What DMT would you recommend for primary progressive MS?

Unfortunately there are no DMTs that have been shown to work in PPMS. The reasons for this are complex and related to many factors; (1) firstly our poor understanding of the mechanisms underlying non-relapsing progressive MS; (2) the assumption that PPMS is not that inflammatory (in my opinion an incorrect assumption); (3) poor application of diagnostic criteria for PPMS* and (4) poor trial design (the EDSS is simply not up to the task of measuring disease progression over a short period of time).

he good news is that there are two well-designed PPMS trials recruiting patients at present: the first and most advanced is the Fingolimod (Novartis) study and the Ocrelizumab (anti-CD20, Roche) is about to start. The latter study is based on the observations from a subgroup analysis of the Rituximab PPMS trial that showed younger patients (<51 years) and those with active MRI scans (Gd-enhancing lesions) responded to treatment; i.e. had a slower rate of disease progression. Please see Hawker et al. Ann Neurol. 2009 Oct;66(4):460-71.

* The original McDonald diagnostic criteria required patients to have an abnormal spinal fluid analysis. However the revisions of these criteria have not made this an absolute requirement, which has altered the natural history of PPMS. Patients with normal CSF analysis do better than those with a negative CSF. 

12 thoughts on “What DMT would you recommend for primary progressive MS?”

  1. Is PPMS all that different from SPMS?I know of a family where the father had PPMS and his son has RRMS. Might suggest that they are the same disease – perhaps it's how your body responds that makes them different?

  2. There's a couple of initiatives which I thought would lead to a better understanding of the mechanisms behind PPMS (and other types of MS)- Lesion Project and the Tissue Bank. However, we still don't seem to have made any big steps in understanding the mechanisms. It's good news that trials are underway – perhaps positive results from these trials will improve the knowledge / understanding of the mechanisms.Out of interest what happened to the 4 types of lesions identified by the lesion project? This was big news several years ago, but seems to have gone cold – I'm assuming the results couldn't be replicated.

  3. I agree that relapse-onset and PPMS are the same disease. I put forward the leprosy hypothesis several years ago to explain the clinical spectrum. It depends on the type of immune response to the underlying cause; a brisk inflammatory response results in relapsing disease or tuberculoid MS and a poorer response results in more indolent disease (PPMS) called lepromatous MS.

  4. The 5 and then 4 lesion pathology classification remains controversial. Outside the tripartite pathology labs of Lassman, Luchinetti & Bruck it is hard to find card-carrying MS pathologists who support the classification system. As a non-pathologist I don't feel qualified to comment.

  5. It's a pity MS couldn't just be an inflammatory disease. It the neuro-degenerative (progressive) aspect that makes it so grim. Do MS researchers ever work with other researchers e.g. MND researchers? There seems to be a range of disease that fall to neurology where (i) the cause and mechanisms aren't understood and (ii) there are no effective treatments for stopping progression / neuro-degeneration. Improvements in technology e.g. better MRIs etc don't seem to make a scratch on our understanding of these diseases! Frustrating for researchers and patients.

  6. Re the neurodegenerative aspects of MS: I believe, as do many others, that the neurodegenerative component of MS is driven by early inflammation. In other words inflammation early in the disease primes the nervous system for future degeneration by damaging and making axons and nerves vulnerable to dying-off later on. If this correct the strategy of aggressive early treatment to suppress all inflammation should prevent the development of progressive MS. This hypothesis is being tested with the Campath-1h or Alemtuzumab trials. Unfortunately, it will take many years, even decades, to answer this question. We will need to wait 10-15 years after Alemtuzumab therapy to see if patients remain well or, hopefully not,come back with secondary progressive MS. COI: I am the principle investigator for the Alemtuzumab trials at Barts and The London and I have consulted for both Genzyme and Sanofi-Aventis.

  7. Prof G,I know three patients who have had Campath – 8, 6 and 5 years since their first infusion (of 2). None have had relapses and all are stable (improvements first year after the infusion). All are thankful for the team in Cambridge for giving them a second chance. Having a drug which stops relapses is a major advance and one that provides stability (no further deterioration) is icing on the cake. Fingers crossed that they continue to see these benefits into the future. They are not deficit free – some deficits from earlier relapses didn't completely resolve themselves, but all are working. Time will tell if there are long term benefits e.g. avoiding the progressive phase. All three would do it again. Do the anti-CD 20 agents look as promising?

  8. Re long-term disease-activity free status post Campat-1h. Is time to starting talking about a cure? I would suggest defining a cure as 20 years disease-activity free (no relapses, disability progression or MRI activity) 20 yrs after the last dose.

  9. Re anti-CD20. The ocrelizumab phase 2 results look very promising; unfortunately it is too soon to draw comparisons. Anti-CD20 appears to have a better safety profile, although one patient died in the ocrelizumab arm from a systemic inflammatory response that may be related to the treatment. Watch this space!

  10. interesting discussion about a cure. As a Campath recipient I'd be happy with long term remission e.g. no disease activity for 5-10 years. More than happy to get further infusions in the future if this keeps the disease under control. a cure to me suggests repair of all damage caused by MS. Perhaps in the next 10-15 years, if Campath is still keeping the disease inactive, some genius will develop drugs to stimulate repair e.g. repair the damaged axons / neurons. campath has been good for me (like the patients above), but i feel a little exposed as last treatment was 5 years ago and haven't taken any drugs. maybe i'll be offered a neuro-protective agent in the future. I had some hope for minocycline but research on this drug for ms seems to have gone cold.best wishes

  11. We need to keep the concept of cure (abolition of all future MS disease activity) and restoration of lost function from previous damage separate! The expectation must not be that a cure will return lost function. Function may improve after a "cure" due to repair from damaged pathways, but the treatments for promoting repair will almost certainly target different mechanisms to those of a cure.

  12. I saw a presentation a couple of years ago about an anti-lingo anti-body which suggested that it might promote some repair. Any idea if this came to anyrthing?

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