By Dean L. Winslow, MD
Professor of Medicine, Division of General Medical Disciplines, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine
Dr. Winslow reports no financial relationships relevant to this field of study.
SYNOPSIS: One hundred forty-two patients within 180 days of their first demyelinating event were randomized to minocycline 100 mg BID vs. placebo. The unadjusted risk of conversion to multiple sclerosis within six months after randomization was 61.0% in the placebo group and 33.4% in the minocycline group. At 24 months, the effect of minocycline was not statistically significant.
SOURCE: Metz LM, Li DKB, Traboulsee AL, et al. Trial of minocycline in a clinically isolated syndrome of multiple sclerosis. N Engl J Med 2017;376:2122-2133.
This double blind, prospective, randomized, placebo-controlled trial was conducted at 12 academic medical centers in Canada from 2009 to 2013. One hundred forty-two patients within 180 days of their first demyelinating event were randomized to minocycline 100 mg BID vs. placebo. Treatment with minocycline or placebo was continued until a diagnosis of multiple sclerosis was established or until 24 months (whichever came first). The primary outcome was conversion to multiple sclerosis by 2005 McDonald criteria within six months after randomization. Secondary outcomes included progression to multiple sclerosis within 24 months and development of new or enlarged lesions on MRI.
The mean age of patients was 36 years, and 68% were female. The unadjusted risk of progression to multiple sclerosis was 61% in the placebo group and 33% in the minocycline group (P = 0.001). After adjustment for number of enhancing lesions on MRI at baseline, there was still a 19% difference (P = 0.01). However, while at 24 months there was still a trend favoring minocycline over placebo (63% vs. 74% progression to multiple sclerosis), this did not achieve statistical significance. Similar changes in lesion volume and lesion number significantly favored the minocycline arm at six months (was statistically significant) and trended toward benefit at 24 months.
Eighty-six percent of patients in the minocycline arm experienced adverse events vs. 61% in the placebo arm. Common drug-related adverse events included rash (15% vs. 3%), dental discoloration (8% vs. 0%), and dizziness (14% vs. 1.4%).
COMMENTARY
The anti-inflammatory effects of tetracyclines (independent of their antimicrobial activity) have been known for years, and clinicians have taken advantage of this. Tetracyclines remain one of the mainstays of rosacea and acne treatment. They have been shown to have pleiotropic anti-inflammatory effects, including inhibition of TNF, IL-1, neutrophil elastase, matrix metalloproteinases, nitric oxide, and reactive oxygen intermediates,1 so there is a theoretical basis for their use in multiple sclerosis. In a small study of relapsing-remitting multiple sclerosis, minocycline treatment reduced the mean number of lesions seen on MRI by 84% compared with the run-in period.2 In another small study, the number of lesions was reduced by 63% in patients treated with minocycline plus glatiramer vs. glatiramer alone.3
While this trial is limited by its relatively small sample size, it is interesting that such an old, well-tolerated, inexpensive drug such as minocycline showed activity in multiple sclerosis similar to that seen in trials of disease-modifying drugs including interferon-B1a, interferon-B1b, teriflunomide, and oral cladribine. It will be interesting to see if the results can be replicated in larger trials, especially of minocycline in combination with more traditional disease-modifying drugs.
REFERENCES
- Nieman GF, Zerler BR. A role for the anti-inflammatory properties of tetracyclines in the prevention of acute lung injury. Curr Med Chem 2001;8:317-325.
- Metz LM, Zhang Y, Yeung M, et al. Minocycline reduces gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis. Ann Neurol 2004;55:756.
- Metz LM, Li D, Traboulsee A, et al. Glatiramer acetate in combination with minocycline in patients with relapsing-remitting multiple sclerosis: Results of Canadian multicenter, double-blind, placebo-controlled trial. Mult Scler 2009;15:1183-1194.
One hundred forty-two patients within 180 days of their first demyelinating event were randomized to minocycline 100 mg BID vs. placebo. The unadjusted risk of conversion to multiple sclerosis within six months after randomization was 61.0% in the placebo group and 33.4% in the minocycline group. At 24 months, the effect of minocycline was not statistically significant.
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