Polymyalgia rheumatica and risk of cerebrovascular accident: A systematic review and meta-analysis
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.190273
Source of Support: None, Conflict of Interest: None
Keywords: Cerebrovascular disease; epidemiology; meta-analysis; polymyalgia rheumatica
Polymyalgia rheumatica (PMR) is one of the most common chronic inflammatory disorders in older adults, characterized by aching and stiffness of limb girdles, constitutional symptoms, and elevated inflammatory markers. PMR is commonly seen in association with giant cell arteritis (GCA), though the pathophysiology behind this association is not well understood. Patients with PMR and/or GCA usually have a good response to corticosteroid-based therapy.
The association between chronic inflammation and premature cardiovascular diseases is well recognized, as an increased incidence of cardiovascular complications among patients with chronic inflammatory disorders such as rheumatoid arthritis, systemic lupus erythematosus, and idiopathic inflammatory myopathy ,,, have been consistently demonstrated in large epidemiological studies. Several in vitro and in vivo studies have suggested that inflammatory cytokines and oxidative stress are the major players for the acceleration of atherosclerosis, as their detrimental effects on the endothelial cell are well documented.,
The patients with PMR might be at an increased risk of cerebrovascular accident (CVA), a common subtype of cardiovascular diseases, as a consequence of a higher inflammatory burden. However, the data on this are still limited, and the results of epidemiologic studies were fairly heterogeneous.,,, Thus, to obtain a more precise and accurate estimate of its effect, we conducted a systematic review and meta-analysis of observational studies that compared the CVA risk in patients with PMR versus non-PMR participants.
Two investigators (P.U. and N.S.) independently searched published studies indexed in MEDLINE and EMBASE database from inception to May 2015 using the search strategy that comprised terms for PMR and CVA as described in supplementary material 1. References of selected retrieved articles were also manually searched. The inclusion criteria were as follows: (1) Observational studies (cross-sectional, case–control, or cohort studies) comparing the risk of CVA in subjects with and without PMR were considered; (2) in the studies, odds ratio (OR), relative risk (RR), hazard ratio, or standardized incidence ratio with 95% confidence intervals (CI) were provided; and (3) subjects without PMR were used as a control group in cohort studies and cross-sectional studies, while subjects without CVA were used as a control group in case–control studies.
Study eligibility was independently determined by each investigator noted earlier in the text. Newcastle–Ottawa quality assessment scale was used to appraise the quality of the included studies. This scale assessed each study in three areas: (1) The selection of the participants for each group, (2) the comparability between the study groups, and (3) the ascertainment of the exposure and the outcome of interest. The senior investigator (C.T.) oversaw this literature review process and resolved any conflicting decisions.
A standardized data collection form was used to extract the following information:First author's name, title of the study, year of publication, year when the study was conducted, study design, country of origin, study size, study population, method used to diagnose PMR and CVA, average duration of follow-up (for cohort studies), baseline characteristics of each group, confounders that were adjusted, and adjusted effect estimates with their corresponding 95% confidence intervals (CIs). To ensure the accuracy of data extraction, this process was independently performed by all investigators. Any data discrepancy was resolved by referring back to the original studies.
Data analysis was performed using Review Manager 5.3 software from the Cochrane Collaboration. Point estimates and standard errors were extracted from each study and were combined by the generic inverse variance method described by DerSimonian and Laird. In light of the high likelihood of between-study variance due to differences in the study design and population, we used a random-effect model rather than a fixed-effect model. As the outcome of interest in this study was relatively uncommon, we used OR of case–control studies and cross-sectional studies as an estimate for RR to combine the data with RR of cohort studies to increase the power and precision of our pooled estimates. Statistical heterogeneity was assessed by Cochran's Q test and I 2 statistic. This statistic quantifies the proportion of total variation across studies that is due to heterogeneity rather than chance. A value of I 2 of 0%–25% represents insignificant heterogeneity, >25% but ≤50% represents low heterogeneity, >50% but ≤75% represents moderate heterogeneity, and >75% represents high heterogeneity. Funnel plot and Egger's linear regression method  were utilized for the evaluation of publication bias using Comprehensive Meta-Analysis version 2.2 software (Biostat, Englewood, NJ, USA).
Our search strategy yielded 391 potentially relevant articles (250 articles from EMBASE and 141 articles from MEDLINE). After exclusion of 131 duplicated articles, 260 articles underwent title and abstract review. Of them, 249 articles were excluded, because they were clearly not observational studies, were not conducted in patients with PMR, or did not report the association of interest, leaving 11 articles for a full-length article review. Six articles were excluded because they reported risk of CVA in patients with giant cell arteritis (GCA) [not PMR],,,,,, while an article was excluded because it compared the risk of CVA between patients with PMR who received and did not receive corticosteroids. Three retrospective cohort studies and one cross-sectional study met our eligibility criteria and were included in our data analyses.,,, [Figure 1] outlines our search methodology and the literature review process. The characteristics and quality assessment of the included studies are illustrated in [Table 1].
The pooled risk ratio of CVA in patients with PMR versus controls was 1.87 (95% CI, 1.43–2.43). The statistical heterogeneity was high, with an I 2 of 91%. [Figure 2] demonstrates the forest plot of this meta-analysis.
We conducted sensitivity analyses to explore the high heterogeneity between studies. First, we excluded the study by Kremers et al., as this study was the only study with cross-sectional design. However, exclusion of this study did not significantly alter the results or I 2 (pooled RR, 1.93; 95% CI, 1.42–2.63; I 2, 94%). In the second sensitivity analysis, we excluded the study by Zoller et al., as this study identified cases from the admission database, leading to a potential bias of including only severe cases. Exclusion of this study dramatically reduced I 2 to 37% and slightly increased the pooled RR to 2.12 (95% CI, 1.79–2.50).
Evaluation for publication bias
Funnel plot to evaluate publication bias is demonstrated in [Figure 3]. The graph is symmetric and, therefore, does not provide a suggestive evidence for publication bias. Furthermore, there was no evidence of publication bias detected by Egger's regression test (P = 0.81).
This is the first systematic review and meta-analysis of published observational studies assessing the risk of CVA in patients with PMR. Our study demonstrates a significant association between PMR and CVA with an overall 1.87-fold increased risk compared with non-PMR controls. All included studies reported a positive association between PMR and CVA, but the RR varied considerably, ranging from 1.54 to 2.30.
There are a few possible explanations for this increased CVA risk. The first explanation is related to chronic inflammation, as the role of inflammation in the initiation and progression of atherosclerosis is well recognized., It has been demonstrated that inflammatory cytokines, oxidative stress, and activated inflammatory cells are deleterious to endothelial integrity., Furthermore, chronic inflammation related to autoimmune diseases has been demonstrated to promote the coagulation system, resulting in a hypercoagulable state.,, These factors may serve as the fundamental pathophysiology for the development of CVA.
Second, patients with PMR often have coexisting GCA. Even in patients without overt symptoms of GCA, subclinical vasculitis is observed in some of them., Endothelial damage from the coexisting vasculitis could further promote the atherosclerosis progression.
It was thought that corticosteroids, the universally used immunosuppressive agent in PMR, could be a contributor to the increased cardiovascular disease risk, as the use of corticosteroids is associated with an increased incidence of the traditional atherosclerotic risk factors such as diabetes mellitus, hypertension, and dyslipidemia. However, a recent study has demonstrated that the use of corticosteroids in patients with PMR was not associated with an increased risk of cardiovascular diseases. In fact, a trend for a protective effect was seen. The authors hypothesized that the anti-inflammatory activity of corticosteroids might offset the metabolic adverse effects.
Even though the studies included in this meta-analysis were of high quality, we acknowledge that there are some limitations. Therefore, the results should be interpreted with caution.
First, most of the included studies were conducted using medical registry database. This type of study is inherently at risk of coding inaccuracy. With this concern, we performed another sensitivity analysis by including only the studies by Kremers et al., and Hancock et al., because those two studies were the studies with a more reliable diagnostic accuracy. The study by Kremers et al., verified the diagnosis of PMR by individual medical record review, while the study by Hancock et al., used the General Practice Research Database (GPRD), which has been validated for diagnostic accuracy., This sensitivity analysis, however, did not yield a significantly different result from the full analysis (RR, 2.01; 95% CI, 1.43–2.84; I 2, 66%). Second, the statistical heterogeneity was high in this meta-analysis. However, our sensitivity analysis showed that the statistical heterogeneity was substantially reduced after the exclusion of the studies with potential selection bias. Third, this is a meta-analysis of observational studies that can only demonstrate an association but could not establish causality. Therefore, we cannot conclude that PMR itself or potential confounders were responsible for the increased risk.
In conclusion, our meta-analysis demonstrated a significantly increased CVA risk, at 87%, among patients with PMR. Physicians should be aware of this association, and an appropriate intervention to modify the traditional cardiovascular risk factors should be incorporated to the routine care for these patients.
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Conflicts of interest
We do not have any financial or nonfinancial potential conflicts of interest.
[Figure 1], [Figure 2], [Figure 3]