In my mind MS disease activity refers to evidence of focal
inflammatory activity, i.e. new lesions on MRI or relapses. In contrast the
gradual progression, or worsening, of disability that occurs in people with SPMS
and PPMS, may or may not occur in the presence of inflammatory 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 be eligible for
treatment.
In the early 2000’s 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 that many of their relapses could not be documented. This was
very frustrating for MSers wanting to start a DMT as many neurologists were not
prepared to accept historical attacks. I remember seeing many MSers for a
second opinion over this issue; a kind of arbitrator to decide who was right
the assessing neurologist who would not accept undocumented historical relapses
over 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 lesions. 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
damage? I take the position that a CISer presenting with a low lesion load is
lucky 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.
Now in 2014 NICE (The National Institute for Health and Care
Excellence) have given 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 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
it use. 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 PPMSer 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?
It is simply because there has been no positive phase 3 studies in this group
of MSers to guide our treatments. 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 in a handful or 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 are now offer
these patient the option of being treated with subcutaneous cladribine. In the
secondary progressive population we still have mitoxantrone on the table.
The following is a diagram that attempts to explain the classification of active MS based on subsets.
Are you eligible for a DMT?
Eligibility criteria for DMTs vary across the world and are
dependent on licensing rules, national guidelines, payers reimbursement policy
and your local MS Team’s prescribing rules. In some parts of the world, for example
the US, MS DMTs are simply given a license for treating relapsing MS and it is
then left up to the neurologist and the patient to negotiate a treatment.
Despite this liberal licensing rule the payers, or insurance companies, set
prescribing policy that is usually based on price. The following are NICE's technology appraisals that dictate how we use DMTs in the UK. These appraisals are based on cost-effective models that are designed to ensure the NHS purchases and used DMTs in a cost-effective way.
