Switching Therapies in Multiple Sclerosis

Fred Lublin, MD: Let’s move into our next segment, which is sequencing therapies. Wallace, I’m going to start with you with this question: How do you monitor response to treatment and disease worsening?

Wallace Brownlee, MBChB, PhD, FRACP: We routinely monitor both clinically and with MRI. The clinical measures that we’re most interested in are relapse rates and disability. There are different ways of measuring disability. The way that is most established is to measure the EDSS [Expanded Disability Status Scale] score, which is largely derived from the results of the neurological examination and walking the patient. Although increasingly, we’re integrating into our clinical practice other measures of disability, including the timed walk test for lower limb function, 9-hole peg test for upper limb function and dexterity, and measures of cognitive impairment like the SDMT [Symbol Digit Modalities Test], which is fairly easy to integrate into clinical practice.

In terms of MRI monitoring, at our center, [the National Hospital for Neurology and Neurosurgery], we undertake at least annual MRI follow-up. We focus on following the brain MRI. We tend to use less and less gadolinium in our center, mainly because we’ve sorted out MRI protocols, and patients are now all receiving a 3D flare scan, which facilitates new lesion detection very easily without the use of gadolinium. After arranging a re-baseline MRI, say 3 to 6 months after starting on a therapy, we’ll then do regular MRI scans to measure response in terms of looking for new T2 lesions.

Fred Lublin, MD: Sven, taking into consideration what we can measure, which Wallace has nicely outlined, how do you make a determination as to when we need to switch?

Sven Meuth, MD, PhD: This is always based on an individual decision. Following this concept of patient empowerment, we normally try to discuss all the decisions together with the patients, and we try to make a joint decision. My opinion is that the decision is largely focused on the efficacy of a drug. The treatment effect concerning the efficacy is normally driven by relapses because these are easy to count and are along the guidelines. I think it is supported by EDSS progression and maybe by new lesions; however, all of the additional measures are, in my opinion, very useful. Wallace mentioned the SDMT, which is important concerning cognition atrophy scores, and the MRI might be important.

However, the treatment decisions are still based mainly on relapse activity and new lesions, and there is also an interesting note. This was also reported in a paper that the patients are much more engaged earlier in treatment decisions, but if it is then not working, the physician is more and more taking over because he or she feels more informed compared to the patient. We start with a joint decision, but sooner or later, the physician takes over in a way.

Fred Lublin, MD: Patricia, how do we figure it out?

Patricia K. Coyle, MD: There are various reasons why you might switch therapy. Breakthrough disease activity in the AAN [American Academy of Neurology] 2018 guidelines said, a year on treatment, if there are 1 or more clinical attacks, worsening on the examination, or 2 or more MRI lesions, it should trigger a discussion about switching.

Adverse events, intolerable adverse events; with multiple options, a patient should not be forced to stay on a treatment that they’re miserable on and hate. A treatment that led to a laboratory disturbing abnormality in liver enzymes, or white blood cell count, or lymphopenia would be a fair reason. Neutralizing antibodies that were persistent in the case of natalizumab would indicate it should be switched, and a changed risk-benefit ratio that was now unacceptable to the patient and the physician would also be a reason to talk about switching. There are multiple reasons that one might switch.

Fred Lublin, MD: Wallace?

Wallace Brownlee, MBChB, PhD, FRACP: I agree with all of those comments. One area of uncertainty is what to do with patients who are progressing on a therapy. So in people who are taking a medication and they’re not experiencing relapses, and their MRI is stable, but their EDSS is worsening. We’re lacking evidence about how best to treat those patients, and that’s something that does need to be addressed going forward.

Fred Lublin, MD: You highlight an important issue, and that is the near absence of decent evidence on defining inadequate treatment response. Adverse effect profile is easy, but inadequate treatment approach is something we haven’t done yet, so it becomes, as Sven started out saying, a very individual thing. It is a conversation with you and the patient. It’s interesting what Sven points out, that patients become engrossed or embedded in their own therapy and become a little more resistant over time to switching than they would be earlier on. That’s an interesting observation, but we need data. Unfortunately, it looks like the data are going to be agent specific because what little data we have that came out of the Barcelona group suggested that the indicators of an inadequate response to interferon didn’t necessarily hold up to be inadequate responses for glatiramer acetate. It’s certainly an area that we need to explore and develop better guidelines for because our patients need it, and our economics need it, and we need to figure out how to do that.