Questions about disease modifying therapies for MS

Here is My Question:
How frequently are patients diagnosed with MS or suspected of having MS but not started on disease modifying therapy (DMT) and what are the criteria for starting DMTs in the absence of certain diagnosis? What makes a neurologist prescribe DMTs? What makes a neurologist not prescribe DMTs but suspect MS over several years?

Answer:
Here are my thoughts to your questions:
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1.  How frequently are patients diagnosed with MS or suspected of having MS but not started on DMTs and what are the criteria for starting DMTs in the absence of certain diagnosis?  Answer:  first off, patients should have a diagnosis of MS or CIS (clinically isolated syndrome) before discussing the appropriate use of DMTs (disease modifying therapies).  Part of the criteria of diagnosing MS is to rule out alternative explanations for the patient’s presentation.  If that has been reasonably done, the DMT discussion is appropriate.  My practice has been to offer a DMT for any patient with confirmed multiple sclerosis (per the 2010 McDonald Criteria) that has reasonable evidence that they are in the “inflammatory phase” of their MS (since this phase is where the DMTs exert their effect).  Evidence for the inflammatory phase includes hx of semi-recent relapse (of concern for this), and MRI evidence of contrast enhancing lesions or interval development of T2 hyper intensities (these are the white spots on the brain scan).  When confirmed MS is present, in my opinion, it is best to treat as we do not have a reparative therapy at present, only therapies that mitigate future inflammation.  Cases where I may hold off on DMTs but simply monitor carefully are the CIS cases where they have very little to no MRI lesions.  For instance, follow-up reports from the optic neuritis treatment trial demonstrated that the more brain lesion that are present on the initial scan, the higher the risk for development of MS.  Conversely, having very low lesion burden on the initial MRI suggests a ~25% chance of developing MS over the next 10 to 15 years.  Those patients, in my opinion, may be best served by monitoring them clinically and with MRI and starting DMT only if they prove to have evidence of persistent inflammatory activity.  The “uncertain diagnosis” that you refer to would include the CIS cases and patients who I strongly suspect they have MS and an exhaustive evaluation of mimicker diagnoses are negative.

2.  What makes a neurologist prescribe DMTs?  Answer:  I suspect you may get slightly different answers to this question, however, I err on the side of treatment for the reasons I detailed above.  It is noteworthy to point out that the very first approved DMT, betaseron, has published 21 year data on disability long-term.  We learned that those who start betaseron early (rather than waiting) had significantly less disability (in the case of this report, mortality) compared to those who had a delay in start of approximately 2 years.  Although I don’t have data for my next point, I do have my personal experience following MS patients since 2001 (at a time where we have a few therapies, and at that point, for only a few years).  I suspect that most, if not all, of our DMTs would show similar findings as that follow-up betaseron study.  The reason I believe so is my anecdotal experience of seeing a much higher proportion of patients in my clinic in wheelchairs back in 2001 compared to today.  When I see patients today in wheelchairs, they typically are the same patients whose MS started before approved therapies were available.  To underscore my point, it is important to remember that we do not have reparative therapeutics at this point in time.  We only have therapies that modify the disease course moving forward.  Hopefully that will change in the near future as we are seeing early development of remyelinating agents (but it should be pointed out that remyelinating agents would not be expected to be helpful for patients who have lost brain or spinal cord tissue—i.e., the axon or wire which the myelin protects is gone).  I have come across a few patients who follow the literature and have decided to forgo treatment now and play the odds that a reparative strategy will be available to them soon.  While I hope for that for them, I cannot recommend such a course.  Treating early is best.

3.  What makes a neurologist not prescribe DMTs but suspect MS over several years?  Answer:  this is an area of debate among MS specialists.  We know that the natural history of MS tends to regress to the mean in respect to relapses and new lesions on MRI over time (i.e., the immune system and MS tends to weaken or burn itself out over time).  As I mentioned earlier, our DMTs are effective during the inflammatory stage of the disease.  So, when do we know that the inflammatory phase is done and we wouldn’t expect any meaningful benefit from the DMT?  The answer is, no one really knows.  Unfortunately, we can’t circle a date on the calendar as the day not to worry about another attack or more lesions on the MRI.  There have been investigations on taking DMTs off and see what happens.  One of my mentors, Dr. John Corboy at the University of Colorado, will be heading up a multi center study that would determine what patient characteristics would indicate that they can safely come off their DMTs.  In the past, I have used a very high bar to come to the conclusion that it would likely be safe to come off DMT:  1) no clinical disease activity (i.e. relapses) and 2) no new lesions on MRI scan over a 10 year interval.  The reason I use this is I find it highly unlikely that a patient can achieve that level of disease control over a decade and it be a result of the DMT they are on.  All current DMTs are partially effective.

Hope this helps.

A. Scott Nielsen MD MMSc
Neurologist and MS Specialist at Kaiser Permanente