David Rubin, MD, on the Management of Acute Severe UC

Effectively managing acute severe ulcerative colitis remains one of the most challenging aspects of the practice of gastroenterology, David T Rubin, MD, told the virtual regional meeting of Advances in Inflammatory Bowel Diseases (AIBD) on September 11.

“This is something that really keeps me up at night, wondering about what we could be missing that would help us treat these patients more effectively,” he said.

Dr Rubin is the Joseph Kirsner Professor of Medicine and chief of the section of Gastroenterology, Hepatology, and Nutrition at the University of Chicago School of Medicine.

He explained that clinical severity in UC has traditionally been defined as more than 6 bloody stools per day, fever, tachycardia, anemia, and/or elevated erythrocyte sedimentation rate (ESR). Fulminant UC is defined as more than 10 stools per day, continuous bleeding, toxicity, abdominal tenderness and distention, the need for transfusion, and colonic dilation on x-ray.

However, Dr Rubin noted, the previous clinical definitions did not include endoscopy. In the updated guidelines published by the American College of Gastroenterology in 2019, “We created an activity index, which now includes remission as one of the categories—which wasn’t even mentioned previously— as well as the measures of endoscopy,” he said. “We also went out of our way to separate activity from severity. So when you’re seeing patients with severe ulcerative colitis, keep in mind the variety of different factors that may be contributing.”

The activity index now includes bowel urgency, Dr Rubin pointed out. While not a traditional endpoint of Mayo score in clinical trials, urgency is now included, “given that we all know that patients who have urgency related to colitis have quite significant morbidity.”

Fulminant UC is defined as progressive, unremitting severe ulcerative colitis, Dr Rubin explained. “It implies there is a time course of progression, it’s often associated with abdominal pain, and it occurs in approximately 5% to 15% of patients.” The etiology of fulminant UC is often not known, “but thinking about different potential contributors is important,” Dr Rubin said. Among some patients it may follow infectious gastroenteritis caused by Clostridioides difficile (C diff) or cytomegalovirus (CMV). Opioids, antibiotics, smoking cessation; nonadherence to maintenance therapy; taking antidiarrheal agents; and pregnancy can be triggers for fulminant UC.

“Suspect the diagnosis,” Dr Rubin said, “and try to identify potential reversible or treatable problems such as infection. Make sure you’re looking for C diff—not just colonization but also the toxin,” and evaluate the patient for megacolon. Early endoscopy with biopsy is recommended.

Hospitalized patients with UC and C diff should be treated with vancomycin, which has been shown to be superior to metronidazole. “Longer vanco exposure, up to 28 days after C diff infection, has a lower rate of recurrence, so you may want to commit to a month of vanco.”

Dr Rubin added, “Interestingly, there’s also data to suggest that a history of C diff sets people up not just to need surgery, but also is predictive of pouches not doing as well,” which should be taken into consideration if patients require colectomy and have a history of C diff infection.

Noting that most gastroenterologists are comfortable and familiar with the Mayo score, Dr Rubin commented that the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) “is more discriminating for risk of colectomy,” he said. It has 3 parameters: vascular pattern, bleeding, and erosions and ulcers. “It’s important not to grade it just to understand the patient’s risk for having surgery, but also to document improvement and know about response to therapy.”

The overall factors associated with risk of colectomy include age at diagnosis under 40 years; extensive colitis; severe endoscopic disease (a Mayo subscore of 3, UCEIS greater than 7); being hospitalized for colitis; having an elevated C-reactive protein (CRP); and having low serum albumin.

“So what do you do with these patients?” Dr Rubin asked. “First of all, by definition, if they’re hospitalized that’s severe colitis. I’m a fan of having patients—even if you just want to give them IV steroids—they should meet our colorectal surgeons early and when they’re stable, as opposed to calling those folks on a Friday afternoon when the patient has suddenly turned the corner and is doing worse. This definitely happens, and it happens when you don’t expect it. So have the surgeons on board and the patient understand that if you’re sick enough to be in the hospital, you should meet the surgeons.”

He also recommended stopping any potential offending agents such as 5-ASAs, to which some patients may be allergic, as well as NSAIDs, narcotics, and anticholinergic agents. Although broad-spectrum antibiotics are not recommended in general, if there is concern that the patient may have toxic megacolon or peritoneal signs, then antibiotics should be considered, Dr Rubin advised.

Patients with active UC do have increased risk of venous thromboembolism, Dr Rubin said. “In fact, that risk when they’re flaring and hospitalized is 8-fold increase compared to patients in remission or those without UC,” he explained. Patients should receive subcutaneous heparin or the equivalent to guard against VTE when they are admitted. “Surgeons are much better at doing this than we are,” Dr Rubin noted. “Surveys show that only about one-third of our colleagues knew to do this.” While the risk of VTE is also age-related, he cautioned, “do not ignore your younger patients with active colitis” when it comes to this risk.

Medical options for the high-risk UC patient include steroids, infliximab, cyclosporine, “and I’ve included tofacitinib as an emerging option,” he explained.

“We know steroids are not for maintenance therapy; if patients aren’t substantially improved within 3 to 5 days of IV steroids, you need to be moving on to a different induction strategy,” Dr Rubin said.  “Steroids are certainly life-saving in colitis. It was an incredible revolution in managing IBD in the 1950s when it was first realized that steroids could be used in severe UC and Crohn’s.” A bolus is as good as continuous infusion, he noted.

“But we also recognize that steroids don’t work in everyone,” Dr Rubin continued. The predictors of failure include the extent of disease, whether the patient is still not improving after 3 days of IV steroids, and low albumin continues to be a predictor of failure. “By the time you get to day 3, if the patient still has a CRP of 45, is still having 8 stools per day, and had severe endoscopic ulcerations at baseline, these are people who you’re really going to need to move on.”

The options include anti-TNFs, cyclosporine, possibly novel agents, and surgery, Dr Rubin explained. There have been a number of studies of infliximab in the hospital setting for severe UC, while other anti-TNFs have no data to support their use. Across the studies of infliximab, there are good response rates.

Knowing the infliximab level early, to determine if it is clearing too rapidly, is also important. Some patients may be “leaking” the infliximab into the stool and not getting adequate drug to treat severe UC. Low albumin appears to be associated with this lack of response, Dr Rubin said. “When I admit a patient with severe UC, who has a low albumin, I’m concerned that a monoclonal antibody in that setting is unlikely to work.”

In considering ways to overcome rapid drug clearance, Dr Rubin noted that a meta-analysis found no association between accelerated infliximab dosing and lower rates of colectomy.

“Just remember that if some of the drug is left due to a longer half-life that may set you up so that you’re not able to consider using cyclosporine,” he advised. “But the opposite direction—trying cyclosporine, with its short half-life and then considering infliximab because cyclosporine can be washed out in a day, may be reasonable.” In any event, he said, “Remember to get your surgeon on board and that for some of these patients, ultimately surgery will be the best option.”

Several older studies showed “quite dramatic results” in severe UC with cyclosporine and steroids, including remission rates of 87% and 93%.  “Cyclosporine was really a very good option years ago and I believe it’s still a very good option now,” Dr Rubin said. There are some contraindications, such as very low cholesterol, poor renal function, age older than 60, and active infection.

“There are patients that can be salvaged” using sequential therapies, such as cyclosporine following infliximab failure and vice versa, Dr Rubin noted. “You’ve just got to be very thoughtful that you’re not just stacking steroids, then cyclosporine and then throwing infliximab into the mix. This can become very dangerous. You have to be thinking about which therapy is on board and if you’ve washed that out before you go to the other.”

“We have tried to popularize this approach of inducing remission with calcineurin induction therapy and bridging to vedolizumab, because it is so safe,” Dr Rubin said. There have been good results with “a very reasonable idea.” Also there has been some success bridging from cyclosporine to ustekinumab. In respect to other small molecules, Dr Rubin said, there is no data on ozanimod but for tofacitinib, used off-label at 10 TID or 15 mg BID, there has been evidence of efficacy. “It’s possible; I’m not here to tell you that you should be using off-label dosing of tofa in hospital, but the principle is the same, avoiding monoclonal antibody leakage.”

“Don’t forget about surgery. You should have your surgeons meeting the patients when they’re admitted,” he said. “We’ve also learned that having all these therapies on board prior to surgery is safe.” In older patients, surgery is probably a better option than medicines, according to some studies. “If you wait until someone is urgently ill or emergent to have their colectomy, you’re waiting too long and all kinds of bad outcomes can occur.”

Dr Rubin acknowledged that patients generally wish to avoid surgery if possible. “Nobody who needs surgery has ever said to me, ‘I want surgery.’ They always want to be sure we’ve tried everything. But we also need to work with expert surgeons and reassure our patients that our job is to save their lives, not necessarily to save their colons in every case.”

--Rebecca Mashaw

Rubin, DT. Management of acute severe ulcerative colitis. Presented at: Advances in Inflammatory Bowel Disease regional meeting. September 11, 2021. Virtual.