The PRSS3P2 and TRY7 deletion copy number variant modifies risk for chronic pancreatitis.

BACKGROUND: PRSS1 and PRSS2 constitute the only functional copies of a tandemly-arranged five-trypsinogen-gene cluster (i.e., PRSS1, PRSS3P1, PRSS3P2, TRY7 and PRSS2) on chromosome 7q35. Variants in PRSS1 and PRSS2, including missense and copy number variants (CNVs), have been reported to predispose to or protect against chronic pancreatitis (CP). We wondered whether a common trypsinogen pseudogene deletion CNV (that removes two of the three trypsinogen pseudogenes, PRSS3P2 and TRY7) might be associated with CP causation/predisposition. METHODS: We analyzed the common PRSS3P2 and TRY7 deletion CNV in a total of 1536 CP patients and 3506 controls from France, Germany, India and Japan by means of quantitative fluorescent multiplex polymerase chain reaction. RESULTS: We demonstrated that the deletion CNV variant was associated with a protective effect against CP in the French, German and Japanese cohorts whilst a trend toward the same association was noted in the Indian cohort. Meta-analysis under a dominant model yielded a pooled odds ratio (OR) of 0.68 (95% confidence interval (CI) 0.52-0.89; p = 0.005) whereas an allele-based meta-analysis yielded a pooled OR of 0.84 (95% CI 0.77-0.92; p = 0.0001). This protective effect is explicable by reference to the recent finding that the still functional PRSS3P2/TRY7 pseudogene enhancers upregulate pancreatic PRSS2 expression. CONCLUSIONS: The common PRSS3P2 and TRY7 deletion CNV was associated with a reduced risk for CP. This finding provides additional support for the emerging view that dysregulated PRSS2 expression represents a discrete mechanism underlying CP predisposition or protection.

Subcutaneous injection of infliximab CT-P13 results in stable drug levels within 14-day treatment cycle in Crohn's disease.

The new subcutaneous (sc) formulation of the infliximab (IFX) biosimilar CT-P13 results in homogeneous serum trough concentrations of IFX at steady state. The present study aimed to investigate in Crohn's disease (CD) patients the intra-individual variations of IFX drug levels at multiple time-points during 2 consecutive cycles of maintenance therapy with CT-P13 sc. PATIENTS AND METHODS: CD patients in clinico-biological remission under maintenance therapy with intravenous (iv) IFX/CT-P13 were switched to CT-P13 sc 8 weeks (W) after the last infusion. They were treated with CT-P13 sc, 120 mg every 2 W. Assessments were performed from 8 W after starting CT-P13 sc and patients had to attend 6 visits on 2 consecutive cycles of treatment (cycles A and B). Visits were scheduled on days 4-6 (visit 1), days 7-9 (visit 2) and day 14 (visit 3) of each cycle, where days 1 and 14 were the days of sc injection of CT-P13. At each visit, peripheral blood was collected to measure serum IFX levels and anti-drug antibodies. RESULTS: Twenty patients underwent 120 evaluations. Large intra-individual variations of serum drug levels of IFX were observed. When pooling the 120 evaluations, the mean drug level was 11.3 ± 4.9 µg/ml, and the median drug level was 10.9 µg/ml (IQR 7.5-15.5). During each cycle, the median drug levels were similar between visits 1 and 2 as well as between visits 1 and 3 and between visits 2 and 3. In cycle A, median drug levels were 11.1 µg/ml (7.8-14.5), 12.0 µg/ml (7.2-16.1) and 11.0 µg/ml (7.5-15.1) at V1, V2 and V3, respectively. Similar results were obtained in cycle B, where median drug levels were 11.6 µg/ml (7.9-14.9), 11.4 µg/ml (8.1-15.2) and 10.9 µg/ml (7.9-15.6) at V1, V2 and V3, respectively. In univariate analysis, we failed to identify factors predictive of low drug levels. CONCLUSIONS: IFX drug levels are quite stable within 14-day treatment cycle, without trough levels in CD patients in remission during the maintenance therapy with CT-P13 sc. In patients with inactive CD under maintenance therapy with CT-P13 sc, therapeutic drug monitoring of IFX can be performed at any time between two CT-P13 sc injections.