Faculty Bibliography

Introduction: Inflammatory bowel disease (IBD) therapy is continuously evolving with novel drugs targeting various inflammatory pathways. Ustekinumab (USK), a monoclonal antibody inhibiting the IL-12/23 pathway, was approved in September 2016 to treat moderate-to-severe Crohn's disease (CD). While safety data in IBD is limited, USK has been used to treat other autoimmune diseases with favorable safety profiles. We aimed to establish rates of adverse events (AE) and demonstrate non-inferiority of AE of USK compared to placebo and other biologics. Methods: MEDLINE, PubMed and Embase databases were searched in May 2017 using terms "ustekinumab" and "clinical trials." Two authors independently performed quality assessment and dual extraction. Randomized control trials comparing USK to placebo or other biologics regardless of disease were included. The primary outcome was the odds ratio (OR) of AE of USK vs placebo, expressed as pooled OR and 95% confidence interval (CI). Secondary outcomes included OR of mild/moderate and serious AE (SAE) in USK vs placebo, USK vs biologics, and low vs high-dose USK, respectively (Table 2). A sub-analysis of outcomes in CD trials was performed. Random effects meta-analysis was performed for all outcomes. Results: 16 papers with 6756 subjects (44% female) were included (Fig 1). Infections were the most common AE (Table 1). The OR of serious AE in USK vs placebo was 0.76 (95% CI 0.56-1.03, Fig 2). The OR of mild-to-moderate AE in the USK vs placebo was 1.12 (95% CI 1.01-1.24), suggesting increased risk of mild/moderate AE with USK (Fig 3). However, this was no longer significant after sub-analysis of the three CD trials. Analysis of 5 trials comparing low vs high-dose USK revealed an OR of 0.96 (95% CI 0.46-2.04) for SAE and 1.17 (95% CI 0.98-1.39) for mild-to-moderate AE. Use of USK was not associated with increased AE compared to other biologics, with OR of 0.91 (95% CI 0.61-1.35) for SAE and 0.98 (95% CI 0.85-1.13) for mild/moderate AE. Heterogeneity was low for all calculations. Conclusion: USK has a comparable safety profile to placebo and other biologics in the treatment of various diseases, although we did find a mildly elevated risk of mild/moderate AE with USK; however, this (Figure Presented) was not seen in CD trials. The favorable safety profile of USK is of clinical importance with the advent of USK in CD and ongoing clinical trials for ulcerative colitis. More data on long-term safety data in the IBD population is needed

Ileal pouch-anal anastomosis (IPAA) is the preferred surgical treatment for patients who undergo colectomy and wish to avoid a permanent ileostomy. The overall outcomes are positive, with an improved quality of life and stable long-term pouch retention. However, certain conditions or disease states may be at a higher risk of pouch dysfunction or failure. For example, obese patients have an increased risk for postoperative complications. In addition, women with a history of obstetric complications and elderly patients with a history of sphincter damage or dysfunction may be at an increased risk for postoperative incontinence, although quality-of-life indices do not necessarily correlate with incontinence scores. Advanced age itself is not a contraindication to pouch surgery, and elderly patients can be considered for IPAA based on individual functionality and comorbidities. Pelvic radiation may lead to pouch dysfunction. Finally, patients with Crohn's disease and indeterminate colitis may have increased complications with IPAA, but highly specific patient selection leads to good rates of pouch retention. This article examines several clinical scenarios that require careful thought prior to considering IPAA.

INTRODUCTION: As our medical armamentarium for IBD continues to expand, it is essential that clinicians understand both optimizing and sequencing of individual and combination therapeutic approaches with available medications. Areas covered: This review summarizes dosing strategies and therapeutic drug monitoring for pharmacologic optimization in IBD. Aminosalicylates remain first-line therapies for mild-to-moderate UC but have limited evidence of efficacy in CD. Budesonide provides an alternative to aminosalicylates when targeted to appropriate sites in the distal small bowel and colon, as do conventional corticosteroids when applied rectally. Systemic steroids are highly efficacious but burdened by toxicity. Thiopurines or methotrexate can be utilized as steroid-sparing agents. Biologic agents targeting TNF remain important for steroid-sparing therapy in moderate-to-severe UC and CD. Newer biologics targeting lymphocyte trafficking and lymphocyte activation are also efficacious for moderate-to-severe IBD. Near future conventional drug options include oral agents such as tofacitinib and mongersen. Expert commentary: Positioning therapies according to the location, phenotypes, and severity, as well as the use of therapeutic and clinical targets, will improve outcomes and minimize toxicities and therapeutic futilities. Future IBD treatment should focus on personalized therapy plans based on genetic determinants, targeted mechanisms of action, and pharmacologic optimization.

OPINION STATEMENT: Infliximab and adalimumab biosimilars have been approved by the FDA and European Medicines Agency and have already been introduced to the international market. Availability into the US market is imminent. Biosimilars are highly similar to the reference biologic product but should not be referred to as, nor equated with, generic medications as no two biosimilars can ever be identical. Regulatory pathways for biosimilar approval consider the totality of evidence for biosimilar approvals, but the preponderance of development relies on analytic and functional testing and allows extrapolation between indications to reduce the financial burden of completing comparative clinical trials for each indication. Neither CT-P13 (infliximab biosimilar) nor ABP 501 (adalimumab biosimilar) was clinically tested in patients with inflammatory bowel disease prior to being submitted for approval by regulatory agencies. The body of available evidence suggests that these drugs will perform similarly to their originators. The pathway for interchangeability of biosimilars has yet to be clarified by federal regulators and currently remains determined by states within the USA. However, preliminary data suggests that switching from originator to biosimilar is safe with minimal differences in clinical efficacy.

OPINION STATEMENT: As new and effective novel therapies in inflammatory bowel disease (IBD) become available, patients are living longer with advancing age and are at increased risk for malignancy. The management of IBD and malignancy involves multiple combinations of chemotherapy agents and IBD drugs, with the potential for interactions between these therapies. Interactions may either potentiate the effectiveness of drug class or exacerbate their common side effects. In this review article, we present a guide on studied interactions between IBD therapies and chemotherapy agents, specifically those of colorectal cancer, breast cancer, non-Hodgkin's lymphoma, and melanoma. The pharmacology and pharmocokinetics of each IBD drug will be discussed. Then, the IBD drug and chemotherapy interactions are summarized in table format. This guide will provide a quick reference to guide clinicians with this challenging management of two disease processes.