With the expansion of the multiple sclerosis (MS) drug armamentarium, it is becoming exceedingly difficult to make informed decisions regarding their comparative efficacy. Experts debate whether first line MS therapy should consist of low- versus high-efficacy drugs and at what age, if any, it is appropriate to withdraw immunomodulatory disease-modifying therapies (DMTs).

This debate is confounded by the widely accepted classification of MS patients into relapsing-remitting (RRMS), secondary-progressive (SPMS), and primary-progressive MS (PPMS) subtypes. While these phenotypical categories prove useful in clinical trial designs and conceptual thinking about MS, they de facto dichotomize the continuous process of MS evolution. Indeed, a patient with MS does not go to sleep one day with RRMS and wake up next day with SPMS. Instead, there is a period, often lasting several patient-years, in which a clinician encounters considerable uncertainty in differentiating RRMS from SPMS. An analogous uncertainty is frequently encountered in differentiating SPMS from PPMS based on ambiguity in recollecting event(s) in a patient’s history which may or may not represent MS relapses.

More importantly, the justification for categorizing MS patients in drug development and clinical care was mechanistically rooted in the long-held belief that the amount of intrathecal inflammation is vastly greater in RRMS than in progressive MS [especially PPMS (1)] patients. This explained the lack of efficacy of immunomodulatory DMTs in progressive MS and justified the exclusion of patients with progressive MS from RRMS trials, irrespective of whether they fulfilled the remaining inclusion criteria. However, this belief was recently disproven by objective data: on one hand, patients with all three MS subtypes were shown to have identical levels of central nervous system (CNS) T- and B-cell-mediated inflammation (2), and, on the other hand, immunomodulation by the B-cell depleting therapy ocrelizumab inhibited disability progression in PPMS (3).

Instead, the alternative hypothesis for the relative lack of efficacy of immunomodulatory drugs in progressive MS resides in two mutually non-exclusive, continuous processes: compartmentalized, terminally differentiated intrathecal inflammation (2), and/or neurodegeneration (4). Compartmentalization of inflammation can be defined as the establishment of a permissive environment for long-term survival and in situ activation of the non-resident immune cells, mediated by the formation of tertiary lymphoid follicles in the CNS tissue (5–7). Compartmentalization is a continuous process that starts at MS onset and evolves over time, which means that it is predominantly (but not exclusively) seen in older subjects with progressive MS (2, 5–7). Compartmentalized inflammation is inaccessible to orally or intravenously administered MS drugs with poor CNS penetrance (8, 9). Additionally, chronic inflammation induces a parallel process called terminal differentiation of immune cells. This causes antigen-specific lymphocytes derived from the cerebrospinal fluid of patients with longstanding MS to proliferate less when compared with T cells derived from MS patients with short disease duration (10). Differentiation is again a continuous process through which naïve cells, which secrete only interleukin-2, but proliferate rapidly, evolve through repeated cycles of antigen-driven activation to cells that produce many different cytokines, but have limited proliferative capacity (10). This may explain the relative lack of efficacy of small-molecule cytostatic agents that target cells in the proliferation cycle in patients with progressive MS.

Alternatively, the immunomodulatory DMTs have relatively low-efficacy in progressive MS because inflammation, although present, may not be the most important driver of disability progression. Indeed, neurodegenerative mechanisms such as mitochondrial dysfunction (11), oxidative damage (12), hypoxia (13–15), endoplasmic-reticulum stress (16), and astroglial toxicity (17) have been identified predominantly (but not exclusively) in progressive MS. Even as it remains unknown which of these (if any) contribute to disability progression, it is rational to assume that these too are continuous, rather than dichotomized processes.

Thus, together with homogeneity of MS susceptibility alleles among phenotypical MS subgroups (18) and epidemiological data that demonstrate that MS patients from all three phenotypical categories achieve major disability milestones at a similar age (19), the aforementioned data support the unifying concept that PPMS and SPMS are biologically indistinguishable and represent the evolved/later stage of the MS disease process (2, 20).

If this concept is true, then the loss of therapeutic efficacy of immunomodulatory DMTs in MS should also be a continuous, rather than dichotomous process. Thus, one can hypothesize that the efficacy of immunomodulatory drugs will negatively correlate with MS duration. Because the exact onset of MS is unknown for most MS subjects, we can restate the hypothesis that efficacy of MS DMTs will negatively correlate with patient age.

Consequently, the primary goal of this project was to perform a meta-analysis of all blinded, randomized clinical trials of immunomodulatory DMTs that reported disability risk reductions to test the null hypothesis that drug efficacy is independent of age. If we can model efficacy of current DMTs as a continuum, we may better predict the benefit of immunomodulatory DMTs for individual patients. Thus, the secondary goal was to develop age-adjusted objective model(s) to compare the efficacy of MS drugs. The resulting optimized models can be used in future research studies (such as those that seek to identify prognostic biomarkers or biological processes that underlie MS severity) to adjust measured data for the efficacy of administered therapies.

This meta-analysis of randomized, blinded clinical trials of MS DMTs against placebo or active comparator demonstrated unequivocally that the efficacy of immunomodulatory DMTs decreases with age. Age predicts IDP by immunomodulatory DMTs more strongly than EDSS. In fact, in higher order models there were no significant three- or two-way interactions between EDSS and variables Age and/or Efficacy (indicator coded as 0 for low and 1 for high); instead, the optimized model consisted of interactions between only Age and Efficacy. The observation that Age and Efficacy jointly predict more than 67% of variance in disability progression highlights that age is a major modulator in the therapeutic efficacy of immunomodulatory drugs.

Before we discuss implications of our findings, we acknowledge the following limitations: (1) lack of trials with mean age <30 and >55 years; (2) all interferon-beta preparations were treated as equivalent to simplify the interferon beta versus placebo regression used for later imputation; (3) the assumption that drugs belonging to the same category (low- and high-efficacy) have comparable efficacies during the entire age-spectrum, which may or may not be correct; (4) trials that compared a new DMT to an active comparator generally disadvantaged the “older” drug. Because inclusion criteria required disease activity, these trials excluded patients who had done well on the comparator therapy (29); and (5) the comparative efficacy estimates for some drugs (e.g., mitoxantrone) are based on a single (and sometimes unusually small) trial and therefore may not be reliable.

These limitations are mostly based on lack of public access to raw datasets from clinical trials even after regulatory approval of tested drugs, and are thus beyond our control. Our study may add impetus to a debate as to whether regulatory agencies should demand publication of raw data from the trials that led to drug approval. Public access to such raw data would significantly strengthen meta-analyses and, in this particular study, would allow for better estimation of therapeutic efficacy for patients younger than 30 and older than 55 years. Whenever even partial age-based subgroup analyses from clinical trials of MS drugs were published (30–32), they were consistent with the results of this meta-analysis (i.e., younger patients always had higher efficacy than older patients, even though the difference may not have reached statistical significance because the trials were not powered for subgroup analyses). Other stated limitations are not linked to lack of raw data, but are still beyond our control. For example, while different mechanisms of action may make one drug (e.g., ocrelizumab) more efficacious in the later stages of MS than other drugs from the same category (e.g., natalizumab), a superiority hypothesis is currently untestable, because it requires prohibitively large cohorts. Thus, we also caution against over-interpretation of DMT efficacy rankings. While low- versus high-efficacy drug categories enhance the model, this meta-analysis does not provide sufficient power for superiority claims of one drug over another if they were not tested against each other directly in clinical trials. Nevertheless, the efficacy ranks given in Figure 4B are based entirely on clinical trial data adjusted for patient age, and thus, should be considered the most objective comparative efficacies currently available in the public domain.

Notwithstanding these limitations, our results inform the decision process when addressing common therapeutic dilemmas, such as the decision to initiate or delay high-potency treatments at an early age. Delaying any DMT, even for a few years, leads to a decrease in cumulative efficacy that cannot be easily regained by opting for more aggressive treatments at a later age. In the fourth decade of life, the efficacies of all DMTs overlap, and, after age 53, the model predicts no therapeutic benefit for the average patient. Interestingly, the upper age limit of 53 years extrapolated from meta-analysis regression models is close to the upper age limit of 55 years implemented in the inclusion criteria of the ocrelizumab (ORATORIO) PPMS trial (3), which was selected based on the age-based subgroup analyses of the rituximab (OLYMPUS) PPMS trial (33).

Thus, a prescribing clinician must consider the possibility that starting or continuing immunomodulatory DMT beyond age 53 will expose an average patient to treatment-associated risks with few, if any, potential benefits. The results of ASCEND trial (Table 1; Figure 3), in which more SPMS patients treated with natalizumab achieved sustained disability progression in comparison with placebo (although the difference did not reach statistical significance), should not be ignored. Rather, in view of this meta-analysis, it should serve as a reminder that aggressive immunomodulatory DMTs may be harmful in older MS patients, irrespective of cumulative side-effects. By limiting migration of immune cells to CNS tissue, drugs like natalizumab may block repair processes, including remyelination, facilitated by immune cells (34–36).

This meta-analysis does not suggest that all patients older than 53 should remain untreated. The model is based on mean outcomes within trial cohorts. Behind every mean lies a distribution (e.g., Gaussian), and where on that distribution a specific patient falls cannot be determined from group data as it likely depends on patient-specific genetic and environmental factors. Indeed, if a patient older than 53 has MS relapses and abundant contrast-enhancing lesions on CNS imaging, s/he is likely to receive higher than average benefit from immunomodulatory DMT. However, these types of patients are rare. If every patient older than 53 years is on immunomodulatory DMT, then this meta-analysis indicates that half of such patients are exposed to cumulative side-effects with little to no potential for therapeutic benefit. Similarly, we do not argue that every MS patient younger than 40.5 years should be started on high-efficacy therapy. Such a recommendation would ignore the fact that some patients have benign disease and may not accumulate substantial disability during a normal life-span. Unfortunately, the lack of validated models of MS severity that can identify patients with benign (or aggressive) MS with acceptable accuracy limits such personalized decisions. Without this central knowledge, the results of this meta-analysis suggest that patients younger than age 40.5, who choose to start low-efficacy DMTs, must be followed closely with clinical examinations and imaging and should be promptly switched to a high-efficacy DMT if/when they develop clinical or radiological evidence of disease activity.

A model of MS severity that can predict MS course with sufficient accuracy would spare patients with mild/benign MS the risks and side-effects of high-efficacy treatments. In fact, the attempt to develop an accurate model of MS severity (i.e., a model that can predict the future rates of accumulation of MS disability based on cross-sectional data) was the motivation for this study. We noticed that observational studies that investigate prognostic biomarkers, or aim to identify biological modifiers of MS severity, are seldom adjusted for the efficacy of administered treatments. Conversely, when treatments are used in complex statistical models as covariates, they do not seem to exert consistent effects. This is incompatible with clinical trial evidence that (some) DMTs exert reproducible efficacy on disability progression and prompted the hypothesis that efficacies of immunomodulatory DMTs are not stable, but instead, change with age. Therefore, observational studies that seek adjustments for efficacy of administered treatments must use a model that considers Efficacy and Age simultaneously.

Although we anticipate that the presented model will facilitate development of more accurate measures of MS severity than the currently available MS severity score (37), until such predictive models are validated, the astute clinician must merge information from group-based analyses with features gathered from a patient’s medical history, neurological examination, and auxiliary tests. We successfully used the graphs provided in this publication to inform discussions between clinicians and elderly MS patients regarding the appropriate timing of DMTs and to convince young patients to not wait until exhausting low-efficacy alternatives before initiating high-efficacy treatment. We expect that MS researchers, clinicians, and patients alike will find our results informative in this complex decision-making process.

BB was responsible for original study concept, model design, and study supervision. MT-M and AW were responsible for acquisition of data. AW, KJ, and MG were responsible for model design and statistical analyses. BB, AW, MT-M, and MG were responsible for drafting the text. All authors were responsible for revision and approval of the final manuscript.

BB declares the following COI: she is co-inventor on several patents related to daclizumab therapy for MS and, as such, has received patent royalty payments from the NIH. The remaining authors have no competing interests to declare.