Regulated genes in psoriatic skin during treatment with fumaric acid esters

Onderdijk, Armanda; Balak, Deepak; Baerveldt, Ewout M.; Florencia, Edwin; Kant, Marius; Laman, Jon D.; IJcken, Wilfred F. J. van; Rácz, Emőke; Ridder, Dick de; Thio, Hok Bing; Prens, Errol P.

doi:10.1111/bjd.13128

Cited by 27 publications

(23 citation statements)

References 43 publications

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“…This approach is similar to the use of phase I drugmetabolizing enzymes, in which cytochrome P450, which is induced by various xenobiotics through the Ah receptor, can be used as indicator of marine pollution (Cajaraville et al, 2000). Daily oral administration of fumaric acid esters over 12 weeks was associated with the increased expression of NRF2 target genes in the skin of patients with psoriasis (Onderdijk et al, 2014). Similarly, a fivefold increase in the mRNA level of NQO1 has been reported in peripheral blood mononuclear cells obtained from cancer patients that received a daily dose of CDDO-Me for 3 weeks (Hong et al, 2012).…”

Section: Biomarkers As Nuclear Factor (Erythroidderived 2)-like 2mentioning

confidence: 99%

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

et al. 2018

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Section: Biomarkers As Nuclear Factor (Erythroidderived 2)-like 2mentioning

confidence: 99%

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

et al. 2018

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“…However, little is known about the physiologic functions of GPR109A in the skin and the possible mechanisms activated by its binding of MMF. In addition, in vitro and animal studies, as well as clinical data, suggest that MMF upregulates the antioxidative transcription factor Nrf2 (Onderdijk et al, 2014;Promsote et al, 2014). Our group is currently attempting to address these questions.…”

Section: Mmf-induced Effects In Keratinocytesmentioning

confidence: 99%

The Antipsoriatic Agent Monomethylfumarate Has Antiproliferative, Prodifferentiative, and Anti-Inflammatory Effects on Keratinocytes

Helwa

Patel

Karempelis

et al. 2014

J Pharmacol Exp Ther

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Monomethylfumarate (MMF) is thought to be the bioactive ingredient of the drug Fumaderm (Biogen Idec, Cambridge, MA), licensed in Germany since 1994 for the treatment of moderate-tosevere psoriasis. Psoriasis is a common inflammatory hyperproliferative skin disorder that involves cross-talk between different cell types, including immune cells and keratinocytes. Psoriatic lesions are characterized by hyperproliferation, aberrant differentiation, and inflammation, with the psoriatic cytokine network maintained by communication between immune cells and keratinocytes. Recently, there is increasing evidence regarding the pivotal role of keratinocytes in mediating the disease process, and these cells can be regarded as safe therapeutic targets. From the data available on human subjects treated with Fumaderm, MMF is an effective antipsoriatic agent with known effects on immune cells. However, little is known about its direct effects on keratinocytes. We hypothesized that MMF has direct antiproliferative, prodifferentiative, and anti-inflammatory effects on keratinocytes. Indeed, MMF dose-dependently inhibited [ 3 H]thymidine incorporation into DNA, indicating a direct antiproliferative action on keratinocytes. MMF significantly increased the protein level of keratin 10, the early keratinocyte differentiation marker, and the activity of transglutaminase, a late differentiation marker. These results are consistent with an ability of MMF to promote keratinocyte differentiation and inhibit proliferation, thereby improving psoriatic lesions. In 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced keratinocytes, MMF significantly inhibited the expression of the proinflammatory cytokines, tumor necrosis factor-a (TNFa), interleukin-6, and interleukin-1a as well as the production of TNFa. Our results support the notion that MMF has direct antiproliferative, prodifferentiative, and anti-inflammatory effects on keratinocytes, highlighting its potential use as a multifactorial antipsoriatic agent.

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“…Onderdijk et al [19] showed using microarray hybridization studies that the glutathione pathway was activated only in the FAE-treated patients and not in the etanercept group. This was evidenced by an upregulation of several GSTs and depletion enzymes in both responding and nonresponding patients, including GPX2, MGST1 and GSTmu3.…”

Section: Discussionmentioning

confidence: 99%

Val/Val glutathione-S-transferase P1 polymorphism predicts nonresponders in psoriasis patients treated with fumaric acid esters

Gambichler

Susok

Zankl

et al. 2016

Pharmacogenetics and Genomics

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Fumaric acid esters (FAE) are beneficial in the treatment of psoriasis. However, about a third of psoriasis patients do not respond to FAE. We aimed to determine whether glutathione-S-transferase (GST) M1 and GSTP1 polymorphisms are associated with treatment outcome in psoriasis patients treated with FAE. We studied 84 psoriasis patients who were treated with FAE for 3 months. FAE nonresponders were defined as having psoriasis area and severity improvement index less than 50% after 3-month therapy. GSTM1 genotyping for gene deletion and GSTP1 exon 5 105 Ile→Val polymorphisms were assessed using a high-resolution melting analysis. A dropout rate of 23.8% (20/84) was found; 25% (16/64) were FAE nonresponders. We observed 42 (84/50%) patients with G 9STM1*0 homozygous alleles and 42 (84/50%) patients with one or two active GSTM1 alleles. The Ile/Ile GSTP1 genotype was observed in 37 (84/44%), the Ile/Val GSTP1 genotype in 38 (84/45.2%) patients and the Val/Val GSTP1 genotype in nine (84/10.7%) patients. There was no significant (P>0.05) association between the GST genotypes assessed and the frequency FAE responder status, except for the Val/Val GSTP1 polymorphism, which was a significant (overall model fit; P=0.0012) predictor for nonresponders with an odds ratio of 43.4 (95% confidence interval: 4.2-511.1). The coefficient of regression was 3.9, with a SE of 1.2 as assessed by logistic regression analysis (P=0.0017). The Val/Val GSTP1 polymorphism predicts nonresponders in FAE treatment of psoriasis patients and may therefore serve as a biomarker that enables a laboratory-based pretreatment selection of patients.

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Regulated genes in psoriatic skin during treatment with fumaric acid esters

Cited by 27 publications

References 43 publications

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

The Antipsoriatic Agent Monomethylfumarate Has Antiproliferative, Prodifferentiative, and Anti-Inflammatory Effects on Keratinocytes

Val/Val glutathione-S-transferase P1 polymorphism predicts nonresponders in psoriasis patients treated with fumaric acid esters

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