Caroline Helwick

June 01, 2017

NEW ORLEANS — With numerous agents for multiple sclerosis (MS) seemingly more effective in halting disease activity than the older "platform" drugs, can a case be made for starting almost all patients with newly diagnosed MS on them?

Delivering the Donald Paty Memorial Lecture at the Consortium of Multiple Sclerosis Centers (CMSC) 2017 Annual Meeting, Brian G. Weinshenker, MD, professor of neurology at the Mayo Clinic, Rochester, argues that despite the robust efficacy of the newer agents, they are not warranted in all patients.

"There is strong evidence for aggressive treatment for patients who present with aggressive forms of MS, but greater efficacy comes with greater risk," Dr Weinshenker said.

He explained that approximately one third of patients will have a fairly indolent disease course and that aggressive treatment can be started if their condition worsens. There is no one "window of opportunity" for treating MS, he maintained.

"At this point I would rarely escalate treatment for progressive disability unless it was accompanied by attacks or evidence of active inflammatory lesions on MRI," he said.

Aggressive Disease Needs Aggressive Kick-Start

Dr Weinshenker emphasized that aggressive disease definitely should be treated aggressively from the start. This was proven in a 2011 study in which mitoxantrone (vs interferon [IFN] β-1b) delayed the probability of confirmed worsening by 1 point on the Expanded Disability Status Scale by 18 months, reduced the annualized relapse rate from 1.1 per year to 0.4 (P < .001), and produced a relapse-free rate of 53% vs 26% (P < .01).

Whether such results can be extrapolated to the newer aggressive drugs has not yet been established. But, he noted, "these are the kind of benefits no one argues against. They offer a pretty strong evidence base for treating aggressive MS aggressively."  

The dilemma, he said, is with "the average patient." In this subset, arguments support an aggressive approach, but he called these "hypotheses that should be questioned":

  • MS is universally a severe disease, and brain atrophy is accelerated in all patients.

  • Clinicians cannot predict which patients will do poorly.

  • There is a narrow window for effective intervention.

  • Aggressive/induction treatments are superior to others.

  • Treatments are adequately safe.

  • Treatments make a long-term difference.

  • Aggressive goals (no evidence of disease activity [NEDA]) are attainable and lead to better outcomes.

"On the surface, these make sense, but remember that while lots of these points are based on some data, they are still hypotheses," he cautioned. "My main message is not that we should reject these hypotheses, but we should be critical of them. We need a continuing search for actual evidence that these theories are, in fact, correct."

Much of MS Is "Benign"

"The reality is that MS is actually a highly variable disease…and in 20% to 40% of cases it's benign," said Dr Weinshenker. In a 20-year population-based study he coauthored, 34% of patients still had an EDSS score less than 3 some 10 years from disease onset, 21% had a score less than 4, and 15% had a score of 0 to 2.

From the data, he determined that patients with no clinical attacks in 5 or 10 years and with an EDSS score less than 2 have a 90% chance of remaining stable. "You might argue whether these patients need any treatment at all," he said. "This points to the need to individualize treatment based on the needs of the patient."

And MS may actually be becoming "more benign," he added, according to recent studies showing that median time to an EDSS score of 6 is now 20-plus years compared with 15 years in studies from the 1990s. Relapse rates in placebo groups in MS trials are also falling. Because these changes are largely seen in patients not receiving treatment, the trend does not reflect more effective drugs.

While a "benign" course cannot be accurately predicted, factors correlate with the likelihood of worsening. Studies have found these to include, at disease presentation, higher lesion burden (>4 lesions), confluence of lesions, presence of oligoclonal bands, male sex, late age at onset (>40 years), motor symptoms or ataxia (vs sensory symptoms or optic neuritis), and frequent early attacks.

"While we still cannot truly predict who will do poorly and would therefore need aggressive treatment, in the average patient we do have a window of opportunity to observe and select those who would be appropriate for aggressive treatment," he said.

MRI — especially for showing the emergence of T1 gadolinium-enhancing lesions — is a good way to monitor patients with mild disease started on platform drugs. "MRI helps refine our ability to prognosticate and stratify a patient's risk, and it informs us which patients should be receiving more aggressive treatment," Dr Weinshenker said.

As for brain atrophy — generally accepted as a fact of life in all patients with MS — its independent effect on disability progression or cognitive dysfunction is unclear. It has been correlated with treatment effects in clinical trials, but as a measure of disease activity, MRI is as good, he noted.  

Early attacks do seem to have a greater effect on disability than later attacks, and it makes sense to treat early, he said, but later initiation of treatment is also effective. In the CARE MS-1 and CARE MS-2 studies of alemtuzumab, relapse rates were reduced over platform drugs in 54.9% of treatment-naive patients and in 49.4% of patients with longer disease duration and treatment failure.

Reductions in sustained disability were also similar. Other studies in secondary progressive MS have shown that disability accumulation can be ameliorated with treatment.

"This suggests that some period of observation does not mean efficacy will be lost," Dr Weinshenker maintained. "Institution of DMT [disease-modifying therapy] can have some benefits anywhere in the course of MS."

Safety: Oldies Are Goodies

The platform agents — IFN β-1a, IFN β-1b, and glatiramer acetate — have been prescribed for more than 20 years and have an excellent long-term safety record. Long-term experience with induction treatments, on the other hand, is generally lacking, "but these agents virtually all have potentially serious medical complications," he reminded the audience.

The approval of ocrelizumab, however, could herald a means of treating aggressively and also safely, although long-term safety has not been shown. On the basis of experience with rituximab (primarily in neuromyelitis optica), the potential exists for hypogammaglobulinemia, which can occasionally be profound and can require intravenous immunoglobulin repletion. 

"Keep in mind this could be another risk we are exposing our patients to with aggressive treatment," he said.  

The evidence that any one MS drug is clearly superior to another is based on "very limited but high-quality" data, he continued. A recent analysis concluded that alemtuzumab, natalizumab, and fingolimod are the most effective drugs at suppressing relapses. However, the authors cautioned that the trials were of short duration, were sponsored by industry, and had some limitations in terms of outcome measures.

Dr Weinshenker emphasized that long-term efficacy has been mostly shown for the platform DMTs, as demonstrated convincingly for IFN β-1b in a 21-year follow-up of patients in the key original trial. Early initiation of the drug (and, thus, greater exposure) was associated with significant benefits over placebo, including a doubling in survival. "The difference was probably due to treatment in the critical early phase of the disease," he said.

He also reminded the audience that safe and effective compounds exist "outside the box." The BENEFIT trial, which included patients with a clinically isolated syndrome, found that a 20-ng/mL increase in serum 25(OH)D (vitamin D) level in the first 12 months of treatment with IFN β-1b or placebo predicted a 57% lower rate of new active lesions (P = .0009); a 57% lower relapse rate (P = .03); and significantly lower T2 lesion volume, brain volume loss, and disability status.

"This is quite a strong effect in an essentially prospective study. It suggests a very safe treatment may have potent effects," he said. Randomized studies of vitamin D's effects are ongoing.

Finally, Dr Weinshenker addressed the recent concept of NEDA, which means no attacks, no new MRI lesions, no change in disability, and atrophy less than 0.4% per year. NEDA is often not achieved with treatment, is not clearly associated with outcomes, and is, in fact, nearly impossible to measure.

"In head-to-head studies…the fold increase is only about 50% greater for test drugs vs comparators," he indicated. "Futile attempts to achieve NEDA can result in excessive switching of agents, with uncertain relative benefits and rapid escalation to treatments with higher risks."

Take a Nuanced Approach

Dr Weinshenker concluded, "A nuanced, individualized approach [to initial treatment] is reasonable…. Observation for the first 5 years, with monitoring clinically and radiographically, allows one to tailor treatment."

His advice was to "make your best guess based on patient profile, then consider in follow-up a combination of relapses, progression and MRI findings…and consider the preferences and attitudes of the patient, especially for potential complications."

Tanuja Chitnis, MD, associate professor of neurology at Harvard Medical School and director of Partners Pediatric MS Center at the Massachusetts General Hospital for Children, Boston, told Medscape Medical News that individualization of treatment will soon become more refined. This means patients requiring an aggressive approach at diagnosis can be more easily identified.

"It's important for clinicians to think about stratifying patients according to risk," she said. "There is more and more information about predictors of a more aggressive disease course. For clinicians, this is something that comes with experience, but there actually are predictive algorithms being developed."

One such algorithm, in fact, has been created by Dr Chitnis and her colleagues, who recently published their results. "It's a new statistical model, using machine-learning, that incorporates clinical information, demographics, and brain and lesion volume," she said. "This is the future."

CMSC's Chief Executive Officer June Halper, MSN, APN-C, MSCN, agreed in an interview that personalized treatment of MS is on the horizon. "Maybe it will be based on genetic profiling. Maybe it will come from a blood test, which is being talked about. But personalized medicine is definitely coming down the pike."

Dr Weinshenker has received royalties from RSR Ltd, Oxford University, and MVZ Labor PD and has consulted for MedImmune and Alexion. Dr Chitnis has consulted for Bayer Healthcare Pharmaceuticals and Novartis. Ms Halper has disclosed no relevant financial relationships.

Consortium of Multiple Sclerosis Centers (CMSC) 2017 Annual Meeting.  Presented May 27, 2017.

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