Summary: This post makes the case for MS being one disease and that PPMS is no different to other types of MS.
This is a repeat post, but it needs saying over and over again. A lot of people simply accept that (1) PPMS in non-inflammatory, (2) that pwPPMS don’t have relapses and (3) PPMS is a different disease to relapse-onset MS.
Dogma 1: PPMS in non-inflammatory – WRONG!
Background: The dynamics of primary progressive multiple sclerosis differ from those of the more common secondary progressive form. The observation by MRI that the frequency of enhancement with gadolinium-DTPA, a marker for blood-brain barrier dysfunction, is significantly less in the primary progressive form, has led to the hypothesis that inflammation is less intense in this group.
Aims: To test this, we have studied postmortem material from 9 cases judged from a retrospective analysis of case notes to show clear clinical evidence of either primary progressive or secondary progressive disease.
Methods: 578 lesions were analysed.
Results: There was significantly more inflammation in secondary progressive multiple sclerosis (as judged by the frequency of perivascular cuffing and cellularity of the parenchyma) than in primary progressive disease.
Conclusions: These observations have implications for therapeutic strategies in progressive multiple sclerosis.
Dogma 2: pwPPMS don’t have relapses – WRONG!
In almost all PPMS trials done to date a proportion, albeit a small proportion, of pwPPMS go onto have relapses. For example in the Rituximab trial in PPMS (Olympus Trial), 11 out of 439 (2.5%) of study subjects had a relapse during the 96 weeks of the trial. In the Ocrelizumab (ORATORIO) study protocol-defined relapses were reported for 11% of subjects in the placebo group and 5% subjects in the ocrelizumab group.
Montalban et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017 Jan 19;376(3):209-220.
Did you know that it not uncommon in siblings pairs with MS for one to have relapse-onset disease and the other to have PPMS? The figure from the UK sibling study is in fact 23% (please see article and table below). This indicates to me that relapse onset and PPMS are the same disease.
(33.7+27) / (84+68.3+33.7+39.3+27+9.7) x 100 = 23%
Kremenchutzky et al. The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease. Brain. 2006 Mar;129(Pt 3):584-94.
It is for the reasons above that there is a strong argument for doing trials on combined populations of progressive MS. In other words, we should combine PPMS and SPMS populations into one study. I am aware that this is a controversial topic, particularly in the eyes of the regulators, but it needs serious and prolonged debate. If we don’t do this then treatments will continue to be licensed for one subtype of progressive MS, and not the other clinical subtype, until additional trials are done. This is not in the interests of pwMS. Additional trials cost money and time. Time is not a something people with progressive MS have on their side. 5-years in the life of someone with progressive MS may be the difference between using a walking-stick and becoming bed-bound.