Behçet's disease, multiple sclerosis, and Vogt-Koyanagi-Harada disease. Clinical extra-ophthalmological features were particularly important in the etiological diagnosis of acute bilateral anterior uveitis and panuveitis. CONCLUSION: This study suggests that clinical extra-ophthalmological features are essential for the etiological diagnosis of uveitis in more than a quarter of patients. It demonstrates once again the value of collaboration between ophthalmologists and other specialists experienced in performing extra-ophthalmological clinical examinations, particularly in patients with acute bilateral anterior uveitis and panuveitis.
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BACKGROUND AND AIM: Granulomatous hepatitis (GH) is associated with various aetiologies, especially inflammatory and infectious disorders. Sarcoidosis is a granulomatous disease in which the liver is the fourth most affected organ. Since epithelioid cell granulomas are not specific to sarcoidosis and since most patients with hepatic sarcoidosis are asymptomatic, valuable diagnostic biomarkers are needed to support the diagnosis of sarcoidosis. This study proposes to assess the diagnostic value of serum angiotensin converting enzyme (sACE) and lymphopenia in GH for sarcoidosis. METHODS: We retrospectively analyzed the records of 90 patients referred to the internal medicine or hepatogastroenterology departments of the Lyon University Hospital (Lyon, France) between March 2002 and January 2020 in a context of GH. RESULTS: In our tertiary center, 38 patients with sarcoidosis were identified among 73 patients with GH. Lymphopenia had a high specificity (85.7%), which increased when combined with elevated (97.0%). Interestingly, specificity increased in patients under 50 years old (100%). CONCLUSIONS: Those results suggests that lymphopenia and sACE may be valuable biomarkers for sarcoidosis diagnosis in GH when combined, especially in younger patients.
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H syndrome is a rare autosomal recessive genetic disorder characterized by the following clinical features: cutaneous hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, short stature, hallux valgus, hyperglycemia, fixed flexion contractures of the toe joints, and the proximal interphalangeal joints. In rare cases, autoinflammatory and lymphoproliferative manifestations have also been reported. This disorder is due to loss-of-function mutations in SLC29A3 gene, which encode the equilibrative nucleoside transporter ENT3. This deficiency leads to abnormal function and proliferation of histiocytes. H syndrome is part of the R-group of histiocytosis. We report two different cases, one was diagnosed in adulthood and the other in childhood. The first case reported is a 37-year-old woman suffering from H syndrome with an autoinflammatory systemic disease that begins in adulthood (fever and diffuse organ's infiltration) and with cutaneous, articular, auditory, and endocrinological manifestations since childhood. The second case reported is a 2-year-old girl with autoinflammatory, endocrine, and cutaneous symptoms (fever, lymphadenopathy, organomegaly, growth delay, and cutaneous hyperpigmentation). Homozygous mutations in SLC29A3 confirmed the diagnosis of H syndrome in both cases. Each patient was treated with Tocilizumab with a significant improvement for lymphoproliferative, autoinflammatory, and cutaneous manifestations. Both cases were reported to show the multiple characteristics of this rare syndrome, which can be diagnosed either in childhood or in adulthood. In addition, an overview of the literature suggested Tocilizumab efficiency.
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Contratura , Perda Auditiva Neurossensorial , Histiocitose , Feminino , Humanos , Adulto , Pré-Escolar , Histiocitose/diagnóstico , Histiocitose/tratamento farmacológico , Histiocitose/genética , Febre , Proteínas de Transporte de Nucleosídeos/genéticaRESUMO
The recently discovered VEXAS syndrome is caused by the clonal expansion of hematopoietic stem or progenitor cells with acquired mutations in UBA1 gene, which encodes for a key enzyme of the ubiquitylation proteasome system. As a result, a shorter cytoplasmic isoform of UBA1 is transcribed, which is non-functional. The disease is characterized by non-specific and highly heterogeneous inflammatory manifestations and macrocytic anemia. VEXAS syndrome is a unique acquired hematological monogenic disease with unexpected association with hematological neoplasms. Despite its hematopoetic origin, patients with VEXAS syndrome usually present with multi-systemicinflammatory disease and are treated by physicians from many different specialties (rheumatologists, dermatologists, hematologistis, etc.). Furthermore, manifestations of VEXAS may fulfill criteria for existing diseases: relapsing polychondritis, giant cell arteritis, polyarteritis nodosa, and myelodysplastic syndrome. The goal of this review is to depict VEXAS syndrome from a hematologic point of view regarding its consequences on hematopoiesis and the current strategies on therapeutic interventions.
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Arterite de Células Gigantes , Síndromes Mielodisplásicas , Humanos , Mutação/genética , Complexo de Endopeptidases do ProteassomaRESUMO
Sarcoidosis is an inflammatory disease that involves the eyes in 10-55% of cases, sometimes without systemic involvement. All eye structures can be affected, but uveitis is the most common ocular manifestation and causes vision loss. The typical ophthalmological appearance of these uveitis is granulomatous (in cases with anterior involvement), which are usually bilateral and with synechiae. Posterior involvement includes vitritis, vasculitis and choroidal lesions. Tuberculosis is a classic differential diagnosis to be wary of, especially in people who have spent time in endemic areas. The diagnosis is based on histology with the presence of non-caseating epithelioid granulomas. However, due to the technical difficulty and yield of biopsies, the diagnosis of ocular sarcoidosis is often based on clinico-radiological features. The international criteria for the diagnosis of ocular sarcoidosis have recently been revised. Corticosteroids remain the first-line treatment for sarcoidosis, but up to 30% of patients require high doses, justifying the use of corticosteroid-sparing treatments. In these cases, immunosuppressive treatments such as methotrexate may be introduced. More recent biotherapies such as anti-TNF are also very effective (as they are in other non-infectious uveitis etiologies).
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INTRODUCTION: The recent description of VEXAS (for vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) challenges the nosological framework of myelodysplastic syndromes. AREAS COVERED: Clonal expansion driven by somatic mutations in cancer genes has been largely described in healthy aging individuals. Regarding hematopoiesis, the prevalence of clonal hematopoiesis has blurred the line between normal and pathological, especially for the definition of myelodysplastic syndromes. VEXAS syndrome further challenges the nosology as this clonal disease of hematopoiesis is also associated with dysplastic features and cytopenias. EXPERT OPINION: In this perspective, we discuss whether VEXAS should be considered a genuine myelodysplastic syndrome and propose a conceptual framework to refine the nosology, based on the distinction of clonal hematopoiesis of indeterminate potential (CHIP), clonal hematopoiesis of hematological significance, and clonal hematopoiesis of other significance.
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Hematopoiese Clonal , Síndromes Mielodisplásicas , Humanos , Hematopoiese Clonal/genética , Mutação , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Hematopoese/genéticaRESUMO
INTRODUCTION: The definite diagnosis of neurosarcoidosis is challenging since it requires a compatible histology of the nervous system. When neurosarcoidosis is suspected, other systemic manifestations are investigated to confirm the diagnosis. A minor salivary gland biopsy (MSGB) is often performed since it is minimally invasive. The objective of the present study was to assess its performance for the diagnosis of neurosarcoidosis. METHODS: A retrospective single-center study included patients who underwent a MSGB in a tertiary neurological university hospital (Lyon, France) between 2015 and 2018. Clinical presentations unlikely to be compatible with neurosarcoidosis were excluded. Positive cases of neurosarcoidosis were defined as definite, probable, and possible cases, according to the latest international neurosarcoidosis diagnostic criteria from the Neurosarcoidosis Consortium Consensus Group. RESULTS: A total of 529 patients underwent a MSGB for clinical manifestations compatible with neurosarcoidosis. Among the 13 who fulfilled the criteria for neurosarcoidosis, only one had a positive MSGB. The sensitivity of MSGB was 7.7% (95% CI [0.2-36.0%]) and the specificity was 100.0% (95% CI [99.3-100%]). CONCLUSION: Considering the low sensitivity of MSGB for the diagnosis of NS, MSGB should be performed in selected indications, including a suspicion of spinal cord sarcoidosis, or when there is a strong clinical, laboratory, and radiological suspicion of NS. MSGB should rather not be performed when the chest CT-scan does not show signs of pulmonary or lymph node sarcoidosis.
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Doenças do Sistema Nervoso Central , Sarcoidose , Humanos , Estudos Retrospectivos , Glândulas Salivares Menores/patologia , Doenças do Sistema Nervoso Central/diagnóstico , Sarcoidose/diagnóstico , Sarcoidose/patologia , BiópsiaRESUMO
Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disorder. FMF is caused by mutations in the MEFV gene, encoding pyrin, an inflammasome sensor. The best characterized pathogenic mutations associated with FMF cluster in exon 10. Yet, mutations have been described along the whole MEFV coding sequence. Exon 10 encodes the B30.2 domain of the pyrin protein, but the function of this human-specific domain remains unclear. Pyrin is an inflammasome sensor detecting RhoA GTPase inhibition following exposure to bacterial toxins such as TcdA. Here, we demonstrate that the B30.2 domain is dispensable for pyrin inflammasome activation in response to this toxin. Deletion of the B30.2 domain mimics the most typical FMF-associated mutation and confers spontaneous inflammasome activation in response to pyrin dephosphorylation. Our results indicate that the B30.2 domain is a negative regulator of the pyrin inflammasome that acts independently from and downstream of pyrin dephosphorylation. In addition, we identify the central helical scaffold (CHS) domain of pyrin, which lies immediately upstream of the B30.2 domain as a second regulatory domain. Mutations affecting the CHS domain mimic pathogenic mutations in the B30.2 domain and render the pyrin inflammasome activation under the sole control of the dephosphorylation. In addition, specific mutations in the CHS domain strongly increase the cell susceptibility to steroid catabolites, recently described to activate pyrin, in both a cell line model and in monocytes from genotype-selected FMF patients. Taken together, our work reveals the existence of two distinct regulatory regions at the C-terminus of the pyrin protein, that act in a distinct manner to regulate positively or negatively inflammasome activation. Furthermore, our results indicate that different mutations in pyrin regulatory domains have different functional impacts on the pyrin inflammasome which could contribute to the diversity of pyrin-associated autoinflammatory diseases.
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Febre Familiar do Mediterrâneo , Inflamassomos , Pirina , Humanos , Febre Familiar do Mediterrâneo/genética , Febre Familiar do Mediterrâneo/metabolismo , Inflamassomos/genética , Inflamassomos/metabolismo , Mutação , Pirina/genética , Pirina/metabolismoRESUMO
PURPOSE OF REVIEW: Two years after the recognition of VEXAS (for Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, we propose an extensive review of the current understanding of VEXAS pathophysiology and therapeutic options. RECENT FINDINGS: Among the nearly 150 articles published about VEXAS, some have provided determinant insights into VEXAS pathophysiology and treatment. Clinical data from retrospective series support the JAK inhibitor ruxolitinib as the most efficient strategy to control inflammation, and interesting results were also described with azacytidine. Allogeneic stem cell transplantation remains the only curative option, but should be proposed to carefully selected patients. SUMMARY: Although waiting for more robust evidence from prospective clinical trials, therapeutic options emerge from retrospective studies. We propose a set of criteria that should be systematically reported to harmonize the evaluation of therapeutic outcomes. This will allow the collection of high-quality data and facilitate their subsequent meta-analysis with the overall aim of improving the management of VEXAS patients.
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Azacitidina , Transplante de Células-Tronco Hematopoéticas , Humanos , Mutação , Estudos Prospectivos , Estudos RetrospectivosRESUMO
Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome with an overall mortality rate of 40%. A multiple-cause-of-death analysis allows for the characterization of mortality and associated causes over an extended period. Death certificates, collected between 2000 and 2016 by the French Epidemiological Centre for the Medical Causes of Death (CepiDC, Inserm), containing the ICD10 codes for HLH (D76.1/2), were used to calculate HLH-related mortality rates and to compare them with the general population (observed/expected ratios, O/E). HLH was mentioned in 2072 death certificates as the underlying cause of death (UCD, n = 232) or as a non-underlying cause of death (NUCD, n = 1840). The mean age at death was 62.4 years. The age-standardized mortality rate was 1.93/million person-years and increased over the study period. When HLH was an NUCD, the most frequently associated UCDs were hematological diseases (42%), infections (39.4%), and solid tumors (10.4%). As compared to the general population, HLH decedents were more likely to have associated CMV infections or hematological diseases. The increase in mean age at death over the study period indicates progress in diagnostic and therapeutic management. This study suggests that the prognosis of HLH may be at least partially related to coexisting infections and hematological malignancies (either as causes of HLH or as complications).