3 Questions We Need to Ask as We Enter the BTK Inhibitor Era

But can't answer with the tools we currently have...

It’s an exciting time to be an MS specialist. Truly. I will never regret this career choice. Getting to work with incredible patients who inspire me daily while being part of a field so alive with discovery and innovation is a privilege I don’t take for granted.

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.

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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.

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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.

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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.

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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.