Induction versus escalation – the debate continues


Initiating moderate efficacy, low-risk therapy is inferior to high-efficacy, high-risk treatment in patients with multiple sclerosis (MS), according to a study published Aug. 16, 2021, in JAMA Neurology. The study’s findings help to resolve a longstanding controversy in the MS community – the question of whether to initiate treatment using an aggressive yet highly effective treatment or take the more conservative approach by beginning with a low-risk, moderately effective therapy.

To address this ongoing debate, researchers examined the effects of escalating therapy versus initiating high-efficacy treatment in two populations. The cohort study used data on 4,861 patients from the Danish and Swedish national MS registries from the date of index DMT initiation (between Jan. 1, 2013, and Dec. 31, 2016) until the last recorded visit at time of data extraction (Oct. 2, 2019). The sample population included 2,700 patients from the Swedish MS Registry and 2,161 patients from the Danish MS Registry. Nearly two-thirds of the patients in the Swedish registry were women (n = 1,867; 69.2%) who were an average age of 36.1 years, and the Danish registry shared a similar distribution with women (n = 1,472; 68.1%) and mean age of 37.3 years.

The study included patients whose ages at baseline with clinically isolated syndrome or relapsing remitting MS (RRMS) ranged from 18 to 55 years. Patients received their first DMT sometime between Jan. 1, 2013, and Dec. 31, 2016. Investigators excluded patients who had primary progressive MS or secondary progressive MS at baseline.

The primary outcome was the time to 24-week confirmed disability. Secondary outcomes include 24-week confirmed disability improvement and milestone Expanded Disability Status Scale (EDSS) of 3-4.

A total of 1,994 Danish patients (92.3%) initiated a low to moderately effective DMT (teriflunomide, 907 [42.0%]) and 165 (7.6%) initiated a highly effective DMT, whereas a total of 1,769 Swedish patients (65.5%) initiated a low to moderately effective DMT (teriflunomide, 64 [2.4%]) and 931 (34.5%) initiated a highly effective DMT. Other DMTs used first line included interferon beta-1a (643 [29.8%]) in the Danish treatment arm. Besides teriflunomide, additional therapies in the Swedish treatment arm included rituximab (484 [17.9%]), and natalizumab (299 [11.1%]), and fingolimod (148 [5.5%]).

The Swedish treatment arm experienced a 24% decrease in the rate of reaching EDSS score of 3 (hazard ratio, 0.76; 95% confidence interval, 0.60-0.97, P = .3) and a 25% decrease in the rate of reaching an EDSS score of 4 (HR, 0.76; 95% CI, 0.61-0.96; P = .01)

According to the researchers, their findings “suggest that there is an association between differences in treatment strategies for RRMS and disability outcomes at a national level.” They concluded that “starting with a more effective therapy and switching to a more effective DMT at treatment discontinuation irrespective of reason seemed to be superior to commencing a conventional first-line DMT and escalation.”

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In light of this recently published study, Daniel Ontaneda, MD, PhD, associate professor of neurology at Case Western Reserve University, Cleveland, and Mark Gudesblatt, MD, the medical director of the comprehensive MS care center at South Shore Neurologic Associates in Patchogue, N.Y., were asked about the ongoing induction versus escalation debate and various components of this enduring controversy.

Dr. Mark Gudesblatt

Dr. Daniel Ontaneda

How did the controversy begin? Why has it continued?

Dr. Gudesblatt: The controversy is very simple because most people only detect change when it smacks them in the face, so you have the approach of: “Start low, go slow, be safe.” If you notice change, then get something better. The problem is change is difficult to accurately evaluate. Change is based on the quality of your exam and documentation. The MRI depends on the quality of the image as well as the reader. If you go from 4 plaques to 8 plaques, you can see the difference, but it’s harder to tell if you go from 27 plaques to 28.

The more damage you accumulate, you reach a threshold where the receptors cannot adapt anymore. Lastly, then there’s the late consequence. Let’s say you have a stroke, your arm is flaccid, and then you develop spasticity 2 years later because of the disease.

What is the right treatment for the right person at the right time when do you change? When do you pull the trigger? Is one plaque too much? Are three plaques too much? How much visual damage? And remember the visual diagnostics we use are not very good – they’re archaic. It’s what we have, and nobody likes it; but everyone falls back on it and the regulatory agencies love it because we don’t have anything better.

Dr. Ontaneda: The platform therapies (Interferon beta-a and -b and glatiramer acetate) have a long history of safety and modest efficacy. As the newer, higher-risk, highly effective therapies became safer by design and risk mitigation strategies, the MS field started asking whether using higher-efficacy medications as first-line therapies would provide greater benefit.

What are the most bothersome risks to the patient in initiating the high-efficacy/
high-risk therapy?

Dr. Ontaneda: Patients mainly are concerned about long-term risks, the most evident is infections but also malignancy.

Are these the same concerns that prescribers have?

Dr. Gudesblatt: No harm is important, but also doing the right thing is important, so you start to walk the line between safety and efficacy. The drug can be dangerous (i.e., infection, PML, etc.), but the disease can be dangerous, too. The dangers of the disease transcend physical disability. They include cognitive ability, which impacts independence, driving, socializing, and so forth. So, when we ask how good doctors are in detecting change in cognition, it’s as good as a coin toss – and that’s bad. So, the question becomes what is the right approach for the right drug for the right time for the right reason?

Has any data provided more compelling evidence that one treatment approach is better than another?

Dr. Ontaneda: There is some observational data comparing the two approaches, notably the study in JAMA Neurology summarized above. That study compared DMT use in two European countries, one in which there was more use of highly effective therapy. This showed that highly effective therapy was associated with better outcomes.

Why would some prescribers prefer to initiate highly effective DMT when a patient relapses on a moderately effective DMT?

Dr. Ontaneda: The idea behind escalation is to use higher-efficacy therapies only when a low- or moderate-effective therapy has not worked. The idea is to minimize risk up front, but we may be missing a critical window of opportunity for treatment.

Dr. Gudesblatt: Ideally, I prefer a simple oral medication. However, because poor adherence results in poorer outcomes, I prefer an infusion because patients benefit from forced adherence.

Is there anything else about this topic you'd like to share that you haven't already covered?

Dr. Ontaneda: We need randomized controlled trials to answer this question, as observational studies have multiple potential biases. Two randomized controlled trials —DELIVER-MS and TREAT-MS—are looking to answer this critical unmet need.