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1.
Nat Commun ; 10(1): 5120, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31719529

RESUMO

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.

2.
Z Rheumatol ; 78(9): 832-838, 2019 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-31197458

RESUMO

This article presents a retrospective analysis of patients who attended a rheumatology specialist practice (with two specialist rheumatologists) between 2016 and 2018 via an appointment arranged by the appointment service office (Terminservicestelle, TSS). Patients were analyzed in a pseudonymized manner and categorized according to the following criteria: 1. patient did not keep the appointment, 2. patient had no inflammatory rheumatic disease, 3. patient suffered from an inflammatory rheumatic disease but had no urgent indications to be seen and 4. patient suffered from an inflammatory rheumatic disease with urgent indications to be seen. Since the start of the TSS at the beginning of 2016 until the end of 2018 a total of 103 patients were allocated to this specialist practice via the TSS. An appointment was offered to 102 patients who underwent further analysis: 4.9% of the patients (n = 5) suffered from an acute inflammatory rheumatic disease and had urgent indications to be seen, 18.63% of patients (n = 19) suffered from an inflammatory rheumatic disease with no urgent indications to attend, 28.43% of patients (n = 29) did not keep the appointment and 48.04% of patients (n = 49) did not have an inflammatory rheumatic disease but other diseases, such as osteoarthritis, fibromyalgia and other forms of chronic pain syndromes. The positive predictive value (PPV) for patients with inflammatory rheumatic disease and urgent indications was 0.05 when all patients were included in the analysis and 0.07 when only patients who showed up were included. This retrospective analysis demonstrates that the TSS does not fulfill its purpose, namely to promptly arrange appointments at a specalist rheumatologist practice for patients with an acute inflammatory rheumatic disease.


Assuntos
Pacientes não Comparecentes , Encaminhamento e Consulta/estatística & dados numéricos , Doenças Reumáticas , Humanos , Pacientes não Comparecentes/estatística & dados numéricos , Estudos Retrospectivos
3.
PLoS One ; 13(12): e0209343, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30586461

RESUMO

BACKGROUND: The TNFSF13B (TNF superfamily member 13b) gene encodes BAFF, a cytokine with a crucial role in the differentiation and activation of B cells. An insertion-deletion variant (GCTGT→A) of this gene, leading to increased levels of BAFF, has been recently implicated in the genetic predisposition to several autoimmune diseases, including multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis. Based on the elevated levels of this cytokine found in patients with giant cell arteritis (GCA) and systemic sclerosis (SSc), we aimed to assess whether this functional variant also represents a novel genetic risk factor for these two disorders. METHODS: A total of 1,728 biopsy-proven GCA patients from 4 European cohorts, 4,584 SSc patients from 3 European cohorts and 5,160 ethnically-matched healthy controls were included in the study. The single nucleotide polymorphism (SNP) rs374039502, which colocalizes with the genetic variant previously implicated in autoimmunity, was genotyped using a custom TaqMan assay. First, association analysis was conducted in each independent cohort using χ2 test in Plink (v1.9). Subsequently, different case/control sets were meta-analyzed by the inverse variance method. RESULTS: No statistically significant differences were found when allele distributions were compared between cases and controls for any of the analyzed cohorts. Similarly, combined analysis of the different sets evidenced a lack of association of the rs374039502 variant with GCA (P = 0.421; OR (95% CI) = 0.92 (0.75-1.13)) and SSc (P = 0.500; OR (95% CI) = 1.05 (0.91-1.22)). The stratified analysis considering the main clinical subphenotypes of these diseases yielded similar negative results. CONCLUSION: Our data suggest that the TNFSF13B functional variant does not contribute to the genetic network underlying GCA and SSc.


Assuntos
Fator Ativador de Células B/genética , Predisposição Genética para Doença , Arterite de Células Gigantes/genética , Escleroderma Sistêmico/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Estudos de Casos e Controles , Estudos de Coortes , Europa (Continente) , Feminino , Redes Reguladoras de Genes/genética , Técnicas de Genotipagem , Arterite de Células Gigantes/patologia , Humanos , Mutação INDEL , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/patologia
5.
RMD Open ; 3(1): e000449, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28955487

RESUMO

The European League Against Rheumatism recommendations for the management of antineutrophil cytoplasmic antibody-associated vasculitis have been recently published. Unique to recommendation development, they were also voted on by members of a learned society. This paper explores the wider validity of the recommendations among people who self-identify as clinicians caring for patients with vasculitis. In addition to the task force, a learned society (European Vasculitis Society-EUVAS) was invited, through online survey, to rate independently the strength of evidence of each recommendation to obtain an indication of the agreement among the final target audience and ultimate end-users of the recommendations. The survey took place in June 2015. Of the 158 EUVAS members surveyed, there were 88 responses (55.7%). There was a large degree of agreement in the voting patterns between EUVAS survey participants and task force members. Notable exceptions were lower grades for the recommendation of the use of rituximab for remission induction in patients with eosinophilic granulomatosis with polyangiitis and for methotrexate and mycophenolate mofetil as remission maintenance agents in patients with granulomatosis with polyangiitis/microscopic polyangiitis by EUVAS members. These results are encouraging and suggest that the voting patterns of the task force are representative of the wider vasculitis community. We recommend future recommendations adopt this approach for data/expert-based treatment guidelines, especially for multisystem diseases.

6.
Clin Exp Rheumatol ; 35 Suppl 103(1): 33-39, 2017 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28281454

RESUMO

OBJECTIVES: The aim of this study was to analyse the role of netting neutrophils in the pathogenesis of granulomatosis with polyangiitis (GPA), especially their interplay with peripheral blood mononuclear cells (PBMCs). METHODS: The amount of cell-free DNA (cfDNA) was determined in sera from GPA patients (pairs active/inactive state of disease, n=18) and from healthy controls (HCs, n=10). Furthermore, we performed in vitro incubation experiments using PBMCs and NETs from patients and HCs for accessing the effect of NETs on PBMC behaviour. We determined proliferation of T- and B-cells (CSFE assay), B-cell maturation (CD38 staining and flow cytometry), production of IgG (ELISpot, ELISA), and secretion of the cytokines IFN-γ, IL-4, IL-10, IL-17A (ELISA). RESULTS: We detected a significant increase in serum cfDNA levels of GPA patients compared to HCs. The concentration of cfDNA was associated with disease activity. NETs of patients and HCs induced proliferation of CD4+ T- cells and CD19+ B-cells and maturation of B-cells. Furthermore, we detected an increase in IL-17A secretion after stimulating PBMCs with NETs. A significant difference between PBMCs from GPA patients and HCs was not detectable. CONCLUSIONS: NETs activate PBMCs of HCs and GPA patients. Our findings give supportive evidence that NETosis plays a role in the pathogenesis of GPA.


Assuntos
Linfócitos B/imunologia , Armadilhas Extracelulares/imunologia , Granulomatose com Poliangiite/imunologia , Ativação Linfocitária , Neutrófilos/imunologia , Comunicação Parácrina , Linfócitos T/imunologia , Linfócitos B/metabolismo , Biomarcadores/sangue , Estudos de Casos e Controles , Proliferação de Células , Células Cultivadas , DNA/sangue , Armadilhas Extracelulares/metabolismo , Feminino , Granulomatose com Poliangiite/sangue , Granulomatose com Poliangiite/diagnóstico , Humanos , Interleucina-17/sangue , Masculino , Neutrófilos/metabolismo , Fenótipo , Linfócitos T/metabolismo , Células Th17/imunologia , Células Th17/metabolismo
7.
Am J Hum Genet ; 100(1): 64-74, 2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-28041642

RESUMO

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analyzed in 2,134 case subjects and 9,125 unaffected individuals from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, p = 1.94 × 10-54, per-allele OR = 1.79; and rs9275592, p = 1.14 × 10-40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, p = 1.23 × 10-10, OR = 1.28; and rs128738, p = 4.60 × 10-9, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis.


Assuntos
Alelos , Predisposição Genética para Doença/genética , Variação Genética , Estudo de Associação Genômica Ampla , Arterite de Células Gigantes/genética , Plasminogênio/genética , Prolil Hidroxilases/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Europa (Continente)/etnologia , Feminino , Humanos , Masculino , Neovascularização Fisiológica , Polimorfismo de Nucleotídeo Único/genética , Risco
9.
Clin Exp Rheumatol ; 35 Suppl 103(1): 94-97, 2017 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27974093

RESUMO

OBJECTIVES: To date, no specific serum marker for giant cell arteritis and polymyalgia rheumatica has been established in routine practice. Therefore, the aim of this study was to examine whether immunoglobulin G4 serum concentrations could be a potential biomarker for the differentiation of both diseases. METHODS: Serum immunoglobulin G4 (IgG4) concentrations were measured in patients with giant cell arteritis (n=41) and polymyalgia rheumatica (n=27) by an in-house enzyme-linked immunosorbent assay. In the subgroup of untreated patients with disease activity (polymyalgia rheumatica n=27, giant cell arteritis n=19) additional parameters of T-helper 2 cell inflammatory responses were analysed. RESULTS: IgG4-values above the prior determined cut-off value of 1400 µg/ml in giant cell arteritis were rare and also significantly less frequent in giant cell arteritis than in polymyalgia rheumatica patients (7.3% vs. 44.4%; p<0.001). The relative risk that patients with clinical features of PMR, presenting without elevated IgG4 levels, have simultaneously GCA was 5.8 compared to those patients with elevated IgG4 levels. In untreated patients absolute counts of eosinophilic leukocytes were lower in giant cell arteritis than in polymyalgia rheumatica (p=0.002) and the cytokines interleukin-4 (p=0.013) and interleukin-10 (p=0.033) were less frequently detectable in giant cell arteritis than in polymyalgia rheumatica. CONCLUSIONS: In giant cell arteritis serum levels of IgG4 usually are within the normal range. In polymyalgia rheumatica however, increased IgG4 serum levels are frequently found. Normal IgG4 serum levels in polymyalgia rheumatica may have predictive value in identifying patients with additional, clinically non-apparent giant cell arteritis.


Assuntos
Arterite de Células Gigantes/sangue , Imunoglobulina G/sangue , Polimialgia Reumática/sangue , Idoso , Biomarcadores/sangue , Diagnóstico Diferencial , Ensaio de Imunoadsorção Enzimática , Feminino , Arterite de Células Gigantes/diagnóstico por imagem , Arterite de Células Gigantes/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Polimialgia Reumática/diagnóstico por imagem , Polimialgia Reumática/imunologia , Valor Preditivo dos Testes , Regulação para Cima
10.
Arthritis Rheumatol ; 68(12): 2953-2963, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27333332

RESUMO

OBJECTIVE: To compare the phenotype, clinical course, and outcome of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-positive granulomatosis with polyangiitis (Wegener's) (GPA) to proteinase 3 (PR3)-ANCA-positive GPA and to MPO-ANCA-positive microscopic polyangiitis (MPA). METHODS: We characterized all MPO-ANCA-positive patients classified as having GPA by the European Medicines Agency algorithm who attended our center, in a retrospective chart review. A second cohort of patients with PR3-ANCA-positive GPA matched for age and sex was characterized. Patients with MPO-ANCA-positive MPA from a recently published cohort were also included in the analysis. All patients were diagnosed and treated according to a standardized interdisciplinary approach at a vasculitis referral center. RESULTS: Comprehensive data were available for 59 patients with MPO-ANCA-positive GPA, and they were compared to 118 patients with PR3-ANCA-positive GPA and 138 patients with MPO-ANCA-positive MPA. We observed a distinct phenotype in MPO-ANCA-positive GPA as compared to the other 2 cohorts. Patients with MPO-ANCA-positive GPA frequently had limited disease without severe organ involvement, had a high prevalence of subglottic stenosis, and had less need for aggressive immunosuppressive therapy (cyclophosphamide/rituximab). The patients with MPO-ANCA-positive GPA were also younger than the MPA patients and were predominantly female (significantly different than the MPA cohort). While GPA patients had higher survival rates compared to MPA patients (due to a high prevalence of pulmonary fibrosis in MPA), patients with MPO-ANCA had significantly lower relapse rates than those with PR3-ANCA. CONCLUSION: Patients with MPO-ANCA-positive GPA show significantly different clinical courses compared to those with PR3-ANCA-positive GPA or MPO-ANCA-positive MPA, which should be considered in their clinical management. Classification according to ANCA specificity may improve the evaluation of relapse risk.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/imunologia , Granulomatose com Poliangiite/imunologia , Peroxidase/imunologia , Adolescente , Adulto , Distribuição por Idade , Idoso , Estudos de Casos e Controles , Ciclofosfamida/uso terapêutico , Oftalmopatias/epidemiologia , Oftalmopatias/etiologia , Feminino , Alemanha , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/tratamento farmacológico , Granulomatose com Poliangiite/epidemiologia , Humanos , Fatores Imunológicos/uso terapêutico , Imunossupressores/uso terapêutico , Nefropatias/epidemiologia , Nefropatias/etiologia , Laringoestenose/epidemiologia , Laringoestenose/etiologia , Masculino , Pessoa de Meia-Idade , Mieloblastina/imunologia , Otorrinolaringopatias/epidemiologia , Otorrinolaringopatias/etiologia , Doenças do Sistema Nervoso Periférico/epidemiologia , Doenças do Sistema Nervoso Periférico/etiologia , Modelos de Riscos Proporcionais , Recidiva , Estudos Retrospectivos , Rituximab/uso terapêutico , Taxa de Sobrevida , Adulto Jovem
11.
Pharmacogenomics ; 17(4): 367-74, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26894931

RESUMO

AIM: Correlation of outcomes of cyclophosphamide (CP) therapy in antineutrophil cytoplasmic antibody-associated vasculitis with genotype polymorphisms in prodrug activating cytochrome P450 enzyme genes CYP2C9 and CYP2C19. PATIENTS & METHODS: One hundred and ninety six patients with antineutrophil cytoplasmic antibody-associated vasculitis treated with CP, either as intravenous pulse or as daily oral medication, were included. Genotypes of CYP2C9 and CYP2C19 were correlated with clinical outcomes (leukopenia, infection, urotoxicity and treatment response). RESULTS: Sixty five (33.2%) patients had variant CYP2C9 and 55 (28.1%) had variant CYP2C19 genotype. In patients bearing variant CYP2C9, leukopenia was documented significantly more frequent than in carriers of wild-type CYP2C9 (55.4 vs 37.4%; odds ratio: 2.08; 95% CI: 1.14-3.80; p = 0.017). The impact of the CYP2C9 genotype was stronger in patients treated with oral CP (69.6 vs 45.6%; odds ratio: 2.73; 95% CI: 1.27-5.89; p = 0.009), but was not present in patients treated with intravenous pulsed CP. We observed less refractory disease courses in patients with variant CYP2C9, not reaching statistical significance. CONCLUSION: Patients with variant CYP2C9 are at increased risk for cyclophosphamide-induced leukopenia but may have a better chance to respond to treatment.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Ciclofosfamida/efeitos adversos , Citocromo P-450 CYP2C9/genética , Imunossupressores/efeitos adversos , Leucopenia/induzido quimicamente , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Resultado do Tratamento , Adulto Jovem
12.
Rheumatology (Oxford) ; 55(1): 71-9, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26297628

RESUMO

OBJECTIVE: To evaluate the clinical presentation and long-term outcome of a vasculitis centre cohort of patients with microscopic polyangiitis (MPA) with respect to organ manifestations, treatment, chronic damage and mortality. METHODS: We performed a retrospective chart review at our vasculitis referral centre. MPA patients admitted between 1991 and 2013 classified by a modified European Medicines Agency algorithm were diagnosed and treated according to a standardized interdisciplinary approach. RESULTS: Comprehensive data from standardized interdisciplinary workups was available for 144 patients (median follow-up 72 months). The overall standardized mortality ratio was 1.40 (95% CI 0.91, 2.07; P = 0.13). We observed a higher mortality [hazard ratio (HR) 4.04 (95% CI 1.21, 13.45), P = 0.02] in 17 patients with MPA-associated fibrosing interstitial lung disease (ILD) and 56 patients with peripheral nervous system involvement [HR 5.26 (95% CI 1.10, 25.14), P = 0.04] at disease onset. One hundred and fifteen patients (79.9%) responded to the initial treatment. Sixty-one (42.3%) achieved complete remission and 54 (37.5%) achieved partial remission. Twenty (13.9%) showed a refractory disease course. CONCLUSION: MPA patients at our tertiary rheumatology referral centre seemed to have a less severe phenotype resulting in a less severe disease course and better outcome than reported in other cohorts. Fibrosing ILD was significantly associated with mortality in this cohort.


Assuntos
Poliangiite Microscópica/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Seguimentos , Alemanha/epidemiologia , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Incidência , Masculino , Poliangiite Microscópica/tratamento farmacológico , Poliangiite Microscópica/epidemiologia , Pessoa de Meia-Idade , Indução de Remissão/métodos , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Fatores de Tempo , Adulto Jovem
13.
Rhinology ; 53(3): 277-85, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26363169

RESUMO

INTRODUCTION: Besides an obvious clinical involvement of the ear, nose and throat (ENT)-region in Eosinophilic Granulomatosis with Polyangiitis (EGPA), systematic data is sparse. Only a few case series and case reports are available that particularly describe rhinological, otological or other manifestations of EGPA in the ENT-region. Therefore, the objective of this study is to systematically describe data on ENT-region involvement in a large series of EGPA patients. METHOD: EGPA patients examined in the Department of Otorhinolaryngology of the Christian-Albrechts-University of Kiel between 1990 and 2010 were included in the study. Criteria for ENT-manifestation were assigned to five subgroups (history, ENT examination, audiological and rhinological diagnostic findings and cranial MRI) and documented cumulatively. EGPA patients were examined in a standardized way based on the validated Ear Nose and Throat Activity Score (ENTAS) or its precursor, including audiological and rhinological diagnostic findings. MRI scans were analysed to further evaluate ENT involvement. RESULTS: A total of 95 EGPA patients were included in the study. In approximately 80% of them, ENT-involvement was documented and the assumption of a frequent rhinological manifestation in patients with EGPA was confirmed. Moreover, the data reveals remarkable evidence for an otological manifestation. A missing correlation between the rhinological and the otological manifestation indicates an independent autoimmune-inflammatory process for this manifestation. CONCLUSION: The data of the largest monocentric study presented here confirms the hypothesis of a frequent ENT involvement in EGPA patients, in whom rhinological and otological manifestations are most common. Therefore, treatment should include long term follow-up and should be managed interdisciplinary.


Assuntos
Eosinofilia/complicações , Eosinofilia/diagnóstico , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/diagnóstico , Otorrinolaringopatias/diagnóstico , Otorrinolaringopatias/etiologia , Adolescente , Adulto , Idoso , Eosinofilia/terapia , Feminino , Granulomatose com Poliangiite/terapia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Otorrinolaringopatias/terapia , Estudos Retrospectivos , Rinomanometria , Adulto Jovem
15.
Eur J Intern Med ; 26(7): 545-53, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25971154

RESUMO

OBJECTIVE: To develop disease-specific recommendations for the diagnosis and management of eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) (EGPA). METHODS: The EGPA Consensus Task Force experts comprised 8 pulmonologists, 6 internists, 4 rheumatologists, 3 nephrologists, 1 pathologist and 1 allergist from 5 European countries and the USA. Using a modified Delphi process, a list of 40 questions was elaborated by 2 members and sent to all participants prior to the meeting. Concurrently, an extensive literature search was undertaken with publications assigned with a level of evidence according to accepted criteria. Drafts of the recommendations were circulated for review to all members until final consensus was reached. RESULTS: Twenty-two recommendations concerning the diagnosis, initial evaluation, treatment and monitoring of EGPA patients were established. The relevant published information on EGPA, antineutrophil-cytoplasm antibody-associated vasculitides, hypereosinophilic syndromes and eosinophilic asthma supporting these recommendations was also reviewed. DISCUSSION: These recommendations aim to give physicians tools for effective and individual management of EGPA patients, and to provide guidance for further targeted research.


Assuntos
Síndrome de Churg-Strauss/diagnóstico , Síndrome de Churg-Strauss/tratamento farmacológico , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/tratamento farmacológico , Comitês Consultivos , Consenso , Gerenciamento Clínico , Europa (Continente) , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Rituximab/uso terapêutico , Estados Unidos
18.
PLoS One ; 8(7): e69022, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23894397

RESUMO

OBJECTIVE: Immunosuppression is cornerstone treatment of antineutrophil cytoplasmic antibody associated vasculitis (AAV) but is later complicated by infection, cancer, cardiovascular and chronic kidney disease. Caveolin-1 is an essential structural protein for small cell membrane invaginations known as caveolae. Its functional role has been associated with these complications. For the first time, caveolin-1 (CAV1) gene variation is studied in AAV. METHODS: CAV1 single nucleotide polymorphism rs4730751 was analysed in genomic DNA from 187 white patients with AAV from Birmingham, United Kingdom. The primary outcome measure was the composite endpoint of time to all-cause mortality or renal replacement therapy. Secondary endpoints included time to all-cause mortality, death from sepsis or vascular disease, cancer and renal replacement therapy. Validation of results was sought from 589 white AAV patients, from two European cohorts. RESULTS: The primary outcome occurred in 41.7% of Birmingham patients. In a multivariate model, non-CC genotype variation at the studied single nucleotide polymorphism was associated with increased risk from: the primary outcome measure [HR 1.86; 95% CI: 1.14-3.04; p=0.013], all-cause mortality [HR:1.83; 95% CI: 1.02-3.27; p=0.042], death from infection [HR:3.71; 95% CI: 1.28-10.77; p=0.016], death from vascular disease [HR:3.13; 95% CI: 1.07-9.10; p=0.037], and cancer [HR:5.55; 95% CI: 1.59-19.31; p=0.007]. In the validation cohort, the primary outcome rate was far lower (10.4%); no association between genotype and the studied endpoints was evident. CONCLUSIONS: The presence of a CC genotype in Birmingham is associated with protection from adverse outcomes of immunosuppression treated AAV. Lack of replication in the European cohort may have resulted from low clinical event rates. These findings are worthy of further study in larger cohorts.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/genética , Caveolina 1/genética , Polimorfismo de Nucleotídeo Único , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/mortalidade , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/terapia , Estudos de Coortes , Europa (Continente) , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Reino Unido
20.
Rheumatology (Oxford) ; 52(7): 1183-9, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23407387

RESUMO

OBJECTIVE: The aim of the study was to characterize the expression of TLR2, TLR4 and TLR9 in PMNs of patients with granulomatosis with polyangiitis (GPA) and to elucidate the role of these receptors in GPA with respect to neutrophil activation. METHODS: The expression of TLR2, TLR4 and TLR9 was determined on ex vivo PMNs in whole blood samples of GPA patients (n = 35) and healthy controls (HCs) (n = 24). Isolated PMNs were stimulated in vitro with TLR agonists and assessed for degranulation, membrane proteinase 3 (mPR3) expression, soluble l-selectin shedding and cytokine production (IL-8) in five GPA patients and five HCs. The priming effects of TLR2 and TLR9 ligation were assessed by measurement of serine protease activity after stimulation with PR3-ANCA. RESULTS: There were no significant differences in the ex vivo expression of TLRs on PMNs in HCs and GPA patients. Stimulation of TLR4 and TLR9 induced MPO release, stimulation with TLR2, TLR4 and TLR9 ligands elicited IL-8 production and stimulation of TLR2 and TLR9 led to an upregulation in mPR3 expression on PMNs with no significant differences between GPA and HC after 1 or 24 h stimulation. Priming of PMNs with TLR2 and TLR9 ligands induced degranulation after subsequent stimulation with PR3-ANCA, which was comparable to priming with TNF-α. CONCLUSION: Expression of TLR2, TLR4 and TLR9 in PMNs and the TLR-induced activation of PMNs was comparable in GPA and HC. mPR3 upregulation by TLR2 and TLR9 stimulation and the priming effect of TLR ligands on PMNs may have a potential implication for triggering disease activity during infection in GPA.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/metabolismo , Ativação de Neutrófilo/fisiologia , Neutrófilos/metabolismo , Receptor 2 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/fisiopatologia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Interleucina-8/metabolismo , Masculino , Metaloproteinase 16 da Matriz/metabolismo , Pessoa de Meia-Idade , Peroxidase/metabolismo , Receptor 4 Toll-Like/metabolismo , Regulação para Cima , Adulto Jovem
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