Introduction
Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting about 1% of the population, mainly women, and significantly increases cardiovascular disease (CVD) risk, shortening lifespan by 5–18 years. Despite improved mortality rates in RA patients, cardiovascular risks remain elevated, with higher rates of myocardial infarction, stroke, and heart failure. RA’s combination of traditional and disease-specific risk factors complicates CV risk estimation. Chronic inflammation in RA accelerates atherosclerosis and worsens CVD outcomes. The impact of RA flares and inflammation on CV risk emphasizes the need for better risk assessment models and therapies. Studies highlight the importance of biomarkers and non-invasive diagnostics for early CVD detection, as many RA patients remain unaware of their heightened risk. Medications like glucocorticoids can exacerbate CVD risk, while treatments like methotrexate may offer protective benefits. In contrast, osteoarthritis (OA) also carries a CVD risk but is not driven by chronic inflammation. This study explores the role of uncontrolled inflammation in RA-related CV risk.
Patients and methods
A total of 201 patients were recruited for a prospective cohort study: 124 with RA (investigation group) and 77 with OA (control group). The study spanned an average of 8 years and 4 months (2008/9-2016/17), excluding patients with any form of cardiovascular disease (CVD) or suspected CVD. CVD exclusions included myocardial infarction, stroke, ischemic cardiomyopathy, and peripheral arterial disease. Heart failure was diagnosed based on symptoms and signs, with further diagnostic tests added as they became available.
RA and OA were diagnosed per the American College of Rheumatology criteria. Participants were monitored for CVD, infections, neoplastic diseases, and changes in RA status. Hospitalized patients were closely tracked using the hospital’s integrated system, with data obtained from medical records, autopsies, and family physicians. At each visit, a comprehensive physical exam, tests, and questionnaires were performed. Blood work and ECG were done to assess health and disease activity, and patients with RA were assessed using DAS28-CRP.
Subgroup analysis for RA inflammation control included patients who missed no more than two visits. Participants in remission had low RA activity for over 60% of the study period; others were classified as having unsatisfactory disease control.
Statistical analyses
Descriptive statistics were used to describe and summarise the study data. Inferential statistics were applied to test the hypotheses. Independent samples t-test was employed to check the significance of mean differences. Depending on Levene’s test results, the t-test assuming equal or unequal variance was used to determine statistical significance between groups. A chi-square test of independence was applied to analyse the relationship between qualitative variables. Fisher’s exact test was employed when assumptions for the chi-square test were not met. The level of significance was set at p < 0,05, whereas 0,05 < p < 0,10 was considered as a tendency (marginally significant).
Results
In 2008/9, 201 participants were included in the study (124 with RA, 77 with OA). By the final visit in 2016/17, 137 remained (82 with RA, 55 with OA), with 58 deaths (41 RA, 17 OA) and six dropouts. The average age at the start was 59.78 years for RA and 64.23 years for OA (OA significantly older, p=0.004). RA participants had a significantly longer disease duration (12.2 years) than OA (5.64 years, p=0.001). At the final visit, average age was 65.5 years for RA and 71.2 years for OA. The RA group had moderate disease activity (DAS28-CRP 4.08), with 90.2% RF-positive.
Glucocorticoid and painkiller use remained high throughout, with slight differences between the groups. Hypertension medication use increased over time, with a higher percentage in the OA group. Statin use also increased, especially in the OA group. The incidence of cardiovascular events or death was 43.9% for RA and 37.5% for OA, with chronic heart failure being the most common diagnosis. CVD caused 70.7% of deaths in the RA group and 58.8% in the OA group.
Table 2. Deceased incidence and cardiovascular risk factor prevalence among deceased.
We compared our findings with 2018 Croatian general population data. In the RA group, 70.7% of deaths were due to CVD, significantly higher than the 44% in the population (p=0.002). In the OA group, 58.8% of deaths were due to CVD, with no significant difference compared to the population (p=0.217). The RA group had a lower BMI and triglyceride levels, higher blood pressure, and more smokers than the OA group. Over time, CV risk factors increased in both groups, with the RA group showing higher HDL levels and a greater prevalence of smoking and high cholesterol.
When comparing with population data, the RA group had a significantly higher proportion of smokers (52.4% vs. 31.1%, p<0.0001) and a higher prevalence of diabetes (32.9% vs. 8.3%, p<0.0001). The OA group also had a higher proportion of diabetes (29.1%, p<0.0001) but no significant difference in smoking.The study observed a surprisingly high death rate, with 58 participants dying during the study (41 RA, 17 OA). The RA group had a significantly shorter lifespan and a higher incidence of CVD-related deaths. Both groups had high CV risk factors, with the RA group having more smokers and slightly higher cholesterol. No significant link was found between modifiable risk factors and CVD deaths. Chronic heart failure was the leading cause of death, with neoplastic diseases being the main non-CVD cause.In a subgroup analysis based on age, participants under 65 in the RA group had better general health (p=0.001), lower DAS28 (p=0.001), HAQ (p=0.001), and VAS (p=0.02) scores, and a lower prevalence of hypertension (p=0.001). They also had a higher prevalence of smoking and lower incidence of CVD and metabolic syndrome. In the OA group, those under 65 had lower HAQ scores (p=0.002), more smokers, and fewer CVD risk factors, with a trend toward lower myocardial infarction incidence.Comparing RA and OA subgroups under 65, RA had a lower prevalence of general heart disease (p=0.023) and a marginally higher incidence of CVD and stroke. For those over 65, the RA group showed a higher prevalence of ex-smokers (p=0.015) and more CVD risk factors (p=0.018), with trends indicating higher disability and incidence of heart failure (p=0.094).In RA patients who achieved long-term remission, disease duration was shorter, with better general health, lower waist-to-hip ratio, less disability, and lower chronic pain scores. This group also had higher total cholesterol, but lower HDL, plasma glucose, and HbA1c. The incidence of CVD was significantly lower in the remission group, which also showed a marginally lower BMI, and lower prevalence of hypertension and diabetes. No differences were observed in other measured.
Conclusion
To cope with the problem of premature CV morbidity and mortality, a multidisciplinary approach for patients with RA is of paramount importance, especially with the cooperation of immunologists and cardiologists for the early detection, prevention, and management of CV risk and diseases. Strict inflammation control plays a central role in achieving these goals and includes developing novel and more effective anti-inflammatory drugs and tightly managing modifiable CV risk factors that contribute to CVD development and aggravate inflammation. Necessary lifestyle modifications include treating hypertension to achieve normal blood pressure values, lowering LDL, controlling diabetes and obesity, ceasing smoking, and adopting other healthy lifestyle habits.
References
1. Symmons DPM. Epidemiology of rheumatoid arthritis: determinants of onset, persistence and outcome. Best Pract Res Clin Rheumatol. 2002;16:707–22.
2. Sakai R, Hirano F, Kihara M, Yokoyama W, Yamazaki H, Harada S, et al. High prevalence of cardiovascular comorbidities in patients with rheumatoid arthritis from a population-based cross-sectional study of a Japanese health insurance database. Mod Rheumatol. 2016;26:522–8.
3. Koivuniemi R, Paimela L, Leirisalo-Repo M. Causes of death in patients with rheumatoid arthritis from 1971 to 1991 with special reference to autopsy. Clin Rheumatol. 2009;28:1443–7.
4. Maradit-Kremers H, Nicola PJ, Crowson CS, Ballman KV, Gabriel SE. Cardiovascular death in rheumatoid arthritis a population-based study. Arthritis Rheum. 2005;52:722–32.
5. Sokka T, Abelson B, Pincus T. Mortality in rheumatoid arthritis: 2008. update. Clin Exp Rheumatol. 2008;26:S35–611.
6. Meune C, Touze E, Trinquart L, Allanore Y. High risk of clinical cardiovascular events in rheumatoid arthritis: levels of associations of myocardial infarction and stroke through a systematic review and meta-analysis. Arch Cardiovasc Dis. 2010;103:253–61.
7. Meune C, Touze E, Trinquart L, Allanore Y. Trends in cardiovascular mortality in patients with rheumatoid arthritis over 50 years: a systematic review and meta-analysis of cohort studies. Rheumatology. 2009;48:1309–13.
8. Avina-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum. 2008;59:1690–7.
9. Meyer PWA, Anderson R, Ker JA, Ally MTM. Rheumatoid arthritis and risk of cardiovascular disease. Cardiovasc J Afr. 2018;29:317–21.
10. Meyer PWA, Anderson R, Ker JA, Ally MTM. Rheumatoid arthritis and risk of cardiovascular disease. Cardiovasc J Afr. 2018;29:317–21.
11. Mitchell DM, Spitz PW, Young DY, Bloch DA, McShane DJ, Fries JF. Prognosis and causes of death in rheumatoid arthritis. Arthritis Rheum. 1986;29:706–14.
12. Van Doornum S, McColl G, Wicks IP. Accelerated atherosclerosis – an extraarticular feature of rheumatoid arthritis? Arthritis Rheum. 2002;46:862–73.
13. Dadoun S, Zeboulon-Ktorza N, Combescure C, Elhai M, Rozenberg S, Gossec L, Fautrel B. Mortality in rheumatoid arthritis over the last fifty years: systematic review and meta-analysis. Joint Bone Spine. 2013;80:29–33.
14. Avina-Zubieta JA, Thomas J, Sadatsafavi M, Lehman AJ, Lacaille D. Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis. 2012;71:1524–9.
15. Soubrier M, Chamoux NB, Tatar Z, Couderc M, Dubost JJ, Mathieu S. Cardiovascular risk in rheumatoid arthritis. Joint Bone Spine. 2014;81:298–302.
