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1.
Arthritis Res Ther ; 21(1): 277, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31829278

RESUMO

OBJECTIVE: In the last few years, anti-CD20 antibody rituximab profoundly changed the therapeutic landscape of granulomatosis with polyangiitis (GPA). Here, we investigated whether natural killer (NK) cells may play a role in rituximab's mechanism of action in GPA. METHODS: B cell depletion, NK cell degranulation, and the expression of CD69 and CD16 on NK cells were measured in a series of in vitro experiments using peripheral blood mononuclear cells (PBMCs). In vivo activation of NK cells was investigated in patients receiving rituximab infusions. Cells were analyzed by seven-color flow cytometry. RESULTS: NK cells from GPA patients were activated by immobilized rituximab. Also soluble rituximab activated NK cells, provided that B cells were present. NK cells degranulated and expressed the activation marker CD69 while CD16 expression was decreased. This activation of NK cells by soluble rituximab was accompanied by a reduction of B cells. The next-generation anti-CD20 antibody obinutuzumab showed stronger effects compared to rituximab on both the reduction of B cells and the activation of NK cells. Finally, we found that rituximab led to the activation of NK cells in vivo, provided that B cells were not depleted due to prior rituximab infusions. CONCLUSION: B cell-bound rituximab activates NK cells in GPA. While NK cells therefore participate in rituximab's mechanism of action in humans, their potential may be more efficiently exploited, e.g., by Fc engineering of therapeutic antibodies.

2.
Ann Rheum Dis ; 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31818805

RESUMO

BACKGROUND: In this study, we investigated the impact of the new haemodynamic definition of pulmonary arterial hypertension (PAH) as proposed by the 6th PH World Symposium on phenotypes and survival in patients with systemic sclerosis (SSc). METHODS: In SSc patients who were prospectively and consecutively screened for PAH including right heart catheterisation in Heidelberg or Zurich, haemodynamic and clinical variables have been reassessed according to the new PAH definition. Patients have been followed for 3.7±3.7 (median 3.4) years; Kaplan-Meier survival analysis was performed. Patients with significant lung or left heart disease were excluded from comparative analyses. RESULTS: The final dataset included 284 SSc patients, 146 patients (49.2%) had mean pulmonary arterial pressure (mPAP) ≤20 mm Hg, 19.3% had mPAP 21-24 mm Hg and 29.4% had mPAP ≥25 mm Hg. In the group of mildly elevated mPAP, only four patients (1.4% of the whole SSc cohort) had pulmonary vascular resistance (PVR) values ≥3 Wood Units (WU) and could be reclassified as manifest SSc-APAH. Twenty-eight (9.8%) patients with mPAP of 21-24 mm Hg and PVR ≥2 WU already presented with early pulmonary vascular disease with decreased 6 min walking distance (6MWD) (p<0.001), TAPSE (p=0.004) and pulmonary arterial compliance (p<0.001). A PVR ≥2 WU was associated with reduced long-term survival (p=0.002). PVR and 6MWD were independent prognostic predictors in multivariate analysis. CONCLUSION: The data of this study show that a PVR threshold ≥3 WU is too high to enable an early diagnosis of PAH. A PVR threshold ≥2 WU was already associated with pulmonary vascular disease, significantly reduced survival and would be more appropriate in SSc patients with mild PAH.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31846032

RESUMO

OBJECTIVE: The development of RA is linked to local infiltration of immune cells and to changes in the phenotype of synovial fibroblasts. Synovial fibroblasts possess the capacity to suppress T cell responses through indoleamine 2, 3-dioxygenase 1 (IDO1)-mediated tryptophan metabolism. However, synovial fibroblasts from RA patients are restricted in this immune-modulatory function. Moreover, hypoxic conditions are detected within synovial tissues of RA patients, with oxygen tensions of only 3.2% O2. This study aims at investigating the effects of hypoxia on the interaction between T cells and synovial fibroblasts, particularly on the T cell-suppressive capacities of synovial fibroblasts. METHODS: Synovial fibroblasts were cultured with Th cells under normoxic and hypoxic conditions (3% O2). Th cell proliferation was detected by flow cytometry. Tryptophan and kynurenine amounts were measured by HPLC. IDO1 expression and signal transducer and activator of transcription 1 (STAT1) phosphorylation were quantified by real-time PCR or western blot, and cytokine secretion by ELISA. RESULTS: Hypoxic conditions strongly diminished the Th cell-suppressive capacities of both OA synovial fibroblasts and RA synovial fibroblasts. Accordingly, IDO1 mRNA and protein expression, STAT1 phosphorylation and tryptophan metabolism were greatly reduced in OA synovial fibroblasts by hypoxia. MMP-3, IL-6, IL-10 and IFNγ secretion were significantly decreased under hypoxia in synovial fibroblast-Th cell co-cultures, while IL-17A levels were elevated. Supplementation with IFNγ, a well-known inducer of IDO1 expression, could rescue neither IDO1 expression nor Th cell suppression under hypoxic conditions. CONCLUSION: Hypoxia strongly affected the crosstalk between synovial fibroblasts and Th cells. By reducing the efficiency of synovial fibroblasts to restrict Th cell proliferation and by increasing the expression of IL-17A, hypoxia might have implications on the pathophysiology of RA.

4.
J Clin Med ; 8(11)2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31752231

RESUMO

Antisynthetase syndrome (ASSD) is a rare clinical condition that is characterized by the occurrence of a classic clinical triad, encompassing myositis, arthritis, and interstitial lung disease (ILD), along with specific autoantibodies that are addressed to different aminoacyl tRNA synthetases (ARS). Until now, it has been unknown whether the presence of a different ARS might affect the clinical presentation, evolution, and outcome of ASSD. In this study, we retrospectively recorded the time of onset, characteristics, clustering of triad findings, and survival of 828 ASSD patients (593 anti-Jo1, 95 anti-PL7, 84 anti-PL12, 38 anti-EJ, and 18 anti-OJ), referring to AENEAS (American and European NEtwork of Antisynthetase Syndrome) collaborative group's cohort. Comparisons were performed first between all ARS cases and then, in the case of significance, while using anti-Jo1 positive patients as the reference group. The characteristics of triad findings were similar and the onset mainly began with a single triad finding in all groups despite some differences in overall prevalence. The "ex-novo" occurrence of triad findings was only reduced in the anti-PL12-positive cohort, however, it occurred in a clinically relevant percentage of patients (30%). Moreover, survival was not influenced by the underlying anti-aminoacyl tRNA synthetase antibodies' positivity, which confirmed that antisynthetase syndrome is a heterogeneous condition and that antibody specificity only partially influences the clinical presentation and evolution of this condition.

5.
Wien Med Wochenschr ; 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31654156

RESUMO

BACKGROUND: AbataCepT In rOutiNe clinical practice (ACTION; NCT02109666) was a 2-year international observational study of patients with moderate to severe rheumatoid arthritis. METHODS: Baseline characteristics, abatacept retention rates, and clinical outcomes were compared by treatment line in the Austrian cohort of ACTION. RESULTS: Of 100 patients enrolled in Austria, 98 (98.0%) were evaluable: 33/98 (33.7%) biologic naïve and 65/98 (66.3%) with ≥1 prior biologic failure. At baseline, biologic-naïve patients had shorter disease duration and lower concomitant corticosteroid use than biologic-failure patients. Overall crude abatacept retention rate was 60.5% and retention rate was higher in biologic-naïve (65.1%) versus biologic-failure (58.0%) patients. Good/moderate EULAR (European League Against Rheumatism) response rates were 85.7% in biologic-naïve and 100% in biologic-failure patients. CONCLUSIONS: In the Austrian cohort of ACTION, overall abatacept retention at 2 years was high, with higher retention rates in patients receiving abatacept as an earlier treatment line. Good/moderate EULAR response rate was higher in biologic-failure than in biologic-naïve patients.

6.
Arthritis Res Ther ; 21(1): 217, 2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31655622

RESUMO

OBJECTIVE: The objective of this randomized, placebo-controlled, double-blind, parallel group, trial was to assess the effect of ambrisentan on mean pulmonary arterial pressure (mPAP) in patients with systemic sclerosis (SSc) and mildly elevated pulmonary hypertension (PH). METHODS: Thirty-eight SSc patients with mildly elevated mPAP at rest between 21 and 24 mmHg and/or > 30 mmHg during low-dose exercise were randomly assigned to treatment with either ambrisentan 5-10 mg/day or placebo. Right heart catheterization and further clinical parameters were assessed at baseline and after 6 months. The primary endpoint was the difference of mPAP change at rest between groups. RESULTS: After 6 months, the two groups did not differ in the primary endpoint (ambrisentan mPAP - 1 ± 6.4 mmHg vs. placebo - 0.73 ± 3.59 mmHg at rest, p = 0.884). However, three patients from the placebo group but none of the ambrisentan group progressed to SSc-associated pulmonary arterial hypertension. Furthermore, ambrisentan treatment showed significant improvements in the secondary endpoints cardiac index (CI) and pulmonary vascular resistance (PVR) at rest (CI 0.36 ± 0.66 l/min/m2 vs. - 0.31 ± 0.71 l/min/m2, p = 0.010; PVR - 0.70 ± 0.78 WU vs. 0.01 ± 0.71 WU, p = 0.012) and during exercise (CI 0.7 ± 0.81 l/min/m2 vs. - 0.45 ± 1.36 l/min/m2, p = 0.015; PVR - 0.84 ± 0.48 WU vs. - 0.0032 ± 0.34 WU, p < 0.0001). CONCLUSION: This is the first randomized, double-blind, placebo-controlled study testing the effect of ambrisentan in patients with mildly elevated mPAP and/or exercise PH. The primary endpoint change in mPAP did only tendentially improve in the ambrisentan group, but the significant improvement of other hemodynamic parameters points to a possible benefit of ambrisentan and will be helpful to design future trials. TRIAL REGISTRATION: www.ClinicalTrials.gov, unique identifier NCT: NCT02290613 , registered 14th of November 2014.

8.
Clin Rheumatol ; 38(11): 3049-3059, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31300979

RESUMO

INTRODUCTION: AbataCepT In rOutiNe clinical practice (ACTION; NCT02109666) was an observational study of patients with rheumatoid arthritis who initiated intravenous abatacept in clinical practice. We aimed to compare abatacept retention rates and clinical outcomes in patients from Germany versus other countries. METHOD: Baseline characteristics, crude retention rates, and clinical outcomes were compared by treatment line in the German cohort at 2 years. In addition, biologic-naïve patients were compared with biologic-naïve patients pooled from other participating countries. RESULTS: In the German cohort, 677/680 (99.6%) patients enrolled were evaluable and 171/677 (25.3%) were biologic naïve. At baseline, abatacept monotherapy was received by a similar proportion of biologic-naïve and biologic-failure patients in the German cohort, but by a greater proportion of biologic-naïve patients in German versus other countries cohort (27.5 vs. 12.9%). The overall crude abatacept retention rate at 2 years in the German cohort was 39.9%; retention rate did not differ significantly by treatment line, but among biologic-naïve patients it was lower in Germany than in the other countries cohort (42.1 vs. 58.7%; log-rank test p < 0.001). At 2 years, good/moderate European League Against Rheumatism (EULAR) response rates in biologic-naïve patients were 85.5% in the German and 92.1% in other countries cohort (p = 0.163). CONCLUSIONS: In the German cohort of ACTION, abatacept retention at 2 years was similar in biologic-naïve and biologic-failure patients. Biologic-naïve patients in German cohort had a significantly lower abatacept retention rate and a trend of lower good/moderate EULAR response rate than those in the other countries cohort. KEY POINTS: • Analyses of data from national patient cohorts provide insight on local treatment patterns. • In the German cohort of the ACTION study, abatacept retention at 2 years was similar in biologic-naïve and biologic-failure patients. • Biologic-naïve patients from the German cohort had a significantly lower abatacept retention rate and a trend of lower good/moderate EULAR response rate than patients from other countries. • Data from large international studies may not be directly applicable to individual countries.

10.
J Clin Med ; 8(7)2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31261785

RESUMO

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the joints. Untreated RA leads to a destruction of joints through the erosion of cartilage and bone. The loss of physical function is the consequence. Early treatment is important to control disease activity and to prevent joint destruction. Nowadays, different classes of drugs with different modes of action are available to control the inflammation and to achieve remission. In this review, we want to discuss differences and similarities of these different drugs.

11.
Clin Rheumatol ; 38(5): 1535, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30972577

RESUMO

The article listed above was initially published with incorrect copyright information. Upon publication of this Correction, the copyright of this article changed to "The Author(s)". The original article has been corrected.

12.
Dtsch Med Wochenschr ; 144(7): 464-469, 2019 04.
Artigo em Alemão | MEDLINE | ID: mdl-30925601

RESUMO

STATE OF THE ART: Innovations in information and communication technology have been used in rheumatology for many years. In 2018 the German Society for Rheumatology established the Commission "Digital Rheumatology". DIGITAL APPLICATIONS IN GERMAN RHEUMATOLOGY: Mobile data acquisition in rheumatological patients is feasible. It offers innovative possibilities in the implementation of modern treatment strategies. Digital applications such as the "Rheuma Check" and the "Bechterew Check" are available to the public at any time to screen for inflammatory rheumatic diseases. Other digital services and modern networks allow a triage of patients. Rhekiss and RABBIT SpA are the first fully digitalised registries to provide short-term data on issues that are not covered by clinical trials of pharmaceutical companies. OUTLOOK: Digitalization in Rheumatology will provide much faster answers to important questions in healthcare research in the future.


Assuntos
Informática Médica , Reumatologia , Telemedicina , Alemanha , Humanos
13.
Curr Rheumatol Rep ; 21(5): 18, 2019 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-30852700

RESUMO

PURPOSE OF THE REVIEW: Idiopathic acute and recurrent pericarditis are rare diseases of unknown origin. Here, we review trigger factors, pathomechanism, and treatment options for acute and recurrent pericarditis. RECENT FINDINGS: Acute pericarditis can be triggered by viral infections, myocardial ischemia, heart catheter interventions, cardiac surgery or seem to occur without any trigger. Earlier reports about viral nucleic acids in the effusion or myocardial autoantibodies in serum were detected only in a minority of patients. The current pathomechanistic concept focuses on the innate immune system. Clinical trials revealed that colchicine and anti-IL1ß-targeted medication were effective to control acute and recurrent attacks. Activation of the innate immune system in pericarditis suggests that autoinflammation contributes to acute and recurrent pericarditis. The efficacy of colchicine and anti-IL1ß-targeted medication in clinical trials indicates that acute and recurrent pericarditis should be regarded as an autoinflammatory disease. Therefore, idiopathic pericarditis should be considered as an autoinflammatory disease.

14.
Clin Rheumatol ; 38(5): 1413-1424, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30790095

RESUMO

OBJECTIVES: Evaluate abatacept retention over 2 years in the AbataCepT In rOutiNe clinical practice (ACTION) study. METHOD: ACTION was an international, observational study of patients with moderate-to-severe rheumatoid arthritis (RA) who initiated intravenous abatacept. Crude abatacept retention rates over 2 years were estimated using Kaplan-Meier analyses in biologic-naive and -failure patients. Clinically relevant risk factors and significant prognostic factors for retention were evaluated using a Cox proportional hazards multivariable model. RESULTS: Overall, 2350/2364 enrolled patients were evaluable; 673 (28.6%) were biologic naive and 1677 (71.4%) had prior biologic failure (1 biologic, 728/1677 [43.4%]; ≥ 2 biologics, 949/1677 [56.6%]). Abatacept retention rate (95% confidence interval [CI]) at 2 years was 47.9% (45.7, 50.0): 54.5% (50.4, 58.3) for biologic-naive vs 45.2% (42.7, 47.7) for biologic-failure patients (log-rank P < 0.001). For patients with 1 and ≥ 2 prior biologic failures, respectively, retention rates (95% CI) were 50.2% (46.3, 53.9) vs 41.3% (38.0, 44.6; log-rank P < 0.001). Main reasons for discontinuation (biologic-naive vs biologic-failure, respectively) were lack of efficacy (61.4 vs 67.7%) and safety (21.3 vs 21.2%). Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) double positivity versus negativity were predictive of higher retention in both biologic-naive (hazard ratio [HR] [95% CI] 0.71 [0.53, 0.96]; P = 0.019) and biologic-failure patients (HR [95% CI] 0.76 [0.62, 0.94]; P = 0.035). CONCLUSIONS: Abatacept initiation as earlier vs later line of therapy in RA may achieve higher 2-year retention rates. RF and anti-CCP seropositivity could predict increased abatacept retention, irrespective of treatment line. TRIAL REGISTRATION: NCT02109666.


Assuntos
Abatacepte/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Corticosteroides/uso terapêutico , Idoso , Estudos de Coortes , Quimioterapia Combinada , Feminino , Humanos , Internacionalidade , Estimativa de Kaplan-Meier , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Fator Reumatoide/sangue , Resultado do Tratamento
15.
Arthritis Rheumatol ; 71(5): 805-816, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30615302

RESUMO

OBJECTIVE: This prospective study was undertaken to evaluate right ventricular function and pulmonary arterial compliance (PAC; ratio of stroke volume to pulse pressure) at rest and during exercise in patients with systemic sclerosis (SSc) with normal mean pulmonary artery pressure (PAP), patients with SSc with mildly elevated mean PAP, and patients with SSc with manifest pulmonary hypertension (PH). METHODS: Patients with SSc (n = 112) underwent clinical assessment and right-sided heart catheterization at rest and during exercise and were divided into 3 groups according to their resting mean PAP values: normal mean PAP (≤20 mm Hg), mildly elevated mean PAP (21-24 mm Hg), and PH (mean PAP ≥25 mm Hg). Results were compared between groups by analysis of variance followed by post hoc Student's t-test. RESULTS: Compared to patients with normal mean PAP, patients with mildly elevated mean PAP had a lower 6-minute walking distance (P = 0.008), lower cardiac index (P = 0.027) and higher pulmonary vascular resistance (P = 0.0002) during exercise, and lower PAC at rest (P = 0.016) and different stages of exercise (P = 0.033 for 25W and P = 0.024 for 75W). CONCLUSION: The results of this study suggest that impaired 6-minute walking distance in SSc patients with mildly elevated mean PAP might be caused by reduced PAC during exercise and reduced right ventricular output reserve, presumably due to impaired coupling between the right ventricle and the pulmonary vasculature. These findings provide further evidence of the clinical relevance of mildly elevated mean PAP in patients with SSc.


Assuntos
Débito Cardíaco/fisiologia , Artéria Pulmonar/fisiopatologia , Escleroderma Sistêmico/fisiopatologia , Resistência Vascular/fisiologia , Disfunção Ventricular Direita/fisiopatologia , Adulto , Idoso , Pressão Sanguínea/fisiologia , Cateterismo Cardíaco , Estudos de Casos e Controles , Complacência (Medida de Distensibilidade) , Ecocardiografia Doppler , Teste de Esforço , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Volume Sistólico/fisiologia , Disfunção Ventricular Direita/diagnóstico por imagem , Teste de Caminhada
17.
Arthritis Res Ther ; 20(1): 278, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30563559

RESUMO

BACKGROUND: CD4+ T cells are of great importance in the pathogenesis of systemic lupus erythematosus (SLE), as an imbalance between CD4+ regulatory T cells (Tregs) and CD4+ responder T cells (Tresps) causes flares of active disease in SLE patients. In this study, we aimed to find the role of aberrant Treg/Tresp cell differentiation for maintaining Treg/Tresp cell balance and Treg functionality. METHODS: To determine differences in the differentiation of Tregs/Tresps we calculated the percentages of CD45RA+CD31+ recent thymic emigrant (RTE) Tregs/Tresps and CD45RA+CD31- mature naive (MN) Tregs/Tresps, as well as CD45RA-CD31+ and CD45RA-CD31- memory Tregs/Tresps (CD31+ and CD31- memory Tregs/Tresps) within the total Treg/Tresp pool of 78 SLE remission patients compared with 94 healthy controls of different ages. The proliferation capacity of each Treg/Tresp subset was determined by staining the cells with anti-Ki67 monoclonal antibodies. Differences in the autologous or allogeneic Treg function between SLE remission patients and healthy controls were determined using suppression assays. RESULTS: With age, we found an increased differentiation of RTE Tregs via CD31+ memory Tregs and of RTE Tresps via MN Tresps into CD31- memory Tregs/Tresp in healthy volunteers. This opposite differentiation of RTE Tregs and Tresps was associated with an age-dependent increase in the suppressive activity of both naive and memory Tregs. SLE patients showed similar age-dependent Treg cell differentiation. However, in these patients RTE Tresps differentiated increasingly via CD31+ memory Tresps, whereby CD31- memory Tresps arose that were much more difficult to inhibit for Tregs than those that emerged through differentiation via MN Tresps. Consequently, the increase in the suppressive activity of Tregs with age could not be maintained in SLE patients. Testing the Tregs of healthy volunteers and SLE patients with autologous and nonautologous Tresps revealed that the significantly decreased Treg function in SLE patients was not exclusively attributed to an age-dependent diminished sensitivity of the Tresps for Treg suppression. The immunosuppressive therapy reduced the accelerated age-dependent Tresp cell proliferation to normal levels, but simultaneously inhibited Treg cell proliferation below normal levels. CONCLUSIONS: Our data reveal that the currently used immunosuppressive therapy has a favorable effect on the differentiation and proliferation of Tresps but has a rather unfavorable effect on the proliferation of Tregs. Newer substances with more specific effects on the immune system would be desirable.


Assuntos
Diferenciação Celular/imunologia , Imunossupressão/métodos , Lúpus Eritematoso Sistêmico/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Fatores Etários , Idoso , Proliferação de Células , Células Cultivadas , Técnicas de Cocultura , Feminino , Humanos , Lúpus Eritematoso Sistêmico/patologia , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo
18.
Eur J Rheumatol ; 5(4): 230-234, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30501849

RESUMO

OBJECTIVE: Approximately 10%-20% of patients with familial Mediterranean fever (FMF) show an inadequate response to colchicine. In our cohort study, patients with FMF with or without amyloidosis and with an inadequate response to colchicine were treated with anakinra or canakinumab. METHODS: Clinical and laboratory parameters, Mediterranean fever (MEFV) mutations, and patient-reported outcomes were analyzed in 31 patients treated with anakinra or canakinumab. RESULTS: In a cohort of 250 adult patients with FMF, 31 patients were treated with anakinra (n=29) or canakinumab (n=2). The median Pras FMF severity score was 8 (range, 5-14) and correlated with the presence of high-penetrance MEFV mutations (p.Met-694-Val or p.Met-680-Ile). The FMF severity score was 11 in patients with two high-penetrance MEFV mutations (68%), 9 in those with a single high-penetrance MEFV mutation (19%), and 7.5 in those without high-penetrance MEFV mutations (13%, p=0.2). FMF-related amyloid A amyloidosis was diagnosed in 12 (39%) patients. Anakinra was used daily in 20 patients, thrice a week in 7, and upon demand during attacks in 2. Two patients were treated with canakinumab. IL-1-blocking treatment showed a rapid (2±3 days) and persistent suppression of FMF symptoms and inflammatory parameters. The frequency of FMF attacks was significantly reduced (p<0.003). Both patient- and physician-reported FMF activity significantly improved (p<0.0001). CONCLUSION: IL-1-blocking therapy was well tolerated over a median period of 2 years and reduced the frequency of FMF attacks in patients with colchicine-resistant FMF.

19.
Respir Res ; 19(1): 216, 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30409145

RESUMO

BACKGROUND: The objective of this study was to assess, whether right atrial (RA) and ventricular (RV) size is related to RV pump function at rest and during exercise in patients with pulmonary arterial hypertension (PAH). METHODS: We included 54 patients with invasively diagnosed PAH that had been stable on targeted medication. All patients underwent clinical assessments including right heart catheterization and echocardiography at rest and during exercise. RV output reserve was defined as increase of cardiac index (CI) from rest to peak exercise (∆CIexercise). Patients were classified according to the median of RA and RV-area. RV pump function and further clinical parameters were compared between groups by student's t-test. Uni- and multivariate Pearson correlation analyses were performed. RESULTS: Patients with larger RA and/or RV-areas (above a median of 16 and 20cm2, respectively) showed significantly lower ∆CIexercise, higher mean pulmonary arterial pressure, pulmonary vascular resistance at rest and NT-proBNP levels. Furthermore, patients with higher RV-areas presented with a significantly lower RV stroke volume and pulmonary arterial compliance at peak exercise than patients with smaller RV-size. RV area was identified as the only independent predictor of RV output reserve. CONCLUSION: RV and RA areas represent valuable and easily accessible indicators of RV pump function at rest and during exercise. Cardiac output reserve should be considered as an important clinical parameter. Prospective studies are needed for further evaluation.


Assuntos
Função do Átrio Direito/fisiologia , Átrios do Coração/diagnóstico por imagem , Ventrículos do Coração/diagnóstico por imagem , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/fisiopatologia , Função Ventricular Direita/fisiologia , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão/fisiologia , Estudos Retrospectivos
20.
Proc Natl Acad Sci U S A ; 115(26): E5980-E5989, 2018 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-29895693

RESUMO

CD8+ T cells are considered prototypical cells of adaptive immunity. Here, we uncovered a distinct CD8+ T cell population expressing the activating natural killer (NK) receptor NKp30 in the peripheral blood of healthy individuals. We revealed that IL-15 could de novo induce NKp30 expression in a population of CD8+ T cells and drive their differentiation toward a broad innate transcriptional landscape. The adaptor FcεRIγ was concomitantly induced and was shown to be crucial to enable NKp30 cell-surface expression and function in CD8+ T cells. FcεRIγ de novo expression required promoter demethylation and was accompanied by acquisition of the signaling molecule Syk and the "innate" transcription factor PLZF. IL-15-induced NKp30+CD8+ T cells exhibited high NK-like antitumor activity in vitro and were able to synergize with T cell receptor signaling. Importantly, this population potently controlled tumor growth in a preclinical xenograft mouse model. Our study, while blurring the borders between innate and adaptive immunity, reveals a unique NKp30+FcεRIγ+CD8+ T cell population with high antitumor therapeutic potential.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunidade Celular , Células Matadoras Naturais/imunologia , Receptor 3 Desencadeador da Citotoxicidade Natural/imunologia , Neoplasias/imunologia , Receptores Fc/imunologia , Linfócitos T CD8-Positivos/patologia , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Células Matadoras Naturais/patologia , Masculino , Neoplasias/patologia
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