Immunomodulators in the management of inflammatory bowel disease

Abstract

Background: Immunomodulators (IM), mainly thiopurines (TP) have been used in the treatment of inflammatory bowel disease (IBD) for over 50 years. Over the last 20 years, the number of drugs available to treat IBD has grown. The role of IM cannot be understated as they alone may control IBD in the long term, and also improve the efficacy of biological agents when given as co-therapy. The newer therapies come at an exceptionally high financial cost, raising issues with affordability and cost effectiveness. Any evaluation of drug treatment needs to take into account the long-term outcomes, particular their efficacy in the reduction of major long-term morbidities related to chronic uncontrolled inflammation. Methods: Three retrospective cohort studies were conducted using the “Sydney IBD Cohort”, updated in 2012, evaluating the surgical outcomes in patients with Crohn’s disease (CD), Ulcerative colitis (UC) and elderly IBD patients. Fourth study was a retrospective, single-centre cohort study of patients with moderate-to-severe CD, assessing the influence of thiopurine on efficacy of adalimumab. Fifth, was a case-based survey conducted worldwide assessing gastroenterologists’ selection of drug treatments based on patients’ comorbidity and age in the management of moderate-to-severe UC. Results: Early IM was associated with significantly lower rates of initial abdominal surgery (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.35–0.69), recurrent abdominal surgery (HR, 0.44; 95% CI, 0.25–0.79) and perianal surgery (HR, 0.30; 95% CI, 0.16–0.56) in CD. «/span»«/p» «p style="text-align:justify"»«span style="color:#000000"»Early TP maintenance significantly decreased the need for colectomy (HR: 0.10, 95%CI: 0.03- 0.43) and proximal progression of disease extent (HR: 0.26, 95%CI: 0.10-0.78), afterpropensity score matching in UC. «/span»«/p» «p style="text-align:justify"»«span style="color:#000000"»TP dosed to therapeutic 6-thioguanine nucleotide levels (6-TGN) at induction were predictors of primary response (Odds ratio (OR): 4.32, 95% CI, 1.41–13.29) and time to failure (OR: 0.37 (0.15–0.89), and therapeutic 6-TGN in semesters were associated with remission semesters (OR 3.71, 95% CI, 1.87–7.34) in CD patients treated with adalimumab. Charlson Comorbidity Index was associated with delayed IM introduction in CD ( HR 0.863; 95% CI, 0.787–0.946) and UC (HR 0.807; 95% CI, 0.711–0.917) but not age. Early IM use was associated with reduced need for surgery in CD (HR 0.177; 95% CI, 0.089–0.351). Comorbidity reduced the probability of prescribing IMs for elderly- (OR: 0.25, 95%CI: 0.16-0.38) and for younger-patients (OR: 0.56, 95%CI: 0.39-0.82) with UC. Conversely, elderly- and younger-patients with comorbidities were more likely to receive Vedolizumab (OR: 2.71, 95%CI: 1.98-3.71 and OR: 1.37, 95%CI: 1.01-1.86, respectively) and colectomy (OR: 5.40, 95%CI: 2.74-10.64 and OR: 4.46, 95%CI:2.25-8.87 respectively].Conclusion: early and sustained IM use is associated with reduced risk of surgery in CD patients in all age groups, including elderly. Similarly, early sustained TP maintenance is associated with reduced risk of colectomy and proximal disease progression in UC. TP dosed to therapeutic levels, improves the primary response and duration of activity of adalimumab. Comorbidity is the main factor influencing the use of IM in the elderly. The results of these studies affirm the position of immunomodulators, particularly thiopurines, in the current day treatment paradigm of IBD.