Janus kinase (JAK) inhibitors are among the fastest-acting therapies available for the treatment of moderate to severe inflammatory bowel disease, and may have a role to play in the care of patients with acute severe ulcerative colitis (UC), Millie Long, MD, told the Advances in Inflammatory Bowel Diseases regional meeting in Boston on April 6.

Dr Long is a professor of medicine, vice chief of education, and director of the fellowship program in the Division of Gastroenterology and Hepatology at the University of North Carolina at Chapel Hill.

Intracellular signaling through the JAK/STAT pathway is integral for many cytokines, she explained. Two JAK inhibitors, tofacitinib and upadacitinib, are approved in the US for use in ulcerative colitis; upadacitinib is also approved for Crohn’s disease and both are approved for certain types of arthritis and skin disease. Several others are under investigation, Dr Long noted.

She reviewed the findings of clinical trials for the JAK inhibitors in ulcerative colitis, including OCTAVE 1 and 2 for tofacitinib and the U-ACHIEVE AND U-ACCOMPLISH trials for upadacitinib. These studies showed that the JAKs acted very quickly, often within a few days, to relieve symptoms of stool frequency, rectal bleeding, and bowel urgency, including among patients with previous lack or loss of response to biologic treatments.

Some paradoxically considering its usual rapidity of action, Dr Long said, “Prolonged induction treatment to 16 weeks was beneficial in almost half of patients with UC who failed to achieve a clinical response after 8 weeks’ induction with upadacitinib 45 mg.”

In Crohn’s disease, upadacitinib achieved clinical remission among approximately half of patients in the U-EXCEL 12-week induction trial, with similar durability of remission at 52 weeks, she reported. In addition, subgroup analyses of trials have demonstrated efficacy of upadacitinib in fistulizing Crohn’s disease, with approximately half of patients achieving complete resolution of fissures and drainage during induction at a dose of 45 mg, and approximately 60% achieving clinical and endoscopic remission at a 30 mg dose during maintenance.

Safety has been of primary interest in regard to JAK inhibitors since the ORAL Surveillance trial of tofacitinib indicated risks of major adverse cardiac events (MACE), pulmonary embolism, deep vein thrombosis and other serious complications. However, Dr Long noted, this trial was conducted among patients with rheumatoid arthritis and specifically weighted to include patients with at least one risk factor for cardiac disease, a history of heart disease, and with about half of the patients either former or present smokers. She added, “Tofacitinib was not associated with a higher incidence of MACE vs TNFi among patients aged more than 65 years and those who never smoked.”

As a result of this study the US Food and Drug Administration requires that patients with IBD be treated first with an anti-TNF before they can be treated with a JAK inhibitor. She also observed that although patients with UC have a higher than average risk of PE or DVT, to date no evidence has been seen of heightened risks of embolism among patients with UC who have been treated with a JAK inhibitor.

The same is true of the association of tofacitinib and malignancy, Dr Long said. Those patients who had never smoked and were under 65 years of age did not show an increased risk of malignancy when treated with the JAK inhibitor.

In her practice, Dr Long explained, “ I consider JAKs in patients with UC and CD with moderate to severe symptoms who have been exposed to advanced therapy.” It is also possible to consider JAK therapy for patients with milder IBD symptoms who have concurrent inflammatory arthritis or dermatologic conditions such as atopic dermatitis.

 “JAKs may have a role in acute severe ulcerative colitis, but we need more data,” she added.

When initiating JAK therapy, Dr Long advises getting baseline labs, including lipids, which can be elevated by this therapy; screening patients for VTE and MACE risk; and vaccinating patients for herpes zoster with the  recombinant, adjuvanted vaccine that is now FDA-approved for ≥18-year-olds on immune suppression She uses tofacitinib at 10 mg BID or 22 mg QD for 8 weeks, and for maintenance. With upadacitinib Dr Long uses a 45 mg QD dose for 8 weeks for patients with UC and 12 weeks for Crohn’s, and then 30 mg QD in maintenance. “I do not reduce dose in maintenance,” she said.

“Patients can see improvement rapidly, but you need to complete induction therapy,” Dr Long advised. “And above all, remember that steroids and poorly controlled disease are worse than any therapy we prescribe.”