SPECIAL REPORT
Numerous head-to-head trials in multiple sclerosis have demonstrated the benefits of treatment with a higher-efficacy versus modest-efficacy disease-modifying therapy (DMT). Examples include the TRANSFORMS (fingolimod vs. interferon-b), CARE-MS (alemtuzumab vs. interferon-b), OPERA I/II (ocrelizumab vs. interferon-b), and ASCLEPIOS I/II (ofatumumab vs. teriflunomide) trials in relapsing MS.
Higher-efficacy DMTs also produce benefits in previously untreated patients, demonstrating their important role as first-line agents. For example, in the subgroup analysis of newly-diagnosed/treatment-naïve patients in the ASCLEPIOS I/II trials, the proportion of patients with 6-month confirmed disability progression (CDP) was 46% lower with ofatumumab vs. teriflunomide (5.4% vs. 10.0%) (Gartner et al. Mult Scler 2022;28:1562-1575). Moreover, ofatumumab was associated with a lower risk of progression independent of relapse activity (PIRA; 3.6% vs. 7.7%), suggesting that higher-efficacy agents may act on both the neuroinflammatory and neurodegenerative components of MS. PIRA remained lower in patients in the ofatumumab initiation vs. switch group at six years (11.1% vs. 16.8%), according to data presented at the American Academy of Neurology annual meeting (Pardo et al. AAN 2024;S31.003). These findings indicate that early losses in neurological function cannot be recovered if effective therapy is delayed.
These studies support the notion that more profound disease suppression early in the clinical course may reduce disability progression over the longer term (Selmaj et al. J Neurol 2024;271:105-115). However, while initiating treatment with a higher-efficacy DMT is emerging as the standard of care, it does not appear to be standard practice.
An MSBase analysis (N=14,717) in 2015 reported that only 10% of patients had been exposed to a higher-efficacy DMT (Kalincik et al. Neurology 2021;96:e783-e797). In the German MS Registry for the period 2014-2019 (N=2658), the starting treatment was a lower-efficacy DMT in 69.3% of cases; in the U.K. MS Registry over that same period (N=1147), 68.3% of patients were started on a platform injectable or oral drug (Stahmann et al. Ther Adv Neurol Disord 2024;17:17562864241233044).
For patients started on a lower-efficacy treatment who clinically worsen, there is often a reluctance among clinicians to escalate therapy, which has been termed therapeutic inertia (Saposnik et al. BMC Neurol 2016;16:58). The prevalence of therapeutic inertia among Canadian neurologists has been reported to be 60%, resulting in less-than-optimal decision-making in about 20% of cases (Almusalam et al. JAMA Netw Open 2019;2:e197093).
While therapeutic inertia is a rather blunt tool to dissect behaviour, it does draw attention to how MS treatments may not be optimized. An international study reported that the three factors most associated with escalation were relapses, baseline EDSS score and MRI activity (Saposnik et al. Mult Scler Relat Disord 2022;58:103404). This is consistent with the criteria outlined in treatment optimization recommendations (Freedman et al. Can J Neurol Sci 2020;47:437-455), but fails to explain the suboptimal use of higher-efficacy DMTs even when clinically indicated.
Several other factors may play a role in the underusage of highly effective therapies. Neurologists who do not specialize in MS are less likely to escalate treatment even in cases of severe MS (Saposnik et al. Mult Scler Relat Disord 2022;57:103389). Inertia is even more pronounced if pregnancy is introduced into the decision-making process. This may indicate that some clinicians are uncertain about how to advise patients about the scheduling of treatments to accommodate pregnancy.
The COVID-19 pandemic raised awareness about potential safety concerns with high-efficacy DMTs which led to substantial reductions in their use. A Vienna MS database analysis compared DMT prescribing in the pre-pandemic (2017-2020) versus pandemic (2020-2021) period (Bsteh et al. Mult Scler Relat Disord 2022;63:103912). The annualized number of prescriptions fell about 17%. There were also substantial reductions in the use of anti-CD20 therapies (-49%), cladribine (-46%) and S1P receptor modulators (-38%).
Pandemic-era recommendations on DMT use may have also worried patients, prompting some to opt for a modest-efficacy treatment. Once patients start treatment with one drug, they are often reluctant to switch, which has been called patient inertia. A suggested cause of this inertia is status quo (SQ) bias, defined as the tendency to maintain a previous decision either by actively choosing the status quo or by doing nothing (Samuelson & Zeckhauser. J Risk Uncertainty 1988;1:7-59).
A study of 211 RRMS patients reported SQ bias in 74.4% (Saposnik et al. Mult Scler Relat Disord 2020:45:102354). SQ bias was associated with depression, prompting the authors to suggest that patients are less likely to change treatments if they have a negative view of their clinical status.
However, it is important to note that SQ bias presupposes that the patient is choosing a clearly inferior option. That may not be the case. The patient may perceive that the status quo is the better option because the long-term risks of MS or the benefit-risk profiles of various treatments have not been adequately explained. The care team may be uncertain post-pandemic about the long-term safety of higher-efficacy treatments, and patients’ decisions will be influenced by that uncertainty. It may be that improvements in medical education are needed to bridge the gap between clinical trial experience and clinical practice so that treatment outcomes can be more fully optimized.