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Fumaric acid esters in the management of psoriasis.

ABSTRACT: Fumaric acid esters (FAE) are small molecules with immunomodulating, anti-inflammatory, and anti-oxidative effects. FAE were introduced as a systemic psoriasis treatment in 1959 and empirically developed further between 1970 and 1990 in Germany, Switzerland, and the Netherlands. The development of FAE as psoriasis treatment did not follow the traditional drug development phases. Nonetheless, in 1994 FAE were approved in Germany for the treatment of severe plaque psoriasis. FAE are currently one of the most commonly used treatments in Germany, and FAE are increasingly being used as an unlicensed treatment in several other European countries. To date, six randomized controlled trials and 29 observational studies have evaluated FAE in a combined total of 3,439 patients. The efficacy and safety profile of FAE is favorable. About 50%-70% of patients achieve at least 75% improvement in psoriasis severity after 16 weeks of treatment. Common adverse events of FAE include gastrointestinal complaints and flushing symptoms, which lead to treatment discontinuation in up to 40% of patients. Lymphocytopenia, eosinophilia, and proteinuria are commonly observed during FAE treatment, but rarely require treatment discontinuation. The long-term safety profile of continuous FAE treatment is favorable without an increased risk for infections, malignancies, or other serious adverse events. There are no known drug-interactions for FAE. The 2009 European evidence-based S3-guidelines on psoriasis treatment recommend FAE and suggest it as a first-line systemic treatment for moderate-to-severe plaque psoriasis. This review is aimed to give an overview of FAE treatment in the management of psoriasis.

SUBMITTER: Balak DM

PROVIDER: S-EPMC5683116 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Fumaric acid esters in the management of psoriasis.

Balak Deepak Mw DM

Psoriasis (Auckland, N.Z.) 20150105

Fumaric acid esters (FAE) are small molecules with immunomodulating, anti-inflammatory, and anti-oxidative effects. FAE were introduced as a systemic psoriasis treatment in 1959 and empirically developed further between 1970 and 1990 in Germany, Switzerland, and the Netherlands. The development of FAE as psoriasis treatment did not follow the traditional drug development phases. Nonetheless, in 1994 FAE were approved in Germany for the treatment of severe plaque psoriasis. FAE are currently one ...[more]

PMID: 29387578

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Project description:To test the hypothesis that dimethyl fumarate (DMF, Tecfidera) elicits different biological changes from DMF combined with monoethyl fumarate (MEF) (Fumaderm, a psoriasis therapy), we investigated DMF and MEF in rodents and cynomolgus monkeys. Possible translatability of findings was explored with lymphocyte counts from a retrospective cohort of patients with MS. In rodents, we evaluated pharmacokinetic and pharmacodynamic effects induced by DMF and MEF monotherapies or in combination (DMF/MEF). Clinical implications were investigated in a retrospective, observational analysis of patients with MS treated with DMF/MEF (n = 36). In rodents and cynomolgus monkeys, monomethyl fumarate (MMF, the primary metabolite of DMF) exhibited higher brain penetration, whereas MEF was preferentially partitioned into the kidney. In mice, transcriptional profiling for DMF and MEF alone identified both common and distinct pharmacodynamic responses, with almost no overlap between DMF- and MEF-induced differentially expressed gene profiles in immune tissues. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated oxidative stress response pathway was exclusively regulated by DMF, whereas apoptosis pathways were activated by MEF. DMF/MEF treatment demonstrated that DMF and MEF functionally interact to modify DMF- and MEF-specific responses in unpredictable ways. In patients with MS, DMF/MEF treatment led to early and pronounced suppression of lymphocytes, predominantly CD8+ T cells. In a multivariate regression analysis, the absolute lymphocyte count (ALC) was associated with age at therapy start, baseline ALC, and DMF/MEF dosage but not with previous immunosuppressive medication and sex. Furthermore, the ALC increased in a small cohort of patients with MS (n = 6/7) after switching from DMF/MEF to DMF monotherapy. Fumaric acid esters exhibit different biodistribution and may elicit different biological responses; furthermore, pharmacodynamic effects of combinations differ unpredictably from monotherapy. The strong potential to induce lymphopenia in patients with MS may be a result of activation of apoptosis pathways by MEF compared with DMF.

Project description:BackgroundPlaque psoriasis has significant impact on patients' quality of life. Topical therapy is considered the treatment mainstay for mild-to-moderate disease according to guidelines. Calcipotriol/betamethasone dipropionate (Cal/BD) [0.005%/0.05%] aerosol foam is indicated for psoriasis vulgaris treatment in adults. Cal/BD foam trials demonstrated improved efficacy and similar safety in this population. Psoriasis treatment is complicated by the broad range of disease presentation, variability and therapeutic options; particularly decisions on transition from topical to non-biologic systemic treatment are difficult. Assessing comparative effectiveness of treatment options provides meaningful value to treatment decisions.ObjectiveTo compare efficacy of Cal/BD foam individual patient data from pooled trials with efficacy of non-biologic systemic treatments based on aggregated patient characteristics and treatment outcomes.MethodsIndividual data from four Cal/BD foam trials in 749 psoriasis patients were pooled to conduct matching-adjusted indirect comparisons. Literature review identified non-biologic systemic treatment trials where methods, populations and outcomes align with Cal/BD foam trials. Of 3090 screened publications, four studies of apremilast, methotrexate, acitretin or fumaric acid esters (FAE) were included.ResultsAfter baseline matching, patients treated with 4 weeks of Cal/BD foam had greater Physician's Global Assessment 0/1 response compared to those treated with 16 weeks of apremilast (52.7% vs. 30.4%; P < 0.001). Patients treated with Cal/BD foam had significantly greater Psoriasis Area and Severity Index (PASI) 75 response at Week 4 compared to 16 weeks of apremilast treatment (51.1% vs. 21.6%; P < 0.001). Cal/BD foam patients demonstrated significantly greater PASI 75 response improvements at Week 4 vs. 12 weeks of methotrexate (50.8% vs. 33.5%; P < 0.001) or acitretin (50.9% vs. 31.7%; P = 0.009), and comparable response to FAE (42.4% vs. 47.0%; P = 0.451).ConclusionsDespite recent treatment advances, unmet needs for psoriasis patients remain. Cal/BD foam offers improved efficacy in baseline matched psoriasis patients compared to apremilast, methotrexate or acitretin, and comparable efficacy to FAE.

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Fumaric acid esters in the management of psoriasis.

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Fumaric acid esters in the management of psoriasis.

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