Monday, November 10, 2014

Questions to ask?

The following is a list of questions you may want to ask your neurologist when a decision is being made about starting a disease-modifying therapy (DMT) for treating multiple sclerosis (MS).

  1. What is multiple sclerosis?
  2. Are you sure that you have MS?
  3. What type of MS do you have? 
  4. What prognostic group do you fall into? 
  5. What is the risk of you not being treated with a DMT? 
  6. Do you have active MS? 
  7. Am I eligible for treatment with a DMT? 
  8. Do you understand the difference between the treatment strategies of maintenance-and-escalation and induction therapy?
  9. Do you understand the concept of treat-2-target of no evident disease activity (NEDA)?

Do you have active MS?

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.