Doxycycline Treatment for Multiple Sclerosis
Doxycycline Treatment for Multiple Sclerosis
Abstract & Commentary
By Gregg L. Caporaso, MD, PhD Assistant Professor of Neurology and Neuroscience, Weill Cornell Medical College Dr. Caporaso reports no financial relationships relevant to this field of study.
Synopsis: Addition of doxycycline to interferon-beta therapy in patients with relapsing-remitting multiple sclerosis might improve control of inflammatory lesions.
Source: Minagar A, et al. Combination therapy with interferon beta-1a and doxycycline in multiple sclerosis: an open-label study. Arch Neurol 2008;65:199-204.
In multiple sclerosis (MS), it is believed that autoreactive lymphocytes in the systemic circulation cross the blood-brain barrier (BBB) to induce inflammatory demyelination in the central nervous system. These lymphocytes express matrix metalloproteinases (MMPs) that proteolyze the extracellular matrix of the BBB, thus facilitating cellular transmigration. Doxycycline has been demonstrated to inhibit MMP-9 activity in laboratory studies. With this is mind, Minagar and colleagues examined the effects of adding doxycycline to the treatment regimen of MS patients who were experiencing breakthrough relapses on interferon beta-1a (IFN beta-1a). In an open-label trial, 15 patients with relapsing-remitting MS (RRMS) who had experienced a relapse within the preceding 2 months were first assessed during a 3-month pretreatment phase while on IFN beta-1a alone and then for a 4-month treatment phase in which doxycycline (100 mg/day) was added.
The mean patient age was 44 years, and 80% of patients were women. Their median duration of RRMS was 4.0 years, with a median expanded disability status score (EDSS) of 3.5 (range 3.0-4.5, consistent with mild disability). The addition of doxycycline was associated with a 39% reduction in gadolinium-enhancing brain lesions, from a pre-treatment median of 8.8 lesions to a post-treatment median of 4.0 lesions. The median decrease in EDSS was 2.3 points. No significant change in serum MMP-9 levels was observed. However, the transendothelial migration of monocytes in vitro was reduced in the presence of post-treatment patient's serum compared to pre-treatment serum. These results raise the possibility that the addition doxycycline to interferon-beta therapy might afford greater anti-inflammatory effects than interferon-beta alone in patients with RRMS. Further, they suggest that doxycycline might mediate these effects by inhibiting the migration of immune cells across endothelial barriers.
Commentary
Tetracycline antibiotics such as doxycycline and minocycline have been receiving much attention as possible treatments for a variety of neurological disorders, including stroke, amyotrophic lateral sclerosis (ALS), Huntington's disease, and, of course, RRMS. Their efficacy in these diseases has been mixed to date, with positive treatment effects described for some (e.g., stroke) and negative effects for others (e.g., ALS). The present study by Minagar et al suggests that the addition of doxycycline to interferon-beta might be beneficial to patients with RRMS who continue to experience breakthrough relapses while on interferon alone. However, their findings should be viewed in light of several weaknesses in their study design, the most significant relating to the statistical phenomenon of "regression to the mean." This refers to the fact that measurements on a non-random sample of some population will tend on subsequent measurements to be closer to the mean for that population. In the present study, patients were selected who had experienced an MS relapse within the 2 months preceding the trial. Based on the pivotal clinical trials of IFN beta-1a, we saw that RRMS patients receiving placebo had on average about one relapse per year; patients who received interferon-beta experienced on average a 29-32% reduction in annual relapse rate. Over 2 years, patients receiving IFN beta-1a experience about a 50% reduction in the number of new gadolinium-positive lesions. Thus, during the 7-month period of the trial by Minagar et al, one would expect few patients on IFN beta-1a to experience another relapse or an increase in the number of gadolinium lesions whether doxycycline was added or not. That is, the patient selection process in this study might have inadvertently skewed the results toward a predictable amelioration of disease status.
Nonetheless, a separate report published by Zabad and colleagues lends credence to a therapeutic role for tetracycline antibiotics in MS.1 In this study, 10 patients with RRMS who had experienced 2 or 3 relapses over the previous 2 years, and who had not been treated with disease-modifying agents (e.g., IFN beta-1a or glatiramer acetate) for at least 6 months, received minocycline (100 mg b.i.d.) for 24 months. The patient demographics in this study were similar to those in the Minagar et al study, though the mean disease duration was nearly 12 years. No patients experienced clinical MS relapses, and, with one exception (a patient whose dosage was halved due to persistent nausea), no gadolinium-enhancing brain lesions were identified by serial MRI scans after 6 months of treatment. Serum levels of 2 putative anti-inflammatory markers (the p40 subunit of interleukin-12 and soluble vascular cell adhesion molecule) were significantly increased by treatment. No change in serum MMP-9 levels was discerned, but direct fluorometric assessment of serum MMP-9 activity revealed marked and persistent reductions in protease activity from 3 months of treatment onward. The small size and design of this study also raises the possibility of the regression-to-the-mean effect, but this seems less likely over the 24-month treatment period.
In both of these studies, most patients tolerated the medications with minimal side effects (transient dizziness and nausea). The positive results raise the possibility of a safe and inexpensive treatment that might be added to the ever-growing armamentarium of MS treatments. We eagerly await the results of an on-going phase-III, randomized, placebo-controlled trial examining the effects of combination therapy with minocycline and glatiramer acetate. Recent results from the randomized, double-blind phase-II study demonstrated a trend toward 60% reductions in gadolinium-enhancing and T2-weighted brain lesions, as well as reductions in relapse rates, in patients receiving combination therapy compared to glatiramer acetate alone.
Reference
1. Zabad RK, et al. The clinical response to minocycline in multiple sclerosis is accompanied by beneficial immune changes: a pilot study. Mult Scler 2007;13:517-526.
Addition of doxycycline to interferon-beta therapy in patients with relapsing-remitting multiple sclerosis might improve control of inflammatory lesions.Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.