Setting the Stage: The Latest Treatment Algorithms in IBD

“Precision medicine can play a role in the care of patients with inflammatory bowel disease, and the positioning of biologics can be informed by network meta-analyses,” William Sandborn, MD, informed the attendees at the virtual Advances in Inflammatory Bowel Diseases 2021 regional meeting on April 16.

Dr Sandborn is the chief of gastroenterology at the University of California San Diego (UCSD).

He explained how treatment sequencing can be facilitated by the work done in network meta-analysis. His colleague at UCSD Siddarth Singh, MD, conducted such an analysis of all approved therapies for moderate to severe ulcerative colitis (UC) and stratified the data according to patients who were biologic naïve and those who had previously failed with biologics, primarily anti-tumor necrosis factor (TNF) agents. The strongest effects were seen with infliximab and vedolizumab, Dr Sandborn explained. “All the drugs are effective but these are the best for clinical remission in naïve pts and for endoscopic improvement,” he said.

Further study of active comparative trials, such as the SUCCESS trial of infliximab and adalimumab in UC, and a trial of infliximab and cyclosporine in hospitalized patients with severe UC, confirmed the results of the meta-analysis that infliximab and vedolizumab “are highly effective induction agents in anti-TNF naïve population,” Dr Sandborn stated.

“But what about those who fail with anti-TNFs and need a second-line treatment?” he noted. Again, using meta-analysis and comparator studies, the strongest effects were found with the Janus kinase (JAK) inhibitor tofacitinib and the interleukin (IL) 12/23 inhibitor ustekinumab. “Other therapies appeared to be less effective in these cases,” Dr Sandborn stated.

“Efficacy isn’t the whole story,” he continued. “There is the safety aspect to consider, as well. The anti-TNFs are associated with granulomatous infections such as tuberculosis, serious infections, non-Hodgkins lymphoma, and demylelination. Tofacitinib has been associated with serious infections, reactivation of herpes zoster, deep vein thrombosis and pulmonary embolism, and hyperlipidemia. Vedolizumab and ustekinumab have much better safety profiles and aren’t associated with any of these adverse effects.”

In biologic-naïve patients, he said, vedolizumab could be more effective, while ustekinumab also works in these patients and could be a reasonable choice due to safety concerns. Both ustekinumab and tofacitinib did best as second-line therapy, Dr Sandborn commented.

Much the same results were seen in studies of treatment for Crohn disease. The same process of network meta-analysis showed that both adalimumab and infliximab have similar effects and are relatively stronger than vedolizumab and ustekinumab for induction of clinical remission in biologic-naïve patients with CD.

The SONIC trial showed that the combination therapy of infliximab and azathioprine performed best in inducing remission in CD without the use of corticosteroids, Dr Sandborn noted. In the top-down study, patients were randomized to steroids, then immunosuppressives, then infliximab, and compared to patients who received early combination treatment of infliximab and azathioprine. “The early combination therapy was much more effective,” he stated.

Infliximab was shown to be more effective than placebo in preventing ulcers and works to induce complete fistula closure, he added.

Dr Sandborn noted that “it will be interesting to see how the results turn out” in the SEAVUE trial, a just-completed study of the safety and efficacy of adalimumab vs ustekinumab as first-line treatment for moderate to severe UC. Those results should be released later this year, he said.

In the realm of second-line therapy for patients with CD who have lost response to a first-line agent, Dr Sandborn stated that ustekinumab has shown the strongest performance. “Ustekinumab has good efficacy and a good safety profile,” he said, while infliximab and adalimumab “have more side effects, although they are highly effective.”

Dr Sandborn discussed the use of a prognostic clinical decision support tool (CDST) for patients with UC. Factors including duration of disease, prior use of anti-TNFs, baseline albumin, and extent of endoscopic disease are scored, with higher scores equaling better chances of achieving steroid-free remission and avoiding colectomy.

“An analogous tool for CD includes factors such as prior bowel surgery, use of anti-TNFs, presence or absence of fistulizing disease, baseline albumin, and C-reactive protein. Patients with higher scores have more positive prognostic factors and do the best,” Dr Sandborn stated.

“When you’re sitting in the clinic with a patient with Crohn’s disease, you kind of think, ‘alright, meta-analysis shows that patients who got infliximab or adalimumab did a little bit better, but my patient really doesn't like that safety profile, so let me use this CDS tool and find out where my patient falls’,” he said. “If they fall into the higher probability group they’ll probably do great with vedolizumab. But if they’re in low probability group, the safety profile isn’t going to help if the drug doesn’t work.”

Dr Sandborn said the key points are that positioning of biologics can be informed by network meta-analysis in both UC and CD. Vedolizumab and ustekinumab are the safest agents in both conditions. And in IBD, “Precision medicine can play a role in the care of patients.”

--Rebecca Mashaw

Sandborn W. Setting the stage: the latest treatment algorithms in IBD. Talk presented at: Advances in Inflammatory Bowel Diseases regional meeting. April 16, 2021. Virtual.