David Rubin, MD, on Optimal and Future Use of JAK Inhibitors for IBD

Tofacitinib and other Janus kinase (JAK) inhibitors offer important advantages in the treatment of patients with inflammatory bowel diseases (IBD), “knocking down multiple pathways of inflammation,” said David T Rubin, MD, at the Advances in Inflammatory Bowel Diseases virtual regional meeting on September 11.

Dr Rubin is the Joseph Kirsner Professor of Medicine and chief of the division of gastroenterology, hepatology, and nutrition at the University of Chicago.

The only JAK inhibitor approved for use in IBD is tofacitinib, which is approved for the treatment of moderate to severe ulcerative colitis (UC). It is also approved for the treatment of psoriatic arthritis and rheumatoid arthritis.

Dr Rubin addressed the US Food and Drug Administration’s recent decision to require an additional “black box” warning about heightened risks for heart attack, stroke, blood clots, and cancer on all JAK inhibitors. The ruling followed the results of a postmarketing phase 4 trial of tofacitinib to determine whether the 5 mg dose presented additional risks of major adverse cardiac events (MACE). Tofacitinib already carried a boxed warning for these risks at the 10 mg dose.

Dr Rubin noted that this trial involved patients aged 50 years or older with rheumatoid arthritis and at least 1 risk factor for cardiovascular disease. The patients were randomized to tofacitinib 10 mg with methotrexate; tofacitinib 5 mg with methotrexate; or an anti-tumor necrosis factor (TNF) —adalimumab or etanercept—also with methotrexate.

The trial revealed “a number of unexpected results, including a higher rate of pulmonary embolism (PE) and a higher rate of death among patients who got 10 mg with methotrexate,” compared to patients who received adalimumab with methotrexate, he explained. As a result, the FDA is  recommending that patients be screened for risk of venous thrombolembolism (VTE), and the dose be reduced to 5 mg whenever possible.

“You can see that in all these methotrexate was used, which is not what we do in our population of IBD,” Dr Rubin said. The higher rates of PE and deaths were not seen in clinical trials for all its approved indications, “nor has this been found in the UC population; this was a phase 4 study in a high risk group using methotrexate. I don’t want to minimize it except to say that the data show this in this particular study.”

The agency had already recommended —and health insurers typically require — that tofacitinib be used only among patients who have failed anti-TNF therapy.

The OCTAVE 1 and 2 clinical trials for tofacitinib tested the JAK inhibitor at 10 mg twice per day. Patients who did not respond fully at the end of 8 weeks  could go to an additional 8-week period at this dosage. Responders were randomized to the OCTAVE Sustain trial at 5 mg or 10 mg twice a day or placebo. The primary endpoint, Dr Rubin explained, was “a stringent definition of clinical remission: a Mayo score 2 or less, with no individual subscore greater than 1 AND a rectal bleeding subscore of 0.”

At week 52 of OCTAVE Sustain, 41% of participants receiving 10 mg BID had met this endpoint, compared to 34% of those receiving 5 mg BID. “This suggests we have some dose options in maintenance,” Dr Rubin said. “But there are some subtleties to this that are important, and this is one of them: patients who failed with anti-TNFs did not do as well when they dropped to 5 mg ; staying at 10 mg seemed to have a better result overall,” while patients who were anti-TNF naïve did better when they dropped to the 5mg dose.

In the RIVETING trial of tofacitinib in UC, patients were randomized to continuing 10 mg BID or dropping to 5 mg BID, Dr Rubin, who was involved in the study, explained. Patients on both doses did well, he noted, “but those in deep endoscopic remission and those who were TNF-naïve were more likely to maintain remission when dropping to 5 mg than others. Now the paradox here is that the FDA is asking us to position tofacitinib after TNF inhibitors, and they’re asking us to consider dropping the dose in a group that has been shown might need a higher dose for maintenance.”

In his own practice at the University of Chicago, Dr Rubin stated, “we have a number of patients who’ve failed on anti-TNFs, who are now on tofacitinib and most continue at 10 mg BID on maintenance. And we actively discuss all of this with them.”

He added that results of a study from the University of Michigan demonstrates that tofacitinib 10 mg BID in hospitalized patients with UC showed some benefit, but was more effective at TID. “This is off-label, we’re not recommending this, certainly not at the higher dose. But remember, UC patients when they’re actively inflamed do have a higher rate of DVTs, yet we haven’t seen that occur. So if this were a prothrombotic therapy in patients who already have a risk, we would expect to have seen a signal by now. I still think that that phase 4 study in RA needs to be interpreted appropriately given the setting.”

One safety signal that was found in earlier trials was the risk of reactivation of herpes zoster, he noted. “We recommend getting vaccinated against shingles,” Dr Rubin said, noting that the vaccine is now approved for patients aged 18 years and older, and can be done after starting therapy.

JAK inhibition affects cholesterol transport through the liver, he added, so patients on these therapies may experience an increase in their lipid levels of as much as 10%. In most cases, except for patients who already have hypercholesterolemia, these increases are not problematic and do not require treatment.

Dr Rubin offered several practical recommendations for using tofacitinib in the management of moderate to severely active UC. It should be administered after anti-TNF failure, and as monotherapy. Baseline laboratory work should include a lipid panel and patients should be screened for VTE risk, based on their personal and family history, the presence of obesity, and immobility.

The induction dose should be 10 mg BID for 8 to 16 weeks, followed by 10 mg or 5 mg BID in maintenance. Patients should be vaccinated for herpes zoster.

“Assess efficacy early,” Dr Rubin advised, checking symptoms within 2 weeks and again at 4 to 6 weeks; the second assessment should include a check of fecal calprotectin and a repeat of the lipid panel. For patients in deep remission, consider reducing the dose to 5 mg BID.

Dr Rubin noted that JAK inhibitors have rapid onset, and are excellent for patients with extraintestinal manifestations, such as joint pain.

Other JAK inhibitors are in trials for UC, including upadacitinib and filgotinib. To date, the phase 2 studies of JAK inhibitors in Crohn disease have not been positive, but real-world experience in a multicenter study “might favor their use in Crohn’s disease of the colon,” Dr Rubin said.

“These therapies offer novel considerations that include the potential for bridging, pulse therapy, and combination therapies with biologics,” Dr Rubin said. “They are all moving forward and racing to the market.”

--Rebecca Mashaw

Rubin, DT. Optimal use and future use of JAK inhibitors for the management of IBD. Presented at: Advances in Inflammatory Bowel Diseases regional meeting. September 11, 2021. Virtual.