Pathophysiological rationale

To start with we can mention arguments from our growing knowledge of physiopathology. In the early relapsing-remitting (RRMS) stage of the disease, the peripheral adaptive immune system in particular plays a role by activating autoreactive B and T cells that penetrate through a damaged blood-brain barrier in the central nervous system (CNS) where they cause a focal inflammation resulting clinically in a surge. This mechanism activates non-adaptive inflammatory responses in the CNS mediated mainly by microglial cells and activated astrocytes. On the other hand, the initial focal inflammation causes, through axonal transaction and demyelisation, an exhaustion of the functional reserve in the CNS, thus triggering secondary degenerative processes like mitochondrial damage, excitotoxicity and oxidative stress. So treatment has as its pathophysiological rationale three arguments. Firstly, our present array of treatments is directed mainly towards the adaptive arm of the immune system, often with limited penetration through the blood-brain barrier, so by definition it will have an effect particularly in the early phase of the disease. Secondly, it is assumed that early treatment will hopefully help to prevent activation of the non-adaptive CNS inflammation. Thirdly, the early, efficient treatment can help to avoid loss of functional reserve that brings about more degenerative mechanisms. Theoretically, therefore, there appears to be a window of opportunity where we are able to intervene early in the disease so as to help avoid irreversible damage and neurodegenerative aspects of the disease.

Epidemiological rationale

Our knowledge of the disease mechanism of MS is obviously incomplete and the disease hypothesis set out above has been questioned (with different arguments). So can we substantiate the above disease theory by observations concerning the clinical course of the disease among patients? In this regard reference is often made to the important paper of Edan and colleagues in 2010. The paper showed that in a cohort of MS patients the disease did indeed progress in two different phases. In phase 1 (EDSS from 0 to 3) the duration was found to be variable, while in phase 2 (EDSS 3 to 6) the evolution occurred at a similar speed independent of how quickly or slowly phase 1 occurred. Moreover, it was noted that while for the group of patients with RRMS onset the duration of phase 1 was influenced by gender, age at the start of MS and the surge history, this was found not to be the case with the primary progressive patients in the cohort. These epidemiological data prove that MS does indeed behave as a disease with two phases, with the researchers speculating that the variability in the first phase correlates with variation in focal inflammatory activity and the second phase reflects the outlined more diffuse inflammatory and neurodegenerative aspects of the disease, which occur independent of the initial focal inflammatory phase. This definitely strengthens the idea of a window of opportunity within which we can make a difference at an early stage of the disease.

Rationale from treatment data

Now we know that both our knowledge of the disease biology and observations concerning the course of MS support the theory of early treatment, the litmus test is obviously a therapeutic intervention. A study by Mar Tintore (2015) showed that in a large Clinical Isolated Syndrome (CIS) cohort the likelihood of reaching EDSS 3 was not only clearly influenced by the inflammatory factors such as the number of lesions on the initial scan or the presence of oligoclonal bands, but in particular that starting early with a DMT (for the 2nd surge) significantly reduced the likelihood of reaching EDSS 3. In other words, early treatment appeared to help avoid progression to phase 2 of the disease. Long term data from studies in which the CIS stage was treated show that the total duration of treatment with interferons reduces the likelihood of transition to secondary progressive MS (SPMS). As these data refer mainly to treatment with classical, less potent first-line treatment type interferons, this gives us substantial hope that more recent and efficient treatment strategies will help to reduce further the likelihood of disability progression. Unfortunately, we do not yet have sufficiently long experience with these drugs to validate this matter. The addressing of cerebral atrophy (a marker of the more degenerative and progressive components of the disease) might offer a possibility to make an estimate. For example, treatments like ocrelizumab and alemtuzumab have demonstrated that they can better slow down cerebral atrophy than classical treatment with interferons. Data covering six years of monitoring in the alemtuzumab study even suggest a reduction of cerebral atrophy within the normal range over this longer period. Hopefully this will result in better prevention of progressive disease in the long term.

In conclusion

Data concerning fundamental pathology, the course of the disease and treatment interventions support the theory of early and efficient treatment as a way of helping to prevent increasing disability and progressive disease.

Note: the cited papers are obtainable on request info@fondation-charcot.org