Brown JWL, Coles A, Horakova D, Havrdova E, et al. Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis. JAMA. 2019;321:175-87.
Key Points:
a) Two disease processes occur at the same time in most persons with MS. One is acute inflammation. The other is tissue degeneration.
b) Degeneration is characterized by chronic, low-grade inflammation, with increasing loss of nerve cells and their processes (axons).
c) In relapsing forms of multiple sclerosis, both processes are present, but one is predominant, the acute inflammatory process.
d) Over time relapses and acute inflammation decrease. However, in up to 80% of individuals, this is followed by gradually progressive disability, a phase of MS called secondary progressive MS.
e) This progressive phase is felt to result from a continuing degeneration of tissue as described above.
f) Progression to secondary progressive MS is frequent, but not inevitable, so a major question in MS management has been, “what role does acute inflammation have in leading to the secondary progressive disease,” and “can secondary progressive MS be prevented by more aggressive treatment of acute inflammation?”
g) This led to two different treatment approaches. One approach was to consider the two disease processes only weakly, if at all, related. Since the course of MS is unpredictable and not invariably disabling, and since powerful immune modulating therapies can have significant toxicities, in the absence of clear predictors of severe disease one should start treatment of relapsing forms of multiple sclerosis with a safe, well-tolerated disease-modifying therapy that does not drastically effect immune function. If relapses are not well controlled, only then should more powerful, and potentially more toxic, immune modulating therapies be prescribed.
h) The other approach was to consider acute inflammation and subsequent degeneration strongly interrelated, with one greatly affecting the other. Thus, early aggressive treatment of acute inflammation with powerful and potentially toxic immune modulating therapies should decrease the risk of subsequently developing progressive disease.
i) Once acute disease is controlled, one can consider switching to a less powerful, less potentially toxic disease-modifying therapy.
j) The above paper is one of the first to show that early treatment of relapsing forms of multiple sclerosis with any disease-modifying therapy significantly reduces the risks of developing progressive MS.
k) The paper also suggests that starting treatment aggressively, with powerful immune modulating therapies, may result in an even greater, albeit modest, decrease in risk of developing progressive MS.
l) These observations support the concept that acute inflammation and tissue degeneration are interrelated, and that by more complete control of early relapsing disease, subsequent degenerative processes are reduced.
m) From my perspective, the “real world” decision regarding starting a powerful, potentially toxic immune modulating therapy in allpatients initially diagnosed with relapsing forms of multiple sclerosis, is not fully settled. Given the great variability of disease severity, choosing a treatment requires an assessment of each individual’s unique pattern of disease, as well as a full discussion of the risks and benefits of such treatment with that individual.
The observations noted above resulted from a large study, performed in 21 countries in 68 different MS treatment centers involving 1555 patients with relapsing forms of multiple sclerosis, followed for a minimum of 4 years, with some followed for more than a decade. The study was prospective, meaning the data were collected at onset with a particular question in mind. It was a “cohort study,” meaning that different populations of patients undergoing different treatments were compared. Characteristics of comparison groups (age, sex, disease duration) were as closely matched as possible. Because of the relative newness of some of the disease-modifying therapy, relatively small numbers of patients were available for some disease-modifying therapies.
Patients were divided based on treatments received for their disease. Treatments provided were interferon-beta, glatiramer acetate, fingolimod, natalizumab, and alemtuzumab. Treatment with either interferon-beta or glatiramer acetate greatly reduced the risk of converting to secondary progressive MS compared to persons not treated for their MS (12% conversion versus 27%). Risk of conversion was even further reduced if these drugs were initiated within the first five years of disease onset. These data alone support the hypothesis that reducing acute inflammation early in the disease mitigates subsequent tissue degeneration. Treatment with fingolimod, natalizumab, and alemtuzumab also reduced the 5-year risks of developing progressive disease compared to untreated patients (7% versus 32% for fingolimod; 19% versus 38% for natalizumab; 10% versus 25% for alemtuzumab). When treatment groups were compared to one another, treatment with the more powerful immune modulating therapies, fingolimod, natalizumab, and alemtuzumab resulted in a reduced risk of developing progressive disease compared to patients treated with interferon-beta or glatiramer acetate (7% versus 12% comparing the combined groups treated either with fingolimod, natalizumab, or alemtuzumab to the combined groups treated with either interferon-beta or glatiramer acetate). Statistical significance was borderline with a p-value of 0.046 (slightly less than a one in twenty probability that the results were due to chance). If patients were switched to either fingolimod, natalizumab, or alemtuzumab within 5 years of initial treatment with interferon-beta or glatiramer acetate, risks of developing progressive disease also were reduced, compared to persons not switched (8% versus 14%). With longer follow-up in all treated groups (up to 14 years in some groups) numbers of patients converting to secondary progressive MS increased, but differences between treated and untreated patients persisted, and even increased further. At 9 years follow-up, 16% in the fingolimod, natalizumab, alemtuzumab group converted to progressive disease versus 27% in the interferon-beta, glatiramer acetate group (p=0.01, meaning a 1 in 100 probability of results being due to chance).
Decades of follow-up in some studies of MS patients show that up to 20% do not develop substantive disability. Exposing such individuals to potentially toxic and lethal drugs would not be warranted. In addition, there is a difference between “statistically significant” and “clinically significant.” Certainly the data provided in this paper support the concept that early treatment of patients with active, relapsing, disease is of great benefit. While there are no absolute ways of identifying individuals at risk for more severe disability, some characteristics are of value (frequent relapses at onset with poor recovery; many destructive lesions on central nervous system MRIs [i.e. “black holes”], more involvement of the spinal cord; African-American background). If such risk factors were present, treatment with potent immune modulating therapies would be justified.
Paper Abstract:
Importance: Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition.
Objective: To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition.
Design, Setting, and Participants: Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years’ follow-up.
Exposures: The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017).
Main Outcome and Measure: Conversion to objectively defined secondary progressive MS.
Results: Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P = .046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P = .03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P < .001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1).
Conclusions and Relevance: Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies’ risks, may help inform decisions about DMT selection.