Wednesday, 24 May 2017

#ResearchSpeak: MS is one disease

How can we change the dogma surrounding PPMS? #MSBlog #ResearchSpeak #1-disease-not-2-or-3-diseases

Certain dogmas about PPMS have crept into the field and have become entrenched as facts that need challenging; in particular that (1) PPMS in non-inflammatory, (2) that pwPPMS don't have relapses and (3) PPMS is a different disease to relapse-onset MS.

Dogma 1: PPMS in non-inflammatory - WRONG!

The following pathology study done at the Institute of Neurology (Queen Square) when I was doing my PhD clearly showed that PPMS is inflammatory, albeit at a slightly lower level than SPMS. The dogma has crept in because we tend to view MS through the spectacles of an MRI; pwPPMS have fewer focal lesions on MRI. This however does not mean that there is no inflammation; focal inflammation is simply occurring at a level below the detection level of the MRI. What MRI sees in relation to focal lesions is simply the tip of the iceberg. The PPMS iceberg simply looks different with less above the surface. In addition, pwMS have oligoclonal IgG in their CSF. If they were no inflammatory you would expect these OCBs to be absent or disappear. 

Revesz et al. A comparison of the pathology of primary and secondary progressive multiple sclerosis. Brain. 1994 Aug;117 ( Pt 4):759-65.

Background: The dynamics of primary progressive multiple sclerosis differ from those of the more common secondary progressive form. The observation by MRI that the frequency of enhancement with gadolinium-DTPA, a marker for blood-brain barrier dysfunction, is significantly less in the primary progressive form, has led to the hypothesis that inflammation is less intense in this group.

Aims: To test this, we have studied postmortem material from 9 cases judged from a retrospective analysis of case notes to show clear clinical evidence of either primary progressive or secondary progressive disease.

Methods: 578 lesions were analysed.

Results: There was significantly more inflammation in secondary progressive multiple sclerosis (as judged by the frequency of perivascular cuffing and cellularity of the parenchyma) than in primary progressive disease.

Conclusions: These observations have implications for therapeutic strategies in progressive multiple sclerosis.

Dogma 2: pwPPMS don't have relapses - WRONG!

In almost all PPMS trials done to date a proportion, albeit a small proportion, of pwPPMS who go onto have relapses. For example in the Rituximab trial in PPMS (Olympus Trial), 11 out of 439 (2.5%) of study subjects had a relapse during the 96 weeks of the trial. In the Ocrelizumab (ORATORIO) study protocol-defined relapses were reported for 11% of subjects in the placebo group and 5% subjects in the ocrelizumab group.

Similarly, about 5% of study subjects in the glatiramer acetate PPMS, or PROMISE, trial had relapses. Unfortunately, the exact number of relapses is not reported in the main manuscript. What is reported is MRI activity; 14% of 938 study subjects had Gd-enhancing lesions on MRI during the study. The latter is the MRI equivalent of relapses. 

Based on this data can we say that PPMS is non-relapsing?

Dogma 3: PPMS is a different disease to SPMS - WRONG!

Did you know that it not uncommon in siblings pairs with MS for one to have relapse-onset disease and the other to have PPMS? The figure from the UK sibling study is in fact 23% (please see article and table below). This indicates to me that relapse onset and PPMS are the same disease.

Chataway et al. Multiple sclerosis in sibling pairs: an analysis of 250 families. J Neurol Neurosurg Psychiatry. 2001 Dec;71(6):757-61.

(33.7+27) / (84+68.3+33.7+39.3+27+9.7) x 100 = 23%

Other arguments in favour of PPMS and SPMS being the same disease relates to genetic and natural history studies. People with PPMS and relapse-onset MSers have the same genetic background. Once people with relapse-onset MS enter the so-called clinical phase of SPMS they progress at exactly the same rate as pwPPMS. 

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.

It is for the reasons above that there is a strong argument for doing trials on combined populations of progressive MS. In other words we should combine PPMS and SPMS populations into one study. I am aware that this is a controversial topic, particularly in the eyes of the regulators, but it needs serious and prolonged debate. If we don't do this then treatments will continue to be licensed for one subtype of progressive MS, and not the other clinical subtype, until additional trials are done. This is not in the interests of pwMS. Additional trials cost money and time. Time is not a something people with progressive MS have on their side. 5-years in the life of someone with progressive MS may be the difference between using a walking-stick and being bed-ridden.

CoI: multiple

1 comment:

  1. Prof G, why does MS have to be so complicated? Is it primarily inflammatory or neuro-degenerative? Is it T cell mediated or B cell mediated? Is it one disease or three? Why do females get MSmore than males? There seem to be a number of fundamental questions that the so-called experts can't give a definitive answer to. Is anyone actually looking at the biology of the disease. The experts are stuck in a rut of trying out treatments and then trying to answer the basic questions. Seems the wrong way round to me.


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