The course of multiple sclerosis is traditionally divided into relapsing-remitting, secondary chronic progressive, and primary chronic progressive multiple sclerosis. Secondary chronic progressive refers to a disease course that initially started with relapses, but after a few years is characterized by a progression of disability independent of relapses. On the other hand, primary chronic progressive multiple sclerosis (PPMS) describes a progressive course from the start without relapses.
If we apply the scientific criteria of PPMS, this particular course of multiple sclerosis is found in at most 10% of MS patients. In many patients who currently present with a progressive course, a careful history will reveal that relapses have occurred in the past (at the onset of the disease). The patient group with “true” primary progressive multiple sclerosis (PPMS) also differs in other features: the disease usually begins later in life between the 5th and 6th decade, unlike relapsing-remitting MS the ratio of men and women with PPMS is equal, and the most frequently encountered clinical presentation type, accounting for 83%, is spastic paraparesis.
One could now speculate that PPMS is a different disease that needs to be differentiated from “real” MS. Interestingly, however, there are no genetic differences between patients with relapsing-remitting MS and PPMS, yes there are even families with identical twins where one twin has primary progressive and the other twin has relapsing-remitting MS. The morphology of MRI lesions and the histological analysis of lesions from patients with relapsing-remitting MS and PPMS also do not differ. Therefore, I think that primary chronic progressive multiple sclerosis (PPMS) is not a different disease, but represents a part of the disease spectrum of multiple sclerosis.
Why do I focus on PPMS so extensively? This is because the active ingredient Ocrelizumab (Ocrevus) was the first (anti-inflammatory) active ingredient to show modulation of the course of PPMS. Since the results were therefore only generated in the special group of primary chronic progressive patients (not secondary progressive), the approval of the drug (for now) only applies to this relatively selected group of patients with a chronically progressive course. (For completeness: Ocrelizumab is also approved for the highly active relapsing form of MS).
If you look at the study data more closely, you can also clearly see that in the study, a group of PPMS patients in particular benefited from Ocrelizumab – namely patients who had not been ill for long, had a relatively low degree of disability and preferably also showed signs of activity in the MRI controls. Accordingly, the European approval authority also formulated the approval of Ocrelizumab for PPMS (which is decisive for the reimbursement of the medication): Treatment is indicated in adult patients with early chronic multiple sclerosis, characterized by the duration of the disease and the degree of disability as well as imaging features typical of inflammatory activity. Translated this means: If Ocrelizumab is used, it should be done early in the course of PPMS, in patients where the degree of disability is still low, i.e., walking ability is preserved, and preferably also active foci are visible on MRI.
This approval is therefore quite limited and covers only a part of the patients with a chronically progressive MS. In my opinion, this does not do justice to patients who might benefit from the new active ingredient.
For this reason, I also advocate moving away from the “old” classification scheme. If we assume that primary chronic progressive multiple sclerosis is part of the spectrum of MS disease and we see in most studies that patients with disease activity in particular benefit from anti-inflammatory therapies, it would probably be much more sensible not to differentiate between relapsing-remitting, secondary progressive, and primary progressive MS in the future, but to speak of active and non-active MS – regardless of disease course and duration. Such a proposal was already made in 2013 by an international working group led by Fred Lublin (Lublin et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014 Jul 15;83(3):278-86) and would give us much more therapeutic freedom with MS than the old subclass designation, which is confusing and hard to understand for many MS patients (and doctors).
