The Case Against Aggressive and Induction Therapy for Multiple Sclerosis

There’s an argument to be made for aggressive multiple sclerosis (MS) treatment. But it’s a very particular argument.

In the Donald Paty Memorial Lecture on the final day of the annual Consortium of Multiple Sclerosis Centers (CMSC) in New Orleans, Brian Weinshenker, MD, argued that aggressive MS treatment should be reserved for aggressive MS conditions.

Weinshenker, a Neurology professor from the Mayo Clinic in Rochester, Minnesota, presented a lecture titled “Induction or Aggressive Treatment for Multiple Sclerosis — Is it Right for Most, Some, or No Patients?”

Weinshenker began the discussion by making reference to the words of the lecture’s namesake — his former colleague Donald Paty, MD, FRCPC, who passed away in 2004.

Drawing from research published 30 years ago, Weinshenker noted Paty had speculated that, only after the evolution of the MS process is understood could clinicians design rational therapies directed towards prevention.

A comprehensive understanding of MS has not yet been achieved, and induction therapy — a strong immunointervention as soon as an MS diagnosis is certain or for patients with a first episode suggestive of MS — has only been practiced since about 2000, Weinshenker said.

He detailed the arguments for aggressive and inductive therapy — that MS is universally severe, clinicians cannot predict who will react poorly to treatments, there is a narrow and early window for intervention, aggressive treatments are superior in efficacy, and most treatments are adequately safe.

“I believe these are all great points, but are hypotheses on limited data,” Weinshenker said. “We shouldn’t reject these hypotheses, we should seek more data on them.”

What’s known is long-term experiences with induction treatments are lacking, and are linked to adverse side effects. Mitoxantrone, also used to treat acute myeloid leukemia, causes cardiology issues such as heart failure, or amenorrhea and serious infections.

Alemtuzumab has also been linked to serious infections, Weinshenker said, as well as autoimmunity issues and serious infusion reaction.

Autologous stem cell transplant (ASCT), graded by Weinshenker as the most dangerous form of approved MS treatment, could lead to MS exacerbation, grade 3 and 4 adverse events (AE), and even death.

This leads Weinshenker to question what the recent US Food and Drug Administration (FDA) approval of ocrelizumab will show in long-term results. While the new drug treatment appears to be highly efficacious in its clinical trials, and has a reported short-term safety, nothing is yet certain.

Weinshenker noted from rituximab results that ocrelizumab might have low opportune for infections over a longer period of time, as well as a risk of hypogammaglobulinemia.

“It remains to be seen how this would play on our patients we put on ocrelizumab, but it’s something we have to consider,” Weinshenker said.

Weinshenker emphasized the limited knowledge of MS itself. All that’s known in MS treatment is the degree of efficacy, he said, so optimized and individualized treatments aren’t available until there’s a more biological understanding of MS.

“In terms of hard data, we have the strongest data for oour platform treatment, because it has been around the longest, but it is hard data and we should take that into consideration,” Weinshenker said.

Citing studies that have suggested no evidence of disease activity (NEDA) rates are shown to be not significantly different between aggressive and platform treatments, and that relapse rates even in placebo treatment groups in MS trials have shown a progressive reduction over time, Weinshenker prosed there’s a small, early window in which aggressive treatment is effective.

“MS has a highly variable prognosis — 20-40% have a benign course,” Weinshenker said. “Observation over the first 5 years of monitoring clinically and radiologically, refines prognosis and allows one to tailor treatment.”

There’s also limited treatment towards the brain-related effects of MS. Current therapies target the disease’ inflammatory activity, Weinshenker said, but atrophy is a secondary effect.

He added that attacking the machinations of the immune systems is not most ideal, and that clinicians should strive for treatments that make the immune system “a partner, not the enemy.”

We make our best guess on the patient profile, then make consideration to combination of relapses, relapse-related disability and MRI activity,” Weinshenker said.

It’s still unclear whether aggressive treatment is actually appropriate for all MS patients, Weinshenker said. There’s more work, and more discoveries, yet to be reached before that is answered.

“I don’t think we should reject the hypotheses that are there, but I think we should be critical of them,” Weinshenker.