Tuesday, 24 April 2018

PML risk in fingolimod

Progressive multifocal leukoencephalopathy after fingolimod treatment

Joseph R. Berger, Bruce A. Cree, Benjamin Greenberg, Bernhard Hemmer, Brian J. Ward, Victor M. Dong and Martin Merschhemke
First published April 18, 2018, DOI: https://doi.org/10.1212/WNL.0000000000005529 loads

Abstract


Objective We describe the characteristics of the 15 patients with fingolimod-associated progressive multifocal leukoencephalopathy (PML) identified from the Novartis data safety base and provide risk estimates for the disorder.

Methods The Novartis safety database was searched for PML cases with a data lock point of August 31, 2017. PML classification was based on previously published criteria. The risk and incidence were estimated using the 15 patients with confirmed PML and the overall population of patients treated with fingolimod.

Results As of August 31, 2017, 15 fingolimod-treated patients had developed PML in the absence of natalizumab treatment in the preceding 6 months. Eleven (73%) were women and the mean age was 53 years (median: 53 years). Fourteen of the 15 patients were treated with fingolimod for >2 years. Two patients had confounding medical conditions. Two patients had natalizumab treatment. This included one patient whose last dose of natalizumab was 3 years and 9 months before the diagnosis of PML. The second patient was receiving fingolimod for 4 years and 6 months, which was discontinued to start natalizumab and was diagnosed with PML 3 months after starting natalizumab. Absolute lymphocyte counts were available for 14 of the 15 patients and none exhibited a sustained grade 4 lymphopenia (≤200 cells/μL).

Conclusions The risk of PML with fingolimod in the absence of prior natalizumab treatment is low. The estimated risk was 0.069 per 1,000 patients (95% confidence interval: 0.039–0.114), and the estimated incidence rate was 3.12 per 100,000 patient-years (95% confidence interval: 1.75–5.15). Neither clinical manifestations nor radiographic features suggested any unique features of fingolimod-associated PML.

Gaussian or "normal" distribution

When Nassim Taleb in his book 'The Black Swan' talks about the impact of the highly improbable, he references 9/11, the Walls St crash, and the so-called experts and "empty suits" who provide a minute by minute narration of the events, but in real terms do not know more on the subject than the general population. According to Taleb the occurrence of a black swan is a rare event, but a single sighting can invalidate a statement based on sightings of swans being white going back a millennia. Interestingly, it took me some time to recognise that the occurrence of PML following immunosuppressant use is an example of a black swan.

Taleb also talks about the pitfall of human/academic arrogance, he calls this GIF (Great Intellectual Fraud), whereby we look at data in terms of normality (the bell shaped curve or Gaussian distribution) and talk of commonalities from the outset at the cost of outliers. This gives rise to a false state of reassurance that we have tamed the rare occurrences, which is far from the truth. This concept also applies to our interpretation of PML risk.

Here, Novartis (who make fingolimod, also known as Gilenya) present the risk and incidence of PML in those on fingolimod. They have 15 cases (12 definite, 3 probable) following fingolimod use up to Aug 2017. This excludes cases that may be attributed to carry over risk from previous natalizumab use over the last 6 months.


The estimate the risk of occurrence of PML is 0.07 per 1000 patients treated (i.e. <1:10,000). The mean age affected was 53, of the 15 cases, 11 were women, and the duration of MS was 4-35 years, 1 had previous cancer, while another had bowel colitis with prior immunosuppressant use. Interestingly, like with the natalizumab risk stratification 14/15 cases had been on fingolimod for >2y. Only 4 of the cases exhibited grade for lymphopenia (i.e. </= 200 cells/ul).
 
The author’s conclude that “the number of PML cases reported so far with fingolimod is too low to trigger any specific interventions at this point in time”. I wonder if they realise that the incidence of PML is a black swan? Their occurrence so rare as to render risk-mitigation strategies effectively useless. And yet as doctors we need guidelines to cushion our intellectual sensibilities.
 
Along these lines below is the existing MHRA (Medicines and Healthcare products Regulatory Agency) for risk of PML on fingolimod.
 
Before starting fingolimod treatment:
  • Perform a full blood count including lymphocyte subsets
  • Perform a baseline cranial MRI scan as a reference, usually within 3 months of starting fingolimod treatment
  • Counsel patients and carers on the risk of PML; advise them on the symptoms to watch out for and to get medical help urgently if they occur
  • If testing for JCV is undertaken, consider that the influence of lymphopenia on the accuracy of the anti-JCV antibody test has not been studied in fingolimod-treated patients

During fingolimod treatment
  • If PML is suspected, stop fingolimod treatment immediately and investigate appropriately, eg MRI scan; ultrasensitive polymerase chain reaction (PCR) assay for JCV DNA
  • Monitor full blood count 3 months after starting fingolimod treatment and at least yearly thereafter
  • We remind you to interrupt fingolimod treatment if lymphocyte count falls below 0.2x109/L, do not restart treatment until lymphocyte levels have recovered
  • When analysing routine MRI scans, pay attention to PML-suggestive lesions
  • Consider further MRI scans as part of increased vigilance in patients considered at high risk of PML, in accordance with national and local recommendations
  • Monitor patients for signs and symptoms or appearance of new neurological dysfunction (eg motor, cognitive, or psychiatric symptoms), bearing in mind that PML can present with features similar to multiple sclerosis
  • Note that patients might still develop a JCV infection, even if they have a normal lymphocyte count and previously tested negative for anti-JCV antibodies

Saturday, 21 April 2018

Prof G the feminist

Three things happened to me this week that made realise that I am a feminist.


Friday, 20 April 2018

Is the B cell idea broken?....Sort of Th17 and Th1 are the problem.

The B cell hypothesis gains momentum with the Pharma Industry, but do our academic colleagues know better and it really is the TH17 cell at the top of the pyramid.

Thursday, 19 April 2018

Vaccines and Vaccinations: The Big Differentiator

I predict vaccines and the timing of vaccinations will in time become a major differentiator between the maintenance therapies and the immune reconstitution therapies (IRTs). 



What do you think? 

Wednesday, 18 April 2018

Guest post: Your attention please: MS hurts!



Visual impairment, sensory disturbances, weakness and fatigue are among the most commons symptoms in MS, but there are others such as pain, which is highly distressing and can easily affect day-to-day life. This symptom is often difficult to describe by patients and is sometimes difficult to diagnose and treat by clinicians.

Tuesday, 17 April 2018

EBV and the not so magnificant 7. A cause of autoimmunity

New genetic research has linked EBV infection to seven autoimmune diseases and include multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis, celiac disease and SLE

What do they have in common?


A glass half full? Benign MS in Australia

Are you a glass-half-full or a glass-half-empty person? 


Monday, 16 April 2018

Reflections on all things MS from Stornoway

We have just finished our 2018 Barts-MS Research Day on Stornoway with the Glasgow-MS team. The experience has been very humbling and quite and an eye-opener in terms of living with a chronic disease, such as MS, on a remote Island.

Barts-MS and Glasgow-MS hugging the Callanish Stones, Western Isles.