Where Does Traditional Therapy Fit in?

SAVANNAH, Ga. — Should patients with myasthenia gravis (MG) continue to undergo the traditional therapy of immunosuppression with drugs like corticosteroids and nonsteroidal agents? Or is it time to embrace a new generation of medications?

In a debate at American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024, a pair of neurologists who specialize in neuromuscular disorders laid out opposing evidence for each approach.

On one hand, Benjamin Claytor, MD, of Cleveland Clinic, Cleveland, argued that “traditional therapy is very effective for the majority of myasthenia gravis patients,” and he said it should be considered first-line.

But Amanda C. Guidon, MD, MPH, of Massachusetts General Hospital and Harvard Medical School, Boston, responded that “the immunosuppression of traditional therapies is too broad: The time to benefit is too long, the burden of side effects is too high, and the cancer risk is too elevated.”

Traditional Therapy: Affordable, Tolerable, and Safe?

Claytor said ideal MG therapies are effective, tolerable, and safe. They’re also affordable, convenient (such as a pill), lead to sustained remission, and can have dosages reduced.

Only traditional therapies — corticosteroids, azathioprine, mycophenolate, and rituximab — meet those last three criteria, he said. Newer therapies, he said, do not.

Claytor highlighted a 2023 Duke University study that tracked 367 patients with MG who were treated with traditional therapies after the year 2000. Of those, 72% reached the treatment goal of minimal manifestations in a median of less than 2 years.

In addition, Claytor noted that the percentage of patients with MG who reach minimal symptom expression ranges from 45% (6 months) to 60% or more (2 years), while studies suggest that newer treatments such as eculizumab (Soliris), efgartigimod (Vyvgart), rozanolixizumab (Rystiggo), and zilucoplan (Zilbrysq) haven’t reached those levels.

As for specific traditional therapies, Claytor said the corticosteroid prednisone is “extremely affordable,” effective, and takes fewer than 2 weeks to work. All patients with MG can take it, he said, and at least 75% of those with mild/moderate disease respond to low doses.

Nonsteroidal Agents, Immune Globulin, Rituximab

He acknowledged side effects from corticosteroids but said doses can be tapered once severity improves. Calcium and vitamin D can be helpful to support bone health, he added.

As for nonsteroidal immunosuppressive treatments, he said they’re easy to administer, increase the likelihood of reaching minimal manifestation status, can be effective at lower doses, and may allow patients to discontinue steroids.

Two other traditional therapies, immune globulin and plasmapheresis, can be appropriate in crisis or impending crisis situations, he said, or as an add-on therapy if steroids and nonsteroidal immunosuppressive therapies don’t work.

What about rituximab? “We’re learning that patients with new-onset disease and younger patients seem to respond better,” Claytor said. While rituximab is expensive, it’s “not even in the same realm” as newer agents if only a dose or two are given, he said.

Steroids Are Ideal in MG? Not so Fast

In her response, Guidon noted that she was assigned to offer a counter-perspective in her presentation, and “personal opinions are not being represented here fully.” She then listed the weaknesses of traditional therapy in MG.

For one thing, she said the drugs don’t work well. She highlighted a 2019 registry study that found “many myasthenia gravis patients remain negatively impacted despite treatment.”

In addition, “we can’t predict who will respond to which therapy…We start drugs and don’t know if we’ll have benefit from 6 months up to 18 months. We also can’t determine minimally effective dose a priori. Some patients require higher doses, and some subtherapeutic doses are actually therapeutic for our patients.”

Broad immunosuppression, she added, boosts the risk for serious infections. “We’ve all heard from our patients that the side effects can be worse than the myasthenia, and next we’re going to talk about the role of corticosteroids in myasthenia.”

As for corticosteroids in particular, “they’re really the best treatment and also the worst treatment.” Efficacy and side effects battle for supremacy in patients, she said, “and you don’t know which is going to win out.”

Kicking Traditional Therapy to the Curb

There are many possible side effects from steroids, she said, including steroid-induced diabetes, which is “profound.” Some patients never recover from it, she said.

On top of all these risks, she said, 20%-30% of patients are resistant to steroids.

As for other treatments, immune globulin and plasmapheresis “aren’t really benign,” Guidon said. They come with potentially serious side effects of their own, as do nonsteroidal immunosuppressive treatments, she said.

Guidon said better treatments are needed to minimize the risks from traditional therapies. “We need targeted therapies that drive disease into remission, can be tapered, are delivered orally or with infrequent self-injections, and don’t require frequent lab monitoring.”

In addition, ideal treatments should “have a good safety data in pregnancy and for breastfeeding and have a favorable side effect profile with no significant long-term cancer risks.”

Claytor had no disclosures. Guidon disclosed consulting/medical advisory board (Alexion Pharmaceuticals, argenx, Regeneron, and UCB), publishing royalties (Oakstone), and other research support (Myasthenia Gravis Foundation of America, Myasthenia Gravis Rare Disease Network, National Institutes of Health, and National Institute of Neurological Disorders and Stroke/BioSensics).