Abstract
BACKGROUND:
A significant proportion of patients with acute severe ulcerative colitis (ASUC) require colectomy.
METHODS:
ASUC patients treated with upadacitinib and IV corticosteroids at five hospitals are presented. The primary outcome was 90-day colectomy rate. Secondary outcomes included frequency of steroid-free clinical remission, adverse events, and all-cause readmissions.
RESULTS:
Of the 25 ASUC patients treated with upadacitinib, 6 (24%) patients underwent colectomy, 15 (83%) patients experienced steroid-free clinical remission, one (4%) patient experiencd a venous thromboembolic event, one (4%) patient experienced COVID-19, while five (20%) patients were readmitted.
CONCLUSION:
Upadacitinib along with IV corticosteroids may be an effective treatment for ASUC.
Keywords: acute severe ulcerative colitis, ulcerative colitis, Janus Kinas Inhibitors, Upadacitinib
Introduction:
First-line treatment for ASUC, intravenous (IV) corticosteroids, is effective at preventing colectomy in 70% of patients.1 Rescue therapy with infliximab and cyclosporine have been shown to further reduce the rate of colectomy in corticosteroid-refractory patients.2,3 Unfortunately, despite the use of rescue infliximab and cyclosporine, 30% of corticosteroid-refractory patients will still require salvage colectomy.4,5
Janus kinase inhibitors (JAKi), oral small molecules that decrease pro-inflammatory cytokine production, are well suited for patients with ASUC due to rapid clinical onset, short-half-life, efficacy regardless of biologic exposure, and the fact that JAKi are not susceptible to colonic drug loss, nor to immunogenicity.6–8 Previous studies have suggested that tofacitinib, a pan-JAKi, is effective in the treatment of ASUC.9–11 Upadacitinib has a theoretical efficacy and safety benefit over tofacitinib due its JAK1-selectivity.
Methods:
We conducted a retrospective study in all patients ≥ 18 years of age who received upadacitinib in combination with IV corticosteroids for ASUC from April 2022 to February 2023 at Michigan Medicine (Ann Arbor, Michigan), Mount Sinai Hospital (New York, New York), University of Colorado Anschutz Medical Campus (Aurora, Colorado), Brooke Army Medical Center (Fort Sam Houston, Texas), and the University of Kentucky (Lexington, Kentucky). ASUC was defined by Truelove and Witts’ criteria.12 Upadacitinib was administered at 45mg daily or at a high-intensity, off-label dose of 30mg two times daily (BID). A dose of 30mg BID was chosen because the majority of upadacitinib is absorbed in the first 6 hours, and the serum levels after 6 hours are nearly the same as an immediate release formulation.13 All patients received IV methylprednisolone 60mg daily while in the hospital followed by oral prednisone (initial dose 40–60mg and tapered by 5–10mg/week).
The primary outcome was 90-day colectomy rate. Secondary outcomes included frequency of steroid-free clinical remission, adverse events, and all-cause readmissions during follow-up. Steroid-free clinical remission was defined as a full Mayo score ≤ 2 with no subscore > 1 without the use of corticosteroids within 14 days. Fisher’s exact test was used to compare 90-day colectomy rate between anti-TNF exposed/naïve and upadacitinib 45mg daily/30mg BID groups.
Results:
Twenty-five patients received upadacitinib in combination with IV corticosteroids for a mean of 3.5 ± 6.0 days. Table 1 provides additional details on patient characteristics and Table 2 provides additional details on hospital and post-discharge course according to prior anti-TNF exposure status. Overall, 18 (72%) patients received upadacitinib 30 mg BID and 7 (28%) patients received upadacitinib 45 mg daily. Six (24%) patients underwent colectomy within 90-days, with four (16%) patients undergoing colectomy during their index admission (mean 5.8 days from initiation of upadacitinib) and two (8%) patients undergoing colectomy following discharge (mean 54 days from initiation of upadacitinib). One of the two patients who had received tofacitinib prior to admission and none of the three patients who received sequential infliximab followed by upadacitinib during the same admission underwent a colectomy. There was no significant difference in the rate of colectomy between anti-TNF exposed and anti-TNF naïve patients (p > .99) or between patients receiving 30mg BID and 45mg daily (p = .64).
Table 1:
Patient Characteristics
| Characteristic | Overall (N = 25)1 | Anti-TNF Naïve (N = 9)1 | Anti-TNF Exposed (N = 16)1 |
|---|---|---|---|
|
| |||
| Treatment Site | |||
| Michigan Medicine | 10 / 25 (40%) | 2 / 9 (22%) | 8 / 16 (50%) |
| Brooke Army Medical Center | 6 / 25 (24%) | 5 / 9 (56%) | 1 / 16 (6.3%) |
| University of Colorado | 4 / 25 (16%) | 2 / 9 (22%) | 2 / 16 (13%) |
| University of Kentucky | 3 / 25 (12%) | 0 / 9 (0%) | 3 / 16 (19%) |
| Mount Sinai | 2 / 25 (8.0%) | 0 / 9 (0%) | 2 / 16 (13%) |
| Age, years | 40.3 (14.6) | 39.0 (12.9) | 41.0 (15.8) |
| Sex | |||
| Male | 13 / 25 (52%) | 5 / 9 (56%) | 8 / 16 (50%) |
| Female | 12 / 25 (48%) | 4 / 9 (44%) | 8 / 16 (50%) |
| Race | |||
| White | 21 / 24 (88%) | 5 / 8 (63%) | 16 / 16 (100%) |
| Black | 2 / 24 (8.3%) | 2 / 8 (25%) | 0 / 16 (0%) |
| Other | 1 / 24 (4.2%) | 1 / 8 (13%) | 0 / 16 (0%) |
| Missing | 1 | 1 | 0 |
| Duration IBD, years | 9.8 (24.5) | 0.6 (0.9) | 15.0 (29.7) |
| Distribution | |||
| Proctitis | 0 / 25 (0%) | 0 / 9 (0%) | 0 / 16 (0%) |
| Left-sided Colitis | 6 / 25 (24%) | 2 / 9 (22%) | 4 / 16 (25%) |
| Pancolitis | 19 / 25 (76%) | 7 / 9 (78%) | 12 / 16 (75%) |
| Duration Outpatient Prednisone, days | 13.0 (20.3) | 8.7 (26.0) | 15.4 (16.8) |
| Number of Prior Advanced Therapy Advanced Therapy Exposures | |||
| 0 Advanced Therapy | 6 / 25 (24%) | 6 / 9 (67%) | 0 / 16 (0%) |
| 1 Advanced Therapy | 10 / 25 (40%) | 3 / 9 (33%) | 7 / 16 (44%) |
| 2 Advanced Therapy | 2 / 25 (8.0%) | 0 / 9 (0%) | 2 / 16 (13%) |
| 3 Advanced Therapy | 6 / 25 (24%) | 0 / 9 (0%) | 6 / 16 (38%) |
| 4 Advanced Therapy | 1 / 25 (4.0%) | 0 / 9 (0%) | 1 / 16 (6.3%) |
| Prior Infliximab Exposure | 16 / 25 (64%) | 0 / 9 (0%) | 16 / 16 (100%) |
| Prior Adalimumab Exposure | 5 / 25 (20%) | 0 / 9 (0%) | 5 / 16 (31%) |
| Prior Golimumab Exposure | 1 / 25 (4.0%) | 0 / 9 (0%) | 1 / 16 (6.3%) |
| Prior Vedolizumab Exposure | 8 / 25 (32%) | 2 / 9 (22%) | 6 / 16 (38%) |
| Prior Ustekinumab Exposure | 4 / 25 (16%) | 0 / 9 (0%) | 4 / 16 (25%) |
| Prior Tofacitinib Exposure | 2 / 25 (8.0%) | 1 / 9 (11%) | 1 / 16 (6.3%) |
| Number of Bloody Bowel Movements | 10.0 (5.6) | 11.3 (4.6) | 9.3 (6.1) |
| Albumin (mg/dL) | 3.0 (0.6) | 2.8 (0.6) | 3.1 (0.5) |
| Baseline CRP (mg/L) | 63.7 (70.9) | 54.7 (76.2) | 68.8 (69.8) |
| Baseline Fecal Calprotectin (mg/kg) | 2,062.8 (1,290.8) | 1,683.6 (1,572.2) | 2,276.2 (1,101.2) |
| Endoscopic Mayo Score | |||
| 2 | 2 / 25 (8.0%) | 0 / 9 (0%) | 2 / 16 (13%) |
| 3 | 23 / 25 (92%) | 9 / 9 (100%) | 14 / 16 (88%) |
Mean (sd) or Proportion (%)
CRP: C-reactive protein; FCP: Fecal Calprotectin; kg: kilogram; L: liters; mg: milligram; mm: millimeters;
Table 2:
Hospital and Post-Discharge Outcomes
| Characteristic | Overall (N = 25)1 | Anti-TNF Naïve, (N = 9)1 | Anti-TNF Exposed (N = 16)1 |
|---|---|---|---|
|
| |||
| Inpatient Upadacitinib Dose | |||
| 30mg twice daily | 18 / 25 (72%) | 7 / 9 (78%) | 11 / 16 (69%) |
| 45mg once daily | 7 / 25 (28%) | 2 / 9 (22%) | 5 / 16 (31%) |
| Inpatient Upadacitinib Duration, days | 3.5 (6.0) | 4.7 (2.2) | 2.9 (7.3) |
| Time to Upadacitinib Initiation, days | 3.1 (2.1) | 2.6 (1.0) | 3.4 (2.5) |
| Length of Stay, days | 8.9 (4.5) | 8.3 (4.5) | 9.2 (4.6) |
| Reduction in CRP (mg/L) Throughout Hospitalization 2 | 46.4 (59.2) | 39.4 (59.8) | 50.3 (60.5) |
| CRP (mg/L) at discharge 3 | 10.2 (17.4) | 4.4 (1.7) | 13.1 (20.9) |
| Discharge Partial Mayo Score 3 | 3.4 (1.8) | 3.1 (1.8) | 3.5 (1.9) |
| Missing | 3 | 1 | 2 |
| Duration Follow-up, days | 191.4 (81.3) | 220.9 (74.1) | 174.9 (82.7) |
| Patients with Follow-up FCP < 250mg/kg 4 | 12 / 15 (80%) | 6 / 7 (86%) | 6 / 8 (75%) |
| Missing | 6 | 0 | 6 |
| Change in FCP (mg/kg) 4 | 1,595 (1,345) | 1,5001 (1,573) | 1,662 (1,184) |
| Missing | 6 | 0 | 6 |
| Time to FCP Follow-up, months | 4.3 (3.3) | 5.8 (3.4) | 2.9 (2.7) |
| Missing | 6 | 0 | 6 |
| Follow-up Endoscopic Mayo Score 4 | |||
| 0 | 8 / 9 (89%) | 6 / 6 (100%) | 2 / 3 (67%) |
| 2 | 1 / 9 (11%) | 0 / 6 (0%) | 1 / 3 (33%) |
| Missing | 12 | 1 | 11 |
| Time to Endoscopic Follow-up, months | 5.5 (3.1) | 4.0 (1.9) | 8.6 (3.0) |
| Missing | 12 | 1 | 11 |
| 90-Day Colectomy Rate | 6 / 25 (24%) | 2 / 9 (22%) | 4 / 16 (25%) |
| Index Admission | 4 / 25 (16%) | 2 / 9 (22%) | 2 / 16 (13%) |
| Post-Discharge | 2 / 25 (8.0%) | 0 / 9 (0%) | 2 / 16 (13%) |
| Steroid-free Remission 5 | 15 / 18 (83%) | 6 / 7 (86%) | 9 / 11 (82%) |
| Missing | 1 | 0 | 1 |
| Upadacitinib Dose Reduction to 30mg 5 | 16 / 19 (84%) | 7 / 7 (100%) | 9 / 12 (75%) |
| Venous Thromboembolic Event | 1 / 25 (4.0%) | 1 / 9 (11%) | 0 / 16 (0%) |
| Major Cardiovascular Events | 0 / 25 (0%) | 0 / 9 (0%) | 0 / 16 (0%) |
| Any Infection | 1 / 25 (4.0%) | 0 / 9 (0%) | 1 / 16 (6.3%) |
| Infection Requiring Antimicrobial Therapy | 0 / 25 (0%) | 0 / 9 (0%) | 0 / 16 (0%) |
| COVID-19 | 1 / 25 (4.0%) | 1 / 9 (11%) | 0 / 16 (0%) |
| Clostridium Difficile | 0 / 25 (0%) | 0 / 9 (0%) | 0 / 16 (0%) |
| Opportunistic Infection | 0 / 25 (0%) | 0 / 9 (0%) | 0 / 16 (0%) |
| Herpes Zoster Infection | 0 / 25 (0%) | 0 / 9 (0%) | 0 / 16 (0%) |
| Post-Surgical Infection 6 | 0 / 6 (0%) | 0 / 2 (0%) | 0 / 4 (0%) |
| Unplanned Readmission | |||
| None | 20/25 (80%) | 8/9 (89%) | 12/16 (75%) |
| Ulcerative Colitis Flare | 3 / 25 (12%) | 0 / 9 (0%) | 3 / 16 (19%) |
| Post-Operative SBO/Ileus | 2 / 25 (8.0%) | 1 / 9 (11%) | 1 / 16 (6.3%) |
CRP: C-reactive protein; FCP: Fecal Calprotectin; kg: kilogram; L: liters; mg: milligram; mm: millimeters; SBO: small bowel obstruction;
Mean (sd) or Proportion (%);
Reduction in CRP throughout hospitalization was calculated for all patients regardless of colectomy status using the difference between baseline CRP and last CRP prior to discharge or colectomy.
CRP at discharge and discharge partial Mayo score were only included for patients who were discharged without undergoing colectomy during index hospitalization (n=21);
Follow-up FCP, change in FCP, and follow-up endoscopic score were only included for patients who did not undergo colectomy during index hospitalization (n=21). Follow-up FCP, change in FCP, and follow-up endoscopic score would have been included if patients underwent colectomy after discharge and completed an FCP or endoscopy prior to colectomy;
Steroid-free clinical remission and successful upadacitinib dose decrease were only calculated in patients who did not undergo colectomy within 90 days of follow-up (n=19);
Post-surgical infection was only evaluated in patients that underwent colectomy (n=6);
Of the patients who did not undergo colectomy, 15 (83%) patients experienced steroid-free clinical remission, and 16 (84%) patients were able to successfully dose reduce upadacitinib to 30mg daily. Among the nine (42.8%) patients who did not undergo colectomy and completed follow-up endoscopy or fecal calprotectin (FCP), 100% experienced endoscopic improvement and 13/16 (81%) had an FCP < 250mg/kg. Adverse events were uncommon with one (4.0%) patient experiencing a post-operative intra-abdominal venous thromboembolic, and one (4.0%) patient experiencing asymptomatic COVID-19. Both patients received upadacitinib 30mg BID. No postsurgical infections were noted in patients undergoing colectomy. No adverse events were observed in the two patients receiving sequential infliximab followed by upadacitinib. Five (20%) patients experienced a readmission with three (12%) patients readmitted due to a UC exacerbation (2 of which required subsequent colectomy) and two (8.0%) patients readmitted for a post-operative ileus or small bowel obstruction. Post-discharge Pneumocystis jirovecii pneumonia or DVT prophylaxis were not routinely used.
Discussion:
Our multi-center experience suggests that upadacitinib in combination with IV corticosteroids may represent a promising therapeutic option for severely inflamed patients with ASUC. Our study found that 76% of patients were able to avoid colectomy with a low incidence of adverse events (8.0%) and readmission (20%). It is important to note that patient who were able to avoid colectomy during their index hospitalization did remarkably well with two (8.0%) additional colectomies within 90-days and 83% of patients achieving steroid-free clinical remission. This suggests that patients were not merely deferring eventual colectomy. However, it should be noted that among the patients who avoided colectomy, 11% still had endoscopic activity and 19% still had a FCP > 250mg/kg, demonstrating that some ASUC patients failed to achieve a complete response to upadacitinib.
It is important to note that the 90-day colectomy rate for upadacitinib (24%) is similar to the estimates reported in CYSIF and CONSTRUCT which compared infliximab (21–29%) to cyclosporine (19–30%) rescue in corticosteroid-refractory AUSC patients; however, the majority of patients included in these trials were biologic naïve and a lower inflammatory burden.14,15
This study has important clinical implications for the growing proportion of patients who have previously failed anti-TNF therapy and are admitted with ASUC. However, it is worth noting that many anti-TNF-naïve patients with ASUC benefited from upadacitinib as well. In our study, several anti-TNF-naïve patients with high CRP and low albumin elected to pursue JAKi therapy first. In addition, at the Brooke Army Medical Center, military personal cannot deploy for active duty with infusion/injectable medications, therefore many patients chose JAKi therapy in order to continue their military service.
Our study is one of the first to report outcomes of patients with ASUC treated with upadacitinib in a real-world setting. Additionally, the study collected data from multiple centers, which increases generalizability. The major limitation to our study is the retrospective and uncontrolled design, which makes it difficult to draw any definitive conclusions about the efficacy of upadacitinib compared to other available therapies.
In conclusion, our multi-center experience suggests that upadacitinib in combination with IV corticosteroids may be an effective and safe treatment strategy for high-risk patients with ASUC. Prospective, randomized controlled trials are necessary to validate these findings.
Grant Support:
JB received a K23 career development award from NIDDK (DK134764)
Abbreviations:
- ASUC
acute severe ulcerative colitis
- BID
twice daily
- CDI
Clostridium difficile infection
- CMV
cytomegalovirus
- CRP
C-reactive peptide
- CT
computer tomography
- CYP
cytochrome P450
- EIA
enzyme immunoassay
- ESR
erythrocyte sedimentation rate
- FDA
federal drug agency
- Hgb
hemoglobin
- IL
interleukin
- IV
intravenous
- JAK
Janus kinase
- TID
three times daily
- TNF
tumor necrosis factor
Footnotes
Disclosures:
JAB received consulting fees from Bristol Myers Squibb, Buhlmann Diagnostics, and Oshi Health. BHC received consulting fees from AbbVie, Bristol Myers Squibb, Janssen, Prometheus, Takeda PDRH received consulting fees from AbbVie, Amgen, Buhlmann Laboratories, Celltrion, Curacle, Genentech, and Eli Lilly. All other authors report no disclosures.
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