Skin inflammatory response and efficacy of anti-epidermal growth factor receptor therapy in metastatic colorectal cancer (CUTACETUX).

Anti-epidermal growth factor receptor (EGFR) monoclonal antibody is a standard treatment of metastatic colorectal cancer (mCRC) and its most common adverse effect is a papulopustular acneiform rash. The aim of the CUTACETUX study was to characterize the skin inflammatory response associated with this rash and its relation to treatment efficacy. This prospective study included patients with mCRC treated with first-line chemotherapy plus cetuximab. Patients underwent skin biopsies before the initiation of cetuximab (D0) and before the third infusion (D28), one in a rash zone and one in an unaffected zone. Expression of Th17-related cytokines (IL-17A, IL-21, IL-22), antimicrobial peptides (S100A7 and BD-2), innate response-related cytokines (IL-1ß, IL-6, TNF-α and OSM), T-reg-related cytokines (IL-10 and TGF-ß), Th1-related cytokine (IFN-γ), Th2-related cytokine (IL-4), Thymic stromal lymphopoietin and keratinocyte-derived cytokines (IL-8, IL-23 and CCL20) were determined by RT-PCR. Twenty-seven patients were included. Levels of most of the cytokines increased at D28 in the rash zone compared to D0. No significant association was observed between variations of cytokines levels and treatment response in the rash zone and only the increase of IL-4 (p = .04) and IL-23 (p = .02) levels between D0 and D28 in the unaffected zone was significantly associated with treatment response. Increased levels of IL-8 (p = .02), BD-2 (p = .02), IL-1ß (p = .004) and OSM (p = .02) in the rash zone were associated with longer progression-free survival. Expression of Th2-related and keratinocyte-derived cytokines in the skin was associated with anti-EGFR efficacy. If this inflammatory signature can explain the rash, the exact mechanism by which these cytokines are involved in anti-EGFR tumor response remains to be studied.

High-Fat Diet-Induced IL-17A Exacerbates Psoriasiform Dermatitis in a Mouse Model of Steatohepatitis.

Recent studies suggest that psoriasis may be more severe in patients with nonalcoholic fatty liver disease, particularly in those with the inflammatory stage of steatohepatitis [nonalcoholic steatohepatitis (NASH)]. Herein, we investigated the impact of diet-induced steatohepatitis on the severity of imiquimod-induced psoriasiform dermatitis. Mice fed with a high-fat diet developed steatohepatitis reminiscent of human NASH with ballooning hepatocytes and significant liver fibrosis. Mice with steatohepatitis also displayed moderate cutaneous inflammation characterized by erythema, dermal infiltrates of CD45(+) leukocytes, and a local production of IL-17A. Moreover, steatohepatitis was associated with an epidermal activation of caspase-1 and cutaneous overexpression of IL-1ß. Imiquimod-induced psoriasiform dermatitis was exacerbated in mice with steatohepatitis as compared to animals fed with a standard diet. Scale formation and acanthosis were aggravated, in correlation with increased IL-17A and IL-22 expression in inflamed skins. Finally, intradermal injection of IL-17A in standard diet-fed mice recapitulated the cutaneous pathology of mice with steatohepatitis. The results show that high-fat diet-induced steatohepatitis aggravates the inflammation in psoriasiform dermatitis, via the cutaneous production of IL-17A. In agreement with clinical data, this description of a novel extrahepatic manifestation of NASH should sensitize dermatologists to the screening and the management of fatty liver in psoriatic patients.

Cardiovascular events in chronic hepatitis C: prognostic value of liver stiffness evolution.

BACKGROUND AND AIMS: Chronic hepatitis C is also a metabolic disease that may increase cardiovascular events. FibroScan is a diagnostic tool for fibrosis and a prognostic tool for cirrhosis complications and mortality. The aim of our study was to investigate the prognostic value of liver stiffness evolution and initial stiffness in cardiovascular events occurring in patients with chronic hepatitis C. PATIENTS AND METHODS: Between 2006 and 2013, chronic hepatitis C patients followed in a reference center with two valid liver stiffness measurements by FibroScan were included. Cardiovascular events occurring after the initial FibroScan were collected retrospectively. 'Rapid stiffness progression' was defined as an evolution of at least 0.3 kPa/year and 'high initial stiffness' as at least 7 kPa. RESULTS: Among 561 patients with chronic hepatitis C, 135 were included, mean follow-up 5.2 years, 56% men, mean age 55.3 years, infected with genotype 1 (71%). Among these, 27 were overweight, 12 had type 2 diabetes, 41 had steatosis, and 89 had been treated. During follow-up, seven patients had a cardiovascular event (four myocardial infarctions, three strokes). Among the 35 patients with rapid stiffness progression, 6% had a cardiovascular event compared with 5% of 100 patients with slow progression (P=1.0). Among the 57 patients with high initial stiffness, 11% had a cardiovascular event compared with 1% of the 78 patients with low initial stiffness (P=0.04). CONCLUSION: In chronic hepatitis C, initial stiffness of at least 7 kPa was associated with cardiovascular events. Rapid progression of liver stiffness does not seem to be associated with these events.