Published in the March 2017 issue of Today’s Hospitalist
OUR UNDERSTANDING of ulcerative colitis and diverticulitis is changing, according to Jonathan Terdiman, MD, who directs the gastroenterology department at University of California, San Francisco. Dr. Terdiman, who spoke at UCSFs management of the hospitalized patient conference last fall, pointed out new developments in treating those conditions, as well as common mistakes clinicians make.
Physicians often don’t recognize soon enough, for instance, when ulcerative colitis patients are failing steroids. Doctors also need to change how they dose infliximab in those patients.
Even more far-reaching: Experts are now developing a new way of thinking about diverticular disease, seeing it as more of an immune disorder than an infection. That new paradigm, Dr. Terdiman explained, could broadly affect treatment and management. [Check out our readers’ poll responses: How do you manage ulcerative colitis and diverticulitis?]
An ulcerative colitis diagnosis
Ulcerative colitis, which ranges from mild to fulminant, comes with many predictors of bad outcome. “By ‘bad outcome,’ we mean people who end up leaving the hospital without their colons,” Dr. Terdiman said.
“Infliximab is not just an induction drug but a maintenance drug.”
Those predictors include stool frequency (more than eight per day, or more than five per day after three days of IV therapy), percentage of bloody stools, a fever of more than 37.5 degrees, a heart rate over 90 beats per minute, and a CRP greater than 25.
Gastroenterologists typically confirm the diagnosis with unprepped sigmoidoscopy. “Ulcerative colitis is visually different from infectious colitis or Crohn’s disease,” he explained. “That’s very relevant in terms of choosing initial and subsequent therapies.” (Biopsies also help establish the diagnosis.)
For patients already diagnosed who come in on therapy, the flex-sig can also reveal if patients’ disease is complicated by infection, cytomegalovirus (CMV) most importantly. While CMV is not as common in newly-diagnosed patients who aren’t immune-suppressed, “in patients with severe ulcerative colitis admitted on these medicines, 20% to 30% have CMV.”
If sigmoidoscopy reveals severe endoscopic colitis with deep or extensive ulcers and mucosal detachment, patients face a better than 50% likelihood of needing a colectomy. Those with moderate endoscopic colitis (either superficial ulcers or deep but nonextensive ulcers) have a 20% chance.
When treating ulcerative colitis, there’s absolutely no rule that patients should routinely receive broad-spectrum antibiotics.
That said, C. diff is very common in ulcerative colitis patients. “We have a 40% rule,” said Dr. Terdiman. “Forty percent of patients admitted for acute or severe ulcerative colitis, with either a new or established diagnosis, have C. diff.” Further, 40% of those with both colitis and C. diff have no prior antibiotic exposure, while 40% of patients with acute or severe ulcerative colitis and C. diff will have a colectomy. Oral vancomycin is first-line therapy.
As for CMV, clinicians debate how important it is to treat. Dr. Terdiman sometimes sees clinicians making this mistake: taking patients off immune suppression to treat the infection. “The severe colitis is driving this, and if patients have scant or few viral inclusions, it may not be necessary to treat the CMV.” He leans to treating both the virus and the colitis, putting patients on ganciclovir or oral valganciclovir.
In the meantime, your goal is to save the patient’s colon, “so you’re going to need pretty potent short-term therapy.” Patients should have hepatitis B serologies sent and be immediately evaluated for latent tuberculosis.
“Make sure they are surface-antibody positive and not surface-antigen positive,” said Dr. Terdiman. But the most urgent task is to start them on IV steroids. “We don’t wait for the infectious workup to come back to do so.” While it probably wouldn’t make much difference to delay steroids for 12 hours, “we don’t wait.”
Dosing IV steroids
IV steroids will rescue between 60% and 80% of these patients. Dosing is basically one milligram per kilogram, so smaller patients receive 40 mg. “We’ll go up to 60 mg for a larger person, but rarely more,” said Dr. Terdiman.
He also emphasized that patients need the full dose all at once. “There’s no benefit to continuous infusion or splitting the dose.” While he sees transferred patients come in on 120 mg four times a day, “that only increases their complication rate and immune suppression without any treatment benefit.”
The other big error that “happens all the time,” Dr. Terdiman said, is continuing patients on steroids for 10 days or two weeks when they’re not turning around.
“Within 72 hours, that patient better be markedly improved,” he said. If on day 3, patients are still having a high fever or CRP or multiple or bloody stools requiring transfusion, “that’s steroid failure. You don’t need to wait until day 5 or day 7.”
Standard of care: infliximab
What’s your next move? Many hospitalists in the audience wanted to start a patient who’s failing steroids on IV cyclosporin. “That’s not what we do anymore,” said Dr. Terdiman. While IV cyclosporin produces a high short-term rescue rate, patients still need to be bridged within several months to an immunosuppressant such as azathioprine or 6-mercaptopurine, which come with high risks and long-term failure rates.
Instead, the standard of care now is to start IV infliximab. “The big difference is that infliximab is not just an induction drug but a maintenance drug,” Dr. Terdiman noted. A meta-analysis published in the April 2016 issue of the American Journal of Gastroenterology comparing infliximab to cyclosporin found that infliximab was associated with a higher treat-ment response rate and a lower 12-month colectomy rate.
There is, however, no advantage to combining the two agents, which would produce too much immunosuppression. “Once you’re committed to one or the other, don’t pile on.” When you pick one of these agents and it fails, “that patient needs a colectomy if he or she is still sick.”
Even with infliximab, you’re not going to save everyone’s colon. One problem is that patients lose too much of the drug and can’t maintain an adequate level. While you can detect infliximab in the stool of all patients who take it, they lose the highest amount in the first days post-infusion—and nonresponders lose much more.
“We used to give this drug once in its standard dose—5 mg per kilogram—and then wait two weeks until the next dose was scheduled,” he said. Instead, “we now very rapidly and aggressively check levels within a couple of days.”
Occasionally, some patients quickly develop an antibody to infliximab. “In that case, you have to switch agents.” Much more commonly, the level of the drug is too low. “You need to give them more infliximab right away, not in two weeks.”
One small study published in the February 2015 issue of Clinical Gastroenterology and Hepatology looked at another infliximab strategy: accelerated dosing.
“Instead of waiting zero, two or six weeks without being guided by levels, they gave patients three doses within two weeks,” Dr. Terdiman pointed out. “They just kept dosing patients, who ended up with much lower colectomy rates.”
He doesn’t use accelerated dosing in his own practice. And he does continue to check patients’ levels “because for some, the standard dose is sufficient.” But he offered this big takeaway: “Don’t be passive. Because we often get low levels back in very sick patients, we give them a double dose for their first dose, then see how they do. We’ll wait no more than three or four days.”
Patients who fail medical therapy within seven or 10 days need a colectomy. “The operation they should always have,” he pointed out, “is a total abdominal colectomy with an end ileostomy and a Hartmann pouch.”
Diverticulosis and diverticulitis
Diverticular disease is very common, said Dr. Terdiman, with 70% of Americans who live to age 80 having diverticulosis, the condition of having diverticula in the colon.
The vast majority of patients remain asymptomatic. Others may have diverticular disease, which includes symptomatic uncomplicated diverticular disease (SUDD) and diverticulitis, which can be acute or chronic and relapsing. A subset of patients with chronic relapsing diverticulitis actually have segmental colitis associated with diverticulitis or SCAD.
Younger diverticulosis patients have much higher complication rates, and their diverticular disease tends to be more aggressive. Age is a risk factor for getting complicated disease, although patients have a decreased risk of complications with an increased age of diagnosis. Risk factors include NSAIDs, steroids and opiates, while statins and calcium channel blockers may be protective.
Further, it is becoming increasingly clear, Dr. Terdiman explained, that diverticulosis—and its progression to diverticulitis—runs in families, with genetic factors liable for as much as 50% of patient risk. “Increasingly, we know that this is an immune disorder, a form of inflammatory bowel disease,” he said. “It’s not really an infectious disease caused by a mechanical obstruction, such as a diverticula.” (See “A new paradigm of diverticular disease.“) Fiber helps reduce patients’ risk of getting complicated disease by 25% or 30%. But nothing else in the diet matters.
“You know this, right?” he asked. “Patients can eat seeds, nuts, popcorn.” The entire “popcorn theory” behind diverticulitis has been debunked, “but I still see patients on restricted diets for no reason. They say, ‘I can’t eat strawberries because of those little seeds,’ and I say, ‘Come on!’ ”
One big problem with uncomplicated diverticulitis: “Everybody is still giving patients antibiotics. I know it’s hard not to, but it’s not necessary.”
A randomized trial enrolling more than 600 patients published in the April 2012 issue of the British Journal of Surgery (BJS) found no difference in recovery time or complication rates between patients who were given antibiotics for uncomplicated diverticulitis and those who weren’t.
The authors of another randomized trial, this one published in the January 2017 BJS, reached the same conclusions. Guidelines issued in 2015 by the American Gastroenterological Association now recommend that antibiotics not be given routinely to patients with uncomplicated diverticulitis.
For patients with acute and complicated diverticulitis, surgery is indicated for those with a perforated colon, diffuse peritonitis or a large bowel obstruction.
“And you shouldn’t wait very long,” said Dr. Terdiman. “The sun shouldn’t set on a large bowel obstruction.”
Also consider surgery for acute diverticulitis patients who fail medical therapy within 72 to 96 hours, those with recurrence during the same admission or a partial obstruction, patients who are immunocompromised, or patients in whom you can’t rule out cancer. But while patients with complicated diverticulitis do need antibiotics and drainage, he added, “they certainly don’t automatically need an operation.”
As for chronic or chronic recurrent diverticulitis, patients’ chances of recurrence are higher if they have complicated disease. The more times diverticulitis recurs, the more likely it is to keep recurring.
“But this is not a progressive disease,” Dr. Terdiman pointed out. “The worst episode is almost always the first, and patients who keep recurring are less likely to end up with really bad complications.” While some patients opt for surgery after multiple recurrences to improve their quality of life, “this is not an illness where the colon gets progressively damaged.”
Phyllis Maguire is Executive Editor of Today’s Hospitalist.
“I was taught that there is no connection, but there is,” said Jonathan Terdiman, MD, who directs the gastroenterology department at University of California, San Francisco, during a hospital medicine conference last fall. “Patients with diverticulosis can have between a two-fold and five-fold greater risk of irritable bowel syndrome.”
These patients also have a disordered microbiome, which Dr. Terdiman said was just beginning to be explored at UCSF. “Stool assays on patients with symptomatic diverticulosis find an abnormal distribution of normal flora, which we call bacterial dysbiosis,” he explained. Biopsies around diverticula, even in patients with only low-grade discomfort, find evidence of chronic, low-grade inflammation.
As a result, clinicians are now developing a new paradigm of diverticulosis and diverticulitis, understanding them as part of a continuum of a chronic inflammatory process determined by patients’ genetic immune response and their microbiome.
“That ranges from very low-grade inflammation, which may appear as uncomplicated, symptomatic disease that we treat with mesalamine and other things, to something more aggressive that can become a true infectious disease and breach bowel integrity,” said Dr. Terdiman. “It’s the same spectrum you see in Crohn’s disease.”
Given that new paradigm, several approaches are being considered to treat symptomatic uncomplicated disease and help prevent acute diverticulitis. One is giving patients anti-inflammatories, as is the case with ulcerative colitis.
“Nobody has yet given these patients infliximab, but we do treat with mesalamine,” he said. As for restoring patients’ microbiome, “we may some day use stool transplant.”
Doctors now are giving patients rifaximin for their bacterial overgrowth and irritable bowel or using low-dose antidepressants. Several small trials have looked at treating patients with rifaxamin, typically with cyclic treatment one week per month. A meta-analysis in the April 2011 issue of Alimentary Pharmacology & Therapeutics found that the number of patients with symptomatic uncomplicated diverticular disease needed to treat with rifaximin to relieve symptoms was three.
“These are small studies, but they’ve been pretty positive in terms of reducing chronic symptoms,” Dr. Terdiman said. “And rifaximin is a super-safe therapy.” Studies have also found symptom relief in patients given a combination of mesalamine and rifaximin.
Two large randomized studies concluded that mesalamine did not prevent acute recurrent diverticulitis. However, a small study published in the February 2013 issue of Digestive and Liver Disease that looked at monthly rifaximin—400 mg twice a day for a week every month for 12 months—plus fiber vs. fiber alone produced “a marked reduction in the rate of acute recurrent diverticulitis.”
“We’re not doing this routinely yet,” he said. “But for patients who keep coming in with real quality-of-life issues, there may be medical therapy.”