Effectiveness, treatment pattern, and safety of ustekinumab in treating bio-naïve patients with Crohn’s disease in the real-world clinical setting in China

To the Editor: Clinical trials have confirmed the efficacy and safety of ustekinumab for treating Crohn’s disease (CD). The international guidelines of the European Crohn’s Colitis Organization also strongly recommend ustekinumab as a first-line biologic agent for treating moderate-to-severe CD.[1] Ustekinumab was approved for treating moderate-to-severe CD in March 2020 in China. More real-world evidence on the effectiveness of ustekinumab in China is required, particularly regarding objective or endoscopic outcomes. In China, the increasing hospitalization rate for CD places a significant economic burden on patients with CD and on healthcare resources. There has been a growing appreciation for the importance of early intervention to achieve endoscopic healing in CD, as it contributes to a higher rate of sustained clinical remission and lower rates of CD-related hospitalization and surgeries. Furthermore, an earlier introduction of ustekinumab in treating CD has evolved in routine clinical practice. Some real-world studies have reported higher rates of clinical, endoscopic, and biological remission after ustekinumab induction in bio-naïve patients than in bio-experienced patients. More evidence is needed to understand the effectiveness of ustekinumab as a first-line biologic agent for CD in the real world. In addition to effectiveness and safety, the evaluation of ustekinumab treatment persistence and concomitant CD-related treatment is vital, as they are critical factors for decisions regarding treatment optimization. To date, there are no clear guidelines on ustekinumab monotherapy or combination therapy for CD. To fill this research gap and provide important insights into the utilization of ustekinumab as a first-line biologic agent for CD in clinical practice, this study investigated the effectiveness, treatment pattern, and safety of ustekinumab in treating bio-naïve patients with CD in a real-world clinical setting in China. This study was approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University (No. [2023]480), Sixth Affiliated Hospital of Sun Yat-sen University (No. 2023ZSLYEC-501), and Sir Run Run Shaw Hospital (No. 20230563), with a waiver of informed consent. This was a multicenter retrospective cohort study. Patients from three tertiary hospitals in China whose medical records were stored in a multicenter research database for inflammatory bowel disease were included. Eligible patients were aged ≥18 years on the index date and had a diagnosis of active CD (i.e., Crohn’s Disease Activity Index ≥150, Harvey–Bradshaw Index ≥5, or determined by a physician) and initiated ustekinumab intravenous induction therapy for the first time between May 20, 2020, and September 16, 2022. Patients who had previously received ustekinumab for any indication other than CD or were exposed to biologics other than ustekinumab were excluded from the study. For each patient, the index date was the date of initiation of ustekinumab induction therapy, the baseline period was six months before the index date, and the observation period was from the index date until death or March 31, 2023. Further details are provided in Supplementary Figure 1, https://links.lww.com/CM9/C510. Effectiveness was measured by endoscopic remission, endoscopic response, (steroid-free) clinical remission, and (steroid-free) clinical response at week 24 (±4 weeks). Changes in C-reactive protein (CRP; mg/L) between baseline and week 24 (±4 weeks), biological remission and biological response at week 24 (±4 weeks), and free of disease progression (i.e., CD complication, or CD-related surgery/hospitalization) during observation were also evaluated. The treatment patterns included ustekinumab treatment persistence, reasons for treatment discontinuation or switch, and CD-related concomitant treatments. Safety was measured by the occurrence of adverse events (AEs) and serious adverse events, each AE outcome (e.g., recovered/resolved or not), each recovered/resolved AE duration, and ustekinumab treatment discontinuation due to AE. See Supplementary Methods, https://links.lww.com/CM9/C510 for details of the endpoint assessments. Descriptive statistics were used to summarize the variables. A paired t-test was used to compare CRP at week 24 (±4 weeks) and baseline. A Kaplan–Meier plot was used to assess time to disease progression. Univariate logistic regression was used to identify the prognostic factors associated with endoscopic remission. Subgroup analyses of the effectiveness outcomes were conducted. We performed two sensitivity analyses to examine the robustness of the main analyses. See the Supplementary Methods, https://links.lww.com/CM9/C510 for further details. A total of 200 patients were included in this study (Supplementary Figure 2, https://links.lww.com/CM9/C510). The patients were mainly male (153/200, 76.5%) and aged <40 years (136/200, 68.0%). Over 50% of the patients had perianal disease and 21.0% had extraintestinal manifestations. The majority had CD for ≤2 years (132/200, 66.0%) and a moderate-to-severe form of CD (107/200, 53.5%) [Supplementary Table 1, https://links.lww.com/CM9/C510]. Among the patients with available endoscopic or clinical outcomes at week 24 (±4 weeks), 46.4% (64/138) and 69.5% (82/118) achieved endoscopic remission and response, respectively; 65.0% (126/194) and 78.5% (150/191) achieved clinical remission and response, respectively; and 64.4% (123/191) and 77.4% (147/190) achieved steroid-free clinical remission and response, respectively [Figure 1]. CRP decreased significantly after ustekinumab initiation, with a mean change of –10.58 mg/L (95% confidence interval [CI]: –14.48, –6.67 mg/L; P <0.001) from baseline to week 24 (±4 weeks). At week 24 (±4 weeks), 53.1% (51/96) of patients achieved biological remission, and 69.8% (67/96) achieved biological response [Supplementary Table 2, https://links.lww.com/CM9/C510]. During follow-up, 5.5% (11/200) of patients had CD complications (median time to event: 3.77 months), and 12.5% (25/200) underwent CD-related surgery/hospitalization (median time to event: 4.27 months) [Supplementary Table 2, https://links.lww.com/CM9/C510]. The corresponding event-free probabilities at 10 months were 93.8% and 87.5% [Supplementary Figure 3, https://links.lww.com/CM9/C510].Figure 1: Proportions of Crohn’s disease patients treated with ustekinumab achieving endoscopic remission and response and (steroid-free) clinical remission and response at week 24 (±4 weeks).Most patients (93.0%, 186/200) persisted with ustekinumab treatment, with a median treatment time of 8.37 months. The occurrence of switching to another biologic agent was 4.0% (8/200), and that of ustekinumab discontinuation was 3.0% (6/200). Most patients (94.5%, 189/200) received ustekinumab monotherapy. Two (1.0%) patients received immunosuppressants, and nine (4.5%) received steroids. See Supplementary Table 1 and Supplementary Figure 4, https://links.lww.com/CM9/C510 for further details. A total of 15 AEs were reported, each occurring in a single patient. Fatigue and mild infusion reactions were the most frequently reported AEs (n = 3 each), followed by mild abdominal pain, nasopharyngitis, and mild elevation in liver enzymes (n = 2 each) [Supplementary Table 3, https://links.lww.com/CM9/C510]. Univariate logistic regression analysis revealed that no covariates were significantly associated with endoscopic remission [Supplementary Figure 5, https://links.lww.com/CM9/C510]. Only borderline-significant results were obtained. Female patients and patients with CRP >15 mg/L were less likely to achieve endoscopic remission than male patients (P = 0.090) and patients with CRP ≤15 mg/L (P = 0.082), respectively. Subgroup analysis also showed higher proportions of (steroid-free) clinical remission in mild active CD than in moderate-to-severe active CD and higher proportions of endoscopic response in those without prior immunosuppressant use or with the Montreal classification of L4 [Supplementary Figures 6–13, https://links.lww.com/CM9/C510]. An important finding of this study is the ability of ustekinumab to achieve endoscopic healing. The proportions of endoscopic remission and endoscopic response at week 24 were 46.4% (64/138) and 69.5% (82/118), respectively, which were clearly higher than those observed in the UNITI[2] and SEAVUE trials in bio-naïve patients with CD.[3] Our findings on endoscopic effectiveness are also consistent with those of previous real-world studies in bio-naïve patients with CD.[4,5] As endoscopic healing is a key goal of CD management, the results of this study reinforce the guideline recommendation on ustekinumab as a first-line biologic agent for patients with CD.[1] Additionally, the CRP levels decreased significantly from baseline to week 24, which is consistent with findings of the SEAVUE trial.[3] These reductions indicate a continuous decline in inflammation burden after ustekinumab initiation, which may reflect the potential of ustekinumab for deep remission in addition to clinical remission. Treatment persistence can be used as a surrogate measure for real-world therapeutic benefits and safety. In this study, 93% of the patients persisted with ustekinumab treatment. High ustekinumab persistence could contribute to sustained remission achieved in the medium term (24 weeks). The JUSTify study also reported a high persistence rate of ustekinumab treatment in bio-naïve patients with CD by 12 months (93.5%).[4] Subgroup analyses showed that bio-naïve patients without prior immunosuppressant therapy were more likely to achieve an endoscopic response than those with prior immunosuppressant therapy. This finding supports the consideration of a “top-down” strategy with early intervention of ustekinumab instead of a gradual “step-up” from conventional therapies for some newly diagnosed patients with CD. Our study provides robust real-world evidence to enhance the profile of ustekinumab as a first-line biologic agent in achieving treatment goals in CD. Identifying an appropriate first-line therapeutic option for patients with CD is essential for improving long-term clinical outcomes and quality of life. Our finding of a high rate of endoscopic remission in bio-naïve patients who were relatively young and had a short CD duration provides physicians with additional evidence of the benefit of early intervention with ustekinumab as a first-line biologic agent. However, this study has several limitations. First, missing data were present because of the retrospective study design. Multiple imputation was conducted to handle missingness. The imputed and original data yielded similar results, suggesting that missing data had a minor influence on result interpretation [Supplementary Figure 14 and Supplementary Table 4, https://links.lww.com/CM9/C510]. Second, data were obtained from tertiary hospitals in China, which could have had a higher coverage of patients with severe CD and comorbidities than other hospitals. Selection bias might have been present, but it was minimized by setting the necessary inclusion criteria to identify the study sample and no sampling among eligible patients. Finally, this study had an observation period of only 24 weeks. Evaluation of the long-term effectiveness of ustekinumab on endoscopic and clinical activities is required. In conclusion, this study demonstrated that almost half of the bio-naïve patients receiving ustekinumab achieved endoscopic remission at week 24. Multiple clinical outcomes also improved consistently, and the magnitude of improvement was more prominent than in previous trials. Most patients received ustekinumab monotherapy, and 93% persisted during follow-up. No serious AEs or unexpected safety signs were observed. Overall, the findings of this study could support the recommendation of ustekinumab as a first-line biological drug for CD as per treatment guidelines. Conflicts of interest This work was funded by Johnson & Johnson Innovative Medicine.

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