In 2018, Michigan Medicine clinical pharmacist Randolph Regal, PharmD, noticed another patient in the hospital for acute severe ulcerative colitis had begun infliximab.

This protocol was expensive and, more importantly, often didn’t work.

He called gastroenterologist Peter Higgins, M.D.

“This expensive and somewhat toxic intravenous medication—which we are using at doses 2- to 6-times higher than those labeled by the FDA—is not working,” Regal remembered saying.

“What else can we try?”

Higgins had good reasons to prescribe infliximab—and keep prescribing it, even if it wasn’t always clear if it was helping.

Most patients are willing to try anything to avoid colectomy, a potentially lifesaving, but irreversible surgery that removes part or all the colon.

So, Higgins and his colleagues prescribed more and more infliximab to overcome the drug being lost in a patient’s stool.

Yet when Regal called him, he had, by coincidence, recently been reviewing data on whether increased doses of the drug were helping. 

“And I said, ‘You know, I think you're probably right,’” recalled Higgins.

He had an idea: tofacitinib, which just that May had become the first Janus kinase (JAK) inhibitor approved for treating ulcerative colitis. (It had previously received FDA approval to treat rheumatoid arthritis.) 

Higgins had reasons to suspect JAK inhibitors could work better for patients who infliximab didn’t help.

Besides, he reasoned, people sick enough to reach the emergency room would not be eligible for clinical trials.

Almost seven years later, this approach, pioneered at Michigan, seems to be paying dividends for patients.

In a cohort of acute severe ulcerative colitis cases, Higgins and his team reported that just 5.6% of patients in 2024 required a colectomy within 90 days, compared to 19.4% in 2018 and 28% a decade ago.

While these trends now seem to be validating the approach, considerable skepticism existed in the field for such an unproven strategy. 

Higgins and Regal were administering 10 mg of tofacitnib three times a day, an off-label dosage necessary to sustain stable levels of the medication.

“When I presented that data initially in Berlin, there was just dead silence in the hall,” Higgins said.

“One guy got up, came up to the microphone, and all he said was, ‘You were very brave,’ and sat down. So, the field wasn't exactly accepting at first.”

The team at Michigan now has a growing amount of published work documenting their progress. 

A paper published in the American Journal of Gastroenterology in March observed six out of 25 (24%) patients requiring a colectomy after going on upadacitinib, tofacitinib’s successor. 

While that colectomy rate is similar to the rates found in clinical trials of infliximab, this study focused on patients who had already not responded to anti-TNF therapies. 

“Patients in those earlier trials of infliximab were essentially new diagnoses who hadn’t failed anything,” said Jeffrey Berinstein, M.D., M.Sc., gastroenterologist and assistant professor at Michigan Medicine, and lead author on the paper. 

“Whereas 90% of the patients in our trial had already failed the biologic. If they went to any other hospital in the United States, they'd be sent right for colectomy, because they already failed first-line therapy.”

All but two patients in the study avoided colectomies after their initial hospitalization, suggesting the drug was not merely delaying an inevitable surgery.

A big advantage of the JAK inhibitors for patients with acute severe ulcerative colitis is the ability for the drug to stay within their systems. 

Michigan’s gastroenterologists believe the steady loss of infliximab in patients had led doctors to use higher doses without any increase in effectiveness.

“Drugs like infliximab, which are called monoclonal antibodies, bind to albumin, which is the protein floating around the blood,” said Berinstein.

“Inflammation in the gut causes albumin to leak out. These JAK inhibitors, which are not affected by that, are sort of perfectly suited for something like ulcerative colitis.”

The JAK inhibitors also seem to lead to better outcomes at higher doses, in contrast to infliximab’s diminishing returns at higher levels.

Furthermore, upadacitinib and tofacitinib come as tablets, allowing for the possibility of easier outpatient treatment. (Infliximab is injected.)

Now the researchers are working to confirm their results through larger studies of upadacitinib for patients who have already failed other treatments.

They hope, eventually, to study JAK inhibitors as a potential first-line therapy for acute severe ulcerative colitis.

In the interim, however, patients at Michigan Medicine with acute severe ulcerative colitis will continue to benefit from the institutions willingness to be at the forefront of new treatment strategies.

“It comes down to just having a pharmacist like Randy Regal, who partnered with Peter Higgins, and was supportive,” Berinstein said.

“It was the ingenuity to recognize that this was an unmet need and that these new medicines could potentially solve it. And it was a willingness to try something new for patients who didn't really have any other options.”

Funding/disclosures: J.A.B. received a K23 career development award from NIDDK (DK134764).

Paper cited: “Effectiveness of Upadacitinib for Patients With Acute Severe Ulcerative Colitis: A Multicenter Experience,” The American Journal of Gastroenterology. DOI: 10.14309/ajg.0000000000002674

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