Molecular profiling and gene expression analysis in cutaneous sarcoidosis: the role of interleukin-12, interleukin-23, and the T-helper 17 pathway.

BACKGROUND: Cutaneous sarcoidosis (CS) skin provides relatively noninvasive access to granulomatous sarcoidosis tissue. OBJECTIVE: We sought to explore the role of the T-helper (Th)1 and Th17 pathways in sarcoidosis. METHODS: We used molecular profiling and gene expression analysis to analyze the Th1 and Th17 pathways and other immune-mediated pathways in CS. Molecular profiles were obtained from sarcoidosis skin lesions (lesional skin [LS]), unaffected skin from patients with CS (non-LS), and the skin of healthy control subjects. Whole blood was collected to compare the molecular profile of sarcoidosis skin lesions and whole blood. RESULTS: Twenty participants were enrolled: 15 with active CS and 5 healthy volunteers. Microarray analyses comparing non-LS and healthy volunteer skin with LS showed several thousand genes differentially expressed (≥2-fold change false discovery rate, P < .01). Targeted selections of genes associated with Th1 and Th17 phenotypes showed a strong Th1 profile of sarcoidosis and expression of interleukin (IL)-23 and IL-23R with limited expression of other Th17 pathway genes. IL-21 and signal transducer and activator of transcription 3 (STAT3) were also dysregulated in skin and whole blood, providing additional evidence for involvement of the IL-12 pathway and potential activation of the Th17 pathway. LIMITATIONS: Measurements were made at a single point in time and may not identify mechanisms that may be identified in patients followed up longitudinally. CONCLUSION: These findings provide novel insight into the dysregulated pathways that may be involved in the pathogenesis of sarcoidosis.

Pharmacokinetics of single and repeat doses of icatibant.

PURPOSE: Icatibant is a bradykinin-2 receptor antagonist approved to treat acute hereditary angioedema attacks in adults. To-date, no thorough investigation of the clinical pharmacokinetic (PK) parameters of icatibant and its primary metabolites has been reported. Here we present the PK results of two phase I clinical studies of icatibant in healthy human volunteers. METHODS: Single- and multiple-dose plasma pharmacokinetics of icatibant were characterized in healthy volunteers. Icatibant concentration-time profiles and PK parameters were derived after a single 30- or 90-mg dose or three 30-mg doses given at 6-hour intervals. RESULTS: Maximal plasma concentrations for the 30-mg (979 ± 262 ng/mL) and 90-mg doses (2,719 ± 666 ng/mL) were achieved at <1 hour postdose. The total plasma icatibant exposure for the 30- and 90-mg doses was 2,191 ± 565 and 6,736 ± 1,230 h · ng/mL, respectively, with elimination half-life values of 1.48 ± 0.35 and 2.00 ± 0.57 hours, respectively. CONCLUSIONS: Single 30- and 90-mg subcutaneous administration of icatibant exhibited dose-proportional PK with no appreciable accumulation upon repeated 30-mg doses administered at 6-hour intervals.