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Takayasu arteritis is a rare inflammatory disease of large arteries. We performed a genetic study in Takayasu arteritis comprising 6,670 individuals (1,226 affected individuals) from five different populations. We discovered HLA risk factors and four non-HLA susceptibility loci in VPS8, SVEP1, CFL2, and chr13q21 and reinforced IL12B, PTK2B, and chr21q22 as robust susceptibility loci shared across ancestries. Functional analysis proposed plausible underlying disease mechanisms and pinpointed ETS2 as a potential causal gene for chr21q22 association. We also identified >60 candidate loci with suggestive association (p < 5 × 10-5) and devised a genetic risk score for Takayasu arteritis. Takayasu arteritis was compared to hundreds of other traits, revealing the closest genetic relatedness to inflammatory bowel disease. Epigenetic patterns within risk loci suggest roles for monocytes and B cells in Takayasu arteritis. This work enhances understanding of the genetic basis and pathophysiology of Takayasu arteritis and provides clues for potential new therapeutic targets.
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Predisposição Genética para Doença/genética , Arterite de Takayasu/genética , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Doenças Inflamatórias Intestinais/genética , Masculino , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
OBJECTIVES: This study aimed to identify plasma proteomic signatures that differentiate active and inactive giant cell arteritis (GCA) from non-disease controls. By comprehensively profiling the plasma proteome of both patients with GCA and controls, we aimed to identify plasma proteins that (1) distinguish patients from controls and (2) associate with disease activity in GCA. METHODS: Plasma samples were obtained from 30 patients with GCA in a multi-institutional, prospective longitudinal study: one captured during active disease and another while in clinical remission. Samples from 30 age-matched/sex-matched/race-matched non-disease controls were also collected. A high-throughput, aptamer-based proteomics assay, which examines over 7000 protein features, was used to generate plasma proteome profiles from study participants. RESULTS: After adjusting for potential confounders, we identified 537 proteins differentially abundant between active GCA and controls, and 781 between inactive GCA and controls. These proteins suggest distinct immune responses, metabolic pathways and potentially novel physiological processes involved in each disease state. Additionally, we found 16 proteins associated with disease activity in patients with active GCA. Random forest models trained on the plasma proteome profiles accurately differentiated active and inactive GCA groups from controls (95.0% and 98.3% in 10-fold cross-validation, respectively). However, plasma proteins alone provided limited ability to distinguish between active and inactive disease states within the same patients. CONCLUSIONS: This comprehensive analysis of the plasma proteome in GCA suggests that blood protein signatures integrated with machine learning hold promise for discovering multiplex biomarkers for GCA.
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OBJECTIVES: To evaluate damage and clinical characteristics associated with damage in Takayasu's arteritis (TAK). METHODS: Patients with TAK enrolled in a multicentre, prospective, observational study underwent standardized damage assessment every 6 months using the Vasculitis Damage Index (VDI) and the Large-Vessel Vasculitis Index of Damage (LVVID). RESULTS: The study included 236 patients with TAK: 92% female, 81% Caucasian; median (25th, 75th percentile) disease duration = 2.6 (0.12, 6.9) years. Eighty-four percent had follow-up: median (25th, 75th) duration 4.1 (1.9, 7.5) years.Items of damage were present in 89% on VDI, 87% on LVVID, in the peripheral vascular (76% VDI, 74% LVVID), cardiac (40% VDI, 45% LVVID) systems. During follow-up, 42% patients had new damage;, including major vessel stenosis/arterial occlusion (8%), limb claudication (6%), hypertension (7%), aortic aneurysm (4%), and bypass surgery (4%). Disease-specific damage accounted for >90% new items. Older age, relapse, and longer duration of follow-up were associated with new damage items; a higher proportion of patients without new damage were on methotrexate (p< 0.05). Among 48 patients diagnosed with TAK within 180 days of enrolment, new damage occurred in 31% on VDI and 52% on LVVID. History of relapse was associated with new damage in the entire cohort while in patients with a recent diagnosis, older age at diagnosis was associated with new damage. CONCLUSION: Damage is present in > 80% of patients with TAK even with recent diagnosis and >40% of patients accrue new, mainly disease-specific damage. Therapies for TAK that better control disease activity and prevent damage should be prioritized.
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Levels of neutrophil extracellular traps (NETs) were measured in plasma of healthy controls (HC, n = 30) and patients with granulomatosis with polyangiitis (GPA, n = 123), microscopic polyangiitis (MPA, n = 61), Takayasu's arteritis (TAK, n = 58), and giant cell arteritis (GCA, n = 68), at times of remission or activity and correlated with levels of the platelet-derived thrombospondin-1 (TSP-1). Levels of NETs were elevated during active disease in patients with GPA (p < 0.0001), MPA (p = 0.0038), TAK (p < 0.0001), and GCA (p < 0.0001), and in remission for GPA, p < 0.0001, MPA, p = 0.005, TAK, p = 0.03, and GCA, p = 0.0009. All cohorts demonstrated impaired NET degradation. Patients with GPA (p = 0.0045) and MPA (p = 0.005) had anti-NET IgG antibodies. Patients with TAK had anti-histone antibodies (p < 0.01), correlating with presence of NETs. Levels of TSP-1 were increased in all patients with vasculitis, and associated with NET formation. NET formation is a common process in vasculitides. Targeting NET formation or degradation could be potential therapeutic approaches for vasculitides.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Armadilhas Extracelulares , Arterite de Células Gigantes , Granulomatose com Poliangiite , Poliangiite Microscópica , Arterite de Takayasu , Trombospondina 1 , Humanos , Masculino , Feminino , Criança , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Armadilhas Extracelulares/metabolismo , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Estudos de Casos e Controles , Granulomatose com Poliangiite/metabolismo , Arterite de Células Gigantes/metabolismo , Poliangiite Microscópica/metabolismo , Arterite de Takayasu/metabolismo , Neutrófilos , Trombospondina 1/metabolismoRESUMO
Markers of extracellular mitochondria are present in giant cell arteritis (GCA) patients. However, their role in promoting inflammation and platelet activation is no known. To investigate this, isolated mitochondria were opsonized with plasma from GCA patients or healthy individuals and incubated with peripheral blood mononuclear cells (PBMCs) or platelets and assessed for inflammatory cytokine production and platelet activation. Plasma from GCA patients promoted increased mitochondrial-mediated cytokine production by PBMCs as compared to healthy controls (p < 0.05). Mitochondria opsonized with plasma factors from patients with GCA induced higher platelet activation as compared to mitochondria opsonized with plasma factors from healthy individuals (p = 0.0015). Platelet levels of P-selectin were associated with disease activity in GCA (r = 0.34, p = 0.01). GCA patients have impaired ability to regulate the clearance of extracellular mitochondria, possibly contributing to excessive inflammation and platelet activation. Targeting key drivers of mitochondrial extrusion and/or their clearance could lead to new therapeutic interventions in GCA.
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Arterite de Células Gigantes , Humanos , Leucócitos Mononucleares , Inflamação , Ativação Plaquetária , CitocinasRESUMO
OBJECTIVE: Following induction of remission with rituximab in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) relapse rates are high, especially in patients with history of relapse. Relapses are associated with increased exposure to immunosuppressive medications, the accrual of damage and increased morbidity and mortality. The RITAZAREM trial compared the efficacy of repeat-dose rituximab to daily oral azathioprine for prevention of relapse in patients with relapsing AAV in whom remission was reinduced with rituximab. METHODS: RITAZAREM was an international randomised controlled, open-label, superiority trial that recruited 188 patients at the time of an AAV relapse from 29 centres in seven countries between April 2013 and November 2016. All patients received rituximab and glucocorticoids to reinduce remission. Patients achieving remission by 4 months were randomised to receive rituximab intravenously (1000 mg every 4 months, through month 20) (85 patients) or azathioprine (2 mg/kg/day, tapered after month 24) (85 patients) and followed for a minimum of 36 months. The primary outcome was time to disease relapse (either major or minor relapse). RESULTS: Rituximab was superior to azathioprine in preventing relapse: HR 0.41; 95% CI 0.27 to 0.61, p<0.001. 19/85 (22%) patients in the rituximab group and 31/85 (36%) in the azathioprine group experienced at least one serious adverse event during the treatment period. There were no differences in rates of hypogammaglobulinaemia or infection between groups. CONCLUSIONS: Following induction of remission with rituximab, fixed-interval, repeat-dose rituximab was superior to azathioprine for preventing disease relapse in patients with AAV with a prior history of relapse. TRIAL REGISTRATION NUMBER: NCT01697267; ClinicalTrials.gov identifier.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Azatioprina , Humanos , Azatioprina/uso terapêutico , Rituximab/uso terapêutico , Imunossupressores/uso terapêutico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Recidiva , Indução de Remissão , Resultado do Tratamento , Ciclofosfamida/uso terapêutico , Anticorpos Anticitoplasma de NeutrófilosRESUMO
OBJECTIVES: ANCA-associated vasculitis (AAV) is a group of multisystem diseases that can have several ocular manifestations. There are published data on ocular manifestations of granulomatosis with polyangiitis (GPA), but few for eosinophilic granulomatosis with polyangiitis (EGPA) or microscopic polyangiitis (MPA). There is little information concerning chronicity, complications, and association with other cranial manifestations of AAV. METHODS: This study retrospectively analysed longitudinal multicentre cohorts of individuals with AAV followed between 2006 and 2022. Data included diagnosis, demographics, cranial manifestations of disease, presence of manifestations at onset of disease and/or follow-up, and ocular complications of disease. Univariate and multivariable logistic regression analysis assessed associations across disease manifestations. RESULTS: Data from 1441 patients were analysed, including 395 with EGPA, 876 with GPA, and 170 with MPA. Ocular manifestations were seen within 23.1% of patients: 39 (9.9%) with EGPA, 287 (32.7%) with GPA, and 12 (7.1%) with MPA at any time in the disease course. There were more ocular manifestations at onset (n = 224) than during follow-up (n = 120). The most common disease-related manifestations were conjunctivitis/episcleritis and scleritis. In multivariable analysis, dacryocystitis, lacrimal duct obstruction, and retro-orbital disease were associated with sinonasal manifestations of GPA; ocular manifestations were associated with hearing loss in MPA. The most common ocular complications and/or damage seen were cataracts (n = 168) and visual impairment (n = 195). CONCLUSION: Ocular manifestations occur in all forms of AAV, especially in GPA. Clinicians should be mindful of the wide spectrum of ocular disease in AAV, caused by active vasculitis, disease-associated damage, and toxicities of therapy.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Síndrome de Churg-Strauss , Granulomatose com Poliangiite , Poliangiite Microscópica , Esclerite , Humanos , Granulomatose com Poliangiite/complicações , Síndrome de Churg-Strauss/complicações , Estudos Retrospectivos , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Poliangiite Microscópica/complicações , Esclerite/etiologia , Anticorpos Anticitoplasma de NeutrófilosRESUMO
OBJECTIVE: To study the prevalence, risk and clinical associations of hypothyroidism among several forms of vasculitis. METHODS: Patients with GCA, Takayasu's arteritis (TAK), PAN and the three forms of ANCA-associated vasculitis [AAV; granulomatosis with polyangiitis (GPA), microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis (EGPA)] enrolled in a prospective, multicentre, longitudinal study were included. RESULTS: The study included data on 2085 patients [63% female, 90% White] with a mean age of 54.6 years (s.d. 17.2). Diagnoses were GCA (20%), TAK (11%), PAN (5%), GPA (42%), microscopic polyangiitis (8%) and EGPA (14%). Hypothyroidism was present in 217 patients (10%) (83% female), with a mean age 59.8 years (s.d. 14.5). Age- and sex-adjusted risk of hypothyroidism was GCA, odds ratio (OR) 0.61 (95% CI 0.41, 0.90); TAK, OR 0.57 (95% CI 0.31, 1.03); PAN, OR 0.59 (95% CI 0.25, 1.38); GPA, OR 1.51 (95% CI 1.12, 2.05); microscopic polyangiitis, OR 1.81 (95% CI 1.18, 2.80) and EGPA, OR 0.82 (95% CI 0.52, 1.30). Among patients with AAV, age- and sex-adjusted risk of hypothyroidism was higher with positive MPO-ANCA [OR 1.89 (95% CI 1.39, 2.76)]. The clinical manifestations of vasculitis were similar in patients with and without hypothyroidism, except transient ischaemic attacks, which were more frequently observed in patients with GCA and hypothyroidism (12% vs 2%; P = 0.001). CONCLUSIONS: Differences in the risk of hypothyroidism among vasculitides may be due to genetic susceptibilities or immune responses. This study confirms an association of hypothyroidism with MPO-ANCA.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Síndrome de Churg-Strauss , Granulomatose com Poliangiite , Hipotireoidismo , Poliangiite Microscópica , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/epidemiologia , Anticorpos Anticitoplasma de Neutrófilos , Síndrome de Churg-Strauss/epidemiologia , Feminino , Humanos , Hipotireoidismo/epidemiologia , Estudos Longitudinais , Masculino , Poliangiite Microscópica/complicações , Poliangiite Microscópica/epidemiologia , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
OBJECTIVES: Only a few small case series, case reports, and one small clinical trial suggested some benefit of leflunomide (LEF) in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and other vasculitides. We analysed the clinical efficacy and tolerability of LEF in a large cohort of patients with various vasculitides. METHODS: This was a retrospective analysis of patients who received LEF for treatment of their vasculitis enrolled in the Vasculitis Clinical Research Consortium (VCRC) Longitudinal Study and in 3 additional centres from the Canadian vasculitis research network (CanVasc). RESULTS: Data for 93 patients were analysed: 45 had granulomatosis with polyangiitis (GPA), 8 microscopic polyangiitis (MPA), 12 eosinophilic granulomatosis with polyangiitis (EGPA), 14 giant-cell arteritis (GCA), 9 Takayasu's arteritis (TAK), and 5 polyarteritis nodosa (PAN). The main reason for initiation of LEF was active disease (89%). LEF was efficacious for remission induction or maintenance at 6 months for 62 (67%) patients (64% with GCA, 89% with TAK, 80% with PAN, 69% with GPA, 75% with MPA, 33% with EGPA); 20% discontinued LEF before achieving remission because of persistent disease activity. Overall, 22 adverse events (gastrointestinal symptoms being the most common) led to drug discontinuation in 18 (19%) patients, of which 12 stopped LEF before month 6, before showing any benefit in 8/12 of these patients. CONCLUSIONS: Leflunomide can be an effective therapeutic option for various vasculitides, especially for non-severe refractory or relapsing ANCA-associated vasculitis or large-vessel vasculitis. No new safety signals for LEF were identified in this population.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Síndrome de Churg-Strauss , Granulomatose com Poliangiite , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Canadá , Humanos , Leflunomida/efeitos adversos , Estudos Longitudinais , Estudos RetrospectivosRESUMO
OBJECTIVES: Evaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial. METHODS: Patients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m2) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse. RESULTS: 188 patients were studied: 95/188 (51%) men, median age 59 years (range 19-89), prior disease duration 5.0 years (range 0.4-34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activity item, and 54/188 (29%) received the higher dose glucocorticoid regimen. 171/188 (90%) patients achieved remission by 4 months. Only six patients (3.2% of the study population) did not achieve disease control at month 4. Four patients died in the induction phase due to pneumonia (2), cerebrovascular accident (1), and active vasculitis (1). 41 severe adverse events occurred in 27 patients, including 13 severe infections. CONCLUSIONS: This large prospective cohort of patients with relapsing AAV treated with rituximab in conjunction with glucocorticoids demonstrated a high level of efficacy for the reinduction of remission in patients with AAV who have relapsed, with a similar safety profile to previous studies.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Antirreumáticos/administração & dosagem , Glucocorticoides/administração & dosagem , Rituximab/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Quimioterapia Combinada , Feminino , Humanos , Quimioterapia de Indução , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVES: To develop and replicate, using data-driven methods, a novel classification system in Takayasu's arteritis based on distribution of arterial lesions. METHODS: Patients were included from four international cohorts at major academic centres: India (Christian Medical College Vellore); North America (National Institutes of Health, Vasculitis Clinical Research Consortium and Cleveland Clinic Foundation). All patients underwent whole-body angiography of the aorta and branch vessels, with categorization of arterial damage (stenosis, occlusion or aneurysm) in 13 territories. K-means cluster analysis was performed to identify subgroups of patients based on pattern of angiographic involvement. Cluster groups were identified in the Indian cohort and independently replicated in the North American cohorts. RESULTS: A total of 806 patients with Takayasu's arteritis from India (n = 581) and North America (n = 225) were included. Three distinct clusters defined by arterial damage were identified in the Indian cohort and replicated in each of the North American cohorts. Patients in cluster one had significantly more disease in the abdominal aorta, renal and mesenteric arteries (P < 0.01). Patients in cluster two had significantly more bilateral disease in the carotid and subclavian arteries (P < 0.01). Compared with clusters one and two, patients in cluster three had asymmetric disease with fewer involved territories (P < 0.01). Demographics, clinical symptoms and clinical outcomes differed by cluster. CONCLUSION: This large study in Takayasu's arteritis identified and replicated three novel subsets of patients based on patterns of arterial damage. Angiographic-based disease classification requires validation by demonstrating potential aetiological or prognostic implications.
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Angiografia por Tomografia Computadorizada/métodos , Arterite de Takayasu/classificação , Arterite de Takayasu/diagnóstico por imagem , Centros Médicos Acadêmicos , Adulto , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/patologia , Análise por Conglomerados , Feminino , Humanos , Incidência , Índia/epidemiologia , Internacionalidade , Masculino , Artérias Mesentéricas/diagnóstico por imagem , Artérias Mesentéricas/patologia , Pessoa de Meia-Idade , América do Norte/epidemiologia , Reprodutibilidade dos Testes , Medição de Risco , Índice de Gravidade de Doença , Artéria Subclávia/diagnóstico por imagem , Artéria Subclávia/patologia , Arterite de Takayasu/epidemiologiaRESUMO
BACKGROUND: Prior work has shown that urinary soluble CD163 (usCD163) displays excellent biomarker characteristics for detection of active renal vasculitis using samples that included new diagnoses with highly active renal disease. This study focused on the use of usCD163 in the detection of the more clinically relevant state of mild renal flare and compared results of usCD163 testing directly to testing of urinary monocyte chemoattractant protein-1 (uMCP-1). METHODS: Patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV, n = 88) were identified within a serially sampled, longitudinal and multicentre cohort. Creatinine-normalized usCD163 and uMCP-1 levels were measured by enzyme-linked immunosorbent assay and, both alone and in combination, were compared between times of active renal AAV and during remission and/or active non-renal AAV. RESULTS: Samples from 320 study visits included times of active renal vasculitis (n = 39), remission (n = 233) and active extrarenal vasculitis (n = 48). Median creatinine levels were 0.9 mg/dL [interquartile range (IQR) 0.8-1.2] in remission and 1.4 mg/dL (IQR 1.0-1.8) during renal flare. usCD163 levels were higher in patients with active renal vasculitis compared with patients in remission and those with active extrarenal vasculitis, with median values of 162 ng/mmol (IQR 79-337), 44 (17-104) and 38 (7-76), respectively (P < 0.001). uMCP-1 levels were also higher in patients with active renal vasculitis compared with patients in remission and those with active extrarenal vasculitis, with median values of 10.6 pg/mmol (IQR 4.6-23.5), 4.1 (2.5-8.4) and 4.1 (1.9-6.8), respectively (P < 0.001). The proposed diagnostic cut-points for usCD163 and uMCP-1 were 72.9 ng/mmol and 10.0 pg/mmol, respectively. usCD163 and uMCP-1 levels were marginally correlated (r2 = 0.11, P < 0.001). Combining novel and existing biomarkers using recursive tree partitioning indicated that elevated usCD163 plus either elevated uMCP-1 or new/worse proteinuria improved the positive likelihood ratio (PLR) of active renal vasculitis to 19.2. CONCLUSION: A combination of usCD163 and uMCP-1 measurements appears to be useful in identifying the diagnosis of subtle renal vasculitis flare.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Anticorpos Anticitoplasma de Neutrófilos/efeitos adversos , Antígenos CD/urina , Antígenos de Diferenciação Mielomonocítica/urina , Biomarcadores/urina , Quimiocina CCL2/urina , Nefropatias/diagnóstico , Adulto , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Feminino , Humanos , Nefropatias/etiologia , Nefropatias/urina , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Receptores de Superfície Celular , UrináliseRESUMO
OBJECTIVES: To describe tracheobronchial disease in patients with granulomatosis with polyangiitis (GPA) and evaluate the utility of dynamic expiratory CT to detect large-airway disease. METHODS: Demographic and clinical features associated with the presence of subglottic stenosis (SGS) or endobronchial involvement were assessed in a multicentre, observational cohort of patients with GPA. A subset of patients with GPA from a single-centre cohort underwent dynamic chest CT to evaluate the airways. RESULTS: Among 962 patients with GPA, SGS and endobronchial disease were identified in 95 (10%) and 59 (6%) patients, respectively. Patients with SGS were more likely to be female (72% vs 53%, P < 0.01), younger at time of diagnosis (36 vs 49 years, P < 0.01), and have saddle-nose deformities (28% vs 10%, P < 0.01), but were less likely to have renal involvement (39% vs 62%, P < 0.01). Patients with endobronchial disease were more likely to be PR3-ANCA positive (85% vs 66%, P < 0.01), with more ENT involvement (97% vs 77%, P < 0.01) and less renal involvement (42% vs 62%, P < 0.01). Disease activity in patients with large-airway disease was commonly isolated to the subglottis/upper airway (57%) or bronchi (32%). Seven of 23 patients screened by dynamic chest CT had large-airway pathology, including four patients with chronic, unexplained cough, discovered to have tracheobronchomalacia. CONCLUSION: SGS and endobronchial disease occur in 10% and 6% of patients with GPA, respectively, and may occur without disease activity in other organs. Dynamic expiratory chest CT is a potential non-invasive screening test for large-airway involvement in GPA.
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Granulomatose com Poliangiite/fisiopatologia , Laringoestenose/diagnóstico por imagem , Estenose Traqueal/diagnóstico por imagem , Traqueobroncomalácia/diagnóstico por imagem , Adulto , Idoso , Broncopatias/diagnóstico por imagem , Broncopatias/etiologia , Feminino , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/diagnóstico por imagem , Granulomatose com Poliangiite/imunologia , Humanos , Laringoestenose/etiologia , Masculino , Pessoa de Meia-Idade , Mieloblastina/imunologia , Peroxidase/imunologia , Tomografia Computadorizada por Raios X , Estenose Traqueal/etiologia , Traqueobroncomalácia/etiologiaRESUMO
OBJECTIVES: The pathogenesis of eosinophilic granulomatosis with polyangiitis (EGPA) remains poorly understood, and may overlap with eosinophilic asthma and primary hypereosinophilic syndrome (HES). The aim of this study was to analyse a panel of serum cytokines and chemokines as markers of disease activity in patients with these conditions. METHODS: The levels of 54 cytokines and chemokines were measured in the sera of 40 patients with active EGPA, 10 of these patients during inactive disease, 6 patients with HES, 8 with asthma, and 10 healthy controls. Serum cytokine/chemokines measured included interleukin (IL)-1α, 1ß, 3, 4, 5, 6, 8, 13, 15, 17A, 17E(25), 18, 23 and 33, soluble IL-2 receptor alpha, eotaxin-1 (CCL11), -2 (CCL24) and -3 (CCL26), macrophage-derived chemokine (MDC/CCL22), macrophage inflammatory protein (MIP)-1a and -1b, and tumour necrosis factor (TNF)-α. Results were compared between disease and control groups using regression analysis, with Bonferroni correction for multiple comparisons (significant p value ≤0.00093). RESULTS: Significant differences were observed only in serum levels of MDC, IL-8, MIP-1a and -1b, TNF-α, each of which were lower in patients with active EGPA than in healthy controls (p<0.0001). Differences between patients with active disease and other disease groups did not reach significance. Paired comparisons between sera from patients with active or inactive EGPA showed no significant difference for any of the studied cytokines or chemokines. CONCLUSIONS: No clear difference in the serum levels of measured cytokines and chemokines helped distinguish between active EGPA or inactive EGPA, or other disease or control groups.
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Asma , Quimiocinas/sangue , Citocinas/sangue , Granulomatose com Poliangiite , Síndrome Hipereosinofílica , Asma/sangue , Asma/diagnóstico , Biomarcadores/sangue , Diagnóstico Diferencial , Feminino , Granulomatose com Poliangiite/sangue , Granulomatose com Poliangiite/diagnóstico , Humanos , Síndrome Hipereosinofílica/sangue , Síndrome Hipereosinofílica/diagnóstico , Masculino , Pessoa de Meia-IdadeRESUMO
We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10(-40), OR = 1.73). A multivariate model including class II amino acids of HLA-DRß1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1(∗)04. An omnibus test on polymorphic amino acid positions highlighted DRß1 13 (p = 4.08 × 10(-43)) and HLA-DQα1 47 (p = 4.02 × 10(-46)), 56, and 76 (both p = 1.84 × 10(-45)) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10(-6), OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10(-6), OR = 1.20), and REL (rs115674477, p = 1.10 × 10(-5), OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function.
Assuntos
Genes MHC da Classe II/genética , Arterite de Células Gigantes/genética , Herança Multifatorial/genética , Estudos de Coortes , Estudos de Associação Genética , Genótipo , Humanos , Análise Multivariada , Razão de Chances , População Branca/genéticaRESUMO
Objectives: To evaluate damage and variables associated with damage in GCA. Methods: Patients with GCA enrolled in a prospective, multicentre, longitudinal study were included. Per-protocol assessments were made with the Vasculitis Damage Index and the Large-Vessel Vasculitis Index of Damage. Results: The study included 204 patients: 156 women (76%), mean age at diagnosis 71.3 years (s.d. 8.3), mean follow-up of 3.5 years (s.d. 1.9). One or more damage item was present in 54% at baseline and 79% at the last follow-up on the Vasculitis Damage Index, and 60% at baseline and 82% at the last follow-up on the Large-Vessel Vasculitis Index of Damage. The most frequently observed damage items were large-artery complications (29% cohort) and ocular (22%). Among 117 patients with new damage, most new items were ocular (63 patients), cardiac/vascular (48) and musculoskeletal (34). Of these, treatment-associated items were frequently observed, including cataracts (46 patients), osteoporosis (22) and weight gain (22). Disease-associated new damage included ischaemic optic neuropathy (3 patients), limb claudication (13), arterial occlusions (10) and damage requiring vascular intervention (10). In univariate analysis, the risk of damage increased 22% for every additional year of disease duration [odds ratio (OR) 1.22 (95% CI 1.04, 1.45)]. In 94 patients enrolled within ⩽90 days of diagnosis of GCA, the risk of new damage at the last follow-up decreased 30% for each additional relapse [OR 0.70 (95% CI 0.51, 0.97)]. Conclusions: Large-artery complications and ocular manifestations are the most commonly occurring items of damage in GCA. Most new damage is associated with treatment. These findings emphasize the cumulative burden of disease in GCA.
Assuntos
Arterite de Células Gigantes/patologia , Índice de Gravidade de Doença , Idoso , Oftalmopatias/etiologia , Feminino , Seguimentos , Arterite de Células Gigantes/complicações , Humanos , Claudicação Intermitente/etiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Prospectivos , Recidiva , Fatores de Risco , Fatores de TempoRESUMO
OBJECTIVES: To determine the prevalence of anti-myeloperoxidase (MPO) antibodies of IgA (IgA anti-MPO) isotype in patients with eosinophilic granulomatosis with polyangiitis (EGPA), and the association of the IgA antibodies with IgG anti-MPO and with disease activity. METHODS: Serum samples from patients with EGPA followed in a multicenter longitudinal cohort were tested by ELISA for the presence of IgA anti-MPO and IgG anti-MPO antibodies. Sera from 87 healthy controls were used to define a positive test. Sera from 168 patients with EGPA (298 samples) were tested. Frequencies of positive testing for IgA anti-MPO were compared between patients with active EGPA, patients in remission, and controls. RESULTS: IgA anti-MPO was detected in 10 of 168 (6%) patients with EGPA (11 of 298 serum samples) compared to 1 of 87 (1%) healthy controls (p=0.10). All 11 samples testing positive for IgA anti-MPO also tested positive for IgG anti-MPO. Ninety samples tested positive for IgG anti-MPO but negative for IgA. Samples taken during active EGPA were positive for IgA anti-MPO in 6/72 cases (8%), compared to 5/226 (2%) during remission (p=0.03). Among samples taken during moderate or high disease activity, 5/41 were positive (12%, p=0.01 compared to remission). CONCLUSIONS: Although IgA anti-MPO antibodies are detectable in some patients with EGPA and may be detectable more frequently during active disease, their presence seems unlikely to provide information beyond what is obtained from conventional IgG anti-MPO.
Assuntos
Anticorpos Anticitoplasma de Neutrófilos/sangue , Síndrome de Churg-Strauss/sangue , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Peroxidase/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Canadá , Estudos de Casos e Controles , Síndrome de Churg-Strauss/diagnóstico , Síndrome de Churg-Strauss/tratamento farmacológico , Síndrome de Churg-Strauss/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Indução de Remissão , Resultado do Tratamento , Estados Unidos , Adulto JovemRESUMO
BACKGROUND: The target sample size for clinical trials often necessitates a multicenter (center of excellence, CoE) approach with associated added complexity, cost, and regulatory requirements. Alternative recruitment strategies need to be tested against this standard model. OBJECTIVES: The aim of our study was to test whether a Web-based direct recruitment approach (patient-centric, PC) using social marketing strategies provides a viable option to the CoE recruitment method. METHODS: PC recruitment and Web-based informed consent was compared with CoE recruitment for a randomized controlled trial (RCT) of continuing versus stopping low-dose prednisone for maintenance of remission of patients with granulomatosis with polyangiitis (GPA). RESULTS: The PC approach was not as successful as the CoE approach. Enrollment of those confirmed eligible by their physician was 10 of 13 (77%) and 49 of 51 (96%) in the PC and CoE arms, respectively (P=.05). The two approaches were not significantly different in terms of eligibility with 34% of potential participants in the CoE found to be ineligible as compared with 22% in the PC arm (P=.11) nor in provider acceptance, 22% versus 26% (P=.78). There was no difference in the understanding of the trial as reflected in the knowledge surveys of individuals in the PC and CoE arms. CONCLUSIONS: PC recruitment was substantially less successful than that achieved by the CoE approach. However, the PC approach was good at confirming eligibility and was as acceptable to providers and as understandable to patients as the CoE approach. The PC approach should be evaluated in other clinical settings to get a better sense of its potential.
Assuntos
Internet , Seleção de Pacientes , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Doenças Raras/diagnóstico , Doenças Raras/tratamento farmacológico , Adulto , Idoso , Feminino , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Inquéritos e QuestionáriosRESUMO
Takayasu arteritis is a rare inflammatory disease of large arteries. The etiology of Takayasu arteritis remains poorly understood, but genetic contribution to the disease pathogenesis is supported by the genetic association with HLA-B*52. We genotyped ~200,000 genetic variants in two ethnically divergent Takayasu arteritis cohorts from Turkey and North America by using a custom-designed genotyping platform (Immunochip). Additional genetic variants and the classical HLA alleles were imputed and analyzed. We identified and confirmed two independent susceptibility loci within the HLA region (r(2) < 0.2): HLA-B/MICA (rs12524487, OR = 3.29, p = 5.57 × 10(-16)) and HLA-DQB1/HLA-DRB1 (rs113452171, OR = 2.34, p = 3.74 × 10(-9); and rs189754752, OR = 2.47, p = 4.22 × 10(-9)). In addition, we identified and confirmed a genetic association between Takayasu arteritis and the FCGR2A/FCGR3A locus on chromosome 1 (rs10919543, OR = 1.81, p = 5.89 × 10(-12)). The risk allele in this locus results in increased mRNA expression of FCGR2A. We also established the genetic association between IL12B and Takayasu arteritis (rs56167332, OR = 1.54, p = 2.18 × 10(-8)).
Assuntos
Loci Gênicos , Predisposição Genética para Doença , Arterite de Takayasu/genética , Feminino , Técnicas de Genotipagem , Antígenos HLA-B/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Subunidade p40 da Interleucina-12/genética , Masculino , Mutação , América do Norte/epidemiologia , Receptores de IgG/genética , Risco , Arterite de Takayasu/etnologia , Turquia/epidemiologiaRESUMO
OBJECTIVE: The aim of this study was to assess the clinical value of absolute eosinophil count, serum IgE, ESR and CRP as longitudinal biomarkers of disease activity and predictors of relapse in eosinophilic granulomatosis with polyangiitis (Churg-Strauss, EGPA). METHODS: Patients were selected from an observational EGPA cohort. Absolute eosinophil count, IgE, ESR and CRP were measured quarterly. Disease activity was defined by validated assessment tools. The association of tests with disease activity was assessed via regression models, adjusting for repeated measures and treatment status. Survival analysis was used to determine if laboratory tests were predictive of the 3 month future flare risk. RESULTS: Seventy-four per cent of 892 study visits in 141 patients occurred while patients were on treatment, mostly during remission or mild disease activity, defined as a BVAS for Wegener's granulomatosis (BVAS/WG) of 1 or 2. Correlations between absolute eosinophil count, IgE, ESR and CRP were mostly low or non-significant (r = -0.08 to 0.44). There were few weak associations with disease activity [absolute eosinophil count: OR) 1.01/100 U (95% CI 1.01, 1.02); ESR: OR 1.15/10 mg/l increase (95% CI 1.04, 1.27)]. When BVAS/WG ≥1 defined active disease, the absolute eosinophil count [hazard ratio (HR) 1.01/100 U (95% CI 1.01, 1.02)] was weakly predictive of flare. When BVAS/WG ≥3 defined active disease, ESR was weakly predictive of flare [HR 1.52/10 mm/h increase (95% CI 1.17, 1.67)]. CONCLUSION: The absolute eosinophil count, IgE, ESR and CRP have limitations as longitudinal biomarkers of disease activity or predictors of flare in EGPA. These findings suggest that novel biomarkers of disease activity for EGPA are needed.