Progressive multifocal leukoencephalopathy associated with fumaric acid esters treatment in psoriasis patients.
BACKGROUND
Fumaric acid esters (FAEs) are a systemic treatment for psoriasis considered to have a favourable long-term safety profile without an increased risk for immunosuppression. However, progressive multifocal leukoencephalopathy (PML), a rare, opportunistic viral infection of the central nervous system, has been linked anecdotally to FAE treatment.


OBJECTIVE
To assess clinical features and outcomes of FAE-associated PML cases.


METHODS
Systematic literature search in multiple databases up to 25th February 2016 for reports of PML in psoriasis patients treated with FAEs.


RESULTS
Eight cases (four male, four female) of FAE-associated PML were identified. Median age was 64 years (range 42-74 years); median FAE treatment duration was 3 years (range 1.5-5 years). Six patients were treated with a formulation containing dimethyl fumarate (DMF) and monoethyl fumarates, and two patients with a DMF formulation. Patients exhibited neurological symptoms, such as aphasia, hemiparesis and dysarthria. PML diagnosis was based on MRI findings and presence of JC virus in cerebrospinal fluid and/or brain tissue. All cases were linked to moderate-to-severe reductions in absolute lymphocyte counts, with nadirs ranging from 200 to 792 cells per mm3. Median exposure to lymphocytopenia was 2 years (range 1-5 years). In all cases, FAE treatment was discontinued; PML was treated with mefloquine plus mirtazapine. Three patients improved, two had stable disease, two had residual symptoms, and one patient died to an immune reconstitution inflammatory syndrome.


CONCLUSIONS
Progressive multifocal leukoencephalopathy is infrequently linked to FAE treatment, but underreporting cannot be excluded. Physicians treating patients with FAEs should be vigilant for the occurrence of PML, and both clinicians and patients should be alert for onset of new neurological symptoms. Periodic monitoring of lymphocyte counts and FAE discontinuation in case of moderate-to-severe lymphocytopenia is recommended to minimize the risk for PML.
Department of Dermatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
D M W
DMW
Balak
Department of Dermatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
E
E
Hajdarbegovic
Medical Library, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
W M
WM
Bramer
Department of Dermatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
H A M
HAM
Neumann
Department of Dermatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
H B
HB
Thio
D000328:Adult; D000368:Aged; D005260:Female; D005650:Fumarates / Q000627:therapeutic use*; D006801:Humans; D007968:Leukoencephalopathy, Progressive Multifocal / Q000097:blood / Q000139:chemically induced*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D011565:Psoriasis / Q000097:blood / Q000188:drug therapy*; D012307:Risk Factors; D016896:Treatment Outcome
D005650:Fumarates