Watchful Waiting

Barts-MS rose-tinted-odometer  ★ ★ ★ ★ ★

I have tried to include all the necessary information on MS DMT treatment decision-making into one easy to use and understand infographic. This infographic explains that when you see a patient with MS you have to decide if they have inactive MS or active MS. If they are active you have to decide how active their MS is (active vs. highly-active vs. rapidly-evolving severe MS). 

You then have to decide on the best treatment approach, i.e. the conventional step-care approach, rapid escalation or flipping the pyramid. To achieve this you need to profile patients into whether or not they have a good, intermediate or poor prognostic profile. Finally, you choose a treatment target, i.e. NEDA-2, NEDA-3, NED-4 or -5, or beyond. 

When I prepared this slide I had a debate with myself about whether or not I should leave off the ‘watchful waiting’ approach, but decided that there may be a place for it for people with inactive MS with a very good prognostic profile. And to be honest with you I have several patients in my own practice who for whatever reason we have adopted a watchful waiting approach. 

The good news is that there is a group of patients who do well with watchful waiting. In this Austrian study below, they looked at the outcome of a group of patients who in partnership with their HCPs had decided against DMTs. This group displayed features, which significantly differed from other patients; they tended to have a higher age at MS onset, were more likely to present with sensory symptoms, have a complete remission of symptoms and have a lower burden of disease on MRI. 

Importantly, watchful waiting in this group of patients seemed to work in that the decision not to start treatment was associated with a lower risk for conversion to secondary progressive MS. 

Interestingly, the group of patients who did not start a DMT against the advice of their HCP did much worse and had a 20% higher risk of converting to SPMS.

The moral of this story is that shared-decision making works and that patients should listen to what their HCPs think. Or HCPs should develop their communication skills explaining why DMTs are beneficial to some, but not all, pwMS. 

Bsteh et al. To treat or not to treat: Sequential individualized treatment evaluation in relapsing multiple sclerosis. Mult Scler Relat Disord. 2019 Dec 23;39:101908.

BACKGROUND: The frequency and long-term prognosis of relapsing multiple sclerosis (RMS) never receiving disease-modifying treatment (DMT) is unclear.

METHODS: We included 1186 RMS patients with a mean of 17.4 years follow-up and divided them into patients treated with any DMT (DMT) and patients untreated by shared (USD) or patient-autonomous decision (UAD).

RESULTS: The USD group displayed features, which significantly differed from the two other groups: higher age at onset, mainly sensory onset symptoms, complete remission of onset symptoms, less T2 and contrast-enhancing T1 lesions on initial brain MRI. In a multivariate cox regression, USD was associated with lower risk for secondary progression (SPMS) conversion (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.55-0.97, p = 0.011) compared to DMT, while UAD was associated with an increased SPMS conversion risk only in the “McDonald era” (HR 1.19, CI 1.02-1.58, p = 0.028).

CONCLUSION: Apart from the doubtless substantial improvement of the overall prognosis of RMS by DMT, it seems likely that not every patient necessarily needs immediate or even “hard and early” treatment. A “watchful waiting” approach with continuous clinical evaluation might be instead a viable option in RMS patients with favorable prognostic features at onset.

CoI: multiple

#OffLabel

I am speaking at the Multiple Sclerosis International Federation (MSIF) Access to Treatment and Healthcare meeting next week in London. My talk is on “Off-label opportunities, barriers and risks in availability and affordability”.

My journey to this point goes back 5-years and started when I was on sabbatical and was visiting countries all over the world and seeing how MS was managed. I soon realised that MSers living in resource-poor environments had poor access to MS disease-modifying therapies and other MS services. This led us to formulate an Essential Off-Label DMT list and to start a social media campaign using the hashtag #OffLabel to get people to adopt off-label prescribing of DMTs. We also developed a protocol for off-label cladribine use and have distributed it widely. 

These activities and other factors nudged the MSIF to make ‘access to treatment’ one of their priorities and led to the MSIF submitting an application to the WHO to get three DMTs, albeit licensed DMTs, onto the essential medicines list (EML). If successful (hopefully we will hear next week – fingers-crossed) we will be able to use this as a springboard to raise awareness of untreated or under-treated MS across the world. It will also raise awareness about MS in low prevalence areas and challenge the prevailing dogma that MS is a rich-world problem. 

Please note our essential off-label DMT list is ‘evidence-based’ or at least anchored to licensed DMTs. The following is a new version of the list.

  1. Azathioprine*
  2. Dimethyl fumarate (generic, licensed for psoriasis)
  3. Cladribine
  4. Cyclophosphamide*
  5. Fludarabine*
  6. Leflunomide
  7. Methotrexate*
  8. Mitoxantrone
  9. Rituximab* 
  10. HSCT

*drugs that are on the 19th WHO Model List of Essential Medicines (April 2015)

I am particularly interested to hear stories about off-label treatments in your countries and if any of you are receiving off-label treatments.

Apart from rituximab use, particularly in Sweden, off-label prescribing is simply not being adopted. Why? I think it takes more than a few people standing on a soap-box to make it happen; what is required is a systems change and a whole lot of nudges to get HCPs to start doing it. This is why I have become so interested in behavioural psychology and behavioural economics, which teaches us why information is simply not enough to change HCP behaviour.

CoI: multiple