An increase in the activity of matrix metalloproteinase-9 (MMP-9) relative to tissue inhibitor of MMP-type 1 (TIMP-1) may be related to formation of new MS lesions, suggesting that serum levels of MMP-9 and TIMP-1 may be surrogate markers of disease activity in relapsing-remitting MS.
This study, conducted in three separate outpatient health care delivery settings, examined the therapeutic expectations of patients with multiple sclerosis (MS) before they initiated interferon beta-1b therapy, the results of current educational procedures to correct unrealistic expectations, and the relationship between post-education expectations and discontinuing therapy. Ninety-nine consecutive patients were seen in a university based outpatient MS clinic, an academic group practice outpatient MS clinic, or a health maintenance organization outpatient neurology clinic. Before the educational sessions, 57% of the patients expressed unrealistically optimistic expectations regarding reduction in attack rate and 34% expressed unrealistically optimistic expectations regarding improvement in functional status. Educational procedures significantly altered unrealistic expectations but the results were sub-optimal since 33% of the patients maintained overly optimistic expectations regarding reduction in attack rate. Post-education unrealistic expectations of improvement in functional status were significantly related to discontinuing therapy within 6 months. Three adverse effects of therapy also were related independently to adherence to treatment: depression and flu-like symptoms were related to discontinuing therapy while soreness at injection site was related to continuing therapy.
The ratio of MMP-9/TIMP-1 may predict MRI activity in SPMS. The effect of IFNbeta-1b in MS, as measured by reduction in new Gd+ lesions, may be partly explained by altering MMP-9/TIMP-1 ratio.
The design and conduct of a randomized, double-blinded, placebo-controlled, multicenter, phase III study of recombinant interferon beta-1a (IFN-beta-1a) as treatment for exacerbating-remitting MS are described, as are baseline characteristics of the study population. The purpose of the study was to determine if 6.0 x 10(6) IU (30 micrograms) of IFN-beta-1a, administered by weekly intramuscular (i.m.) injections, was effective in delaying the onset of sustained disability. The primary outcome measure was time to onset of treatment failure, defined as a worsening on the Kurtzke Expanded Disability Status Scale (EDSS) of greater than or equal to 1.0 point compared with baseline, persisting for at least 6 months. An intent-to-treat design was used. The primary outcome measure was analyzed using the Mantel-Cox log-rank statistic and Kaplan-Meier survival curves. Secondary outcomes included quantitative measures of upper and lower extremity function, neuropsychological test performance, functional and quality of life assessments and several measures derived from annual brain MRI studies. Entry criteria included prestudy exacerbation rates of at least 0.67 per year and EDSS scores of 1.0-3.5. A total of 301 MS patients were randomly assigned to receive weekly i.m. injections of IFN-beta-1a or placebo. The average age of the study population at entry was 37 years; 92% were Caucasian and 73% were women. The mean prestudy disease duration was 6.5 years, mean prestudy exacerbation rate was 1.2 per year and the mean EDSS score was 2.3. The randomization yielded well-balanced treatment arms. Various aspects of the study are discussed, including: (1) the decision to focus study design on sustained disability; (2) the rationale for the treatment regimen; (3) measures taken to assure the reliability of the primary outcome measure; and (4) a description of the secondary outcome measures.
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