Regulated genes in psoriatic skin during treatment with fumaric acid esters.

BACKGROUND: Fumaric acid esters (FAEs) are widely used in Europe for the treatment of psoriasis because of their clinical efficacy and favourable safety profile. However, the mechanisms of action by which FAEs improve psoriasis remain largely unknown. OBJECTIVES: To identify pathways and mechanisms affected by FAE treatment and to compare these with pathways affected by treatment with the antitumour necrosis factor (anti-TNF)-α biologic etanercept. METHODS: In a prospective cohort study, 50 patients with plaque psoriasis were treated with FAEs for 20 weeks. Nine patients were randomly selected for gene expression profiling of plaque biopsies from week 0 and week 12. The groups consisted of FAE responders [> Psoriasis Area and Severity Index (PASI)-75 improvement] and nonresponders (< PASI-50 improvement). Changes in gene expression profiles were analysed using Ingenuity Pathway Analysis (IPA) and the outcome was compared with gene expression affected by etanercept. RESULTS: Response to FAE treatment was associated with a ≥ 2-fold change (P < 0.05) in the expression of 458 genes. In FAE responders the role of interleukin-17A in the psoriasis pathway was most significantly activated. Glutathione and Nrf2 pathway molecules were specifically induced by FAE treatment and not by etanercept treatment, representing an FAE-specific effect in psoriatic skin. In addition, FAE treatment specifically induced the transcription factors PTTG1, NR3C1, GATA3 and NFκBIZ in responding patients. CONCLUSIONS: FAE treatment induces glutathione and Nrf2 pathway genes in lesional skin of patients with psoriasis. In responders, FAEs specifically regulate the transcription factors PTTG1, NR3C1, GATA3 and NFκBIZ, which are important in normal cutaneous development, and the T-helper (Th)2 and Th17 pathways, respectively.

Ustekinumab improves psoriasis-related gene expression in noninvolved psoriatic skin without inhibition of the antimicrobial response.

BACKGROUND: Ustekinumab is a fully human anti-p40 monoclonal antibody which neutralizes interleukin (IL)-12 and IL-23, thereby interfering with T-helper (Th)1/Th17 pathways and keratinocyte activation, and is highly effective in the treatment of psoriasis. During ustekinumab treatment, some of our patients noticed reduced koebnerization of noninvolved skin and less new plaque formation. OBJECTIVES: To determine whether ustekinumab improves psoriasis-related gene expression and tape-strip responses in noninvolved skin. METHODS: Before and 4 weeks after ustekinumab treatment, noninvolved skin was tape-stripped. After 5 h, biopsies were taken from untouched and tape-stripped skin. The mRNA expression of psoriasis-related markers such as NGF, GATA3 and IL-22RA1, and several antimicrobial peptides (AMP) was quantified. Leucocyte counts and a broad range of inflammatory serum proteins were analysed to gain insight into the systemic alterations. RESULTS: Four weeks following a single ustekinumab injection, NGF showed a significant decrease, whereas GATA3 and IL-22RA1 expression increased, indicative of reduced responsiveness to epidermal triggering. This was accompanied by an increase of the inflammation-related serum proteins GPNMB, MST1 and TRADD. The baseline and tape-strip-induced mRNA expression of the AMP human ß-defensin-2 (hBD-2), S100A7 and LL-37 remained unaltered. Clinically, after 4 weeks, eight out of 11 patients showed a 50% psoriasis area and severity index (PASI) improvement, which was accompanied by a significant reduction in serum hBD-2 levels. No changes were noted in total leucocytes, C-reactive protein and erythrocyte sedimentation rate. CONCLUSIONS: These findings indicate that ustekinumab reduces psoriasis-related gene expression in noninvolved psoriatic skin, making it more resistant to exogenous triggering, without disturbing its antimicrobial response. In parallel, ustekinumab modulates important circulating inflammation-related proteins.

Depression in patients with hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic recurrent inflammatory skin disease with abscess formation and scarring predominantly in the inverse areas. The disease is often difficult to treat and patients experience a decreased quality of life (QoL). It is hypothesized that depression is more common in HS patients than among other dermatological patients. OBJECTIVES: To evaluate the prevalence of depression in patients with HS. METHODS: In total 211 HS patients were included in the study and 233 were dermatological control patients. Their QoL and depression scores were assessed using the Dermatology Life Quality Index (DLQI) and the Major Depression Inventory (MDI) questionnaires. HS severity was recorded with a questionnaire and Hurley stages were extracted from the case records. RESULTS: The DLQI was significantly higher for HS patients than for the control patients, 8.4 ± 7.5 vs. 4.3 ± 5.6 (P < 0.0001) and correlated with Hurley stage severity scores. Mean MDI scores were significantly higher for HS patients, 11.0 vs. 7.2 (P < 0.0001). However, clinically defined depression rates according to the International Classification of Diseases, 10th edition (ICD-10) criteria were not significantly higher in HS patients compared to controls (9% vs. 6%). CONCLUSIONS: HS is a chronic skin disease with major impact on QoL even when compared to other dermatological diseases. MDI scores in HS patients correlate with disease severity. This correlation could indicate that the MDI represents a valid measure of disease related morbidity that may serve as an outcome measure in future studies and a relevant point of intervention for individual patients.