Slaying dogma in PPMS; which head should we cut off? #MSBlog #MSResearch
“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) PPMSers 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 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 PPMSers have fewer focal lesions on MRI. This however does not mean that there is no inflammation; focal inflammation is simply occurring at a sub-MRI level. 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.”
“The following pathology study done at 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 PPMSers have fewer focal lesions on MRI. This however does not mean that there is no inflammation; focal inflammation is simply occurring at a sub-MRI level. 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.”
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.
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| Slaying the dogma beast: which head should we cut-off? |
Dogma 2: PPMSers don’t have relapses – WRONG!
“In almost all PPMS trials done to date a proportion, albeit a small proportion, of PPMSers 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.”
Hawker et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009 Oct;66(4):460-71.
“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. Can we say that PPMS is non-relapsing?”
Note: “Please note that I have started refer to Gd-enhancing lesions as sub-clinical relapses in the hope that NICE will begin to accept MRI activity as a surrogate for clinical relapses. “
Wolinsky et al. Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol. 2007 Jan;61(1):14-24.
Dogma 3: PPMS is a different disease to SPMS – WRONG!
“In almost all PPMS trials done to date a proportion, albeit a small proportion, of PPMSers 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.”
Hawker et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009 Oct;66(4):460-71.
“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. Can we say that PPMS is non-relapsing?”
Note: “Please note that I have started refer to Gd-enhancing lesions as sub-clinical relapses in the hope that NICE will begin to accept MRI activity as a surrogate for clinical relapses. “
Wolinsky et al. Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol. 2007 Jan;61(1):14-24.
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.”
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| (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. PPMSers and relapse-onset MSers have the same genetic background. Once relapse-onset MSers enter the clinical phase of SPMS they progress at exactly the same rate as PPMSers.”
“It is for the reasons above that there is a strong argument for doing trials on combined populations of progressive MSers. In other words we should combine PPMS and SPMS populations into one study. I am aware that this is a controversial topic but it needs debate. If we don’t do this then treatments will only be licensed for one subtype of progressive MS, and not the other clinical subtype, until additional trials are done. 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 progressive MSers may be the difference between using a walking-stick and being bed-ridden.”
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PPMS, I think, is not MS and is something similar in symptom's, but a different neurological disease. It's holding back development strategies by bunching them all together. PPMS is much more sever in its pathogenis.
When you look at the pathology and the clinical course i rhink it is essentially the same as secondart progressive disease.
I think PPMS may be similiar to ADEM which is an acute demyelinating disease. It is thought that MRI changes in ADEM may not occur until recovery, not during the active phase. This is what happened to me prior to being diagnosed with RRMS. So, if there is no remision in PPMS, lesions may not be detectable: http://www.ncbi.nlm.nih.gov/m/pubmed/11415907/