Long-term Efficacy of Immunomodulatory Therapy in Multiple Sclerosis
According to data presented at the 56th Annual Meeting of the American Academy of Neurology, initiation of intramuscular interferon beta-1a (Avonex) therapy at the time of a first demyelinating event significantly slows the rate of conversion to clinically definite multiple sclerosis (MS) over 5 years.1 Moreover, immediate initiation of Avonex therapy reduced annualized relapse rates and the development of new or enlarging T2 lesions over 5 years compared to treatment initiated a median of 2.5 years later (termed the delayed-treatment group), after the first demyelinating event. These results support the recommendation to initiate immunomodulatory therapy in high-risk patients at the time of a first demyelinating event to provide long-term benefits for the patient with MS. In a related study, investigators determined the only factors independently associated with increasing brain atrophy in patients with MS after a first clinical demyelinating event were change in T2 lesion volume and number over 5 years.2 The results of this study emphasize the predictive value of T2 signal abnormalities early in the course of MS.
Results From the CHAMPIONS Study
CHAMPIONS,1 an open-label extension study of CHAMPS (Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study),3 included 203 patients from 32 participating sites. Following randomization in CHAMPS, study participants were offered but not required to take Avonex treatment for up to 5 years. Patients were followed every 6 months until the last patient completed his or her 5-year evaluation. In CHAMPIONS, patients who originally received Avonex in the CHAMPS study were considered the immediate-treatment group (n = 100) and patients who originally received placebo (n = 103) were considered the delayed-treatment group (median time to treatment initiation = 29 months in delayed-treatment group). Baseline demographic, clinical, and magnetic resonance imaging (MRI) characteristics were well matched in the 2 CHAMPIONS treatment groups. Outcomes included the rate of development of clinically definite MS, relapse rate, measures of disability, and MRI measures.
At the conclusion of the 5-year study period, early treatment with Avonex significantly delayed the onset of clinically definite MS in the immediate-treatment group compared to the delayed-treatment group. Overall, 36% of the immediate-treatment group versus 49% of the delayed-treatment group developed clinically definite MS by 5 years (unadjusted rate ratio 0.65; 95% Confidence Interval (CI), 0.43-0.97; P = .03) (Table 1). These results remained significant after adjusting for baseline variables independently associated with outcome (adjusted rate ratio = 0.57; 95% CI, 0.38-0.86; P = .008).
R. Philip Kinkel, MD, Director, Multiple Sclerosis Center at Beth Israel Deaconess Medical Center, Boston, Massachusetts, advised, "These results suggest that high-risk first-attack patients benefit, in terms of a reduction in measures of disease activity, from prompt initiation of Avonex therapy compared to delayed, but early, initiation of therapy." To underscore his point, Dr. Kinkel pointed out that, "58% of the delayed-treatment group actually initiated therapy before receiving a diagnosis of clinically definite multiple sclerosis. Although we refer to this group as the delayed-treatment group, these patients initiated therapy much earlier in the course of their disease than is customary. The mere fact that immediate initiation of therapy showed modest benefits on measures of disease activity (ie, relapses and new MRI T2 lesions) over 5 years compared to this delayed, but early initiation of therapy is very significant." Speculating why these changes may have occurred, Dr. Kinkel stated that earlier initiation of immunomodulatory agents may have halted the inflammatory process, thus restricting a more widespread immune attack.
Dr Kinkel concluded by pointing out that, "Further studies are needed to develop or verify predictors of disease activity (eg, surrogate markers) that may be used by patients and clinicians to help them decide if they should initiate therapy immediately after the onset of multiple sclerosis-related symptoms. While it is true that this study revealed a significant reduction in disease activity, only 50% of the delayed-treatment group developed clinically definite multiple sclerosis over 5 years, and few patients developed any measurable disability. But until we develop better markers or predictors of future disease activity, we must base our treatment decisions on the CHAMPS and CHAMPIONS entry criteria and study results."
The Development of Brain Atrophy After a First Demyelinating Event
According to an analysis of MRI data from the CHAMPIONS study,2 baseline T2 lesion volume, and change in T2 lesion volume and number are the only factors independently associated with increasing brain atrophy after a first clinical demyelinating event. Moreover, investigators observed that patients presenting with a first clinical demyelinating event and an abnormal cranial MRI scan had little evidence of brain atrophy at onset, but did demonstrate the development of brain atrophy over the subsequent 5 years in over 50% of patients; for this reason, brain atrophy is an important treatment consideration.
"Brain parenchymal fraction decreased by at least 1% in 59% of these patients," reported Dr. Kinkel referring to patients in this analysis. "There was a median reduction of at least 1% in brain parenchymal fraction even in patients with no clinical or MRI evidence of disease activity at 5 years. Factors other than clinical or MRI measures of disease activity may be responsible for the development of atrophy, even in patients not fulfilling the clinical or MRI criteria for multiple sclerosis," suggested Dr. Kinkel. Decrease in brain parenchymal fraction indicates an increase in brain atrophy.
The study included 165 CHAMPIONS patients with a baseline or 6-month MRI scan (obtained from CHAMPS) and a 5-year MRI scan (from CHAMPIONS) available for the determination of brain parenchymal fraction. Investigators assessed brain parenchymal fraction changes from baseline to 5 years and from 6 months to 5 years (the latter analysis to eliminate the transient effect of baseline steroids on brain parenchymal fraction).
Least squares regression modeling was used to determine baseline and on-study factors associated with the development of brain atrophy. Baseline factors included CHAMPS randomization group, age, qualifying event, gender, baseline brain parenchymal fraction, T2 lesion volume, and gadolinium-enhancing lesion number. On-study factors included the development of clinically definite MS, number of confirmed relapses, 5-year Expanded Disability Status Scale (EDSS), 5-year Multiple Sclerosis Functional Composite (MSFC) score, 5-year change in T2 lesion volume, number of new or enlarged T2 lesions over 5 years, and number of gadolinium-enhancing lesions at 5 years.
The median baseline brain parenchymal fraction in the CHAMPIONS cohort was 0.857, which was identical to the original CHAMPS cohort. Overall, brain parenchymal fraction decreased a median of 1.146% from 6 months to 5 years. This decrease was slightly less when assessing change from baseline to 5 years, which, according to Dr. Kinkel, was due to the reduction in baseline brain parenchymal fraction by the effect of acute steroid treatment.
Among study participants, only 18% experienced no significant decrease (<0.5% or less than twice the coefficient of variation of the brain parenchymal fraction measurement) in brain parenchymal fraction over 5 years. Brain parenchymal fraction decreases of ≥0.5% but less than <1% were demonstrated in 23% of patients; reductions of 1% to 2% were seen in 38%; reductions of 2% to 3% were seen in 15%; and reductions of >3% occurred in 6% of patients, Dr. Kinkel reported.
Multiple baseline and on-study factors were associated with a decrease in brain parenchymal fraction over 5 years, including baseline T2 lesion volume and number, the development of clinically definite MS over 5 years, the number of relapses over 5 years, the EDSS and MSFC scores at 5 years and change in T2 lesion number and volume over 5 years. However, in multivariate analysis the only factors independently associated with the development of measurable brain atrophy over 5 years were change in T2 lesion number and T2 lesion volume (baseline T2 lesion volume was also marginally associated with a decrease in brain parenchymal fraction over 5 years). Despite these associations, none of these factors adequately predicted the development of brain atrophy.
This study demonstrates that patients presenting with a first clinical demyelinating event and an abnormal cranial MRI scan show little evidence of brain atrophy at onset, but do demonstrate increased rates of atrophy over the next 5 years in a significant number of patients. Importantly, the observation that baseline T2 lesion volume and change in T2 volume and number are the only factors independently associated with increasing brain atrophy emphasizes the predictive value of T2 signal abnormalities early in the course of the disease.
1. Kinkel RP, Kollman C, Glassman A, Simon J, O'Connor P, Murray TJ for the CHAMPIONS study group. Interferon beta-1a (Avonex) delays the onset of clinically definite MS over 5 years of treatment: results from CHAMPIONS Study. Neurology. 2004;62(Suppl 5):A261.
2. Kinkel RP, Kollman C, Glassman A, et al. The development of brain atrophy 5 years after a first clinical demyelinating event. Neurology. 2004;62(Suppl 5):A424.
3. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med. 2000;343:898-904.