How do we colour in each block of this cube?
Making a decision about which DMT to prescribe, or preferably to help your patients make a decision, many of my colleagues mix up their priorities. For example, some mix-up baseline prognostic profiling and disease activity, and then some of them throw disease-stage or disability progression into the mix. I think this occurs because these factors are somewhat related, but only tell part of the story.
Disease activity (DA) – Disease activity (DA) really refers to the here-and-now and what has happened in the last 12-24 months. DA does affect prognostic profiling (PP), but it is only one component of PP.
DA refers to recent focal inflammatory activity and hence is defined as relapses in the last 2 years and focal MRI activity, i.e. new or enlarging T2 lesions and Gd-enhancing lesions, in the last 12 months. More recently raised at Barts-MS we have also incorporated raised CSF neurofilament levels in the last 12 months.
In the UK/NHS we have 4 categories of DA:
- Rapidly evolving severe
Inactive MS – 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 said that you could have worsening disability as part of the progressive phase of the disease without focal inflammatory activity. 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.
Active MS – Most neurologists require evidence of disease activity in the last 24 months, with most accepting a 12-month window if there is MRI support. Our current criteria for active MS incorporates MRI into the definition, which allows us to treat so-called high-risk patients with CIS.
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. Another category refers to treatment-naive MSers with two attacks in a 12 month period with MRI evidence of activity during this period.
Rapidly-evolving severe MS – Rapidly-evolving severe MS (RES) is defined as two disabling attacks in a 12 month period with MRI evidence of activity during this period.
Prognostic Profiling (PP) – Prognostic profiling (PP) really refers to baseline factors that have been linked to poor prognosis. Although several of DA metrics are associated with a poor prognosis they are a small part of the prognostic profiling metrics I personally use. The following is a list of 24 prognostic factors I tend to use in clinical practice. In general, if you have four or less you fall into the good prognostic category, five to eight the intermediate prognostic category and if nine or more the poor prognostic category.
- Age of onset (<40 vs. >40 years) (1)
- Sex (F vs. M) (1)
- Sites: unifocal vs. multifocal onset (1)
- Motor: no vs. yes (1)
- Cerebellar: no vs. yes (1)
- Bladder: no vs. yes (1)
- Impairment: no vs. yes (1)
- Learner: yes vs. no (1)
- Recovery: complete vs. partial or no recovery from initial relapses (1)
- Relapse rate: low/ ≤ 2 vs. high / >2 in the first 2 year (1)
- Early disability: EDSS < 3.0 vs. EDSS ≥ 3.0 within 5 years (1)
- Baseline lesion load: low / <9 T2 vs. ≥ 9 T2 lesions (1)
- Active: no Gd-enhancing vs. Gd-enhancing lesions (1)
- Posterior fossa lesions: no vs. yes (1)
- Spinal cord lesions: no vs. yes (1)
- Brain atrophy: no vs. yes (1)
- OCBs (oligoclonal IgG bands): no vs. yes (1)
- Raised neurofilament levels: no vs. yes (1)
- Vitamin D levels: low vs. normal (1)
- Smoker: no vs. yes (1)
- diabetes/prediabetes: no vs. yes (1)
- Hypertension: no vs. yes (1)
- Hypercholesterolaemia: no vs. yes (1)
- obesity: no vs. yes (1)
Total Score out of 24
Disease Stage (DS) – Disease stage (DS) simply refers to the amount of damage accumulated, i.e. how disabled you are. We tend to overlap this with disease descriptors early in the disease course, simply to help deal with treatment guidelines and to set the scene for changing our worldview of MS; i.e. away from a neurological/clinical perspective to a biological perspective (pathology). If we changed our worldview of MS we would almost certainly want to treat MS in the asymptomatic stage to prevent disability. Please note that we still live in an EDSS-centric world and hence the EDSS is used by most people to define disability.
In an ideal world, we would include other metrics, in particular, cognition, to define MS-related disability and include end-organ damage markers (brain volume loss) or other metrics that measure reserve capacity. The latter is critical in defining the resilience of your nervous system to deal with insults in the future including physiological or normal ageing.
The following is my classification system of DS:
- Radiologically isolated syndrome (RIS) with no apparent disability (EDSS = 0)
- Clinically isolated syndrome (CIS) with no apparent disability (EDSS = 0)
- MS with no apparent disability (EDSS = 0)
- MS with mild physical disability (EDSS=1.0-3.0)
- MS with moderate physical disability (EDSS=3.5-5.5)
- MS with severe physical disability (EDSS=6.0-6.5)
- Advanced MS with profound physical disability(EDSS >=7.0)
Although DS may affect treatment decisions we need to get away for the idea that to be treated effectively, i.e. with highly-effective treatments, you need to be disabled. Our current philosophy is to treat early to prevent disability.
In the following slideshow, I try and put all these factors together in a 3D graph. Please note that the grey cubes represent an evidence-free zone and DMTs are typically not used in MSers with these attributes. We are trying to change this with our #TreatEarly, #BrainHealth, #PreventMS and #ThinkHand campaigns.
The colour scheme to denote the level of DMT by risk category is an estimate. I have included this to try an illustrate the complexity of decision making that is involved in selecting DMTs when considering only three factors. This gets even much more complex when you start to incorporate personal factors.
I predict this post will be very controversial. So let me know your thoughts.