Primary NON-responsiveness and loss of response rates in inflammatory bowel disease patients using biologic agents and factors affecting these ratios

Aim: Inflammatory bowel disease, comprised of Crohn's disease and Ulcerative colitis, represents chronic idiopathic inflammatory diseases of the gastrointestinal tract typified by immune dysregulation. The use of biologic agents in the early stages of inflammatory bowel diseases reduced IBD related surgery and complication ratios. It has been shown that different pathogenic pathways can sustain bowel damage in IBD so that two patients with similar clinical phenotypes can have different inflammatory pathways activated and, thus, respond to different targeted therapies. There is also evidence that, within the same patient, the immune system can exhibit a significant plasticity and change the inflammatory pathways that are activated during the course of disease. In light of these findings determining whether the reason for failure is a primary or secondary non-response is paramount to successfully treat these patients. The aim of our study is to determine the rates for primary non responsiveness and loss of response and also the factors that may affect the response rates, drug intolerance rates and drug persistency rates for biologic naive patients. Methods: In our study we reviewed 6548 patients files whom were followed by Ankara University Faculty of Medicine Gastroenterology department with diagnosis of Ulcerative Colitis, Crohn's disease, De Novo Crohn's disease and Indeterminate Colitis/İnflammatory Bowel Disease Unclassified between January 2006 and January 2022 retrospectively. 695 patients who were older than 18 years old and received at least one biologic agent are included for our study. We reviewed demographic characteristics, disease features like localisation, disease duration and severity, extra-intestinal manifestations, smoking, family history, prior and concomitant immunmodulatory drug use for our patients. We also evaluated the intolerance rates,history of hospitalization required enfections, tuberculosis, herpes labialis and zona zoster enfections for these agents. The clinal responses at 12,24,36 and 52nd week are recorded and compared their clinical responses and persistency rates between different biologic agents. Results: Primary non responsiveness in our cohort occured in %7,6 patients of Adalimumab group, in %8,1 patients of İnfliximab group, %0 of Certolizumab pegol group, %0 of Golimumab group and %28,6 of Vedolizumab patients (p=0,25, the number of patients whom 12th week responses were assessed, ADA n=356, INF n=249, CZP n=11, VED n=7, GOL n=3). Non-responsiveness or loss of response at 52th week were seen in %34 of Adalimumab patients, %31,3 of Infliximab patients, %36,4 of Certolizumab pegol patients, %33,3 of Golimumab patients and %42,9 of Vedolizumab patients (p=0,93). Infliximad had the best clinical response rates at 52 week. (p=0,91) When we assess the effectiveness of concomitant azathioprine and biologic monotherapy in therapy naive Crohn's disease; clinical response rates at 12 and 52 week are higher in Infliximab combination therapy group than in Infliximab mono therapy group (p=0,87). However a similar effect did not occur amongst those treated with Adalimumab (p=0,59). In therapy naive Ulcerative colitis patients, Adalimumab and Infliximab monotherapy had higher response rates at 12 and 52 week than combination therapy with these agents. (respectively p=0,33, p=0,22) In therapy naive patients patients with EIM have higher clinical response rates than patients without EIM. Especially ulcerative colitis patients with EIM have statistically higher response rates at 24, 36 and 52 week. (respectively, p=0,019, p=0,019 and p=0,016) Smoking status did not effect prominently our clinical response rates but our results were not statistically significant. Although there was no significant difference in the effect of disease duration on clinical response rates, response rates were higher in patients with disease duration longer than 5 years. However our results statistically differ only clinical responses at 52 week in ulcerative colitis patients (p=0,032). We also investigated the drug persistency rates for first line therapy; at 12 and 24. month persistency rates for Adalimumab and Infliximab did not differ significantly but after 24 month persistency rates are higher for Infliximab. However our results were not statistically significant. (Crohn p=0,66 and UC p=0,59). Conclusions: Biologic agents are effective treatment options for Ulcerative Colitis and Crohn's disease. For determining the first line therapy, many network analyses showed no significant superiority or inferiority among these agents. Nevertheless in our study. Infliximab was superior at 52 week clinical responses and had higher drug survival rates. Patient and disease characteristics can predict the clinical response. In our study, we observed that EIM and disease duration can be used for predicting response. Key Words: Inflammatory Bowel Disease, Crohns Disease, Ulcerative Colitis, Biologic agents, Adalimumab, Infliximab, primary non-responsiveness, loss of response, Drug persistency