Effects of glucocorticoids on cardiovascular risks in patients with rheumatoid arthritis

Kam Shojania, MD FRCPC (biography and disclosures) and Neda Amiri, BSc MD (biography and disclosures)

What I did before

Over one million Canadians have inflammatory arthritis (1).  Among all causes of disability, it ranks first among women and second in men (1).

Rheumatoid arthritis (RA) presents as an inflammatory, peripheral polyarthritis that is symmetric. Untreated disease can lead to deformity, leading to physical impairment (2). Diagnosis is made using the American College of Rheumatology’s 2010 guidelines (3).

Early recognition and treatment with disease-modifying agents is crucial in treatment of disease and prevention of joint injury. Detailed guidelines regarding management and treatment of RA are prescribed elsewhere (4). However, general recommendations include:

1)      Care by an expert in rheumatic diseases (Such as a rheumatologist)

2)      Non-pharmacological measures including patient education and physical therapy

3)      Immediate initiation of a disease-modifying anti-rheumatic drug (DMARD)

4)      Use of anti-inflammatory medications such as non-steroidal anti-inflammatory drugs (NSAIDS) and glucocorticoids (GCs) only as adjuncts

RA is also found to be a risk factor for accelerated atherosclerosis (5,6). On average, the risk of cardiovascular disease is comparable to that of patients with diabetes (7). This risk is accentuated in patients with long standing disease or a high inflammatory burden (5, 6). Multiple etiologies have been proposed to account for this increased risk (8) including chronic systemic inflammation, presence of traditional cardiovascular risk factors, reduced mobilization, and adverse effects of anti-inflammatory treatments such as NSAIDS and GCs (9).

Traditionally, GCs have been used as a bridge before patients see therapeutic effects of DMARD therapy. They are also used in short periods to reduce disease activity while awaiting a clinical response from DMARDs in cases of flare. Therefore, managing patients who had been on low dose steroids for prolonged periods was not an uncommon occurrence.

What changed my practice

As known, GCs are associated with hypertension, diabetes, dyslipidemia (10), acceleration of atherosclerosis, and coagulation abnormalities (11,12).

In patients with RA, some observational studies had suggested that the increased mortality may be due to use of glucocorticoids (13). However, the prescription of GCs to patients with more severe symptoms was a confounding factor.  On the other hand, conflicting studies suggested that low dose GCs might have a cardio-protective effect through their anti-inflammatory action and improvement in patients’ lipid profile at low doses (14,15).

In January of 2013, the journal of Rheumatology featured a UBC based study looking at the immediate and past cumulative effects of oral GCs on the risk of acute myocardial infarction (MI) in patients with RA (16). Using the population based RA cohort in the province of British Columbia, the authors followed patients diagnosed with RA between 1990-2006. Approximately 33% of the patients received at least one prescription of GCs. Overall, patients who used GCs were older, had more comorbidities and were on higher number of medications. GC users were on steroids approximately 17% of the time, with a median dose of 5 mg and duration of 71 days per GC course. The authors investigated four different time-dependent GC exposures. In all of these multivariable models, GCs were associated with an increased risk of MI. Current GC use alone (regardless of the dose and duration) was associated with a 68% increased risk (HR = 1.68, 95% CI 1.14-2.47). An additional 13% risk increase per additional 5 mg/day was seen for current dose of GCs (HR = 1.14, 95% CI 1.05-1.24). Cumulative duration of GCs yielded HR 1.14 (95% CI 1.0-1.29) for each additional year of past exposure. Each additional gram of total past GC dose was associated HR 1.06 (95% CI 1.02-1.10). These risks were independent of age, sex, comorbidities, indicators of RA severity, and use of NSAIDS.

What I do now

Rheumatoid arthritis is a chronic inflammatory condition that has been described to be associated with an increased risk of cardiovascular disease. This risk appears to be multifactorial in nature. However, there is emerging evidence that glucocorticoids play a role. Most recently, a 2013 published study in the Journal of Rheumatology, demonstrated that there is a both an immediate and long-term effect through cumulative exposure of GCs on an individual’s risk of myocardial infarction.

In addition to affecting blood glucose levels, the interaction of GCs with the vascular and endothelial smooth muscle, destabilization of the atherosclerotic plaques, and promotion of a prothromobotic environment is thought to be some of the causes of this observed effect.

Based on these findings, I aim to eliminate the use of glucocorticoids in patients with RA. No longer is “only 5 mg per day” is a “low-enough” dose of steroids. To achieve better pain control in these patients, I increase the dose of DMARDs or use additional agents. In cases of RA flares, I will use the lowest possible dose of GCs when required and titrate down this class of drugs as quickly as possible. When larger joints (knees, ankles, and wrists) are affected, intra-articular injection of steroids can also aid in achieving faster relief while awaiting for DMARDs to take affect.

Although NSAIDS may provide some relief, these agents do not prevent progression of the disease. Moreover, they carry their own side effects profile, including contributing to gastrointestinal ulcers, worsening of blood pressure, and affecting renal function (17-19).

It can be a difficult and frustrating waiting period for both patients and their physicians during flares. An initiative of the BC Medical Association, Rapid Access to Consultative Expertise (RACE)(20) is a free phone access line that allows physicians to speak directly with a specialist including a rheumatologist to seek some care guidance.

References:

1. The Arthritis Society. Arthritis Facts and Statistics. Access Date: March 2013. (View)
2. Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet. 2001;358(9285):903. (View with CPSBC or UBC)
3. An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative.  2010 Rheumatoid Arthritis Classification Criteria. Arthritis Rheumm. 2010;62(9):2569–2581. (View)
4. Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 Recommendations for the Use of Nonbiologic and Biologic Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis. Arthritis Rheum. 2008;59(6):762-84. (View)
5. Young A, Koduri G, Batley M, et al. Mortality in rheumatoid arthritis. Increased in the early course of disease, in ischaemic heart disease and in pulmonary fibrosis. Rheumatology (Oxford). 2007;46:350-57. (Request from CPSBC or view with UBC)
6. Nurmohamed MT. Cardiovascular risk in rheumatoid arthritis. Autoimmun Rev. 2009;8:663-67. (View with CPSBC or UBC)
7. Peters MJ, van Halm VP, Voskuyl AE, et al. Does rheumatoid arthritis equal diabetes mellitus as an independent risk factor for cardiovascular disease? A prospective study. Arthritis Rheum. 2009;61:1571-79. (Request from CPSBC or view with UBC)
8. Gkaliagkousi E, Gavriilaki E, Doumas M, et al. Cardiovascular risk in rheumatoid arthritis: pathogenesis, diagnosis, and management.  J Clin Rheumatol 2012;18(8):422-30. (View with CPSBC or UBC)
9. Shoenfeld Y, Gerli R, Doria A, et al. Accelerated atherosclerosis in autoimmune rheumatic diseases. Circulation. 2005;112:3337Y3347. (View free article)
10. Sholter DE, Armstrong PW. Adverse effects of corticosteroids on the cardiovascular system. Canadian J Cardiol 2000;16:505-11. (Request from CPSBC)
11. Raynauld JP. Cardiovascular mortality in rheumatoid arthritis: how harmful are corticosteroids? [editorial]. J Rheumatol 1997; 24:415–6. (Request from CPSBC or request print from UBC)
12. Girod JP, Brotman DJ. Does altered glucocorticoid homeostasis increase cardiovascular risk? Cardiovasc Res 2004;64:217–26. (View free article)
13. Saag K, Koehnke R, Caldwell J. Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events. Am J Med 1994;96:115-23. (Request from CPSBC or view with UBC)
14. Svenson KL, Lithell H, Hallgren R, et al. Serum lipoprotein in active rheumatoid arthritis and other chronic inflammatory 
arthritides. Arch Intern Med 1987;147:1917–20. (Request from CPSBC or view with UBC)
15. Boers M, Nurmohamed MT, Doelman CJ, et al. Influence of glucocorticoids and disease activity on total and high density lipoprotein cholesterol in patients with rheumatoid arthritis. Ann Rheum Dis 2003;62:842–5. (View free article)
16. Aviña-Zubieta JA, Abrahamowicz M, De Vera MA, Choi HK, Sayre EC, Rahman MM, et al. Immediate and past cumulative effects of oral glucocorticoids on the risk of acute myocardial infarction in rheumatoid arthritis: a population-based study. Rheumatology. 2013;52:68-75. (Request from CPSBC or view with UBC)
17. Huerta C, Castellsague J, Varas-Lorenzo C, et al. Nonsteroidal anti-inflammatory drugs and risk of ARF in the general population. Am J Kidney Dis. 2005;45(3):531-9. (View with CPSBC or UBC)
18. Pope JE, Anderson JJ, Felson DT. A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure. Arch Intern Med. 1993;153:477-84. (Request from CPSBC or view with UBC)
19. Gottlieb S. Cardioprotective effects of aspirin compromised by other NSAIDs. BMJ. 2003; 327:520. (View with CPSBC or UBC)
20. https://www.bcma.org/rapid-access-consultative-expertise-race-program, RACE Hotline By Dr. Daniel Dodek

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Effects of glucocorticoids on cardiovascular risks in patients with rheumatoid arthritis

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