Interferon beta-1a for brain tissue loss in patients at presentation with syndromes suggestive of multiple sclerosis: a randomised, double-blind, placebo-controlled trial
Filippi M, Rovaris M, Inglese M, Barkhof F, De Stefano N, Smith S and Comi G ;
Commented by , 22 Nov 2004
Background
CNS atrophy is considered to be a marker of irreversible tissue damage in multiple sclerosis (MS) and correlate with clinical disability. Recently it has been shown that cerebral atrophy can be measured within a 3- month period in active MS (ref. 1).
Early immunomodulatory treatment in clinically isolated syndromes (CIS) prolong conversion to clinically definite MS (CDMS) and slow the accumulation of T2 weighted MRI activity. The question is whether tissue loss is reduced as well, which the current study seeks to answer.
Aim
To investigate if interferon beta-1a reduces tissue loss in CIS and if these changes correlate with MRI markers of disease activity.
Methods
The study design was randomized, double blinded, placebo controlled and incorporated patients with CIS from the ETOMS trial (ref. 2). MRI brain volume was measured at baseline, months 12 and 24, from 131, 111 and 112 patients, who received active treatment (subcutaneous injections of 22 microgram interferon beta-1a once a week) and 132, 98 and 99 patients receiving placebo respectively.
Normalized brain parenchymal volume and percent brain volume changes (PBVC) were estimated by fully automated segmentation. The primary endpoint of the study was conversion to CDMS (clinical relapse), and PBVC was a tertiary measure. Statistical analysis was intention to treat and ANCOVA was used to compare groups. Brain volume data were not corrected for multiple comparisons.
Results
- Patients who received treatment with interferon beta-1a had lower conversion rate to CDMS compared with placebo (31% vs. 47%; OR 0.52; p=0,0115).
- Mean PBVC was significantly reduced at all timepoints (treatment –0.62%, -0.61% and -1.18 vs. placebo -0.83%, -0.67% and -1.68%; p<0.0001).
- A significant treatment effect was detected 24 months from baseline (p=0.0031).
- New lesions correlated weakly with changes in BPVC during the second year in treated patients.
Dr Blinkenberg's comments
The study shows a treatment effect of interferon beta-1a on conversion to CDMS, which previously has been demonstrated using a different pharmaceutical preparation (CHAMPS study) (ref. 3 ).
The current study shows that tissue loss is reduced in the group receiving interferon beta-1a, which argues for a neuroprotective treatment effect. These results seem robust, especially since interferon beta is known to reduce the volume of MS related inflammatory edema, which induce "pseudo atrophy" and skew data in favor of the placebo group.
The study has special interest since it focuses on a key issue in MS pathophysiology regarding coupling between inflammation and tissue loss. On one hand the authors show a weak correlation between MRI disease activity and BPVC, and on the other hand they find a significant effect of early anti-inflammatory treatment on tissue loss.
There are a number of reasons which could explain the mismatch between MRI activity and BPVC, the most important being ongoing subclinical disease activity before disease onset, and diffuse pathology in normal appearing white matter. In this respect the study argues for a closer relationship between inflammation and tissue loss in the initial phase of the disease, and strengthens the incitement for early immunomodulatory intervention in MS.
References
1. Hardmeier M, Wagenpfeil S, Freitag P, Fisher E, Rudick RA, Kooijmans-Coutinho M, Clanet M, Radue EW, Kappos L. Atrophy is detectable within a 3-month period in untreated patients with active relapsing remitting multiple sclerosis. Arch Neurol 2003; 60 (12); 1736-1739.
2. Comi G, Filippi M, Barkhof F, Durelli L, Edan G, Fernandez O, Hartung H, Seeldrayers P, Sorensen PS, Rovaris M, Martinelli V and Hommes OR. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 2001; 357 (9268); 1576-1582.
3. Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, Simonian NA, Slasor PJ, Sandrock AW. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 2000; 343 (13); 898-904.