Effectiveness and safety of dupilumab in the treatment of atopic dermatitis in children (6-11 years): data from a French multicentre retrospective cohort in daily practice.

BACKGROUND: Dupilumab is the first biotherapy available for the treatment of moderate-to-severe childhood atopic dermatitis (AD). OBJECTIVE: The aim of this study was to evaluate the effectiveness and safety of dupilumab in daily practice. METHODS: Patients aged 6-11, who had received a first dose of dupilumab, were included in this multicentre retrospective cohort study. The primary endpoint was change in SCORAD after 3 months of treatment. Secondary endpoints were change in IGA score at 3 months, proportion of patients with SCORAD50 and SCORAD75, description of adverse events and proportion of children in our cohort who would be excluded from pivotal phase 3 clinical trial. RESULTS: Eighty patients were included. After 3 months of treatment, there was a significant decrease in SCORAD (mean: 21.8 ± 13.8 vs 53.9 ± 18.5; P < 0.0001) and IGA (1.3 ± 0.8 vs 3.5 ± 0.7; P < 0.0001). Conjunctivitis was observed in 11.3% (n = 9/80); three patients experienced dupilumab facial redness (DFR); 17.5% (n = 14/80) reported injection site reactions; 6.3% (n = 5/80) discontinued treatment. 61.2% (n = 49/80) children were ineligible in the phase 3 trial. LIMITATIONS: There is no control group. Because it was a real life study based on information from patient medical records in a French multicentre cohort, we cannot rule out the presence of reporting bias generated by the use of patient reported characteristics and missing information. CONCLUSION: These real-life data confirm the efficacy and safety of dupilumab in children with moderate to severe AD extended to dyshidrosis and atopic prurigo, but it also revealed a lower frequency of DFR and conjunctivitis. However, administration in injectable form may be a barrier in this age group.

Regulation of lipoprotein metabolism by thiazolidinediones occurs through a distinct but complementary mechanism relative to fibrates.

Thiazolidinediones are antidiabetic agents, which not only improve glucose metabolism but also reduce blood triglyceride concentrations. These compounds are synthetic ligands for PPAR gamma, a transcription factor belonging to the nuclear receptor subfamily of PPARs, which are important transcriptional regulators of lipid and lipoprotein metabolism. The goal of this study was to evaluate the influence of a potent thiazolidinedione, BRL49653, on serum lipoproteins and to determine whether its lipid-lowering effects are mediated by changes in the expression of key genes implicated in lipoprotein metabolism. Treatment of normal rats for 7 days with BRL49653 decreased serum triglycerides in a dose-dependent fashion without affecting serum total and HDL cholesterol and apolipoprotein (apo) A-I and apo A-II concentrations. The decrease in triglyceride concentrations after BRL49653 was mainly due to a reduction of the amount of VLDL particles of unchanged lipid and apo composition. BRL49653 treatment did not change triglyceride production in vivo as analyzed by injection of Triton WR-1339, indicating a primary action on triglyceride catabolism. Analysis of the influence of BRL49653 on the expression of LPL and apo C-III, two key players in triglyceride catabolism, showed a dose-dependent increase in mRNA levels and activity of LPL in epididymal adipose tissue, whereas liver apo C-III mRNA levels remained constant. Furthermore, addition of BRL49653 to primary cultures of differentiated adipocytes increased LPL mRNA levels, indicating a direct action of the drug on the adipocyte. Simultaneous administration of BRL49653 and fenofibrate, a hypolipidemic drug that acts primarily on liver through activation of PPAR alpha both decreased liver apo C-III and increased adipose tissue LPL mRNA levels, resulting in a more pronounced lowering of serum triglycerides than each drug alone. In conclusion, both fibrates and thiazolidinediones exert a hypotriglyceridemic effect. While fibrates act primarily on the liver by decreasing apo C-III production, BRL49653 acts primarily on adipose tissue by increasing lipolysis through the induction of LPL expression. Drugs combining both PPAR alpha and gamma activation potential should therefore display a more efficient hypotriglyceridemic activity than either compound alone and may provide a rationale for improved therapy for elevated triglycerides.

Tissue-specific expression of the human gene for lecithin: cholesterol acyltransferase in transgenic mice alters blood lipids, lipoproteins and lipases towards a less atherogenic profile.

Lecithin:cholesterol acyltransferase (LCAT) is a key enzyme in the reverse cholesterol pathway but its role in lipid metabolism is still unclear. We have generated mice transgenic for a 7-kb genomic DNA fragment comprising the 6 exons and 5 introns of the LCAT gene with 1932 bp of 5' flanking and 908 bp of 3' flanking sequences. One line had integrated about 30 copies and expressed about 40-fold increased LCAT activity in a human test system. The expression showed correct tissue specificity of the human LCAT gene. Increased LCAT activity resulted in a decrease of plasma triacylglycerols below 50% of fasting controls. This reduction was seen in all lipoprotein fractions. Lipoprotein lipase activity did not change significantly, whereas hepatic triacylglycerol lipase increased markedly. Plasma total cholesterol was similar in fasting transgenic and control mice, but low-density lipoprotein and very low-density lipoprotein cholesterol were reduced to about 50%. High-density lipoprotein cholesterol increased about 20%, accompanied by a correspondingly increased size and a higher cholesterol efflux-stimulating activity of transgenic LCAT high-density lipoprotein. Both apolipoprotein A-I and A-II plasma concentrations increased in transgenic mice. Plasma triacylglycerol and cholesteryl ester fatty acid distribution showed an increased proportion of palmitic acid, whereas oleic, linoleic and arachidonic acid decreased, thus resembling more closely the human situation. Overexpression of the human LCAT gene provokes major changes in plasma lipoprotein and apolipoprotein concentrations, resulting in a less atherogenic plasma lipoprotein profile through a reduction in atherogenic and an increase in anti-atherogenic lipoproteins.