A comprehensive review of the use of corticosteroids among patients with rheumatoid arthritis (RA) shows that the incidence, severity, and impact of the adverse events (AEs) of low-dose regimens in RA trials are modest and often not statistically different from placebo, a finding that may serve to restore greater use of low-dose glucocorticoid therapy in RA. Yet further studies on low doses of glucocorticoids are indicated to weigh the overall risks and the benefits, researchers concluded in the August 26 online edition of Annals of Rheumatic Disease.¹

Specifically, data from the 4 low-dose trials show that bone loss over 2 years on low-dose prednisolone was not different than placebo. However, the high doses used in one study were associated with greater loss of bone mineral density.

"The overall fear of glucocorticoid toxicity in RA, as quoted in textbooks and review articles, is probably overestimated based on extrapolation from observations with higher-dose therapy," reported lead investigator José AP da Silva, MD, a rheumatologist at Hospitais da Universidade de Coimbra in Portugal. "The balance of risk and benefits of low-dose therapy clearly differs from that of medium- and high-dose therapy, of which the mechanisms of action of glucocorticoids may be different."

To reevaluate the safety of glucocorticoids, a task force comprising leading rheumatologists and an endocrinologist from Europe and the US performed a literature review of studies evaluating the AEs of glucocorticoids and also analyzed the toxicity data from 4 long-term low-dose (<e;10 mg of prednisone a day) trials on the effect of glucocorticoids on patients with early active RA. The trials included the ACR low-dose glucocorticoid study, the Low-Dose Prednisolone Therapy (LDPT) study, the Utrecht prednisolone trial, and the West of Scotland Early Rheumatoid Arthritis Trial (WOSERACT), as well as the Combination Therapy in Early Rheumatoid Arthritis (COBRA) trial.  

There were no cases of new-onset diabetes in any of the 4 low-dose prednisolone studies. Also, while glucocorticoid treatment is a known risk factor for dyslipidemia and atherosclerosis, low-dose glucocorticoid treatment does not seem to affect the development of cardiovascular disease, researchers noted, pointing out however that a trial duration of 2 years is relatively short for the development of these complications. Additionally, glucocorticoid-induced hypertension is dose-related and less likely to occur with medium or low-dose prednisolone therapy, researchers found.

Incidences of arrhythmia and sudden death are very rare and mostly limited to patients receiving high-dose pulse glucocorticoids. No such events were reported in the 4 studies of low-dose steroids or the COBRA trial. Dermatologic AEs, including iatrogenic Cushing's syndrome, catabolic effects, steroid acne, and hair effects are relatively uncommon and a minor concern with low-dose glucocorticoid treatment, the review suggests. Peptic ulcer disease risk is more closely treated with concomitant nonsteroidal anti-inflammatory drug (NSAID) use, and there were no cases of pancreatitis in the 4 low-dose studies.

High-risk patients may need monitoring

Overall, "the definitive associations of low-dose glucocorticoids with many adverse effects remain elusive," the researchers report. "Routine toxicity monitoring for patients on low-dose glucocorticoid therapy is not currently justifiable or cost effective based on existing evidence."

However, patients with additional risk factors such as osteoporosis, obesity, hypertension, and a family history of diabetes or glaucoma merit more careful observation.

Prevailing negative view based on medical literature

"There have been so many misconceptions about prednisone glucocorticoids for years, and many of these misconceptions have been perpetuated in the side-effect realm by people writing chapters in medical textbooks," says Doyt L. Conn, MD, a professor of medicine at Emory University School of Medicine in Atlanta, Georgia. However, he points out, it has been known for decades that low doses of prednisone are effective with minimal side effects, yet these studies take a back seat to studies showing adverse effects with high doses.

"Despite the fact that most medical textbooks emphasize side effects and de-emphasize benefit, most rheumatologists were and are using low doses of prednisone in RA," Dr. Conn tells CIAOMed, adding that many questions remain; for example, whether high doses given initially then titrated down have a different effect than starting at low doses, and/or whether twice a day dosing is better than a 10 mg or 7.5 single dose.

Dr. Conn explains that while very few side effects were detected in the studies analyzed, the studies were not done to analyze AEs. "One would like to determine if there are long-term effects on bone or osteoporosis from low doses, particularly in patients started on calcium and D at the initiation of prednisone," he says, adding that such studies would also have to look at predisposing factors in addition to low doses of prednisone such as the effect of body weight, the aggravation of diabetes in patients with diabetes, and blood pressure in patients with hypertension.

Reference

1.       Da Silva JAP, Jacobs JWG, Kirwan JR, et al. Ann Rheum Dis [serial online]. August 26, 2005. Available at: http://ard.bmjjournals.com/cgi/content/abstract/ard.2005.037879v1. Accessed September 20, 2005.