I attended a meeting last week where a KOL (key opinion leader) in the field of multiple sclerosis (MS) made the point that relapses and focal MRI activity (Gd-enhancing and new or enlarging T2 lesions) are MS, i.e. they are the disease and that suppressing relapses and MRI activity is what we aim to achieve with our disease-modifying therapies (DMTs). Do you agree?

I have spent the better part of a decade coming to the opposite conclusion that relapses and focal MRI activity are not the disease. They represent the immune system’s response to what is causing MS and that the real MS is smouldering MS.

If relapses and focal MRI activity were MS, then:

* Baseline relapse rates and MRI activity should be predictive of outcome

* Changes in disease activity over time are predictive of outcome

* Changes in disease activity due to DMTs should predict the outcome

These three criteria are called the Prentice criteria and are philosophical approaches to defining a surrogate outcome measure. Unfortunately, relapses and focal MRI activity don’t fulfil the Prentice criteria; therefore, they can’t be the disease by definition.

1. Baseline relapse rates and MRI activity should be predictive of outcome

In relapse-onset MS, the relapse rate and MRI activity in the first 2-5 years do predict the outcome. However, this does not hold up for people with primary progressive MS (pwPPMS). It could be argued that people with pwPPMS have had the disease longer by the time they present and get diagnosed; hence, the rule still holds that early activity is the disease and predicts the outcome. Unfortunately, we don’t have long-term follow-up data on very early PPMS or RIS-PPMS.

2. Changes in disease activity over time are predictive of outcome

Outside the initial 5-year window, the data on relapse rates and MRI activity predicting clinical outcomes is weak. This is one of the paradoxes in the field of MS and has been referred to in the past as the MRI-clinical paradox. If MRI activity was MS, it should predict the outcome regardless of where you are in the course of the disease.

3. Changes in disease activity due to DMTs should predict the outcome

This is where evidence against MS disease activity being MS is most substantial. It is clear from clinical trials that if you are on a DMT, then MS disease activity on therapy is a poor prognostic sign. However, the outcome is not predicted if you are on a placebo or no treatment. If MS is focal inflammatory disease activity, then it should predict outcome regardless of what treatment you are on. From a philosophical perspective, this point is critical and tells us that focal inflammation (relapses and MRI activity) cannot be MS. It is remarkable how many people don’t appreciate this point and ignore it.

Here are some examples to illustrate this point. Ocrelizumab exposure

The observation that pwMS with increasing ocrelizumab exposure do better despite a ceiling effect on relapses and MRI activity tells us that something is happening beyond focal inflammation. It has been shown that following the administration of ocrelizumab 600 mg every 6 months, serum concentrations of the drug are higher among subjects weighing <60 kg and lower among subjects weighing >90 kg, compared to subjects weighing 60-90 kg. This dose effect can be seen in levels of B-cell depletion but is not reflected in the reduction of relapses or focal lesions on MRI, as all levels of ocrelizumab exposures were associated with almost complete suppression of focal inflammatory disease activity. However, a dose effect is observed, with more significant prevention of disability progression in people with both relapsing and PPMS with higher levels of peripheral B-cell depletion.

This tells us that there is a disconnect between the pathological processes driving focal inflammation and those responsible for non-relapsing disability progression or smouldering MS. Based on these observations, we are now testing high-dose ocrelizumab (1200 mg or 1800 mg vs. 600 mg every 6 months) in two clinical trials (ClinicalTrials.gov Identifiers: NCT04117529 and NCT04548999). The hypothesis is that higher ocrelizumab exposure can target peripheral deep-tissue B-cells and CNS-resident B-cells, which drive smouldering MS beyond focal inflammatory events.

Ofatumumab vs. Teriflunomide

Ofatumumab, a fully humanised monoclonal anti-CD20 therapy, is superior to teriflunomide in suppressing relapses and focal inflammatory MRI activity but is no better than teriflunomide at slowing the rate of brain atrophy over 2 years. Despite its relatively modest impact on focal inflammation, teriflunomide’s effect on end-organ damage or smouldering MS is the same as that of ofatumumab.

Tolebrutinib vs. Teriflunomide or Placebo

More recently are the lessons from the Tolebrutinib phase 3 trials. Tolebrutinib is a second-generation BTK inhibitor (BTKi) with a dual mode of action. It inhibits BTK in B-cells and is an anti-inflammatory therapy. In both the relapsing and non-relapsing progressive MS trials, it had a relatively modest impact on relapses and focal MRI activity. In the relapsing trials (Gemini 1 & 2), tolebrutinib was not superior to teriflunomide in suppressing relapse activity, i.e. the relapse rates were similar, and it was inferior to teriflunomide in suppressing Gd-enhancing lesions.

Teriflunomide was superior to tolebrutinib in suppressing Gd-enhancing lesions but had a similar effect on new T2 lesions. This could be referred to as a Gd-enhancing-T1/T2-lesion paradox, implying that new Gd-enhancing lesions are less likely to form chronic T2 lesions in subjects treated with tolebrutinib. This indicates that tolebrutinib is changing the biology of how MS lesions evolve; i.e. it is doing something to the acute Gd-enhancing lesions that makes it less likely to leave a scar or new T2 lesion. Based on these preliminary observations, I suspect that in addition to fewer T2 lesions, tolebrutinib will also suppress the development of paramagnetic rim (PRLs) and slowly expanding lesions (SELs), both associated with worse MS outcomes.

However, despite being inferior to teriflunomide in suppressing focal inflammatory activity, tolebrutinib was superior to it when it came to disability progression., i.e. it has an impact on smouldering MS-associated worsening (SAW) but not relapses.

Tolebrutinib, therefore, dissociates relapses from disability progression and ‘proves’, yes proves, that these two processes are likely to be independent of each other with the caveat that relapses can be associated with some disability progression called relapse-associated worsening or RAW.

This treatment effect on smouldering MS was seen in the relapsing (Gemini 1&2 trials) and non-relapsing SPMS trials (Hercules trial). Subjects in the Hercules trial were also more likely to have significant disability improvement, with a trend in the relapsing or Gemini trials. The disability improvement data is critical and tells us that something is happening centrally to promote recovery of function in subjects on tolebrutinib.

Based on these observations, I don’t know how anyone can claim that focal MS disease activity is MS. My interpretation is that focal MRI activity is simply the immune system’s response to the cause of the disease. The real MS is in the tissue against which the immune system may or may not react. I call this the field hypothesis of MS.

The field hypothesis

If you have an MS relapse or attack in one particular area of the brain or spinal cord, you are more likely to have subsequent attacks in this area. Something locally in a specific anatomical area triggers recurrent attacks in the same site.

What underlies the field effect? One explanation is that the area damaged by the initial attack is more likely to trigger autoimmune responses in the future due to the local up-regulation of so-called second, or danger, signals. The latter occurs in response to the factor produced as part of the initial inflammatory event. For T-cells to become activated, they need an antigen-specific signal via the T-cell receptor and an additional signal via co-stimulation.

The obvious question is what triggers relapses in the field or CNS. Possibly a virus, like an isolated seed or flower in a wheat field? Why do I say this? Firstly, when pwMS were treated with interferon-gamma, a cytokine that stimulates immune responses, they relapsed. The interesting thing about these interferon-gamma-induced relapses is that they occurred in sites previously affected by MS. When I discussed this observation with the late Hillel Panitch, who was the principal investigator on the gamma-interferon trial, he thought that this observation was fundamental and was telling us something important about MS.

Another observation that supports the abnormal field hypothesis is the rebound post-natalizumab. This suggests that whilst you keep T and B cells out of the nervous system with natalizumab, the field (brain and spinal cord) becomes more abnormal. When you let these cells back in, they detect the abnormal field and run amok, trying to clear the field of the offending agent. This happens with IRIS (immune reconstitution inflammatory syndrome) and PML. When natalizumab is washed out, the immune system finds the JC virus and tries to clear it by initiating an inflammatory process. Some of us think that rebound post-natalizumab is a form of IRIS in response to the virus that causes MS.

Another observation comes from...