Ulcerative Colitis: Adopting the AGA's Guidelines

David T. Rubin, MD; Joseph D. Feuerstein, MD; Millie D. Long, MD, MPH


October 06, 2020

This transcript has been edited for clarity.

David T. Rubin, MD: There have been significant advances in our understanding of the management of ulcerative colitis (UC). These advances need to be communicated to our colleagues and our patients so that we can provide better care and, hopefully, change the natural history of the disease and produce better outcomes.

Joseph D. Feuerstein, MD: Recently, the American Gastroenterological Association (AGA) developed a new set of guidelines for the management of patients with moderate to severe UC. These are unique from many other available guidelines in that they focus on a very evidence-based approach to managing these patients. The guidelines provide a detailed evaluation of all the available evidence in the form of a meta-analysis, which applied a number of different PICO (population, intervention, comparator, and outcome) questions and then assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology.

Rubin: The challenge is that some important management questions for patients with UC are not directly answered by available evidence. The other challenge is that as soon as we publish a guideline, we are greeted by newer pieces of evidence, newer trials, or even new therapies that are approved by the US Food and Drug Administration, which then render those guidelines out of date. Therefore, when we look carefully at available guidelines, we should also focus on the general principles of management so that we can continue to apply them as new evidence evolves.

Choosing the Best Drug First

Feuerstein: There are a number of questions that clinicians have when managing patients with moderate to severe UC. One that often comes up is how to determine which drug to use. Unfortunately, we don't currently have any good tests to determine which is the best drug to use when first managing a patient with moderate to severe UC.

Millie D. Long, MD, MPH: The tests we have to differentiate how a patient will respond to an individual therapy are not good at this point. However, we do have excellent tests, like colonoscopy, to help us understand the degree of inflammation and a patient's disease severity.

Rubin: I agree with my colleagues that we don't have a therapeutic biomarker, whether some tissue or serum test, that tells us which therapy we should use. On the other hand, we certainly know what goals we have for achieving remission. Specifically, we want patients to have cessation of rectal bleeding, normalization of their bowel frequency, and objective measures that their inflammation is under control.

Feuerstein: As we know, not every drug is equally effective when it comes to the management of patients with moderate to severe UC. In these guidelines, the AGA looked at available evidence for each of the drugs and performed a network meta-analysis to help us determine which is the most effective. This process led the guidelines' authors to conclude that, for an initial start, infliximab or vedolizumab is probably the most effective drug.

Long: Infliximab combined with an immunomodulator is actually superior to either of those agents alone, which is something we do need to take into consideration when we initiate infliximab. The VARSITY trial, which compared adalimumab with vedolizumab, actually showed an approximately 9% superiority in clinical remission at week 52 for the latter treatment.

Rubin: The VARSITY trial was the first head-to-head biological therapy trial in UC. And while there are strengths to this eagerly anticipated trial, we also realize that it leaves some questions unanswered.

For example, neither arm in the study allowed for dose escalation, which we all recognize is something that occurs quite often in our patients with UC. The real-world application of these data is therefore limited in that regard.

The second issue is that there wasn't a great adjustment for concomitant immunomodulators or steroid sparing. Although the overall doses of steroids at the end of the trial were low, and steroid avoidance is a maintenance strategy that we recommend strongly, it is hard to necessarily apply this to our overall practice.

Other Factors to Consider When Selecting Treatment

Long: In regard to positioning therapies for UC, we unfortunately have a lower level of evidence in these guidelines. We don't have large randomized controlled trials to inform this question. Instead, the AGA guidelines utilized a level of evidence derived from network meta-analysis, which indirectly compares efficacy rates across various trials.

This showed us that, particularly in patients who have previously been on an anti–tumor necrosis factor (anti-TNF) medication for UC, there may be classes of drugs that are better than others in regard to efficacy post anti-TNF medication.

Rubin: I agree with my colleagues that we were limited by the available evidence. But there are some reasonable principles that a clinician needs to keep in mind. As much as we want everyone to feel better immediately, the reality is that some people are still ambulatory and functioning well, in whom we have a little more time than others.

In the absence of additional head-to-head trials, we are left to think carefully about a number of factors, one of which is that if you're going to use infliximab, the quality of evidence supports doing it in combination with azathioprine. More recently, albeit without the same strength of evidence, we do substitute methotrexate in some patients.

Feuerstein: Most likely, the first drug should probably be infliximab or vedolizumab. If these drugs do not work, then the most effective drug would be either ustekinumab or tofacitinib.

Long: In regard to comparing individual drugs for UC, we really have to consider three factors associated with the individual patient. These include the need for speed (ie, the onset of action), the patient's comorbidity in terms of the safety of a therapy, and the overall preference from the patient's perspective in order to help them with adherence.

Feuerstein: One of the challenges we continue to face in 2020 is managing our patients with acute severe UC. Even now, we still have a number of patients who are hospitalized with severe flares of UC. While we know that intravenous steroids are effective for the management of these patients, the challenge is that we have a very limited number of drugs to treat them and get them out of the hospital when they have acute severe UC.

Long: We will often treat them with IV corticosteroids but, unfortunately, not all patients respond to them. And once they get into this ongoing inflammatory cycle, they can ultimately require emergency surgery. Their nutrition could be down and they can have a low albumin. In patients with a low albumin, a biologic medication can be wasted in the stool. It's excreted before it can actually get to an appropriate level in their system.

One of the things we know about infliximab, the only biologic agent that we have right now for acute severe UC, is that it needs to be at therapeutic concentrations. So, individuals have been using higher doses of infliximab.

Feuerstein: While we do know the outpatient dosing of infliximab — typically the 5-mg/kg dose at week 0, 2, and 6, followed by maintenance dosing — the correct dose and interval for acute severe UC is still unclear. Many clinicians have opted for a higher 10-mg/kg dose to induce patients into remission. And many have used a rapid induction interval, dosing it at week 0 and maybe even 72 hours after the initial dosing, and then perhaps 1 or 2 weeks later.

Rubin: I want to point out that the data supporting accelerated dosing for infliximab as a salvage therapy are quite limited. When you look at hard outcomes, like avoiding colectomy at 30 or 90 days, the available data don't necessarily support that strategy.

Long: Additionally, we have cyclosporine, which is a small molecule that could be used to induce remission for acute severe UC. This agent cannot be used for maintenance of remission, but the patient could be transitioned to an alternate agent for maintenance.

When Insurers' and Practitioners' Goals Differ

Feuerstein: When managing our patients with moderate to severe UC, we often think about which drug is going to be most effective. However, we have to obtain insurance approval for these drugs that are quite expensive. Historically, the management of UC was done through a step-up therapy. However, the current management offered by these AGA guidelines is more geared toward treating the disease based on its severity. Many insurance companies still require us to use a step therapy system, though.

Long: We have data showing that after a patient has been on a biologic, such as an anti-TNF medication, their response to a subsequent biologic will be less. We've seen this time and time again in our randomized controlled trials. So we do want to put our best foot forward first for the patient. Step-up therapy doesn't allow us to take into account the individual patient characteristics if we're being mandated to start a therapy.

Feuerstein: The concept of step therapy is one in which the insurance company is able to control costs while still providing high-quality, cost-effective care to their members. However, the evidence supporting this approach is almost nonexistent.

Rubin: We have to develop better cost-effectiveness analyses and push back when payers have rebates and contracts with pharmaceutical companies that are prioritizing specific therapies over others, and that also includes diagnostic tests.

Long: The pressure for step therapy is not coming at us from a patient-centered place. In fact, it's coming at us from a cost-control place. And so, as pharmaceutical companies can broadly discount certain agents to insurers, insurers are driving toward those agents without taking into consideration the individual patient and their risk factors, including those that may predict a better response to another therapy.

Rubin: As we've gotten better at predicting the outcomes of patients who have active disease and gotten more efficient at determining whether a therapy is going to work by early disease assessment and inflammation measuring, we should be able to move on quickly, without the hassles, the appeals, and the denials that continue to characterize a lot of our treatment strategies.

The Bottom Line

Feuerstein: In many ways these updated AGA guidelines are quite helpful to the practicing clinician in determining the management strategy for patients with moderate to severe UC. It takes you through a step-by-step approach of what to do in the management of these patients.

Long: If there's one thing to get out of these guidelines, it's that I want to get more patients on appropriate therapy. I want to limit the use of corticosteroids as maintenance. I want to limit the use of recurrent courses of corticosteroids to try to induce and continue remission in a patient who clearly meets the criterion of disease severity for initiation of a biologic or advanced therapy.

Rubin: This has been an important discussion with my colleagues Dr Long and Dr Feuerstein. Both are experts at reviewing the evidence and publishing guidelines, and are also clinicians who are thoughtful about taking care of their patients.

The bottom line of our current guidelines for UC is that we want to make sure patients achieve remission. This is now defined as both improvement in their symptoms to the point where they can function normally, which we know is directly related to an improved quality of life, as well as the knowledge that we have also controlled the disease process. The main point of guidelines like these is to elevate everyone's care so that we can be on the same page in terms of trying to provide the best treatment for people who live with these difficult conditions.

David T. Rubin, MD, is professor in the department of medicine and chief of gastroenterology, hepatology, and nutrition at University of Chicago Medicine. Rubin is lead author of ACG Clinical Guideline: Ulcerative Colitis in Adults, published in 2019.

Joseph D. Feuerstein, MD, is associate clinical chief of gastroenterology at Beth Israel Deaconess Medical Center in Boston. Feuerstein is lead author of the AGA Clinical Practice Guidelines on the Management of Moderate to Severe Ulcerative Colitis, published in 2020.

Millie D. Long, MD, MPH, is associate professor of medicine at the University of North Carolina at Chapel Hill. Long is also an author of ACG Clinical Guideline: Ulcerative Colitis in Adults, published in 2019.

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