Increased ischemic stroke, acute coronary artery disease and mortality in patients with granulomatosis with polyangiitis and microscopic polyangiitis

doi:10.1016/j.jaut.2018.09.004

Journal of Autoimmunity

Volume 96, January 2019, Pages 134-141

https://doi.org/10.1016/j.jaut.2018.09.004 Get rights and content

Highlights

•
Patients with AAV have a four times more risk of ischemic stroke or coronary artery disease that in the general population.
•
Cardiovascular mortality in associated-ANCA vasculitis (AAV) patients is 1.5 times more than in the general population.
•
Monitoring for this complication and vigilance in modifying risk factors are warranted in this patient population.

Abstract

Objective

The aim of our study was to assess major cardiovascular event incidence, predictors, and mortality in ANCA-associated vasculitis (AAV).

Methods

We conducted a retrospective cohort study of all GPA or MPA, according to Chapel Hill Consensus Conference classification criteria, diagnosed between 1981 and 2015. Major cardiovascular event was defined as acute coronary artery disease, or ischemic stroke, or peripheral vascular disease requiring a revascularization procedure. We calculated the comparative morbidity/mortality figure (CMF) and we used Cox proportional hazards regression models to assess the risk of coronary artery disease, ischemic stroke associated with AAV, after adjusting for covariates.

Results

125 patients, 99 GPA (79,2%) and 26 MPA (20,8%), were followed 88.4 ± 78.3 months. Ischemic stroke incidence was four times higher than in the general population (CMF 4,65; 95% CI 4,06-5,31). Coronary artery disease incidence was four times higher than in the general population (CMF 4,22; 95% CI 1,52-11,68). Smoking habits and history of coronary artery disease were strongly associated with coronary artery disease occurrence (adjusted HR 8.8; 95% CI 2.12–36.56, and adjusted HR 10.3; 95% CI 1.02–104.5, respectively). ENT flare-up was an independent protective factor for coronary artery disease occurrence. We did not identify factors significantly associated with stroke occurrence. The age-adjusted mortality rate was 22.5 per 1000 person-years. Mortality in AAV was 1.5 times higher than in the general population (CMF 1.56; 95% CI 1.34–1.83).

Conclusion

AAV have a significantly increased risk of mortality, ischemic stroke, and coronary artery disease.

Introduction

ANCA-associated vasculitis (AAV) encompasses a group of auto-immune diseases, including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EPGA) and pauci-immune glomerulonephritis that are characterized by inflammation and necrosis of small and medium-sized vessel [1]. Current treatment approaches have greatly improved the survival [2,3], however both morbidity and mortality are still significant [4], from persistent low-grade activity and permanent damage caused by the acute phase of vasculitis or its treatment [5] and disease relapses. This increased risk is mainly due to cardiovascular complications.

As for other chronic systemic inflammatory diseases [6], premature and accelerated atherosclerosis has emerged during the last decade as an important facet of AAV. Experimental data showed that, in addition to lipid accumulation, arterial inflammation, attributable to Th1 and Th17 and resulting from increased cytokines production, were associated with accelerated subclinical atherosclerosis [7,8]. Epidemiological studies showed the higher frequency of subclinical atherosclerosis in patients with AAV [[9], [10], [11], [12]]. Whereas the increased risk of cardiovascular diseases is well established in other chronic systemic inflammatory diseases [[13], [14], [15], [16]], data on cardiovascular disease risk in AAV patients are scarce [[17], [18], [19], [20]].

The aim of this study was to assess the incidence of the first major cardiovascular event and its predictors in a cohort of GPA and MPA patients.

Section snippets

Study population

We conducted a retrospective review of medical records of all patients diagnosed with a small and medium-sized vessels vasculitis at Toulouse University Hospital, a tertiary referral center for systemic vasculitis, between 1981 and 2015. After thorough medical chart review, patients were included if they 1) met the classification criteria proposed by the 2012 Chapel Hill Consensus Conference [1] for GPA or MPA with histologically confirmed necrotizing vasculitis and/or ANCA-positive serum, 2)

Demographics and cardiovascular risk factors

We identified 361 relevant medical records for the 1981–2015 period. One hundred twenty-five of these patients met the selection criteria for study inclusion (Fig. 1), 99 GPA (79,2%) and 26 MPA (20,2%) with a mean follow-up of 88.4 ± 78.3 months. There were 65 males (52%) and 60 females (48%). Mean age at disease onset was of 61.3 ± 15.7 years. Prior to AAV recognition, 45 (36%) had high blood pressure, 20 (16%) had hyperlipidemia, 37 (29.6%) were smokers, 9 (7.2%) had diabetes mellitus, 6

Discussion

The main findings of this study are as follows. First, ischemic stroke incidence in our AAV cohort was four times higher than in the general population. These results remained significant in each MPA and GPA group. This study provides the first evidence that ischemic stroke is an important complication of AAV. Second, smoking habits and a history of coronary artery disease before AAV diagnosis were strongly associated with coronary artery disease occurrence during follow-up, while ENT flare-ups

Conclusion

Despite recent advances, AAV patients still have a significantly increased risk of mortality, ischemic stroke, and coronary artery disease. Further studies are required to validate these results. However, monitoring for these complications and attempts strict management of cardiovascular risk factors are warranted in this population as part of the long-term management of these conditions.

Conflicts of interest and funding

The authors have no conflict of interest regarding this work or any other financial interests.

Declarations of interest

None.

Funding source

This study is academic, funded by Toulouse University Hospital.

Author contributions

1)
conceived and designed the study: MM, GP,
2)
analyzed and interpreted the data: MM, GP
3)
contributed reagents, materials, analysis tools or data: all authors
4)
wrote the paper: MM, GP

Ethics approval

This study received approval and authorization from the Commission Nationale de l’Informatique et des Libertés (n°DR-2017-2097045v0).

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Citation Excerpt :
Although an increased risk of thrombotic outcomes has previously been described in autoimmune rheumatic diseases such as rheumatoid arthritis or systemic lupus erythematosus [9–11], data are insufficient on thrombotic outcomes risk in patients with AAV. Several studies have reported inconsistent results regarding the risk of AMI, stroke, or VTE in patients with GPA or MPA [8,12–15]. Furthermore, previous studies evaluating comorbidities in AAV are limited to a small number of cases because of the rarity of the disease and the difficulty with its diagnosis.
To investigate the incidence and risk of cerebro-cardiovascular comorbidities (stroke, acute myocardial infarction, venous thromboembolism, and pulmonary embolism) in anti-neutrophil cytoplasmic antibody-associated vasculitis using nationwide Korean population-based medical claims data.
We identified 1905 patients with newly diagnosed anti-neutrophil cytoplasmic antibody-associated vasculitis during 2009–2019. Incidence rates and hazard ratios with 95% confidence intervals were calculated to estimate the risk of cerebro-cardiovascular comorbidities in these patients and compared to age- and sex-matched controls (1:10) using the Cox proportional hazards model.
Most patients had microscopic polyangiitis (42.5%), followed by granulomatosis with polyangiitis (29.1%) and eosinophilic granulomatosis with polyangiitis (28.4%). The annual incidence rate of anti-neutrophil cytoplasmic antibody-associated vasculitis in 2019 was 0.55 per 100,000 person-years. Cerebro-cardiovascular comorbidities occurred in 12.6%. Stroke was most common (64.6%), followed by venous thromboembolism (34.6%), pulmonary embolism (18.3%), and acute myocardial infarction (5.4%). Korean patients with anti-neutrophil cytoplasmic antibody-associated vasculitis were at a significantly (2.3 times) higher overall risk for cerebro-cardiovascular comorbidities than the general population (adjusted hazard ratios, 4.5, 3.1, and 2.0 times higher for pulmonary embolism, venous thromboembolism, and stroke, respectively). These findings were similar for patients with each subtype of anti-neutrophil cytoplasmic antibody-associated vasculitis.
This is the first nationwide population-based study to demonstrate a significant risk of cerebro-cardiovascular comorbidities as complications of anti-neutrophil cytoplasmic antibody-associated vasculitis in Korean patients. Knowing these risks may enable personalized patient care and improve overall survival.
Epidemiology of granulomatosis with polyangiitis and microscopic polyangiitis in adults in France
2022, Journal of Autoimmunity
Background.
Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are rare systemic necrotizing vasculitis. The national incidence and prevalence of GPA/MPA and patient mortality remain unknown in France. A real-life study using retrospective data from the French National Health Data System was set up to describe the epidemiology and demographic characteristics of hospitalized GPA and MPA patients, overall and by disease.
Methods.
All adult patients (≥18 years of age) hospitalized for GPA (ICD-10 M31.3) or MPA (ICD-10 M31.7) between 01 and 01–2010 and 31-12-2017 and affiliated to the General health insurance Scheme (covering 76% of the French population) were included in this national retrospective observational study. Descriptive analyses, univariate and multivariable logistic models, Kaplan-Meier survival analysis, and Cox models were performed.
Results.
The study involved 4445 prevalent GPA patients (including 1578 incident patients) and 1833 prevalent MPA patients (878 incident patients). Distinction between GPA and MPA diagnosis could not be made for 303 patients (149 incident patients). In people aged over 20 years, the age-standardized incidence rates of GPA and MPA were 0.5 and 0.3/100,000 person-years, respectively and the age-standardized prevalence rates were 10 and 4/100,000 person-years, respectively. The standardized mortality ratios in GPA and MPA patients aged over 20 years were 2.0 and 2.7, respectively, and remained constant. Renal failure, pulmonary and urinary tract infections, as well as coronary disease were more frequent among MPA than GPA patients. One-year survival rates among GPA and MPA patients were 96% (95%CI 94%–97%) and 94% (92%–95%), respectively. Five-year survival rates among GPA and MPA patients were 81% (95% CI 79%–83%) and 72% (68%–75%), respectively. After adjusting for comorbidities, the risk of death was still higher in MPA (hazard ratio 1.26 [95%CI 1.06–1.50]) than in GPA patients.
Conclusions.
Despite advances in the therapeutic management of patients, mortality rates are still high and stable over time, highlighting the need for improved management.
Predictors of cardiovascular events in patients with primary systemic vasculitis: A 5 years prospective observational study
2021, European Journal of Internal Medicine
: Granulomatosis with polyangiitis (GPA) is one of antineutrophil cytoplasmic autoantibody (ANCA) – associated systemic vasculitis and is characterised by inflammation of blood vessels. Systemic vasculitis exhibits an enhanced cardiovascular morbidity and cardiovascular disease (CVD) has become a leading cause of death in this group of patients.
: The aim of the present study was to assess the prevalence of clinical manifestation of atherosclerosis and its relation with classic risk factors for atherosclerosis, echocardiographic parameters and laboratory findings in GPA patients.
: The group of consecutive patients with GPA were followed in the study.
: One hundred six patients with GPA (mean age 50.4 ± 14.9 yrs, 67 female) were prospectively followed for 5.1 ± 1.6 yrs. In 19 patients (18%) cardiovascular disease (9 acute coronary syndromes, 4 symptomatic peripheral vascular diseases and 6 strokes) occurred in association with GPA. In a multivariate model, only age was predictive of cardiovascular events in this group of patients (OR=1.078, 95% CI: 1.025–1.134, p = 0.003). During observation in patients without CVD the level of hs-CRP and D-dimer were significantly reduced on the follow-up visit (p = 0.041, p = 0.0002). On the other hand, in patients with CV events there was no significant differences in both markers’ concentrations despite clinical remission.
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Les personnes atteintes de vascularite à ANCA présentent un risque accru d’événements cardiovasculaires. L’objectif de cette étude était d’évaluer les facteurs prédictifs d’événements cardiovasculaires chez des patients atteints de granulomatose avec polyangéite ou de granulomatose éosinophilique avec polyangéite.
Il s’agit d’une étude longitudinale rétrospective menée sur des patients de la cohorte du réseau de recherche Canadian Vasculitis de Toronto. Les caractéristiques au moment du diagnostic ont été collectées. Pendant la période de suivi, les événements cardiovasculaires non mortels ont été déterminés à partir de l’indice VDI (séquelles liées à la vascularite) et la mortalité a été enregistrée avec les causes de décès. Des modèles de régression de Cox ont été élaborés pour identifier les facteurs prédictifs d’événements cardiovasculaires, définis comme un AVC ou un infarctus du myocarde.
Au total, 336 patients ont été inclus : 231 (69 %) atteints de granulomatose avec polyangéite et 105 (31 %) de granulomatose éosinophilique avec polyangéite. L’âge moyen au moment du diagnostic était de 44 ans (± 18) et 44 % des patients étaient des hommes. Le taux d’incidence du critère combiné de l’ensemble des événements mortels et non mortels était de 7,2 événements pour 1000 années–patient. Dans un modèle multivarié, les antécédents familiaux d’événements cardiovasculaires et un score BVAS (Birmingham Vasculitis Activity Score) plus élevé au moment du diagnostic étaient prédictifs d’événements cardiovasculaires (odds ratio et intervalle de confiance à 95 % : 3,46 [1,06–11,28] et 1,09 [1,02–1,16], respectivement). Une analyse de sous-groupe n’a pas montré d’association entre les caractéristiques cardiovasculaires ou spécifiques à la maladie et la survenue d’événements cardiovasculaires dans la granulomatose éosinophilique avec polyangéite.
Dans cette cohorte de patients atteints de granulomatose avec polyangéite et de granulomatose éosinophilique avec polyangéite, des facteurs de risque traditionnels et spécifiques à la maladie étaient prédictifs d’événements cardiovasculaires. Des études prospectives complémentaires devraient permettre de préciser leurs effets, ainsi que ceux d’autres facteurs de risque modifiables, sur le risque cardiovasculaire dans la vascularite à ANCA.

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Increased ischemic stroke, acute coronary artery disease and mortality in patients with granulomatosis with polyangiitis and microscopic polyangiitis

Highlights

Abstract

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Study population

Demographics and cardiovascular risk factors

Discussion

Conclusion

Conflicts of interest and funding

Declarations of interest

Funding source

Author contributions

Ethics approval

Am. J. Med.

Int. J. Cardiol.

Lancet Lond. Engl.

Presse Med. Paris Fr 1983

Am. J. Cardiol.

Pharmacol. Ther.

2012 revised international Chapel Hill consensus conference nomenclature of vasculitides

Arthritis Rheum.

Rituximab versus cyclophosphamide for ANCA-associated vasculitis

N. Engl. J. Med.

Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis

N. Engl. J. Med.

Outcomes from studies of antineutrophil cytoplasm antibody associated vasculitis: a systematic review by the European League against Rheumatism systemic vasculitis task force

Ann. Rheum. Dis.

Damage caused by Wegener's granulomatosis and its treatment: prospective data from the Wegener's Granulomatosis Etanercept Trial (WGET)

Arthritis Rheum.

IL-17 and Th17 cells in atherosclerosis: subtle and contextual roles

Arterioscler. Thromb. Vasc. Biol.

Evidence for C-reactive protein's role in (CRP) vascular disease: atherothrombosis, immuno-regulation and CRP

J. Thromb. Thrombolysis

Increased prevalence of subclinical atherosclerosis in patients with small-vessel vasculitis

Heart Br. Card Soc.

Accelerated atherosclerosis in patients with Wegener's granulomatosis

Ann. Rheum. Dis.

Factors associated with major cardiovascular events in patients with systemic necrotizing vasculitides: results of a longterm followup study

J. Rheumatol.

Atherosclerosis in ANCA-associated vasculitides

Ann. N. Y. Acad. Sci.

High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors

Arthritis Rheum.

Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis

Circulation

Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study

Am. J. Epidemiol.

Premature morbidity from cardiovascular and cerebrovascular diseases in women with systemic lupus erythematosus

Arthritis Rheum.

Increased morbidity from ischemic heart disease in patients with Wegener's granulomatosis

Arthritis Rheum.

Increased incidence of cardiovascular events in patients with antineutrophil cytoplasmic antibody-associated vasculitides: a matched-pair cohort study

Arthritis Rheum.

A model to predict cardiovascular events in patients with newly diagnosed Wegener's granulomatosis and microscopic polyangiitis

Arthritis Care Res.