Author Topic: (Abst.) Fatal toxic epidermal necrolysis in patient on teriflunomide for MS  (Read 1856 times)

0 Members and 1 Guest are viewing this topic.

Offline agate

  • Administrator
  • *****
  • Posts: 9822
  • MS diagnosed 1980
  • Location: Pacific Northwest
This is the text of the article by Gerschenfeld et al. in Multiple Sclerosis Journal (July 2015), with illustrations and references omitted:

Quote
Teriflunomide is a new disease-modifying therapy for
relapsing forms of multiple sclerosis (RMS) which
has been shown to reduce relapse rate and disability
progression. Until now, no lethal adverse event had
been reported. We herein report the first case of a fatal
toxic epidermal necrolysis (TEN) in a patient on teriflunomide
treatment.

A 46-year-old Caucasian woman was admitted to our
intensive care unit (ICU) for TEN. Her medical history
included a RMS diagnosed in 2005, with an
Expanded Disability Status Scale of one and two sensitive
relapses per year. Previous treatments, including
β-1a interferon and dimethyl-fumarate, had been
suspended for poor tolerance (flu-like symptoms and
rash). Teriflunomide was initiated as an alternative
treatment. No other medication was reported except
for occasional self-medication with paracetamol and
ibuprofen with good tolerance. At day 19 of drug
onset, she had transitory flu-like symptoms with complete
healing in five days with paracetamol. Fever and
asthenia appeared on day 28. Teriflunomide was discontinued.
The following day, she presented with
catarrh, vulvar pruritus, odynophagia and an erythematous
macular eruption of the face and upper trunk.
She was hospitalized on day 30 and developed acute
respiratory failure requiring mechanical ventilation.
TEN was suspected and she was referred to our ICU
on day 34. Upon admission, clinical features included
diffuse erythema, confluent flaccid blisters with positive
Nikolsky’s sign, 95% of detached-detachable
skin leading to extensive areas of de[bride]d skin
 and erosions of all mucosae. The TENspecific
severity-of-illness score was 5 (predictive
mortality of 83%). Fibre-optic bronchoscopy showed
mucosal detachment of the trachea and the bronchial
tree. Microbiologic (human immunodeficiency virus
serology, Mycoplasma pneumoniae serology and polymerase
chain reaction, blood and urine cultures) and
auto-immunity tests were negative. Skin biopsy
revealed bullous disjunction at the dermo-epidermal
junction, non-specific C3 granular deposit
on immunostaining and epidermal necrosis, ruling out
alternative causes and confirming the diagnosis of
TEN. Supportive skin cares were performed.
Ciclosporin (1.5 mg/kg per 12h) was introduced.

Teriflunomide was the only causative drug retained
according to an algorithm of drug causality for TEN
based on the following criteria: time latency between
beginning of drug and index-day, drug present in the
body before index-day, information on prechallenge/
rechallenge and dechallenge, notoriety of the drug,
and alternative causes. Its clearance was accelerated
with daily enteral administration of cholestyramine
(24g). Plasma concentrations decreased from 11.3 to
3.0 μg/ml in four days, corresponding to a theoretical
2.1-day half-life. Still, the patient’s clinical condition
worsened with no cutaneous healing and multiple
organ dysfunctions, leading to death on day 39.

TEN is a rare mucocutaneous disease, most frequently
caused by medications. Death often follows infections
complications or hydroelectrolytic disorders. Although
leflunomide has been previously associated with TEN,
this case is, to the best of our knowledge, the first
reported with its active metabolite, teriflunomide.
Whether predisposing conditions, such as peculiar
HLA type, may be involved in the occurrence of TEN
associated with leflunomide or teriflunomide is
unknown. Teriflunomide is a non-dialysable biliary excreted
drug with an intestinal reabsorption cycle
accounting for a long 19-day half-life. Early drug
withdrawal of the causative drug is a key aspect of the
early management of TEN patients. However, in this
case, the long half-life of teriflunomide, albeit accelerated
by a washout procedure, was associated with a
fatal outcome. Patients under teriflunomide should be
carefully monitored during the first weeks following
treatment initiation. When TEN is suspected, teriflunomide
should be stopped and cholestyramine administration
considered in order to accelerate its biliary
clearance.

Acknowledgements

We thank doctors Anne Hulin and Raymond
Karkouche for their respective help in performing
teriflunomide plasma concentrations and histologic
examination of skin biopsy.

Conflict of interest

The authors declare that there is no conflict of
interest.
 
« Last Edit: October 12, 2015, 12:39:47 pm by agate »
MS Speaks--online for 17 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010. Glatopa (glatiramer acetate 40mg 3 times/week) since 12/16/20.