Glucocorticoid Use in Rheumatoid Arthritis Management Focus of Ongoing Debate

Off to an Overzealous Start?

“The first 50 years of data on glucocorticoids are really poor,” says Dr. Boers. “Although glucocorticoids were among the very first drugs to be tested in clinical trials—high-quality studies designed by Sir Bradford Hill—these were not followed by larger studies to adequately determine the balance of benefit and harm at the optimal dose.” Reports of dramatic clinical responses were enough to justify wide prescription of the drugs (and to earn the discoverers the Nobel Prize for Medicine in 1950).

Dr. Boers

Unfortunately, says Theodore (Ted) P. Pincus, MD, clinical professor, Rush University Medical Center, Chicago, “Many doctors felt that if a little is good, a lot must be better. More importantly, in the 1950s–1970s, steroids were given as monotherapy, rather than the current practice of including methotrexate and/or other DMARDs or biologics in RA, cyclophosphamide or mycophenolate in SLE.” When prednisone was the sole antiinflammatory drug, “It seemed that one needed to give much higher doses,” he explains. Very quickly, though, the adverse effects of these higher doses became clear. “If you give patients more than 5 mg a day for several months, the adrenal glands shut down,” says Dr. Pincus, and the side effects—weight gain, diabetes, hypertension, etc.—begin to accumulate. Dr. Pincus has written about the historical uses of steroids, and notes that by the late 1950s steroids were being used mostly on a short-term basis as “bridge therapy,” or for life-threatening extra-articular disease.⁴

Dr. Pincus

Prof. Maurizio Cutolo, MD, president of the European League Against Rheumatism (EULAR) and director, Research Laboratories, Academic Division of Clinical Rheumatology and Postgraduate School on Rheumatology in the Department of Internal Medicine at the University of Genoa, Italy, a coauthor with Dr. Pincus on the historical retrospective about glucocorticoids,⁴ notes that much of the disagreement about use of steroids emanates from these earlier patterns. Given at the wrong dosages, steroids inhibit endogenous production of glucocorticoids, producing dependency on higher and higher dosages, and the cascade of dangerous side effects leading to hypertension, osteoporosis, glaucoma and the like.

Dr. Boers adds that these side effects were not dismissed by the drugs’ discoverers. Having read Dr. Hench’s Nobel acceptance speech, Dr. Boers says that Hench was “already aware of the dangers of inappropriately high doses and that physicians should not be treating patients with very high doses for prolonged periods of time.”

Low Doses Best?

Even among those who advocate low-dose steroid therapy, agreement on the best treatment regimen is hard to come by. For example, what amount is a safe and effective low dose: 7.5 mg, 5 mg—or the 3 mg that Dr. Pincus prescribes for his patients and for which he has documented significant differences vs. placebo in a withdrawal clinical trial?5 Dr. Pincus notes that many rheumatologists believe he does not prescribe enough for his patients. “It is possible that higher doses such as 5, 7.⁵ or 10 mg might have greater efficacy and effectiveness, but there appears little doubt that doses of 3 mg are effective,” says Dr. Pincus. “These findings are, of course, confounded in part by most of these patients having taken methotrexate or another DMARD. But that’s the point. No patient with a chronic rheumatic disease should be treated with prednisone only, which almost never controls chronic inflammation optimally, while practices suggesting high-dose prednisone were developed when prednisone was the only agent used as monotherapy.”