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Pots Home Standing Test

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The essentials, before you begin

What you’re testing for. POTS is a condition that affects the autonomic nervous system, which controls automatic body functions like heart rate and blood pressure, among others. When a person with POTS stands up, their heart beats much faster than normal leading to symptoms like dizziness or fatigue.

Who should consider testing for POTS? Testing for POTS can be meaningful if you have symptoms of orthostatic intolerance, particularly lightheadedness, palpitations, presyncope, generalized weakness, or blurred vision that occur with standing and improve with lying down.

The home standing test is a screening tool. It can raise suspicion but it cannot fully diagnose. POTS is a diagnosis that requires a clinician to rule out other causes (dehydration, medications, thyroid disease, adrenal issues, arrhythmias, anemia, structural heart disease, and more). But the test can give you and your clinician meaningful information and help start the conversation.

When not to do this test at home. If you have known cardiac disease, arrhythmias (abnormal cardiac rhythm, such as A-fib), a history of falls with injury, or you tend to lose consciousness rather than just feel lightheaded, do this test with your clinician rather than alone. If you are currently acutely ill, dehydrated, or newly on a medication that affects heart rate or blood pressure, wait for a more representative day.

What you need

A heart rate monitor of some kind. This can be:

• A blood pressure cuff that measures heart rate in addition to blood pressure. This is beneficial to measure how your BP also changes with position change. You can buy this at any pharmacy or online.

• A chest strap heart rate monitor

• A fingertip pulse oximeter

• A fitness tracker or smartwatch with continuous heart rate display

A wall you can lean against

A quiet room with no interruptions

About 20 minutes of free time

A notebook, phone note, or the printable protocol at the end of this post to record your numbers

If you can, get a family member or a friend to help you.

The test

Step 1. Lie flat and quiet for at least 10 minutes.

Turn your phone face-down. Don’t scroll, don’t read anything stimulating, don’t get up to check something. This is the resting phase, and the numbers depend on you actually being at rest. Bathroom before you start.

Step 2. Take your resting heart rate.

At the end of the 10 minutes, still lying down, record your heart rate. Take it again a minute later and average the two. Write both numbers down.

Step 3. Stand up and lean lightly against a wall.

Shoulders and buttocks touching the wall, heels 6-8 inches out from the baseboard. This is a supported stand not rigid attention.

Step 4. Record your heart rate at 1, 3, 5, and 10 minutes of standing.

Stay against the wall the entire time. Don’t shift weight, don’t cross your ankles, don’t fidget as those small movements activate the calf muscles and can artificially lower your heart rate.

Step 5. Record your symptoms as they happen.

Lightheadedness, palpitations, nausea, brain fog, tingling, visual changes, ringing in the ears, feeling faint, warmth in the face, cold hands, tremor.

Step 6. Sit or lie down

Record how you feel after the test and note how quickly symptoms resolve.

Interpreting your numbers

POTS is defined by a specific pattern. When you stand, your heart rate rises by at least 30 beats per minute above your lying-down rate within 10 minutes of standing (or 40 bpm if you are under 20) without a significant drop in blood pressure, and with symptoms.

A more transient spike in the first minute or two that then settles back down is common and not specific for POTS.

If your heart rate rises but you are also experiencing a significant drop in blood pressure, that points toward orthostatic hypotension rather than POTS, a different condition with different management.

Symptoms matter as much as numbers. Some patients have a clear POTS heart rate pattern with modest symptoms. Others have significant symptoms with borderline numbers. Both are worth taking to a clinician. As I said earlier, this test is meant to be a conversation starter.

What to do with your results

If your test suggests POTS. Bring the numbers to your clinician. Ask them to look at the pattern with you. Depending on your other conditions, the right next referral may be to cardiology, to a neurologist with autonomic expertise, or to an internist familiar with dysautonomia. Your physician may also give you direction on beneficial lifestyle changes. Be aware that not every clinician is comfortable evaluating for POTS, and even less are comfortable treating POTS.

If your test is normal but you have significant symptoms. A negative home test does not rule out POTS. Symptoms can fluctuate day to day; your hydration status, sleep, hormones, and stress load all affect the numbers. If your symptoms are real and consistent, the test being negative on one occasion should not close the door. You can repeat the test on another day, Or you may need a formal tilt table test in an autonomic lab that is more sensitive than the home version.

If you have MS, hEDS, small fiber neuropathy, or a rare neuroimmune condition. Even a mild positive result is worth raising. Dysautonomia is a well-documented comorbidity of these conditions, and may be a missing piece contributing fatigue, brain fog, or exercise intolerance.

If your test is unremarkable and your symptoms are mild. That’s useful information too. It doesn’t rule out other forms of autonomic dysfunction, but it makes classical POTS less likely as the explanation.

In your corner,

Dr. Freeman

“Doctor, I am tired.”

She says it the way you report a fact you’ve stopped expecting anyone to act on. Flat. A little apologetic, even, as though the exhaustion is a personal failing she’s come to confess. Forty-two years old. She has three kids and a fatigue so complete that some mornings the shower undoes her. She steps out, sits on the edge of the bed, and has to lie back down before she can dress. Dinner gets made in stages, with a horizontal pause between chopping and cooking. The school pickup line is a feat of planning.

She has multiple sclerosis, diagnosed a few years ago, well controlled on high-efficacy therapy. Her scans have been quiet and her last relapse is far behind her. Though this is my first time meeting her, her previous neurologist having just retired, I know that by every measure I usually reach for, her MS is behaving. And yet here she is, describing a life narrowed to the distance between one horizontal surface and the next.

It would have been easy and it would have been wrong to write this down as MS fatigue, nod sympathetically, and move on. Fatigue is the most common symptom in MS and one of the most disabling. It is also, too often, where the conversation stops. The label is so available, so expected, that it can absorb everything that walks through the door looking tired, and become an excuse for not doing anything.

So I slow down and ask her to walk me through a bad day.

The detail that changes everything

It wasn’t activity that wiped her out, exactly. It was being upright. Standing at the stove. Standing in line. Standing in the shower. She felt more human lying down and emptied out the moment she got vertical. Heat made it dramatically worse. A hot summer afternoon had her retreat to her air-conditioned bedroom. Every so often, in those upright moments, her heart would race and she’d feel oddly short of breath, as if she’d jogged up a flight of stairs, while standing perfectly still. She didn’t bring up this last fact on her own, ashamed that I would dismiss her as being deconditionned, but I have learned to ask these questions.

That pattern is not the signature of classic MS fatigue. MS fatigue tends to deepen as the day wears on and doesn’t particularly care what position you’re in. Heat worsens it too, so heat alone doesn’t tell us much. But the posture dependence, the racing heart, the breathlessness on standing: that’s the autonomic nervous system raising its hand.

I asked her to do a simple test at home: lie quietly for at least 10 minutes then check her heart rate while lying down. Next, stand up slowly and try to continue standing for 10 minutes, checking her heart rate at 1, 3, 5, and 10 min after standing. She sent me the numbers. Lying down: 70 beats per min (bpm). Standing: 145 bpm.

A jump of seventy-five beats, with no drop in blood pressure to explain it.

That is postural orthostatic tachycardia syndrome or POTS, and it had been masquerading as her “MS fatigue” the entire time and gone unaddressed.

Das Kranke Kind by Lovis Corinth, 1918. Courtesy National Gallery of Art, Washington.

Why this hides in plain sight in MS

Here is the part that should change the questions we ask. POTS and broader autonomic dysfunction are not rare bystanders in MS. They’re common, and we miss them constantly. And chances are, you’ve never heard of them.

So first, a quick word on what we’re actually talking about. Your autonomic nervous system is the part of your nervous system that runs the background tasks you never think about: heart rate, blood pressure, digestion, body temperature, the automatic adjustments that keep you steady when you stand up. When that system misfires, we call it dysautonomia. POTS is one specific kind of dysautonomia where standing triggers an excessive heart rate increase without a significant blood pressure drop. This is most often caused by the body failing to tighten the blood vessels properly, with blood pooling in the legs, and the heart compensating by racing. POTS isn’t a heart problem or a fitness problem. It’s a signaling problem.

In a large comparative study using the gold standard tilt-table testing, POTS showed up in about 19% of people living MS, compared with roughly 10% of people without MS who had orthostatic symptoms. Cast the net wider, beyond strict POTS to any measurable autonomic abnormality and the numbers climb startlingly: up to 84% of MS patients show some autonomic dysfunction, with orthostatic intolerance (intolerance to being upright) affecting around half.

It also tracks with how active the disease is. In one study, POTS turned up in 32% of patients during a relapse versus under 7% in remission. Over a six-year follow-up, the share of MS patients with symptomatic dysautonomia nearly doubled, and relapses raised the odds of developing it almost fourfold. The autonomic nervous system, it turns out, is paying close attention to what the immune system is doing.

So why does it get missed? Because MS and POTS hand you the same opening complaint: *I’m exhausted.* From my experience in the clinic, people don’t walk in saying “I have orthostatic intolerance.” They tell me they are tired. If we accept the most familiar explanation that MS is just making you tired without asking the next question, the treatable cause stays hidden in plain sight.

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How to tell if you have POTS

The good news is that the detecting POTS is mostly free. It takes a good history and in a set of vital signs you can get at the bedside.

POTS-related fatigue is positional, worse on standing, better lying down. It’s frequently worst in the morning, when the orthostatic heart rate surge is more pronounced, and it often travels with company: palpitations, lightheadedness, presyncope, breathlessness on standing. Confusingly, it can also show up as a flat, non-positional tiredness in nearly half of patients, which is exactly why the bedside test matters.

The practical move is almost embarrassingly simple: check heart rate and blood pressure lying down, then standing, at one, three, five, and ten minutes. A rise of at least 30 beats per minute on standing — 40 in adolescents — without a drop in blood pressure points toward POTS. When suspicion stays high despite normal bedside numbers, a formal tilt-table test settles it. The COMPASS-31 questionnaire is a validated way to screen for the broader autonomic symptom burden, and it correlates strongly with how fatigued patients actually feel.

None of this requires advanced equipment. It requires curiosity.

What’s actually going wrong

When I explain POTS to my patients, I try to resist the urge to make it sound like one tidy thing, because it isn’t. In MS especially, the autonomic trouble tends to come from several directions at once.

Some of it is central. MS lesions can land in the brain’s autonomic control circuitry — the insula, cingulate, hypothalamus, brainstem — the network that controls involuntary body functions, coordinates responses to stress, and maintains internal balance. Damage or dysregulation of the central autonomic network can scramble the signal.

Some of it is peripheral. MS is increasingly recognized as affecting the small nerve fibers outside the brain and cord, and small-fiber neuropathy is a well-known driver of the most common POTS subtype, where the blood vessels in the legs fail to clamp down on standing and blood pools, forcing the heart to race to compensate. Small fiber neuropathy can be confirmed with a simple skin punch biopsy, and in my clinic, I have diagnosed many of my MS patients with small fiber neuropathy. In my experience, these individuals tend to have worse pain and fatigue than those without detectable small fiber neuropathy.

And some of it appears to be autoimmune in a more direct sense. A growing body of work has found that many people with POTS harbor antibodies against the body's own adrenergic and muscarinic receptors, the very receptors that regulate the cardiovascular response to standing. In laboratory studies, these antibodies can impair the ability of blood vessels to constrict and can directly activate cardiac receptors, offering a plausible molecular explanation for the racing heart. The findings are intriguing but not yet definitive: the autoantibody associations have not been consistently replicated across cohorts, and leading experts caution that no causative antibody has been convincingly established. Still, the pattern fits a broader theme: POTS frequently co-occurs with other autoimmune conditions, often follows an immune trigger like infection, and in some patients may respond to immunomodulatory treatment.

There’s even a feedback loop worth discussing here, because it captures something essential about how I think about all of this. The autonomic nervous system isn’t just a passive victim of MS, it helps regulate the immune system. When it falters, the body’s built-in brake on inflammation can loosen, which may, in turn, feed more disease activity. Brain, immune system, autonomic nerves are not three separate stories, but one.

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Why it matters: this is treatable

Here is the reason I won’t let “it’s just MS fatigue” stand unchallenged. POTS opens a door that classic MS fatigue often doesn’t.

The first-line treatments aren’t even prescriptions. Increasing fluid and salt intake, and wearing compression garments can meaningfully reduce the orthostatic surge. Exercise can also be very effective for POTS, but it has to be done the right way, starting with activities done entirely on the floor or in a reclined position like swimming or recumbent biking rather than upright workouts, and building up slowly over weeks. It's important to tell the difference between normal tiredness after exercise and a crash that leaves you feeling worse for days, which is a sign the plan needs adjusting, not pushing through. For people with MS, this balance matters even more, because MS brings its own fatigue and heat sensitivity into the mix.

When medication is warranted, options like ivabradine or low-dose beta-blockers can blunt the racing heart, though beta-blockers need a careful hand in MS because they can deepen fatigue. Midodrine helps some patients who also have low blood pressure but calls for caution in anyone with MS-related bladder dysfunction. In a small series of MS patients whose POTS was finally recognized and treated, two-thirds were able to return to their daily activities.

Two-thirds. After months or years of being told they were simply tired.

There’s a longer-game point, too. Controlling MS aggressively and early may itself protect the autonomic nervous system. Escalating to high-efficacy disease-modifying therapy was associated with a markedly lower risk of objective autonomic dysfunction down the line. Treating the disease well isn’t separate from treating the autonomic nervous system. It may be part of it.

Back to the clinic

I don’t want to wrap this in a bow. POTS in MS is genuinely complex and the evidence is still maturing. Fatigue remains poorly understood and not every fatigued patient has a hidden orthostatic problem waiting to be found. And more importantly, while treatable, POTS is not always reversible.

But stories like this one are precisely why I keep returning to the same conviction: the most powerful diagnostic tool I have is the next question. My patient didn’t need a new scan or an exotic test. She needed someone to notice that her exhaustion had a specific pattern and to take that pattern seriously.

She came in to confess her fatigue like it was a failing. She left with a diagnosis, a plan, and the beginning of her life back.

If you’re living with MS and your fatigue is worse on your feet, eases when you lie down, and sometimes comes with a pounding or racing heart: that’s worth saying out loud at your next visit, in exactly those words. It’s not a complaint. It’s a clue.

In your corner,

Dr. Freeman

Want to know if you may have POTS?

I wrote an article in the Skills and Practices section of this publication on how to test at home. It comes with a printable tip sheet.

You can follow the link here.

References

Adamec I, Lovrić M, Žaper D, Barušić AK, Bach I, Junaković A, Mišmaš A, Habek M. Postural orthostatic tachycardia syndrome associated with multiple sclerosis. Auton Neurosci. 2013 Jan;173(1-2):65-8. doi: 10.1016/j.autneu.2012.11.009. Epub 2012 Dec 14. PMID: 23246200.

Winder K, Linker RA, Seifert F, Wang R, Lee DH, Engelhorn T, Dörfler A, Fröhlich K, Hilz M. Cerebral lesion correlates of sympathetic cardiovascular activation in multiple sclerosis. Hum Brain Mapp. 2019 Dec 1;40(17):5083-5093. doi: 10.1002/hbm.24759. Epub 2019 Aug 12. PMID: 31403742; PMCID: PMC6865522.

Foschi M, Giannini G, Merli E, Mancinelli L, Zenesini C, Viti B, Guaraldi P, Cortelli P, Lugaresi A. Frequency and characteristics of dysautonomic symptoms in multiple sclerosis: a cross-sectional double-center study with the validated Italian version of the Composite Autonomic Symptom Score-31. Neurol Sci. 2021 Apr;42(4):1395-1403. doi: 10.1007/s10072-020-04620-1. Epub 2020 Aug 10. PMID: 32776288; PMCID: PMC7955976.

Adamec I, Bach I, Barušić AK, Mišmaš A, Habek M. Assessment of prevalence and pathological response to orthostatic provocation in patients with multiple sclerosis. J Neurol Sci. 2013 Jan 15;324(1-2):80-3. doi: 10.1016/j.jns.2012.10.006. Epub 2012 Nov 3. PMID: 23127354.

Ruška B, Adamec I, Crnosija L, Gabelić T, Barun B, Junakovic A, Krbot Skoric M, Habek M. Evolution of autonomic nervous system abnormalities in multiple sclerosis: a 6-year follow-up. J Neurol Neurosurg Psychiatry. 2025 Oct 15;96(11):1093-1098. doi: 10.1136/jnnp-2024-335376. PMID: 40274400.

Guido G, Valsasina P, Morozumi T, Preziosa P, Romanò F, Rocca MA, Filippi M. Functional Connectivity Alterations of the Central Autonomic Network in Multiple Sclerosis: Links to Fatigue and Aerobic Training Effects. Neurol Neuroimmunol Neuroinflamm. 2026 Jul;13(4):e200585. doi: 10.1212/NXI.0000000000200585. Epub 2026 May 11. PMID: 42118052; PMCID: PMC13174567.

COMPASS-31 [https://www.hattrevaluationtools.eu/compass-31/]

She’d come for a second opinion mostly to humor her sister. She felt fine. No relapses in years. She walked into my office with no cane and no obvious problem.

Then we pulled up her MRIs.

Three new lesions over two years. None of them had caused a symptom she could feel. Her previous neurologist had noted them in his reports and changed nothing.

She wasn’t stable. She was accumulating damage quietly, the way MS so often does.

In MS care, we have a phrase for what we should be aiming for: “No evidence of disease activity”. Disease activity in MS means evidence that your immune system is attacking the brain or spinal cord right now. Not damage from years ago, but new injury happening on the current timeline.

It generally shows up as:

• A relapse: new symptoms (blurred vision, numbness, weakness, imbalance) that come on over hours to days and last more than 24 hours. This is disease activity you can feel.

• A new lesion on MRI: a fresh spot of inflammation in the brain or spinal cord, with or without active gadolinium enhancement. This is disease activity whether or not you feel it. Most new lesions never produce a symptom a patient would notice: they happen in regions with redundancy, or they’re small enough to be quietly absorbed. But they aren’t harmless.

For a long time, no evidence of active disease was the aspirational goal. I think about it differently now. NEDA is the floor, not the ceiling. It’s the outcome we should expect (not just hope for) when someone is on the right treatment, monitored properly, and with the right diagnosis.

When patients aren’t getting there, it almost always comes down to one of three things.

You are on the wrong drug.

MS therapies fall, broadly, into three camps: platform, moderate-efficacy and high-efficacy. Platform therapies, which we don’t call low-efficacy to not hurt their feelings, are the good ol’ injectable drugs, the interferons and glatiramer acetate. Moderate-efficacy therapies are primarily our oral agents: teriflunomide, the fumarate class (e.g. dimethyl fumarate) and the S1P modulators (e.g. fingolimod). High-efficacy treatments are our immunotherapies (B-cell therapies, natalizumab, alemtuzumab) as well as cladribine.

The evidence has been clear for years now. Starting with high-efficacy treatment, especially early in disease, leads to fewer relapses, less disability accumulation, and better long-term outcomes than the older approach of starting low and escalating only after damage has been done. The brain doesn’t get those years back. If you need to see the evidence for yourself, start with this article I co-authored: High-Efficacy Therapies for Treatment-Naïve Individuals with Relapsing–Remitting Multiple Sclerosis

And yet many people are still on therapies that aren’t controlling their disease. Sometimes the conversation about high-efficacy options never happened. Sometimes it’s a “let’s wait and see” stance that quietly stretches into years. Sometimes the initial choice was perfectly reasonable but isn’t working anymore and no one has cared to look or ask the next question.

There’s another scenario worth naming: when even the right high-efficacy drug, used early, isn’t fully controlling the disease. Situations like these are called “highly active” disease, or refractory and they represent another area where I think there is a quiet gap. Clinical trials are an option that often gets overlooked yet has the potential to provide access to mechanisms we don’t yet have on the shelf. Hematopoietic stem cell transplants, CAR-T therapies, and other agents are currently being tested in refractory disease. Some of these will pan out and some won’t. That’s the nature of trials. But enrolling typically means careful monitoring, no cost for the study drug, and a real shot at something the approved menu can’t yet offer. A lot of highly specialized trials run out of academic MS centers. If your community neurologist isn’t tracking what’s open, asking for a one-time consultation referral is a reasonable thing to do.

You have the wrong neurologist.

I want to say this carefully, because most of my colleagues are excellent. But MS care has a quiet problem called therapeutic inertia. This is the tendency to leave things alone even when the data say it’s time to change course.

It looks like this: a new lesion appears on MRI. The neurologist notes it but doesn’t act. A year later, another one, dismissed. The patient feels fine, so change doesn’t seem urgent. But MS is rarely urgent in the moment. It’s urgent over a decade.

A proactive MS neurologist does a few things consistently:

- Orders MRIs on a regular schedule, typically annually, and more often after a treatment switch, using a standardized protocol that allows real comparison year over year.

- Reads the MRI themselves, not just the radiology report. Subtle activity gets missed otherwise.

- Considers serum biomarkers like neurofilament light chain (NfL), or multianalyte panels, which can pick up damage even when the scan looks quiet, or confirm a subtle change.

- Treats stability as the standard, not a stroke of luck. When new activity appears, they lean in and have a conversation about why and what to change.

If your visits are mostly “see you in a year, keep doing what you’re doing,” or “if it’s not broken why fix it” without a careful review of your history and imaging, it may be worth asking more questions. Or asking them somewhere else.

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You have the wrong diagnosis.

This is the one I most want you to know about, because it’s the most invisible.

MS is a clinical and radiologic diagnosis. There’s no single test that confirms it. And there are conditions that can look strikingly like MS on a scan or in a clinic note but aren’t MS, and don’t respond to MS drugs.

The list is longer than people realize. NMOSD (neuromyelitis optica spectrum disorder) and MOGAD (MOG antibody-associated disease) are the most important to rule out. They require different treatment, and some MS therapies can actually make them worse. Small vessel ischemic disease, B12 deficiency, Susac syndrome, CADASIL, sarcoidosis, and certain infections can all produce white matter lesions that mimic MS.

When someone is on the right drug, monitored properly, and still worsening, the question isn’t always “what’s the next drug?” Sometimes it’s “are we treating the right disease?”

Going back to basics with a careful re-review of the original MRI, the spinal fluid, the antibody testing, the clinical story has changed the diagnosis for more patients than I can count. Sometimes that conversation is hard. Often it’s the opening to a treatment that finally works.

And what’s above the floor?

If no evidence of disease activity is the floor, what’s the ceiling?

It’s a moving target, and it’s where MS care is heading. Preserving brain volume. Preventing the slow, smoldering progression that happens independent of relapses (what we call PIRA, progression independent of relapse activity). Protecting cognition, mood, sleep, fatigue.

From a pharmacologic standpoint, we are not all the way there yet. We’re getting closer. But we need not forget what we can address without the prescription pad. Comorbidities such as high blood pressure, elevated cholesterol, diabetes, obesity accelerate disability in ways no MS drug can fully offset. Smoking is a strong, independent driver of progression, and worth stopping at any stage of disease. Adequate vitamin D, regular aerobic exercise, treating sleep apnea and depression, protecting sleep itself. These aren’t lifestyle extras. They’re disease-modifying in their own right, and they compound with whatever drug you’re on.

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What I’d want you to take with you

If you have MS, NEDA is a reasonable outcome to expect. Not a miracle. A baseline.

Getting there usually means three things working together: a treatment matched to your disease rather than to inertia; a neurologist who watches closely and responds when something changes; and, when the picture doesn’t add up, the willingness to ask whether the diagnosis itself still fits.

You’re allowed to ask your neurologist what your last MRI showed compared to the one before.

You’re allowed to ask whether a higher-efficacy option might be appropriate.

You’re allowed to ask whether NMOSD and MOGAD antibodies have ever been checked.

You’re allowed to ask whether serum biomarker testing would be useful.

You are about to ask what you can do to protect your brain health and prevent disability progression.

You are allowed to ask if there is a clinical trial you would benefit from.

And when you ask, you deserve an answer. Not a flippant one. One rooted in evidence.

Good MS care isn’t passive. It shouldn’t feel like waiting. And it certainly shouldn’t feel like you are not being heard.

Then, near the end of the visit, she said what she had really come to ask.

She had two daughters, ages 6 and 8. What was their risk of developing MS? And what, if anything, could she do to protect them?

I get some version of this question in clinic nearly every week. Sometimes it comes from a newly diagnosed mother like her. Sometimes from the adult sibling of a patient. Sometimes from a grandparent who noticed that MS “runs in the family” and wants to know what that means for a grandchild. The question is almost always the same underneath: is there something I can do, now, to change the odds?

For most of my career, the honest answer has been: not really. I’d offer reassurance that the absolute risk remained low even in first-degree relatives, and a few general suggestions about healthy lifestyle. But what my patients really want is a plan grounded in biology.

This is changing now. For the first time in the history of this disease, primary prevention of MS is no longer an esoteric notion but a serious scientific enterprise. A coherent story is forming about what causes MS to develop. There are modifiable risk factors with real causal evidence behind them. And there are now clinical trials designed to address those risk factors, opening the door to preventing the disease before it starts.

This column is about what we know, what we are testing, and what a mother of two girls can reasonably do today.

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What We Learned from Watching the Families

The best way to understand what is happening before MS begins is to study people who are at high risk and follow them forward. That is what the Genes and Environment in Multiple Sclerosis (GEMS) study, launched by Philip De Jager and colleagues in 2011, was designed to do. GEMS recruited over 2,600 first-degree relatives of people with MS, collected biosamples, captured detailed environmental exposures, and followed them over time.

Two findings from this work are worth dwelling on.

The first is that first-degree relatives of people with MS develop MS at up to 30 times the rate of the general population. In absolute terms, this is still a low probability, most first-degree relatives will never develop MS, but it is substantially higher than the background rate, and it confirms what clinicians have long known from family history alone: shared genes and shared environments matter.

The second is that the prodromal phase of MS is measurable. Using a combined genetic and environmental risk score, the GEMS team could identify a subgroup of first-degree relatives at roughly twice the average family-member risk. These individuals are not destined to develop MS. But they are the population in whom preventive intervention might plausibly show a signal.

Running in parallel with GEMS has been a remarkable line of work using the US Department of Defense Serum Repository, a collection of over 60 million stored serum samples from active-duty military personnel. Because these samples were taken years before any clinical event and then archived, they allow us to look backward in time at the biology of people who went on to develop MS.

What those samples have shown is sobering. Serum neurofilament light chain, a marker of neuroaxonal injury, is elevated on average six years before the first clinical symptom of MS. Six years. In other words, neurons are being damaged and the immune system is dysregulated long before the first episode of optic neuritis or the first sensory symptom that prompts an MRI. By the time a person walks into a clinic with blurry vision, the disease has been underway, silently, for the better part of a decade.

The same repository gave us the most compelling evidence yet that Epstein-Barr virus is a cause, not a correlate, of MS. In the 2022 Bjornevik and Ascherio analysis, people who became infected with EBV had a 32-fold increased risk of developing MS compared to those who remained uninfected. This dramatic increase was specific to EBV, no other virus showed a similar effect. Even more striking: of the 35 people who developed MS and were initially EBV-negative, all but one became infected with EBV before their MS diagnosis. The timing, the specificity, and the sheer magnitude of the effect together make a compelling case that EBV infection is essentially a prerequisite for developing MS.

Put these findings together and a picture emerges. MS begins years before symptoms. It is preceded by measurable immune and neuroaxonal changes. And its biology is set in motion, at least in part, by an environmental exposure almost all of us encounter.

What Actually Drives MS Risk

If we are going to attempt to prevent MS before any sign of disease, we need to know which risk factors are causal, not merely associated. While there is much we still don’t know, four risk factors stand out right now.

EBV infection is, as discussed, essentially a prerequisite. The risk of developing MS is roughly 32 times higher after EBV infection compared to those who remain EBV-negative, an effect not observed for any other virus tested.

Vitamin D insufficiency has long been linked to higher MS risk in observational studies. But observational studies can be misleading: people with low vitamin D might share other characteristics that actually explain the increased risk. To get around this problem, researchers have used a technique called Mendelian randomization, which looks at people who are genetically predisposed to have lower vitamin D levels. Because these genetic variants are randomly assigned at birth, they act like a natural experiment. These genetic studies support the idea that low vitamin D genuinely contributes to MS risk, rather than just being a statistical coincidence.

Adolescent obesity shows a similar pattern. Mendelian randomization studies have supported a causal relationship between elevated BMI in adolescence and adult MS risk.

Smoking (including passive exposure) increases MS risk meaningfully and also worsens the disease course once MS is established. The effect is dose-dependent. To my knowledge, e-cigarettes have not been studied with regard to MS. Theoretical concerns exist however, based on the lung irritation hypothesis and preclinical data showing e-cigarettes disrupt blood-brain barrier integrity and promote neuroinflammation.

What is notable about this list is that three of the four factors are modifiable, and the fourth, EBV, is becoming a vaccine-preventable exposure. This is the menu from which primary prevention strategies are being built.

The First Generation of Prevention Trials

The single most important development in MS prevention science is the arrival of EBV vaccines in clinical trials.

Two major EBV vaccine programs entered clinical testing in 2022. Moderna’s mRNA-1189 uses the same mRNA technology as the COVID-19 vaccines to teach the immune system to recognize the proteins EBV uses to break into cells. Early trials in people aged 12 to 30 showed the vaccine was safe and triggered a strong immune response, and it is now moving toward larger trials. The second program, developed by the National Institutes of Health (NIH), attaches a key EBV surface protein to tiny particles that help the immune system mount a stronger response. Both vaccines are still in early testing focused on safety and immune response, not yet on whether they actually prevent infection or disease.

The historical context here matters, and it is more encouraging than it might first appear. An earlier gp350 subunit vaccine tested in EBV-seronegative students did not prevent EBV infection, but it reduced symptomatic infectious mononucleosis by approximately 80%. At first glance, this may sound like a failure: the vaccine did not keep the virus out. But the distinction between asymptomatic EBV infection and symptomatic mononucleosis turns out to matter a great deal for MS.

Studies have consistently shown that people who develop symptomatic mono have a higher MS risk than those who are infected with EBV without ever getting sick. It’s not just whether you were infected, it’s how your body responded. People infected as young children, who typically never notice it, appear to have lower MS risk than those infected as teenagers or adults who develop full-blown mono. The leading theory is that mono’s intense immune response with high levels of virus and widespread inflammation creates conditions that make the immune system more likely to later attack the body’s own tissues.

If this theory is correct, a vaccine doesn’t necessarily need to block EBV infection entirely. A vaccine that prevents mono, turning what would have been a severe infection into a silent one, could still meaningfully reduce MS risk, even if the virus quietly takes up residence in the body. Partial protection may be enough.

Moderna is also developing a second vaccine, mRNA-1195, which takes a different approach. Rather than preventing EBV infection in the first place, this “therapeutic vaccine” is designed for people who are already infected, aiming to help their immune system keep the dormant virus under tighter control. It is now being tested in people with relapsing MS in an international Phase 2 study called the Horizon trial (clinicaltrials.gov), to see whether strengthening the body’s control over EBV can slow MS disease activity and progression. This isn’t about preventing MS, it’s about treating it. But the trial also serves as a critical test of the EBV-MS connection: if suppressing EBV helps control MS, it would be powerful evidence that the virus is truly driving the disease.

Beyond vaccines, researchers are exploring other ways to target EBV. Antiviral drugs already used for other viral infections are being evaluated for future MS trials. EBV-specific T-cell therapies take a different approach: patients receive laboratory-trained immune cells designed to find and destroy EBV-infected cells that may be driving their MS. One such therapy, ATA188, was tested in progressive MS but did not meet its primary goal of improving disability; earlier small-scale trials of similar approaches showed benefit in some patients. EBNA-1 inhibitors, originally developed for EBV-related cancers, are also being considered. None of these is yet a proven MS treatment, but together they represent a pipeline that didn’t exist five years ago.

The Design Problem

Imagine you want to run a trial to prevent MS. You would enroll people who have never had MS, randomize them to either an intervention (a vaccine, say, or a behavioral intervention, or a drug), and follow them forward to see whether they develop MS at different rates.

The problem is immediately obvious. Most people, even most at-risk first-degree relatives, will never develop MS. Background incidence is low. To detect a preventive effect, you need either a very large population, a very long follow-up, or a very high-risk subgroup, ideally all three. A traditional trial of this design, powered to show a meaningful effect on MS incidence, would need tens of thousands of participants followed for years or decades. The costs are enormous. The scientific patience required is extraordinary.

There are several ways the field is trying to make this tractable.

The first is to enrich the study population. GEMS and similar cohorts show us how to identify first-degree relatives at the highest end of the genetic-and-environmental risk distribution. Studying these individuals rather than the general population could dramatically improve statistical power at a manageable sample size.

The second is to use intermediate biomarker endpoints rather than clinical MS as the outcome. If we have a biomarker that reliably predicts eventual MS, and that biomarker responds to a preventive intervention, we may be able to demonstrate biological efficacy without waiting a decade for clinical events to accrue. Serum NfL is at this time the most serious candidate, given that elevations precede clinical onset by six years. Subclinical MRI lesion development is another. Refined immune biomarkers, especially EBV-related immune signatures, are under active investigation.

The third is to focus on interventions where the bar for demonstrating net benefit is lower, because the intervention is safe, inexpensive, and carries its own independent health benefits. An EBV vaccine that prevents infectious mononucleosis does not need to demonstrate a reduction in MS incidence to be clinically useful. The MS benefit, if it emerges, is essentially a bonus. This lowers the activation energy for the first generation of primary prevention strategies considerably.

The fourth is to accept that the field will need to run these trials in stages, starting with the populations most at risk, gathering biomarker evidence first, then moving to larger populations once the preliminary signals are solid. The ethical calculus of who to enroll in a prevention trial, how much baseline risk justifies exposure to an experimental intervention, is itself a serious conversation that is only now beginning to happen in a structured way.

None of this is easy. But the tools are assembling. The risk-stratification methods are in development. The biomarkers are maturing. The vaccine platform is functional. Whether future trials will succeed is genuinely unknown. That they are now serious scientific enterprises, rather than distant aspirations, is already a considerable change.

What I Told Her

I want to go back to the mother with her two daughters. As a mom and a doctor, I see her strength in confronting her own diagnosis and I want to bring her the best answers we have because I know her daughters are everything to her just like my kids are everything to me. Here is what I would tell her.

First, the absolute risk to her daughters is low, even with a first-degree relative with MS. Most children of mothers with MS will never develop the disease.

Second, there are concrete things she can do, grounded in real evidence, to reduce that risk further. Support a healthy weight through adolescence, because adolescent obesity is one of the most robust modifiable risk factors for adult MS. Make sure they never smoke (or even vape), and minimize their exposure to smoke from others. Encourage regular physical activity, not as a specific MS prevention measure but as part of the broader health picture that reduces inflammation and supports overall metabolic health. Ensure reasonable sun exposure and dietary vitamin D intake through childhood and adolescence; I do not recommend routine vitamin D level monitoring in children, but insufficiency should be avoided.

Third, keep an eye on the EBV vaccine space. If and when an EBV vaccine becomes licensed, she should have a serious conversation with her daughters’ pediatrician about vaccination before adolescence, the period when EBV infection is most likely to become clinically manifest and when MS risk begins its slow climb. Even if the MS benefit takes decades to prove, the vaccine would prevent infectious mononucleosis, which is itself worth preventing.

Fourth, be attentive, but not hypervigilant. If either daughter ever has unexplained neurological symptoms, especially those consistent with demyelination, optic neuritis, unexplained numbness or weakness, Lhermitte’s sign, it should be evaluated promptly. But the goal is not to generate MS anxiety in children. The goal is to raise informed, healthy young adults.

And finally, I told her what I am telling you, the reader. The landscape is changing. What we can offer at-risk families today is more than what we could offer five years ago, and in another five or ten years, it will be more than what we can offer today. The path to primary prevention is shorter than it was, and the work to walk that path is actively underway.

For a mother sitting in my office asking what she can do for her children, that is not nothing. It is, in fact, quite a lot.

References:

1. Bjornevik K, Munger KL, Cortese M, et al. Serum Neurofilament Light Chain Levels in Patients With Presymptomatic Multiple Sclerosis. JAMA Neurology. 2020;77(1):58-64.

2. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal Analysis Reveals High Prevalence of Epstein-Barr Virus Associated With Multiple Sclerosis. Science. 2022;375(6578):296-301.

3. Bjornevik K, Münz C, Cohen JI, Ascherio A. Epstein-Barr Virus as a Leading Cause of Multiple Sclerosis: Mechanisms and Implications. Nature Reviews Neurology. 2023;19(3):160-171.

4. Aloisi F, Giovannoni G, Salvetti M. Epstein-Barr Virus as a Cause of Multiple Sclerosis: Opportunities for Prevention and Therapy. Lancet Neurology. 2023;22(4):338-349.

5. Pender MP, Csurhes PA, Smith C, et al. Epstein-Barr Virus-Specific T Cell Therapy for Progressive Multiple Sclerosis. JCI Insight. 2018;3(22):124714.

6. Ioannides ZA, Csurhes PA, Douglas NL, et al. Sustained Clinical Improvement in a Subset of Patients With Progressive Multiple Sclerosis Treated With Epstein-Barr Virus-Specific T Cell Therapy. Frontiers in Neurology. 2021;12:652811.

7. Rosso M, Chitnis T. Association Between Cigarette Smoking and Multiple Sclerosis: A Review. JAMA Neurology. 2020;77(2):245-253.

8. Høglund RAA, Meyer HE, Stigum H, et al. Association of Body Mass Index in Adolescence and Young Adulthood and Long-Term Risk of Multiple Sclerosis: A Population-Based Study. Neurology. 2021;97(23):e2253-e2261.

9. Hagman E, Putri RR, Danielsson P, Marcus C. Pediatric Obesity and the Risk of Multiple Sclerosis: A Nationwide Prospective Cohort Study. International Journal of Obesity. 2025;49(6):1031-1036.

10. Mokry LE, Ross S, Ahmad OS, et al. Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study. PLoS Medicine. 2015;12(8):e1001866.

11. Zhang Y, Liu H, Zhang H, et al. Causal Association of Genetically Determined Circulating Vitamin D Metabolites and Calcium With Multiple Sclerosis in Participants of European Descent. European Journal of Clinical Nutrition. 2023;77(4):481-489.

She had done everything right.

Diagnosed with relapsing-remitting MS in her late thirties, she started a disease-modifying therapy promptly and stayed on it. Over the years she moved to a more potent agent, and by the time I saw her in clinic in her mid-fifties, her inflammation was well-controlled. No recent relapses, stable MRI. On paper, a treatment success.

But she wasn’t doing well.

Over the previous two years she had developed progressive cognitive difficulties: word-finding problems, memory lapses, trouble concentrating at work. She had recently quit her job because of it. She also carried a longstanding diagnosis of obstructive sleep apnea that had never been treated, and she had been pre-diabetic for years, a fact that had never quite made it to the center of her MS care. Every visit, she would come back to the same question: her inflammation is controlled. So why is she declining?

Around the same time, her younger sister came to see me. She was 47, had been noticing progressive imbalance and leg weakness for a little over a year, and after a full workup was diagnosed with primary progressive MS. She started on a DMT. As the two of them processed the diagnosis together, they asked the question I imagine many siblings in this situation ask: *could this have been prevented?*

I didn’t have a satisfying answer. But I’m increasingly convinced that we need one and that finding it requires us to rethink what MS care actually is.

The Treatment Decade Has Been Remarkable. And It Has Exposed a Gap.

The past twenty years have delivered a genuine revolution in MS therapeutics. We now have more than twenty approved disease-modifying therapies. The most effective among them reduce relapse rates so significantly that people can now expect to live free of disease activity. For many people living with MS, especially those diagnosed early and started on high-efficacy treatment promptly, the prognosis has changed substantially.

And yet. Disability still accumulates. Cognitive decline still happens, often insidiously, even in people whose MRIs look stable. Quality of life remains significantly impaired for a large proportion of the MS population. And we do not prevent a single case of MS.

The reason, I think, is that we have built an extraordinarily sophisticated system for suppressing one dimension of MS pathology, inflammatory lesion activity, while leaving much of the rest of the disease largely unaddressed. Disease-modifying therapy is necessary, even transformative. For most people living with MS, it should be non-negotiable. But it is only part of the equation. The rest — lifestyle, comorbidities, sleep, mental health — we have treated as someone else’s problem, or no one’s problem, or a problem to be handled later.

That gap between what our best therapies achieve and what our patients actually need is where preventive neurology begins.

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What Preventive Neurology Actually Means

The term sounds like it might refer to prevention in the colloquial sense, eating well, exercising, the kind of advice that gets dismissed as obvious or insufficient. It is something more specific and more ambitious than that.

Preventive neurology is the systematic application of evidence-based risk reduction strategies across the full arc of neurological disease before it starts, after diagnosis, and throughout the disease course. It encompasses three distinct tiers.

Primary prevention means preventing MS onset itself: identifying and modifying the risk factors that cause the disease to develop in the first place. This is the newest and perhaps most exciting frontier. The science here has moved rapidly recently. We now know that Epstein-Barr virus infection is essentially a prerequisite for MS, that obesity in adolescence and low vitamin D levels are causally implicated, that smoking meaningfully increases risk. We have the first clinical trials testing whether pharmacological intervention in people with early radiological abnormalities, before any clinical event, can delay or prevent the disease. The possibility of actually preventing MS, which would have seemed fanciful a decade ago, is now a legitimate scientific goal.

Secondary prevention means intervening early after diagnosis to decrease the risk of progression, preserve function, and improve quality of life through means that go beyond DMTs. This includes lifestyle interventions, such as exercise, sleep, diet, smoking cessation that have stronger evidence behind them than most clinicians appreciate. It includes aggressive management of comorbidities like hypertension, diabetes, and depression, which independently accelerate disability in ways that DMTs do not address. It includes treatment of obstructive sleep apnea, which mediates a substantial fraction of cognitive impairment in people living with MS. It is, in short, the comprehensive care that the first patient I described deserved and largely didn’t receive.

Tertiary prevention means minimizing disability and maximizing function in established disease. Cognitive rehabilitation, fall prevention, fatigue management, mental health support. This is not giving up. It is recognizing that there is always something meaningful to preserve or recover, and that the goal of MS care is a full and engaged life, not just a stable MRI.

Why This Conversation Is Happening Now

Several things have converged to bring preventive neurology to the center of MS discourse.

The science has matured. The causal role of EBV in MS confirmed by a landmark 2022 study following over ten million US military personnel has opened the door to genuine primary prevention strategies, including vaccine development.[1] Mendelian randomization studies have strengthened the causal case for vitamin D, obesity, and smoking as MS risk factors, not merely correlates. Large long-term cohort studies have quantified the impact of lifestyle factors on disability trajectories in ways that are clinically meaningful. One recent Swedish study found that high levels of physical activity were associated with a 36% reduction in the risk of confirmed disability worsening over 15 years.[2] Numbers like that are not background noise. They belong in the clinic.

The treatment landscape has also created a new urgency. Precisely because we have become so effective at controlling inflammation, we are now watching a different phenomenon more clearly: disability that accumulates in the absence of clinical relapses, driven by compartmentalized CNS inflammation, neurodegeneration, and the compounding effect of untreated comorbidities. Addressing this, what we now call progression independent of relapse activity, or PIRA, requires tools that go beyond our current DMT armamentarium.

Many people living with MS have been watching the development of BTK inhibitors, a new class of drugs designed to cross the blood-brain barrier and target precisely the smoldering neuroinflammation thought to drive progression, with real hope. That hope has been met with real frustration. Tolebrutinib, the furthest along of the class, showed a meaningful reduction in disability progression in clinical trials, but received a complete response letter from the FDA in December 2025, citing safety and efficacy concerns. Other agents in the class are still in development, and the biology remains compelling but no approved therapy targeting PIRA exists today, and the path to one has proven longer and harder than many anticipated. For people living with progressive disease who have been waiting, that is genuinely difficult news. The feeling of watching the clock while the regulatory process runs its course, of wanting to act but being told there is nothing yet to act on, is one I hear in clinic regularly.

It is partly that frustration that makes preventive neurology so important right now. Because while the pipeline evolves, the evidence for lifestyle interventions, comorbidity management, and behavioral strategies is already here. Exercise, sleep, metabolic health, mental health — these are not consolation prizes. They target overlapping biology. They are actionable today. And for people who want to do something meaningful for their health rather than wait passively, they represent a real and evidence-based way to take control.

And practically speaking, the people most affected by MS are asking for exactly this. They want to be active participants in their own disease management. They want to know what they can do. For too long, our answer has been inadequate: take your medication, come back in six months.

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What This Series Is About

Over the next three weeks, I’ll be exploring the prevention revolution in MS in depth.

We’ll look at the primary prevention evidence: what we actually know about preventing MS onset, what the EBV science means for families, and where the most promising clinical trials are heading. We’ll dig into secondary prevention: the lifestyle and comorbidity evidence that should be reshaping how we practice MS neurology right now. And we’ll examine what it takes to actually implement preventive care at scale: what a working model looks like, what the barriers are, and what the field needs to prioritize in the decade ahead.

My aim is to make this series useful for everyone who cares about the future of MS whether you are living with the disease, caring for someone who is, working in the MS space in industry or advocacy, or practicing as a clinician. The evidence belongs to all of you. So does the conversation about what to do with it.

Because one thing I am certain of, after years in this field and after caring for patients like the two sisters I described at the start: the status quo is not good enough. We can do more. The science says we can. The question is whether we will build the care model to make it real.

I believe we will. This series is my attempt to help move that forward.

Next week: Can MS actually be prevented? The evidence on EBV, smoking, vitamin D, obesity — and the challenges of designing trials targeting MS before it starts.

[1] Kjetil Bjornevik et al., Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science375,296-301(2022).DOI:10.1126/science.abj8222

[2] Hedström AK, Olsson T, Piehl F, et al., Beneficial impact of physical activity on multiple sclerosis disability progression. Journal of Neurology, Neurosurgery & Psychiatry 2026;97:209-216. 10.1136/jnnp-2025-336738

But perhaps the hardest season of all comes just after the new year, when health plans reset, coverage changes, and a wave of reauthorizations begins. Too often, that wave brings something else with it: denials for medications and therapies that had already been approved and were working.

This happens when employers switch insurers, when plan structures change, or when individuals are forced to select new coverage in the marketplace. These decisions are almost always driven by cost. But the downstream consequences are not abstract, they are deeply human.

2026 has been an especially difficult transition. With new federal policies, rising healthcare costs, and increasing consolidation in provider markets, we are seeing sharp increases in premiums and significant instability, particularly for small employers and individuals. I am not an economist, and I won’t attempt to unpack all the “why.” What I can speak to are the consequences for people like you and me, and especially for those living with chronic illness like MS, where staying on a treatment that works is essential not just for daily function, but for preventing future disability.

So let me tell you what I am seeing.

Over the past few months, more patients have walked into my office telling me their premiums doubled, from ~$600 to over $1200 per month, forcing them into plans that “don’t cover much.”
I have had patients ask me if there is any other way to access their treatment because they are being priced out of insurance entirely.
I have seen medication costs skyrocket to the point where patients are choosing between their health and putting food on the table.

I have seen our nurses work tirelessly to prevent gaps in treatment after plan changes.
I have seen medications that kept patients stable for years suddenly denied because they are not on a new formulary.
I have spent evenings writing urgent appeal letters, while my children waited for me to finish work that no one reimburses.

I have seen “STAT” appeals downgraded to non-urgent, leaving patients waiting months for decisions that cannot wait.
I have seen avoidable hospitalizations while we sit in those queues.
I have seen the look on patients’ and care partners’ faces when yet another appeal is denied.

Preventing someone from accessing a therapy that has kept them stable is not only morally wrong, it is economically irrational. It requires a kind of magical thinking to believe that a patient who achieved remission on a high-efficacy therapy will remain stable without it, or on a lower-efficacy alternative. And yet, this is exactly what the system repeatedly asks us to accept.

When patients are forced off effective therapies, we see what follows: relapses, hospitalizations, loss of function, costs that are far greater, both financially and humanly, than the treatment that was working in the first place.

The disregard for continuity of care reveals how far we still are from a truly person-centered system. Clinicians continue to advocate through peer-to-peer calls, appeal letters, and external reviews, often in hours that go unseen and unreimbursed. Meanwhile, entire plans of care can be dismantled by insurers with little explanation, and evidence of long-term stability is often not enough to secure continued access.

Patients are left with impossible choices: navigate complex assistance programs that require time and resources they may not have, or switch to a therapy they are not confident will work as well. For people living with a chronic illness, changing medications can feel like a monumental decision even when it is necessary. Being forced into that change erodes trust in ways that are hard to rebuild.

For clinicians, this work is now part of care, but it comes at a cost. In a system driven by productivity metrics and volume, this added burden contributes to burnout and, increasingly, to clinicians leaving medicine altogether.

Current “continuity of care” protections, often called transition-of-care laws, offer only partial relief. At the federal level, they focus primarily on maintaining access to providers, not medications. At the state level, protections are inconsistent and typically temporary, offering a bridge of 30 to 90 days at best.

In practice, these laws provide a window, not a guarantee. They buy time to appeal, to request exceptions, to scramble for alternatives. But they do not ensure that patients can remain on the therapies that are keeping them well. For conditions like complex and chronic neurological illnesses, where treatment interruption carries real risk, this gap between temporary protection and long-term stability is not just inconvenient, it is dangerous.

A more person-centered approach would embrace a simple principle: stable patients should remain on stable therapies.

This would mean requiring insurers to honor effective treatments after plan changes, mandating continuity of medication coverage for chronic conditions, and limiting step therapy when a patient has already demonstrated benefit. It would mean faster, clinically informed appeals and greater transparency around denials.

At its core, it would shift the system from prioritizing short-term cost containment to protecting long-term outcomes, function, and trust.

These protections are even more critical for people living with rare diseases. For them, finding a treatment that works can take years, years of uncertainty, dismissal, and searching. When a therapy finally makes a difference, it is not just a medication, it is a lifeline.

To have that lifeline suddenly taken away is a level of suffering that is difficult to put into words.

We can do better.

We cannot accept a system where patients are destabilized because their employer changed plans or because costs continue to rise. We cannot accept that formularies shaped by rebate negotiations take precedence over clinical judgment, lived experience, and common sense.

And we should not accept that staying well is treated as optional.

My hope was that, by sharing my interpretation of the available data, I could help put this complex and emotionally charged information into context.

But what has unsettled so many of us after the FDA’s letter is not just the safety signal itself, but the deeper question it forces us to confront:

💡 When a drug carries real risk, should it still be considered for approval, and what degree of evidence do patients deserve in return?

This isn’t just a regulatory question. It’s a moral one. A clinical one.

Progressive MS remains one of the greatest unmet needs in Neurology. For many patients, progression may not be dramatic, but it is devastating. It is slow, grinding, and relentless. Moving becomes harder. Thinking takes more effort. Memory slips away. Fatigue reshapes daily life. Independence narrows quietly, year after year. In that context, the idea that we might only approve therapies with pristine safety profiles begins to feel disconnected from reality. If the standard for approval were zero serious adverse events, many of the therapies we now consider transformative in Neurology, and certainly in Oncology, would never have reached patients.

So yes, risky drugs must remain on the table. For some patients, the alternative is not safety. It is certainty of decline.

We often talk about benefit–risk as if it were a calculation: benefit on one side, risk on the other, weigh them carefully and decide. But benefit–risk is not an exact ratio. Benefit in MS, particularly in progressive MS, is often heterogeneous. It may be modest on average, but meaningful for a subset of patients. Risk, on the other hand, may be rare but catastrophic, falling on a small number of individuals with potentially devastating consequences. Those two realities don’t cancel each other out neatly. The ethical challenge is not deciding whether benefit outweighs risk in the abstract. It’s deciding whether we understand who benefits, who is at risk, and how we can protect patients while offering choice.

Risky therapies may be necessary. They may even be transformative. But the riskier the drug, the higher the bar for clarity on benefit. This is not about demanding certainty. Medicine has never offered that. It is about proportionality. When a drug’s risks are minimal, we can tolerate ambiguity in benefit. A modest effect, a trend in the right direction, or population-level averages may be enough. But as risk increases, especially when that risk includes rare, severe, or irreversible harm, the ethical threshold shifts.

People living with MS deserve more than protection from harm, and more than access to innovation. They deserve to know:

• What kind of benefit is being offered

• How meaningful that benefit may be in daily life

• How likely they personally are to experience it

If this moment pushes our field toward smarter trial designs and greater collaboration to provide our patients with the answers they need, then the delay will not have been entirely wasted. Sometimes the hardest pauses are the ones that move us forward more responsibly.

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Tolebrutinib trials: FDA’s comments on design and population selection

Below are my thoughts on some of the comments the FDA made regarding the design of the tolebrutinib studies, particularly HERCULES, and the effectiveness data that was presented.

The FDA’s Complete Response Letter to Sanofi regarding tolebrutinib is publicly available here:

https://download.open.fda.gov/crl/CRL_NDA219624_20251223.pdf

The FDA’s first argument is that the HERCULES trial population itself is not sufficiently well defined.

Sanofi, like other manufacturers conducting BTK inhibitor trials in MS, chose to define its study population as non-relapsing rather than non-active secondary progressive MS. In other words, participants were required to have no recent clinical relapses, but not necessarily an absence of MRI activity.

I agree with the FDA that the target population is not well defined.

Tolebrutinib is a drug with a dual theoretical mechanism: it acts on the peripheral immune system, through modulation of B cells, and it is also thought to exert effects within the central nervous system, through modulation of microglia. Its promise in progressive MS rests largely on the latter, its potential to address compartmentalized, smoldering inflammation that drives progression independent of relapses.

By including patients with active disease, the trial blurs an important line. It becomes difficult to determine whether the observed benefit reflects an effect on progression biology within the CNS, or whether it is driven, at least in part, by suppression of peripheral inflammatory activity.

That distinction matters.

If the drug’s apparent efficacy is mediated through its effect on disease activity, then we already have therapies that are more effective at controlling peripheral inflammation and carry less risk than tolebrutinib. In that context, accepting a higher safety burden becomes much harder to justify.

I gather from this statement that the FDA requested additional subgroup data from Sanofi. And I know many of us have been asking for such analyses. As the full extent of the subgroup findings have not yet been published, we are limited to what is reported in the FDA’s letter.

According to that summary, when the FDA examined how tolebrutinib performed across different subgroups, the treatment effect appeared strongest in participants who had evidence of active inflammation on MRI at baseline, specifically, those with T1 gadolinium-enhancing lesions. In this subgroup, which represented about 13% of the study population, tolebrutinib was associated with a clear reduction in the risk of progression. In contrast, among participants without gadolinium-enhancing lesions at baseline, the estimated treatment effect was smaller. The confidence interval for this group crossed 1, meaning the result did not quite meet conventional thresholds for statistical significance.

These subgroup analyses are not sufficient to conclude that tolebrutinib does not slow progression in people with non-active SPMS. Subgroup analyses are inherently exploratory, and absence of statistical significance is not the same as absence of effect. Still, the pattern is notable. This does not close the door on tolebrutinib’s potential role in non-active SPMS, but it does give me pause and it reinforces why clearer population definition and more precise benefit signals matter so much when we are asked to accept higher risk.

This is entirely correct in my opinion.

In my own practice, the patients with whom I had discussed the possibility of switching to tolebrutinib prior to this FDA decision were individuals experiencing gradual disability progression despite being on high-efficacy disease-modifying therapies, with no evidence of ongoing disease activity on MRI or serum biomarkers.

That is the population for whom a drug like tolebrutinib would, in theory, offer something distinct.

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Is there a way forward for tolebrutinib?

Yes, I believe there could be a way forward for tolebrutinib.

From my interactions with the folks at Sanofi, I believe they care deeply about meeting the needs of people living with progressive MS. They now have a 12-month window to put forward their strongest case. In my view, for tolebrutinib to have a meaningful chance of approval, two parallel strategies will be essential: refining the target population and stratifying risk.

Better defining the target population and window of opportunity

When I look back at what has been the most transformative shift in MS therapeutics, the widespread adoption of high-efficacy treatments stands out. That transformation did not occur because of a single breakthrough, but through two sequential developments. First, therapies with strong efficacy and acceptable safety profiles, most notably B-cell–directed treatments, became available. But just as importantly, the MS community collectively defined the right window of opportunity for their use: early in the disease course.

That insight fundamentally changed clinical practice. Instead of waiting for treatment failure and escalating stepwise, we moved toward earlier, proactive intervention. The result was twofold: better control of relapses and disability accumulation, and fewer adverse events, as we treated younger patients with fewer comorbidities and lower infection risk. Had we continued to reserve these therapies for later stages of disease, their full potential would never have been realized.

The same principle must apply to therapies developed for progressive MS. It is not enough to develop drugs that might target progression, we must also develop a clear understanding of how to use them. That challenge can be distilled into two questions: who stands to benefit most, and when is the optimal time to intervene?

This is where uncertainty persists with tolebrutinib.

The population with the greatest unmet need includes those who continue to experience disability progression despite optimal control of inflammatory disease activity. I deliberately avoid traditional labels such as RRMS, SPMS, or PPMS. MS is one disease, and progression independent of overt inflammatory activity occurs across labels. I see these patients every week in my clinic. Their steady decline is devastating, not just clinically, but personally.

Many do everything asked of them. They exercise, eat well, take recommended supplements, educate themselves, and remain deeply engaged in their care. And yet, despite their best efforts, progression continues. These are the individuals most willing to accept risk to slow the relentless course of their disease. I believe Sanofi needs to rise to this challenge and examine this population with particular care.

One starting point would be a deeper exploration of existing data from the HERCULES trial and its long-term extension. At the ACTRIMS 2025 meeting, Sanofi presented intriguing subgroup analyses from GEMINI I and II and HERCULES, suggesting greater delays in progression among individuals with paramagnetic rim lesions (PRLs) at baseline. Because PRLs are thought to reflect chronic active lesions marked by ongoing microglial activation, these findings raise the possibility that identifying patients with microglial-driven pathology could help refine the target population for tolebrutinib.

The challenge, of course, is that PRL detection is not yet routine and remains difficult to operationalize in everyday practice. For that reason, attention may need to shift toward biomarkers that are more readily deployable, such as serum glial fibrillary acidic protein (GFAP), to determine whether they can help identify patients most likely to benefit.

Finally, tolebrutinib’s approval in the United Arab Emirates since August 2025 presents a unique opportunity. Real-world use, if paired with a thoughtful and rigorous Phase 4 program, could help answer questions that clinical trials alone cannot, particularly around effectiveness, safety, and patient selection. Close partnership with prescribers in the UAE may allow Sanofi to generate the kind of pragmatic data needed to reduce uncertainty and clarify where tolebrutinib fits in the treatment of MS progression.

Predicting risk

This may be an unpopular opinion, but I do not think the situation we are facing with tolebrutinib is directly comparable—at least not yet—to what happened with natalizumab (Tysabri). I have written more about this previously, but the key distinction is this: once cases of PML began to emerge after natalizumab’s approval, it quickly became clear that the risk was not entirely idiosyncratic. Prior treatment exposure and duration of therapy were identified early as major risk factors, and the addition of JC virus serostatus ultimately allowed us to personalize treatment decisions in a meaningful way.

With tolebrutinib-associated drug-induced liver injury, the risk currently appears less predictable, and that is the central challenge. If liver injury is treated as purely idiosyncratic, it becomes difficult to justify exposing patients to that risk. History suggests, however, that many serious cases of drug-induced liver injury initially appear unpredictable, until patterns are carefully sought.

The path forward is not to dismiss the risk, but to understand it. That means systematically comparing patients who develop liver injury with those who do not, and looking beyond routine liver tests to identify clinical, biological, genetic, and pharmacokinetic factors that confer susceptibility. Rare toxicity becomes more acceptable when it is no longer mysterious.

What would truly change the conversation is evidence that liver injury risk can be anticipated, detected early, or meaningfully reduced through patient selection and monitoring. Mechanism-informed biomarkers, pharmacogenomic signals, exposure–response analyses, and real-world validation of safety strategies could transform a diffuse safety concern into a stratified risk. That is the difference between asking patients to take a leap of faith and offering them an informed choice.

In diseases with serious unmet need, like progressive MS, risk IS acceptable, but only when it is understood, contextualized, and paired with clear evidence of benefit.

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Why MS progression trials need to change—and how

Beyond the specifics of tolebrutinib, the recent letter from the U.S. Food and Drug Administration to Sanofi offers lessons for how future trials in progressive MS should be designed, especially if the goal is to demonstrate benefit in patients with non-active disease.

At the heart of the FDA’s message is a simple but increasingly unavoidable truth: population definition matters more than ever.

For decades, clinical trials in multiple sclerosis followed a familiar template. Define a diagnostic category, enroll a broad population, randomize, and wait. That approach served us well in an era when relapses were frequent, inflammatory activity was easy to capture, and treatment effects were large enough to measure over relatively short periods of time.

But progressive MS has exposed the limits of that model.

Progression is slow, heterogeneous, and biologically complex. Patients who share the same diagnostic label may be driven by very different underlying mechanisms. As therapies move beyond suppressing inflammation toward targeting CNS-intrinsic processes, the cost of imprecision becomes harder to ignore.

The FDA’s letter did not just raise concerns about one drug. It highlighted a deeper tension: our traditional trial designs are struggling to keep up with the biology we are now trying to treat.

That tension is why I believe the field needs to move toward a different way of thinking about trials: one that is more biology-driven, patient-centered, and ultimately platform-based.

Biology-driven trials: aligning mechanism with population

Being biology-driven means asking, from the outset, whether the mechanism of the drug, the biology of the enrolled population, and the outcomes being measured actually align.

One of the FDA’s core concerns was interpretability. When trials enroll patients with different underlying drivers of disease, it becomes difficult to know why a drug appears to work or whether it is offering something meaningfully distinct from existing therapies.

Biology-driven trials are designed with this problem in mind. Their goal is not to eliminate heterogeneity altogether, but to reduce the kind of heterogeneity that matters mechanistically. When biology, mechanism, and population are misaligned, subgroup analyses proliferate after the fact. When they are aligned, trials become easier to interpret, and regulators, clinicians, and patients can have greater confidence in what the results actually mean.

Biomarkers offer a way to move past heterogeneous diagnostic categories and ask more precise questions:

• Is progression accelerating or stable?

• Is there evidence of inadequately controlled inflammatory activity?

• Are there features suggesting ongoing compartmentalized CNS inflammation?

Blood-based markers, imaging features, and digital measures do not replace clinical judgment but they add critical context. They allow trials to enrich for patients who are biologically aligned with a drug’s proposed mechanism, rather than hoping that a broad population will contain enough responders to generate a signal.

It is time for the MS research community to better leverage these existing tools in research and broaden their implementation and access in clinical practice, so patients can be matched to the right trials based on their individual biology.

Patient-centered: starting with people, not protocols

A patient-centered trial model begins with a simple but profound shift in perspective.

Instead of asking, “How do we recruit patients into this trial?” it asks,
“How do we build a system that allows patients to participate in research over time, as their disease evolves?”

In traditional clinical trials, participation is episodic. Patients are screened once, enrolled once, and then exit the research ecosystem when the trial ends or when they no longer meet eligibility criteria. For a disease like MS, where biology, disability, treatment exposure, and life circumstances change over years, this episodic approach is poorly aligned with reality. It treats patients as static snapshots rather than as individuals on a trajectory, and in doing so, it misses valuable information about how disease evolution, prior therapies, and accumulated burden shape both response and risk.

A patient-centered model would treat research participation as longitudinal rather than transactional. Patients consent once to share data over time, to remain visible to the research ecosystem even when they are not actively enrolled in a trial, and to be recontacted as new opportunities emerge. Their clinical history, imaging, biomarkers, and outcomes do not disappear when a protocol ends, they continue to inform future questions. Additionally, by following patients over time, we reduce the burden on individuals to constantly search for trials and instead place that responsibility on systems designed to match the right patient to the right study at the right moment.

Platform trials: building infrastructure that learns over time

Platform trials have the potential to bring these ideas together.

A platform trial is a different way of running investigational studies, one designed to learn continuously rather than starting from scratch each time. Instead of testing one drug in one trial and then shutting everything down, a platform trial creates a standing research framework with shared patients, shared comparison groups, and shared measurements. New treatments can be added as they become available, and ineffective ones can be dropped, without restarting the entire trial process.

In plain terms, it is like building a permanent testing ground rather than a series of pop-up experiments. Patients do not have to keep re-enrolling, fewer people receive placebo, and researchers can more quickly learn who benefits from which intervention.

For progressive MS, where change is slow and biology varies from person to person, this approach offers a path to clearer answers while making better use of patients’ time and trust.

At the core of such a platform would be a standing, longitudinal patient cohort: deeply phenotyped, consented once, and followed over time. Trials are then layered onto that infrastructure, matching patients to studies based not just on diagnosis, but on biology, trajectory, and timing.

Key features would include:

• clinical, imaging, and biomarker data collected longitudinally

• Continuous reassessment of trial eligibility as disease evolves

• Enrichment strategies based on mechanism, not just diagnostic labels

• The ability to test multiple interventions within a shared framework

While platform trials have not yet been fully embraced in progressive MS, similar models have emerged in other neurologic conditions. Initiatives such as ALS MyMatch in amyotrophic lateral sclerosis, DIAN-TU in genetically determined Alzheimer’s disease, and GBM AGILE in glioblastoma all reflect a shared philosophy: building patient-centered, biology-driven research ecosystems capable of answering complex questions in high-need diseases.

Building this kind of infrastructure for progressive MS nationally, and perhaps internationally, will require teamwork, a shared vision, agreement on target populations, standardized biomarker and imaging pipelines, harmonized outcome measures, and a safety infrastructure that matches the potential risks of future therapies. It will also require rethinking governance and funding models to ensure that the ecosystem is durable. It is not easy, but it is exciting!

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Conclusion

Taken together, the FDA’s letter should not be read as a rejection of innovation in progressive MS, but as a signal that the next phase of progress will demand greater precision. Therapies like tolebrutinib are forcing us to confront a new reality: when benefits are likely to be heterogeneous and biology-dependent and when risks are real, we need to go beyond broad labels, one-off trials, or post hoc explanations. Patient-centered, biomarker-driven trials offer a way to align mechanism, population, and outcome from the start, while honoring the urgency felt by people living with MS progression. If we are going to ask patients to accept greater uncertainty and greater risk, we owe them trials that are clearer, smarter, and built for the complexity of the disease we are trying to treat.

Caring for people living with progressive MS has become one of the most challenging aspects of modern MS care. The disease can be relentless, and once progression begins, our options to meaningfully alter its course remain painfully limited. Against that backdrop, this decision landed heavily for clinicians, researchers, and, most importantly, for people living with progressive disease.

The FDA’s Complete Response Letter is publicly available here:

https://download.open.fda.gov/crl/CRL_NDA219624_20251223.pdf

I believe it is important for us, as a community, to carefully dissect and reflect on what this letter actually says. It is a complex document that approaches the problem from multiple angles (safety, effectiveness, target population, and trial design) and it is not always straightforward. Reasonable experts may read this letter and come away with different interpretations. That, in itself, is not a failure; it is part of the process of grappling with difficult and consequential decisions.

In a previous piece, I wrote that the art and science of modern MS care lies in pairing innovation with vigilance, optimism with responsibility. I reflected on past examples in MS where serious complications only became fully apparent after FDA approval. There is no doubt in my mind that safety must come first. MS is a marathon, not a sprint. Without an acceptable safety profile, no medication, no matter how promising, can have a meaningful or lasting impact on the millions of people living with this disease.

With that in mind, I propose that we look objectively at what we know from the trial data and from the FDA’s letter about the safety concerns associated with tolebrutinib. We will examine not only how concerning these signals are in isolation, but also how they compare with liver safety profiles of other BTK inhibitors already approved in different conditions, and how they fit within the broader historical context of drug development and regulatory caution in MS.

In a future piece, I will explore more deeply what this letter signals for the future of clinical trial design and drug development in progressive MS. The FDA’s concerns raise fundamental questions about how we define progression, how precisely we select and describe patient populations, and whether our current clinical descriptors truly capture the biology we aim to treat. They also challenge us to examine whether traditional endpoints and subgroup analyses are sufficient for regulatory decision-making in this space. Ultimately, how we respond to these signals may shape which therapies ever make it to patients.

Safety concerns at the forefront

“The Division has determined that the data are insufficient to support a claim of slowing disability accumulation independent of relapse activity, particularly in the context of the significant risk of DILI, because of the reliance on post hoc analyses; the uncertainties regarding the concept of disability accumulation independent of relapse activity; the limitations of the mechanistic rationale; and the negative results of Study EFC16035 [PERSEUS trial of tolebrutinib in PPMS] on cCDP.”
— FDA Complete Response Letter to Sanofi

At its core, the FDA’s decision comes down to benefit–risk balance. While tolebrutinib showed signals of efficacy in some analyses, meeting its primary endpoint in non-relapsing secondary progressive MS and demonstrating secondary effects on confirmed disability worsening in relapsing MS trials, what ultimately tipped the scale was safety. The FDA identified a concerning rate of severe drug-induced liver injury (DILI), including a fatal case. The agency made it clear that even meaningful efficacy signals cannot offset a safety risk of this magnitude unless the benefit is both unequivocal and uniquely necessary. In this case, the FDA concluded that the observed benefits were neither sufficiently robust nor clearly attributable to the intended population of people with non-relapsing secondary progressive MS.

What are DILI and Hy’s Law?

DILI, or drug-induced liver injury, refers to liver damage caused by a medication rather than by viral hepatitis, alcohol, or other medical conditions. Clinically, DILI spans a wide spectrum from asymptomatic laboratory abnormalities, such as mild ALT or AST elevations that resolve on their own, to severe hepatitis, liver failure, transplantation, and death. The challenge is that the most dangerous forms of DILI are often unpredictable, not clearly dose-dependent, and not reliably prevented simply by “being careful.”

When the FDA refers to Hy’s Law cases, it is not invoking a technicality, it is raising a warning flare. A Hy’s Law case describes a specific and concerning pattern: hepatocellular injury (markedly elevated ALT or AST) accompanied by jaundice (elevated bilirubin), without an alternative explanation. Historically, the presence of Hy’s Law cases during development has been associated with a meaningful risk of severe liver injury once a drug is used more broadly.

This matters because clinical trial populations are not the real world. Trial participants are carefully selected: they tend to be younger, have fewer comorbidities, and agree to frequent visits and laboratory monitoring. Once a drug enters routine clinical practice, those guardrails disappear. Patients may have unrecognized underlying conditions, competing medications, or inconsistent access to laboratory testing. Even the most attentive clinician cannot fully control those variables. This is why the FDA places such weight on a Hy’s Law signal: it remains one of the strongest pre-market predictors of rare but life-threatening hepatotoxicity.

How concerning was the DILI signal with tolebrutinib?

In its Complete Response Letter, the FDA described the risk of severe DILI with tolebrutinib as “substantial and unusually high,” not only within the context of MS, but across drug development more broadly. The agency reported six cases meeting Hy’s Law criteria among approximately 2,700 Phase 3 participants, including one patient who required a liver transplant and later died.

This is the key point. The concern was not that liver enzymes were occasionally elevated. It was the presence of rare, severe, and potentially fatal liver injury: the kind of risk that fundamentally alters the benefit–risk calculus in a chronic disease where treatment may continue for years.

Why might liver injury occur frequently with tolebrutinib?

One possible contributor to the liver safety signal observed with tolebrutinib relates to drug selectivity, or how precisely a medication engages its intended biological target. More selective agents are designed to act narrowly on BTK, whereas less selective compounds may interact with additional proteins or signaling pathways beyond their primary target. In the liver, where drug metabolism and immune regulation are tightly intertwined, such off-target interactions may disrupt normal hepatic balance in some individuals. Rather than producing predictable, dose-related toxicity, this can manifest as rare liver injury that is difficult to anticipate or prevent.

How does this compare to other FDA-approved BTK inhibitors?

BTK inhibitors are not new to the FDA. Several are already approved in hematologic and oncologic indications—a very different clinical context—and their labels make it clear that liver enzyme elevations do occur. However, the pattern seen with these agents generally resembles laboratory abnormalities rather than a clustered signal of Hy’s Law cases, liver transplant, or death.

Currently, four BTK inhibitors are FDA-approved for hematologic or oncologic use (ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib), and one, remibrutinib, is approved for chronic spontaneous urticaria. Notably, remibrutinib is also being studied in MS.

Among these agents, the hepatic safety profile appears most favorable for remibrutinib. In its pivotal trials, no potential Hy’s Law cases were identified, and rates of transaminase elevations were very low. This may relate to its highly selective BTK inhibition and its binding to an inactive BTK conformation, which may limit off-target effects.

Acalabrutinib shows more variable rates of transaminase elevations depending on trial design and whether it is used in combination therapy. In the ECHO trial (mantle cell lymphoma treated with bendamustine and rituximab), AST increased in 53% and ALT in 44% of patients, with Grade 3–4 elevations in 5% and 7%, respectively. In monotherapy trials, however, rates were notably lower, with ALT elevations around 15–20% and AST elevations around 13–17%.

Zanubrutinib generally demonstrates low rates of transaminase elevations in clinical trials, most commonly Grade 1–2. However, a single documented Hy’s Law case after approximately 30 months of treatment serves as an important reminder that severe DILI can occur, even if rarely, long after treatment inception. In that case, a hepatocellular injury pattern was observed, with complete resolution after drug discontinuation.

Pirtobrutinib has also shown relatively low rates of Grade 3–4 transaminase elevations (approximately 1.6–2.8%), broadly comparable to other more selective BTK inhibitors.

Ibrutinib, by contrast, has documented post-marketing cases of hepatic failure, including acute and fatal events, though specific Hy’s Law cases have not been well described in the literature. In clinical trials, AST elevations occurred in approximately 25% of patients, with Grade 3–4 elevations in about 3%.

This comparison requires nuance. These data are not directly comparable to MS trials: they involve different diseases, different baseline risks (including hepatic involvement and polypharmacy), different trial designs, and different standards for laboratory reporting.

Still, the directional signal matters. Liver enzyme elevations are common across the BTK inhibitor class, but the FDA’s concern with tolebrutinib centers on a pattern consistent with severe, clinically consequential DILI, including multiple Hy’s Law cases and a transplant-associated death. That combination, not isolated lab abnormalities, is what causes regulators to pause and reassess.

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Why a REMS may not be enough for severe DILI

What is a REMS program?

A REMS, or Risk Evaluation and Mitigation Strategy, is a safety program required by the FDA when a medication carries serious known or potential risks that cannot be adequately managed through standard labeling alone. The goal of a REMS is straightforward in theory: to reduce the likelihood or severity of serious harm while still allowing patients access to a medication that may offer meaningful benefit.

In practice, a REMS can include one or more of the following components:

• Special patient education (such as medication guides or consent forms explaining risks)

• Provider certification or training requirements

• Mandatory laboratory monitoring

• Pharmacy restrictions (limiting dispensing to certain pharmacies)

• “No test, no drug” rules, in which medication cannot be dispensed without up-to-date safety labs

Idiosyncratic DILI is fundamentally hard to risk-manage

The most concerning forms of DILI are idiosyncratic, meaning they are not predictable based on dose, duration, or obvious clinical risk factors, and they are not reliably prevented by avoiding certain comorbidities. While we do not have full public details of the REMS program Sanofi proposed for tolebrutinib, it appears to have included frequent liver monitoring, with weekly labs likely for a defined period after treatment initiation rather than indefinitely.

For many drugs, liver tests function as a smoke detector, not a fire extinguisher. Monitoring ALT, AST, and bilirubin can sometimes identify early injury and prompt drug discontinuation. But the FDA’s concern here is that tolebrutinib may cause rare, severe, and occasionally rapidly progressive liver injury, events in which stopping the drug may come too late for some patients. When the potential outcome is liver failure, transplant, or death, “we’ll monitor closely” may not be an adequate mitigation strategy.

A REMS assumes near-perfect real-world execution and real life is never perfect

REMS programs work best under ideal conditions: labs are easy to obtain, results return quickly, clinicians consistently review them, patients can reliably comply, and systems enforce “no lab, no drug” rules.

In real-world practice, however, friction is unavoidable. Missed lab appointments, delayed results, holiday gaps, insurance changes, travel, alert fatigue in electronic health records, and unclear lines of responsibility between neurology, primary care, and pharmacy all introduce vulnerability. If the residual risk after imperfect adherence remains high, the FDA may reasonably conclude that a REMS cannot render the benefit–risk balance acceptable.

Risk tolerance in MS is different than in oncology and a REMS doesn’t change that

In oncology, patients and regulators may accept higher toxicity because the alternative is often limited survival. MS is fundamentally different. Treatment is typically long-term, and many patients will live for decades with the disease. In that context, even very rare catastrophic adverse events become difficult to justify, particularly when the benefit signal is modest or uncertain and potential exposure could be widespread.

A REMS can reduce some risk, but it cannot erase the ethical and clinical weight of rare, irreversible harm in a chronic disease.

Haven’t we gone through this already in MS?

No, this is not Tysabri

It is natural to look for historical parallels in moments like this, but the comparison to Tysabri (natalizumab) ultimately falls short in my opinion. Tysabri entered the MS landscape as the first truly high-efficacy therapy at a time when many patients had exhausted the available injectable options. Its clinical benefit was large, immediate, and unmistakable, transforming outcomes for thousands of people who had failed platform therapies. Crucially, its most devastating risk, progressive multifocal leukoencephalopathy (PML), was not observed during clinical trials and only emerged after post-marketing use.

In real-world data, the estimated risk of PML during the first two years of treatment ranged from approximately 0.01 to 1 per 1,000 patients per year. Importantly, this risk was not entirely idiosyncratic. Early on, risk factors such as prior use of immunosuppressive therapy were identified, and the later introduction of anti-JCV antibody testing allowed clinicians to individualize treatment decisions and meaningfully stratify risk. That context changed everything for patients and prescribers. Even then, it is also fair to wonder whether Tysabri would have been reintroduced after the initial PML cases had it been 2020 rather than 2006, when multiple safer high-efficacy options already existed.

Tolebrutinib presents a fundamentally different scenario. Here, serious safety signals, specifically severe drug-induced liver injury, were already visible during clinical development. Unlike PML with Tysabri, these events occurred before approval, not after. If such a drug were used broadly, it is reasonable to anticipate that clinically significant liver injury would occur at a higher frequency than PML ever did with natalizumab. At the same time, the magnitude of benefit appears more modest: a reported 31% delay in time to confirmed disability progression is unlikely to have the same life-transforming impact that Tysabri offered many patients in the mid-2000s. Taken together, this is not a story of extraordinary benefit tempered by rare, late-emerging risk, but one of moderate benefit—or in the FDA’s own words, uncertain benefit, though I will debate this in my next piece— confronting early and serious safety warnings.

Why this feels closer to Zinbryta

In many ways, the FDA’s response to tolebrutinib feels closer to the lesson of Zinbryta than to Tysabri. Zinbryta (daclizumab) was approved by the FDA in 2016 for relapsing forms of MS and withdrawn worldwide in 2018, less than two years later, not because it lacked efficacy, but because of serious, unpredictable immune-mediated toxicity. These toxicities included severe autoimmune hepatitis, fulminant liver failure, immune-mediated encephalitis and meningoencephalitis, and fatal outcomes, sometimes in patients who had previously appeared stable on therapy.

Importantly, meaningful safety signals were already present during Zinbryta’s clinical development. Immune-mediated liver injury and broader signs of immune dysregulation were observed in trials. A review by Giovannoni and colleagues of three clinical studies of daclizumab (SELECT, DECIDE, and OBSERVE) identified three Hy’s Law cases with probable causality among 2,236 trial participants, a signal that, in retrospect, should have carried more weight. For context, the FDA reports six Hy’s Law cases among approximately 2,700 participants in the tolebrutinib program.

Rather than prompting a fundamental pause, the Zinbryta safety signal was managed through increasingly intensive monitoring requirements and a REMS that ultimately proved insufficient once the drug entered real-world use. The tragedy of Zinbryta was not that it failed to work, although by the time it was withdrawn, its efficacy had been surpassed by B-cell therapies, but that early warnings were rationalized away, and catastrophic outcomes continued despite safeguards.

Seen through that lens, the FDA’s decision on tolebrutinib reads less like regulatory paternalism and more like institutional memory: a clear unwillingness to approve a therapy when serious, unpredictable harm is already visible before approval and cannot be convincingly mitigated by monitoring alone.

None of this diminishes the urgency we all feel when caring for people living with progressive MS, or the disappointment that follows when a promising therapy stumbles. Safety is only one side of the equation but it is the side that must be addressed first. In the next piece, I will turn deliberately to the other half of this story: what the tolebrutinib data and the FDA letter do and do not tell us about clinical benefit, and what this means for the future of drug development in MS. Because thoughtful progress in this space will require holding both truths at once: the need to protect patients from harm, and the equally pressing need to move the field forward.

What makes this current moment feel particularly pivotal is the expected arrival of BTK inhibitors — medications that, unlike our existing disease modifying therapies (DMTs), don’t just target the peripheral immune system. They also reach the brain’s own immune cells, the microglia, long implicated in the slow smoldering biology of progression.

Recently, Roche announced positive results from two major trials of fenebrutinib, a BTK inhibitor, in both relapsing and primary progressive MS. According to their press release:

“The first (FENhance 2) of two pivotal RMS studies met its primary endpoint, showing investigational fenebrutinib significantly reduced relapses compared to teriflunomide. In a pivotal PPMS study (FENtrepid), fenebrutinib slowed disability progression at least as effectively as OCREVUS, the only approved therapy in PPMS.”

This news comes as we’re also impatiently awaiting the FDA’s decision on another BTK inhibitor, tolebrutinib, which met its primary endpoint in the HERCULES trial for non-relapsing secondary progressive MS.

I’ve been in this field long enough to appreciate just how transformative the past two decades have been. I remember the excitement around Tysabri, our first high-efficacy DMT. Then Gilenya, the first oral therapy. Then the sweeping change brought by Ocrevus and the wave of B-cell–depleting therapies. Each era brought both hope and humility.

Because the approval of a new class of medications isn’t the end of the story — it’s the beginning. And from my perspective, it comes with responsibility.

As clinicians, our first responsibility is to keep patients safe. Clinical trials give us invaluable safety data, but much of what we ultimately learn emerges later, from real-world use. PML, the dreaded brain disease caused by the reactivation of the JC virus, for example, was not seen during Tysabri’s trials but surfaced after approval. The same with Gilenya, when rare but serious cardiac complications were recognized later and reshaped how we start the medication today.

Ensuring safety means constantly balancing benefit and risk: identifying who is most likely to benefit (and sparing those unlikely to) and making sure those who do respond can stay safely on therapy. That, to me, is the art and science of modern MS care: pairing innovation with vigilance, optimism with responsibility.

From Relapses to Progression: A Harder Story to Read

As we step into this new era of BTK inhibitors, therapies that promise to finally target the progressive component of MS, we’re confronted with profound questions:

Who is the right candidate?

When is the optimal window to intervene?

And how will we know, with confidence, whether a treatment is helping or not?

Right now, what we know comes from trial publications: if you take a group of individuals labeled as having “progressive MS” by their neurologist who didn’t have a clinical relapse in recent years, starting a BTK inhibitor reduces the risk of progression events as measured by the EDSS, a disability scale that leans heavily on walking ability. We also know that a subset of patients will develop liver enzyme abnormalities, and in rare cases, these will be serious. What we don’t know yet is how to apply this knowledge to individual patients who will inevitably look different from typical trial participants.

There is every reason to be excited about the data we’ve seen so far. These results represent real scientific progress and genuine hope for people living with MS. More options, especially for progression, are something the field has been waiting decades for. And I am wholeheartedly here for that.

But if we don’t ask the harder questions about who will benefit, who won’t, and how we’ll know, we risk swinging in either direction: underutilizing treatments that could have changed someone’s trajectory, or overutilizing them in ways that expose people to unnecessary risk.

In relapsing MS, the story has always been more straightforward. We’ve had a clear framework for activity — relapses — and reliable surrogate markers — new MRI lesions — that let us judge treatment effectiveness with reasonable clarity. When a treatment works, it’s usually obvious. When it doesn’t, that too becomes clear relatively quickly.

Progressive MS is a different story. It unfolds slowly, subtly, and often against the backdrop of aging, vascular changes, lifestyle factors, and comorbidities that blur the line between “MS progression” and what some of us call “progression independent of MS.”

We still don’t have tools that can reliably tell us, early on, who is progressing or why. We lack strong surrogate markers that capture the biology of progression the way MRI captures relapsing disease. And without those, it will be incredibly difficult to determine whether a treatment is appropriate and whether it’s working.

An example from the clinic

Let’s take an example that captures the challenges clinicians and people living with MS will face as we enter this new era.

Jeannine is a 62 year old woman on Ocrevus experiencing worsening of lower extremity weakness and spasticity. She started to use a cane 12 years ago following a particularly severe relapse, but now relies more and more on her walker to go around. She tells me that everything has felt harder this past year. She is eager to feel better and read about BTK inhibitors online. She wonders if she should plan to switch to one of these medications when they become available.

If you just look at the surface, you may think it is a straightforward answer. Our patient is experiencing worsening, why not try a BTK inhibitor? This may be where the conversation ends if doctor and patient have only 15 min to spend together, as is so often the case in modern medicine. But fortunately, I have more time, and I don’t like easy answers.

As we continue talking and scratch beyond the surface, I learn that she recently divorced, had to move from the house where she had lived in for 25 years to an apartment, and has become more sedentary this past year. She’s not sure what came first: did her neurologic function worsen because she’s been less active, or did she slow down because everything was getting harder?

She also reports more trouble finding words or staying focused, but she has been so overwhelmed and anxious with these life changes that she hasn’t slept well in months. Healthy routines have slipped, and she has gained 30 pounds over the past year.

When we finish talking, I complete a thorough exam. And while she feels certain that things are worse, I’m not seeing much change. Her strength is stable. Her gait over 25 feet is unchanged. Is she truly worsening if no meaningful change is detected on exam? I think so, but how frustrating it is to not be able to affirm her lived experience. And if she is indeed worsening, is microglial activation the primary driver or are deconditioning, mood, stress, and sleep playing an equal or even greater role?

Jeannine’s case highlights not only how difficult it can be to identify progression clinically, but how complex it is to interpret the lived experience of progression without tangible biomarkers of underlying biology. It also underscores the challenge and the responsibility of caring for whole persons, not diseases in isolation, each with their own circumstances, stressors, and stories.

Seeing the Invisible: How Digital Tools Can Help Us Measure Progression in the Real World

Where do we go from here, when our traditional tools aren’t good enough to detect the signals of progression early and clearly? When a 20-minute visit every 6 months cannot fully make sense of the 363 days between visits? An neurologic exam or EDSS score can’t capture fluctuations in gait at 4 p.m. or whether cognitive endurance is slipping by Friday afternoon. Even in well-controlled trials, only about 30% of progressive patients meet EDSS-defined progression. Does that mean the others are stable? No, it means our tools are blunt.

If we can’t detect progression as it starts, how can we identify who is best suited for treatments targeting progression? How can we measure their impact in a patient-centered way?

This is where digital biomarkers have the potential to transform our approach.

Over the past few years, we’ve seen a wave of innovation aimed at quantifying what used to be invisible — moment-to-moment function, consistency of movement, cognitive resilience, and lived experience — through both active and passive monitoring strategies.

Active monitoring tools require participation: answering patient-reported outcome surveys or completing structured tests at home through an app or platform. These data, collected at regular intervals in real-world settings, reveal performance trends that can uncover early decline before a 6-month or annual visit. Active monitoring shines because its structured, reproducible snapshots are like small controlled experiments we can repeat over time.

Passive monitoring is the quieter background layer that doesn’t ask you to do anything. Your smartwatch tracks sleep and activity; phone sensors pick up how you walk, type, or speak; motion detectors in your hallway can track gait speed as you move through the day. Instead of a snapshot, passive data give us a movie: continuous information about how you actually move, rest, and interact with your environment. It’s less polished, less structured, more difficult to interpret, but it reflects life as it is lived, not as it is tested.

In the hopefully near future, these tools will help us capture what we can’t see in clinic:

• Subtle, real-world declines in mobility, dexterity, or cognition

• Day-to-day variation that reflects fatigue, recovery, or resilience

• Digital “trajectories” that show whether a person is steadily declining, fluctuating, or truly stable

And importantly, I believe they will help us detect change much earlier than our current clinical measures. If we are heading into an era where treatments might be most effective early in the progressive phase, before irreversible tissue injury accumulates, then early detection becomes everything. Digital biomarkers may help us identify the window of opportunity for those therapies with much greater precision.

But capturing the lived experience of progression is only part of the solution. It tells us that something is changing, not necessarily why.

That brings us to the next set of innovations that will redefine how we evaluate progression, not just clinically, but biologically.

Looking Beneath the Surface: Serum and Imaging Biomarkers That Shed Light on Biology

Just as digital tools will provide a lens into day-to-day function, emerging serum and imaging biomarkers will allow us to peer into the underlying biology, the part we can’t observe, even with perfect monitoring.

Serum neurofilament light (NfL) has been a breakthrough in measuring inflammatory disease activity. In our clinic we use the MS Disease Activity (MSDA) test by Octave Bioscience, a multi-analyte panel that relies heavily on sNfL to calculate a score of disease activity (low/moderate/high). This test has been very useful in helping us understand who may or may not be responding to our current DMTs that target the peripheral inflammatory component of the disease.

Unfortunately, biomarkers like sNfL or the MSDA test are less informative for the slow-burn mechanisms of progression such as microglial activation, which is the target of BTK inhibitors. And a next generation of biomarkers is beginning to take shape.

Glial fibrillary acidic protein (GFAP), a biomarker of astrocytic injury, can predict disability progression and brain volume loss. Yet this innovation has not made its way into most MS clinics. Real-world implementation is often the limiting step hindering broad access to innovations: clinics need commercially available tests they can order with reimbursement strategies that don’t leave patients in the dark about whether they’ll be footing the bill. I am very interested in future developments that will make this technology, or possibly more sensitive multi-analyte tests, available in routine practice.

In the imaging field, advances have been equally compelling. Paramagnetic rim lesions (PRLs) are a specific type of MS lesion seen on specific MRI images called susceptibility-based sequences. They appear as dark rims around white-matter lesions, reflecting iron-laden, chronically activated microglia. Unlike acute inflammatory lesions, PRLs represent the slow, smoldering inflammation of chronic active MS lesions, a key mechanism believed to drive progression independent of relapses.

Because they capture this “chronic active” biology, PRLs have been proposed as a marker of progression risk, linked to worsening ambulation, greater brain atrophy, and cognitive decline. They offer a unique window into microglial activity, making them potentially valuable for evaluating who may be a good candidate for BTK inhibitors. But while promising, PRLs are not ready for routine use. Their detection varies across MRI scanners and protocols, and interpreting them reliably requires specific expertise many centers lack. They also represent only a subset of chronic active lesions and evolve slowly over years, which limits their utility for rapid treatment monitoring. We would need standardized imaging protocols and broader education of radiologists and neurologists before PRLs could be used at scale.

Conclusion

As we enter the BTK inhibitor era, we have a responsibility to rethink how we understand MS progression as a multidimensional process that touches biology, function, and lived experience.

Digital tools, serum biomarkers, and advanced imaging each offer part of the story. If we can harness these technologies, make them more broadly available, and weave them together with sound clinical judgement, we will gain a clearer and more patient-centered view of progression which will enable us to make more personalized treatment decisions.

If we want to use these new therapies wisely and equitably, this is the direction we must consider: toward a future where we can finally see progression as it unfolds (or even before it starts) and intervene when it matters most.

My clinic schedule changed a couple of months ago, and Mondays have become my longest days. I wear many hats as a clinician, researcher, educator, and clinic director and I used to think I’d prefer to ease into the week, using Mondays to get organized amid all those (sometimes competing) responsibilities. But this new rhythm has turned out to be a gift. Though fast and furious, Mondays now leave me with a full heart and words of wisdom from my patients that stay with me all week.

This week, I saw one of the very first patients I met after moving from France to Texas 13 years ago. Together, we’ve been through it all: the good years when her MS was stable and she was thriving in her career; then the storms—the real one, when Hurricane Harvey destroyed her home in 2017, and the metaphorical ones that followed as her MS progressed until she could no longer walk well on her own. But then came spring again: she reinvented her life, found joy where she was instead of looking in the rearview mirror, and began to thrive once more, differently, but fully.

As I left the clinic tonight, she texted to thank me for encouraging her and for the hug we shared. But the truth is, I’m the one who leaves inspired, strengthened by the grit, grace, and resilience of my patients.

To those of you who sometimes wonder if your life matters or if you’re making a difference: you are. The strength and wisdom you share with us carry us through and help us care for others more deeply. You are a gift. Thank you for letting us walk through the storms—and the springs—of life with you.

MS progression in practice

Last week, we dove into the history of MS clinical descriptors, the language we use to define “progression” and how it came to shape the MS world (especially the world of clinical trials). We sorted through the acronyms and categories that look tidy on paper. But as any clinician or person living with MS knows, the real story is never that neat.
People with MS are not a collection of symptoms or scores. They are whole persons, with histories and circumstances that can’t be captured by any acronym.

Let me introduce you to Rima.

Rima is 48 and has lived with MS for 22 years. She was diagnosed at a time when treatment options were scarce and daily injections were the norm. She still remembers feeling like a human pincushion, faithfully giving herself shots that too often failed to prevent new relapses. When oral medications arrived, she switched, hopeful, but the disease still simmered. Finally, six years ago, she moved to a B-cell therapy, and since then, things have been calmer: no relapses, no new lesions, quiet MRIs year after year.

She built a full life through it all. A demanding career as a paralegal, two teenagers, a marriage that weathered every storm. She’s vegan, disciplined, and walks daily. Her life, she says, has been good; busy, yes, but deeply meaningful.

Then, slowly, things began to change.

At first, it was subtle: searching for words, struggling to stay organized. Then came moments she couldn’t ignore, forgetting how to do tasks that once felt effortless. She told herself it was stress, grief maybe, after losing her sister to cancer, a loss that left a void she still feels every day. But time passed, and things didn’t improve. They worsened.

This year, for the first time in her 15 years at the firm, she was called into her director’s office. A conversation about performance. A conversation she never imagined she’d have.

As she told me this story, tears streamed down her face. Her husband sat beside her, gentle but worried. He’d noticed it too—the forgetfulness, the frustration, the anxiety that now wraps around her nights. She can’t sleep, wakes drenched in sweat, and often starts her days with pounding headaches.

And yet, when I examine her, the findings are subtle, almost deceptively so. She walks unassisted. There’s just a trace of imbalance if you look closely. But not much else.

This is the reality of MS care, the part that doesn’t fit on a spreadsheet. Symptoms that can’t be captured by scales. Lives that can’t be distilled into labels. And that’s where the real practice of medicine happens: in the spaces between definitions.

A Framework to Understand MS Progression in Practice

Situations like Rima’s are not rare. Making sense of them, so that we can truly help and make sound treatment decisions, isn’t always straightforward. Over the years, I’ve come to rely on a simple three-step process that brings structure and clarity to the complexity of MS progression.

Step 1: Listen

Identifying progression in a clinical trial dataset takes a good statistician and a powerful computer. Identifying it in the real world takes time and active listening.

Patients rarely come to clinic with tidy datasets in their pockets (though I hope neurodigital biomarkers will get us there soon). They come with stories. And those stories hold more information than any lab result or MRI scan.

I like to let my patients speak first, unfiltered, in their own words. Then I ask questions to deepen my understanding:
“Are there things you could do last year that you can’t do now?”
“What hobbies or activities have you had to give up?”
“Have coworkers, friends, or family noticed any changes?”

Listening is our first responsibility. Objective data is essential, of course: a detailed exam can uncover subtle worsening, and bedside tools like the Symbol Digit Modalities Test (SDMT) can reveal meaningful cognitive changes over time. But it all begins with listening.

Step 2: See the Whole Picture

When someone with MS experiences worsening, it doesn’t always mean that MS is to blame. This nuance is often lost in the world of clinical trials, where every change is assumed to be disease-driven. In reality, MS doesn’t exist in a vacuum.

Take Rima. Are we certain her cognitive difficulties are due to MS alone? Her story reminds us how many threads are intertwined in a person’s health:

• Grief and depression can cloud concentration and memory.

• A strict vegan diet, if not carefully supplemented, can lead to vitamin B12 deficiency, which itself causes cognitive impairment.

• At 48, perimenopause could be contributing to memory lapses, poor sleep, and hot flashes.

• And sleep apnea, present in up to half of people with MS, can cause non-restorative sleep, morning headaches, and brain fog.

Before attributing worsening to MS, we must take inventory of all possible contributors. This process takes time, curiosity, and compassion. But how many of us have seen someone with “progressive MS” suddenly improve after a hip replacement or successful treatment of another condition? Context matters.

Step 3: Understand What’s Driving It

As we discussed last week, true MS progression can occur in two main contexts:

• Relapse-Associated Worsening (RAW): progression linked to new inflammatory activity

• Progression Independent of Relapse or MRI Activity (PIRA or PIRMA): progression that unfolds quietly, without visible inflammation

These reflect distinct biological processes, and understanding which one is at play guides treatment.

Relapse-associated worsening stems from focal inflammation in the central nervous system. In the real world, though, it isn’t always obvious. A patient might not have a dramatic relapse but could show subtle stepwise changes alongside new MRI lesions. That’s why my first task is always to assess for evidence of disease activity, both clinically and radiologically. In my clinic, I also use serum biomarkers to detect inflammatory activity and guide whether escalation to a higher-efficacy DMT is warranted.

If progression persists despite optimized therapy and no evidence of disease activity, we begin to suspect other mechanisms, most notably microglial activation, the slow, smoldering process thought to drive neurodegeneration.

Emerging imaging and blood biomarkers may soon help us recognize this form of progression more precisely, but they haven’t yet made their way into routine care. That’s about to shift. As BTK inhibitors, drugs that act on both B cells and microglia, enter the field, understanding these underlying mechanisms will become essential in daily practice.

And that’s where we’ll go next week: exploring the innovations on the horizon that may finally help us address progression more effectively and more thoughtfully than ever before.

Progression is defined as “the process of developing or moving gradually toward a more advanced state.” It sounds straightforward enough. Yet in multiple sclerosis, the concept has proven anything but simple. Over the years, clinicians and researchers have proposed a succession of definitions and catchy acromyms to capture a process that is difficult to grasp, harder to measure, and sometimes impossible to pinpoint with certainty.

In this first part of our series on MS progression, I want to walk you through the evolving history of how the MS community has perceived and defined this elusive but crucial concept.

The Initial Clinical Course Descriptors

In 1996, Fred Lublin and colleagues published the first formal clinical course descriptors of multiple sclerosis. [1] They divided the disease into four categories: relapsing-remitting (RRMS), secondary progressive (SPMS), primary progressive (PPMS), and progressive-relapsing (PRMS). Progressive forms of MS were described as nearly continuous worsening though minor remissions and plateaus were allowed.

At the dawn of the MS therapeutic era, a common language had become essential. Multicenter clinical trials depend on enrolling relatively homogeneous patient populations with a predictable enough course to reveal whether a treatment makes a difference. The new clinical course descriptors accomplished exactly that. They were rapidly adopted into trial eligibility criteria and provided the structure needed to propel MS therapeutic research forward, a framework that arguably helped fuel the breakthroughs that followed.

Incorporating these terms into clinical practice, however, proved far messier. On one hand, the new vocabulary gave patients and clinicians shared words to describe lived experiences that had previously felt inarticulate or invalidated. For some, it was empowering to have a name for what they were feeling. For others, it brought confusion and fear. Progression in MS is rarely linear; it can be subtle, fluctuate over time, and resist neat categorization. Labeling someone as having “progressive MS” often felt premature or even cruel, a declaration of inevitability rather than a description of the present. “Progressive” became a heavy word in the clinic room, carrying with it an air of finality.

Clinicians, too, were uneasy. The classification system was rooted in clinical observation rather than biology. At the time, we lacked the imaging and biomarker data to meaningfully correlate clinical courses with underlying pathology.

By 2014, the need for refinement was clear. Lublin and colleagues updated the descriptors, [2] adding modifiers and integrating MRI findings to capture disease activity more precisely. The update acknowledged that people with relapsing disease can still experience disability worsening, and that those with progressive disease may have long periods of stability. These nuances introduced complexity and, at times, confusion but also a necessary recognition: progression is not confined to a single MS subtype. It can emerge across the spectrum, challenging our efforts to define the disease in simple, binary terms

Understanding Disability Progression Across the Spectrum of MS

While the 2014 clinical course descriptors have not yet been updated, the MS research community has turned its attention toward understanding how people with MS accumulate disability, regardless of which diagnostic “box” they fall into. Over the past decade, a growing body of evidence has confirmed that progression is not confined to the progressive forms of MS.

Starting in 2018, several pivotal studies analyzed large clinical trial datasets and real-world cohorts, revealing two distinct pathways to disability accumulation:

• Relapse-Associated Worsening (RAW): Disability that follows a clinical relapse, typically due to incomplete recovery.

• Progression Independent of Relapse Activity (PIRA): Disability accumulation that occurs without a preceding relapse.

A landmark study involving more than 27,000 patients followed for up to 15 years [3] demonstrated that PIRA often begins early in the disease course, even in those with relapsing-remitting MS, and gradually becomes the dominant driver of disability accumulation over time.

More recently, the acronym PIRMA (progression independent of relapse and MRI activity) has emerged and further refines the concept. PIRMA describes disability progression that occurs even if there are no overt relapses and MRI scans also appear stable, as disease activity can happen beneath the surface in MS.

This distinction between RAW and PIRA/PIRMA is not just semantic; it reflects fundamentally different biology and has profound therapeutic implications.

RAW is driven by peripheral inflammatory processes: immune cells activated outside the central nervous system that cross the blood–brain barrier to form new lesions and cause relapses. When the damage from these focal attacks is severe enough that axons are damaged and repair mechanisms fall short, residual disability remains. Because RAW is inflammation-driven, it can often be mitigated, even prevented, by today’s high efficacy disease-modifying therapies, which suppress focal inflammatory activity.

PIRA/PIRMA, on the other hand, stems from chronic, compartmentalized inflammation within the central nervous system itself, slow neurodegeneration, mitochondrial dysfunction, and the gradual failure of repair and plasticity mechanisms, processes that accelerate with aging. Unlike RAW, these changes persist despite effective control of relapses and MRI activity and can be manifest even in people optimally treated with high-efficacy DMTs.

In short, RAW is what our current therapies can prevent; PIRA is what remains.

Capturing subtle worsening

Although PIRA has been increasingly recognized as the key driver of disability accumulation across the MS spectrum, clinicians have criticized its current definition for relying too heavily on motor-based measures such as the EDSS, the disability scale most commonly used in clinical trials. More recent efforts have aimed to broaden this definition, incorporating additional assessments to make it more meaningful in clinical practice. Some have even proposed a new term altogether: smouldering-associated worsening (SAW).

The concept, introduced by Scalfari and colleagues in 2024, sought to expand beyond the EDSS-driven definition of PIRA to include more delicate shifts, motor or cognitive, that unfold even when inflammation appears to be under control. [4] It was also an attempt to tie these clinical observations to the biology we increasingly recognize: that progression can arise from slow, persistent processes within the brain itself, not just from new inflammatory storms.

It’s an appealing idea, and the name, SAW, has a certain poetry to it. Yet I can’t help but wonder whether we truly need another acronym. Perhaps, instead of multiplying definitions, we might do better to broaden PIRA itself, to let it breathe and stretch enough to encompass the nuances we see in our patients.

“Smouldering disease,” as the authors describe it, captures something vast, an umbrella of chronic neuroinflammation, neurodegeneration, failing repair mechanisms and impaired plasticity. It’s a compelling image, but perhaps too sweeping to serve as a compass in clinical trials, especially now that therapies are emerging to target these biological fires more individually.

And so we return to a familiar tension: the one between clinical simplicity and biological complexity. Every new term promises precision but risks losing practicality. The art, perhaps, lies in finding definitions and frameworks that illuminate without obscuring, and that serve both science and the people who live with the disease we are trying to understand.

I, for one, look forward to the next revision of the MS Clinical Course Descriptors by the International Advisory Committee on Clinical Trials in Multiple Sclerosis; [5] an update that will, I believe, bring together the lessons of the past decade and set the stage for the next wave of discoveries in how we understand and treat progression.

Next on the Unpacking MS Progression Series…

In part 2, I’ll take you inside my clinic to show how these definitions meet real patients, and how I make sense of it all in daily practice. Stay tuned.

References:

[1] Lublin, F. D., Reingold, S. C. & Sclerosis*, N. M. S. S. (USA) A. C. on C. T. of N. A. in M. Defining the clinical course of multiple sclerosis. Neurology 46, 907-911. (1996).

[2] Lublin, F. D. et al. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology 83, 278–286 (2014).

[3] Lublin, F. D. et al. How patients with multiple sclerosis acquire disability. Brain 145, awac016- (2022).

[4] Scalfari, A. et al. Smouldering‐Associated Worsening in Multiple Sclerosis: An International Consensus Statement on Definition, Biology, Clinical Implications, and Future Directions. Ann. Neurol. 96, 826–845 (2024).

[5] NMSS website (accessed October 2025) https://www.nationalmssociety.org/news-and-magazine/momentum-magazine/from-the-community/updating-how-we-classify-ms

Late September, I was in Barcelona for ECTRIMS, the world’s largest conference on MS and related disorders. Sunshine. 9,500 attendees. The latest breakthroughs in MS science. Every conversation and presentation seemed to echo the same message: MS is one disease, a biological continuum with a spectrum of clinical expressions.

And yet, as I sat in sessions about unifying biology, another reality was unfolding back home. My inbox filled with messages from staff: dozens of requests to “update” my patients’ diagnoses using the new ICD-10-CM codes for MS subtypes.

Until now, we had a single administrative code—G35. Simple, unified, reflective of what we know biologically. Then, quietly and without warning, new codes appeared. Suddenly, MS had been subdivided into eight administrative categories, fragmenting on paper what scientists had finally agreed was one disease.

MS as one disease

Research tells the true story: beneath the diagnostic labels, the same biology is at work. Inflammation, demyelination, axonal injury, and neurodegeneration occur across the full spectrum of MS. Brain scans reveal overlapping patterns of new lesions and atrophy. Under the microscope, the pathology is indistinguishable. In short, the biology is unified; the differences lie in degree and timing, not in kind.

Even the so-called transition from relapsing to secondary progressive MS, which new diagnostic codes mark as a distinct boundary, unfolds gradually. Many patients straddle that line for years.

This shared biology is echoed in treatment response. Therapies developed for “relapsing MS” also benefit people with progressive disease when inflammatory activity persists. The same drugs work across subtypes because they target the same underlying process.

Defining subtypes serves an important purpose, particularly in clinical trials, where they allow researchers to assemble more homogeneous groups and evaluate treatments against consistent endpoints. But they are clinical constructs, not biological divides. For people living with MS, this distinction matters deeply. It reminds us that your disease is not defined by a code or a checkbox, but by your individual course. Seeing MS as one disease allows us to move beyond rigid categories and embrace its true continuum, recognizing that while administrative systems may require labels, the lived experience of MS is far more fluid.

Why ICD-10 codes matter?

You might ask, why does this matter? Aren’t ICD-10 codes just bureaucratic shorthand?
Well, in reality, they carry tremendous weight in how care is delivered.

Every diagnosis entered into an electronic health record is translated into one of these codes. Those codes then ripple outward. To insurance companies deciding whether to cover a medication, to hospital billing systems determining reimbursement, to registries tracking outcomes, and even to researchers analyzing patterns of disease.

For a person living with MS, that ripple can feel like a wave. The “wrong” code can mean the difference between timely access to treatment or weeks of frustrating delays. Inconsistent coding can close doors to rehabilitation, clinical trials, or specialty programs that rely on those same diagnostic labels. And for clinicians, these codes shape quality metrics, workloads, and even how resources are distributed within their health systems.

That’s why the rollout of new ICD-10 codes isn’t just a bureaucratic footnote. It’s a shift with real consequences for patients, clinicians, and the future of MS care.

How is this going to play out in the real world?

Let’s imagine what this looks like in real life.

Maria is 48 and has been living with MS for more than a decade. Early on, she experienced relapses, but a high-efficacy therapy stopped all visible disease activity. In the past few years, however, she’s noticed a gradual decline in mobility, a right foot drop that’s become more pronounced.

At her next visit, Maria’s neurologist expresses concern about her immune markers and recurrent infections. Together, they decide it’s time to switch to a different medication, something that will give her immune system a break. Before wrapping up, her neurologist mentions the new ICD-10 codes. Because Maria has shown progression after a few initial relapses, it makes sense to use the secondary progressive MS code. And since she hasn’t had a relapse in years, they agree that “non-active secondary progressive MS” (G35.C2) best describes her current status.

The prescription is sent, and the insurance claim goes out with the new code.

Two weeks later, Maria receives a letter: her medication has been denied. The explanation is blunt: the treatment is not approved for non-active SPMS. Yet, under the previous umbrella MS code, it had been on formulary and covered without issue.

Maria’s biology hasn’t changed. Her disease hasn’t changed. Only the administrative label has.

Both she and her neurologist know that while she hasn’t had a relapse in years, the risk remains if treatment stops. But continuing her current therapy is too dangerous. Maria is devastated when she learns that no disease-modifying therapy is covered under her plan for non-active SPMS.

Her neurologist, already exhausted by the wave of changes these new codes have unleashed, steels himself for another peer-to-peer review. The next morning at 8 a.m., the insurance company’s pharmacist calls. The neurologist explains Maria’s case, passionately outlining why she still needs therapy.

“Does Maria have non-active SPMS?” the pharmacist asks.

“Yes,” he answers, “that’s the best descriptor for her right now, but her history and what we know about MS tell us she’s likely to relapse without treatment.”

“I’m sorry,” the pharmacist replies. “If the diagnosis is non-active SPMS, I can’t approve this medication. You can file an appeal.”

By lunchtime, Maria’s neurologist is drained. He spends his break drafting an appeal letter and faxes it immediately. Two weeks later, Maria receives another denial. She is left without treatment options.

Maria’s story may be fictional for now, but I suspect we will see many such cases within a matter of months, if not weeks. As the case-study illustrate, clinicians and patients make decisions for treatment based on future risk, whereas diagnostic codes are descriptors of past clinical course often already modified by the use of medications. The fact that payers can decide (and deny) coverage based on codes that are not aligned with our approach to clinical decision-making will have far-reaching consequences for patients and the clinicians who care for them.

At the patient level, we can expect delays in treatment, confusion, and distress when coverage is denied for reasons outside their control. Clinicians will have to explain why a chart now says “non-active SPMS” or “active SPMS”, labels that may feel like an unexpected reclassification or, worse, like a door closing on treatment.

At the clinic level, staff are already overwhelmed by the administrative burden of resubmitting orders for medications, rehabilitation, and equipment under updated ICD-10 codes. With the inevitable rise in denials, those willing to fight will spend even more time on appeals, time taken away from patient care. I suspect that it will be difficult to convey the nuances of MS pathobiology and clinical decision-making when the new coding system is so black and white, and many of these appeals may remain denied.

Where do we go from here?

The honest answer is: I don’t know.

Most of us felt blindsided by the rollout of these new diagnostic codes. How clinicians respond will be worth watching and I suspect it’ll look different across settings.

Most clinicians will do what they have to do for billing and insurance, meaning they’ll use the new codes even if they don’t fully agree with the distinctions. But there’s already frustration that these codes don’t reflect how we actually understand MS biology.

Neurologists are likely to anticipate denials when prescribing disease-modifying therapies, especially for people labeled with “non-active SPMS,” a category that currently has no approved treatment options, even though treatment may be needed to stay non-active. To navigate this, some may document even subtle signs of activity - a faint MRI change, a questionable relapse - to justify coding as “active SPMS” so their patients don’t lose access to therapy. Others may use the G35.D “Unspecified MS” code instead, though how payers will interpret that remains to be seen.

At this point, people living with MS need to be aware of the change. Ask your doctor which code they plan to use and how it might affect coverage for your medications or services.

Clinicians, for our part, need support and clarity, as well as flexibility from payers. Professional and patient organizations like the American Academy of Neurology, National MS Society, and MS Association of America should start collecting real-world examples of potential harm caused by coding-related denials. These stories matter. They often drive the revisions and policy updates that data alone can’t.

And I’d also challenge manufacturers to stay engaged, to keep supporting access to medications, even as denials increase.

I’m deeply interested in your thoughts on this.

• If you’re living with MS, have these new codes affected your care?

• If you’re a clinician, how are you approaching the new requirements?