For too long, multiple sclerosis (MS) has been described with an air of quiet fatalism, a chronic, debilitating disease managed primarily by reducing relapses, but not fully addressed in terms of its continuous, underlying disability progression. This smoldering process often is not easily visible because of its progressive nature. Patients are told to manage expectations, while clinicians are taught to define success by the absence of magnetic resonance imaging (MRI) lesions and relapses.

That fatalistic view is not just outdated, it’s harmful. Nearly one-third of people living with MS (32.7 percent) report low levels of optimism, a mindset that can undermine adherence, participation, and engagement in care.

Taken together, these insights (psychological and biological) demand that we rethink how we view and treat MS. To truly alter the trajectory, we must move beyond focal inflammation and relapse control to directly protecting the nervous system and address the ongoing, steady neurodegeneration.

At a high level, to truly change outcomes, we should adopt a new clinical mindset. Four practical shifts can help clinicians and researchers better serve patients and accelerate progress.

1. Recognize that we’ve been treating only half the disease

MS progression stems from two overlapping processes:

• Relapse-associated worsening (RAW): The inflammatory attacks that cause new lesions and relapses.
• Progression independent of relapse activity (PIRA): A diffuse, smoldering neurodegenerative process invisible on routine scans.

A Brain (2022) meta-analysis by Fred Lublin et al. showed that roughly half of all disability accumulation in MS arises from PIRA, even in the earliest stages during the relapsing phase of the disease. Currently approved anti-inflammatory drugs target RAW effectively, but the study found that they leave PIRA largely unaddressed.

Even when MRI scans appear unchanged and relapses are absent, many patients continue to experience confirmed disability worsening (CDW) over time. Analyses show that sustained changes in everyday function, such as mobility, cognition, balance, and fine motor control, can accumulate gradually and are often driven by mechanisms independent of relapse activity. The difference may appear subtle annually, but over multiple years it can mean the transition to progressive MS, even in patients who appear “stable.”

To truly change the trajectory in MS treatment, we must look beyond inflammation control toward directly protecting the nervous system, including through new therapeutic mechanisms.

Continued education across the field is essential: Neurologists, clinicians, treatment centers, medical insurers, and patients alike must stay informed about emerging options and ensure they are accessible and applied in practice. That’s easier said than done, but awareness is the first step.

2. Redefine success: Measure what truly matters

Many patients who are told their MRI scan is “stable” still sense decline. A neurologist may congratulate a patient on having “no new lesions,” yet over the same period, that patient’s evening run may have shrunk from five miles to three. This disconnect between patient experience and clinical benchmarks is well recognized and increasingly measurable.

Clinical research confirms that much of this “silent” worsening happens beneath the threshold of relapse detection. In pooled analyses of the OPERA I and II clinical trials, investigators found that the majority of confirmed disability accumulation in relapsing MS occurred independently of relapse activity, driven instead by underlying neurodegeneration. Similarly, an Italian registry study of more than 16,000 MS patients found that 72.3 percent of sustained disability accumulation events were attributed to PIRA.

These findings underscore the need to redefine what “stability” means in MS. True stability should reflect preserved mobility, cognition, and quality of life, not merely the absence of new lesions on an MRI.

3. Embrace innovation: Pair anti-inflammatory and neuroprotective strategies

Currently approved MS therapies focus on immune modulation, which is an essential approach that targets focal inflammation and relapse activity. Yet growing evidence suggests this strategy addresses only part of the disease process. To influence long-term outcomes and address PIRA, treatment must also protect the brain itself.

Interestingly, nature provides an example of how immune adaptation can alter disease activity. During pregnancy, a natural period of immune adaptation and increased immune tolerance, women with MS experience a marked reduction in disease activity, especially in the second and third trimester, even after discontinuing treatment. Gene-expression studies, such as those by Montarolo et al., have shown that Nurr1 (NR4A2) (a nuclear receptor known to regulate inflammation and support neuronal survival) is upregulated during pregnancy. This finding suggests the existence of natural, neuroprotective pathways that the body can activate under specific physiological conditions. Pregnancy and its intrinsic biological pathways could offer additional rationale to inform about new treatments that support and potentially activate the nervous system’s own protective mechanisms.

Research is now driving new therapies designed to pharmacologically mimic or enhance these natural protective mechanisms. Activating pathways such as Nurr1 may help shield neurons, the cells responsible for transmitting signals, and glial cells, which support and protect those neurons, from chronic stress while dampening inflammatory signals, bridging the gap between immune modulation and genuine neuroprotection. For example, vidofludimus calcium, the first and only Nurr1 activator in development for MS at this point, has shown encouraging clinical phase 2 data both in relapsing-remitting MS as well as in progressive MS.

For clinicians, the takeaway is clear: MS treatment should no longer focus solely on suppressing inflammation and managing relapses. A dual approach targeting both the immune system and the brain’s intrinsic defense systems may offer the best path toward preserving function and slowing progression.

4. Communicate with compassion: Bridge data and experience

Progress in MS depends as much on empathy as on innovation. Terms like “non-active disease” can be misleading, suggesting stability even as disability quietly advances. Patients deserve honest context: Inflammation and neurodegeneration are distinct but interconnected, and we are finally learning to target both.

Still, communication gaps persist. In a survey of more than 4,500 people living with MS, only 63.7 percent said their treatment goals were regularly discussed with their health care provider. That disconnect matters. When patients don’t fully understand what their therapy is addressing, or what it isn’t, it can erode trust, adherence, and engagement in care.

Effective MS care requires more than data; it demands dialogue. When clinicians explain how new science aims to protect, not merely suppress, they replace resignation with informed optimism.

A future defined by science and hope

MS is not destiny; it’s biology, complex, adaptable, and increasingly within our reach to influence. Mechanisms like Nurr1 activation remind us that the nervous system contains its own blueprints for repair.

Patients deserve more than managed decline. They deserve to believe in improvement and to see it supported by data. As clinicians and researchers, our role is to redefine success, embrace innovation, communicate with compassion, and challenge the quiet fatalism that has shadowed this disease for too long.

Progress begins when we stop treating only half the disease and start believing that improvement is possible.

Andreas Muehler is a physician executive.