The Optimal Use of JAK inhibitors: Risks, Benefits, and the Role of Selectivity

Any discussion of the optimal use of Janus kinase (JAK) inhibitors in the management of inflammatory bowel disease (IBD) must account for the risks and benefits of these novel small molecule agents, Millie Long, MD, told the attendees at the first virtual regional meeting of Advances in Inflammatory Bowel Diseases 2021 on March 6, 2021.

Dr Long is an associate professor of medicine in the Division of Gastroenterology and Hepatology at the University of North Carolina at Chapel Hill.

She explained that the 4 types of JAKs (1, 2, 3, and TYK-2) and the seven signal transducer and activator of transcriptions (STATs) create what is known as the JAK-STAT pathway. Signaling occurs through different combinations, Dr Long explained, that different safety and efficacy profiles. JAK inhibitors are now being used or are being studied for treatment of conditions ranging from alopecia to systemic lupus erythematosus to ulcerative colitis (UC).

The key, she said, “is to find the right combination of these to help us control inflammation and minimize any safety concerns.”

Tofacitinib is now approved for the induction and maintenance of UC. “There are a number of advantages to this JAK inhibitor,” Dr Long explained. “It has oral administration. It has rapid absorption and a short serum half-life. And unlike many of our biologic therapies, it actually has no immunogenicity. This does equate to its being able to be started and stopped and that can be useful, depending on how you’re using it in your practice.” That lack of immunogenicity also makes it an effective treatment for patients previously exposed to anti-tumor necrosis factor (TNF) therapy.

There are some disadvantages to tofacitinib as well, Dr Long explained. “There are increased risks of infection,” including herpes zoster and pneumonia. There have been cases of worsening anemia, although none have been reported among patients with UC being treated with tofacitinib. Regular monitoring is also needed of lymphocytes, hemoglobin, lipids, and liver enzymes. Other safety issues also have arisen—including possible increased risk of deep vein thrombosis (DVT) and cardiovascular events.

The OCTAVE 1 and 2 trials “really demonstrated an appropriate induction of remission at 8 weeks with a delta of between 10% and 13% compared with placebo,” she explained.
“In terms of maintenance, you can see that at week 52, 34% to 40% of patients were able to maintain remission; this was at a mixture of 5 mg or 10mg twice daily.”

The long-term extension trial, OCTAVE Open, enrolled 142 patients who had achieved remission of UC in the phase 3 OCTAVE Sustain trial. These patients were followed for 36 months, beginning with a dose of 5 mg twice daily, with dose increase to 10 mg allowed due to confirmed flare. More than two-thirds of the participants were in remission at 12 months and almost three-quarters showed endoscopic improvement, Dr Long reported. No new risks were identified throughout the 36-month trial. At 36 months, Dr Long said, “about half of these individuals were still in remission.”

Dr Long also shared data recently released from the RIVETING trial, which investigated tofacitinib dose reduction among patients with UC in stable remission. This double-blind, randomized controlled trial followed 140 patients on tofacitinib to determine the safety and efficacy of reducing the dose of tofacitinib from 10 mg twice daily to 5 mg twice daily. These patients had been treated with tofacitinib for more than 2 years and had been in stable remission for more than 6 months, defined and had taken no corticosteroids in the previous 4 weeks. “This really was an ideal population” for this study, Dr Long noted.

The investigators looked at adverse events and found no difference in the safety of tofacitinib at 5 mg or 10 mg twice daily, “but efficacy was different,” Dr Long remarked. Of patients who had prior exposure to anti-TNFs, 74% of those on the reduced dose of 5 mg of tofacitinib twice daily achieved clinical remission at 6 months, while more than 91% who were treated with 10 mg twice daily reached clinical remission in the same period. “Remember that tofacitinib is now positioned after anti-TNFs, based on the FDA recommendations, so all of our patients will fit into this category,” she noted. Patients with a Mayo Endoscopic Score of 1 had a more than 20% difference in achieving clinical remission with the higher dose of tofacitinib.

“I think this is very useful information in your practice,” Dr Long stated. “You can recognize those risk factors associated with failure of dose reduction, which will help you to triage who should and shouldn’t be dose-reduced.” She added, “I take these data to heart in my own practice, with the FDA recommendation calling for the lowest possible dose to sustain remission. For some patients, frankly, the lowest dose may be that 10 mg twice daily.”

 “We also need to think about the safety considerations surrounding tofacitinib,” Dr Long stated, including infectious complications. The risk of herpes zoster “leads that list,” but there is potential for prevention, she said. “In my practice, certainly for those over 50, I will give the Shingrix vaccination to help prevent this complication.”

FDA has placed a black box warning on tofacitinib based on postmarketing clinical trial data among patients with rheumatoid arthritis (RA). An interim analysis showed that the patients— all aged 50 years or older and with at least 1 cardiovascular risk factor—were at increased risk for pulmonary embolism (PE) and death on the 10 mg twice-daily dose of tofacitinib.

Dr Long stated that these risks have not been seen in the population with UC nor in real-world data. However, the FDA issued a drug safety communication on February 4 stating that preliminary results from the ORAL Surveillance Study in RA showed a safety signal for tofacitinib indicating a possible increased risk of major adverse cardiovascular events and adjusted malignancies, Dr Long explained. “We need more data but I think it’s important to discuss these things with patients and to minimize risks.”

There are a number of other JAK inhibitors in the pipeline, she noted. “Tofacitinib is an effective therapy for induction and maintenance of remission in IBD,” but future selective JAKs may have improved safety profiles.

--Rebecca Mashaw

Long, M. Optimal use of JAK inhibitors for the management of IBD. Presented at: Advances in Inflammatory Bowel Diseases regional meeting. March 6, 2021. Virtual.