MAUI, HAWAII (FRONTLINE MEDICAL NEWS) – Prolonged corticosteroid therapy for inflammatory bowel disease (IBD) was associated with a significantly increased mortality risk compared with anti–tumor necrosis factor therapy in a landmark study spotlighted by Edward V. Loftus Jr., MD, at the Gastroenterology Updates, IBD, Liver Disease meeting.

This was one of several key studies on safety issues involving IBD medications published in the past year. Others highlighted by Dr. Loftus and copanelist William J. Sandborn, MD, included a study that provided persuasive evidence that TNF inhibitors modestly increase lymphoma risk in IBD patients to a degree similar to that of thiopurines, and several reports addressing the question of whether preoperative use of vedolizumab in patients undergoing major abdominal operations for IBD boosts postoperative infection risk.

Mortality impact of prolonged steroids vs. anti-TNF therapy

A retrospective cohort study of more than 13,000 Medicare and Medicaid patients with IBD demonstrated that those on prolonged corticosteroid therapy – defined as more than 3,000 mg of prednisone or its equivalent in a 12-month period – had a significantly higher mortality rate compared with IBD patients on an anti-TNF agent.

That will come as an unpleasant surprise to many physicians. There is a widespread reluctance to turn to continuous chronic immunosuppression via anti-TNF therapy in patients with challenging IBD, particularly in elderly individuals with multiple comorbid conditions. Many physicians have heard and read so much about the biologics’ risks of serious adverse events that they opt instead for multiple courses of corticosteroids for disease control. This is a serious mistake, emphasized Dr. Loftus, professor of medicine and director of the IBD Interest Group at the Mayo Clinic in Rochester, Minn.

“When you say, ‘Oh, I’ll just give that patient another prednisone taper, he doesn’t want to start taking a TNF inhibitor,’ you’re actually doing the patient harm. You’re actually affecting the patient’s life expectancy when you do that,” he declared. “The message is, yes, steroids are cheap, steroids are easy, nobody’s afraid of steroids, but you should be afraid of steroids.”

The 1,879 Crohn’s disease patients who entered the cohort as new users of anti-TNF therapy had a subsequent mortality incidence rate of 21.4 per 1,000 person-years, compared with a rate of 30.1 per 1,000 person-years in the 7,694 who entered the study period as prolonged steroid users. In a multivariate analysis accounting for 57 potential confounding factors, this translated to a highly significant 22% relative risk reduction in mortality in the patients who went with anti-TNF therapy (Am J Gastroenterol. 2018 Jan 16. doi: 10.1038/ajg.2017.479 ).

A similar trend was seen in the ulcerative colitis cohort. The 459 ulcerative colitis patients who entered the cohort as new anti-TNF therapy users had a mortality incidence rate of 23.0 per 1,000 person-years, compared with a rate of 30.9 in the 3,224 who received more than 3,000 mg of prednisone in the next 12 months. This represented a 14% relative risk reduction, although this favorable trend did not achieve statistical significance, perhaps because of the smaller size of the ulcerative colitis cohort.

In addition to demonstrably greater life expectancy, anti-TNF therapy offered additional benefits: a 32% reduction in the risk of major adverse cardiovascular events and a 46% lower incidence of hip fracture.

Dr. Sandborn, professor of medicine and chief of the division of gastroenterology at the University of California, San Diego, spun the study data another way: “It shows the number needed to kill is 33. So for every 33 patients you put on prolonged corticosteroids, you’re killing one extra patient by doing that. Of course, you probably blame it on their age and comorbidities, but this is it. This is the data.”

TNF blockers, thiopurines, and lymphoma

The use of thiopurines for treatment of IBD is widely recognized to be associated with a small but real increased risk of lymphoma. Now a large French national study has demonstrated for the first time that anti-TNF therapy for IBD is also associated with an increased risk that needs to be discussed with patients. And in IBD patients on combination therapy with both classes of medication, that risk jumps to 6.1-fold greater than in unexposed IBD patients ( JAMA 2017 Nov 7;318[17]:1679-86 ).

Dr. Loftus and Dr. Sandborn urged their colleagues to keep this increased risk in perspective in counseling patients by focusing on the modest absolute increase in risk rather than the scarier-sounding relative risk. Notably, two-thirds of lymphomas in the French study occurred in patients not on thiopurines or anti-TNF agents.

“The most interesting thing to me is that we worry and worry about lymphoma, and guess what? In this study and in multiple other studies, the majority of lymphomas occurring in IBD patients have nothing to do with their medications. They’re due to the usual risk factors for lymphoma, which include age and male gender,” Dr. Loftus observed.

The French study included more than 189,000 IBD patients followed for a median of 6.7 years, during which 336 cases of lymphoma occurred. The incidence rate was 0.26 cases per 1,000 person-years in unexposed patients. The rate was significantly higher at 0.54 per 1,000 person-years in those on thiopurine monotherapy, increased to a similar extent at 0.41 cases per 1,000 person-years in patients on anti-TNF monotherapy, and 0.95 per 1,000 person-years in those on combination therapy.

In a multivariate analysis, the lymphoma risk was an adjusted 2.6-fold greater in patients exposed to thiopurine monotherapy than in unexposed patients, 2.41-fold greater in patients exposed to anti-TNF monotherapy, and 6.1-fold greater in those exposed to combination therapy.

“The point I want to make is the lymphoma rates in the thiopurine monotherapy and anti-TNF monotherapy groups are not significantly different. So the claim that’s been out there that the increased lymphoma risk in IBD patients can be completely explained by thiopurines is wrong. This study is showing us that with anti-TNF monotherapy there is still a low-level risk of lymphoma,” Dr. Loftus said.

“It is somewhat eyebrow-raising when you see that relative risk of 6.1, and that’s what patients are going to focus on, but when you counsel patients you have to redirect them to the absolute risk. You can say, ‘Even on combination therapy, your risk is 1 in 1,000,’ ” the gastroenterologist said.

Dr. Sandborn said the lymphoma signal hadn’t been spotted previously because the individual registries of IBD patients on anti-TNF agents are too small to allow for identification of a small increase in risk. The French investigators overcame that limitation by tapping into the country’s national health care system.

“This is a huge dataset and I think the message is unequivocal,” Dr. Sandborn said.

He noted that strongly risk-averse patients may find ustekinumab (Stelara) and vedolizumab (Entyvio) to be attractive treatment options. Neither has any link to lymphoma.

Preoperative vedolizumab and postoperative infection risk

“The overall safety profile of vedolizumab is pretty good,” Dr. Loftus observed. “The one unanswered question is its safety when used within 8-12 weeks of a major abdominal operation.”

It’s a clinically relevant question because vedolizumab selectively inhibits leukocyte migration into the intestinal tract, which could provide a mechanism for impaired postoperative wound healing in patients undergoing major abdominal surgery. And sooner or later a high proportion of IBD patients have a major abdominal operation.

Dr. Loftus and his coinvestigators kicked off a controversy by reporting a 37% incidence of surgical site infections in IBD patients who received vedolizumab within 30 days of a major abdominal operation in a retrospective chart review of the Mayo Clinic experience, a postoperative infection rate strikingly higher than in their patients on anti-TNF or nonbiologic therapy ( J Crohns Colitis. 2017 Feb;11[2]:185-90 ).

This prompted investigators at the University of Chicago to look retrospectively at their institutional experience. They reported no increased risk in IBD patients on vedolizumab ( Am J Gastroenterol. 2017 Sep;112[9]:1423-9 ). Neither did Belgian gastroenterologists at the Catholic University of Leuven ( J Crohns Colitis. 2017 Oct 27;11[11]:1353-61 ).

Most recently, the Mayo Clinic group along with gastroenterologists at three other U.S. centers collaborated in a multicenter retrospective review of 146 adult IBD patients who received vedolizumab within 12 weeks before major abdominal surgery and 289 who received anti-TNF therapy. In a multivariate analysis, perioperative use of vedolizumab was independently associated with a 5.8-fold increased risk of developing a surgical site infection (J Inflamm Bowel Dis. 2018 Mar 19. doi: 10.1093/ibd/izx076 ).

Dr. Sandborn, who like Dr. Loftus was a coauthor of the multicenter study, drew back to look at the big picture.

“Is vedolizumab really causal? I doubt it, although it’s remotely possible. But I bet vedolizumab therapy is a really good marker for sick patients, and sick patients have worse operative outcomes, so we ought to be conservative with their surgery. My read of this is this [postoperative infection risk] isn’t unique to vedolizumab. Just be careful with sick patients when you’re operating and do more conservative surgeries,” he said.

Both gastroenterologists reported serving as consultants to and receiving research grants from numerous pharmaceutical companies.