Barts-MS rose-tinted-odometer: zero-★s (still seeing red)
Did you know that MS disease activity defines if you are eligible for therapy and which therapy?
The following is a list of definitions that are generally applied to MS in England.
Inactive: Patients with MS with no relapses or imaging features of disease activity in the last 2 years.
Active: Patients with active disease are defined as having one or more relapses in the preceding 2 years and/or evidence of one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared with a previous MRI in the last two years.
Highly active: Patients with high disease activity despite treatment with a platform DMT. This group is defined as patients who have failed to respond to a full and adequate course of a platform or other DMT. Patients should have had at least one relapse in the previous year while on therapy and one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared with a previous MRI.
Rapidly evolving severe or RES: Patients with rapidly evolving severe relapsing-remitting multiple sclerosis defined by two or more disabling relapses in 1 year, and one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared with a previous MRI.
Disabling relapse: if the relapse is severe enough to affect the social and/or occupational functioning of the patient.
The problem with these definitions is that they entrench the clinico-radiological worldview of MS and are not based on biology or for that matter data. For example, the RES definition was a negotiation between Biogen representatives and the EMA to get natalizumab licensed in Europe. RES MS was not a prespecified population and there were no requirements for study to subjects to have an increasing lesion load on MRI or to have prior relapses classified as disabling or non-disabling to be included in the AFFIRM study (phase 3 natalizumab study). So in reality the RES population is hypothetical. Despite this, the concept of RES MS has stuck and is likely to be entrenched in our MS algorithms for the foreseeable future, unless we challenge these definitions.
So if you are NEDA-2, i.e. have no relapses or focal MRI activity in the last 2 years, you have inactive MS. The latter definition is independent of disability worsening, accelerated brain volume loss, raised neurofilament levels, worsening cognition, accelerated retinal nerve fibre loss, slowly expanding lesions or progressive spinal cord atrophy. In other words, the definitions are based on clinical relapses and focal MRI activity, which is our concept of active inflammation. None of our current definitions for treatment acknowledges smouldering disease; hopefully, this will change in time.
Clearly, these definitions are subject to change or hacking as technology evolves. So if you move from a 3 tesla to a 7 tesla MRI you may find it easier to show a change in lesion load due to the better definition of lesions and the ability to see cortical lesions. Simply increasing the number of MRI scans will increase the sensitivity of the measure of activity, particularly if you are using Gd-enhanced MRI scans.
The definition that worries me the most is RES. The number of people with RES is getting smaller simply because we tend not to let someone diagnosed with MS after one relapse wait to have a second relapse before treating them. Therefore the number of patients with RES is going down and this is why so few pwMS are eligible for cladribine, alemtuzumab and natalizumab as first-line therapies. The only highly effective therapy that is allowed first-line for active MS is ocrelizumab. So if you want to flip the pyramid and start on one of the other top-tier DMTs you have to either start on ocrelizumab or wait and hope you have a disabling attack within 12 months of your first attack to become eligible for natalizumab or one of the licensed IRTs (alemtuzumab or cladribine).
Waiting and hoping to become RES is what I call watchfully waiting 2.
This watchful waiting for the next disabling attack to become eligible is really incompatible with the concept of time-is-brain and hence access to IRTs are not really a first-line option for the majority of people with recently diagnosed MS.
I hope this makes sense? The following is NHS England’s DMT treatment algorithm that explains things using a flow diagram.MS-Treatment-Algorithm-v2
General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.