Mark S. Freedman, MD, CSPQ, FANA, FAAN, FRCPC
University of Ottawa; Ottawa Hospital Research Institute

Key Takeaways

  • The transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS) can be easily missed. Data have shown that it takes, on average, 3 to 5 years for clinicians to realize that their patient has transitioned to SPMS for a number of reasons: they aren’t looking for the transition, they are misled by stable magnetic resonance imaging (MRI) scans and an absence of relapses, or they simply aren’t asking the right questions.
  • Most important in managing the transition to SPMS is to recognize when progression occurs, and the key is to ask the right questions about changes in your patient’s abilities and development of new symptoms.
  • Although counterintuitive, lack of relapse is an important feature of SPMS. RRMS is characterized by clinical relapses and new lesions on MRI; however, as a patient transitions to SPMS, the natural history is to have fewer relapses and fewer active MRI scans.
  • On the surface, the calm clinical appearance of SPMS looks like a good response to therapy, but it is a mistake to use this finding as a read-out that you’re winning the battle. Clinicians often misread the clues that a patient is transitioning and that drug therapy has stopped working.
  • Telltale signs of progression include age older than 45 years and a 20- to 25-year duration of disease. If the patient has already evolved to level 3 to 4 on the Expanded Disability Status Scale, they are probably experiencing SPMS.
  • Re-evaluation of drug therapy at the time of transition is important because drugs that are effective for RRMS will no longer be effective against progressive disease, and the patient will need to be switched to an agent proven to slow progression.

Mark S. Freedman, MD, CSPQ, FAAN, FRCPC, is professor of medicine, neurology, at the University of Ottawa, Ontario, Canada; director of the Multiple Sclerosis Research Unit, Neurology, at the Ottawa Hospital-General Campus; and senior scientist in the neuroscience program at the Ottawa Hospital Research Institute. He is a fellow of the American Neurological Association and the American Academy of Neurology.

Dr Freedman has more than 25 years of experience in the management of patients with MS and has been the principal investigator on numerous clinical trials of therapeutic agents for MS.

Is progression from RRMS to SPMS inevitable?

No, it’s not inevitable. There are patients who never experience progression. For most patients with RRMS, however, it does happen. It is a question of time and rapidity. Progression might happen earlier, rather than later, for some, but others will experience a course that is more rapid.

There are also patients who have a nonprogressive form of progressive disease. That sounds like an oxymoron, but those patients are labeled as having progressive disease because, at some point, they reach a level of disability or impairment that tells us they have become disabled in the absence of relapse. So, there has been progression up to this point but, when you follow them henceforth, they don’t continue to progress.

Are there any biomarkers for identifying who is likely to progress?

The usual biomarker for MS — the one that has stood the test of time for the past 25 years — is MRI, but it gives no indication of progression. In fact, there is no imaging characteristic that uniquely defines progression. Research has suggested that “slowly evolving lesions” or an increased number of cortical lesions can be indicative of progression, but these findings are based on research-grade sequential MRI scans, which are not part of everyday practice.
The only way to identify progression is when it’s happening or after it’s happened but, at that point, interceding with medicine is like closing the barn door once the horse is gone, because medications are less effective then. If we had a biomarker that could help us identify those patients likely to experience progression earlier, we could intercede earlier with more effective medicines to prevent the progression from occurring.
One biomarker that we have been exploring, among others, is glial fibrillary acidic protein. This protein is produced by astrocytes, which are involved in scarring. We have learned that progression in the nervous system is probably associated with scarring.1
We also have been looking at neurofilament light-chain protein, which can be measured in serum,2,3 as it correlates better with inflammation and has been used to identify earlier forms of MS. We think there is a relationship between a decrease in the level of neurofilament light-chain protein — or less change — and an increase in the level of glial fibrillary acidic protein. This might be a sign of SPMS, but that is yet to be proved.

Does observation of the central vein sign help predict SPMS?

The central vein sign has nothing to do with disease progression; it is more of a diagnostic entity. A lot of people are given a misdiagnosis of MS when evaluated by MRI alone; I see this all the time. A patient has symptoms that might be construed as MS; they undergo MRI and without further investigation or consultation with an MS specialist are mislabeled as having MS. In those cases, symptoms of their true problem will continue. The patient is deemed to be a nonresponder to treatment for MS and keeps shopping for other medications, only to find out they’re being treated for the wrong disease.
An MRI scan that shows a lot of white spots can suggest many conditions other than MS, because MRI is not at all specific for MS. Clinicians who believe they can make an MS diagnosis based solely on MRI findings are making a big mistake. One of the big confounders on MRI is vascular lesions, which often comes up in the differential. If we see white-matter lesions, a radiologist will suggest considering both microvascular and demyelinating disease, but how do you tell the difference without obtaining a tissue specimen? The pathology of MS is a central vein sign surrounded by an area of inflammation, so the central vein sign helps differentiate MS lesions from non-MS diseases by using susceptibility-weighted imaging, which shows venous structures.

The goal in SPMS is no longer to reduce relapses but to stave off and slow disease progression, or so-called disability worsening. And although it’s the same goal as in relapsing disease, most of the drugs that work for RRMS have proved ineffective in slowing progression at the SPMS stage.

Are there reliable criteria or tests that point to SPMS?

No. For primary progressive MS, there are the published McDonald criteria4 but nobody on the McDonald criteria committee wanted to touch SPMS (I was part of that committee) because there aren’t good data that tell you when someone has transitioned to SPMS until they have already been progressive for 6 months to a year. If I see a patient today and my examination suggests that they’ve gotten worse than at my previous examination, and they haven’t had a relapse in between, that tells me that maybe they’re into the progressive phase. I’ll have the patient come back in 6 months and, if they’ve worsened, then I’m confident that they have progressive disease, but now it has taken 6 months to a year to make that diagnosis.

Do you have any way to know when to anticipate progression to MS?

Now that there is a treatment for SPMS, payers want to be able to pay for a drug that will work for these patients. There’s a lot of incentive to try and define SPMS, but we still don’t have solid criteria or a proven biomarker to know when it is happening.
The MSProDiscussTM is a validated tool to help clinicians determine if a patient is transitioning to SPMS. The clinician inputs information specific to the patient’s status, and the tool provides a series of questions the clinician should be asking the patient to ascertain whether they are moving into the progressive stage of disease.
One of the first questions MSProDiscussTM asks is for the Expanded Disability Status Scale (EDSS) score, which remains the standard disability tool in clinical practice. Usually, once a patient reaches level 3 to 4 on the EDSS, progressive disease should be suspected. Other MSProDiscussTM questions are about general mobility. How does the disease affect this patient’s ability to keep up with activities of daily living and work-related activities? Do patients still have time for leisure activities? How well are they able to continue with their favorite hobbies? Do they find themselves slower, cognitively?
Time is against you in MS. Once a patient has had the disease for 20 to 25 years, there’s a good chance it will evolve into SPMS, in which they might be getting worse physically, slowing down mentally, and having more general symptoms, such as difficulty walking a long distance. These are subtle signs that, when factored in with the EDSS score, duration of disease, lack of relapse, and slow evolution of symptoms, allow you to say, with a fair degree of certainty, that the patient’s MS is transitioning into SPMS.
The MSProDiscussTM tool is not definitive. It provides the probability of transition to SPMS and suggests how far a patient might already be in making that transition. Also, it can identify when someone is definitely not there yet.

Symptoms of Progression From RRMS
Symptoms of Progression From RRMS
Signs of progression from RRMS include age older than 45 years, 20- to 25-year duration of disease, continued and worsening symptoms, and EDSS score of 3 to 4.

In your practice, how do you prepare patients for progression?

There’s a lot of emphasis placed on this effort. Clinicians might close their eyes to it and just stay the course with therapies that aren’t working because they figure that there’s no point telling the patient about a change in status when there are no good treatments for progressive disease. It would be much better, however, to switch a patient to a different drug that has at least a chance of working or to enroll them in one of the many clinical trials for SPMS. At our center, we have a number of trials looking at new drugs for SPMS. I’d rather put my patients into one of those studies and give them a chance than continue with something futile. 

Do SPMS therapies in clinical trials have different targets?

They do. Many trials underway are looking at different therapies, such as Bruton tyrosine kinase (BTK) inhibitors, 4 of which are under investigation. BTK is an enzyme that changes and activates certain proteins at a subcellular level and has been used for years as a target for the treatment of various hematologic malignancies. There is a lot of hope for the BTK inhibitors in SPMS because there is a thought that one of the driving forces in progression are microglia, and BTK inhibitors are recognized as being effective not only in reducing B cells but also in affecting proinflammatory microglia in the brain. Other studies at our site involve cell-based trials and high-dose lipoic acid. 

Do you reset treatment goals once you have determined that a patient has experienced progression?

Yes. The goal in SPMS is no longer to reduce relapses but to stave off and slow disease progression, or so-called disability worsening. And although it’s the same goal as in relapsing disease, most of the drugs that work for RRMS have proved ineffective in slowing progression at the SPMS stage.
There is no way of knowing if you are winning when you are treating progressive disease without a biomarker for therapy. When you do a clinical study, you give half the people the drug and, in follow-up, you learn that the people who didn’t get the drug got worse faster. The people who took active drug still got worse but did so more slowly and to a lesser extent than the patients receiving placebo. In real life experience, when there is no placebo comparator arm, you give a patient a drug and when they worsen, they think the drug isn’t working.
This makes it a hard sell to patients, so it would be nice to have a marker to measure against so you can tell if the medication is doing anything beneficial. You need some feedback for patients, and this would be a big step forward in therapy — whether it’s siponimod for SPMS or ocrelizumab for primary progressive MS. In both cases, we’re faced with the same dilemma: When patients get worse, how do we know they’re still benefiting from drug therapy?

The Q&A was edited for clarity and length.


Mark S. Freedman, MD, CSPQ, FANA, FAAN, FRCPC, reported affiliations with Actelion; Bayer AG; Biogen, Inc.; Celgene; Chugai Pharmaceutical Co., Ltd.; Clene Nanomedicine, Inc.; EMD Serono, Canada; Genzyme Canada, Inc.; Merck Serono; Novartis International AG; Roche Holding AG; Pendopharm, Inc.; Sanofi-Aventis; and Sanofi-Genzyme.


1. Kalatha T, Hatzifilippou E, Arnaoutoglou M, Balogiannis S, Koutsouraki E. Glial and neuroaxonal biomarkers in a multiple sclerosis (MS) cohort. Hell J Nucl Med. 2019;22(Suppl 2):113-121.
2. Varhaug KN, Torkildsen Ø, Myhr KM, Vedeler CA. Neurofilament light chain as a biomarker in multiple sclerosis. Front Neurol. 2019;10:338. doi:10.3389/fneur.2019.00338
3. Hyun J-W, Kim Y, Kim G, Kim S-H, Kim HJ. Longitudinal analysis of serum neurofilament light chain: a potential therapeutic monitoring biomarker for multiple sclerosis. Mult Scler. 2020;26(6):659-667. doi:10.1177/1352458519840757
4. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-173. doi:10.1016/S1474-4422(17)30470-2

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Reviewed March 2021