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Journal ArticleDOI

Which Patients with Giant Cell Arteritis Will Develop Cardiovascular or Cerebrovascular Disease? A Clinical Practice Research Datalink Study.

01 Jun 2016-The Journal of Rheumatology (Journal of Rheumatology Publishing Company)-Vol. 43, Iss: 6, pp 1085-1092

TL;DR: Patients with GCA are more likely to develop cerebrovascular disease or CVD than age-, sex-, and location-matched controls and further work is needed to understand how this risk may be mediated by specific behavioral, social, and economic factors.

AbstractObjective. To evaluate the risk of cerebrovascular disease and cardiovascular disease (CVD) in patients with giant cell arteritis (GCA), and to identify predictors. Methods. The UK Clinical Practice Research Datalink 1991–2010 was used for a parallel cohort study of 5827 patients with GCA and 37,090 age-, sex-, and location-matched controls. A multivariable competing risk model (non-cerebrovascular/CV-related death as the competing risk) determined the relative risk [subhazard ratio (SHR)] between patients with GCA compared with background controls for cerebrovascular disease, CVD, or either. Each cohort (GCA and controls) was then analyzed individually using the same multivariable model, with age and sex now present, to identify predictors of CVD or cerebrovascular disease. Results. Patients with GCA, compared with controls, had an increased risk SHR (95% CI) of cerebrovascular disease (1.45, 1.31–1.60), CVD (1.49, 1.37–1.62), or either (1.47, 1.37–1.57). In the GCA cohort, predictors of “cerebrovascular disease or CVD” included increasing age, > 80 years versus < 65 years (1.98, 1.62–2.42), male sex (1.20, 1.05–1.38), and socioeconomic status, most deprived quintile versus least deprived (1.34, 1.01–1.78). These predictors were also present within the non-GCA cohort. Conclusion. Patients with GCA are more likely to develop cerebrovascular disease or CVD than age-, sex-, and location-matched controls. In common with the non-GCA cohort, patients who are older, male, and from the most deprived compared with least deprived areas have a higher risk of cerebrovascular disease or CVD. Further work is needed to understand how this risk may be mediated by specific behavioral, social, and economic factors.

Topics: Cohort study (55%), Cohort (54%), Relative risk (52%), Epidemiology (50%)

Summary (2 min read)

INTRODUCTION

  • The risk of events is highest in the first year(2, 4), potentially implicating high-dose glucocorticoid use(5, 6), or increased levels of inflammation, as seen in the general population(7) and other rheumatic diseases(8, 9).
  • In addition, a study of 271 patients from the UK demonstrated no associations with pre-existing hypertension or atherosclerosis, but did find an association with social deprivation, with an OR of 4.2 (95% CI 1.3 to 13.6) for a severe ischaemic manifestation, between the most and least deprived quintiles(12).
  • The Clinical Practice Research Datalink (CPRD), previously known as the General Practice Research Database (GPRD), covers a population of 14 million patients from 500 general practices in the UK(21).

MATERIALS AND METHODS

  • Study design using the CPRD A 20-year parallel cohort (patients with GCA and matched controls) was observed from 01/01/1991 to 31/12/2010 for the outcomes of cerebrovascular and cardiovascular disease.
  • Non-GCA controls were matched to patients with GCA (6:1) on year of birth, gender and general practice.
  • Ethical approval was given by the CPRD Independent Scientific Advisory Committee.

Outcome measures

  • The authors defined three binary outcomes using CPRD Read codes.
  • The first was “cerebrovascular disease” which was compiled using Read codes for stroke or transient ischaemic attack (TIA) or cerebrovascular disease.
  • The second was “cardiovascular disease” and was compiled using Read codes for ischaemic heart disease (IHD) or myocardial infarction (MI) or cardiovascular disease.
  • The third, “cerebrovascular disease or cardiovascular disease” (CDCD) identified patients with either the first outcome or second outcome.

Definition of GCA and controls

  • Patients with GCA had an incident GCA Read code between.
  • Patients were aged ≥40(20) with at least 12 months of CPRD defined up-to standard (UTS) data prior to their index diagnosis; patients were excluded if they had a previous diagnosis of cerebrovascular or cardiovascular disease.
  • Controls did not have a diagnosis of GCA or polymyalgia ever recorded in the CPRD, and they had at least 12 months UTS follow-up recorded prior to the date of diagnosis of the matched GCA patient; controls were excluded if they had a previous diagnosis of cerebrovascular or cardiovascular disease.

Cardiovascular risk factors

  • Read codes were used to identify a history of hyperlipidaemia and hypertension.
  • Prescriptions for at least 75% of the year, in any year out of the previous five prior to diagnosis of GCA or the matched time point in controls, were needed to confirm previous lipid-lowering, antihypertensive or diabetic treatment.
  • Smoking and alcohol variables were categorised as ‘current’, ‘ex’ and ‘never’.
  • The body mass index (BMI) variable was the closest recorded before the start of the exposed to risk period.
  • The Index of Multiple Deprivation (IMD) combines information from seven domains of deprivation: income; employment; education, skills and training; health deprivation and disability; crime; barriers to housing and services and living environment, to provide a set of relative measures of deprivation for small areas, or neighbourhoods (known as Lower-layer Super Output Areas) across England(22).

Analysis

  • Descriptive statistics were used to compare patient characteristics of the GCA and control cohorts.
  • The risk of incident cardiovascular or cerebrovascular disease with GCA compared with non-GCA cohorts was then calculated.
  • Each interaction term was individually tested in the initial multivariable model; significant terms (p<0.1) were then used to build the final multivariable model.
  • A sub-group analysis for each of the thirteen geographical regions was also performed to investigate variations in the relative risk of cardiovascular or cerebrovascular disease.
  • All statistical analyses were performed using Stata SE v12.0 (StatCorp, College Station, TX, USA).

Descriptive statistics

  • The relative risk of cerebrovascular or cardiovascular disease.
  • The models were adjusted for risk factors (as described earlier).
  • Cumulative incidence plots also demonstrated differences in the risk of “cardiovascular or cerebrovascular disease” when stratified by GCA versus non-GCA diagnosis (increased risk with GCA), gender (increased risk amongst males with GCA), smoking (increased risk amongst current smokers with GCA) and socioeconomic status (increased risk amongst patients from most deprived areas and GCA) .

DISCUSSION

  • Patients with GCA are fifty percent more likely to develop incident cerebrovascular or cardiovascular disease than age, gender and practice matched controls, in line with previous studies (2, 4).
  • This study provides new information about the importance of cardiovascular risk factors within this population.
  • Social deprivation is known to be associated with cardiovascular disease within the general population(17); this study demonstrates that this is also true of patients with GCA.
  • The proportion of missing data that was imputed, particularly for IMD (45%), was large.
  • In practice, this study suggests that clinicians should be alerted to the fact that patients with GCA are at increased risk of cardiovascular and cerebrovascular disease, particularly if they have pre-existing hypertension, are older, male or live in an area of higher social deprivation.

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Robson, J. C., Kiran, A., Maskell, J., Hutchings, A., Arden, N.,
Dasgupta, B., Hamilton, W. T., Emin, A., Culliford, D., & Luqmani, R.
(2016). Which patients with giant cell arteritis will develop
cardiovascular or cerebrovascular disease? A clinical practice
research datalink study.
Journal of Rheumatology
,
43
(6), 1085-1092.
https://doi.org/10.3899/jrheum.151024
Peer reviewed version
Link to published version (if available):
10.3899/jrheum.151024
Link to publication record in Explore Bristol Research
PDF-document
This is the author accepted manuscript (AAM). The final published version (version of record) is available online
via at http://www.jrheum.org/content/43/6/1085. Please refer to any applicable terms of use of the publisher.
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This document is made available in accordance with publisher policies. Please cite only the
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Giant cell arteritis and cardiovascular risk
1
Which patients with giant cell arteritis will develop cardiovascular or
cerebrovascular disease? A Clinical Practice Research Datalink study
Joanna C Robson*. Consultant Senior Lecturer in Rheumatology,
Faculty of Health and Applied Sciences, University of the West of England,
Bristol, & Hon Senior Lecturer, School of Clinical Sciences at South
Bristol, University of Bristol, & Hon Consultant in Rheumatology, University
Hospitals Bristol NHS Trust. Academic Rheumatology Unit,The Courtyard, Bristol
Royal Infirmary, Bristol, BS2 8HW. Tel: +44 (0) 117 342 22904, Fax: +44 (0)117 342
3841, Jo.Robson@uwe.ac.uk
Amit Kiran. Statistician, Nuffield Department of Orthopaedics, Rheumatology and
Musculoskeletal Science, University of Oxford, Nuffield Orthopaedic Centre, Windmill
Road, Oxford, OX3 7HE.
Joe Maskell. Data manager, Faculty of Medicine, University of Southampton,
Southampton General Hospital, South Academic Block, Tremona Road,
Southampton, SO16 6YD.
Andrew Hutchings. Lecturer, Department of Health Services Research and Policy,
London School of Hygiene and Tropical Medicine Room, 15-17 Tavistock Place,
London, WC1H 9SH.

Giant cell arteritis and cardiovascular risk
2
Nigel Arden. Professor of Rheumatology, Nuffield Department of Orthopaedics,
Rheumatology and Musculoskeletal Science, University of Oxford, Nuffield
Orthopaedic Centre, Windmill Road, Oxford, OX3 7HE.
Bhaskar Dasgupta. Professor of Rheumatology, Southend University Hospital NHS
Trust, Prittlewell chase, Westcliff-on-sea, SS0 0RY.
William Hamilton. Professor of Primary Care Diagnostics, University of Exeter Medical
School, College House, EX1 2LU
Akan Emin. UK Cardiothoracic Transplant Research Fellow, Clinical Effectiveness
Unit, The Royal College of Surgeons of England, 35-43 Lincoln's Inn Fields, London,
WC2A 3PE.
David Culliford. Senior Medical Statistician, Faculty of Medicine, University of
Southampton, Southampton General Hospital, South Academic Block, Tremona
Road, Southampton, SO16 6YD.
Raashid Luqmani. Professor of Rheumatology, Nuffield Department of Orthopaedics,
Rheumatology and Musculoskeletal Science, University of Oxford, Rheumatology
Dept, Nuffield Orthopaedic Centre, Windmill Road, Oxford OX3 7HE.
*Corresponding Author

Giant cell arteritis and cardiovascular risk
3
Competing Interest
List of competing interests: 1) Joanna Robson (JR), Joe Maskell (JM), Andrew
Hutchings (AH), Nigel Arden (NA), Bhaskar Dasgupta (BD), Willie Hamilton (WH),
David Culliford (DC), Akan Emin (AE) and Raashid Luqmani (RL) received a grant
from the NIHR Research for Patient Benefit (RfPB) Programme to fund this study. JR,
AK, JM, AH, NA, BD, WH, DC, AE and RL had no support from any commercial
companies for the submitted work; 2) AK, JM, AH, WH, DC, AE have no relationships
with companies which might have an interest in the submitted work in the previous 3
years. NA has the following relationships; consultancies for Flexion (PharmaNet), Lily,
Merck, Q-Med, Roche and Smith & Nephew; grants/ grants pending with Novartis,
Pfizer, Schering-Plough and Servier and received payment for lectures from Amgen,
GSK, NiCox and Smith & Nephew. BD has the following relationships; board
membership Roche, Servier, GSK-advisor in GCA; consultancy for Mundi
Pharma,GSK,Novartis on PMR. RL has the following relationships; consultancies for
Nordic Pharma, Chemocentryx, Human Genome Science, GSK; grants/grants
pending with Roche and GSK. 3) JR, AK, JM, AH, NA, BD, WH, DC, AE, RL their
spouses, partners, or children have no financial relationships that may be relevant to
the submitted work; and 4) JR, AK, JM, NA, WH, DC, AE, RL have no non-financial

Giant cell arteritis and cardiovascular risk
4
interests that may be relevant to the submitted work. AH and BD are members of the
group that produced the British Society of Rheumatology/ British Health Professionals
in Rheumatology 2010 guidelines for the management of giant cell arteritis. BD, AH,
RL are members of the group updating these guidelines.
Contributors
All authors contributed to the study proposal, design of the analysis and interpretation
of the findings. JR and AK produced the analysis plan. JM was responsible for data
extraction. AK and AH undertook the analysis with input from JR and RL. All authors,
internal and external, had full access to the data (including statistical reports and
tables) in the paper and can take responsibility for the integrity of the data and the
accuracy of the data analysis. JR wrote the first draft of the paper which was revised
by all authors. JR and AK will act as guarantors.
Acknowledgements: Nil.
Funding: Grant from the NIHR Research for Patient Benefit (RfPB) Programme.
Funders reviewed the study design protocol but had no role in collection, analysis,
interpretation of data, writing of the report, or decision to submit the article for
publication.
Word count: 3127

Citations
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Journal ArticleDOI
Abstract: Giant cell arteritis (GCA) is a granulomatous vasculitis of the aorta and its medium-sized branch vessels. CD4 T cells, macrophages, and dendritic cells (DCs) build granulomatous infiltrates that injure the vessel wall and elicit a maladaptive response to injury. Pathological consequences include fragmentation of elastic membranes, destruction of the medial layer, microvascular neoangiogenesis, massive outgrowth of myofibroblasts, and lumen-occlusive intimal hyperplasia. Antigens have been suspected to drive the local activation of vasculitogenic CD4 T cells, but recent data have suggested a more generalized defect in the threshold setting of such T cells, rendering them hyperreactive. Under physiological conditions, immune checkpoints provide negative signals to curb T cell activation and prevent inflammation-associated tissue destruction. This protective mechanism is disrupted in GCA. Vessel wall DCs fail to express the immunoinhibitory ligand programmed cell death ligand-1, leaving lesional T cells unchecked. Consequently, programmed cell death protein-1-positive CD4 T cells can enter the immunoprivileged vessel wall, where they produce a broad spectrum of inflammatory cytokines (interferon-γ, IL-17, and IL-21) and have a direct role in driving intimal hyperplasia and intramural neoangiogenesis. The deficiency of the programmed cell death protein-1 immune checkpoint in GCA, promoting unopposed T cell immunity, contrasts with checkpoint hyperactivity in cancer patients in whom excessive programmed cell death ligand-1 expression paralyzes the function of antitumor T cells. Excessive checkpoint activity is the principle underlying cancer-immune evasion and is therapeutically targeted by immunotherapy with checkpoint inhibitors. Such checkpoint inhibitors, which unleash anticancer T cells and induce immune-related toxicity, may lead to drug-induced vasculitis.

60 citations


Journal ArticleDOI
TL;DR: GCA is associated with increased risk of dying from large-vessel disease, other cardiovascular diseases and potentially treatment-related co-morbidities and these findings help provide better insights into the outcomes of GCA.
Abstract: Objectives Comprehensive analyses of cause-specific death patterns in GCA are sparse. We studied the patterns and time trends in GCA-related mortality using a large death certificate database. Methods We obtained multiple-cause-of-death data from the French national death certificate database for 1980-2011. GCA-associated deaths were defined as decedents ⩾55 years old with GCA listed as an underlying or non-underlying cause of death. Time trends of death rates were analysed and the mean age at death with GCA and in the general population ⩾55 years old were calculated. Standardized mortality odds ratios (SMORs) were calculated for 17 selected causes of death (based on 2000-11 data). Results The analyses pertained to approximately 15 000 death certificates listing GCA (including approximately 6300 for 2000-11). Annual standardized death rates for GCA increased to a peak in 1997 and then decreased (Spearman's correlation test, both P < 0.0001). Mean age at death was higher for GCA than for general population decedents (Student's t-test, P < 0.0001). GCA deaths were frequently or strongly associated with aortic aneurysm and dissection (1.85% of death certificates, SMOR: 3.09, 95% CI: 2.48, 3.82), hypertensive disease (20.78%, SMOR: 2.22, 95% CI: 1.97, 2.50), diabetes mellitus (11.27%, SMOR: 1.96, 95% CI: 1.72, 2.23), certain infectious and parasitic diseases (12.12%, SMOR: 1.76, 95% CI: 1.55, 2.00) and ischaemic heart disease (16.54%, SMOR: 1.45, 95% CI: 1.35, 1.64). Conclusion GCA is associated with increased risk of dying from large-vessel disease, other cardiovascular diseases and potentially treatment-related co-morbidities. These findings help provide better insights into the outcomes of GCA.

24 citations


Journal ArticleDOI
TL;DR: The role of infectious agents has repeatedly been studied with regard to Staphylococcus aureus, associated with relapse in granulomatosis with polyangiitis, and Herpes zoster, potentially contributing to GCA development.
Abstract: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and giant cell arteritis (GCA) are the most common primary systemic vasculitides of the adult population, while polymyalgia rheumatica (PMR) is a clinical syndrome often associated with GCA. Incidence and prevalence rates of AAV have been increasing in the last decades, whereas those of GCA and PMR have remained stable. The mutual interplay between environmental and genetic risk factors leading to the development of these diseases has been further analyzed in the last years. The role of infectious agents has repeatedly been studied with regard to Staphylococcus aureus, associated with relapse in granulomatosis with polyangiitis, and Herpes zoster, potentially contributing to GCA development. Remission of disease and prevention of disease-related complications are the most important outcomes for all systemic vasculitides. Although these goals are achieved in the majority of patients receiving modern therapies, the prevention of treatment-related complications, especially glucocorticoid side effects, is still an unmet need that is common to AAV, GCA, and PMR.

23 citations


Journal ArticleDOI
TL;DR: Questions remain about the best treatment regimens and biomarkers to monitor disease activity and predict flare after discontinuation of treatment, including the tapering of treatment for giant cell arteritis and polymyalgia rheumatica.
Abstract: Giant cell arteritis (GCA) is the most common type of primary vasculitis in Western countries. Polymyalgia rheumatica (PMR) is the second most common inflammatory rheumatic disease of the elderly after rheumatoid arthritis. Glucocorticoids are the cornerstone of treatment for GCA and PMR, which are interrelated diseases. Glucocorticoids are effective, but adverse effects occur in a high proportion of patients. Careful use of glucocorticoids and the application of preventive strategies can minimize these adverse effects. Possible long-term complications of GCA include aneurysm and stenosis of vessels, even in patients with apparently clinically inactive disease; acute blindness is rare during glucocorticoid treatment. In PMR, whether subclinical chronic inflammation can lead to long-term damage is less clear. Management of both GCA and PMR is hampered by the lack of universally accepted definitions of remission and other disease states, such as low disease activity or vessel damage without active disease. In this Review, we outline current evidence on the monitoring and long-term management of patients with GCA and PMR, including the tapering of treatment.

12 citations


Journal ArticleDOI
TL;DR: Evidence is mounting that overall mortality in GCA patients is at best slightly higher than expected in relation to general population mortality data, but GCA is associated with an increase in morbidity and mortality specifically related to aortic aneurysm or other cardiovascular causes.
Abstract: Knowledge of the natural history and epidemiology of giant cell arteritis (GCA) is growing. With the recent conceptual change, GCA is no longer considered a disease with mandatory cranial symptoms but, rather, a larger disease spectrum also including idiopathic aortitis in people older than 50 and polymyalgia rheumatica with large-vessel involvement. The incidence peak between age 70 and 80 years, greater frequency in females and greater occurrence in Nordic countries are well-established epidemiological characteristics. Conversely, the notion that the incidence of GCA is increasing is challenged by several recent population-based studies suggesting a trend reversal for about 15 to 20 years. The known link with the allele HLA-DRB1*04 was confirmed by a genome-wide association study that also found associations with two other genetic polymorphisms. Recent studies indicating a link with varicella zoster virus infection have invigorated the hypothesis of an infectious cause for GCA. Smoking is the most solidly recognized environmental risk factor, but other traditional cardiovascular risk factors do not seem to predispose to GCA. Evidence is mounting that overall mortality in GCA patients is at best slightly higher than expected in relation to general population mortality data, but GCA is associated with an increase in morbidity and mortality specifically related to aortic aneurysm or other cardiovascular causes. Further studies are needed to integrate the current knowledge into a single etiological model.

10 citations


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TL;DR: Criteria for the classification of giant cell (temporal) arteritis were developed by comparing 214 patients who had this disease with 593 patients with other forms of vasculitis, and 2 other variables were included: scalp tenderness and claudication of the jaw or tongue or on deglutition.
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1,981 citations


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TL;DR: CRP concentration has continuous associations with the risk of coronary heart disease, ischaemic stroke, vascular mortality, and death from several cancers and lung disease that are each of broadly similar size.
Abstract: BACKGROUND: Associations of C-reactive protein (CRP) concentration with risk of major diseases can best be assessed by long-term prospective follow-up of large numbers of people. We assessed the associations of CRP concentration with risk of vascular and non-vascular outcomes under different circumstances. METHODS: We meta-analysed individual records of 160 309 people without a history of vascular disease (ie, 1.31 million person-years at risk, 27 769 fatal or non-fatal disease outcomes) from 54 long-term prospective studies. Within-study regression analyses were adjusted for within-person variation in risk factor levels. RESULTS: Log(e) CRP concentration was linearly associated with several conventional risk factors and inflammatory markers, and nearly log-linearly with the risk of ischaemic vascular disease and non-vascular mortality. Risk ratios (RRs) for coronary heart disease per 1-SD higher log(e) CRP concentration (three-fold higher) were 1.63 (95% CI 1.51-1.76) when initially adjusted for age and sex only, and 1.37 (1.27-1.48) when adjusted further for conventional risk factors; 1.44 (1.32-1.57) and 1.27 (1.15-1.40) for ischaemic stroke; 1.71 (1.53-1.91) and 1.55 (1.37-1.76) for vascular mortality; and 1.55 (1.41-1.69) and 1.54 (1.40-1.68) for non-vascular mortality. RRs were largely unchanged after exclusion of smokers or initial follow-up. After further adjustment for fibrinogen, the corresponding RRs were 1.23 (1.07-1.42) for coronary heart disease; 1.32 (1.18-1.49) for ischaemic stroke; 1.34 (1.18-1.52) for vascular mortality; and 1.34 (1.20-1.50) for non-vascular mortality. INTERPRETATION: CRP concentration has continuous associations with the risk of coronary heart disease, ischaemic stroke, vascular mortality, and death from several cancers and lung disease that are each of broadly similar size. The relevance of CRP to such a range of disorders is unclear. Associations with ischaemic vascular disease depend considerably on conventional risk factors and other markers of inflammation. FUNDING: British Heart Foundation, UK Medical Research Council, BUPA Foundation, and GlaxoSmithKline.

1,781 citations