Immediate Clinical Impacts on UC and Crohn Disease: Previewing Advances From the ACG 2022 Annual Meeting

Arun Swaminath, MD
Lenox Hill Hospital, New York City

Key Takeaways

  • Because new findings reveal that patients with ulcerative colitis (UC) experience longer remission on a 30-mg daily maintenance dose of upadacitinib, clinicians should consider prescribing this dose level, even to people over the age of 65 who had previously been kept at lower dosages due to risk of cardiac events. This should be done in collaboration with a cardiologist and after examining individual patient data.
  • Ustekinumab and tofacitinib have similar UC steroid-free remission rates at 12 to 16 weeks and 52 weeks, but patients using tofacitinib displayed more inflammatory markers. The long-term goal is to keep patients stable and healthy, but it is also important to consider how these drugs apply to the patients exposed to them.
  • When determining medication dosage for Crohn disease, focus on hard end points, such as inflammation levels and biologic disease markers. If patients experience persistent symptoms once they are in technical remission, offer other treatment options before adjusting the medication dosage, as external factors such as anxiety and stress could be the underlying cause.

From October 21 to October 26, 2022, gastroenterologists from around the world gathered in Charlotte, North Carolina, for the American College of Gastroenterology (ACG) 2022 Annual Scientific Meeting and Postgraduate Course. This year’s meeting included more than 180 live and live streamed sessions, along with more than 840 posters and e-posters covering topics from ulcerative colitis (UC) to Crohn disease and more.

Arun Swaminath, MD, is an associate professor of medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell in New York City and chief of gastroenterology at Lenox Hill Hospital in New York City. His focus includes clinical care for patients with Crohn disease and colitis, as well as the development of new biologic therapies for patients with inflammatory bowel disease (IBD) who are unresponsive to standard therapy. Dr Swaminath spoke with Gastroenterology Advisor to share insights into the most recent research on Crohn disease and UC presented at ACG 2022.

In your opinion, what was the most immediate, practice-changing data on IBD presented at this year’s conference?

The most immediately applicable and practice-changing clinical data that could help patients right away related to the findings on upadacitinib. When I learned that the daily 30-mg maintenance dose performs better than the 15-mg dose, I put that into practice right away. I recently had a patient where that data applied in a very real way. I had him on a lower dose, wary of upping his prescription, but thanks to this quick, digestible, and clinically relevant drug management data, I felt confident adjusting his dose to the 30-mg level.

The just-referenced study found that patients with UC treated with 30 mg of upadacitinib daily following an 8-week induction period experienced longer periods of remission and lesser disease severity.1 Should this dose become the standard for maintenance therapy in UC? Are there any advantages for certain patient subgroups, such as those over the age of 65, remaining at the daily 15-mg dose?

I think there is a danger in suggesting that any one subgroup should be ruled out from dosing recommendations. The patient I just mentioned was an older man who has atrial fibrillation, so I had always worked closely with his cardiologist. When he started on upadacitinib, he did not respond well to several other drugs but went into remission on the induction dose, which involves the highest dosing levels of the treatment. It was impressive: He came off steroids and entered remission on the 15-mg maintenance dose, which we switched to because of the risk of cardiovascular events with upadacitinib. After 3 or 4 weeks, he had a fairly severe flare, and I just increased his dose to 30 mg. That is why I do not follow a standard rule of giving patients over 65 a lower dose; it may not be as simple as that. Instead, we have to be much more calculating and work closely with the patient’s cardiologist because if that lower dose fails, people are at risk for bleeding, terrible quality of life, and colectomy. In the past, the balance has always been toward avoiding a major heart event, but maybe we are being too cautious, and it could be better to look at the takeaways from the abstract and the individual patient’s situation.

The VEGA study2 found that patients with moderate to severe UC achieved higher rates of clinical remission, endoscopic improvement, and endoscopic normalization when given induction treatment guselkumab plus golimumab, followed by guselkumab monotherapy, versus guselkumab or golimumab alone. How does this combination therapy compare to induction therapy with upadacitinib? How can clinicians decide which initial course of treatment might be most suitable for specific cases of UC?

I find it difficult to compare results from two studies head to head because there are too many different variables. Both options have limits. A combination therapy of 2 biologics for induction is not standard management, and phase 3 studies are just happening now. If those results show benefits, it could become a first-line strategy; those study results are necessary because many of us already implement this practice as an off-label therapy when others fail. The labeling for upadacitinib warns of blood clots and cardiovascular events, which is also the case with tofacitinib, so by definition it is positioned in patients who have already failed anti-tumor necrosis factor (anti-TNF) drugs, and it cannot be a first line option. Now, we see the true question: Is your second option 2 drugs together vs 1 pill? We still do not know the answer because there is no long-term data on combination therapy, and we saw one or two opportunistic infections in the combination study therapy group, so we need much more safety information before we can make a reasoned decision about which is a more appealing strategy.

Now, we look for biologic remission because even if the patient is feeling good, there could still be some smoldering disease that will flare up eventually. It is our goal to keep you stable, healthy, and safe long term, so if a drug gives me clinical, steroid-free, and biochemical remission, that is a great option.

One study presented at ACG found that among patients with anti-TNF failure, there are no differences in UC steroid-free remission rates between ustekinumab and tofacitinib at 12 to 16 weeks or at 52-week follow-ups, but patients treated with tofacitinib displayed more inflammatory markers.3 Given these findings, when might a clinician still prefer to prescribe tofacitinib over ustekinumab?

In gastroenterology, we are all moving toward “puffer” end points, or what results we would be satisfied with. Initially, we settled for clinical remission as a good end point, and then we wanted steroid-free remission. Now, we look for biologic remission because even if the patient is feeling good, there could still be some smoldering disease that will flare up eventually. It is our goal to keep you stable, healthy, and safe long term, so if a drug gives me clinical, steroid-free, and biochemical remission, that is a great option. Between these 2 drugs, however, we are dealing with different populations because ustekinumab can be a first-line treatment, but tofacitinib cannot — by definition, it has to be for someone who did not respond well to anti-TNF medication. The populations exposed to these 2 drugs are going to be slightly different, so the drug options probably will not apply to the same patients.

Another study presented suggested that intravenous induction with risankizumab dramatically improved abdominal pain and stool frequency for patients with Crohn disease, yet maintenance doses below 360 mg daily did not produce significant relief from stool frequency.4 How might a clinician assess disease activity following the induction period to determine the appropriate daily maintenance dose?

There is a difference between end points of patient-reported outcomes, which are now mandated by the US Food and Drug Administration (FDA), and the actual state of disease. When you look at reported stool frequency, this is a good end point for tracking purposes, but a lot of patient complaints do not track with the disease we need to control, meaning that healing the colon and solving inflammation does not always correlate to a reduction in other peripheral symptoms that may be related to anxiety and stress instead of disease. This makes it very difficult for us to truly figure out which is the thing that is important when evaluating patient-related outcomes. If a patient’s average daily stool frequency went from 10 to 3, it is clear that all will be happy, but if the average daily stool frequency went from 4 to 3, that is not so clinically relevant. I will really pay attention to colonoscopy results and biomarkers, as those are better indicators of disease control. When looking at other end points, such as disease stool frequency, they will not change my dose recommendations, but they may prompt me to offer something else to address persistent symptoms. Basically, I choose hard end points for dosing and dose escalation, and then I focus on everything else in my tool bag to try and provide patient relief from other nagging symptoms.

This Q&A was edited for clarity and length.

Disclosure

Arun Swaminath, MD, reported affiliations with Prometheus Biosciences; Janssen Biotech, Inc.; and Takeda Pharmaceuticals U.S.A., Inc.

References

1. Feagan BG, Parkes G, Juillerat P, et al. Benefits of high versus low dose upadacitinib as maintenance treatment in ulcerative colitis patients who were responders to 8-week induction with upadacitinib: results from the U-ACHIEVE phase 3 maintenance trial. Paper presented at: American College of Gastroenterology (ACG) 2022 Annual Scientific Meeting and Postgraduate Course; October 21-26, 2022; Charlotte, NC.
 
2. Feagen BG, Sands BE, Sandborn WJ, et al. Induction combination therapy with guselkumab and golimumab followed by guselkumab monotherapy maintenance: results of the phase 2a randomized, double-blind, proof-of-concept VEGA study. Paper presented at: American College of Gastroenterology (ACG) 2022 Annual Scientific Meeting and Postgraduate Course; October 21-26, 2022; Charlotte, NC.
 
3. Dalal RS, Sharma PP, Bains K, Pruce JC, Allegretti JR. One-year comparative effectiveness of ustekinumab versus tofacitinib for ulcerative colitis after anti-tumor necrosis factor failure. Paper presented at: American College of Gastroenterology (ACG) 2022 Annual Scientific Meeting and Postgraduate Course; October 21-26, 2022; Charlotte, NC.
 
4. Louis E, Torres J, Lindsay JO, et al. Induction and maintenance treatment with risankizumab leads to symptomatic relief in patients with moderate to severe Crohn’s disease. Paper presented at: American College of Gastroenterology (ACG) 2022 Annual Scientific Meeting and Postgraduate Course; October 21-26, 2022; Charlotte, NC.

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Reviewed November 2022