Management of Crohn's disease in poor responders to adalimumab

Nanne KH de Boer,1 Mark Löwenberg,2 Frank Hoentjen3 1Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, the Netherlands; 2Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands; 3Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, the Netherlands Abstract: Anti-tumor necrosis factor therapy with adalimumab is an effective therapy for the induction and maintenance of remission in moderate to severe Crohn's disease. Although a large proportion of patients show a favorable clinical response to adalimumab, therapy failure is common. In this review, we provide a practical overview of adalimumab therapy in patients with Crohn's disease, with a specific focus on the clinical management of adalimumab failure. In the case of inadequate efficacy, a thorough assessment is required to confirm inflammatory disease activity and rule out noninflammatory causes. Evaluation may include biomarkers (fecal calprotectin and serum C-reactive protein), colonoscopy, and/or magnetic resonance enterography/enteroclysis. Furthermore, adalimumab trough levels and antibodies to adalimumab are informational after the confirmation of active inflammation. In the case of low or undetectable adalimumab trough levels, dose escalation to 40 mg weekly is recommended, whereas high antibody titers or adverse events frequently require switching to an alternative anti-TNF agent such as infliximab. Active inflammation despite therapeutic adalimumab trough levels requires alternative strategies such as switching to drugs with a different mode of action or surgical intervention. Keywords: anti-TNF, biological, inflammatory bowel disease, loss of response, inflixima

Genetic Risk Scores Identify Genetic Aetiology of Inflammatory Bowel Disease Phenotypes

Background and Aims: Inflammatory bowel disease [IBD] phenotypes are very heterogeneous between patients, and current clinical and molecular classifications do not accurately predict the course that IBD will take over time. Genetic determinants of disease phenotypes remain largely unknown but could aid drug development and allow for personalised management. We used genetic risk scores [GRS] to disentangle the genetic contributions to IBD phenotypes. Methods: Clinical characteristics and imputed genome-wide genetic array data of patients with IBD were obtained from two independent cohorts [cohort A, n = 1097; cohort B, n = 2156]. Genetic risk scoring [GRS] was used to assess genetic aetiology shared across traits and IBD phenotypes. Significant GRS-phenotype (false-discovery rate [FDR] corrected p &lt;0.05) associations identified in cohort A were put forward for replication in cohort B. Results: Crohn's disease [CD] GRS were associated with fibrostenotic CD [R2 = 7.4%, FDR = 0.02] and ileocaecal resection [R2 = 4.1%, FDR = 1.6E-03], and this remained significant after correcting for previously identified clinical and genetic risk factors. Ulcerative colitis [UC] GRS [R2 = 7.1%, FDR = 0.02] and primary sclerosing cholangitis [PSC] GRS [R2 = 3.6%, FDR = 0.03] were associated with colonic CD, and these two associations were largely driven by genetic variation in MHC. We also observed pleiotropy between PSC genetic risk and smoking behaviour [R2 = 1.7%, FDR = 0.04]. Conclusions: Patients with a higher genetic burden of CD are more likely to develop fibrostenotic disease and undergo ileocaecal resection, whereas colonic CD shares genetic aetiology with PSC and UC that is largely driven by variation in MHC. These results further our understanding of specific IBD phenotypes.</p