Author Topic: (Abst.) Fatal toxic epidermal necrolysis in patient on teriflunomide for MS  (Read 1642 times)

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Offline agate

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From Multiple Sclerosis Journal, July 22, 2015:

Quote
Fatal toxic epidermal necrolysis in a patient on teriflunomide treatment for relapsing multiple sclerosis

Gaspard Gerschenfeld
Service de Réanimation Médicale, Assistance Publique – Hôpitaux de Paris, Groupe Henri Mondor – Albert Chenevier, Créteil, France

Amandine Servy
Service de Dermatologie et Centre de Référence des dermatoses bulleuses immunologiques et toxiques, Assistance Publique – Hôpitaux de Paris, Groupe Henri Mondor – Albert Chenevier, Créteil, France

Laurence Valeyrie-Allanore
Service de Dermatologie et Centre de Référence des dermatoses bulleuses immunologiques et toxiques, Assistance Publique – Hôpitaux de Paris, Groupe Henri Mondor – Albert Chenevier, Créteil, France

Nicolas de Prost
Service de Réanimation Médicale, Assistance Publique – Hôpitaux de Paris, Groupe Henri Mondor – Albert Chenevier, Créteil, France/Université Paris est Créteil, Faculté de Médecine de Créteil, Groupe de Recherche Clinique CARMAS, Créteil, France

Jérôme Cecchini
Service de Réanimation Médicale, Assistance Publique – Hôpitaux de Paris, Groupe Henri Mondor – Albert Chenevier, Créteil, France/Université Paris est Créteil, Faculté de Médecine de Créteil, Groupe de Recherche Clinique CARMAS, Créteil, France
Service de Réanimation Médicale, Assistance Publique – Hôpitaux de Paris, Groupe Henri Mondor – Albert Chenevier, 51, Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil Cedex, France. jerome.cecchini@hmn.aphp.fr


We report a case of toxic epidermal necrolysis in a 46-year-old woman on teriflunomide treatment. Such a severe adverse cutaneous drug reaction with this new therapy for relapsing forms of multiple sclerosis should be early recognized in order to ensure the rapid withdrawal of the drug.

The abstract can be seen here.
« Last Edit: July 23, 2015, 09:10:02 pm by agate »
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Offline agate

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I've been trying to find out  more about this but so far haven't had any further information.

The Aubagio Website does have a .pdf file called "A Guide to the Accelerated Elimination Procedure for Aubagio" which includes this statement:

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Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported rarely in rheumatoid arthritis patients receiving leflunomide, with a similar risk expected for teriflunomide; therefore, stop treatment and use accelerated elimination if a severe skin reaction develops.

The accelerated elimination procedure involves 11 days of cholestyramine and activated charcoal. Aubagio usually takes up to 2 years to be eliminated from the body but with the accelerated elimination procedure eliminating it takes 11 days.

http://www.aubagio.com/media/pdf/Guide_to_Accelerated_Elimination_Procedure_for_AUBAGIO(R)(teriflunomide).pdf
MS Speaks--online for 13 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010.

Offline agate

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I came across these revised guidelines for Aubagio by the Department of Veterans Affairs--they were revised in June 2015:

http://www.pbm.va.gov/PBM/clinicalguidance/criteriaforuse/Teriflunomide_Criteria_for_Use_Rev_June_2015.pdf
MS Speaks--online for 13 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010.

Offline agate

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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 »
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Offline agate

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Presented at the ECTRIMS conference in Barcelona (October 7-10, 2015):

Quote
Teriflunomide-induced fatal toxic epidermal necrolysis in a patient with multiple sclerosis

F. Derouiche, SCF Avicenne, Mulhouse, France

Abstract: EP1339


Abstract Category: Risk management for disease modifying treatments

Introduction:

Teriflunomide is an immunomodulating agent with proven efficacy in multiple sclerosis. Although its overall safety is good. We report a case of a fatal toxic epidermal necrolysis with Teriflunomide.

Case report:

This 46-year-old woman had multiple sclerosis, diagnosed in 2005. She was treated successively with subcutaneous Interferon beta 1a from 04/2009 to 05/2011, Intramuscular Interferon 1a, from 03/2013 to 09/2013 and Diméthyl Fumarate from 05/2013 to 11/2014. All these treatments were stopped because of adverse events. Teriflunomide was started in 01/2015.

Two weeks later, the patient developed febrile maculopapular rash that rapidly spread to the whole of the integument with ulceration of the oral, ocular, nasal and vag`inal mucosa. Despite discontinuing Teriflunomide, initiation of the wash out procedure and her admission in the Intensive care unit, she died after a week following an acute respiratory distress syndrome and a multi organ failure.

Discussion:

The main adverse effects of Teriflunomide consist of diarrhea, nausea, liver enzyme elevation, hypertension, alopecia, and allergic skin reactions. A few cases of toxic epidermal necrolysis have been reported with Leflunomide but never withTeriflunomide.

Conclusion:

Close monitoring for severe skin reactions is in order when using Teriflunomide.

Disclosure: No disclosure
« Last Edit: November 16, 2015, 09:06:18 am by agate »
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Offline agate

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The risk of TEN (toxic epidermal necrolysis) in connection with Aubagio is discussed in this article, which is a comprehensive summary of MS treatments (although Zinbryta has been misspelled as Zimbrata, apparently). The article is entitled "Steering through complexity: management approaches in multiple sclerosis," by Bruce Cree and  Hans-Peter Hartung, in Current Opinion in Neurology (June 2016):

http://journals.lww.com/co-neurology/Fulltext/2016/06000/Steering_through_complexity___management.10.aspx?cid=MR-eJP-Newsletter-Neurology-Neurology-WCO-NoPromo

This is what the article says about Aubagio:

Quote





Teriflunomide is the only oral therapy that has not yet been associated causally with PML. Unfortunately, a fatal case of toxic epidermal necrolysis (TEN) was causally linked to teriflunomide [32]. Several other cases of severe cutaneous reactions have been reported, and the prescriber information was updated.

TEN is a known complication of leflunomide, a drug for the treatment of rheumatoid arthritis that was not observed in the clinical development program of teriflunomide. A rare but high-risk adverse event poses challenges for positioning this oral therapy that also carries boxed warnings regarding hepatotoxicity and teratogenicity with similar efficacy to autoinjectable medications. Teriflunomide also has a lengthy half-life due to gastrointestinal reabsorption and requires cholestyramine or activated charcoal for rapid elimination. Otherwise, long-term data from the TEMSO extension trial and the pooled analysis of all four placebo-controlled trials with duration of treatment up to 12 years and a cumulative exposure exceeding 6.800 patient years showed a good safety profile
MS Speaks--online for 13 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010.