TORONTO—The advent of disease-modifying therapies for the treatment of multiple sclerosis (MS) clearly has had a positive effect on patients living with the disease. Less clear, however, is how best to determine whether a patient is responding well to treatment and when treatment should be modified to optimize outcomes, given the limited options available.

In an effort to define suboptimal treatment response in patients with MS on the basis of progression of disability, Mary Lou Myles, MD, an Assistant Clinical Professor of Neurology at the University of Alberta in Edmonton, presented recommendations developed by the Canadian Multiple Sclerosis Working Group at the 18th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

Four main issues were addressed in creating the guidelines. “The first was how we can best measure disability progression in clinical practice; second, at what time intervals we should be looking at assessing disability progression; third, what could we take from the literature in terms of trying to define a meaningful change in progression and one that was greater than we would expect on treatment; and then, finally, coming up with recommendations for when we should consider modification of treatment based on disability outcome,” noted Dr. Myles.

QUANTIFYING DISABILITY

Currently, disability is assessed based on history, patient perception, and neurologic examination. “But it was felt that if we are going to be basing treatment changes on progression of disability, we should be trying to have a quantifiable measure—the EDSS [Expanded Disability Status Scale] being the most logical, most widely used,” Dr. Myles remarked.

However, “it was recognized in general clinical practice that there are inconsistencies in the use of the ambulation portion of the EDSS and potential variability on some measures unrelated to true progression,” with up to 20% day-to-day variability in the 25-foot timed walk and up to 1.5 points on the EDSS 10-point scale on walking distance observed in stable populations, Dr. Myles said. This necessitates improvement to the measurement of how far patients can walk on a good day without aid or rest. The self-reported 12-Item MS Walking Scale was found to be reliable, valid, and responsive to change, she noted.

Cognition, especially as it relates to quality of life and employability, is also important to assess. “Unfortunately, at this point, there are no easy to use, standardized scales,” she said. Unanswered questions about cognition include what to do about isolated changes and, if treatment is modified on the basis of cognition alone, “whether we can reasonably expect that to benefit the patient.”

Confounding factors that can adversely affect disability include depression, infection or illness, heat, time of day, and “whether someone was in a current relapse. Also, side effects of treatment, such as an increase in spasticity with interferon, might produce what looks like an apparent worsening of the disease,” Dr. Myles said. Assessment of depression was believed to be very important. “There are formal screening tools available, but probably the most practical is the two-item scale that’s endorsed by the US Preventive Services Task Force,” she said, which asks, “Over the past two weeks, have you felt down, depressed, or hopeless?” and “Over the past two weeks, have you felt little interest or pleasure in doing things?”

PROGRESSION ASSESSMENT

The second issue examined was when progression should be assessed. “The intervals at which people were being assessed and conclusions drawn seemed to vary considerably,” she said. An annual assessment may be adequate in stable patients; however, when disability progression is suspected, patients should be assessed every three months, with disability confirmed at six months.

“Every effort should be made to differentiate between transient treatment failure and permanent failure, and in doing this, we should consider the baseline EDSS of patients, the history of recent relapses, and which functional subscale is responsible for the apparent increased EDSS, to ensure that it’s not variable from one point to the next and therefore more likely to represent a transient rather than a permanent treatment failure,” Dr. Myles said.

CLINICALLY MEANINGFUL CHANGES

The group also attempted to define “meaningful progression.” It has been shown that clinical trials that define progression as a 1-point increase in EDSS at three or six months may include a considerable proportion of patients for whom transient treatment has failed, yet who did well over time, she said. This led to the recommendation that disability progression be confirmed over time. A patient’s perception of disability may not correlate with his or her EDSS score; therefore, “a quantifiable measure alone, without considering qualitative aspects, is also inadequate.”

“Ideally, we suggested an observation period of a year, recognizing that there may be exceptions. And that was to rule out transient treatment failure and because we felt that some of the apparent progression of disability that might occur in the first few months of treatment might be related to disease activity that had occurred prior to treatment initiation,” Dr. Myles added, “and also, with the limited treatment options available, we did not want to be rushing into changes in treatment before a therapy had been given an adequate time to establish whether or not it was going to be effective.”

WHEN TO CONSIDER TREATMENT MODIFICATIONS

In this regard, patients may serve as their own controls, with the clinician asking, “How did they do before we started treatment? What was the rate of progression of disability, and has it been positively influenced by the initiation of treatment?”

Another approach is to examine what happens long term in untreated patients (ie, a placebo group in a clinical trial or data from natural history studies). One natural history study has shown that it took a median of 23 years to reach an EDSS rating of 3—but this was in an unselected MS population. In pivotal clinical trials, “even in patients selected for active disease, a minority progress over two or three years, so we should expect that most patients will do well and will not progress in the short term,” related Dr. Myles. In addition, “our expectations of therapy have to be in line with a modest benefit that is shown in these studies.” We are not yet at the point where we can expect complete cessation of disease activity.

Dr. Myles summarized the recommendations for determining when clinicians should be sufficiently concerned to consider treatment modifications based on disease progression (see Table). She noted that changes “of medium concern at six months could be considered [to warrant] a high level of concern at 12 months” because they thus would be truly representative of irreversible disability rather than transient treatment failure, and therefore of greater concern.

Issues not specifically addressed by the guidelines were whether a second confirmed progression, even if of a lower magnitude, should be considered more significant; and if treatment modifications should differ depending on whether a patient has relapsed remitting or secondary progressive MS, she acknowledged.

“In clinical practice, we should look toward standardized and quantifiable measures” to gauge disability progression and determine when a modification of treatment should be considered, Dr. Myles said. The next step is to test and validate the recommendations from the Canadian Multiple Sclerosis Working Group in the clinical practice setting. If patients “have developed secondary progressive disease and have progressed to the point where they are not ambulatory, then there would be general agreement that they have failed the treatment. In many other cases, however, it can be more difficult to determine when a change in treatment should be considered, and there is a need for guidelines such as these to help us. There is so much individual variability that there will be challenges ahead as we try to apply these types of guidelines to defining individual treatment failure. But it becomes probably the hardest decision of all when we’ve completely run out of options.”

NR

—Debra Hughes

Suggested Reading
Freedman MS, Patry DG, Grand’Maison F, et al, on behalf of the Canadian MS Working Group. Treatment optimization in multiple sclerosis. Can J Neurol Sci. 2004;31:157-168.

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