Do you have PPMS? This post is for you. #MSBlog #ClinicSpeak
Primary progressive MS (PPMS) = relapse-onset MS = MS
A lot of assumptions about PPMS have crept into the field and have become entrenched; we call these dogmas. We need to challenge the dogma; 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.
Primary progressive MS (PPMS) = relapse-onset MS = MS
A lot of assumptions about PPMS have crept into the field and have become entrenched; we call these dogmas. We need to challenge the dogma; 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!
This pathology study done at Queen Square from the early 1990s clearly shows that PPMS is inflammatory, albeit at a slightly lower level than relapse-onset MS. 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 below the threshold 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. The positive ocrelizumab PPMS, or Oratorio, study supports PPMS as being inflammatory.
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.
Chataway et al. Multiple sclerosis in sibling pairs: an analysis of 250 families. J Neurol Neurosurg Psychiatry. 2001 Dec;71(6):757-61.
This pathology study done at Queen Square from the early 1990s clearly shows that PPMS is inflammatory, albeit at a slightly lower level than relapse-onset MS. 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 below the threshold 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. The positive ocrelizumab PPMS, or Oratorio, study supports PPMS as being inflammatory.
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: 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 therefore make the claim that PPMS is non-relapsing?
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 therefore make the claim that PPMS is non-relapsing?
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 is not that 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.
 |
| (33.7+27) / (84+68.3+33.7+39.3+27+9.7) x 100 = 23%
Other arguments in favour of PPMS and relapse-onset MS 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 apparent 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. The latter will simply be going back to chronic progressive MS classification that existed before we split MS in different subtypes. 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 someone with clinically-apparent progressive MSers may be the difference between using a walking-stick and being bed-ridden. In short, pwPPMS have unfortunately missed out in the relapsing phase of the disease. They are simply unlucky that a new lesion did not occur in a clinically-eloquent site to cause a relapse and bring them to the attention of a neurologist earlier in the course of their disease. They only present when they have lost their reserve capacity. The good news is we now have a positive trial of ocrelizumab. Let's hope the regulators and payer allow pwPPMS access to ocrelizumab. |