Pedro Zapater1,2,3, Susana Almenara1, Ana Gutiérrez2,4, Laura Sempere4, Marifé García5, Raquel Laveda6, Antonio Martínez6, Michael Scharl7, José I Cameo4, Raquel Linares3, José M González-Navajas2, Reiner Wiest8, Gerhard Rogler4, Rubén Francés2,3,4. 1. Servicio de Farmacología Clínica, Hospital General Universitario de Alicante, Alicante, Spain. 2. CIBERehd, Instituto de Salud Carlos III, Madrid, Spain. 3. Universidad Miguel Hernández, San Juan de Alicante, Spain. 4. Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Alicante, Spain. 5. Servicio de Digestivo, Hospital Universitario de Elche, Alicante, Spain. 6. Hospital Clínico Universitario de San Juan, Alicante, Spain. 7. Department of Gastroenterology and Hepatology, University Hospital of Zürich, Zürich, Switzerland. 8. Department of Gastroenterology, University Clinic for Visceral Medicine, Inselspital, Bern, Switzerland.
Abstract
BACKGROUND: Patients with Crohn's disease (CD) responding to anti-tumor necrosis factor (anti-TNF) show great variability in serum drug levels, even within the therapeutic range. We aimed at exploring the role of inflammatory, genetic, and bacterial variables in relation to anti-TNF through levels in CD patients. METHODS: Consecutive CD patients receiving stable doses of infliximab or adalimumab were included. Clinical and analytical parameters were recorded. Cytokine response, bacterial DNA translocation, and several immune-related genes' genotypes were evaluated, along with serum through anti-TNF drug levels. A linear regression analysis controlled by weight and drug regimen was performed. RESULTS: One hundred nineteen patients were initially considered. Five patients on infliximab and 2 on adalimumab showed antidrug antibodies in serum and were excluded. One hundred twelve patients were finally included (62 on infliximab, 50 on adalimumab). Fourteen patients on infliximab and 15 on adalimumab (22.6% vs 30%, P = 0.37) were receiving an intensified drug regimen. C-reactive protein (CRP), fecal calprotectin, Crohn's Disease Activity Index, leukocyte count, and albumin levels in plasma were not significantly associated with infliximab or adalimumab levels in the multivariate analysis. Serum interleukin-10 (IL-10) levels were directly related to infliximab (Beta = 0.097, P < 0.0001) and adalimumab levels (Beta = 0.069, P = 0.0241). The best multivariate regression model explaining the variability of serum infliximab and adalimumab levels included IL-10. Predicted drug levels by this model robustly fitted with actual drug levels (R2 = 0.841 for infliximab, R2 = 0.733 for adalimumab). CONCLUSION: Serum IL-10 is significantly related to serum anti-TNF levels in CD patients, showing how the disposition of anti-TNF drugs is significantly influenced by the degree of immunological activation.
BACKGROUND:Patients with Crohn's disease (CD) responding to anti-tumornecrosis factor (anti-TNF) show great variability in serum drug levels, even within the therapeutic range. We aimed at exploring the role of inflammatory, genetic, and bacterial variables in relation to anti-TNF through levels in CDpatients. METHODS: Consecutive CDpatients receiving stable doses of infliximab or adalimumab were included. Clinical and analytical parameters were recorded. Cytokine response, bacterial DNA translocation, and several immune-related genes' genotypes were evaluated, along with serum through anti-TNF drug levels. A linear regression analysis controlled by weight and drug regimen was performed. RESULTS: One hundred nineteen patients were initially considered. Five patients on infliximab and 2 on adalimumab showed antidrug antibodies in serum and were excluded. One hundred twelve patients were finally included (62 on infliximab, 50 on adalimumab). Fourteen patients on infliximab and 15 on adalimumab (22.6% vs 30%, P = 0.37) were receiving an intensified drug regimen. C-reactive protein (CRP), fecal calprotectin, Crohn's Disease Activity Index, leukocyte count, and albumin levels in plasma were not significantly associated with infliximab or adalimumab levels in the multivariate analysis. Serum interleukin-10 (IL-10) levels were directly related to infliximab (Beta = 0.097, P < 0.0001) and adalimumab levels (Beta = 0.069, P = 0.0241). The best multivariate regression model explaining the variability of serum infliximab and adalimumab levels included IL-10. Predicted drug levels by this model robustly fitted with actual drug levels (R2 = 0.841 for infliximab, R2 = 0.733 for adalimumab). CONCLUSION: Serum IL-10 is significantly related to serum anti-TNF levels in CDpatients, showing how the disposition of anti-TNF drugs is significantly influenced by the degree of immunological activation.