Abstract
Upadacitinib is an oral new selective JAK1 inhibitor that has been approved for treating adult patients with moderately to severely active ulcerative colitis. However, a growing number of studies are needed on the effectiveness of upadacitinib in the treatment of acute severe ulcerative colitis. This study was mainly aimed to describe the clinical and endoscopic effectiveness of upadacitinib 45 mg in Chinese acute severe ulcerative colitis patients following eight weeks of treatment. In this study, we examined all patients with acute severe ulcerative colitis from Xijing IBD Center, Xi’an, China, with acute severe ulcerative colitis. All patients were initially given oral upadacitinib 45 mg. Clinical indicators, C-reactive protein, and erythrocyte sedimentation rates were collected. Clinical response and clinical remission were assessed using modified Mayo. Endoscopic evaluation was performed carried out using the Mayo Endoscopic Score and Ulcerative colitis endoscopic index of severity score. A total of 14 patients who received upadacitinib were included in the study period. All patients exhibited a clinical response to 45 mg upadacitinib initially. All patients completed the 8-week induction. The clinical remission rate was 28.6% after eight weeks. Two patients revealed endoscopic remission at 14.3%. The pathology improved in 50.0% of patients. The 8-week surgical resection rate was 7.1%, with the 16-week surgical resection rate being 14.3%. Adverse events included herpes simplex virus infection and increased thrombin time. The results of our study support the short-term effectiveness and safety of upadacitinib in acute severe ulcerative colitis, providing new choices for patients’ treatment. However, more extended investigation needs to be performed on the long-term effectiveness and safety.
Keywords: Acute severe ulcerative colitis, Upadacitinib, Inflammatory bowel disease, Endoscopy
Introduction
Ulcerative colitis (UC) is a common inflammatory disease caused by results from a dysregulated immune response induced by a complex interaction between host genetics, the intestinal microbiome, and environmental factors. Although it mainly involves the colon and rectum, its pathophysiologic mechanism is incompletely characterized [1]. The disease has a varying extent and severity, where approximately 20% of patients with UC develop acute severe ulcerative colitis (ASUC) during the course of their disease, a potentially life-threatening condition that requiring early aggressive intervention and hospitalization [2]. According to the Truelove and Witts criteria, ASUC is defined as hospitalized UC patients with ≥ 6 bloody bowel movements/day with at least one of the following: heart rate > 90 beats/min, temperature > 37.8 °C, hemoglobin < 105 g/L, or Erythrocyte Sedimentation Rate (ESR) > 30 mm/h [3].
Treatment options for ASUC are restricted including intravenous corticosteroids, infliximab or cyclosporine when corticosteroid treatment failed [4]. However, the response rates to these treatments vary, and colectomy rates still remain high (approximately 30%) despite advances in therapy [5]. The lack of adequate, rapid therapies may cause relapses, reduced quality of life (QoL), and a significant disease burden for patients [6, 7]. With the advent of small-molecule drugs, significant advances have been found in the overall treatment of ASUC [8–11]. Janus kinase inhibitors (JAKinibs) belong to a class of targeted small molecules that blocking signaling activation to mediate downstream inflammation in the gut, joints, and skin [12]. Upadacitinib is an oral new selective JAK1 inhibitor that has been approved by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and Chinese Food and Drug Administration (CFDA) for treating adult patients with moderately to severely active UC [13, 14].
The effectiveness and safety of upadacitinib for the ASUC still remain unclear. An Australian study of six patients receiving upadacitinib for ASUC were followed for 16 weeks after discharge. Based on clinical, biochemical, and intestinal ultrasound (IUS) results, upadacitinib may exert a safe and effective salvage therapeutic effect in these ASUC patients [15]. However, the effectiveness and safety of upadacitinib in Chinese IBD patients is unknown. Therefore, this study mainly aimed to describe the clinical and endoscopic effectiveness of upadacitinib 45 mg in Chinese ASUC patients following 8 weeks of treatment.
Materials and methods
Study design and patient population
This study was a monocentric study. Patients with inflammatory bowel disease (IBD) were identified using the inpatient records of Xijing Digestive Diseases Hospital in China.
The inclusion criteria included: (i) age ≥ 18 years; (ii) hospitalized patients; (iii) diagnosed with IBD before 2019 according to the Chinese consensus on diagnosis and treatment of inflammatory bowel disease [16]; (iv) patients met with ASUC criteria according to Truelove and Witts as well as Chinese IBD consensus; (v) patients who were consent to the study. Exclusion criteria were: (i) patients with CD; (ii) patients who failed to satisfy ASUC criteria; (iii) ASUC patients responded well to glucocorticoid treatment; (iv) ASUC patients responded well to infliximab treatment; (v) other patients who were limited to treat with upadacitinib; (vi) patients who were not willing to be engaged in this study.
Outcome assessment
Baseline demographic data including sex, age, duration of disease, prior therapies, extraintestinal manifestations and comorbidity were collected for all the patients. In addition, patients were followed for up to 8–64 weeks, starting with oral upadacitinib.
The study’s primary endpoint is the eight-week clinical response evaluated by the modified Mayo (mMayo) score recommended by the US FDA guidance issued in 2016 [17]. Clinical response was evaluated considering decrease of 3 or greater and 30% or more significant from the baseline in the total Mayo score [18]. Clinical remission was defined as a total Mayo score ≤ 2, with no individual sub-score > 1 [18]. Secondary endpoints include improvements in clinical indicators like BMI and stool count and CRP and ESR. Endoscopic evaluation was performed through the Mayo Endoscopic Score and ulcerative colitis endoscopic index of severity (UCEIS) score [19]. The Nancy Index consists of three histologic items that define five levels of disease activity [20].
Analysis and ethics
We assessed clinical, endoscopic, and histological improvements following 8 weeks of follow-up using a paired sample Wilcoxon signed rank test. Continuous variables are indicated as the median (interquartile range). For both co-primary and secondary outcomes, P < 0.05 was considered to be of statistical significance. All results should be considered as exploratory. Data were explored using IBM SPSS Statistics version 27. This study was conducted following the guidelines of the Declaration of Helsinki and proved by the Medical Ethics Committee of the First Affiliated Hospital of the Air Force Medical University (reference number: KY20232125-C-I). Informed consent was obtained from all patients.
Results
Totally 14 patients with ASUC were included in the study. Altogether 11 patients exhibited non-response to previous corticosteroids. Corticosteroid non-response was determined using the day 3 Oxford criteria with over four bowel motions daily or a C-reactive protein [CRP] of > 15 mg/L [21]. However, three patients refused corticosteroids due to the consideration of hormonal side effects and were treated directly with infliximab, a second-line treatment for ASUC. All patients were intravenously given infliximab. Two patients developed C. difficile infection, and another two presented with Cytomegalovirus infection. One patient was T-SPOT positive but with no sign of tuberculosis and regular chest CT. C. difficile infection was subject to treatment with vancomycin, and Cytomegalovirus was subject to treatment with Ganciclovir. The patient with T-SPOT positive was prophylactic given isoniazid. All 14 patients exhibited loss of response to previous corticosteroids or biologic treatment, and they refused colectomy. Based on the effectiveness, and rapid onset of action of upadacitinib in UC patients, these patients showed consent to 45mg upadacitinib as a salvage therapy. After the induction time of 8 weeks for 45mg upadacitinib, colonoscopy was carried out.
Patients were followed for 8–32 weeks, with all patients completing 8 weeks of endoscopic follow-up (Fig. 1). The median age of the patients was 41.5 years (range min–max: 18–68), with seven patients being female (50.0%). One patient had ankylosing spondylitis, one patient had a hematoma of the lower extremity, and one patient had arthralgia. All patients were performed endoscopic examination at baseline, where 12/14(85.7%) was E3 and 2/14(14.3%) was E2 (Table 1). On admission, all patients met with Truelove and Witts criteria for ASUC (Table 2), with a median Bloody bowel of 7 movements/day (range min–max: 6–10 movements/day), and median ESR of 40 mm/h (range min–max: 10–111 mm/h). Baseline median CRP was 32.1 mg/L, median platelet was 363.5 × 10E9/L, and median albumin was 37.1 (g/L).
Fig. 1.
Patient inclusion flowchart
Table 1.
Basic characteristics of the patients during admission
| Case | Age | Sex | Duration of disease (years) | Extent of disease | Prior therapies | Extraintestinal manifestations/Comorbidity |
|---|---|---|---|---|---|---|
| 1 | 45 | F | 4 | E3 | 5-aminosalicylic acid, infliximab, vedolizumab | – |
| 2 | 56 | F | 2 | E3 | 5-aminosalicylic acid, glucocorticoid, infliximab | – |
| 3 | 47 | F | 14 | E3 | 5-aminosalicylic acid, glucocorticoid, azathioprine, infliximab, adalimumab, vedolizumab | – |
| 4 | 38 | F | 5 | E2 | 5-aminosalicylic acid, infliximab | – |
| 5 | 41 | M | 1 | E3 | Glucocorticoid, infliximab | Ankylosing spondylitis |
| 6 | 38 | F | 1 | E3 | 5-aminosalicylic acid, glucocorticoid, infliximab | – |
| 7 | 51 | M | 1 | E3 | 5-aminosalicylic acid, glucocorticoid, infliximab | – |
| 8 | 68 | M | 3 | E3 | 5-aminosalicylic acid, glucocorticoid, infliximab, vedolizumab | – |
| 9 | 27 | M | 3 | E2 | 5-aminosalicylic acid, glucocorticoid, infliximab, tofacitinib | Arthralgia |
| 10 | 33 | F | 7 | E3 | 5-aminosalicylic acid, glucocorticoid, Methotrexate, infliximab, adalimumab | – |
| 11 | 34 | M | 8 | E3 | 5-aminosalicylic acid, glucocorticoid, infliximab | Hematoma of the lower extremity |
| 12 | 46 | M | 1 | E3 | 5-aminosalicylic acid, glucocorticoid, infliximab | – |
| 13 | 18 | M | 1 | E3 | 5-aminosalicylic acid, infliximab | – |
| 14 | 42 | F | 5 | E3 | 5-aminosalicylic acid, glucocorticoid, infliximab | – |
Table 2.
Clinical examination during the admission
| Case | Bloody bowel (movements/day) | Heart rate (beats/min) | Temperature (°C) | Hemoglobin (g/L) | ESR (mm/h) | CRP (mg/L) | Platelet (X10E9/L) | Albumin (g/L) |
|---|---|---|---|---|---|---|---|---|
| 1 | 6 | 93 | 36.4 | 124 | 41 | 5.47 | 360 | 42.6 |
| 2 | 10 | 104 | 36.5 | 138 | 30 | 45 | 367 | 39.6 |
| 3 | 7 | 84 | 36.1 | 96 | 78 | 6.18 | 667 | 40.1 |
| 4 | 10 | 97 | 36.5 | 112 | 34 | 26.9 | 476 | 38.6 |
| 5 | 10 | 90 | 38.6 | 141 | 71 | 86.4 | 295 | 44.2 |
| 6 | 6 | 98 | 36.2 | 116 | 27 | 143 | 359 | 31.0 |
| 7 | 6 | 96 | 36.5 | 124 | 13 | 4.41 | 291 | 35.6 |
| 8 | 6 | 100 | 36.5 | 139 | 10 | 15.5 | 280 | 40.2 |
| 9 | 8 | 98 | 36.5 | 89 | 111 | 119 | 397 | 30.7 |
| 10 | 8 | 78 | 36.6 | 101 | 56 | 35.2 | 538 | 27.5 |
| 11 | 7 | 92 | 36.5 | 77 | 66 | 58.7 | 731 | 30.2 |
| 12 | 10 | 78 | 36.5 | 81 | 11 | 44.8 | 338 | 24.7 |
| 13 | 7 | 98 | 36.5 | 74 | 39 | 28.9 | 482 | 29.7 |
| 14 | 6 | 72 | 36.3 | 101 | 72 | 14.4 | 330 | 45.8 |
All 14 patients had used 5-aminosalicylic acid, three used vedolizumab, two used adalimumab, and one used tofacitinib (Table 1). All 14 patients finished eight weeks 45mg upadacitinib induction and endoscopy examination. Through 8 weeks and 16 weeks, respectively, one patient proceeded to uncomplicated colectomy owing to poor clinical response, while 12 remained colectomy-free. The 8-week surgical resection rate was 7.1%, with 16-week surgical resection rate being 14.3%. After eight weeks of follow-up, clinical scores (p < 0.001), number of stools (p < 0.001) and ESR level (p = 0.004) were significantly improved (Table 3). Four patients (28.6%) achieved clinical remission. The mean mMayo score decreased from 10.4 to 4.4 (Fig. 2A). Obviously ten patients had an increased BMI, and three patients had a constant BMI (Fig. 3A). The stool frequency decreased in all patients (Fig. 3C). ESR levels decreased in 78.6% (11/14) of patients and increased in 21.4% (3/14). Following eight weeks, the mean ESR levels decreased from 47.1 to 20.3 (Fig. 3D).
Table 3.
Paired sample Wilcoxon signed rank test for the mean changes between baseline and 8 weeks in completers
| Baseline | After 8 weeks | Z value | P value | |
|---|---|---|---|---|
| Modified mayo score | 11 (9, 11.25) | 4.5 (2, 5) | − 3.194 | 0.001 |
| Mayo endoscopic score | 3 (3, 3) | 1.5 (1, 2) | − 3.109 | 0.002 |
| UCEIS score | 7 (7, 8) | 3.5 (1, 5.25) | − 3.077 | 0.002 |
| Nancy index | 4 (3, 4) | 3 (2, 4) | − 2.46 | 0.014 |
| Hemoglobin | 106.5 (87, 127.5) | 112.5 (84, 130.5) | − 0.22 | 0.826 |
| C-reactive protein | 32.05 (12.35, 65.63) | 4.755 (0.80, 10.71) | − 3.045 | 0.002 |
| BMI | 19.55 (17.35, 22.90) | 20.05 (17.86, 23.28) | − 2.046 | 0.041 |
| Number of stools | 7 (6, 10) | 2 (1.75, 3) | − 3.307 | < 0.001 |
| ESR | 40 (23.50, 71.25) | 12.5 (6.75, 23.50) | − 2.543 | 0.011 |
Fig. 2.
Modified mayo score, UCEIS score, Mayo endoscopic score and Nancy Index at baseline and after 8 weeks of upadacitinib 45 mg daily. UCEIS score: Ulcerative colitis endoscopic index of severity
Fig. 3.
BMI and CRP and after 8 weeks of upadacitinib 45 mg daily. The number of stools and ESR after 8 weeks of upadacitinib 45 mg daily, and change in bowel movement and ESR after 8 weeks compared to baseline. BMI body mass index, CRP C-reactive protein, ESR erythrocyte sedimentation rate
After eight weeks of follow-up, endoscopic (p < 0.001) and histologic scores (p = 0.007) were obviously improved (Table 3). Two patients exhibited endoscopic remission after 8 weeks of follow-up (14.3%) (Fig. 2B). The mean Mayo endoscopic score reduced from 3 to 1.5 (Fig. 2C), and the mean UCEIS score decreased from 7.4 to 3.5 after 8 weeks (Fig. 2B). The pathology improved in seven out of 14 patients 50.0%) with a mean Nancy Index decreased from 3.6 to 3 following 8 weeks (Fig. 2D).
One patient (7.14%) was tested with herpes simplex virus positive from serum but no sign of skin lesion, who was also provided with ganciclovir for antiviral therapy. In addition, we also observed slightly increased thrombin time in five patients (35.71%) during the 8-week follow-up, while no venous thromboembolism was observed after thorough blood vessel ultrasound screening (Table 4). All patients were informed of the possible side effect of hypercoagulable state and venous thromboembolism. For the patients who had high risk of thromboembolism, anticoagulants treatment like low molecular weight heparin or rivaroxaban was indicated. Additionally, the rest would go for regular monitoring. None of the other patients had major adverse events such as serious uncontrollable infection, major adverse cardiovascular events, venous thromboembolism, or malignancy. For the patient with ASUC and arthralgia, the symptoms of arthralgia also disappeared following 3 days of oral 45 mg upadacitinib.
Table 4.
Adverse events after 8-week follow-up
| Adverse events | Case | Severity | Countermeasures |
|---|---|---|---|
| Herpes simplex virus positive | 1 | No sign of skin lesion | Given ganciclovir for antiviral therapy |
| Increased thrombin time | 5 | No venous thromboembolism | Regular monitoring |
Discussion
This study describes the potential role of upadacitinib as a salvage therapy for patients with ASUC. During the follow-up of 8 weeks, 28.6% revealed clinical remission. The 8-week surgical resection rate was 7.1%, and 16-week surgical resection rate was 14.3%. Endoscopic remission was 14.3% after 8-week induction. Extraintestinal manifestations including ankylosing spondylitis were also improved in one patient, and joint pain completely disappeared in another patient. Adverse events included herpes simplex virus infection and elevated thrombin time, but was subject to treatment with anti-virus or anticoagulants medicine, without any clinical manifestation. Moreover, no severe infection nor venous thromboembolism occurred.
Our study was the first report of effectiveness and safety of upadacitinib for Asian ASUC patients. On aspects of the clinical score, U-ACHIEVE study showed that at week 8, 26% of patients who received 45 mg upadacitinib achieved clinical remission. In the U-ACCOMPLISH induction study, clinical remission was achieved in 33% of patients. Our study demonstrated that clinical remission rate was 28.6%. On perspectives of the endoscopic score, U-ACHIEVE study [22] showed that 14% achieved endoscopic remission. Similarly, in the U-ACCOMPLISH induction study [23], endoscopic remission was realized in 18%. Our study indicated that 14.3% receiving achieved endoscopic remission. On aspects of the pathology score, the rates of pathological improvement in the two studies were 37% and 30%, respectively. Our study suggested that 50.0% of patients achieving pathology improvement. Comparatively, our study had a slightly higher pathology improved rate. It is possible that bias occurred due to the small volume of patients in this study. In addition, it could also be due to the fact that these patients were treated with glucocorticoids and infliximab before upadacitinib induction.
Upadacitinib is approved by the FDA for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and nonradioactive axial spondylitis in adults [23]. The efficacy and safety of upadacitinib in patients with ankylosing spondylitis has also been revealed [24]. Common adverse reactions to upadacitinib include headache, nausea, nasopharyngitis, elevated creatine phosphokinase, elevated low-density lipoprotein levels, acne, thrombosis, herpes zoster, opportunistic infections (cytomegalovirus colitis and cytomegalovirus infection), thrombosis, and neutropenia/lymphopenia [23, 25, 26]. In this study, one patient was tested with herpes simplex virus positive from serum but no sign of skin lesion, who was also provided with ganciclovir for antiviral therapy. All we also observed slightly increased thrombin time in five patients during the 8-week follow-up, but no venous thromboembolism was observed after thorough blood vessel ultrasound screening. Therefore, care needs to be taken when using upadacitinib to inform patients of the possible side effects of hypercoagulability, venous thromboembolism, and herpes simplex virus infection, which requiring regular screening.
The strengths of this study including are presented as following: (1) Firstly, our study is the first study in Asia on the effectiveness and safety of upadacitinib in ASUC, which provides a novel treatment idea for ASUC patients. (2) Secondly, all patients completed the 8-week induction and all completed endoscopy, which provided the endoscopic evaluation of upadacitinib in ASUC. (3) Thirdly, most patients (10/12) were exempted from surgical treatment, improving their quality of life. However, this study still had the following limitations. (1) Firstly, the number of cases in this study is limited because of the off-label use of upadacitinib for ASUC at this time. (2) Secondly, not all patients were given intravenous corticosteroids because of the side effects and rejected by two patients. Nevertheless, all of them were given Infliximab showing no response. (3) Thirdly, the follow-up time is only 8–32 weeks now, which needs longer follow-up. Currently, all the patients are still in the following now.
In conclusion, the results of our study showed the effectiveness and safety of upadacitinib in the treatment of ASUC patients. The long-term effectiveness and safety need to be further evaluated in further studies.
Author contributions
Jie Liang involved in project administration (lead); formal analysis (supporting); conceptualization (lead); supervision (equal); and writing—review and editing (lead). Jiaqi Zhang involved in data curation (lead); investigation (equal); writing—original draft (lead); and formal analysis (lead). Ruixia Li involved in data curation (equal); investigation (equal); writing—original draft (equal); and formal analysis (equal). Ling Chen involved in investigation (supporting) and methodology (supporting). Fang Wang involved in writing—review and editing (supporting). He Zhou involved in investigation (supporting). Xiaoning Liu involved in formal analysis (supporting). Zhenzhen Fan involved in methodology (supporting). Yanting Shi involved in writing—review and editing (supporting). Tong Wu involved in supervision (equal) and writing—review and editing (supporting). Kaichun Wu involved in conceptualization (supporting) and writing—review and editing (supporting).
Funding
This work was supported by the following Independent Funds: Natural Science Foundation of Shaanxi Province, Key Industrial Innovation Project Fund (2023-ZDLSF-44); Airforce Foundation and Young Changjiang Scholars of the Ministry of Education (JL); National Natural Science Foundation of China General Program (No. 82370588); Medical Personnel Training and Promotion Program of Xijing Hospital (XJZT24QN41); National Natural Science Foundation of China Major Research Program Integration Project (No. 92259302) and Independent Funds of the Key Laboratory (CBSKL2022ZZ34).
Data availability
No datasets were generated or analyzed during the current study.
Declarations
Conflict of interest
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Jiaqi Zhang and Ruixia Li.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
No datasets were generated or analyzed during the current study.