Do you have active MS?

MS Disease Activity

Active MS is term that's increasingly being used to refer to evidence of focal inflammatory activity, i.e. new lesions on MRI or relapses. In contrast the gradual worsening of disability that occurs in people with more advanced MS (which may, or may not, occur in the presence of focal inflammatory activity) has many potential causes, only one of which is focal inflammation. Inflammation damages axons, or nerve processes. When the lesion develops it can cut, or transect, the axons, demyelinate them or stop them from working. This is due to the effects of inflammatory mediators.

Relapses: When a new MS lesion occurs in an eloquent part of the central nervous system it causes new, or an exacerbation of old, symptoms that are usually interpreted as a relapse. Relapses by definition involve new symptoms, or an exacerbation of old symptoms, that last at least 24 hours in the absence of an infection or a fever.

Intermittent symptoms or pseudorelapses: Unfortunately, a large number of pwMS experience frequent intermittent symptoms that come on when they are tired, after exercise or have a raised body temperature from a fever, exercise, hot bath or a warm environment. These intermittent symptoms are usually quite stereotyped and last minutes to hours. They are indicative of a previously damage pathway.

Asymptomatic lesions: Most of the focal MS disease activity that occurs does not cause any overt symptoms because the brain has a way of compensating for damage. For every clinical relapse there at least 10 or more lesions that come, and potentially go, on MRI. Therefore what we see clinically in terms of relapses is the tip of the iceberg. Even standard MRI is relatively insensitive at detecting and monitoring MS disease activity. The standard MRI misses new lesions that are smaller than 3-4 mm in size and does not detect the majority of lesions that occur in the grey matter of the brain. Therefore MRI activity is also the tip of the iceberg. This is one of the reasons we have starting using spinal fluid, or CSF neurofilament levels, as a marker of this microscopic activity.

Disease activity: Most neurologists require evidence of disease activity in the last 12 months, with some of us accepting a 24 month window if there is no serial MRI support. The corollary of this is if you have had no relapses in the last 24 months, and serial MRI studies covering this period show no new lesions, then your MS is defined as being inactive. This does not mean your MS is necessarily stable. I have already said you could have worsening disability as part of the progressive phase of the disease. If you have so called inactive MS you need to be monitored, as inactive MS may reactivate and you could then become eligible for treatment.

In the early 2000s we used to define disease activity using clinical criteria only; i.e. you needed to have at least 2 documented relapses in the last 2 years to be eligible for DMT. This meant you needed to be seen by a neurologist so that he/she could examine you to confirm abnormalities on examination compatible with a relapse. The problem with this is that many MSers who didn’t have rapid access to a neurologist would recover from their attack before being assessed, so many of their relapses could not be documented. This was very frustrating for MSers wanting to start a DMT, as some neurologists were not prepared to accept historical attacks. I remember seeing lots of MSers for a second opinion over this issue, as a kind of arbitrator to decide who was right: the assessing neurologist who would not accept undocumented historical relapses, or the patient who knew they had had a relapse. I tended to give patients the benefit of the doubt, particularly if they had MRI evidence to support recent disease activity. How could we deny MSers access to a DMT because they couldn’t be seen in timely way to have their relapse documented in the clinical notes?

In 2009 our criteria incorporated MRI into the definition to allow us to treat so called high-risk patients with CIS (clinically-isolated syndromes compatible with demyelination). These criteria required CISers to have 9, or more, T2 lesions on MRI or at least one Gd-enhancing lesion. These MRI criteria were based on the McDonald diagnostic criteria at the time. I personally have never agreed with them. What makes someone with 2 lesions on MRI different from someone with 20 lesions on MRI? It could simply be that the person with 20 lesions has had asymptomatic MS longer than the person with 2 lesions on MRI. If we adopt the principle of treating MS early to prevent damage, why would we want to wait for the CISers to acquire more lesions and hence more damage before offering them a treatment? I take the position that a CISer presenting with a low lesion load is lucky in that they presented early with their disease and hence have a greater opportunity to benefit from early treatment. The CISer with a high lesion load unfortunately is the unlucky one. This dilemma is really only a UK problem; outside of the UK almost all neurologists offer CISers DMTs if they have two or more lesions on MRI.

In 2014 NICE (The National Institute for Health and Care Excellence) gave us permission to use alemtuzumab in adults with active relapsing MS defined clinically or on MRI (see below). This could mean defining activity based on MRI only. I doubt NICE, or the EMA, realise the implications of this ruling. I suspect the "or" refers to re-treatment criteria and not the treatment criteria to initiate treatment. It would be hard to justify, in the current climate, starting alemtuzumab in MSers without any recent clinical activity, i.e. relapses. In fact, some of my colleagues are refusing to offer alemtuzumab at all; they have taken the position that the therapy is too risky to justify its use as a first or even second line therapy. I have debated their position in the past and think it is unacceptable.

Rapidly-evolving severe MS

For those of you who have active MS there is a further two subdivisions you need to know about. The first is so called rapidly-evolving severe MS (RES), defined as two disabling attacks in a 12 month period with MRI evidence of activity during this period. This subgroup is eligible for natalizumab and fingolimod.

Highly-active MS

The other subgroup is so-called highly active MS. These are MSers with unchanged or increased relapse rate, or ongoing severe relapses compared with the previous year, despite treatment with beta interferon, or another so-called first-line DMT. The latter definition is part of the NICE final appraisal determination for fingolimod. Please note that this exposes a quirk in the NHS system in that fingolimod can only be prescribed as a second-line therapy. In contrast natalizumab can be used as a first-line treatment in patients who fulfil the definition for having rapidly-evolving severe MS and alemtuzumab for MSers who have active MS defined clinically or on MRI.

What these definitions don’t address is what we do with SPMSers and PPMSers with worsening disability and no recent relapses (last 2 years) who have new focal and/or Gd-enhancing lesions on their MRI. At present we don’t really have prescribing guidelines that cover these patients. Why not? Although ocrelizumab has been licensed to treat early active PPMS it has yet to be green-lighted by NICE. Although there has been a recent positive phase 3 trial of a drug called siponimod in SPMS it has yet to assessed by the regulators. Apart from these two DMTs all the other phase 3 trials in non-relapsing progressive MS have been negative. However, if you adopt the scientific principle that inflammation is bad for MS you would want to a treatment to tackle this inflammation. This is why we have used rituximab in the past to treat young PPMSers with Gd-enhancing lesions; this is based on the positive subgroup analysis of the phase 2 rituximab in PPMS trial. However, in the UK NHS England have stopped individual funding requests (IFRs) applications to cover this indication; rituximab is simply too expensive for the NHS to be used off license. For this reason we now offer these patients the option of being treated with subcutaneous cladribine. In the secondary progressive population mitoxantrone is still used in many centres, but we have stopped using it and prefer rituximab or subcutaneous cladribine, as they have better safety profiles.

The following is a slideshow that attempts to explain the NHS classification of active MS and what your odds are of being a responder.