Active vs. Smouldering SPMS

Does active secondary progressive MS simply mean relapsing secondary progressive MS? What about smouldering MS?

I was chairing an MS teaching course this week and inevitably, with the licensing of siponimod by the FDA for treating clinically-isolated syndromes, relapsing-remitting MS and active SPMS the discussion kept coming back to the topic of SPMS.

The predominant questions were:

1. When does SPMS begin?
2. How do you diagnose SPMS?
3. Who should diagnose SPMS?
4. What is active SPMS?
5. How do we manage patients who develop SPMS on an existing DMT, but have no relapses or MRI activity?

Firstly, I have aversion to the use of the term progression. As a term, it implies an improvement, which in the context of MS it is clearly not. Therefore, I would prefer it if we could use the term ‘worsening’.

Other reasons for substituting the term worsening for progression is to help patients come to terms with their disease. As soon as you say to a patient you have SPMS they think they have developed a new disease, which can’t be treated and hence it is only downhill from here. This is incorrect. We now have therapies that slow down the worsening in this phase of the disease and in reality it is not a new disease, but simply a more advanced stage of one disease MS.

Another reason for dropping the term progressive is the consequences the label of SPMS has for treatment. In the NHS you are meant to stop DMTs as soon as someone becomes SPMS. The logic behind this is that the currently licensed therapies have not been shown to modify progressive MS, therefore, the treatments should be stopped. The real reasons behind the stopping criteria are economic and have nothing to do with the science. Therefore, if you simply write down worsening MS NHS England can’t haul you over the coals for ignoring their stopping criteria. In other words ‘worsening MS’ could become a euphemism for ‘progressive MS’.

When does SPMS begin?

At the very beginning. The underlying pathological processes that cause worsening MS, i.e. loss of axons and neurones, is there from the start of the MS disease process and defining a point in time when SPMS starts is so unreliable that I would question its utility. We know that the continued and cumulative loss of neurones and axons start in the asymptomatic phase of MS and continues throughout its course. The only reason why pwMS don’t notice they have SPMS early on in the course of their disease is that they compensate for the damage and only become aware of worsening when the compensatory mechanisms become exhausted. When patients who stress their nervous systems, by doing extreme sports or activities, notice worsening MS much earlier.

How do you diagnose SPMS?

To quote Fred Lublin “I know it when I see it, but don’t ask me to define it”. This is based on the following ruling by supreme court judge Potter Stewart (1915–1985) in relation to pornography:

“I shall not today attempt further to define the kinds of material I understand to be embraced within that shorthand description [hard-core pornography], and perhaps I could never succeed in intelligibly doing so. But I know it when I see it, and the motion picture involved in this case is not that.”

We debated using George Eber’s definition of a retrospective clinical diagnosis and compared them to the more recent metric driven definitions as proposed by Cambridge and MS-Base. What is clear that both of these definitions are driven by the EDSS and a neurological, rather than a biological, worldview of MS.

I propose using a more inclusive definition of worsening MS and to include biomarkers to supplement the clinical definition. I also think we need to go beyond the neurological examination and EDSS and include ‘neurological stress tests’ that are multi-dimensional and include cognition, vision and a more in-depth functional assessment of the nervous system. My two cases studies from earlier this week illustrate why. Can you think of a reason why the marathon runner who develops a dropped foot, from fatigable weakness at 10 miles, when a year ago it was happening at the 15-mile mark, doesn’t have worsening (or secondary progressive) MS? This is why I am drawn to the philosophy of George Ebers’ definition, we just need to expand it to go beyond the EDSS.

Who should diagnose SPMS?

It was clear that a large number of people on the course thought neurologists or HCPs should be the only ones who can diagnose SPMS. This is bulls*!#& and quite patronising to people with the disease. Almost all the patients who spoke on the course, where self-aware of worsening neurological function, and didn’t need their neurologist to tell them they had worsening MS or SPMS for that matter. This is why I am keen to adapt our EDSS calculator to include a function to alert pwMS they have worsening MS. This will prompt them to ask their neurologist why they are getting worse. Please note that MS disease activity (focal inflammation and smouldering MS) may not be the only reason why pwMS may notice a worsening of their disability.

People with worsening MS need a work-up to establish why they are getting worse. It is important to exclude comorbid physical disease, such as poor nutrition, hypothyroidism, spinal cord compression due to another problem for example a prolapsed disc or tumour, sleep disorders, which can exacerbate symptoms and masquerade as worsening, low-grade urinary tract infections, side effects from medications, MS disease activity, mental health issues, in particular depression, etc.

By self-monitoring and documenting worsening disability empowers you to ask the questions and to get the answers you need.

What is active SPMS?

This is the million dollar question. The FDA has adopted the Lublin definition of progressive disease with superimposed relapses and/or MRI activity (new or enlarging T2 lesions and/or Gd-enhancing lesions). As most MSologists accept MRI activity to indicate sub-clinical relapses the FDA really means active SPMS is relapsing-SPMS and excludes, non-relapsing or smouldering SPMS. Clearly, this restriction on siponimod is data-driven, i.e. siponimod had no effect, or very little effect, on smouldering MS.

In my opinion, this clinico-MRI definition is too restrictive. Patients with MS who are worsening clinically and have biological evidence of ongoing inflammation, for example, raised neurofilament levels, and markers of worsening, for example, accelerated brain atrophy and slowly expanding lesions, must have some form of MS activity to explain their worsening. We know from post-mortem studies that people with advanced MS have evidence of ‘active inflammation’ in their brains and spinal cords, which is why we are pushing for treating these more advanced patients with anti-inflammatory medication, but are targeting pathways with reserve function to assess the treatment effect. Maybe a simple away around this impasse is to refer to this type of active MS as smouldering MS, i.e. you can’t see any flames, but the coals are still burning.

Why is this important? It is important because unless we get a DMT licensed to treat smouldering MS we can’t begin to build our treatment pyramid. Is there evidence that the current DMTs have an effect on smouldering MS? Yes, I do. In the Natalizumab in SPMS trial (ASCEND study), which was a study of predominantly smouldering MS, has a robust effect of slowing of worsening of upper limb function and on peripheral blood neurofilament levels. Similarly, the low-dose oral methotrexate had an impressive impact on upper limb function in advanced chronic-progressive MS. Again the majority of the population in the low-dose methotrexate trial would have had smouldering MS (worsening disability in the absence of relapse and focal MRI activity).

How do we manage patients who develop SPMS on an existing DMT, but have no relapses or MRI activity?

This is a hard nut to crack as we are in a relatively evidence-free zone. I have no idea if switching someone who has worsening disability, but inactive MS according to the Lublin criteria, to another DMT would make any difference. In this situation, I have started doing lumbar punctures and a CSF neurofilament (NFL) measurement and if their NFL levels are raised I offer them a switch, usually to an off-label option as this sort of switch is not allowed by our NHS England guidelines. This also deals with the issue of not obeying NHS England guidelines on stopping treatment. I covered this exact scenario when I discussed sister 2 in my recent ‘Variance’ post.

Different definitions of secondary progressive MS

Ebers = At least 1 year of continuous deterioration, regardless of the rate of worsening. Transitory plateaus and trivial temporary improvements in the relentlessly progressive course are allowed in the long term. Steady progression is the rule when evaluations are done at yearly intervals (Kremenchutzky et al. The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease. Brain. 2006 Mar;129(Pt 3):584–94.).

Cambridge = secondary progression is two consecutive sustained accumulation of disability events, the second from the new EDSS baseline established after the first SAD event, and in which the increase in EDSS occurred independently of relapses (Tuohy et al. Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy. J Neurol Neurosurg Psychiatry. 2015 Feb;86(2):208–15.).

MS-Base = a 3-strata progression magnitude in the absence of relapse, confirmed after 3 months within the leading functional system, and required an EDSS step ≥4 and pyramidal score ≥2 (Lorscheider et al. Defining secondary progressive multiple sclerosis. Brain. 2016 Sep;139(Pt 9):2395–405.).

Lublin = steadily increasing objectively documented neurologic dysfunction/disability without unequivocal recovery (fluctuations and phases of stability may occur) (Lublin et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014 Jul 15;83(3):278–86.).

Definition of active MS

Lublin = Clinical: relapses, acute or subacute episodes of new or increasing neurologic dysfunction followed by full or partial recovery, in the absence of fever or infection and/or Imaging (MRI): occurrence of contrast-enhancing T1 hyperintense or new or unequivocally enlarging T2 hyperintense lesions (Lublin et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014 Jul 15;83(3):278–86.).

CoI: multiple