Tackling ischaemic heart disease in rheumatoid arthritis

G. D. Kitas1,2, and N. Erb1

1 Department of Rheumatology, Dudley Group of Hospitals NHS Trust and
2 Department of Rheumatology, Division of Immunity and Infection, The Medical School, University of Birmingham, UK

Rheumatoid arthritis (RA) is the commonest form of chronic inflammatory arthritis. It causes significant disability and the efforts of the scientific community have concentrated on controlling symptoms, decelerating joint damage and improving function. However, it has been known for 50 yr [1] that RA is also associated with increased mortality [2, 3]. For severe RA, this compares to that of major killers such as triple-vessel coronary heart disease (CHD) and some lymphomas [4, 5]. Despite advances in treatment, the mortality of RA does not appear to have changed over the last three decades [6, 7]. Its control, therefore, merits at least as much attention as the reduction of disability. An obvious target is reduction of cardiovascular mortality, which accounts for almost half of all deaths in RA [2, 3, 8]. In this article we describe the nature and significance of the problem, discuss the evidence for the involvement of atherosclerotic CHD, outline the role of classical and some novel cardiovascular risk factors, introduce potential lines for intervention, and provide a literature base for the interested reader.

With the exception of a few studies [913], most epidemiological work suggests that cardiovascular mortality is increased in RA, with standardized mortality ratios of between 1.13 and 5.15 [1425]. This very wide range may reflect variable susceptibility of the populations studied (e.g. geographic, genetic and dietary differences), different management practices [for both RA and cardiovascular disease (CVD)] or dissimilar study designs (e.g. inception vs established disease cohorts) [7].

There are only two possible explanations for excessive cardiovascular deaths in RA: CVD is either more prevalent or more deadly in RA patients than in general population counterparts. CVD collectively accounts for much of the comorbidity of RA [26, 27]. Rheumatoid heart disease, although common on echocardiography or autopsy, rarely has haemodynamic consequences; it is therefore an unlikely cause for the increased cardiovascular mortality of RA [28]. Instead, evidence is mounting that the main cause of cardiovascular death in RA is ischaemic heart disease (IHD). This is supported by studies showing that the incidence and/or prevalence of ischaemic cardiac pathologies, such as myocardial infarction (MI), congestive heart failure (CHF) and coronary death, are increased in RA compared with controls [18, 20, 22, 29, 30]. Using myocardial perfusion SPECT (single photon emission computed tomography) scans under pharmacological stress, we have shown that the prevalence of stable IHD in RA (50%) is twice that in closely matched osteoarthritic controls (27%). RA was an independent predictor of IHD in the total population studied [31]. Half of the RA patients with confirmed IHD had clinically silent disease, which has also been noted using 24-h Holter monitoring [32]. In a separate study we found that a fifth of RA patients who sustained an acute coronary syndrome (ACS: unstable angina, Q-wave or non-Q-wave MI) did not have chest pain on presentation, compared with none of the controls. Recurrent ACS was more common, occurred earlier and was associated with more deaths in these RA patients than in case-matched controls [33]. There is therefore sufficient evidence to suggest that the major cause of increased cardiovascular death in RA is IHD rather than other cardiac pathologies, and that IHD is both more common and more likely to lead to death in RA than in the general population.

Interestingly, this general picture is reminiscent of type-2 diabetes mellitus (DM). Excessive cardiovascular morbidity (including silent IHD) and mortality in type-2 DM are of similar magnitude to those now emerging for RA. Like DM, RA appears to be an independent risk factor for the development of IHD. The prevalence of the two conditions is not dissimilar, particularly in the 45 to 75+ age groups (RA vs DM: females, 1.67–2.99% vs 1.0–2.9%; males, 0.58–2.18% vs 1.6–4.6%) [31, 34–39; D. Symmons, personal communication]. In the context of the prevention, diagnosis, therapy and socioeconomic consequences of IHD, RA may be of similar importance to type-2 DM.

In the general population, the commonest cause of IHD is atherosclerotic CHD. The higher frequencies of stable IHD, first and recurrent ACS, and related deaths in RA could all be explained on the basis of accelerated formation and increased instability of coronary atherosclerotic plaques, compared with the general population. There is currently very little direct evidence for this. Most work has concentrated on the intima-media thickness (IMT) of the carotid arteries. In the general population, IMT is a marker of early atherosclerosis and subsequent vascular events. Studies in RA suggest that IMT is increased compared with controls, indicating accelerated carotid atherosclerosis [40]. There are no comparative studies of the nature and extent of involvement of the coronary vasculature and the characteristics of atherosclerotic plaques between RA patients and controls. However, there are several overlapping lines of indirect evidence lending credence to this scenario. They point to potential causes (and therefore potential areas for intervention) and include (i) the presence of an adverse CHD risk factor profile in RA, (ii) evidence establishing chronic inflammation as a major pathogenic mechanism in atherosclerosis, and (iii) the association of inflammatory burden with cardiovascular events or death.

Several studies in the general population have identified classical risk factors for the development of CHD. These include modifiable factors, such as smoking, diabetes, hypertension, high total [or low-density lipoprotein (LDL)] and low high-density lipoprotein (HDL) cholesterol, and fixed factors, such as age and male sex. Put together, these factors account for about half of all CHD events in the general population. Obesity and sedentary lifestyle are also important. Many novel factors have been described and may account for events that cannot be explained by the presence of classical risk factors. These include, among many others, homocysteinaemia, prothrombotic factors and serological markers of systemic inflammation, such as C-reactive protein (CRP) and serum amyloid A.

Smoking may be a risk factor for the development of RA [4147] and may be associated with its severity [4850]. Although smoking was not found to be a predictor of cardiovascular events or death in a single study of seropositive RA patients [51], it is a logical target for modification in the RA population. The prevalence of diabetes is not increased in RA [51], but insulin resistance, itself thought to promote atherosclerosis [52], has been reported in RA and other systemic inflammatory diseases [53, 54].

Hypertension is common in RA [26, 27] but it is not clear whether it is commoner than in controls. We have found that more than half (56%) of RA patients with no known cardiovascular comorbidity (including hypertension) have a systolic blood pressure higher than 140 mmHg, but this is equally common in osteoarthritis controls. Other investigators have found higher diastolic blood pressure in RA patients than in community controls [55]. Many epidemiological studies have shown an association between non-steroidal anti-inflammatory drugs (NSAIDs) and hypertension, but clinical trials aimed at proving this relationship had mixed findings. Two large meta-analyses [56, 57] confirm that NSAIDs cause clinically significant increases in blood pressure in patients receiving antihypertensive therapy; increases in normotensive individuals are smaller and possibly clinically insignificant. The newer cyclooxygenase (COX)-2 inhibitors (coxibs) have effects on blood pressure similar to those of traditional NSAIDs. Both COX-1 and COX-2 are expressed in renal tissue. Blocking the production of renal prostaglandins, whether in a selective or non-selective manner, can lead to reduced renal function and fluid retention, which can aggravate hypertension [58]. This is important, because even a small increase of 5–6 mmHg in diastolic blood pressure increases the risk of cardiovascular and cerebrovascular events by 15 and 67% respectively [59]. Hypertension should therefore be actively sought and targeted as a risk factor in patients with RA. Use of NSAIDs and coxibs should be judicious, and hypertensive patients receiving such drugs should be monitored for loss of blood pressure control and have their antihypertensive therapy adjusted if necessary. The choice of antihypertensive agents may be problematic in this population, because of other comorbidities and polypharmacy. The combination of NSAIDs and ACE (angiotensin-converting enzyme) inhibitors, for example, is commonly nephrotoxic, particularly in the elderly [60].

In the general population, the risk of vascular events has a positive association with total or LDL cholesterol and an inverse association with HDL cholesterol. Dyslipidaemia has been well documented in RA [61] and appears to be associated with the acute-phase response. During active RA, total and LDL cholesterol may be elevated or reduced [6264], but HDL is consistently reduced, leading to an unfavourable lipid profile [6366]. Control of disease activity with several drugs [64, 67] or the use of cyclosporin [68] may lead to elevation of all lipid levels. This raises important issues about the optimal timing of lipid assessment and its utility in the cardiac risk assessment of rheumatoid patients, which need to be resolved in large prospective studies of cardiac risk factors specific to RA. However, some interventions may make sense at this stage. Studies in RA, lupus and even diabetes suggest that the antimalarials may both reduce the levels of total and LDL cholesterol and/or increase HDL, resulting in an advantageous lipid profile [66, 6974]. This, together with a good safety record and the beneficial effects on RA control, when used in combination with other disease-modifying anti-rheumatic drugs (DMARDs) [75], suggests that antimalarials may be a good option in RA from the cardiovascular perspective. Hormone replacement therapy has mainly beneficial effects on lipids [68] and may be appropriate for many RA patients for osteoporosis prophylaxis. However, the recent Women's Health Initiative study showed increased risk of CHD events among treated women [76]. An interesting option requiring evaluation in RA is the use of statins. Statins have a proven beneficial effect on lipid profiles and reduce cardiovascular events in the general population [7779], irrespective of cholesterol levels [80]. They may also have anti-inflammatory and immunomodulatory effects [8186] relevant to both atherosclerotic and rheumatoid pathology, they may have beneficial antihypertensive effects [87], and they may reduce the risk of osteoporotic fracture [88].

Lipids and hypertension may relate to obesity and the sedentary lifestyle, which are now considered major CHD risk factors in their own right. Modest reduction in weight and/or increase in physical activity may provide significant survival benefits [8991]. Such lifestyle modifications may seem difficult but are not impossible in RA [9294] and may lead to multiple benefits, including a reduction in cardiovascular risk.

Homocysteinaemia is an independent CHD risk factor, possibly through multiple effects on endothelial cells, LDL oxidation and haemostasis [95, 96]. Methotrexate (MTX) can reduce folate and thus increase homocysteine levels. High levels of homocysteine have been described in RA, including in patients receiving MTX or MTX and sulphasalazine [97102]. It remains unclear whether this is important in the context of the cardiovascular mortality of RA. One study has shown a significant increase in the mortality of RA patients with pre-existing CVD treated with MTX compared with other DMARDs [103]. In contrast, another study reported significantly reduced mortality in cardiovascularly unselected RA patients treated with MTX [104], probably because of its superior control of inflammation compared with other DMARDs. Further research is necessary to clarify this. For the time being, it makes sense to ensure that all MTX-treated RA patients receive adequate folate supplementation [105]; it may also be reasonable to avoid MTX, if possible, for the treatment of RA in patients with pre-existing CVD.

Inflammation in RA may have significant prothrombotic effects. These may contribute to both the severity of stable atherothrombotic coronary disease and worse outcome after ACS. Fibrinogen [106] and other thrombotic risk factors [107] (e.g. tissue plasminogen activator, D-dimers, von Willebrand factor) are elevated [55] and may associate with cardiovascular events in RA [108]. Several of the drugs used in RA may affect thrombotic variables and, because of practice changes, there is an urgent need to define these effects. Antimalarials may have beneficial antithrombotic properties [72, 109] but this needs to be confirmed. NSAIDs (e.g. naproxen) have well-described aspirin-like antiplatelet effects and are reported to reduce vascular events in RA [110], slow atherosclerosis in animal models [111] and reduce mortality after MI as effectively as aspirin in the general population [112]. However, the evidence for this should be viewed with caution [113]. Some NSAIDs (e.g. ibuprofen) appear to antagonize aspirin-induced platelet inhibition, whereas others (e.g. diclofenac) do not [114]. The coxibs may [115] or may not [114] interfere with the antithrombotic effect of aspirin and may even have prothrombotic effects themselves [116], probably by decreasing vascular prostacyclin production [117]. Whether this leads to increased cardiovascular events [118, 119] is still a matter of debate. On current evidence, it would be inappropriate to withhold aspirin in patients receiving it for cardiovascular protection, whether or not they are receiving NSAIDs or coxibs. The administration of ibuprofen in patients receiving aspirin may also need to be avoided.

Atherosclerosis, like RA, is a chronic inflammatory condition [120] and may even have an autoimmune component [121]. Immunohistochemical studies suggest significant similarities between the mechanisms responsible for chronic synovitis and damage in the rheumatoid joint and the generation and rupture of the atherosclerotic plaque. These include the cellular infiltrates, adhesion molecule expression, the cytokine milieu and free radical and degradative enzyme release [3, 120125]. The importance of inflammation is further supported by work in animal models [126129] and epidemiological work in the general population showing that several serological markers of systemic inflammation may associate with cardiovascular outcomes [130132]. The best studied is CRP: its level is a good predictor of future MI or ischaemic stroke in the general population, whether or not there is pre-existing CVD [130133]. It remains unknown whether CRP reflects underlying inflammatory mechanisms or is itself pathogenically involved through effects on endothelial cells and macrophages.

It is obvious that the systemic inflammation of RA can be linked to accelerated atherosclerosis, IHD and cardiovascular death in many different ways. It follows that an increased inflammatory burden should be associated with more cardiovascular events and death, whereas its effective control should be associated with better outcome. The current evidence, although indirect, appears to support this. Disease activity, as assessed by the erythrocyte sedimentation rate [51], joint swelling [134] or a composite activity score [135], has been shown to be associated with cardiovascular events, cardiovascular death and overall mortality respectively. The effects of various treatments for RA are less clearly defined: DMARDs do not appear to increase overall mortality. In contrast, effective control of inflammatory activity appears to confer survival benefits [22, 104, 136138], but it remains to be proven in most cases whether this is due to improved cardiovascular outcomes. It will be interesting to see the effects of the anti-tumour necrosis factor (TNF) agents in the future. At present, any assumptions would be premature. Treatment of CHF with anti-TNF agents has a sound theoretical basis (overexpression of TNF-{alpha} associated with negative inotropic effects, left ventricular dysfunction, cardiomyopathy and pulmonary oedema). Yet trials of the anti-TNFs in CHF suggest that they may lead to worsening CHF, increased hospitalization and more deaths rather than clinical improvement.

The cause of increased cardiovascular morbidity and mortality in RA is likely to be multifactorial. Further research is needed to disentangle the interdependence of most of the factors discussed above, separate cause from effect, and assign relative importances to them, so that informed interventions can be implemented. This may be a much greater challenge in RA than it is in the general population, but we can learn from work in other conditions. We have already drawn a parallel between RA and type-2 diabetes. The excess cardiovascular risk in DM is thought to relate partly to the direct effects of hyperglycaemia and partly to its adverse effects on risk factors [139]. Although strict glycaemic control showed a clear benefit in microvascular complications, it does not appear to affect macrovascular disease markedly [140]. Because of this, recent guidelines provide a framework for aggressive classical risk factor targeting and reduction in patients with DM and other high-risk groups [141]. We can follow a similar approach while we try to clarify the role of systemic inflammation in RA and find the best way to suppress it without compromising the vasculature. By recognizing that RA patients are a high-risk group, we can seek actively and treat aggressively their classical cardiovascular risk factors in both the primary and secondary care settings.

Notes

Correspondence to: G. D. Kitas, Department of Rheumatology, Dudley Group of Hospitals NHS Trust, The Guest Hospital, Tipton Road, Dudley, West Midlands DY1 4SE, UK. E-mail: g.d.kitas{at}bham.ac.uk Back

References

  1. Cobb S, Anderson F, Bayer W. Length of life and cause of death in rheumatoid arthritis. N Engl J Med 1953;249:553–6.[ISI]
  2. Goodson N. Coronary artery disease and rheumatoid arthritis. Curr Opin Rheumatol 2002;14:115–20.[CrossRef][ISI][Medline]
  3. van Doornum S, McColl G, Wicks IP. Accelerated atherosclerosis. An extraarticular feature of rheumatoid arthritis? Arthritis Rheum 2002;46:862–73.[CrossRef][ISI][Medline]
  4. Pincus T, Callahan LF. Rheumatology function tests: grip strength, walking time, button test and questionnaires document predict longterm morbidity and mortality in rheumatoid arthritis. J Rheumatol 1992;19:1051–7.[ISI][Medline]
  5. Pincus T, Callahan LF. Taking mortality in rheumatoid arthritis seriously: predictive markers, socioeconomic status and comorbidity. J Rheumatol 1986;13:841–5.[ISI][Medline]
  6. Gabriel SE, Crowson CS, O'Fallon WM. Mortality in rheumatoid arthritis: have we made an impact in 4 decades? J Rheumatol 1999;26:2529–33.[ISI][Medline]
  7. Ward MM. Recent improvements in survival in patients with rheumatoid arthritis: better outcomes or different study designs? Arthritis Rheum 2001;44:1467–9.[CrossRef][ISI][Medline]
  8. Reilly PA, Cosh JA, Maddison PJ, Rasker JJ, Silman AJ. Mortality and survival in rheumatoid arthritis: a 25 year prospective study of 100 patients. Ann Rheum Dis 1990;49:363–9.[Abstract]
  9. Linos A, Worthington JW, O'Fallon WM, Kurland LT. The epidemiology of rheumatoid arthritis in Rochester, Minnesota: a study of incidence, prevalence, and mortality. Am J Epidemiol 1980;111:87–98.[Abstract]
  10. Lindqvist E, Eberhardt K. Mortality in rheumatoid arthritis patients with disease onset in the 1980s. Ann Rheum Dis 1999;58:11–4.[Abstract/Free Full Text]
  11. Sokka T, Mottonen T, Hannonen P. Mortality in early ‘saw-tooth’ treated rheumatoid arthritis patients during the first 8–14 yr. Scand J Rheumatol 1999;28:282–7.[CrossRef][ISI][Medline]
  12. Kroot EJ, van Leeuwen MA, van Rijswijk MH et al. No increased mortality in patients with rheumatoid arthritis: up to 10 yr of follow up from disease onset. Ann Rheum Dis 2000;59:954–8.[Abstract/Free Full Text]
  13. Riise T, Jacobsen BK, Gran JT et al. Total mortality is increased in rheumatoid arthritis: a 17 year prospective study. Clin Rheumatol 2001;20:123–7.[ISI][Medline]
  14. Monson RR, Hall AP. Mortality among arthritics. J Chron Dis 1976;29:459–67.[ISI][Medline]
  15. Allebeck P, Ahlbom A, Allander E. Increased mortality among persons with rheumatoid arthritis, but where RA does not appear on death certificate—eleven year follow-up of an epidemiological study. Scand J Rheumatol 1981;10:301–6.[ISI][Medline]
  16. Prior P, Symmons DPM, Scott DL, Brown R, Hawkins CF. Cause of death in rheumatoid arthritis. Br J Rheumatol 1984;23:92–9.[ISI][Medline]
  17. Mutru O, Laakso M, Isomaki H et al. Ten year mortality and causes of death in patients with rheumatoid arthritis. Br Med J 1985;290:1797–9.[ISI][Medline]
  18. Mutru O, Laakso M, Isomaki H, Koota K. Cardiovascular mortality in patients with rheumatoid arthritis. Cardiology 1989;76:71–7.[ISI][Medline]
  19. Jacobsson LTH, Knowler WC, Pillemer S et al. Rheumatoid arthritis and mortality: a longitudinal study in Pima Indians. Arthritis Rheum 1993;36:1045–53.[ISI][Medline]
  20. Myllykangas-Luosujarvi R, Aho K, Kautianen H, Isomaki H. Cardiovascular mortality in women with rheumatoid arthritis. J Rheumatol 1995;22:1065–7.[ISI][Medline]
  21. Turesson C, Jacobsson L, Bergstrom U. Prevalence and mortality of extraarticular rheumatoid arthritis. Arthritis Rheum 1997;40:741.[ISI]
  22. Wallberg-Jonsson S, Ohman ML, Rantapaa-Dahlqvist S. Cardiovascular morbidity and mortality in patients with seropositive rheumatoid arthritis in Northern Sweden. J Rheumatol 1997;24:445–51.[ISI][Medline]
  23. Symmons DPM, Jones MA, Scott DL, Prior P. Long-term mortality outcomes in patients with rheumatoid arthritis: early presenters continue to do well. J Rheumatol 1998;25:1072–7.[ISI][Medline]
  24. Kvalvik AG, Jones MA, Symmons DPM. Mortality in a cohort of Norwegian patients with rheumatoid arthritis followed from 1977 to 1992. Scand J Rheumatol 2000;29:29–37.[CrossRef][ISI][Medline]
  25. Goodson NJ, Wiles NJ, Lunt M et al. Increased mortality in seropositive patients during the early years of inflammatory polyarthritis [abstract]. Rheumatology 2001;40(Suppl. 1):71.
  26. Mikuls TR, Saag KG. Comorbidity in rheumatoid arthritis. Rheum Dis Clin North Am 2001;27:283–303.[ISI][Medline]
  27. Kroot EJJA, van Gestel AM, Swinkels HL et al. Chronic comorbidity in patients with early rheumatoid arthritis: a descriptive study. J Rheumatol 2001;28:1511–7.[ISI][Medline]
  28. Kitas GD, Banks MJ, Bacon PA. Cardiac involvement in rheumatoid disease. Clin Med JRCPL 2001;1:18–21.
  29. Gabriel SE, Crowson CS, O'Fallon WM. Comorbidity in arthritis. J Rheumatol 1999;26:2475–9.[ISI][Medline]
  30. 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.[CrossRef][ISI][Medline]
  31. Banks M, Flint J, Bacon PA, Kitas GD. Rheumatoid arthritis is an independent risk factor for ischaemic heart disease [abstract]. Arthritis Rheum 2000;43(Suppl. 9):S385.
  32. Wislowska M, Sypula S, Kowalick I. Echocardiographic findings, 24 hour electrocardiographic Holter monitoring in patients with rheumatoid arthritis according to Steinbrocker's criteria, functional index, value of Waaler–Rose titer and duration of disease. Clin Rheumatol 1998;17:369–77.[ISI][Medline]
  33. Banks MJ, Pace A, Kitas GD. Acute coronary syndromes present atypically and recur more frequently in rheumatoid arthritis than matched controls [abstract]. Arthritis Rheum 2001;44(Suppl.):S53.
  34. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229–34.[Abstract/Free Full Text]
  35. Ismail AA, Gill GV. The epidemiology of type 2 diabetes and its current measurement. Bailliere's Clin Endocrinol Metab 1999;13:197–220.
  36. Fisher M. Diabetes and myocardial infarction. Bailliere's Clin Endocrinol Metab 1999;13:331–43.
  37. Castells I, Salinas I, Rius F et al. Inducible myocardial ischaemia in asymptomatic type 2 diabetic patients. Diabetes Res Clin Practice 2000;49:127–33.[CrossRef][ISI][Medline]
  38. Kuller LH, Velentgas P, Barzilay J, Beauchamp NJ, O'Leary DH, Savage PJ. Diabetes mellitus. Subclinical cardiovascular disease and risk of incident cardiovascular disease and all cause mortality. Arterioscl Thromb Vasc Biol 2000;20:823–9.[Abstract/Free Full Text]
  39. Barzilay JI, Spiekerman CF, Kuller LH et al. Prevalence of clinical and isolated subclinical cardiovascular disease in older adults with glucose disorders: the cardiovascular health study. Diabetes Care 2001;24:1233–9.[Abstract/Free Full Text]
  40. Jonsson SW, Backman C, Johnson O et al. Increased prevalence of atherosclerosis in patients with medium term rheumatoid arthritis. J Rheumatol 2001;28:2597–602.[ISI][Medline]
  41. Hernandez Avila M, Liang MH, Willett WC et al. Reproductive factors, smoking, and the risk for rheumatoid arthritis. Epidemiology 1990;1:285–91.[Medline]
  42. Heliovaara M, Aho K, Aromaa A, Knekt P, Reunanen A. Smoking and risk of rheumatoid arthritis. J Rheumatol 1993;20:1830–5.[ISI][Medline]
  43. Voigt LF, Koepsell TD, Nelson JL, Dugowson CE, Daling JR. Smoking, obesity, alcohol consumption and the risk of rheumatoid arthritis. Epidemiology 1994;5:525–32.[ISI][Medline]
  44. Silman AJ, Newman I, 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.[ISI][Medline]
  45. Symmons DPM, Bankhead CR, Harrison BI et al. Blood transfusion, smoking, and obesity as risk factors for the development of rheumatoid arthritis: results from a primary care-based incident case-control study in Norfolk, England. Arthritis Rheum 1997;40:1955–61.[ISI][Medline]
  46. Uhlig T, Hagen KB, Kvien TK. Current tobacco smoking, formal education, and the risk of rheumatoid arthritis. J Rheumatol 1999;26:47–54.[ISI][Medline]
  47. Hutchinson D, Shepstone L, Moots R, Lear JT, Lynch MP. Heavy cigarette smoking is strongly associated with rheumatoid arthritis (RA), particularly in patients without a family history of RA. Ann Rheum Dis 2001;60:223–7.[Abstract/Free Full Text]
  48. Saag KG, Cerhan JR, Kolluri S, Ohashi K, Hunninghake GW, Schwartz DA. Cigarette smoking and rheumatoid arthritis severity. Ann Rheum Dis 1997;56:463–9.[Abstract/Free Full Text]
  49. Wolfe F. The effect of smoking on clinical, laboratory, and radiographic status in rheumatoid arthritis. J Rheumatol 2000;27:630–7.[ISI][Medline]
  50. Masdottir B, Jonsson T, Manfredsdottir V et al. Smoking, rheumatoid factor isotypes and severity of rheumatoid arthritis. Rheumatology 2000;39:1202–5.[Abstract/Free Full Text]
  51. 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.[ISI][Medline]
  52. Reaven GM. Banting Lecture 1988: Role of insulin resistance in human disease. Diabetes 1988;37:1595–607.[Abstract]
  53. Svenson KL, Lundqvist G, Wide L, Hallgren R. Impaired glucose handling in active rheumatoid arthritis: relationship to the secretion of insulin and counter-regulatory hormones. Metabolism 1987;36:940–3.[ISI][Medline]
  54. Paolisso G, Valentini G, Giugliano D et al. Evidence for peripheral impaired glucose handling in patients with connective tissue diseases. Metabolism 1991;40:902–7.[ISI][Medline]
  55. McEntegart A, Capell HA, Creran D et al. Cardiovascular risk factors, including thrombotic variables, in a population with rheumatoid arthritis. Rheumatology 2001;40:640–4.[Abstract/Free Full Text]
  56. Pope JE, Anderson JJ, Felson DT. A meta-analysis of the effects of non-steroidal anti-inflammatory drugs on blood pressure. Arch Intern Med 1993;153:477–84.[Abstract]
  57. Johnson AG, Nguyen TV, Day RO. Do non-steroidal anti-inflammatory drugs affect blood pressure? A meta-analysis. Ann Intern Med 1994;121:289–300.[Abstract/Free Full Text]
  58. Simon LS, Smolen JS, Abramson SB et al. Controversies in COX-2 selective inhibition. J Rheumatol 2002;29:1501–10.[Medline]
  59. Collins R, Peto R, MacMahon S et al. Blood pressure, stroke and coronary heart disease. Part 2, short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 1990;335:827–38.[ISI][Medline]
  60. Adhiyaman V, Asghar M, Oke A, White AD, Shah IU. Nephrotoxicity in the elderly due to co-prescription of angiotensin converting enzyme inhibitors and nonsteroidal anti-inflammatory drugs. J R Soc Med 2001;94:512–4.[Abstract/Free Full Text]
  61. Situnayake RD, Kitas GD. Dyslipidaemia and rheumatoid arthritis. Ann Rheum Dis 1997;56:341–2.[Free Full Text]
  62. Svenson KL, Lithell H, Hallgren R, Selinus I, Vessby B. Serum lipoprotein in active rheumatoid arthritis and other chronic inflammatory arthritides. I. Relativity to inflammatory activity. Arch Intern Med 1987;147:1912–6.[Abstract]
  63. Lakatos I, Harsagyi A. Serum total, HDL, LDL cholesterol, and triglyceride levels in patients with rheumatoid arthritis. Clin Biochem 1988;21:93–6.[ISI][Medline]
  64. Lazarevic MB, Vitic I, Mladenovic V, Myones BL, Skosey JL, Swedler WI. Dyslipoproteinemia in the course of active rheumatoid arthritis. Semin Arthritis Rheum 1992;22:172–8.[CrossRef][ISI][Medline]
  65. Rantapaa-Dahlqvist S, Wallberg-Ionsson S, Dahlen G. Lipoprotein (a), lipids, and lipoproteins in patients with rheumatoid arthritis. Ann Rheum Dis 1991;50:366–8.[Abstract]
  66. Lee YH, Choi SI, Ji ID, Seo HS, Song GG. Lipoprotein(a) and lipids in relation to inflammation in rheumatoid arthritis. Clin Rheumatol 2000;19:324–5.[CrossRef][ISI][Medline]
  67. 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.[Abstract]
  68. Mantel-Teeuwisse AK, Kloosterman JME, Maitland-van der Zee AH et al. Drug-induced lipid changes: a review of the unintended effects of some commonly used drugs on serum lipid levels. Drug Safety 2001;24:443–56.[ISI][Medline]
  69. Wallace DJ, Metzger AL, Stecher VJ, Turnbull BA, Kern PA. Cholesterol-lowering effect of hydroxychloroquine in patients with rheumatic disease: reversal of deleterious effects of steroids on lipids. Am J Med 1990;89:322–6.[ISI][Medline]
  70. Powrie JK, Shojaee-Moradie F, Watts GF, Smith GD, Sonksen PH, Jones RH. Effects of chloroquine on the dyslipidemia of non-insulin-dependent diabetes mellitus. Metabolism 1993;42:415–9.[ISI][Medline]
  71. Petri M, Lakatta C, Magder L, Goldman D. Effect of prednisone and hydroxychloroquine on coronary artery disease risk factors in systemic lupus erythematosus: a longitudinal data analysis. Am J Med 1994;96:254–9.[ISI][Medline]
  72. Petri M. Hydroxychloroquine use in the Baltimore Lupus Cohort: effects on lipids, glucose and thrombosis. Lupus 1996;5(Suppl. 1):S16–22.[ISI][Medline]
  73. Munro R, Morrison E, McDonald AG, Hunter JA. Madhok R, Capell HA. Effect of disease modifying agents on the lipid profiles of patients with rheumatoid arthritis. Ann Rheum Dis 1997;56:374–7.[Abstract/Free Full Text]
  74. Tam LS, Gladman DD, Hallett DC, Rahman P, Urowitz MB. Effect of antimalarial agents on the fasting lipid profile in systemic lupus erythematosus. J Rheumatol 2000;27:2142–5.[ISI][Medline]
  75. O'Dell JR, Leff R, Paulsen G et al. Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulphasalazine, or a combination of the three medications: results of a two year, randomised, double-blind, placebo-controlled trial. Arthritis Rheum 2002;46:1164–70.[CrossRef][ISI][Medline]
  76. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. J Am Med Assoc 2002;288:321–33.[Abstract/Free Full Text]
  77. Shepherd J, Cobbe SM, Ford I et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995;333:1301–7.[Abstract/Free Full Text]
  78. Downs JR, Clesrfield M, Weis S et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. J Am Med Assoc 1998;279:1615–22.[Abstract/Free Full Text]
  79. Law MR, Wald NJ, Thompson SG. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease? Br Med J 1994;308:367–72.[Abstract/Free Full Text]
  80. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: A randomised placebo-controlled trial. Lancet 2002;360:7–22.[CrossRef][ISI][Medline]
  81. Frenette PS. Locking a leukocyte integrin with statins. N Engl J Med 2001;345:1419–21.[Free Full Text]
  82. Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med 2000;6:1399–402.[CrossRef][ISI][Medline]
  83. Munford RS. Statins and the acute phase response. N Engl J Med 2001;344:2016–8.[Free Full Text]
  84. Albert MA, Danielson E, Rifai N, Ridker PM. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. J Am Med Assoc 2001;286:64–70.[Abstract/Free Full Text]
  85. Ridker PM, Rifai N, Pfeffer MA et al. and the cholesterol recurrent event investigators. Inflammation, pravastatin, and the risk for coronary events after myocardial infarction in patients with average cholesterol levels. Circulation 1998;98:837–44.
  86. Rosenson RS, Tangney CC, Casey CC. Inhibition of proinflammatory cytokine production by pravastatin. Lancet 1999;353:983–4.[ISI][Medline]
  87. Tonolo G, Melis MG, Formato M et al. Additive effects of simvastatin beyond its effects on LDL cholesterol in hypertensive type 2 diabetic patients. Eur J Clin Invest 2000;30:980–7.[CrossRef][ISI][Medline]
  88. Pasco JA, Kotowicz MA, Henry MJ, Sanders KM, Nicholson GC. Statin use, bone mineral density and fracture risk. Geelong osteoporosis study. Arch Intern Med 2002;162:537–40.[Abstract/Free Full Text]
  89. Nabel EG. Coronary heart disease in women—an ounce of prevention. N Engl J Med 2000;343:572–4.[Free Full Text]
  90. Aronne LJ. Treating obesity: a new target for prevention of coronary heart disease. Prog Cardiovasc Nurs 2001;16:98–106.[Medline]
  91. Liu S, Manson JAE. What is the optimal weight for cardiovascular health? Br Med J 2001;322:631–2.[Free Full Text]
  92. Minor MA, Lane NE. Recreational exercise in arthritis. Rheum Dis Clin North Am 1996;22:563–77.[ISI][Medline]
  93. Westby MD. A health professional's guide to exercise prescription for people with arthritis: a review of aerobic fitness activities. Arthritis Care Res 2001;45:501–11.[ISI]
  94. van den Ende CHM, Breedveld FC, le Cessie S, Dijkmans BAC, de Mug AW, Hazes JMW. Effect of intensive exercise on patients with active rheumatoid arthritis: a randomised clinical trial. Ann Rheum Dis 2000;59:615–21.[Abstract/Free Full Text]
  95. Clarke R, Daly L, Robinson K et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991;324:1149–55.[Abstract]
  96. Boushey CJ, Beresford SA, Omenn GS et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. J Am Med Assoc 1995;274:1049–57.[Abstract]
  97. Roubenoff R, Dellaripa P, Nadeau MR et al. Abnormal homocysteine metabolism in rheumatoid arthritis. Arthritis Rheum 1997;40:718–22.[ISI][Medline]
  98. Morgan SL, Baggott JE, Lee JY, Alarcon GS. Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm, low dose methotrexate therapy for rheumatoid arthritis: implications for cardiovascular disease prevention. J Rheumatol 1998;25:441–6.[ISI][Medline]
  99. Pettersson T, Friman C, Abrahamsson L, Nilsson B, Norberg B. Serum homocysteine and methylmalonic acid in patients with rheumatoid arthritis and cobalaminopenia. J Rheumatol 1998;25:859–63.[ISI][Medline]
  100. Hernanz A, Plaza A, Martin-Mola E, de Miguel E. Increased plasma levels of homocysteine and other thiol compounds in rheumatoid arthritis women. Clin Biochem 1999;32:65–70.[CrossRef][ISI][Medline]
  101. Haagsma CJ, Blom HJ, van Riel PL et al. Influence of sulphasalazine, methotrexate, and the combination of both on plasma homocysteine concentrations in patients with rheumatoid arthritis. Ann Rheum Dis 1999;58:79–84.[Abstract/Free Full Text]
  102. van Ede AE, Laan RFJM, Blom HJ et al. Homocysteine and folate status in methotrexate-treated patients with rheumatoid arthritis. Rheumatology 2002;41:658–65.[Abstract/Free Full Text]
  103. Landewe RBM, van den Borne BEEM, Breedveld FC, Dijkmans BAC. Methotrexate effects in patients with rheumatoid arthritis with cardiovascular comorbidity. Lancet 2000;355:1616–7.[CrossRef][ISI][Medline]
  104. Choi HK, Herman MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 2002;359:1173–7.[CrossRef][ISI][Medline]
  105. Erb N, Kitas GD. Homocysteine modulation as a reason for continuous folic acid supplementation in methotrexate-treated rheumatoid arthritis patients. Rheumatology 2001;40:715–6.[Free Full Text]
  106. Ernst E, Resch K. Fibrinogen as a cardiovascular risk factor: a metaanalysis. Ann Intern Med 1993;118:956–63.[Abstract/Free Full Text]
  107. Lee AJ, Fowkes FG, Lowe GD et al. Fibrin D-dimer, haemostatic factors and peripheral arterial disease. Thromb Haemost 1995;74:828–32.[ISI][Medline]
  108. Wallberg-Jonsson S, Cederfelt M, Rantapaa-Dahlqvist S. Hemostatic factors and cardiovascular disease in active rheumatoid arthritis: an 8 year follow-up study. J Rheumatol 2000;27:71.[ISI][Medline]
  109. Wallace DJ, Linker-Israeli M, Metzger AL, Stecher VJ. The relevance of antimalarial therapy with regard to thrombosis, hypercholesterolemia and cytokines in SLE. Lupus 1993;2(Suppl. 1):S13–5.[ISI][Medline]
  110. Watson DJ, Rhodes T, Cai B, Guess HA. Lower risk of thromboembolic cardiovascular events with naproxen among patients with rheumatoid arthritis. Arch Intern Med 2002;162:1105–10.[Abstract/Free Full Text]
  111. Pratico D, Tillmann C, Zhang ZB, Li H, FitzGerald GA. Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice. Proc Natl Acad Sci USA 2001;98:3358–63.[Abstract/Free Full Text]
  112. Ko D, Wang Y, Berger AK, Radford MJ, Krumholz HM. Nonsteroidal antiinflammatory drugs after acute myocardial infarction. Am Heart J 2002;143:475–81.[CrossRef][ISI][Medline]
  113. Ray WA, Murray KT. Aspirin: redundant in users of nonaspirin, nonsteroidal antiinflammatory agents? Am Heart J 2002;143:381–2.[CrossRef][ISI][Medline]
  114. Catella-Lawson F, Reilly MP, Kapoor SC et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001;345:1809–17.[Abstract/Free Full Text]
  115. Hennan JK, Huang J, Barrett TD et al. Effects of selective cyclooxygenase-2 inhibition on vascular responses and thrombosis in canine coronary arteries. Circulation 2001;104:820–5.[Abstract/Free Full Text]
  116. Lipsky PE, Brookes P, Crofford L et al. Unresolved issues in the role of cycloxygenase-2 in normal physiologic processes and disease. Arch Intern Med 2000;160:913–20.[Abstract/Free Full Text]
  117. Fitzgerald GA. Cardiovascular pharmacology of nonselective nonsteroidal anti-inflammatory drugs and coxibs: clinical considerations. Am J Cardiol 2002;89(Suppl.):26D–32D.[ISI][Medline]
  118. Bombardier C, Laine L, Reicin A et al., the VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343:1520–8.[Abstract/Free Full Text]
  119. Mukherjee D, Nissen SE, Topol El. Risk of cardiovascular events associated with selective COX-2 inhibitors. J Am Med Assoc 2001;286:954–9.[Abstract/Free Full Text]
  120. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999;340:115–26.[Free Full Text]
  121. Sherer Y, Shoenfeld Y. Atherosclerosis. Ann Rheum Dis 2002;61:97–9.[Abstract/Free Full Text]
  122. Pasceri V, Yeh ETH. A tale of two diseases. Atherosclerosis and rheumatoid arthritis. Circulation 1999;100:2124–6.[Free Full Text]
  123. Liuzzo G, Kopecky SL, Frye RL et al. Perturbation of the T-cell repertoire in patients with unstable angina. Circulation 1999;100:2135–9.[Abstract/Free Full Text]
  124. Liuzzo G, Goronzy JJ, Yang H et al. Monoclonal T cell proliferation and plaque instability in acute coronary syndromes. Circulation 2000;102:2883–8.
  125. Kitas GD, Banks MJ, Bacon PA. Accelerated atherosclerosis as a cause of cardiovascular death in RA. Pathogenesis 1998;1:73–83.
  126. Mach P, Schonbeck U, Sukhova GK, Atkinson E, Libby P. Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature 1998;394:200–3.[CrossRef][ISI][Medline]
  127. Nicoletti A, Kaveri S, Caligiuri G, Bariety J, Hansson GK. Immunoglobulin treatment reduces atherosclerosis in apo E knockout mice. J Clin Invest 1998;102:910–8.[Abstract/Free Full Text]
  128. Zhou X, Nicoletti A, Elhage R, Hansson GK. Transfer of CD4(+) T cells aggravates atherosclerosis in immunodeficient apolipoprotein E knockout mice. Circulation 2000;102:2919–22.[Abstract/Free Full Text]
  129. Nicoletti A, Paulsson G, Caligiuri G, Zhou X, Hansson GK. Induction of neonatal tolerance to oxidized lipoprotein reduces atherosclerosis in ApoE knockout mice. Mol Med 2000;6:283–90.[ISI][Medline]
  130. Rader DJ. Inflammatory markers of coronary risk. N Engl J Med 2000;343:1179–82.[Free Full Text]
  131. Koenig W. Heart disease and the inflammatory response. Br Med J 2000;321:187–8.[Free Full Text]
  132. Danesh J, Whincup P, Walker M et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. Br Med J 2000;321:199–204.[Abstract/Free Full Text]
  133. Morrow DA, Ridker PM. C-reactive protein, inflammation and coronary risk. Med Clin North Am 2000;84:149–61.[ISI][Medline]
  134. Jacobsson LT, Turesson C, Hanson RL et al. Joint swelling as a predictor of death from cardiovascular disease in a population study of Pima Indians. Arthritis Rheum 2001;44:1170–6.[CrossRef][ISI][Medline]
  135. Chehata JC, Hassell AB, Clarke SA et al. Mortality in rheumatoid arthritis: relation to single and composite measures of disease activity. Rheumatology 2001;40:447–52.[Abstract/Free Full Text]
  136. Mitchell DM, Spitz PW, Young DY, Bloch DA, McShane DJ, Fries JF. Survival, prognosis, and causes of death in rheumatoid arthritis. Arthritis Rheum 1986;29:706–14.[ISI][Medline]
  137. Lehtinen K, Isomaki H. Intramuscular gold therapy is associated with long survival in patients with rheumatoid arthritis. J Rheumatol 1991;18:524–9.[ISI][Medline]
  138. Krause D, Schleusser B, Herborn G, Rau R. Response to methotrexate treatment is associated with reduced mortality in patients with severe rheumatoid arthritis. Arthritis Rheum 2000;43:14–21.[CrossRef][ISI][Medline]
  139. Bierman EL. Atherogenesis in diabetes. Arterioscler Thromb 1992;12:647–56.[ISI][Medline]
  140. Turner RC, Millns H, Neil HAW et al. for the United Kingdom Prospective Diabetes Study Group. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: UK prospective diabetes study (UKPD:23). Br Med J 1998;316:823–8.[Abstract/Free Full Text]
  141. Joint British recommendations on prevention of coronary heart disease in clinical practice: summary. British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society, British Diabetic Association. Br Med J 2000;320:705–8.[Free Full Text]