Observation of the efficacy of upadacitinib as salvage therapy for refractory pediatric inflammatory bowel disease

The treatment goals for inflammatory bowel disease (IBD) include inducing and maintaining remission, preventing relapse, and halting disease progression.1-3 The use of biologic therapies has yielded improved outcomes, but some patients may not respond or could experience side effects. For nonresponders to biologic monotherapy, dual biologic treatment with or without Janus kinase (JAK) inhibitors could be an option.4 Several JAK inhibitors are used in IBD treatment,5 including upadacitinib (UPA), an oral JAK1 inhibitor. UPA is approved for adults with ulcerative colitis (UC) and Crohn's disease (CD), but is prescribed off-label for pediatric patients because of the lack of specific trials and regulatory approval. To date, only one single-center retrospective study has evaluated its safety and efficacy in adolescents with refractory IBD.6 In this study, we retrospectively analyzed clinical data from pediatric patients treated with UPA at a single center to assess its efficacy and safety, offering insights into its use for pediatric IBD. This retrospective cohort study collected data from pediatric IBD patients treated with UPA at Beijing Children's Hospital, from September 2023 to October 2024. Inclusion criteria were: (1) age of 0–18 years; (2) diagnosis with pediatric CD or UC per the 2019 Expert Consensus7; (3) UPA treatment for ≥6 months; and (4) active disease observed on colonoscopy before treatment. Exclusion criteria included >30% missing data or concurrent steroid use. Clinical records of pediatric patients, including demographic data, disease duration, Paris classification, disease activity, laboratory tests, endoscopic scores, prior medication history, concurrent medications with UPA, and adverse events (AEs), were retrieved from the hospital's medical system. For CD patients, clinical activity was measured using the Pediatric Crohn's Disease Activity Index (PCDAI). Clinical remission was defined as a PCDAI < 10, and clinical response was defined as a ≥15-point decrease from baseline. Endoscopic activity was evaluated using the simple endoscopic score for Crohn's disease (SES-CD), with endoscopic remission defined as an SES-CD ≤ 2 and endoscopic response defined as a ≥50% reduction in SES-CD. For UC patients, clinical activity was assessed using the Pediatric Ulcerative Colitis Activity Index (PUCAI). Clinical remission was defined as a PUCAI < 10, and clinical response was defined as a ≥20-point decrease or reduction in severity. Endoscopic remission was defined as a Mayo score of 0 or 1, with endoscopic response defined as a ≥1-point reduction in the Mayo score. AEs during UPA treatment, including the type of AE, daily dosage at onset, and time from treatment initiation to AE occurrence, were recorded. The focus was on infections, hypersensitivity reactions, gastrointestinal perforation, thromboembolic events, cardiovascular issues, lipid abnormalities, leukopenia, anemia, liver dysfunction, and malignancies. The primary endpoints were the clinical response and remission rates at 12 weeks and 6 months and the endoscopic response and remission rates at 12 weeks. The secondary endpoints included changes in serological and nutritional markers and the occurrence of AEs by 12 weeks and 6 months. Data with a normal distribution are presented as the means ± SDs, and between-group comparisons were made using t-tests. Nonnormally distributed data are expressed as medians, along with ranges, and comparisons were performed using the Mann‒Whitney U test. A p-value < 0.05 indicated statistical significance. Count data are presented as frequencies (n) and percentages (%). This study included eight pediatric IBD patients (six with UC and two with CD), comprising four males and four females. The median age at diagnosis was 8.0 years (range: 3.0–12.2), and the median age at initiation of UPA treatment was 10.7 years (range: 3.7–15). The median duration from disease onset to UPA treatment was 2.55 years (range: 0.7–4.8). Disease activity and location are detailed in Table 1. Five patients received a daily dose of 45 mg, while the remaining three started with 30 mg. UPA was administered as monotherapy in two patients and in combination with ustekinumab in six patients. All patients had previously been treated with at least two biologics without achieving sustained remission (Table S1). Among the six UC patients, the baseline PUCAI score was 67.5 (range: 55–75). After 1 week of treatment, the PUCAI decreased to 19.2 (range: 0–35), with steroid-free clinical remission and response rates of 33.3% (2/6) and 100% (6/6), respectively. After 8 weeks, the PUCAI further decreased to 14.1 (range: 0–40), with steroid-free clinical remission and response rates of 66.7% (4/6) and 100% (6/6). By 6 months, the PUCAI had decreased to 8.3 (range: 0–15), and steroid-free clinical remission and response rates of were 83.3% (5/6) and 100% (6/6), respectively. For the two CD patients, the baseline PCDAI was 36.3 (range: 27.5–45). After 1 week of treatment, the PCDAI decreased to 5 (range: 0–10), with clinical remission and response observed in one patient each. After 12 weeks, the PCDAI further improved to 2.5 (range: 0–5), indicating clinical remission in both patients. At 4 months, one patient relapsed after a reduction in the UPA dosage and was subsequently treated with a combination of ustekinumab. By 6 months, both patients remained in clinical remission with a PCDAI of 2.5 (range: 0–5). Among the six UC patients, the baseline Mayo endoscopic score was 2.67 (range: 2–3). By Week 12, it had decreased to 1.67 (range: 1–2), with endoscopic remission and response rates of 33.3% (2/6) and 66.7% (4/6), respectively. For the two CD patients, the baseline SES-CD was 18 (range: 15.0–21.0). By Week 12, it had decreased to 6, indicating an endoscopic response in both patients. After 12 weeks of treatment, all patients presented significantly lower white blood cell counts ([7.4 ± 2.66] × 109/L vs. [12.3 ± 4.58] × 109/L) and fecal calprotectin levels (769.6 [26.9, 1800] μg/g vs. 1800 μg/g) (p < 0.05). Although C-reactive protein (CRP) (3.6 ± 10.25 mg/L vs. 36.3 ± 43.45 mg/L) and the erythrocyte sedimentation rate (ESR) (14.9 ± 18.11 mm/h vs. 23.4 ± 11.26 mm/h) tended to decrease, the differences were not statistically significant. With respect to nutritional status, after 6 months of treatment, serum albumin levels (47.9 ± 9.35 g/L vs. 33.5 ± 8.91 g/L) and body mass index (BMI) (20.87 ± 6.14 kg/m2 vs. 14.9 ± 3.23 kg/m2) improved significantly (p < 0.05). The hemoglobin level also tended to increase from baseline (115.6 ± 14.27 g/L vs. 98.9 ± 23.13 g/L), but the difference was not statistically significant. No serious AEs were observed in the eight patients treated with UPA. One patient developed varicella-zoster virus infection at Week 8, discontinued UPA for antiviral therapy, recovered, and resumed UPA without recurrence, maintaining clinical remission. Another patient experienced thrombocytopenia after 2 weeks, which was resolved by reducing the UPA dose from 45 to 30 mg. Lipid monitoring revealed no elevation in cholesterol or triglycerides. Here, we report our experience using UPA in the treatment of pediatric IBD patients at a single center. Our results suggest that UPA may be effective for children with refractory IBD, providing valuable real-world insights into its use in this population. In this study, the clinical response and remission rates in pediatric UC and CD patients treated with UPA were higher than those reported in phase III adult clinical trials.8, 9 This may be due to differences in the definition of clinical remission, with adult trials using stricter criteria. Additionally, seven of the eight patients in our study were also treated with the IL-12/23 monoclonal antibody ustekinumab. Recent studies have shown that dual therapy contributes to increased rates of mucosal healing. Combining biologics or novel small-molecule drugs may be an effective option for refractory IBD patients.10-12 Our study suggests that combined treatment with UPA and IL-12/23 monoclonal antibody, results in good clinical remission and response rates in pediatric IBD patients, which is consistent with the findings of Spencer et al.6 Most UPA clinical trials involve patients without prior use of biologic therapy,8, 9 whereas our study focused on children with extensive prior biologic exposure and unsatisfactory outcomes. Thus, our study further confirms the efficacy of UPA in refractory IBD patients. Additionally, we observed a rapid onset of action, with high clinical remission and response rates within 1 week, offering benefits for managing severe disease activity and quickly assessing drug effectiveness to avoid unnecessary exposure in nonresponders. In this study, three patients under 12 years of age and weighing less than 20 kg achieved induced remission with 30 mg/day UPA. There was no significant difference in the clinical or endoscopic remission rates between those who received 45 mg for induced remission and those who did not. Our single-center study revealed that UPA had a favorable safety profile, with only one case of varicella-zoster infection observed in a patient who was not fully vaccinated for varicella. This study has several limitations. As a retrospective, observational study with a small sample size, it may be subject to statistical bias. Furthermore, with only 6 months of follow-up, the long-term effectiveness remains uncertain. This study was approved by the Ethics Committee of Beijing Children's Hospital ([2024]-E-125-R), and informed consent was waived. This research was funded by the Natural Science Foundation of Beijing, China, grant number 7244340 and the National Key Research and Development Program of China, grant number 2023YFC2706503. The authors declare no conflicts of interest. 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