This report was reviewed for medical and scientific accuracy by: William H. Stuart, MD, Medical Director, MS Center of Atlanta, Georgia

Introduction

William H.Stuart,MD,Medical Director, MS Center of Atlanta, Georgia

As recently as this past week, I had the opportunity to see a young woman whom I had seen 21 years ago at the age of 20, with acute optic neuritis and some minimal left-arm symptoms. In that pre-MRI period, only a suspicion of MS could be made, all other tests being negative. She remained asympto-matic for the intervening 21 years and now is pre-senting with chronic progressive symptoms affect-ing memory, gait, and distal lower-extremity sensa-tion. Her MRI scan has significant T2 lesion load and atrophy.

Healthy in all other respects with actuarial probabil-ity of living well into her 70s or 80s, she now faces the possibility of relentless progressive disease throughout the next 35 to 40 years. What better case would illustrate the points made in Dr. Galetta’s 10 summary points regarding early treat-ment of optic neuritis? In retrospect, would the reg-ular treatment of this patient even with injectable medications on a weekly basis have been consid-ered excessive? What are the socioeconomic issues in this still-young individual now facing the poten-tial for significant restriction in her life activity through the next four decades?

The availability of effective early treatment that will modify the clinical and MRI progression of MS, as demonstrated in the Avonex/CHAMPS trial, must be interpreted and projected toward its benefit for the individual patient and not the population at risk. The socioeconomics and cost-effectiveness of treatment in medicine are public health issues and are inappropriate considerations when an individ-ual physician deals with an individual patient. As Dr. Galetta has pointed out, the CHAMPS results, when compared to other pivotal phase III trials that included patients at a later stage of illness, has demonstrated the ability to offset the progression to increased T2 lesion load and atrophy, both MR measures that indicate unfavorable prognosis. It would seem appropriate, if we are to change the clinical demographics of multiple sclerosis patients, that physicians begin considering much earlier treatment. The current data, indicating that fewer than 50% of MS patients appropriate for treatment are receiving it in the United States, is a telling indictment of either indifference or the lack of understanding of these newer concepts regarding MS pathology and progression. MS patients would like us to move a little more quickly.

Update on the CHAMPS Data

Steven L.Galetta,MD,Director,Neuro- Ophthalmology,Van Meter Professor of Neurology, University of Pennsylvania School of Medicine, Philadelphia

The CHAMPS trial (Controlled High Risk Subjects Avonex Multiple Sclerosis Prevention Study) clearly established the benefit of Avonex treatment in patients considered to be at high risk for developing clinically definite MS (CDMS). Additional analyses from this trial have solidified this mandate. The updated findings were presented at this meeting by Steven L. Galetta, MD, a CHAMPS investigator.

The ONTT demonstrated that patients with isolated acute demyelinating syndromes and brain lesions on MRI scans were at high risk for developing MS. These findings provided the rationale to study inter-feron beta-1a (Avonex, Biogen, Inc.) versus placebo in a group of high-risk patients. Earlier trials had already established a beneficial effect in reducing disability and relapses in relapsing-remitting MS (RRMS) patients treated with Avonex.

The CHAMPS study was initiated at 50 centers across the United States and Canada. Patients had an acute isolated demyelinating event involving the optic nerve, spinal cord, or brainstem/cerebellum. In addition, each patient had two or more clinically silent brain MR lesions that were at least 3 mm in size, and one of which was periventricular or ovoid. All patients received IV methylprednisolone within 14 days of symptom onset, followed by an oral prednisone taper. Patients were randomized to receive weekly intramuscular injections (IM) of Avonex or placebo.

The primary outcome measure was the develop-ment of CDMS, defined by the appearance of new neurologic or ophthalmologic events or progressive neurologic deterioration. Serial brain MRI studies provided secondary outcome measures.

CHAMPS was terminated early in February of 2000 after showing that Avonex may reduce the conver-sion to CDMS in high-risk patients by about half. Even more compelling was the MR data, which found that 82% of the placebo group developed new but silent MR lesions by 18 months. “This finding emphasizes that many demyelinating lesions may go undetected clinically. In addition, it shows that a large number of high-risk patients have ongoing demyelination,” Dr. Galetta pointed out.

Data from a subgroup analysis were also presented. The benefit of interferon beta-1a was seen regardless of whether the patient presented with optic neuri-tis, a spinal cord syndrome, or brainstem/cerebellar dysfunction. Furthermore, treatment benefit was observed irrespective of baseline MRI T2 lesion number or volume.

Ten Reasons to Treat High-Risk Optic Neuritis Patients Early By Steven L. Galetta, MD

* Natural history studies suggest that MS is not benign: 50% of patients convert to a progres-sive course within 10 years, and approximately 90% do so within 25 years.

* Fatigue and cognitive dysfunction may occur without evidence of new T2 lesions on MR imaging.

* MR scans show early brain atrophy, black holes on T1-weighted images, and decreased N-acety-laspartate (NAA), a neuronal marker. Black holes and NAA are suggestive of axonal dropout or dysfunction.

* In CHAMPS, 82% of untreated patients devel-oped a new subclinical MR lesion within 18 months of study onset.

* Pathologic studies show that axonal degenera-tion occurs early in the disease and in acute plaques.

* ETOMS patients experienced a 24% reduction in progression to CDMS, while similar patients in the CHAMPS study demonstrated a 44% reduction. Patients in the ETOMS study appeared to have more advanced disease, by both clinical and MR data.

* The cost-effectiveness of early treatment is debatable, but some studies show substantial cost savings, particularly when viewed over the long term.

* Various studies with Avonex (interferon beta-1a) across the spectrum of disease suggest that therapy is more effective early in the disease course. CHAMPS showed a reduction in new attacks in high-risk patients by about half. The initial Avonex study in relapsing-remitting patients found a 32% reduction in new attacks and a 37% reduction in disability progression.

* The Early Treatment of MS (ETOMS) study, using 22 µg (low dose) Rebif (interferon beta-1a, Ares-Serono) once a week subcutaneously, showed clinical benefit in monosymptomatic patients but not in relapsing-remitting patients, substantiating the importance of early treat-ment. (Rebif has not been approved by the FDA for use in the United States.)

* In long-term follow-up, placebo-treated patients in the original Rebif and glatiramer acetate (Copaxone, Teva Marion) trials are not doing as well as patients initially randomized to active treatment.