Hans Herfarth, MD, on JAK-STAT Inhibitors for Ulcerative Colitis

Drugs that act on the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway show excellence efficacy and fast onset of action in the treatment of ulcerative colitis (UC), Hans Herfarth, MD, said at the April 2 Advances in Inflammatory Bowel Diseases meeting in Raleigh, North Carolina.

Dr Herfarth is a professor of medicine at the University of North Carolina at Chapel Hill.

His presentation focused on reviewing both clinical trials and real-world data on the safety and efficacy of tofacitinib and upadacitinib, both of which have been approved for use in the treatment of UC after a patient has experienced failure with a first-line agent.

Dr Herfarth reviewed the OCTAVE trial of tofacitinib in UC and the compared results to those of a network meta-analysis of 17 studies and those of the TOUR study, a prospective real-world cohort of patients with UC treated with the JAK inhibitor.

The meta-analysis reviewed 6 full-text articles and 11 abstracts in conference proceedings that included 1162 patients, most of whom had already been exposed to biologics patients. Overall, he noted, 62% of patients showed clinical response at 8 weeks while 64% demonstrated response at 12 to 16 weeks at a dose of 10 mg bid; 35% achieved remission at 8 weeks with 47% achieving remission at 12 to 16 weeks.

In 5 studies, 46% of patients prolonged induction up to 16 weeks at 10 mg bid, Dr Herfarth stated. None of these studies reported any major cardiovascular adverse events (MACE) or thromboembolic events; 13 studies reported herpes zoster among a 3.4% of participants.

The TOUR multicenter prospective cohort studied efficacy and safety of tofacitinib among 96 patients with UC; 95% had failed 1 anti-TNF, while 67% had failed 2 biologics. By day 28, 66.7% of all patients had clinical response and 51.0% had achieved remission, Dr Herfarth explained. Of these patients, 39.6% had steroid-free clinical response and 30.2% were in remission.

The TOUR study further showed that the Simple Clinical Colitis Activity Index (SCCAI) had dropped from almost 6 to 4.6 by day 3, 3.8 at day 7, and 3.2 by week 8. The colectomy rate among these patients was 5.0%. In regard to adverse events, 3.1% of patients developed shingles while 10.4% developed infections that required treatment with antibiotics.

Tofacitinib demonstrated significant efficacy in treating urgency among patients with UC, as well, Dr Herfarth reported. Among the patients in the TOUR study, 53.0% described urgency as grade 1 (“hurry”); 40% rated their urgency as grade 2, or “immediately”; and 7% reported fecal incontinence, or grade 3. On day 3 30.0% of these patients reported improvement in urgency of at least 1 point. At week 8, 84% reported having mild or no urgency.

In the RIVETING trial of 140 patients who had been treated with tofacitinib 10 mg BID for ≥ 6 and maintained stable remission for 6 months of more, half of the patients were dose-reduced to 5 mg BID while half remained on the 10 mg dose. Of patients reduced to 5 mg bid, 77.1% maintained Mayo score remission; 90.0% of patients in 10 mg bid maintained remission. Adverse event and serious adverse event rates were similar across treatment groups; no deaths were reported

Dr Herfarth noted that ALL patients with IBD are at a 2-fold risk of herpes zoster (shingles) when compared to the general population. In addition, he said, everyone more than 50 years of age can be considered at high risk of shingles, as well as those with a history of shingles and those of Asian ancestry. Tofacitinib appears to convey a 2- to 6-fold risk of herpes zoster, compared with the 2- to 3-fold risk seen with corticosteroids, a 3-fold risk with thiopurines, and a 2-fold risk with anti-TNFs. “Every IBD patient older than 18 years who is immunosuppressed or is at risk of needing immunosuppression should be vaccinated with this vaccine,” he stated, with the exception of pregnant or nursing women, in whom the Shingrix vaccine was not studied.

Patients with UC are also at higher risk than the general population for deep vein thrombosis (DVT) and pulmonary embolism (PE), he said. A study revealed that 1 case of DVT and 1 of PE occurred in both the induction and maintenance cohorts—both among patients treated with

Induction cohort: 1 DVT, 1 PE, both in the placebo group. All patients in the overall cohort who experienced DVT or PE were treated with 10 mg and had other risk factors for PE.

Concerns about tofacitinib’s association with major adverse cardiovascular events (MACE) and cancer resulted from the study of oral tofacitinib among patients with rheumatoid arthritis (RA), Dr Herfarth stated. Both MACE and cancer occurred more often in patients >65 years being treated with tofacitinib.

However, he explained, in the Oral Rheumatoid Arthritis Trial (ORAL) of tofacitinib, MACE occurred among patients more than 50 years of age, with at least 1 cardiovascular risk factor, and all patients were also being treated with methotrexate. He further noted that RA itself is associated with higher risks for MACE and cancers, including nonmelanoma skin cancer.

The newest JAK-STAT inhibitor, upadacitinib, shows substantial promise in the treatment of both Crohn disease and UC, Dr Herfarth stated. In the U-ACCOMPLISH study of patients with UC, 33.5% of patients randomized to upadacitinib 45 mg achieved remission in week 8, compared to 4.1% in the placebo group. In U-ACHIEVE, 26.1% of 474 patients also achieved remission at week 8. The U-ACHIEVE randomization of 746 responders resulted in 52% of patients treated with 30 mg upadacitinib were in remission at week 51, while 42% on 15 mg were in remission, compared to 12.0% on placebo.

Review of the studies of and experience to date with tofacitinib shows “real-world efficacy data are comparable to clinical trial experience,” Dr Herfarth said. “JAK inhibition has a rapid onset of clinical efficacy.” Dose reductions of tofacitinib in biologic-experienced or mildly endoscopic active patients is risky, he stated, while the risks of MACE and cancer may be increased among patients older than 65 years of age who have cardiovascular risk factors.

“Upadacitinib is highly effective and may represent the most effective therapy for UC patients other than infliximab,” he concluded.

--Rebecca Mashaw

Herfarth H. JAK-STAT. Presented at: Advances in Inflammatory Bowel Diseases. April 2, 2022. Raleigh, North Carolina.