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TRACEY M. FARRAGHER, MSc, PhD,
Research Fellow;

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IAN N. BRUCE, MD, FRCP,
Reader in Rheumatology
University of Manchester,
ARC Epidemiology Unit,
Stopford Building, Oxford Road,
Manchester, M13 9PT, United Kingdom

Address reprint requests to Dr. Bruce. E-mail: ian.bruce@manchester.ac.uk

It is well established that rheumatoid arthritis (RA) is associated with reduced life expectancy^1-3. While the absolute increase in mortality risk varies between studies⁴, most found that the majority of these excess deaths result from cardiovascular disease (CVD)^3,5,6, in particular, atherosclerotic CVD^7,8.

The risk of myocardial infarction in RA patients is, for example, increased by a factor of 2 to 3^6-8. Premature CVD mortality and morbidity in RA has been the subject of much investigation, and both traditional and nontraditional CVD risk factors have been implicated^9-12. Traditional CVD risk factors found to be associated with atherosclerosis in RA include age, smoking, hypertension, and dyslipidemia^10-12. However, traditional risk factors alone do not fully explain the excess CVD risk in RA. Other nontraditional factors are hypothesized to play a role, in particular the burden of inflammation as indicated by the C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR)^9,13,14. In a community-based cohort of patients with inflammatory polyarthritis, Goodson, et al also noted that excess CVD mortality was confined to patients who were rheumatoid factor-positive⁵. These markers of inflammation and inflammatory burden confer additional risk of CVD death in those with RA after adjusting for traditional CVD risk factors and comorbidities¹⁵.

If RA is associated with increased CVD risk compared to the general population and this is in part due to chronic inflammation, then other inflammatory rheumatic diseases, such as ankylosing spondylitis (AS) and psoriatic arthritis (PsA) might also be hypothesized to have increased CVD risk. There are, however, a limited number of studies that have examined these conditions in relation to both mortality and the contribution of CVD to any observed excess deaths. In a community-based cohort of patients with PsA, for example, no excess mortality was noted¹⁶. In contrast, Wong, et al found in a hospital-based PsA cohort that mortality was increased, principally due to respiratory rather than cardiovascular deaths¹⁷. More recently, Peters, et al reviewed studies that investigated CVD mortality and morbidity and/or CVD risk factors in AS and PsA. They concluded that while there were a limited number of studies, there was evidence of increased CVD risk in AS and PsA¹⁸. CVD mortality in both conditions was associated with disease duration and severity, as well as traditional CVD risk factors, e.g., smoking, lipid profile, and hypertension. In addition, there was evidence that HLA-B27 status, increased platelet count, and fibrinogen may also play a role. It is clear, however, that compared to RA, the evidence base to support the hypothesis of increased CVD risk in PsA and AS is much less definitive, and many questions remain unresolved.

Han and colleagues' cross-sectional comparison of cardiovascular diseases and risk factors in RA, PsA, and AS patients, presented in this issue of The Journal, is an interesting contribution to this debate¹⁹. From a large health plan database in the US, the prevalence ratios of CVD diagnoses and risk factors in these 3 conditions were compared with unaffected population-matched controls (1:4 ratio). From almost 3 million individuals in the analysis, prevalence ratios of the cardiovascular diagnoses (ischemic heart disease, atherosclerosis, peripheral vascular disease, congestive heart failure, and cerebrovascular disease) and cardiovascular risk factors (type II diabetes, hyperlipidemia, and hypertension) were higher in the patients with RA, PsA, and AS. In addition, the use of cardiovascular drugs was also higher in all 3 patient groups.

There are, however, issues relating to these types of data and subsequent analyses that may limit their generalizability to the population as a whole. Health plan data do not necessarily represent the population within which they are based, due to the selection criteria of the particular plan²⁰. In addition, selection criteria for the study may further restrict the population studied. In the data used by Han, et al, while the analysis uses a large dataset with impressive numbers, in fact only 25% of all adults enrolled to the health plan in the selected timeframe were eligible for inclusion¹⁹. It is unlikely that this proportion of people would be fully representative of all those in the health plan, and more important, it is therefore likely to be an unrepresentative sample of the general population.

The data presented are largely based on a working population, and only those continuously enrolled in the plan for a 2-year period and who had at least one interaction with the health plan were included. Therefore, for example, subjects who died during this 2-year period would automatically be excluded. Such restrictions will presumably reduce the numbers with chronic inflammatory conditions or cardiovascular comorbidities, and would serve to minimize any differences observed. The prevalence ratios for all conditions mentioned may therefore be significant underestimates of the true risk in the population. Conversely, only those that made a claim or had an interaction with the health plan were included, which may serve to bias estimates in the opposite direction, since those with preexisting conditions are more likely to utilize the health plan. It is by no means clear in the analysis which is the dominant source of confounding, and therefore the prevalence ratios reported may be much higher or lower than the true CVD risk status of the 3 populations.

The use of cross-sectional studies to assess if RA, PsA, or AS patients are at risk of CVD also has the disadvantage that information on the temporal relationship of these conditions is lacking; in particular, this means that from this study we cannot determine whether inflammatory rheumatic conditions increase the risk of CVD or whether CVD predisposes to inflammatory rheumatic disease^21,22. In the current study this problem is further compounded by the inclusion of both prevalent and incident cases. Further, no adjustment for potential confounders was carried out, either of those factors compared between the patient groups (type II diabetes, hyperlipidemia, and hypertension), or of other traditional CVD risk factors (e.g., smoking, family history, weight, and comorbidities).

A potential explanation for increased prevalence ratios of CVD and risk factors in the 3 patient groups is that of diagnostic suspicion bias. Subjects with a chronic condition such as RA, PsA, or AS are more likely to be screened and investigated to explain symptoms such as chest pain or ankle swelling. Having contact with the healthcare system will also increase opportunities to participate in a planned or opportunistic cardiovascular risk screening program. Therefore much of the increase in CVD and risk factors reported may simply reflect this bias. One clue to this is the increased prevalence of hyperlipidemia noted among RA patients¹⁹. Previous work has found that total and/or LDL-cholesterol concentrations in patients with RA are lower than in controls^23,24. Therefore, in the US, where LDL-cholesterol is the key lipid target on which intervention guidelines are based²⁵, one would expect a lower or comparable prevalence of hyperlipidemia in patients with RA. The finding of more hyperlipidemia in RA strongly suggests that this population is systematically different from those reported previously and casts some doubt on the other conclusions and estimates reported by the authors.

Ideally, to further study CVD risk in AS or PsA, large-scale prospective studies are required. Such studies should have predetermined definitions for each risk factor and outcome, all of which should be ascertained by the same approaches in both cases and controls. Prevalent and incident cases can also be distinguished in such a study design, which would help determine the direction of any association seen. Such studies will enable us to begin to understand for each condition the true magnitude of CVD risk, as well as the relative importance and contribution of traditional cardiovascular risk factors, inflammation, and therapeutic agents of relevance to this risk.

We know that atherosclerotic cardiovascular disease is a major problem in both systemic lupus erythematosus and RA. If, as we suspect, inflammation has a key role in the genesis of atherosclerosis, then studying the seronegative arthropathies, where different inflammatory mechanisms are likely to be dominant, may have a lot to teach us. The study by Han, et al adds to the evidence that CVD may well be a significant problem in AS and PsA. Well designed prospective studies are now needed to confirm these observations and to help determine whether increased risk of CVD in PsA and AS is primarily driven by traditional risk factors, chronic inflammation, or the consequences of treatment.

REFERENCES

Search PubMed for:

2. Wolfe F, Mitchell DM, Sibley JT, et al. The mortality of rheumatoid arthritis. Arthritis Rheum 1994;37:481-94. [MEDLINE]

3. Riise T, Jacobsen BK, Gran JT, Haga HJ, Arnesen E. Total mortality is increased in rheumatoid arthritis. A 17-year prospective study. Clin Rheumatol 2001;20:123-7. [MEDLINE]

4. Ward MM. Recent improvements in survival in patients with rheumatoid arthritis: better outcomes or different study designs? Arthritis Rheum 2001;44:1467-9. [MEDLINE]

5. Goodson NJ, Wiles NJ, Lunt M, Barrett EM, Silman AJ, Symmons DP. Mortality in early inflammatory polyarthritis: cardiovascular mortality is increased in seropositive patients. Arthritis Rheum 2002;46:2010-9. [MEDLINE]

6. Solomon DH, Karlson EW, Rimm EB, et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation 2003;107:1303-7. [MEDLINE]

7. Maradit-Kremers H, Crowson CS, Nicola PJ, et al. Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study. Arthritis Rheum 2005;52:402-11. [MEDLINE]

8. del Rincon I, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum 2001;44:2737-45. [MEDLINE]

9. Snow MH, Mikuls TR. Rheumatoid arthritis and cardiovascular disease: the role of systemic inflammation and evolving strategies of prevention. Curr Opin Rheumatol 2005;17:234-41. [MEDLINE]

10. Silman AJ, Newman J, MacGregor AJ. Cigarette smoking increases the risk of rheumatoid arthritis. Results from a nationwide study of disease-discordant twins. Arthritis Rheum 1996;39:732-5. [MEDLINE]

11. Goodson NJ, Silman AJ, Pattison DJ, et al. Traditional cardiovascular risk factors measured prior to the onset of inflammatory polyarthritis. Rheumatology Oxford 2004;43:731-6. [MEDLINE]

12. Hazes JM, Dijkmans BA, Vandenbroucke JP, de Vries RR, Cats A. Lifestyle and the risk of rheumatoid arthritis: cigarette smoking and alcohol consumption. Ann Rheum Dis 1990;49:980-2. [MEDLINE]

13. Wallberg-Jonsson S, Johansson H, Ohman ML, Rantapaa-Dahlqvist S. Extent of inflammation predicts cardiovascular disease and overall mortality in seropositive rheumatoid arthritis. A retrospective cohort study from disease onset. J Rheumatol 1999;26:2562-71. [MEDLINE]

14. Goodson NJ, Symmons DP, Scott DG, Bunn D, Lunt M, Silman AJ. Baseline levels of C-reactive protein and prediction of death from cardiovascular disease in patients with inflammatory polyarthritis: a ten-year followup study of a primary care-based inception cohort. Arthritis Rheum 2005;52:2293-9. [MEDLINE]

15. 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. [MEDLINE]

16. Shbeeb M, Uramoto KM, Gibson LE, O'Fallon WM, Gabriel SE. The epidemiology of psoriatic arthritis in Olmsted County, Minnesota, USA, 1982-1991. J Rheumatol 2000;27:1247-50. [MEDLINE]

17. Wong K, Gladman DD, Husted J, Long JA, Farewell VT. Mortality studies in psoriatic arthritis: results from a single outpatient clinic. I. Causes and risk of death. Arthritis Rheum 1997;40:1868-72. [MEDLINE]

18. Peters MJ, van der Horst-Bruinsma IE, Dijkmans BA, et al. Cardiovascular risk profile of patients with spondylarthropathies, particularly ankylosing spondylitis and psoriatic arthritis. Semin Arthritis Rheum 2004;34:585-92. [MEDLINE]

19. Han C, Robinson DW Jr, Hackett MV, Paramore LC, Fraeman KH, Bala MV. Cardiovascular disease and risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. J Rheumatol 2006;33:2167-72.

20. Symmons DPM. Population studies of musculoskeletal morbidity. In: Silman AJ, Hochberg MC, editors. Epidemiology of the rheumatic diseases. 2nd ed. Oxford: Oxford University Press; 2001:5-28.

21. Elwood JM. Critical appraisal of epidemiological studies and clinical trials. 2nd ed. Oxford: Oxford University Press; 1998.

22. Silman AJ, Macfarlane GJ. Epidemiological studies: a practical guide. 2nd ed. Cambridge: Cambridge University Press; 2002.

23. Dessein PH, Stanwix AE, Joffe BI. Cardiovascular risk in rheumatoid arthritis versus osteoarthritis: acute phase response related decreased insulin sensitivity and high-density lipoprotein cholesterol as well as clustering of metabolic syndrome features in rheumatoid arthritis. Arthritis Res 2002;4:R5. [MEDLINE]

24. Svenson KL, Lithell H, Hallgren R, Vessby B. Serum lipoprotein in active rheumatoid arthritis and other chronic inflammatory arthritides. II. Effects of anti-inflammatory and disease-modifying drug treatment. Arch Intern Med 1987;147:1917-20. [MEDLINE]

25. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol In Adults. Executive Summary. Third Report of The National Cholesterol Education Program (NCEP) (Adult Treatment Panel III). JAMA 2001;285:2486-97. [MEDLINE]