Recent years have seen advancement in treatment options for Inflammatory Bowel Disease (IBD). New agents, with new mechanisms of action, are being tested via clinical trials along with new availability for routine clinical use. From a clinical standpoint, the myriad of treatment options make this an exciting time to practice medicine.
We will discuss the different classes of medications, what is currently approved for both Crohnâ€™s Disease (CD) and Ulcerative Colitis (UC), the mechanisms of action, differentiating characteristics and general consideration of use.
Anti-Tumor Necrosis Factor (Anti-TNF)
TNF-alpha has been known as a major source of systemic and gut inflammation in IBD. Thus, anti-TNF agents have been, and continue to be, a very effective treatment option that promotes induction, response and remission of moderate to severe UC/CD. This class of treatment is characterized as a monoclonal antibody that is directed against TNF-alpha and has been in the treatment algorithm for CD and UC for nearly 20 years.
Currently approved and available anti-TNF agents are as follows: adalimumab (Humira, approved for CD and UC), certolizumab pegol (Cimzia, approved for CD), golimumab (Simponi, approved for UC), infliximab (Remicade, approved for CD and UC), and biosimilars for adalimumab and infliximab (approved for CD and UC).
Clinical response can be seen as soon as two weeks with these agents and is more effective when initiated earlier in the course of disease. They are approved for other dermatological and rheumatological issues, often which concurrently manifest with both CD and UC.
Anti-integrin has been shown to reduce gut inflammation in IBD without systemic effects, including potential infections.
The currently approved and available anti-integrin inhibitor agent is vedolizumab (Entyvio, approved for CD and UC). This class of treatment selectively inhibits alpha-4-beta-7 integrin from binding with mucosal addressin cell adhesion molecule 1 (MADCAM1). Thus, it inhibits leukocytes from binding to the gut.
Due to its mechanism of action, onset of clinical response with vedolizumab may be slower (up to 10 weeks) when compared to anti-TNF agents, especially in CD.
IL-12 and IL-23 Inhibitors
The currently approved and available IL-12/IL-23 inhibitor is ustekinumab (Stelara, approved for CD and UC). This class of treatment is an anti-p40 antibody that inhibits IL-12 and IL-23 pathways, which are thought to be highly active in IBD.
Ustekinumab has a favorable safety experience based on the experience of psoriasis patients who are treated with it, though the treatment dose in UC/CD is higher. Clinical response for both CD/UC has been seen as soon as two weeks after treatment initiation.
Janus Kinase Inhibitors
The currently approved and available Janus kinase (JAK) inhibitor is tofacitinib (Xeljanz, approved for UC). It is an orally administered small molecule inhibitor of the Janus kinus enzyme. The JAK-STAT pathway is a highly complex pathway involved in systemic and gut inflammation.
Tofacitinib is currently approved after failure of a biologic agent (namely anti-TNF). Improvement in rectal bleeding can be seen as soon as two weeks after treatment initiation. Some concerns about increased risk of herpes zoster infection and thromboembolic events should prompt clinicians to use the lowest therapeutic dose to maintain remission.
Clinicians should assess for the presence of both tuberculosis (latent or active) and viral hepatitis B for all patients with IBD who will be going on any immune suppression treatment (including steroids).
For tuberculosis (TB) testing, QuantiFERON-gold release assays are becoming the preferred pre-treatment testing modality over a tuberculin skin test (PPD). The advantages of TB-gold testing include its ease of use, low cost, wide availability and ease of documentation.
If the patient is seronegative for hepatitis B, they should receive the vaccination. If the patient is a carrier for Hepatitis B surface antigen (HBsAg), they should receive antiviral agents to avoid a hepatitis B flare or liver failure.
The use of live vaccines should be avoided in IBD patiients on active immune suppression therapy. These vaccines include measlesâ€“mumpsâ€“rubella, yellow fever, live attenuated influenza vaccine (nasal mist), live varicella, oral polio and BCG.
For inactive vaccines, such as pneumococcal vaccine, inactive herpes zoster or shingles (Shingrix), human papilloma and hepatitis A, treatment should be initiated prior to biological therapy. When necessary, these inactive vaccines can be administered during immune suppressive therapy, although their efficacy may be reduced.
The field of inflammatory bowel disease is, in some aspects, becoming more complex. While several new treatment strategies for therapeutic drug level monitoring have been promoted by the gastroenterology guideline committees, formal recommendations of what drug levels to target in order to promote clinical response and remission are still being developed. Other limitations include the out-of-pocket cost of the tests and variations in the assay results based on which company is used. For this reason, the recommendation is to familiarize oneself with one company in order to gain more experience with result interpretation.
In terms of treatment positioning, there is a daily influx of data, from both independent researchers and pharmaceutical companies, touting the superiority of one medication over the other. Head-to-head comparisons of different drugs are underway, but often design flaws limit true and real-world application. Simply put, the decision to start one medication over the other should be based on the experience and comfort of the provider and preference of route of delivery and other concerns expressed by the patient.
Nitin K. Gupta, MD
Dr. Gupta is a board-certified gastroenterologist at Atlanta Gastroenterology Associates specializing in inflammatory bowel diseases. Previously, he served as Director of Inflammatory Bowel Disease at the University of Mississippi Medical Center. He has been published in several peer-reviewed journals, includingÂ Science,Â Nature,Â American Journal of Gastroenterology,Â andÂ New England Journal of Medicine. He received his medical degree from Vanderbilt University and completed both a clinical and research fellowship in gastroenterology at Harvard Medical School.