Neurologists and patients with multiple sclerosis are on the horns of a dilemma: How to best employ new disease-modifying drugs that are potent enough to induce life-changing remissions and too new to have amassed long-term safety data.

Before 2010, when fingolimod was approved, such a quandary was unthought-of. Patients with relapsing-remitting MS had two options: beta interferons and glatiramer acetate or natalizumab. Now, with the addition of alemtuzumab, ocrelizumab and other high-potency monoclonal antibodies, there are more options offering more hope – and posing more questions.
“I suppose to talk about what’s happening now, we have to talk about where we began with MS therapeutics,” said John R. Rinker, MD, a neurologist at the University of Alabama, Birmingham, Multiple Sclerosis Center. “Interferon beta and glatiramer were never regarded as much more than modestly effective. Patients, regardless of how mild or severe their disease, were faced with the same set of choices, and the same hope: that by reducing some disease activity we could delay disability and improve quality of life.”

This modest clinical goal continued unchallenged until natalizumab changed everything in 2004. AFFIRM, just one of the monoclonal antibody’s three pivotal trials, found a 67% decrease in relapse rate and a 50% reduction in persistent new disability compared to placebo. A later post hoc analysis determined that 37% of treated patients experienced both a complete absence of clinical disease activity and an absence of progression based on imaging activity.

“Suddenly we could see a real efficacy difference between the newer bioengineered agents and the older agents,” Dr. Rinker said in an interview. “And now, we are beginning to have to decide which patients should be treated more aggressively with these powerful new drugs. The discussion since then has centered on patient selection. Which patients can be treated with the older safer drugs, that are not as effective, and which patients should receive the newer, more potent therapeutics,” that confer their own set of known risks, and still lack long-term safety data.

Dr. John R. Rinker


Induction or escalation therapy?

The advent of these powerful drugs poses yet another MS treatment dilemma: when should the approach be induction or escalation therapy?

Escalation is a familiar concept, Emmanuelle LePage, MD, wrote last spring in the French journal, Revue Neurologique (Rev Neuro 2018; 174: 449-457). Treatment starts with the safest disease-modifying drugs (glatiramer, beta interferons, teriflunomide, and fingolimod) and progresses upward through the monoclonal antibodies, finally landing – if necessary – at autologous bone marrow transplants and high-dose cyclophosphamide.

“The advantage of an escalation scheme is to allow many patients to have satisfying control of the disease while receiving relatively safe drugs and never escalating to more aggressive therapy” unless that becomes necessary, wrote Dr. LePage, a neurologist at University Hospital Pontchaillou, Rennes, France. The trade-off is that this approach may not adequately control relapses that irreversibly accumulate disability.

Induction, on the other hand, begins with a short-term course of highly-effective treatment, hitting the disease hard and early with the goal of extinguishing disease activity and, hopefully, benefitting long-term outcomes. “The aim of this strategy is to prevent early structural damage related to inflammatory-mediated demyelination and axonal loss,” Dr. LePage wrote. “This induction treatment strategy may also be a useful and conservative way to use these highly effective therapies while minimizing exposure and the subsequent safety risks.”

Once a patient achieves remission during induction, treatment can de-escalate to a long-term maintenance therapy with some of the safer agents. This approach is conceptually similar to the induction therapy approach to rheumatoid arthritis, in which aggressive treatment can modify disease progression if given during an early window of opportunity before joint damage occurs.

But while the therapeutic theory may be similar, the clinical picture is not, Dr. Rinker said.

“With RA there is more of this window of opportunity where you can see how things are going, and even have a chance to play catch-up because there can be some natural healing of the joints. In the central nervous system, the capacity for repair is much less. Patients who experience vision loss after a relapse may never have normal visual acuity again in that eye. The cost of disease activity in early MS is much higher, much sooner than it is in RA.”

The comparatively brief exposure time to the induction agent is a central feature of this approach, Dr. LePage noted. “The key to the success of induction is to use (these drugs) for the minimum amount of time needed to gain adequate control over disease activity … Considering the potentially serious side effects of the therapeutic candidates for an induction, this strategy has generally been reserved for patients with very active or aggressive disease at onset. In these patients, it is recognized that the risk of early disability is high, and that once neurological function is lost it cannot be restored. In such patients, this disease-inherent risk of poor outcomes can be considered to outweigh the risk of potentially serious side effects of powerful drugs.”
The aim of this strategy is to prevent early structural damage related to inflammatory-mediated demyelination and axonal loss.

Which patients are the most appropriate candidates?

There are no formal guidelines designating which patients are most appropriate for induction therapy. But some papers have discussed common clinical characteristics that can help guide a decision.

In the Journal of Neurology last year, Gabriel Pardo, MD of the Oklahoma Medical Research Foundation, and David E. Jones, MD of the University of Virginia described some characteristics of patients suitable for induction treatment:
  • Younger than 40 years
  • Aggressive relapsing MS, with at least two severe relapses in the prior 12 months
  •  At least two gadolinium-enhancing lesions of brain imaging
  •  Increased risk of rapid disability accumulation (a high relapse rate in the first 2-5 years and a short first inter-attack interval).
  •  African descent

Credit: James King-Holmes/Science Source

Daily injections of beta-interferon help to halve the number of attacks in people in the early stages of MS. This treatment, although expensive, offers hope and relief to MS sufferers while scientists try to find a cure for MS.		 Dr. LePage agreed, for the most part, writing that candidates should have a diagnosis of pure relapsing MS; young age; highly active disease with at least 2 relapses in the prior 12 months; severe relapse resulting in an EDSS score of 4 or more; an EDSS score increase of at least 2 points in the previous 12 months, and at least two enhancing lesions.

Dr. Rinker doesn’t subscribe to any algorithm.

“There’s no single factor that will tip me one way or the other. In most cases it ends up being an individualized decision. I try to make a two-way discussion with patients. I listen to their story and I gauge what kind of effects MS has had on them so far. Is this someone with only intermittent rare symptoms followed by good recovery, without a lot of lesions or residual disability? Then I would probably be more inclined to value safety over efficacy” when planning the therapeutic approach. “But someone else of the same age, who has had one or two attacks and didn’t recover fully or who has residual symptoms affecting ambulation or use of a limb, or who has a heavy disease burden on imaging, I’m going to be much more concerned that this is an active inflammatory version of MS. In those cases, I may be more inclined to start with a more aggressive therapy or start with a first-generation therapy but have a low threshold to escalate to something more aggressive.”

Patient desires also play a big role in the decision, he said. “You have to consider the risk tolerance of each patient. Often, they have more fear of the adverse effects of a medicine than of the MS itself. I can’t really explain that, but sometimes I find myself making the argument that their illness may be scarier than the treatments. This can be a process, getting a patient from being skeptical about treatment to believing the treatment can help, and that it is worth the potential side effects.”