Clinic-speak: end-organ damage

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

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