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CD4+Foxp3+ regulatory T (Treg) cells are central modulators of autoimmune diseases. However, the timing and location of Treg cell-mediated suppression of tissue-specific autoimmunity remain undefined. Here, we addressed these questions by investigating the role of tumor necrosis factor (TNF) receptor 2 (TNFR2) signaling in Treg cells during experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. We found that TNFR2-expressing Treg cells were critical to suppress EAE at peak disease in the central nervous system but had no impact on T cell priming in lymphoid tissues at disease onset. Mechanistically, TNFR2 signaling maintained functional Treg cells with sustained expression of CTLA-4 and Blimp-1, allowing active suppression of pathogenic T cells in the inflamed central nervous system. This late effect of Treg cells was further confirmed by treating mice with TNF and TNFR2 agonists and antagonists. Our findings show that endogenous Treg cells specifically suppress an autoimmune disease by acting in the target tissue during overt inflammation. Moreover, they bring a mechanistic insight to some of the adverse effects of anti-TNF therapy in patients.
Assuntos
Encefalomielite Autoimune Experimental/imunologia , Esclerose Múltipla/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Medula Óssea/patologia , Antígeno CTLA-4/metabolismo , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/patologia , Humanos , Camundongos , Camundongos Knockout , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/agonistas , Receptores Tipo II do Fator de Necrose Tumoral/antagonistas & inibidores , Receptores Tipo II do Fator de Necrose Tumoral/genética , Transdução de Sinais/imunologia , Linfócitos T Reguladores/metabolismoRESUMO
Therapeutic management of acquired von Willebrand syndrome (AVWS) can be challenging, particularly in cases of AVWS associated with monoclonal IgM such as Waldenström macroglobulinemia (WM) where several therapeutic options may be ineffective. Here, we describe the case of an 88-year-old patient who developed AVWS during follow-up for WM. The presence of a severe bleeding symptomatology not controlled by several therapies (plasma-derived von Willebrand factor, plasmapheresis) led us to introduce a supplementation with recombinant von Willebrand factor, vonicog α (Veyvondi, Takeda, Japan), starting at a dose of 50 IU/kg/d. This supplementation allowed clinical (no further bleeding) and biological (hemoglobin level, von Willebrand factor parameters) improvements. Because of the persistence of bleeding risk factors, the treatment was maintained at a prophylactic dose (20 UI/kg three times a week), without recurrence of bleeding events for a period of 9 months.
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We aimed to review the clinical and biological presentation of granulomatosis associated with immune-checkpoint inhibitors (ICI) in patients with melanoma and to explore its association with classical sarcoidosis as well as with cancer response to ICI. To this end, a retrospective study on 18 melanoma patients with histologically proven ICI-induced granulomatosis over a 12-year period in a single center, as well as on 67 similar cases reported in the literature, was conducted. Results indicate ICI-induced granulomatosis is an early side effect (median time to onset: 2 months). Its clinical presentation, with predominant (90%) thoracic involvement, histopathological appearance and supposed underlying biology (involving the mTOR pathway in immune cells, Th17 polarization and TReg dysfunction) are indistinguishable from those of sarcoidosis. Moreover, it appears to be associated with ICI benefit (>65% objective response rate). Evolution is generally favorable, and symptomatic steroid treatment and/or ICI discontinuation are rarely necessary. ICI-associated granulomatosis is critical to explore for several reasons. Practically, it is essential to differentiate it from cancer progression. Secondly, this "experimental" sarcoidosis brings new elements that may help to address sarcoidosis origin and pathophysiology. Its association with ICI efficacy must be confirmed on a larger scale but could have significant impacts on patient management and biomarker definition.
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OBJECTIVE: To analyse the clinical patterns of sarcoidosis triggered by immune checkpoint inhibitors (ICIs) in patients with cancer. PATIENTS AND METHODS: The ImmunoCancer International Registry is a big data-sharing multidisciplinary network from 18 countries dedicated to evaluating the clinical research of immune-related adverse events related to cancer immunotherapies. RESULTS: We identified 32 patients with biopsy-proven sarcoidosis. Underlying cancer included mainly melanoma (n = 24). Cancer immunotherapy consisted of monotherapy in 19 cases (anti-PD-1 in 18 and ipilimumab in 1) or combined ipilimumab + nivolumab in 13. The time median interval between initiation of ICI and sarcoidosis diagnosis was 3 months (range, 2-29 months). The use of combined ICI was associated with a shorter delay in developing sarcoidosis symptoms. The disease was symptomatic in 19 (59%) cases with mostly cutaneous, respiratory and general symptoms. The organs involved included mainly the mediastinal lymph nodes (n = 32), the lungs (n = 11), the skin (n = 10) and the eyes (n = 5). Pulmonary computed tomography studies showed bilateral hilar lymphadenopathy in all cases. There was no severe manifestation. Specific systemic therapy was required in only 12 patients (37%): oral glucocorticoids in 9, and hydroxychloroquine in 3. ICIs were held in 25 patients (78%) and definitively discontinued in 18 (56%) patients. Seven patients continued ICI treatment with a second flare in one case. In six additional patients, an ICI was reintroduced with no harm, and sarcoidosis relapsed in one of them. CONCLUSION: Our study shows that ICI-related sarcoidosis seems to have a specific profile, possibly more benign than that of idiopathic sarcoidosis, and does not necessarily imply ICI discontinuation.
Assuntos
Inibidores de Checkpoint Imunológico/administração & dosagem , Imunoterapia/efeitos adversos , Sarcoidose/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Biópsia , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Ipilimumab/efeitos adversos , Ipilimumab/uso terapêutico , Pulmão/efeitos dos fármacos , Linfonodos/efeitos dos fármacos , Masculino , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Nivolumabe/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Adulto JovemRESUMO
PURPOSE: Sarcoid-like granulomatosis (SLG) reaction caused by immunotherapy remains poorly understood. This study aims to investigate the outcome of patients with cancer and SLG associated with immunotherapy. PATIENTS AND METHODS: Between April 2016 and June 2020, 434 patients with immunological adverse events were screened from the ImmunoTOX assessment board of Gustave Roussy, an academic cancer centre in France. Among them, 28 patients had SLG associated with immunotherapy (SLG cohort) and 406 patients had other immunological adverse events (control cohort). Clinical characteristics and outcome of patients were compared from SLG and control cohort. RESULTS: The SLG cohort consisted of 28 patients, 14 women and 14 men, with the median (range) age of 56.5 (28.7-75.3) years. Patients in the SLG cohort with sarcoidosis were asymptomatic (only radiographical finding) in 13 (46.4%) cases; otherwise, the most frequent symptoms were dyspnoea in 8 (28.6%) patients and cough in 5 (17.8%) patients. The computerised tomography scan found sarcoidosis localisations in mediastinal or peri-hilar thoracic lymph nodes in 26 (92.9%) patients, and lung parenchymal involvement was found in 14 (50.0%) patients. The radiographic Scadding stages for sarcoidosis classification were distributed in stages 0, I, II, III and IV in 2 patients (7.1%), 13 patients (46.4%), 11 patients (39.3%), 1 patient (3.6%) and 1 patient (3.6%), respectively. Compared with patients with other immunological toxicities (cohort control), patients with sarcoidosis presented most frequently with melanoma (75.0% versus 21.9% of patients; p < 0.001) and more often received combined therapies of anti-programmed cell death 1 plus anti-cytotoxic T-lymphocyte antigen 4 protein (46.4% versus 12.6% of patients; p = 0.002). Patients with sarcoidosis had an improved overall survival (OS); the median OS was not reached in the SLG cohort and 40.4 months in the control cohort, hazard ratio = 0.232 (95% confidence interval: 0.086-0.630) (p = 0.002). CONCLUSION: Sarcoidosis-like reactions in patients receiving immunotherapy were reported as non-severe immunological reactions in most cases and were correlated with improved OS. SLG should not be misdiagnosed as tumour progression in patients receiving immunotherapy treatment for cancer.
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Granuloma/induzido quimicamente , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias/tratamento farmacológico , Sarcoidose/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno CTLA-4/antagonistas & inibidores , Feminino , Granuloma/diagnóstico por imagem , Granuloma/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico por imagem , Neoplasias/imunologia , Neoplasias/mortalidade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Sarcoidose/diagnóstico por imagem , Sarcoidose/mortalidade , Índice de Gravidade de Doença , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Adulto JovemRESUMO
Type 2 heparin-induced thrombocytopenia (HIT 2) is a rare pro-thrombotic disorder occurring in patients treated with heparin. It is defined as a clinical-biological syndrome associating the sudden onset of a thrombocytopenia, characterized by a drop of more than 50% of the initial platelet count, and thrombosis. We report two cases of HIT 2 occurring in patients with major bleeding tendency. The first HIT occurred in a patient whose management, in accordance with current guidelines, made it possible to control the thrombocytopenia and the anticoagulation despite the complexity of adapting and monitoring treatments in the context of recent cerebral hemorrhage. The second refers to an autoimmune HIT, which occurred in a patient whose management required the use of alternative therapies to the standard treatments suggested for HIT 2, to correct the severe refractory thrombocytopenia.
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Transtornos da Coagulação Sanguínea/terapia , Hemorragia/prevenção & controle , Heparina/efeitos adversos , Trombocitopenia/induzido quimicamente , Trombocitopenia/terapia , 4-Hidroxicumarinas/administração & dosagem , Idoso , Anticoagulantes/efeitos adversos , Arginina/administração & dosagem , Arginina/análogos & derivados , Transtornos da Coagulação Sanguínea/complicações , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Hemorragia/etiologia , Humanos , Indenos/administração & dosagem , Trombose Intracraniana/tratamento farmacológico , Trombose Intracraniana/etiologia , Trombose Intracraniana/cirurgia , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos/métodos , Ácidos Pipecólicos/administração & dosagem , Sulfonamidas/administração & dosagem , Vitamina K/administração & dosagem , Vitamina K/antagonistas & inibidoresRESUMO
CASE PRESENTATION: A 27-year-old Lebanese man was admitted to our department for multiple pulmonary lesions. The patient had reported persistent fever, cough, shortness of breath, and weight loss since his return from Lebanon 6 weeks earlier. He had been diagnosed with a severe form of Behçet disease 4 years ago, for which the ongoing treatment was a corticosteroid therapy associated with methotrexate and infliximab.
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Actinomicose/diagnóstico por imagem , Pneumopatias/diagnóstico por imagem , Actinomicose/complicações , Actinomicose/terapia , Adulto , Humanos , Pneumopatias/complicações , Pneumopatias/terapia , Masculino , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: To describe the clinical presentation, distribution of lesions, treatment, and outcomes of osseous sarcoidosis. METHODS: A French retrospective multicenter study of patients with biopsy-proven sarcoidosis analyzed patients with 1) a biopsy-proven granuloma without caseous necrosis, and either 2) osseous clinical manifestations, or 3) abnormal osseous imaging. Sarcoidosis patients with osseous involvement (cases) were compared with 264 age- and sex-matched sarcoidosis patients with no osseous manifestations (controls). RESULTS: In the osseous sarcoidosis group (n=88), forty-two (48%) patients had osseous-related symptoms involving the axial (69%) and/or appendicular (58%) skeleton. On imaging, the most commonly affected bones were in the spine (52%), pelvis (42%), hands (22%) and femur (19%). Compared with controls, cases had higher rates of mediastinal (93% vs. 47%) and extra-thoracic lymph node involvement (66% vs. 21%), pulmonary (90% vs. 65%) and cutaneous involvement (44% vs. 23%) (all P<0.0001), and hypercalcemia (8.5% vs. 2%, P=0.014). Spleen/liver and gastrointestinal involvement were less frequent in the osseous sarcoidosis group (29% vs. 45%, and 1% vs. 17%, respectively, P<0.0001). Response rates to with glucocorticoids alone, glucocorticoids plus methotrexate or glucocorticoids plus hydroxychloroquine were 23/44 (52%), 9/13 (69%) and 4/6 (67%), respectively. CONCLUSION: In patients with osseous sarcoidosis the spine and pelvis were the most commonly affected bones. Compared with controls, cases with osseous sarcoidosis have higher rates of thoracic and extra-thoracic lymph node involvement, pulmonary and cutaneous involvement, and hypercalcemia. Most patients with osseous sarcoidosis had a good response to glucocorticoids in combination with methotrexate or hydroxychloroquine.
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Doenças Ósseas/diagnóstico , Doenças Ósseas/tratamento farmacológico , Linfonodos/patologia , Sarcoidose/diagnóstico , Sarcoidose/tratamento farmacológico , Adulto , Biópsia por Agulha , Estudos de Casos e Controles , Quimioterapia Combinada , Feminino , França , Glucocorticoides/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Imuno-Histoquímica , Imageamento por Ressonância Magnética/métodos , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
A 54-year-old French man was admitted for evaluation of a chronic nodular lesion of the tongue and mandibular lymphadenopathy. He reported active tobacco and cannabis smoking as well as excessive alcohol use. He also reported frequent use of cocaine for several months and a past addiction to IV heroin. He had traveled abroad as a journalist and lived for several months in Columbia and Venezuela 12 years ago. His medical history included chronic hepatitis C infection successfully treated with interferon and ribavirin 6 years ago and high BP.
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Granuloma/diagnóstico , Itraconazol/administração & dosagem , Linfadenopatia , Nódulos Pulmonares Múltiplos/diagnóstico , Paracoccidioidomicose , Doenças da Língua , Antifúngicos/administração & dosagem , Biópsia/métodos , Diagnóstico Diferencial , Granuloma/etiologia , Humanos , Linfadenopatia/diagnóstico , Linfadenopatia/etiologia , Masculino , Pessoa de Meia-Idade , Nódulos Pulmonares Múltiplos/etiologia , Paracoccidioides/isolamento & purificação , Paracoccidioidomicose/complicações , Paracoccidioidomicose/diagnóstico , Paracoccidioidomicose/tratamento farmacológico , Paracoccidioidomicose/fisiopatologia , Doenças da Língua/etiologia , Doenças da Língua/patologia , Resultado do TratamentoRESUMO
BACKGROUND: Cardiovascular disease (CVD) is the main cause of death in systemic lupus erythematous (SLE) patients. The Framingham score underestimates the risk for CVD in this population. Our study aimed to determine whether serum high-sensitivity cardiac troponin T (HS-cTnT) might help to identify SLE patients at risk for CVD. METHODS: The presence of carotid plaques was prospectively assessed by ultrasound in 63 consecutive SLE patients asymptomatic for CVD and 18 controls. Serum HS-cTnT concentration was measured using the electrochemiluminescence method. Factors associated with carotid plaques were identified and multivariate analysis was performed. RESULTS: Framingham score was low in both SLE patients (median 1 (range 1-18%)) and controls (1 (1-13%)). Nevertheless, 23 (36.5%) SLE patients, but only 2 (11.1%) controls (p = 0.039), had carotid plaque detected by vascular ultrasound. In the multivariate analysis, only age (p = 0.006) and SLE status (p = 0.017) were independently associated with carotid plaques. Serum HS-cTnT concentration was detectable (i.e. >3 ng/L) in 37 (58.7%) SLE patients and 6 (33.3%) controls (p = 0.057). Interestingly, 87% of SLE patients with carotid plaques, but only 42.5% of SLE patients without plaques (p < 0.001), had detectable HS-cTnT. Conversely, 54.5% of SLE patients with detectable HS-cTnT, but only 11.5% with undetectable HS-cTnT (p < 0.001), had a carotid plaque. In the multivariate analysis, only body mass index (p = 0.006) and HS-cTnT (p = 0.033) were statistically associated with carotid plaques in SLE patients. Overall, the risk of having a carotid plaque was increased by 9 (odds ratio 9.26, 95% confidence interval 1.55-90.07) in SLE patients in whom HS-cTnT was detectable in serum. CONCLUSION: Serum HS-cTnT level is high and associated with carotid plaques in SLE patients who are at an apparently low risk for CVD according to the Framingham score. HS-cTnT may be a useful biomarker for SLE-associated atherosclerosis.
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Aterosclerose/sangue , Biomarcadores/sangue , Lúpus Eritematoso Sistêmico/complicações , Troponina T/sangue , Adulto , Aterosclerose/complicações , Aterosclerose/diagnóstico , Doenças Cardiovasculares/complicações , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Placa Aterosclerótica/complicações , Fatores de Risco , Sensibilidade e EspecificidadeRESUMO
AIMS: Acute pericarditis may be the heralding manifestation of various systemic inflammatory diseases (SIDs). The aim of this study was to identify clinical indicators for SIDs in patients admitted for acute pericarditis with pericardial effusion. METHODS: All consecutive adult patients hospitalized in a Department of Internal Medicine over a 10-year period for acute pericarditis with pericardial effusion were retrospectively reviewed. Patients with cancer and tuberculosis were excluded. A structured clinical panel for extra-cardiac symptoms of SIDs was applied. SIDs were classified using current international criteria. RESULTS: Ninety-nine patients were admitted for acute pericarditis with pericardial effusion. After exclusion, 74 (49.7â±â19.7 years, 56.7% women) patients were analyzed. Among them, 23 (23.2%) patients had a SID that was revealed by pericarditis in 12 cases. Systemic lupus erythematosus, undifferentiated connective-tissue disease, and Sjogren's syndrome accounted for 75% of the SID. Patients with SIDs were younger (Pâ<â0.001), more frequently of female sex (Pâ=â0.025), and had a higher frequency of extra-cardiac symptoms (Pâ<â0.001) including arthralgia, myalgia, Raynaud phenomenon, and skin rash, as compared with patients with idiopathic pericarditis (nâ=â51). Overall, after exclusion of neoplasm and tuberculosis, the probability of SIDs in patients admitted with an acute pericarditis with pericardial effusion was 89.7% in patients younger than 50 who had extra-cardiac symptoms. Conversely, the probability fell to 8.4% in patients older than 50 with no extra-cardiac symptoms. CONCLUSION: Both age and extra-cardiac symptoms suggest an underlying SID as a possible cause of acute pericarditis.