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Oral methylprednisolone found noninferior to IV steroids for MS relapse

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Higher oral steroid formulations needed

This study robustly addressed a question of high importance in clinical practice and with important implications for patients. Moreover, the time window chosen for this study, of only 14 days between onset of symptoms and treatment, compared with the longer time periods of previous studies, is more suitable to establish the role of route administration in relapse recovery, allowing exploration of the effects of steroids on acute inflammation. Windows longer than 14 days reduce the potential beneficial effects on inflammation (the period of enhancement in a new lesion is about 4 weeks) and increase inter-patient variability.

The major limitation of Dr. Le Page and colleagues’ study was the absence of MRI data to support the clinical findings, considering the established modest intra-rater and inter-rater concordance. The use of the same assessor for each patient throughout the study significantly reduced but did not eliminate this bias.

Even with some limitations, the study by Dr. Le Page and colleagues is a milestone in the history of treatment for multiple sclerosis and will lead to a change in clinical practice with relevant advantages for both patients and the community, with potential applications in many other disorders when short courses of high-dose steroids are needed. Despite accumulating evidence for the equal effects of intravenous and oral high-dose steroids, oral administration has not entered clinical practice, except in a few countries, and is mostly not considered as a treatment scheme for relapses in clinical trials, perhaps because in most countries formulations of high-dose steroids for oral administration are not available. In the study by Dr. Le Page and colleagues, 10 tablets were needed to reach the cumulative daily dosage of 1,000 mg of methylprednisolone. More efforts are needed to obtain adequate oral formulations, and we hope that the clear results of this clinical trial will promote actions to address this issue.

Dr. Giancarlo Comi and Dr. Marta Radaelli are with the department of neurology at Vita-Salute San Raffaele University and Hospital San Raffaele in Milan. Dr. Comi declared having received consulting fees from Novartis, Teva, Sanofi, Genzyme, Merck Serono, Biogen, Bayer, Serono Symposia International Foundation, Roche, Almirall, Chugai, and Receptos. Dr. Radaelli declared no competing interests. These comments were taken from their accompanying editorial(Lancet 2015;386[9997];937-9).


 

FROM THE LANCET

References

High-dose oral methylprednisolone was noninferior to intravenous steroids for improving disability after multiple sclerosis relapse, according to a study published online in The Lancet.

The findings “support the use of oral methylprednisolone 1,000 mg per day for 3 days to treat MS relapses,” wrote Dr. Emmanuelle Le Page of Rennes (France) University Hospital and her associates. “Oral delivery is simpler and less invasive, more convenient for a quick primary and community care response, and allows obvious savings in cost and logistics,” they added. This also was the first trial with enough power to detect a difference between comparable doses of steroids begun early after relapse onset, they said.

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Intravenous methylprednisolone is recommended as first-line treatment for MS relapses, but can be expensive and inconvenient, the investigators said. Authors of a recent Cochrane review found no differences in recovery between patients given high-dose oral or IV methylprednisolone, but concluded that the studies were underpowered. Based on their suggestions, Dr. Le Page and associates randomized 199 adults with relapsing-remitting MS to receive 1,000 mg oral or IV methylprednisolone once daily for 3 days, starting within a week of relapse onset. The researchers powered the study based on a predetermined efficacy margin of 15%. The primary efficacy endpoint was the percentage of patients who improved on day 28 by at least 1 point on their most affected score of the Kurtzke Functional System Scale, without needing more steroids (Lancet 2015;386[9997]:974-81).

In all, 81% of patients who received oral steroids and 80% of those who received IV therapy met this endpoint. Rates of treatment-associated adverse events also were similar between the two groups, except that patients were more likely to report insomnia on oral therapy (77% vs. 64%; P = .039). “This was also reported in the meta-analysis, and might be due to prolonged bioavailability,” the researchers wrote. They recommended giving oral methylprednisolone in the morning to help avert the problem.

The French Health Ministry, Ligue Française contre la Sclérose En Plaques, and Teva Pharmaceutical Industries funded the study. Dr. Le Page reported receiving consulting fees and grant funding from Novartis, Biogen, Teva, and Genzyme Sanofi Aventis. Five coauthors reported financial relationships with several public entities, foundations, and pharmaceutical companies. The other four coauthors declared no competing interests.

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