Clinic-speak: end-organ damage

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End-organ damage: can we prevent it? #ClinicSpeak #MSResearch #MSBlog

“I am often asked why I went into medicine, neurology and
MS. I am not sure, but as I was exposed to chronic disease at a young age I
became interested in medicine.”

“My father had an autoimmune disease of the kidney that
caused his kidneys to fail when I was approximately 10 years of age. When I was 12 he
started dialysis and he waited a further 10 years before agreeing to have a kidney
transplant. The tragedy was that when he was a teenager he had intermittent
blood in his urine that was never taken seriously by his doctor, or himself, so
he was never investigated properly or treated. By the time he presented with headaches
due to severe secondary hypertension he was in chronic renal failure. In other words the
inflammation in his kidneys had caused irreparable end-organ damage. The
nephrologist who saw him said ‘if only I had got to you sooner with immune therapies
I would have had a chance of saving your kidneys’
.”

“Fortunately my father lived in an era when salvage kidney therapy was possible; he had peritoneal dialysis, haemodialysis and a kidney
transplant. All three of these innovations are modern miracles and are now part
of routine clinical practice. In a previous era he would have died a young man. The lessons I learnt from father’s case were (1)
get a good doctor who takes things seriously and (2) early diagnosis and
treatment is better than salvage therapy.  These lessons are as pertinent to my practice
as an MSologist today as they were in my father’s case 40 years ago. Unfortunately for
MSers we don’t have salvage therapy; we can’t repair or transplant the brain or
spinal cord. Therefore, your best chance of avoiding end-organ damage is early
effective therapy and getting yourself a good neurologist who takes things
seriously.”

“In almost every MS clinic I do I see the difference between
MSers who have either had a delay in getting a diagnosis, or a delay in getting
access to an effective therapy, compared to those MSers with early access to optimal
therapies with no evident disease activity (NEDA). The latter MSers are leading
near normal lives, whereas the former have to live with the consequences of
end-organ damage. For those who need reminding, the blue or symptomatic line in
my tube map is end-organ damage.”

“Can we prevent end-organ damage? Of course we can, which is
why I get so frustrated by therapeutic nihilists who claim that our treatments
don’t work and that they have too many risks to warrant their use. I saw an MSer in my
clinic yesterday who has highly active MS and has been on natalizumab for over
4 years. She previously failed interferon-beta therapy. Since she has been on
natalizumab she has had no evident disease activity (NEDA) and lives a near normal
life apart from having to come up to hospital once a month for her infusion. She has a full-time
job, runs regularly, has an active social life and has no major symptomatic
problems. In other words her MS is behaving as if it is benign. The problem is
she is JCV seropositive with a high titre, or antibody level, and therefore has a 1 in 118
chance of getting PML. I recommended to her that she should switch to fingolimod.
She refused. She doesn’t want to take the chance of her MS coming back. Should
I force her to switch? Yes or no?”





“The compromise we have reached is that she is
having 3-monthly MRIs and 6-monthly JCV antibody levels done. She has agreed to
switch to fingolimod if her antibody levels increase substantially, i.e. by 0.5
units. There is some early data that suggests a rising antibody titre to JCV is
a risk factor for developing PML. She will obviously stop natalizumab if she
develops asymptomatic PML as diagnosed by MRI monitoring; there is data showing
that MSers who present with symptomatic PML do worse than MSers with asymptomatic
PML. This is why we now offer our risk MSers at high-risk of developing PML the
option of having 3-monthly MRIs with the aim of detecting PML early. The other potential
option I discussed with her was the possibility of alemtuzumab treatment if
and when NICE, and NHS England, allow us to use the drug in the NHS.”



“The following abstract and figures refers to the PML risk profiling based on anti-JCV antibody titres.”



Plavina et al. Use of JC virus antibody index to stratify risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients with multiple sclerosis. ENS 2013 Multiple Sclerosis I: Therapeutics


Objectives: In MSers treated with natalizumab, the presence of anti-JCV antibodies (JCV Ab+), prior use of immunosuppressants (IS), and increased duration of natalizumab treatment, especially greater than 2 years, are known risk factors for progressive multifocal leukoencephalopathy (PML). With polyomaviruses, higher levels of antibodies have been correlated with increased viral burden and increased disease risk. It is not known whether JCV Ab levels correlate with PML risk in natalizumab-treated MSers. The objective of this analysis is to examine the association between JCV Ab index (JCV antibody level as measured using the STRATIFY JCV DX Select assay) and PML risk in natalizumab-treated MSers. 

Methods: Analyses involved JCV Ab index data from JCV Ab+ MSers enrolled in clinical studies or clinical practice. A cross-sectional analysis of JCV Ab index data from MSers without PML was first performed to assess potential relationships between JCV Ab index and known risk factors (natalizumab treatment duration <=24 vs >24 monthly infusions and prior IS use). P values were calculated using a Wilcoxon rank sum test. The association between JCV Ab index and PML was then assessed using all available longitudinal data. Odds ratios (ORs) were estimated from generalised estimating equations with a logit link. The predicted probabilities were then used to update the current PML risk estimates for JCV Ab+ MSers with high/low Ab index by applying Bayes theorem. 

Results: JCV Ab index data were available from 71 natalizumab-treated PML MSers at least 6 months prior to PML diagnosis and from 2522 non-PML JCV Ab+ MSers. JCV Ab index was not found to be associated with number of natalizumab infusions (P=0.39) nor prior IS use (P=0.43), but was significantly associated with PML risk (P<0.001). Estimated ORs were at least 4 for high versus low JCV Ab index in JCV Ab+ MSers. Updated PML risk estimates and longitudinal stability of JCV Ab index will be presented. 

Conclusion: Risk of PML in JCV Ab negative natalizumab-treated MSers is very low (0.07 per 1000). In JCV Ab+ MSers who have low JCV Ab index, the risk of PML is several-fold lower than the risk currently attributed to all JCV Ab+ MSers. Utilisation of JCV Ab index allows for further clinically meaningful stratification of PML risk in JCV Ab+ natalizumab-treated MSers.





“The figures in the bottom table are derived from Table 2 above and present the data in a different way, rather as per thousand an absolute risk. You have to realise that these figures are derived from relatively small numbers, i.e. 51 cases of PML. But the data is what it is and will not be confirmed by anyone else. I assume as more cases emerge the data set will be updated. The implications of this data is that many MSers who are doing well on natalizumab and have low titres, or a low index, may choose to stay on natalizumab rather than switch. In those MSers who are high risk and have elected to stay on natalizumab I would recommend 3 monthly MRI monitoring for early signs of PML. The idea behind the latter strategy is to detect PML very early and wash-out natalizumab. It is clear that if PML is picked up in the asymptomatic phase and managed quickly MSers do much better; this is highlighted in slides 35 and 36 of the Biogen-Idec slide deck below.”



Conflicts: multiple

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

7 comments

  • "Unfortunately for MSers we don’t have salvage therapy; we can’t repair or transplant the brain or spinal cord."
    Not yet, but with your good work, the day when that happens will come sooner. Thanks. Have a great year.

  • I'm very sorry to hear about your father. You honor us by sharing such a deeply personal experience. I apologize for being extremely blunt, but given the stakes we face as patients, I can't respond any other way.

    You raise what is the truly horrifying dilemma of Natalizumab and ms. I'm one of those who was diagnosed late, and living with permanent symptoms. I won't attempt to choose for your patient. But for me, Tysabri is a non-starter. No doubt it improves quality of life while you're on it. But rebound effect is highly scary, and none of the likely outcomes of PML are anything I would want to survive and live with. The best possible outcome of PML from my perspective (for me, not anyone else) would be a quickly fatal result. Odds are, based on the prognostic indicators you've posted on this blog, I have between 5 and 30 years with treatment to live with tolerably mild ms. I can choose later whether severe ms is something I want to live with, or you may come up with something better than Tysabri.

    If you wanted to change my mind, you would need to say a lot more about this rare occurrence called 'asymptomatic' PML. I didn't know that was even possible.

    • Regarding asymptomatic PML. I will prepare a post on this.

      Rebound is a thing of the past if you transition to a highly-effective drug without a wash-out.

    • Thank you for your reply, and for your post on asymptomatic pml. It's not your fault ms is such a bad disease. I hope there can be some effort made to teach future gp's both to spot early neurological symptoms and how important it is to recognize ms early. Like many, I was not treated with respect when I tried to investigate symptoms.

  • Linda Jean said
    I believe my ms is viral. I had mono when I was 16.diagnosed at 60. I am 67 now.
    I stopped after 2 yrs on copaxone as i thought it was worthlwssx and annoying. I take nothing. Mris show over 9 lesions in my brain. I have no mobility issues. Just terrible constant and ever increasing nerve pain. I have relapsing muscle spasms. Fatigue is not bad at the moment.

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