Off-Label Use of Upadacitinib in Crohn’s Disease: A Case Series

Background: Upadacitinib (UPA) is an oral, once-daily JAK inhibitor approved by the FDA in May 2023 for use in moderate to severe Crohn’s disease after failure of first line treatment with anti-TNF agents, following approval for use in ulcerative colitis in March 2022. During the 12-week induction trials, bio-naive and bio-experienced patients had statistically significantly improvement in disease burden clinically, and on endoscopy. The 52-week maintenance trial demonstrated 37-47% of patients had clinical improvement/remission and 27-40% had endoscopic improvement on variable maintenance dosing. The aim of this single center cohort study is to report the subjective, endoscopic, and biochemical outcomes of UPA for Crohn’s disease prior to its approval in our tertiary referral patient population. Methods: Between 3/2022 and 5/2023, 16 patients in our IBD database with inadequately controlled Crohn’s disease were started on off-label 45mg UPA using a 12-week induction period, followed by 30mg daily. Results: Eleven of the patients were women (11/16, 68.8%), 10/16 (62.5%) were Caucasian and the remainder 6/16 (37.5%) patients were African American. All patients were bio-experienced with an average of 2.3 ± 1.03 prior biologics; 14 patients had prior exposure to steroids. Twelve (12/16, 75%) patients had a positive response to UPA, either biochemically or endoscopically; three patients had colonoscopies with improvement in inflammation, with an average SES-CD score pre-UPA of 18.6 ± 11.37, and post-UPA of 2 ± 1.73. Nine patients (56.3%) have seen either improvement in inflammatory markers or subjective symptom burden. Pre-UPA C-reactive protein (CRP) averaged 5.3 ± 1.3 (normal 0-1 mg/dL) and pre-UPA fecal calprotectin (FC) averaged 302 ± 230 (normal < 50 ug/g) with improvement of CRP to 0.48 ± 0.08 and FC to 68.5 ± 61.5 after UPA initiation. One of these patients was able to undergo ileostomy reversal after multiple complications from uncontrolled Crohn’s including bowel perforation. Two patients were considered a medication failure. One of these patients was admitted multiple times for a flare with perirectal abscesses requiring drainage and the other had no subjective improvement. Both were ultimately switched to Risankizumab. Another patient has been unable to tolerate dose reduction due to hematochezia and has started a prednisone taper, but is continuing UPA. The final patient presented recently with a small bowel obstruction and elevated FC, with ongoing discussions regarding potential failure of the medication. No serious adverse events were reported, although symptoms of acne, migraines, and palpitations were reported. Conclusions: Pre-approval off-label observational data from our institution corroborate the effectiveness of UPA for Crohn’s disease with 75% of patients responding, even in a bio-experienced population, with some patients reporting onset of action of drug within 1-2 weeks, with limited adverse events. Though sequencing biologics is not standardized and requires shared-decision making conversations with patients, this specific JAK-inhibitor is a welcome addition to the armamentarium.