FT. WORTH, TEX—Given available evidence, early, aggressive treatment is warranted in all patients at risk for multiple sclerosis (MS). While many clinicians would agree with that statement, some feel the jury is still out. According to speakers at the annual meeting of the Consortium of Multiple Sclerosis Centers, the debate has yet to be won.

On the “pro”active side, the rationale for early therapy is threefold, said Richard A. Rudick, MD, of the Mellen Center for Multiple Sclerosis Treatment and Research in Cleveland, Ohio: the availability of safe and effective—albeit expensive—drugs for patients with relapsing–remitting MS and clinically isolated syndromes; the difficulty of identifying benign cases in the early stages of MS, with clinical symptoms underestimating disease activity and degree of pathology; and evidence that treatment with interferon beta has beneficial effects on CNS inflammation compared with placebo.

On the “con”servative side, Brian Weinshenker, MD, of the Mayo Clinic in Rochester, Minnesota, said, “there really is no disagreement that some patients do have a benign course, although it is true that it is difficult to identify them reliably very early in the course of their disease. To ask them to take a long-term therapy for an indefinite period of time that is expensive, and has moderate side effects, and for which we cannot very well monitor the efficacy of treatment in individual patients, is a very big request to make of a patient, and requires a very high standard of proof. I personally don’t feel that that standard has been met yet.”

UNTIL MORE IS KNOWN, ARE WE BETTER SAFE THAN SORRY?

According to Dr. Rudick, predictors of long-term outcome include T2 lesion load at onset; data from one study suggest that a patient with 10 lesions on magnetic resonance imaging (MRI) after presenting with symptoms of optic neuritis has an approximately 35% chance of having difficulty walking in 10 years. In another study, age at onset was predictive, with 18% of those younger than 40 following a benign course compared with 2% of those older than 40, Dr. Rudick noted. One explanation may be accumulating evidence that demonstrates a destructive pathologic process in the early stages of MS, leading to the hypothesis that MS is progressive, but that clinical deterioration is delayed until a threshold of tissue destruction is exceeded. If true, the best way to measure disease progression may be by MRI and the Multiple Sclerosis Functional Composite (MSFC), as Dr. Rudick and colleagues showed in a recent study in Neurology.

Other as-yet-unanswered questions include whether anti-inflammatory drugs become less effective as MS progresses, whether patients at different stages of MS are differentially responsive to treatment with anti-inflammatory drugs, and whether late-stage progressive deterioration can be blocked or delayed by early anti-inflammatory therapy. Until these questions are answered, Dr. Rudick recommends erring on the side of caution by diagnosing and treating MS and suspected MS early and aggressively.

CONSERVATIVE VOICE OF REASON OR RESISTANT NAYSAYER?

Dr. Weinshenker outlined the “dilemmas” faced in not routinely starting treatment early, including increased pressure from patients who may have little disability and few attacks for years but who have been told they should be on long-term therapy, either by other patients with MS or by neurologists from whom they’ve sought another opinion.

“For those who would argue that very early treatment is necessary, it’s easy to be viewed as willing to fight for the patient, [as] doing what’s best for the patient,” he said. On the other hand, by arguing to delay treatment, “it’s easy to feel that one is an agent of HMOs [health maintenance organizations], the National Health Services, [or] other cost-control bureaucracies, so it’s easy to feel [that one is] on the wrong side.”

“Those who would argue to treat early would say that early treatment may delay or prevent long-term disability. Those who say that we should wait until it’s determined that the patient has active disease would say yes, that’s theoretically possible but … you have to be careful going from theoretical possibilities to indications that things are proven. Short-term benefits have not always been shown to lead to long-term benefits. There may be an early benefit with interferon that may disappear, or the benefit that’s accrued over time may become increasingly obvious, and in terms of the most critical robust outcomes over the long term, [this benefit] may well be very important. Either is now a potential conclusion that will be determined from future carefully designed studies to assess long-term treatment efficacy. But current studies following patients on Avonex therapy certainly indicate that a substantial proportion of patients reach relatively advanced levels of disability in spite of being on disease-modifying therapy most of the time, so current therapies still leave much to be desired,” Dr. Weinshenker said.

“Those who would argue to treat early would say that we can’t afford to wait because irreversible brain injury—either disability or a number of surrogate measures like cerebral atrophy, increased NAA [N-acetyl aspartate] or on MR spectroscopy black holes—may occur very early, and you’ve seen the pathological support for that. However, those who would counter and say we should wait until the disease is demonstrated to be in an active state would say that the natural history is very variable, and why not observe the course until we can determine which patients seem to have active disease before we initiate therapy? It’s probably true that only a very small minority of patients develop the early, severe, irreversible disability that happens so quickly that we can’t pick it up with clinical and MRI monitoring. Even if some patients do develop rapid, irreversible axonal damage, are we certain that the treatments currently available could have altered the course of [disease for] such patients? I certainly see many patients on a long-term therapy … who are not doing very well. Now, does that mean they are getting no benefit from the drug? Perhaps not, but certainly there are some patients who are clear-cut treatment failures. I’m sure we all have such patients,” Dr. Weinshenker remarked.

“Those who would argue to treat early would say these treatments may be cost-effective: They reduce hospitalizations and reduce the need for treatment for relapses. Late treatment may not result in total catch-up of disability, at least based on some preliminary data from long-term follow-up. Those who would argue to treat late point out the expense and inconvenience and the adverse effects and would also point out the fact that neutralizing antibodies occurred. Although we are not fully certain of the significance of those neutralizing antibodies, there’s a very good chance that they lead to substantial loss of efficacy of these agents.”

According to Dr. Weinshenker the options are fairly clear. “At this point we can either proceed with early treatment for all patients, or we can adopt a selective approach.” If it is ultimately demonstrated that current disease-modifying agents do have significant long-term benefits, “perhaps we could argue that we should initiate treatments from the first symptom,” he said. What remains unknown, however, is to what extent their benefits are distributed over the population. “We know that there’s a 30% reduction in attacks. Would that mean that every patient experiences a 30% reduction? Or does that mean that some patients get no benefit and other patients get a major benefit? We’ve done relatively little to answer that question, which is really a critical question.”

NR