Introduction
Ulcerative colitis (UC) is a chronic inflammatory condition involving the colon characterized by diarrhea, rectal bleeding, abdominal pain, and weight loss.1 Over the last 20 years, numerous biologic and small molecule therapies that target different biologic pathways have been approved for UC. This revolution in therapeutic advancements has led to substantial improvement in disease outcomes.
Despite the growing number of available treatments for UC, the positioning and sequencing of these targeted therapies remain a challenge given the scarcity of available data to drive medical decision-making.2 Specifically, the efficacy of using a second medication from the same class after failing to respond to an initial therapy with the same mechanism of action is often reduced.3 Current guidelines advocate for considering a different class of therapy rather than using a second therapy in the same class in patients who have experienced nonimmunologic nonresponse or loss of response.1,4 However, these guidelines do not adequately account for differences in molecular pharmacokinetics and patient pharmacodynamics. As a result, providers are often willing to use infliximab after adalimumab failure or risankizumab after ustekinumab failure especially as patients cycle through therapies, leaving fewer remaining options.
Upadacitinib is an oral inhibitor of Janus kinase (JAK)-1 selective small molecule that was recently approved for moderate to severely active UC.5 Recent clinical trial data and network meta-analyses suggest that upadacitinib is more effective than tofacitinib for induction of clinical remission in outpatients with moderate to severe UC.5,6 However, initial trials of upadacitinib excluded patients with a previous exposure to tofacitinib, a nonselective JAK inhibitor. As a result, the efficacy of upadacitinib in patients with a previous exposure to tofacitinib remains largely unknown.5 Understanding the effectiveness of upadacitinib after a prior JAK inhibitor failure represents a major knowledge gap, limiting our ability to provide evidence-based treatment to many of our treatment-refractory patients. In this study, we aimed to evaluate the real-world experience of upadacitinib in patients with UC who had previously failed to maintain an adequate response to tofacitinib at our institution.
Methods
Patient Selection
We retrospectively identified adult patients with UC who were 18 years of age or older and received upadacitinib after prior exposure to tofacitinib between January 2022 and February 2023 at Michigan Medicine (Ann Arbor, Michigan). Medical charts were then reviewed to ensure the diagnosis of UC and prior tofacitinib exposure were accurate, to obtain demographics (age and sex), disease information (disease duration and extent), prior steroid use, and to determine clinical course (reviewed by J.L. and J.A.B.).
Outcomes
Our primary outcome was clinical remission. Our secondary outcomes included clinical response, steroid-free clinical remission, endoscopic response, endoscopic remission, change in fecal calprotectin (FCP), colectomy-free survival, upadacitinib continuation, and frequency of adverse events. The partial Mayo score (pMayo), which consists of the rectal bleeding subscore (RBS), stool frequency subscore (SFS), and physician’s global assessment (scored from 3-9), was used to assess clinical response, clinical remission, and steroid-free clinical remission. Clinical remission was defined as a pMayo ≤2. Clinical response was defined as a decrease in pMayo score of ≥1 point and a decrease in rectal bleeding subscore ≥1 point or an absolute RBS of ≤1. Steroid-free clinical remission was defined as clinical remission per pMayo where patients were corticosteroid-free for ≥30 days prior to the time of last follow-up. Endoscopic response was defined as a Mayo endoscopic score (MES) of ≤1 without friability. Endoscopic remission was defined as an MES of 0. End points used were consistent with the U-ACHIEVE Upadacitinib induction trial.5 Clinical and biomarker outcomes were only calculated in patients who did not undergo colectomy. Data were expressed as counts with percentages for categorical variables or means with standard deviations (SD) for continuous variables.
Results
Sixteen UC patients with a prior tofacitinib exposure and subsequent upadacitinib use were identified. The mean age was 37.5 ± 15.8 years, with an average disease duration of 7.9 ± 5.3 years. Of the 16 patients, 7 (44%) were female, and 14 (88%) were white. Four patients (25%) had left-sided colitis, and 12 patients (75%) had pancolitis. The median duration of outpatient prednisone was 139.3 ± 202.8 days, with half of the patients using steroids at least 30 days prior to initiating upadacitinib. Tofacitinib treatment failure was described as primary nonresponse in 8 patients (50%), partial response in 4 patients (25%), and loss of response in 4 patients (25%). Five patients (31%) had been exposed to 2 advanced therapies, 4 patients (25%) to 3 advanced therapies, 6 patients (38%) to 4 advanced therapies, and 1 patient (6.2%) to 5 advanced therapies, with the majority being previously exposed to infliximab (n = 12, 75%) or adalimumab (n = 11, 69%). The mean baseline pMayo score was 7 ± 2.1. The mean baseline fecal calprotectin level was 859.4 ± 752.7. 2 mg/kg. Of the 15 patients who underwent endoscopic evaluation at baseline, 4 patients (27%) had an MES of 2, and 9 patients (60%) had an MES of 3 (Table 1).
Table 1.
Baseline patient characteristics.
| Characteristic | N = 16a |
|---|---|
| Age, years | 37.5 (15.8) |
| Biologic Sex | |
|---|---|
| Male | 9/16 (56%) |
| Female | 7/16 (44%) |
| Race | |
|---|---|
| White | 14/16 (88%) |
| Black | 1/16 (6.2%) |
| Other | 1/16 (6.2%) |
| Duration IBD, years | 7.9 (5.3) |
| Distribution | |
|---|---|
| Proctitis | 0/16 (0%) |
| Left-Sided Colitis | 4/16 (25%) |
| Pancolitis | 12/16 (75%) |
| Duration Outpatient Prednisone, days | 139.3 (202.8) |
| Steroid Use > 30 days | 8/16 (50%) |
| Prior Advanced Therapy Exposures | |
|---|---|
| 2 Advanced Therapies | 5/16 (31%) |
| 3 Advanced Therapies | 4/16 (25%) |
| 4 Advanced Therapies | 6/16 (38%) |
| 5 Advanced Therapies | 1/16 (6.2%) |
| Prior Infliximab Exposure | 12/16 (75%) |
| Prior Adalimumab Exposure | 11/16 (69%) |
| Prior Golimumab Exposure | 1/16 (6.2%) |
| Prior Vedolizumab Exposure | 7/16 (44%) |
| Prior Ustekinumab Exposure | 4/16 (25%) |
| Reason for Prior Tofacitinib Failure | |
|---|---|
| No Response | 8/16 (50%) |
| Partial Response | 4/16 (25%) |
| Loss of Response | 4/16 (25%) |
| Baseline Partial Mayo Score | 4.7 (2.1) |
| Baseline Fecal Calprotectin (mg/kg) | 859.4 (752.7) |
| Baseline Mayo Endoscopic Score | |
|---|---|
| Mayo 1 | 2/15 (13%) |
| Mayo 2 | 4/15 (27%) |
| Mayo 3 | 9/15 (60%) |
| Missing | 1 |
aMean (SD) or Proportion (%).
Upadacitinib was taken for a mean of 199.7 ± 108.3 days over a mean follow-up duration of 244.3 ± 111.9 days. Five patients (36%) achieved both clinical remission and steroid-free clinical remission during the follow-up. The mean FCP level during follow-up was 178.8 ± 188.3 mg/kg, with a mean reduction of 762.4 ± 717.5 mg/kg from baseline. Out of the 8 patients with available endoscopic follow-up, 5 (62%) demonstrated endoscopic response, while 2 patients (25%) achieved endoscopic remission. Two out of the 16 patients (12%) required colectomy during the follow-up period. Nine patients (56%) successfully tapered their dose of upadacitinib to 30 mg. Thirteen patients (93%) continued upadacitinib treatment throughout the follow-up period, and one patient (8%) switched to vedolizumab due to lack of adequate response with upadacitinib. Five patients (31%) experienced an infection (mild COVID-19 infection, 1 herpes zoster encephalitis [unvaccinated], 1 clostridium difficile infection, and 1 self-limited enteric E. coli infection [6.2% each]), with 2 of these patients (12%) requiring antimicrobial therapy. No venous thromboembolic events, major cardiovascular events, opportunistic infections, or postsurgical infections were reported (Table 2).
Table 2.
Outcomes.
| Characteristic | N = 16a |
|---|---|
| Upadacitinib Duration, days | 199.7 (108.3) |
| Duration Follow-up, days | 244.3 (111.9) |
| Clinical Response | 8/14 (57%) |
| Clinical Remission | 5/14 (36%) |
| Corticosteroid-free Remission | 5/14 (35%) |
| Follow-up FCP (mg/kg) | 178.8 (188.3) |
| Missing | 2 |
| Reduction in FCP (mg/kg) | 762.4 (717.5) |
| Time to FCP Follow-up, months | 5.8 (4.2) |
| Missing | 4 |
| Endoscopic Response | 5/8 (62%) |
| Endoscopic Remission | 2/8 (25%) |
| Time to Endoscopic Follow-up, months | 6.9 (4.4) |
| Missing | 8 |
| Colectomy Rate | 2/16 (12%) |
| Successful Taper to Upadacitinib 30mg | 9/16 (56%) |
| Upadacitinib Continuation | 13/14 (93%) |
| Venous Thromboembolic Event | 0/16 (0%) |
| Major Cardiovascular Events | 0/16 (0%) |
| Any Infection | 5/16 (31%) |
| Infection Requiring Antimicrobial Therapy | 2/16 (12%) |
| Corona Virus (COVID)-19 | 1/16 (6.2%) |
| Clostridium Difficile Infection | 1/16 (6.2%) |
| Opportunistic Infection | 0/16 (0%) |
| Herpes Zoster Infection | 1/16 (6.2%) |
| Postsurgical Infection | 0/16 (0%) |
aMean (SD) or proportion (%). Clinical and biomarker outcomes were only included for patients who did not undergo colectomy. Postsurgical infection was only evaluated in patients who underwent colectomy; Abbreviation: FCP, fecal calprotectin.
Discussion
This study provides valuable insights into the use of upadacitinib in UC patients who previously failed to respond to or lost response to tofacitinib. This is one of first and largest examination of the real-world experience with upadacitinib in tofacitinib-refractory UC patients. The observed effectiveness of upadacitinib in patients with a prior tofacitinib exposure (35% clinical remission and steroid-free clinical remission, 62% endoscopic response, 25% endoscopic remission, and 88% colectomy-free survival) is more modest than a recent real-world cohort study by Friedberg et al looking at clinical outcomes at 4 and 8 weeks.5,7 In the Friedberg study, 9 patients with active UC and a prior tofacitinib exposure were treated with upadacitinib. Of these patients, 77.8% experienced clinical response and clinical remission, while 100% achieved steroid-free remission.7 Although it should be noted that it is difficult to compare our real-world data, which was collected over a mean follow-up duration of 244.3 ± 111.9 days to induction data. The fact that only 2 patients (12%) underwent colectomy and 13 patients (93%) were able to remain on upadacitinib (albeit with lower rates of patients meeting clinical and endoscopic end points) over 244 days speaks to the viability and durability of this approach. Overall, considering these variations in study design and patient population, the relatively high rates of clinical and endoscopic response and remission observed in this high-risk population are encouraging.
Several limitations should be considered when interpreting the results of this study. First, the study had a relatively small sample size of 16 patients, which may limit the generalizability of the findings. Second, the retrospective nature of our study, which inherently relies on the availability and accuracy of medical records, introduces the possibility of missing or incomplete data. Third, the uncontrolled design makes it challenging to ascertain the specific efficacy and safety profile of upadacitinib in comparison to other therapies.
Despite these limitations, the results of this study suggest that upadacitinib may still be effective in patients with a prior tofacitinib failure. A notable proportion of patients achieved clinical remission and corticosteroid-free remission, highlighting the potential of upadacitinib as a therapeutic option for this challenging patient population. Our study raises the possibility that prior nonresponse or loss of response to a medication may not preclude the use of a different medication in the same class. Given the absence of head to head clinical trials, current guidelines do not consider pharmacokinetic and pharmacodynamic differences in the relative strength of immunosuppression between different agents in the same class.1,3,6 This study also highlights the need for better treatment strategies, particularly for patients with multiple prior therapy exposures. The high number of advanced therapy exposures in this cohort reflects the complexity of managing ulcerative colitis and the limited efficacy of our current treatment strategies. To overcome the therapeutic efficacy ceiling, more research is needed to explore the effectiveness and safety of combining JAK inhibitors with other biologics.8
In summary, while upadacitinib shows promising effectiveness and safety in UC patients who have previously failed to respond to or lost response to tofacitinib, larger multicenter prospective studies are needed to validate these findings.
Contributor Information
Jake Levine, Department of Internal Medicine, Michigan Medicine, Ann Arbor, MI, USA.
Jey McKibbin, Department of Pharmacy Services, Michigan Medicine, Ann Arbor, MI, USA.
Rebecca Ham, Department of Pharmacy Services, Michigan Medicine, Ann Arbor, MI, USA.
Shirley Cohen-Mekelburg, Department of Internal Medicine, Michigan Medicine, Ann Arbor, MI, USA; Division of Gastroenterology and Hepatology, Michigan Medicine, Ann Arbor, MI, USA; Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI, USA; VA Center for Clinical Management Research, VA Ann Arbor Health Care System, Ann Arbor, MI, USA.
Shrinivas Bishu, Department of Internal Medicine, Michigan Medicine, Ann Arbor, MI, USA; Division of Gastroenterology and Hepatology, Michigan Medicine, Ann Arbor, MI, USA.
Kevin Tang, Division of Gastroenterology and Hepatology, Michigan Medicine, Ann Arbor, MI, USA.
Peter D R Higgins, Department of Internal Medicine, Michigan Medicine, Ann Arbor, MI, USA; Division of Gastroenterology and Hepatology, Michigan Medicine, Ann Arbor, MI, USA.
Jeffrey A Berinstein, Department of Internal Medicine, Michigan Medicine, Ann Arbor, MI, USA; Division of Gastroenterology and Hepatology, Michigan Medicine, Ann Arbor, MI, USA; Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI, USA.
Funding Source
J.A.B. is supported by a NIDDK K23 DK134764.
Conflicts of Interest
P.D.R.H. received consulting fees from AbbVie, Amgen, Genentech, JBR Pharma and Lycera. J.A.B. received consulting fees from Buhlmann Diagnostics Corp, Bristol Myers Squibb, and Oshi Health. All other authors report no disclosures.
Data Availaibility
Data, analytic methods, and study materials will be made available upon request to the corresponding author.
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