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Low-Dose Prednisone Inclusion in a Methotrexate-Based, Tight Control Strategy for Early Rheumatoid Arthritis

TO THE EDITOR: The article by Bakker and colleagues (1) presents impressive control of disease activity in patients with rheumatoid arthritis (RA), which ironically may have attenuated the apparent treatment effect of prednisone. Overall, 67% of patients who received no prednisone had no erosions—only 11% fewer than the 78% of patients treated with 10 mg/d of prednisone for 2 years, albeit a statistically significant difference. The strongest treatment effects that were maintained over 2 years involved patient functional status, which generally is more significant than laboratory and radiographic data to predict work disability and mortality in patients with RA (2). Although unequivocal advantages are documented for 10-mg/d prednisone treatment added to tight control with methotrexate (and adalimumab if indicated by Disease Activity Score 28), 10 mg of prednisone may not necessarily be “low-dose,” as noted in the report (1). No statistically significant differences in adverse events were seen over 2 years (1). However, over long periods, 10 mg/d of prednisone is associated with increased osteoporosis, atherosclerosis, infection, adrenal suppression, and mortality rates, even when discontinued after 2 years (2). Randomized trials reported after initiation of the CAMERA-II (Computer Assisted Management in Early Rheumatoid Arthritis-II) trial have documented clinical and radiographic efficacy of prednisone, 5 mg/d (3), and clinical efficacy of prednisone, 3 mg/d (2). Clinical effectiveness of long-term use of 3-mg/d prednisone was found in more than 90% of patients treated after 1990, when almost all patients received concomitant methotrexate treatment (2). Patients could titrate their dose and discontinue prednisone, but most chose to continue doses of 1 to 4 mg/d over long periods, despite bruising and skin-thinning in some patients. Hypertension, diabetes, and cataracts were not increased over expected numbers (2), consistent with the CAMERA-II trial and population-based evidence comparing moderate (7.5 mg/d) with high doses (4). Doses of prednisone less than 5 mg/d do not suppress the hypothalamic–adrenal– pituitary axis (2). These comments in no way detract from the excellently executed Utrecht study. Nonetheless, Annals readers should be aware that, although not documented as elegantly, initial and long-term use of prednisone, 3 to 5 mg/d, might also clinically and structurally enhance methotrexate therapy, with a considerably lower likelihood of adverse effects (2). Furthermore, although costs are higher, biological agents may be safer than 10 mg/d of prednisone over long periods, analogous to evidence that less than 5 mg/d of prednisone may be safer than nonsteroidal anti-inflammatory drugs. As noted a decade ago, “long-term very low doses of prednisone for patients with rheumatoid arthritis may be as helpful as high doses are harmful” (5), and 10 mg/d may not be “low-dose” or needed for most patients.