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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.
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.

4.
J Rheumatol ; 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30936287

RESUMO

OBJECTIVE: Scleroderma renal crisis (SRC) is a severe life-threatening manifestation in patients with systemic sclerosis (SSc). However, the knowledge about risk factors for SRC is limited. We determined here the frequency of SRC and identified risk factors for the prediction of SRC. METHODS: Based on regular followup data from the German Network for Systemic Scleroderma, we used univariate and multivariate generalized estimating equations to analyze the association between clinical variables, SSc subsets, therapy [i.e., angiotensin-converting enzyme inhibitors (ACEi), corticosteroids], and the occurrence of SRC. RESULTS: Data of 2873 patients with 10,425 visits were available for analysis with a mean number of registry visits of 3.6 ± 2.8 and a mean time of followup of 3.6 ± 3.8 years. In total, 70 patients developed SRC (70/2873, 2.4%). Of these patients, 57.1% (40/70) were diagnosed with diffuse cutaneous SSc, 31.4% (22/70) with limited cutaneous SSc, and 11.4% (8/70) with SSc-overlap syndromes. Predictive independent factors with the highest probability for SRC were positive anti-RNA polymerase antibodies (RNAP), a history of proteinuria prior to SRC onset, diminished DLCO, and a history of hypertension. Interestingly, positive antitopoisomerase autoantibodies did not predict a higher risk for SRC. Further, patients with SRC were significantly more frequently treated with ACEi and corticosteroids without being independently associated with SRC. CONCLUSION: In this cohort, SRC has become a rare complication. By far the highest risk for SRC was associated with the detection of anti-RNAP and proteinuria.

5.
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.

6.
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
8.
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.

9.
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
10.
Front Immunol ; 9: 2584, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30487791

RESUMO

The activity and function of T-cells are influenced by the intra- and extracellular redox milieu. Oxidative stress induces hypo responsiveness of untransformed T-cells. Vice versa increased glutathione (GSH) levels or decreased levels of reactive oxygen species (ROS) prime T-cell metabolism for inflammation, e.g., in rheumatoid arthritis. Therefore, balancing the T-cell redox milieu may represent a promising new option for therapeutic immune modulation. Here we show that sulforaphane (SFN), a compound derived from plants of the Brassicaceae family, e.g., broccoli, induces a pro-oxidative state in untransformed human T-cells of healthy donors or RA patients. This manifested as an increase of intracellular ROS and a marked decrease of GSH. Consistently, increased global cysteine sulfenylation was detected. Importantly, a major target for SFN-mediated protein oxidation was STAT3, a transcription factor involved in the regulation of TH17-related genes. Accordingly, SFN significantly inhibited the activation of untransformed human T-cells derived from healthy donors or RA patients, and downregulated the expression of the transcription factor RORγt, and the TH17-related cytokines IL-17A, IL-17F, and IL-22, which play a major role within the pathophysiology of many chronic inflammatory/autoimmune diseases. The inhibitory effects of SFN could be abolished by exogenously supplied GSH and by the GSH replenishing antioxidant N-acetylcysteine (NAC). Together, our study provides mechanistic insights into the mode of action of the natural substance SFN. It specifically exerts TH17 prone immunosuppressive effects on untransformed human T-cells by decreasing GSH and accumulation of ROS. Thus, SFN may offer novel clinical options for the treatment of TH17 related chronic inflammatory/autoimmune diseases such as rheumatoid arthritis.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Reumatoide/tratamento farmacológico , Inflamação/tratamento farmacológico , Isotiocianatos/farmacologia , Linfócitos T/imunologia , Brassicaceae/imunologia , Células Cultivadas , Regulação para Baixo , Glutationa/metabolismo , Humanos , Imunossupressão , Interleucina-17/metabolismo , Interleucinas/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Cultura Primária de Células , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Linfócitos T/efeitos dos fármacos
11.
Front Immunol ; 9: 534, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29599781

RESUMO

Extracellular vesicles (EVs) are released from nearly all mammalian cells and different EV populations have been described. Microvesicles represent large EVs (LEVs) released from the cellular surface, while exosomes are small EVs (SEVs) released from an intracellular compartment. As it is likely that different stimuli promote the release of distinct EV populations, we analyzed EVs from human lymphocytes considering the respective release stimuli (activation Vs. apoptosis induction). We could clearly separate two EV populations, namely SEVs (average diameter <200 nm) and LEVs (diameter range between 200 and 1000 nm). Morphology and size were analyzed by electron microscopy and nanoparticle tracking analysis. Apoptosis induction caused a massive release of LEVs, while activated T-cells released SEVs and LEVs in considerably lower amounts. The release of SEVs from apoptotic T-cells was comparable with LEV release from activated ones. LEVs contained signaling proteins and proteins of the actin-myosin cytoskeleton. SEVs carried cytoplasmic/endosomal proteins like the 70-kDa heat shock protein 70 (HSP70) or tumor susceptibility 101 (TSG101), microtubule-associated proteins, and ubiquitinated proteins. The protein expression profile of SEVs and LEVs changed substantially after the induction of apoptosis. After apoptosis induction, HSP70 and TSG101 (often used as exosome markers) were highly expressed within LEVs. Interestingly, in contrast to HSP70 and TSG101, gelsolin and eps15 homology domain-containing protein 3 (EHD3) turned out to be specific for SEVs irrespective of the stimulus causing the EV release. Finally, we detected several subunits of the proteasome (PSMB9, PSMB10) as well as the danger signal HMGB1 exclusively within apoptotic cell-released LEVs. Thus, we were able to identify new marker proteins that can be useful to discriminate between distinct LEV subpopulations. The mass spectrometry proteomics data are available via ProteomeXchange with identifier PXD009074.


Assuntos
Vesículas Extracelulares , Linfócitos T , Apoptose , Células Cultivadas , Humanos , Leucócitos Mononucleares , Proteínas/metabolismo , Proteômica
12.
Amyloid ; 25(1): 37-45, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29364741

RESUMO

BACKGROUND: To investigate obesity as susceptibility factor in patients with idiopathic AA amyloidosis. METHODS: Clinical, biochemical and genetic data were obtained from 146 patients with AA amyloidosis. Control groups comprised 40 patients with long-standing inflammatory diseases without AA amyloidosis and 56 controls without any inflammatory disease. FINDINGS: Patients with AA amyloidosis had either familial Mediterranean fever (FMF) or long-standing rheumatic diseases as underlying inflammatory disease (n = 111, median age 46 years). However, in a significant proportion of patients with AA amyloidosis no primary disease was identified (idiopathic AA; n = 37, median age 60 years). Patients with idiopathic AA amyloidosis were more obese and older than patients with AA amyloidosis secondary to FMF or rheumatic diseases. Serum leptin levels correlated with the body mass index (BMI) in all types of AA amyloidosis. Elevated leptin levels of more than 30 µg/l were detected in 18% of FMF/rheumatic + AA amyloidosis and in 40% of patients with idiopathic AA amyloidosis (p = .018). Finally, the SAA1 polymorphism was confirmed as a susceptibility factor for AA amyloidosis irrespective of the type of the disease. CONCLUSIONS: Obesity, age and the SAA1 polymorphism are susceptibility factors for idiopathic AA amyloidosis. Recent advances in treatment of FMF and rheumatic disorders will decrease the incidence of AA amyloidosis due to these diseases. Idiopathic AA, however, might be an emerging problem in the ageing and increasingly obese population.


Assuntos
Amiloidose , Predisposição Genética para Doença , Leptina/sangue , Obesidade , Polimorfismo Genético , Proteína Amiloide A Sérica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Amiloidose/sangue , Amiloidose/epidemiologia , Amiloidose/etiologia , Amiloidose/genética , Febre Familiar do Mediterrâneo/sangue , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/epidemiologia , Febre Familiar do Mediterrâneo/genética , Feminino , Humanos , Leptina/genética , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/genética , Doenças Reumáticas/sangue , Doenças Reumáticas/complicações , Doenças Reumáticas/epidemiologia , Doenças Reumáticas/genética , Proteína Amiloide A Sérica/metabolismo
14.
Rheumatology (Oxford) ; 56(12): 2102-2108, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28968868

RESUMO

Objective: To provide outcome data concerning pregnancies exposed to the Interleukin-1 (IL-1) inhibitors prior to conception in both men and women, during pregnancy and breast feeding. Methods: Retrospective data were collected from members of the International Society for Systemic Autoinflammatory diseases and collated in a single centre. A uniform data collection sheet was used to obtain standardized data including maternal age and diagnosis, type, duration of and response to IL-1 blockade, pregnancy duration, delivery, mode of feeding and neonatal development. Results: There were 31 maternal-exposed pregnancies from seven countries and we report the first data on paternal exposure: six to anakinra and five to canakinumab, with no negative outcomes. We also report the first data on canakinumab-exposed pregnancies: eight pregnancies that resulted in the delivery of seven healthy infants of normal gestational age and birthweight. There were 23 anakinra-exposed pregnancies resulting in the birth of 21 healthy infants, and one baby with unilateral renal agenesis and ectopic neurohypophysis. There were two first trimester miscarriages affecting a mother with active disease. There were no serious neonatal infections. Fourteen infants were breast fed with no complications. There were no reports of developmental delay, with follow-up of up to 10 years (median 18 months). Conclusion: This series substantially increases the published experience of IL-1 blockade and reproduction including the first data on canakinumab and on paternal exposure to these agents. Data are generally reassuring, although the case of renal agenesis is the second reported in an anakinra-exposed pregnancy.


Assuntos
Antirreumáticos/efeitos adversos , Doenças Autoimunes/tratamento farmacológico , Interleucina-1/antagonistas & inibidores , Exposição Materna/efeitos adversos , Exposição Paterna/efeitos adversos , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Doenças Autoimunes/complicações , Peso ao Nascer , Aleitamento Materno/efeitos adversos , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Masculino , Gravidez , Resultado da Gravidez , Estudos Retrospectivos , Adulto Jovem
15.
Eur J Immunol ; 47(9): 1535-1549, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28665018

RESUMO

Cell activation and apoptosis lead to the formation of extracellular vesicles (EVs) such as exosomes or microvesicles (MVs). EVs have been shown to modulate immune responses; recently, MVs were described to carry microRNA (miRNA) and a role for MVs in the pathogenesis of autoimmune diseases has been discussed. Here we systematically characterized MVs and exosomes according to their release stimuli. The miRNA content of viable or apoptotic human T lymphocytes and the corresponding MVs was analyzed. miRNA, protein and surface marker expression, as well as cytokine release by human monocytes was measured after EV engulfment. Finally, miRNA expression in T lymphocytes and MVs of healthy individuals was compared with those of systemic lupus erythematosus (SLE) patients. We demonstrate that, depending on the stimuli, distinct subtypes of EVs are released, differing in size and carrying a specific RNA profile. We observed an accumulation of distinct miRNAs in MVs after induction of apoptosis and the transfer of functional miRNA by MVs into human monocytes. MVs released from apoptotic cells provoke less of an inflammatory response than those released from viable cells. MiR-155*, miR-34b and miR-34a levels in T lymphocytes and corresponding MVs were deregulated in SLE when compared to healthy individuals.


Assuntos
Exossomos/metabolismo , Vesículas Extracelulares/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , MicroRNAs/metabolismo , Fagócitos/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Apoptose , Comunicação Celular , Células Cultivadas , Exossomos/química , Vesículas Extracelulares/química , Feminino , Humanos , Imunomodulação , Masculino , MicroRNAs/genética , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Nanopartículas , Tamanho da Partícula
16.
Ann Rheum Dis ; 76(6): 942-947, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27707729

RESUMO

Cryopyrin-associated periodic syndrome (CAPS) is a rare, heterogeneous disease entity associated with NLRP3 gene mutations and increased interleukin-1 (IL-1) secretion. Early diagnosis and rapid initiation of IL-1 inhibition prevent organ damage. The aim of the study was to develop and validate diagnostic criteria for CAPS. An innovative process was followed including interdisciplinary team building, item generation: review of CAPS registries, systematic literature review, expert surveys, consensus conferences for item refinement, item reduction and weighting using 1000Minds decision software. Resulting CAPS criteria were tested in large cohorts of CAPS cases and controls using correspondence analysis. Diagnostic models were explored using sensitivity analyses. The international team included 16 experts. Systematic literature and registry review identified 33 CAPS-typical items; the consensus conferences reduced these to 14. 1000Minds exercises ranked variables based on importance for the diagnosis. Correspondence analysis determined variables consistently associated with the diagnosis of CAPS using 284 cases and 837 controls. Seven variables were significantly associated with CAPS (p<0.001). The best diagnosis model included: Raised inflammatory markers (C-reactive protein/serum amyloid A) plus ≥two of six CAPS-typical symptoms: urticaria-like rash, cold-triggered episodes, sensorineural hearing loss, musculoskeletal symptoms, chronic aseptic meningitis and skeletal abnormalities. Sensitivity was 81%, specificity 94%. It performed well for all CAPS subtypes and regardless of NLRP3 mutation. The novel approach integrated traditional methods of evidence synthesis with expert consensus, web-based decision tools and innovative statistical methods and may serve as model for other rare diseases. These criteria will enable a rapid diagnosis for children and adults with CAPS.


Assuntos
Síndromes Periódicas Associadas à Criopirina/diagnóstico , Biomarcadores/sangue , Osso e Ossos/anormalidades , Proteína C-Reativa/metabolismo , Doença Crônica , Síndromes Periódicas Associadas à Criopirina/sangue , Síndromes Periódicas Associadas à Criopirina/complicações , Síndromes Periódicas Associadas à Criopirina/etiologia , Perda Auditiva Neurossensorial/etiologia , Humanos , Meningite Asséptica/etiologia , Doenças Musculoesqueléticas/etiologia , Proteína Amiloide A Sérica/metabolismo , Urticária/etiologia
17.
Arthritis Res Ther ; 18(1): 204, 2016 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-27624647

RESUMO

BACKGROUND: The role of natural killer (NK) cells in granulomatosis with polyangiitis (GPA) is poorly understood. We recently reported that peripheral blood NK cell percentages correlate with the suppression of GPA activity (cohort I). The purpose of the current study was to further characterize NK cell subsets, phenotype and function in a second GPA cohort (cohort II). METHODS: Peripheral blood lymphocyte subsets were analyzed at a clinical diagnostic laboratory. Clinical data were extracted from medical records and patients were grouped according to their activity state (remission vs. active/non-remission). Separate analysis (cohort II, n = 22) and combined analysis (cohorts I and II, n = 34/57) of NK cell counts/percentages was performed. NK cell subsets and phenotypes were analyzed by multicolor flow cytometry. Cytotoxicity assays were performed using (51)Cr-labeled K562 target cells. RESULTS: In cohort II, NK cell counts were lower than the lower limit of normal in active GPA, despite normal percentages due to lymphopenia. NK cell counts, but not other lymphocyte counts, were significantly higher in remission. Combined analysis of cohorts I and II confirmed decreased NK cell counts in active GPA and increased percentages in long-term remission. Follow-up measurements of six patients revealed increasing NK cell percentages during successful induction therapy. Multicolor analysis from cohort II revealed that in active GPA, the CD56(dim) subset was responsible for decreased NK cell counts, expressed more frequently CD69, downregulated the Fc-receptor CD16 and upregulated the adhesion molecule CD54, the chemokine receptor CCR5 and the activating receptor NKG2C. In remission, these markers were unaltered or marginally altered. All other receptors investigated (NKp30, NKp44, NKp46, NKG2D, DNAM1, 2B4, CRACC, 41BB) remained unchanged. Natural cytotoxicity was not detectable in most patients with active GPA, but was restored in remission. CONCLUSIONS: NK cell numbers correlate inversely with GPA activity. Reduced CD56(dim) NK cells in active GPA have an activated phenotype, which intriguingly is associated with profound deficiency in cytotoxicity. These data suggest a function for NK cells in the pathogenesis and/or modulation of inflammation in GPA. NK cell numbers, phenotype (CD16, CD69, NKG2C) or overall natural cytotoxicity are promising candidates to serve as clinical biomarkers to determine GPA activity.


Assuntos
Granulomatose com Poliangiite/imunologia , Células Matadoras Naturais/imunologia , Subpopulações de Linfócitos/imunologia , Adulto , Idoso , Antígeno CD56/imunologia , Estudos de Coortes , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo
18.
J Rheumatol ; 43(8): 1566-74, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27252419

RESUMO

OBJECTIVE: Rituximab (RTX) has been used successfully for the treatment of severe Jo1 antibody-associated antisynthetase syndrome. The aim of this retrospective study was to evaluate the effect of RTX in severe Jo1 antisynthetase syndrome and determine predictive factors for response. METHODS: There were 61 patients with Jo1 antisynthetase syndrome identified; 18 of these received RTX. One patient was lost to followup. The remaining 17 patients and 30 out of 43 patients who were treated with conventional immunosuppressive (IS) drugs were followed for a mean of 35 months and 84 months, respectively. RESULTS: Polymyositis/dermatomyositis (95%) and interstitial lung disease (ILD; 66%) were the dominant clinical manifestations. Detection of anti-Ro52 antibodies (43%) was significantly associated with acute-onset ILD (p = 0.016) with O2 dependency, and patients with high concentrations of anti-Ro52 (20%) had the highest risk (p = 0.0005). Sixteen out of 18 patients (89%) showed a fast and marked response to RTX. Among those patients who were highly positive for anti-Ro52, response to RTX was seen in 7 out of 7 cases (100%), but no response to cyclophosphamide (n = 4), cyclosporine A (n = 3), azathioprine (n = 9), methotrexate (n = 5), or leflunomide (n = 2) was observed. One patient treated with RTX died of pneumonia. CONCLUSION: RTX is effective in the treatment of severe forms of Jo1 antisynthetase syndrome. In our retrospective study, the presence of high anti-Ro52 antibody concentrations predicts severe acute-onset ILD and nonresponse to IS drugs. In contrast to conventional IS, RTX is equally effective in patients with Jo1 antisynthetase syndrome, independent of their anti-Ro52 antibody status.


Assuntos
Autoanticorpos/análise , Dermatomiosite/tratamento farmacológico , Imunossupressores/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Miosite/tratamento farmacológico , Ribonucleoproteínas/imunologia , Rituximab/uso terapêutico , Adulto , Idoso , Dermatomiosite/imunologia , Feminino , Humanos , Doenças Pulmonares Intersticiais/imunologia , Masculino , Pessoa de Meia-Idade , Miosite/imunologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
19.
Ann Rheum Dis ; 75(5): 924-32, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-25985971

RESUMO

BACKGROUND: Cross-talk between synovial fibroblasts (SF) and immune cells is suggested to play a crucial role in inflammation and chronification of rheumatoid arthritis (RA). The contribution of B cells in this process is poorly defined. METHODS: Here, primary B cells from healthy donors were polyclonally activated and cocultured with SF of non-synovitic origin from patients with osteoarthritis. RESULTS: In B-SF cocultures the concentrations of interleukin 6 (IL-6) and IL-8 increased manifold compared with single cultures even under physical separation and remained stable for several days after B-cell removal. Intracellular staining confirmed SF as key producers of IL-6 and IL-8, and B cells as main producers of tumour necrosis factor alpha (TNFα) and IL-1ß. Blocking experiments with a combination of anti-TNFα-antibodies and rIL-1RA significantly reduced SF cytokine production by up to 90%, suggesting that B-cell-derived TNFα and IL-1ß were crucial mediators of SF activation. Interestingly, B-cell cytokine production, CD25 expression and proliferation decreased in cocultures by at least 50%, demonstrating a negative regulatory loop towards the activated B cells. Inhibition of activin receptor-like kinase 5, a crucial component of the tumour growth factor ß (TGFß) signalling pathway, partly restored B-cell proliferation, suggesting a contribution of SF-derived TGFß in B-cell suppression. Besides cytokines, B-cell-activated SF also upregulated secretion of matrix metalloproteases such as MMP-3, thereby acquiring potential tissue destructive properties. This was confirmed by their invasion into human cartilage in the severe combined immunodeficiency mouse fibroblast invasion model in vivo. CONCLUSIONS: Interaction with activated B cells leads to conversion of non-arthritic SF into SF with a proinflammatory and aggressive RA-like phenotype, thereby suggesting a new, so far unrecognised role for B cells in RA pathogenesis.


Assuntos
Linfócitos B/imunologia , Cartilagem Articular/imunologia , Fibroblastos/imunologia , Ativação Linfocitária/imunologia , Osteoartrite/imunologia , Animais , Artrite Reumatoide/imunologia , Técnicas de Cocultura , Citocinas/biossíntese , Xenoenxertos , Humanos , Tolerância Imunológica/imunologia , Mediadores da Inflamação/metabolismo , Interleucina-1beta/imunologia , Metaloproteinases da Matriz/biossíntese , Camundongos SCID , Transdução de Sinais/imunologia , Líquido Sinovial/imunologia , Fator de Crescimento Transformador beta/imunologia , Fator de Necrose Tumoral alfa/imunologia
20.
Rheumatology (Oxford) ; 55(4): 689-96, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26667214

RESUMO

OBJECTIVE: Cryopyrin-associated periodic syndrome (CAPS) is a heterogeneous group of diseases characterized by excessive IL-1ß release resulting in severe systemic and organ inflammation. Canakinumab targets IL-1ß and is approved at standard dose for children and adults with all CAPS phenotypes. Limited data are available for the real-life effectiveness of canakinumab in patients living with CAPS. Therefore the aim of the study was to evaluate the real-life dosing and effectiveness of canakinumab in CAPS. METHODS: A multi-centre study of consecutive children and adults with CAPS treated with canakinumab was performed. Demographics, CAPS phenotype and disease activity, inflammatory markers and canakinumab treatment strategy were recorded. Treatment response was assessed using CAPS disease activity scores, CRP and/or serum amyloid A levels. Comparisons between age groups, CAPS phenotypes and centres were conducted. RESULTS: A total of 68 CAPS patients at nine centres were included. All CAPS phenotypes were represented. Thirty-seven (54%) patients were females, the median age was 25 years and 27 (40%) were children, and the median follow-up was 28 months. Overall, complete response (CR) was seen in 72% of CAPS patients, significantly less often in severe (14%) than in mild CAPS phenotypes (79%). Only 53% attained CR on standard dose canakinumab. Dose increase was more commonly required in children (56%) than in adults (22%). Centres with a treat-to-target approach had significantly higher CR rates (94 vs 50%). CONCLUSION: Real-life effectiveness of canakinumab in CAPS was significantly lower than in controlled trials. Treat-to-target strategies may improve the outcome of children and adults living with CAPS.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Adolescente , Adulto , Fatores Etários , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Interleucina-1beta/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
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