2015-09-11 15:36:24 UTC

Inflammatory Bowel Disease: User's Guide to Biologics

Sept. 11, 2015

There is an important need for comparative and cost effectiveness data to define strategies with the best value.

Barrett Levesque

Barrett G. Levesque, MD

Assistant Professor of Medicine, University of California San Diego; Director, Academic Research, Robarts Clinical Trials; Inflammatory Bowel Disease Center, Division of Gastroenterology and Hepatology, University of California San Diego, La Jolla, CA, USA.

This article was published in the August/September 2015 issue of AGA Perspectives.

In 1993, Sander Van Deventer and colleagues wrote in the Lancet: “We report a girl with Crohn’s disease who was not responsive to medical therapy but in whom complete but temporary remission could be achieved by treatment with tumor necrosis factor (TNF) monocolonal inhibitors. Over two weeks, two infusions of anti-TNF (chimerical monocolonal c-A2, supplied by Centocor, Malvern USA) were given at 10mg/kg. Symptoms immediately improved after her first dose, and they reported complete endoscopic remission lasting three months.

During the subsequent two decades after perhaps the boldest translational science leap from bench to bedside in the history of gastroenterology, multiple clinical trials have validated the efficacy of anti-TNF therapy for IBD. This efficacy was found despite inefficient symptomatic endpoints in Crohn’s disease and with only partial understanding of the pharmokinetics and pharmacodynamics of the drugs. The questions remain, how do we use these drugs to both induce and maintain remission in a chronic disease? How do we go reliably and safely beyond the three months of remission in that first patient?

In more than two decades, much data has accumulated with which to try to answer these questions.The totality of that data is beyond the scope of this column but forms the backbone of any user’s guide. However, there is still an important need for comparative and cost effectiveness data to define strategies with the best value. I propose the “top-10” rules to consider for a user’s guide for biologics

It Depends: When I was a wide-eyed IBD fellow, Dr. Ken Schroeder began his advice in response to many questions with “It depends.” Similarly, the specifics for applying these rules of thumb will depend on a myriad of factors that you encounter in clinic and on a quickly evolving evidence base. Future tests of value, whether economic simulation modeling, comparative effectiveness trials or newer methodologies, such as the cluster-randomization trial, will help guide us to well-informed clinical decision making with biologic therapy.
If at first you don’t succeed, try to optimize your approach when trying again. Consider combination therapy, another dosing mechanism or another mechanism of action. Consider clinical trials before bowel damage or complications occur
You can’t drive far on an empty gas tank. Remember to check the concentration of the drug when you have persistent symptoms despite your therapy. Plenty of antibody and no drug is unlikely to treat disease. High drug clearance may lead to failure or relapse. Primary non-response means that there is drug present, but it is not effective.
Consider setons and antibiotics with biologics for fistulas.They can help reduce the risk of abscess and improve healing rates.
There is not a “scar-be-gone-mab.” Stenosis that does not resolve with therapy may need surgery and allow a second chance for that biologic to be effective after recovery of the patient.
All that leads to diarrhea is not IBD. As we know, Clostridium difficile, bile salt diarrhea and IBS can lead to symptoms that are not amendable to biologics. Confirm the presence of inflammation with accurate tests.
A biologic is a foreign protein to that individual. Non-self proteins are prone to antibody formation. Have a plan to try to reduce that risk. Combination therapy clearly reduces antibody formation and is a choice for many patients, and therapeutic monitoring may be another way to lower this risk..
Measure twice, treat once. Whether with a note in your report about the presence or absence of ulcers, a video or perhaps a reliable score, measure what you are aiming for and how it changes after you treat it. Define the disease diagnosis, extent and severity with endoscopy and imaging. Rule out pelvic or abdominal abscesses with appropriate imaging before starting biologics. Choose the appropriate therapy, then start your treatment and measure for improvement in your target.
Buckle up before takeoff. Remember to rule out latent infections, consider age and gender, and discuss risks and benefits carefully before starting the therapy. Discuss risks of disease progression, steroids and risks of biologics in the context of their potential benefits.
Have a strategy. Before the clinic visit, know the plan you are going to follow. I suggest a treat-to-target strategy of aiming for mucosal improvement and adequate drug concentrations. At a minimum, based on the REACT trial, consider early combination therapy in Crohn’s disease patients in order to reduce the chance of complications, hospitalizations and surgery.2
References

1.Derkx B, Taminiau J, Radema S, et al. Tumour-necrosis-factor antibody treatment in Crohn’s disease. Lancet 1993;342:173-4.

2.Khanna R, Levesque BG, Bressler b, et al. Early combined immunosuppression for the management of Crohn’s disease: A community-based cluster randomized trial. J. Crohn’s Colitis 2014;8:S2-S3. .

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