Treating Multiple Sclerosis: Why Wait?

Abstract & Commentary

By Susan Gauthier, DO, MS, Assistant Professor of Neurology and Neuroscience, Weill Cornell Medical College. Dr. Gauthier reports no financial relationships relevant to this field of study.

Synopsis: Glatiramer acetate significantly delayed the onset of clinically definite multiple sclerosis (MS) in patients having a clinically isolated event and brain lesions consistent with MS.

Sources: Comi G, Martinelli V, Rodegher M, et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): A randomized, double-blind, placebo- controlled trial. Lancet 2009; 374:1503-1511

Multiple sclerosis (MS) is a chronic inflammatory disorder with an initial relapsing phase that eventually transitions into the secondary progressive stage causing significant ambulatory and cognitive disability. The early relapsing phase of the disease is characterized by the development of inflammatory lesions, which are easily demonstrated on MRI. Axonal degradation, which is felt to be the major cause of sustained and progressive disability, begins at the earliest stages although it becomes more prominent as the disease enters the secondary stage. All of the currently FDA-approved self-injection therapies for MS have demonstrated a beneficial effect in the relapsing phase of the disease, which is reflective of their anti-inflammatory effect; however, none have been found to be beneficial for patients with secondary progressive MS. Given the correlation of axonal injury and inflammation in MS,1 decreasing inflammation at the earliest stages of the disease may influence the ultimate disease course. Therefore, the treatment of MS has transitioned into treating at the earliest stages.

Glatiramer acetate (GA) is the last of the four injectable therapies to be tested in patients with a clinically isolated syndrome (CIS), meaning patients with one neurological event and lesions consistent with MS on a brain MRI. In the current study by Comi and colleagues, two groups of CIS patients with unifocal neurological symptoms and at least two brain lesions (≥ 6 mm in size) were randomized to receive placebo or GA for up to 36 months. The study was powered to a primary endpoint of time to conversion to clinically definite MS (CDMS). There was a preplanned interim analysis of those randomized to the placebo arm, at which time 48% of patients had completed the study, 34% of which converted to CDMS. A 45% reduction in the risk of conversion to CDMS was found in the GA group; given the strong positive result, the study was stopped. Further evidence of a benefit was demonstrated in the 115% delay (336 vs. 772 days) in conversion to CDMS for the first quartile of patients receiving GA as compared to placebo. Secondary endpoints included various MRI metrics; new T2-hyperintense lesions, new gadolinium enhancing lesions, and new T1-hypointense lesions were all in favor of GA. There was no difference between the groups in degree of brain atrophy over time.


This study of GA demonstrated a similar delay in developing CDMS in patients with CIS as found in previous studies of interferon beta-1a (both IM and 22 mcg SQ formulations) and interferon beta-1b.2-4 There were some minor differences in the study designs, although all required characteristic MS lesions on a brain MRI; thus, patients were at high risk for developing the disease. The MRI criterion in the GA study was less stringent as compared to the other CIS studies, wherein a specific location or shape was not essential; however, the lesion size was required to be larger (at least 6 mm). Interestingly, patients with gadolinium-enhanced lesions at baseline appeared to respond better to GA, which corresponds to the interferon beta-1a IM study but conflicts with the other interferon studies. Thus, the characteristics associated with a treatment response in CIS patients have yet to be identified.

Given that four studies have demonstrated a similar benefit for early treatment initiation in MS, there appears to be little reason for not treating CIS patients. The key is to ensure that patients are truly at risk for CDMS, which relates to the clinical symptoms and the proper identification of characteristic MS lesions on a brain MRI. Importantly, the long-term influence of these therapies on the course of MS has yet to be established. However, given our current understanding of the disease, early treatment can only be beneficial.


1. Dutta R, Trapp BD. Pathogenesis of axonal and neuronal damage in multiple sclerosis. Neurology 2007;68 (22 Suppl 3):S22-31.

2. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 2000;343:898-904.

3. Kappos L, Polman CH, Freedman MS, et al. Treatment with interferon beta-1b delays conversion to clincally definite and McDonald MS in patients with clinically isolated syndrome. Neurology 2006;67:1242-1249.

4. Comi G, Filippi M, Barkhof F, et al. Effect of early interferon therapy treatment on conversion to definite multiple sclerosis: A randomized study. Lancet 2001; 357:1576-1582.