we are about to cure ms in the nest 10 years even though we do not know its cause no

7/30/2019 We Are About to Cure MS in the Nest 10 Years Even Though We Do Not Know Its Cause NO

1/4

Multiple Sclerosis Journal

18(6) 784785

The Author(s) 2012

Reprints and permissions:

sagepub.co.uk/journalsPermissions.nav

DOI: 10.1177/1352458512446522

msj.sagepub.com

MULTIPLE

SCLEROSIS MSJ

JOURNAL

Rebuttal

What would a cure of multiple sclerosis look like?

Well, with a course ofMSmiracure all inflammatory

activity would be stopped; damage accrued until that point

would be completely repaired; there would be no possibil-ity of late disease recurrence or progressive disease, even

decades later; all with an acceptable safety profile; and with

no further treatment ever required.

I doubt we will never achieve this, let alone within 10

years. I have five arguments.

First, could we ever prevent all further inflammatory

activity, without understanding the cause of multiple scle-

rosis? Here we are doing pretty well, both in terms of con-

trolling the disease and understanding its cause. The

recent magisterial genetic studies1 demonstrate that the

immune system is at the heart of the pathogenesis of mul-

tiple sclerosis, and we have a large armamentarium ofdrugs and manoeuvres that affect the immune system. In

terms of a cure, we would first look to those treatments

that permanently remould the immune system to a more

benign form: autologous haematopoietic stem cell trans-

plantation and (in my potentially biased opinion) alemtu-

zumab (Campath-1H). These are undoubtedly effective

therapies, at the cost of significant side-effects, but even

they do not stop all further inflammatory activity in all

patients. For instance, in a small trial where both treat-

ments were combined, 5/21 patients relapsed at some

point after treatment.2 In theory, more specific therapies,

might lead to better benefitrisk ratios. But the current

selective approaches (for instance, altered peptide ligandsor TCR/T cell vaccination) are not terribly effective, no

doubt limited by our ignorance of quite which pathways

we should interfere with. And there is a nagging worry

that Hans Lassman might be right: and that some of the

inflammation underlying multiple sclerosis might be

trapped behind a closed bloodbrain barrier, which is a

problem because this cannot be crossed by nearly all of

the drugs we currently use in multiple sclerosis.

Second, we will not be able to repair damage already

accrued, at least not in the near future. Currently, we

identify people with multiple sclerosis when the CNS is

damaged, causing symptoms and /or MRI scars. We will

never be able to predict who will get multiple sclerosis

before such damage has occurred.3 So, even if we had the

perfect immunotherapy to prevent all subsequent disease

activity, we will always be faced with how to reverse the

scars of demyelination, axon and neuronal loss and gliosis.

We are making progress on understanding the mechanisms

of remyelination, leading to rational drug targets,4 but there

is little understanding of how to re-grow neurons.

Third, and perhaps most worryingly, it is possible that

even if we stop inflammation as early as possible, the pro-

gressive phase would emerge nonetheless. Personally I

doubt this. But there is a respectable body of opinion,

mainly from Lyon,5 that progression is due to non-inflam-

matory mechanisms and is entirely independent from the

inflammation which produces relapses. If that turns out to

be true, then we are in real trouble: we have little idea of themechanism and almost no idea how to start with treatment.

Perhaps one of the current neuroprotective drugs might,

by accident, do the job (and, of these, my favourite is ami-

loride, from Lars Fuggers work).6

Which brings me to my next point, which is pragmatic:

even if a target was identified today that could lead to a cure

for multiple sclerosis, it would not be available to people

with multiple sclerosis in 10 years. In the US (where things

are speedier than the EU) it takes on average 13 years to get

a drug into the clinic. There are numerous road blocks to

developing drugs. In response to this, Francis Collins first

move, when he became director of the U.S. NationalInstitutes of Health, was to set up the US$723-million

National Center for Advancing Translational Sciences. Our

We are about to cure MS in thenext 10 years, even though wedo not know its cause: No

Alasdair Coles

Department of Clinical Neuroscience, University of Cambridge,

Addenbrookes Hospital, Cambridge, UK.

Corresponding author:

Alasdair Coles, Department of Clinical Neuroscience, University of

Cambridge, Addenbrookes Hospital, Hills Road, Cambridge

CB2 0QQ, UK.

Email: [email protected]

MSJ18610.1177/1352458512446522ColesMultipleSclerosisJournal

Controversies in Multiple Sclerosis


2/4

Coles 785

own David Cameron has also responded by promising, in

November 2011, 180 million to set up a government

Biomedical Catalyst Fund to invest in U.K. health and life

sciences companies, and to accelerate access of seriously ill

patients to novel drugs.

Finally, no other autoimmune disease can be cured, so

why expect multiple sclerosis to be? In medicine, we onlytalk about a cure in surgical and infectious diseases, and

sometimes in cancer therapy; but not in autoimmunity.

Despite the great advances in the treatment of rheumatoid

arthritis, a PubMed search on cure and rheumatoid arthri-

tis gets just 21 hits, which are either rhetorical or barmy.

Even with the most radical treatment, autologous hae-

mopoietic stem cell transplantation, disease breaks through

in 50% of patients.7 But, also I am signed up to the view

that autoimmune diseases are the cost of our increasingly

hygienic and infection-free environment; so, as we push

development and clean industrialization, so we will see yet

greater incidence of autoimmunity.

So, I am afraid, multiple sclerosis is with us for more

than 10 years. In fact, I predict that the disease, or variants

of it, will be modern humans constant companion. And our

predicament will continue to be the pressure to diagnose

early and treat aggressively, being held back by concern for

adverse effects.

References

1. International Multiple Sclerosis Genetics Consortium; Well-

come Trust Case Control Consortium 2. Genetic risk and a

primary role for cell-mediated immune mechanisms in mul-

tiple sclerosis.Nature 2011; 476: 214219.

2. Burt RK, Loh Y, Cohen B, et al. Autologous non-myeloablative

haemopoietic stem cell transplantation in relapsingremitting

multiple sclerosis: a phase I/II study. Lancet Neurol2009; 8:

244253.

3. Sawcer S, Ban M, Wason J and Dudbridge F. What role for

genetics in the prediction of multiple sclerosis? Ann Neurol

2010; 67: 310.

4. Huang JK, Jarjour AA, Nait Oumesmar B, et al. Retinoid X

receptor gamma signaling accelerates CNS remyelination.

Nat Neurosci 2011; 14: 4553.

5. Confavreux C, Vukusic S and Adeleine P. Early clinical

predictors and progression of irreversible disability in

multiple sclerosis: an amnesic process. Brain 2003; 126:

770782.

6. Vergo S, Craner MJ, Etzensperger R, et al. Acid-sensing ion

channel 1 is involved in both axonal injury and demyelinationin multiple sclerosis and its animal model. Brain 2011; 134:

571584.

7. Snowden JA, Passweg J, Moore JJ, et al. Autologous

hemopoietic stem cell transplantation in severe rheumatoid

arthritis: a report from the EBMT and ABMTR.J Rheumatol

2004; 31: 482488.


3/4

Copyright of Multiple Sclerosis (13524585) is the property of Sage Publications, Ltd. and its content may not

be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written

permission. However, users may print, download, or email articles for individual use.


4/4

Copyright of Multiple Sclerosis Journal is the property of Sage Publications, Ltd. and its content may not be

copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written

permission. However, users may print, download, or email articles for individual use.

we are about to cure ms in the nest 10 years even though we do not know its cause no

Documents