The report in The Lancet queried whether early discontinuation of glucocorticoids could prevent characteristic side effects and asked how the drugs could be discontinued without sparking glucocorticoid withdrawal syndrome.
The answers were tackled in the SEMIRA study, a large European trial led by Charité-Universitätsmedizin Berlin. The trial includes more than 250 participants recruited from nearly 40 research trial centers in six different countries.
While continuous glucocorticoid regimens were found to be more effective at controlling disease activity, the authors also determined that discontinuation was successful in most cases.
Background information in the article points out that glucocorticoids, such as cortisone, are highly effective in controlling inflammatory diseases. Yet the risks are significant, with severe side effects from long-term use including cardiovascular disorders, osteoporosis, and infections.
In addition, the drugs suppress the adrenal glands, impairing the body’s ability to produce its own cortisone. As a result, patients suffer fatigue, nausea, and low blood pressure and, in some cases, even death.
“An appropriate period of gradual dose reduction—known as tapering—is essential to enable the body to adapt to a reduced supply of this substance and prevent withdrawal syndrome. Tapering glucocorticoids without triggering a recurrence of inflammation is a common challenge faced by many medical specialties,” the authors explain.
“We had not previously had access to data from double-blind, randomized, placebo-controlled trials which compared a tapering regimen for low-dose prednisone—the most common glucocorticoid used—with continued use of low-dose prednisone. In the SEMIRA trial, our comparative analysis focused on rheumatoid arthritis, a condition commonly treated with glucocorticoids," adds first author Gerd-Rüdiger Burmester, MD, Head of the Medical Department, Division of Rheumatology and Clinical Immunology on Campus Charité Mitte.
The double-blind, multicenter, two parallel-arm, randomized controlled trial was conducted at 39 centers from France, Germany, Italy, Russia, Serbia, and Tunisia between October 21, 2015, and June 9, 2017. Included were adult patients with rheumatoid arthritis receiving tocilizumab and glucocorticoids 5 to 15 mg per day for 24 weeks who had received prednisone 5 mg per day for 4 weeks or more and had stable low disease activity, confirmed by a Disease Activity Score for 28 joints—erythrocyte sedimentation rate (DAS28-ESR) of 3.2 or less 4 to 6 weeks before and on the day of randomization. Participants were randomly assigned 1:1 to either continue masked prednisone 5 mg per day for 24 weeks or to taper masked prednisone reaching 0 mg per day at week 16.
All patients also received tocilizumab—162 mg SC every week or 8 mg/kg IV every 4 weeks—with or without csDMARDs maintained at stable doses during the entire 24-week study.
Defined as the primary outcome was the difference in mean DAS28-ESR change from baseline to week 24, with a difference of more than 0.6 defined as clinically relevant between the continued-prednisone group and the tapered-prednisone group.
Results indicate that, in all 128 patients assigned to the continued-prednisone regimen, disease activity control was superior to that in all 131 patients assigned to the tapered-prednisone regimen. In fact, the estimated mean change in DAS28-ESR from baseline to week 24 was 0.54 (95% CI, 0.35-0.73) with tapered prednisone and −0.08 (–0.27-0.12) with continued prednisone (difference 0.61 [0.35-0.88]; P <.0001). Researchers reported that those results favored continuing prednisone 5 mg per day for 24 weeks.
Treatment was regarded as successful—defined as low disease activity at week 24, plus absence of rheumatoid arthritis flare for 24 weeks and no confirmed adrenal insufficiency—in 77% of patients in the continued-prednisone group versus 65% of patients in the tapered-prednisone group (relative risk 0.83; 95% CI, 0.71-0·97). Serious adverse events occurred in seven (5%) patients in the tapered-prednisone group and four (3%) patients in the continued-prednisone group, although no patients had symptomatic adrenal insufficiency.
“In patients who achieved low disease activity with tocilizumab and at least 24 weeks of glucocorticoid treatment, continuing glucocorticoids at 5 mg per day for 24 weeks provided safe and better disease control than tapering glucocorticoids, although two-thirds of patients were able to safely taper their glucocorticoid dose,” the authors conclude.
“The fact that glucocorticoid tapering was associated with a treatment success rate of 65 percent is of enormous significance for shared decision-making involving patients. It will now be possible to decide, on a case-by-case basis, whether glucocorticoid treatment should continue or whether tapering should be attempted,” Dr. Burmester emphasized, adding, “Our results also set the scene for studies to investigate glucocorticoid tapering in other clinical settings—for instance in the fields of allergology, neurology and dermatology—where these drugs are also used, and where there is a certain level of uncertainty regarding the risks and benefits of discontinuing treatment.”
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