Secondary loss of response to infliximab in pediatric Crohn’s disease: real-world experience in China

Introduction

Crohn’s disease (CD) is a chronic non-specific granulomatous disease that can affect the entire digestive tract. Twenty-five percent of CD cases occur in childhood or adolescence. The incidence of CD ranges from approximately 0.1 to 13.9 per 100,000, varying widely by geography, with the greatest incidence in North America and Europe (1). The incidence of CD in children has been on the rise worldwide in recent years, with a more pronounced increase in newly industrialized countries such as Asia, the Middle East, and Africa, with an increasing or stabilizing trend in North America, Europe, and Oceania (2).

With the emergence of biologic agents such as anti-tumor necrosis factor alpha (TNF-α) monoclonal antibodies, the treatment strategies for pediatric CD have undergone significant change. Multiple studies have demonstrated that anti-TNF-α monoclonal antibodies effectively induce and maintain clinical and endoscopic remission in pediatric CD patients (3,4). The 2020 European Crohn’s and Colitis Organization-European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ECCO-ESPGHAN) guidelines recommend that CD patients with perianal lesions, stricture or penetrating behavior, extensive lesions, deep colonic ulcers, or severe growth retardation should receive early treatment with anti-TNF-α drugs (5).

Infliximab (IFX) and adalimumab (ADA) are the most widely used anti-TNF-α monoclonal antibodies for pediatric CD patients. While the patients have a high response rate to IFX during the initial induction phase, 10% to 30% and 23% to 60% of patients experience primary non-response and secondary loss of response (LOR), respectively (6,7). Currently, there is limited analysis of secondary LOR to IFX in Chinese pediatric CD patients. With the increasing use of IFX, secondary LOR to this drug seriously affects CD patients. Early identification of patients at risk for secondary LOR to IFX would improve the quality of life of CD patients and reduce the medical burden by close follow-up and optimization of treatment strategies. This study aimed to determine the IFX secondary LOR rate in Chinese pediatric CD patients, identify the relevant factors affecting the secondary LOR, and optimize patient treatment regimens. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-344/rc).

Methods

Study design and participants

This study is a single-center retrospective cohort study. Sixty-nine CD patients treated with IFX at the Department of Gastroenterology of Beijing Children’s Hospital were selected between September 2015 and December 2022. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Ethics and Review Committee of the Beijing Children’s Hospital, Capital Medical University (No. 2025-E-125-R). Informed consent was obtained from the children’s parents.

Inclusion criteria were: (I) CD diagnosis met the criteria established by the “Modified Porto Criteria for the Diagnosis of Inflammatory Bowel Disease in Children and Adolescents” (8); (II) patient was 0-18 years of age; (III) patient had received their first IFX treatment and completed all four IFX infusions; (IV) a clinical response at the 14th week of IFX treatment was observed; and (V) no history of treatment with other biological agents. Exclusion criteria were: (I) patient with contraindications for the use of IFX such as severe infection, active tuberculosis, lymphoma, or other malignant tumors; (II) patient with primary non-response at the 14th week of IFX (primary non-response is defined as patients with a decrease in Pediatric Crohn’s Disease Activity Index (PCDAI) ≤12.5 at week 14) (9); and (III) patients with poor compliance, and thus unable to receive timely IFX.

The start and end observation points for this study were set as the initiation and cessation of IFX, the transfer of a pediatric patient to an adult hospital, or December 31, 2023.

All patients were administered 5–10 mg/kg IFX at weeks 0, 2, and 6, followed by administration at 8-week intervals. IFX was used for inducing and maintaining remission in moderate-to-severe pediatric CD, in patients who cannot tolerate EEN or fail to achieve remission after EEN or glucocorticoid induction therapy, and in patients with a high risk of poor outcomes, including extensive disease, deep colonic ulcers, growth retardation, severe perianal lesions, structuring, and penetrating lesions. In response to the clinical evidence of disease recurrence, concomitant immunosuppressive therapy (azathioprine and methotrexate) is permitted, the IFX dose can be intensified (up to 10 mg/kg per dose), and the interval between infusions can be shortened.

The specific observation indicators were as follows.

Clinical variables

Disease severity was determined using PCDAI scores, categorizing patients into four subgroups: clinical remission (<10.0 points), mild disease (10.0–27.5 points), moderate disease (30.0–37.5 points), and severe disease (≥40 points). The CD patients are classified into different subtypes according to the Paris classification. According to growth delay, CD was divided into G0 and G1 (10).

Clinical variables include gender (male/female), very early onset CD (VEO-CD) (yes/no), disease duration before IFX (<6; ≥6 months), IFX induction dose (<7; ≥7 mg/kg), body mass index (BMI) Z-score (≤−1; >−1), perianal lesions (yes; no), disease severity (mild; moderate and severe disease), location (L2; L1/L3), upper gastrointestinal tract involvement (yes; no), behavior (B1; B2/B3), growth delay (yes; no), C-reactive protein (CRP) before IFX (≤12; >12 mg/L), ESR (≤20; >20 mm/h), white blood cell (WBC) (≤10×10⁹/L; >10×10⁹/L), hemoglobin (Hb) (<110; ≥110 g/L), platelet (PLT) (≤400×10⁹/L; >400×10⁹/L), albumin (ALB) (<35; ≥35g /L), the efficacy of IFX induction therapy (clinical response, clinical remission), IFX monotherapy (yes; no), IFX combined with hormone therapy (yes; no), and IFX combined with immunomodulators therapy for more than 6 months (yes; no).

Variables based on endoscopic score

The Crohn’s disease endoscopic index of severity (CDEIS) was used to evaluate colon mucosal inflammation by endoscopy (11). A CDEIS score of <3 points indicated endoscopic remission, scores of 3–<9, 9–<12, and ≥12 points suggest mildly active, moderately active, and severely active disease, respectively.

Variables for the main outcome

These variables included secondary LOR to IFX in CD patients and the timing of the secondary LOR. The patients were regularly followed through outpatient clinics, hospitalization, or telephone calls to assess their treatment and disease recurrence.

IFX efficacy assessment

A clinical disease activity index score was measured in the 14th week of IFX treatment after the IFX induction therapy. A decrease of ≥15 points from baseline for the PCDAI score was defined as a clinical response and a PCDAI score of <10 points was defined as clinical remission. Secondary LOR to treatment is defined as disease recurrence during maintenance therapy with IFX (PCDAI >15 points).

Grouping

CD patients with the clinical response at the 14th week of IFX treatment continued to receive IFX maintenance treatment whether the patient experienced secondary LOR during the maintenance treatment determined whether they were assigned to the secondary LOR group or the responder group.

Statistical analysis

SPSS 22.0 software was used for data processing and analysis. Measurement data conforming to normal distribution were expressed as mean ± standard deviation, non-normally distributed measurement data were expressed as median (Q1, Q3), and count data were expressed as n (%). The Kaplan-Meier method calculated cumulative secondary LOR rates in CD patients. The Log-rank test was used for univariate analysis of secondary LOR in CD patients treated with IFX, and the Cox proportional hazards regression model was used for multivariate prognostic analysis. A two-sided P<0.05 was considered statistically significant.

Results

Baseline characteristics of the study population

Between September 2015 and December 2022, 85 CD patients began treatment with IFX in our hospital, and 69 were eligible for inclusion (Figure 1). The baseline characteristics are presented in Table 1. There were 41 males and 28 females, with an onset age of 11.3 (8.5, 13.0) years; 6 out of 69 cases (8.7%) had VEO-CD. The median age at first IFX administration was 12.0 (9.3, 13.7) years, with the median disease duration before IFX administration 7.6 (3.4, 16.8) months. The average initial dose of IFX for this group of patients was (6.8±1.2) mg/kg. The duration of IFX medication was 21.5 (13.4, 36.1) months, and the number of IFX injections was 13.0 (9.0, 21.5).

Figure 1 Flow chart of this study. ADA, adalimumab; CD, Crohn’s disease; IFX, infliximab.

The 69 CD patients had a PCDAI score of 39.0±16.5. Of the 69 cases, 53 (76.8%), 43 (62.3%), and 35 (50.7%) were assigned to the subgroup of moderate or severe disease, B1 type of disease behavior, and L3 type of lesion site, respectively. In addition, 33.3% of CD patients had perianal lesions, with a growth delay of 15.9%. Sixty-six CD patients completed colonoscopy before IFX. For the CDEIS score, 3, 19, 21, and 23 of 66 cases showed endoscopic remission, mild, moderate, and severe, respectively.

Treatments for CD received before IFX were exclusive enteral nutrition (15/69, 21.7%), glucocorticoids (23/69, 33.3%), azathioprine (12/69, 17.4%), methotrexate (1/69, 1.4%) and thalidomide (1/69, 1.4%). Three patients had previously had ileal resection plus ileostomy, one ileocolic resection plus intestinal anastomosis, and one ileocolic resection plus ileostomy.

Ten patients (14.5%) received IFX combined with glucocorticoids. Twenty-three (33.3%) patients received IFX in combination with azathioprine for more than 6 months, and the average treatment duration of azathioprine was 24.1±12.9 months. Seven (10.1%) patients received IFX in combination with methotrexate for more than 6 months, and the average treatment duration of methotrexate was 19.4±7.3 months. Twenty-six (37.7%) patients received IFX only.

Follow-up visits

This patient group was followed for 21.5 (13.4, 36.1) months. As of the last follow-up, there were 18 patients (26.1%, 18/69) in the secondary LOR group and 51 (73.9%, 51/69) in the responder group.

In this study, therapeutic drug monitoring (TDM) was performed on 34 patients with CD at the 14th week of IFX treatment. Among them, 6 patients were in the secondary LOR group and 28 patients in the responder group. Results indicated that the IFX concentration at week 14 in the secondary LOR group was significantly lower than that in the responder group (2.550±1.532 vs. 6.654±4.801 µg/mL, t=3.724, P=0.001). Due to low IFX concentrations, 16 CD patients chose to increase IFX dosage, or shorten the IFX administration interval, or combine with immunosuppressants to enhance IFX efficacy.

In the secondary LOR group, 7 patients discontinued IFX, 11 underwent optimization of IFX, and 5 regained a clinical response, while 6 failed to regain a clinical response. One patient was found to harbor a hemizygous mutation in the XIAP gene, c.664C>T (p.R222X) based on DNA sequencing, this patient was diagnosed with X-linked lymphoproliferative syndrome type 2 and was finally cured through allogeneic hematopoietic stem cell transplantation. Based on DNA sequencing, one patient was found to harbor a hemizygous mutation in the FOXP3 gene, c.758T>C (p.L253P); this patient’s parents refused treatment and discontinued the medication independently. The details are presented in Figure 1.

As depicted in Figure 2, the median time for developing secondary LOR during IFX maintenance therapy was 16.2 (11.6, 29.2) months. Kaplan-Meier analysis revealed that the cumulative secondary LOR rates of 69 CD patients after 1, 2, and 3 years of IFX were 15.7%, 27.3%, and 30.9%, respectively.

Figure 2 Cumulative secondary loss of response during IFX maintenance therapy for 69 CD patients. CD, Crohn’s disease; IFX, infliximab.

Univariate analysis of factors influencing secondary LOR in CD patients treated with IFX

Univariate analysis suggested that a BMI Z-score ≤−1 (χ²=4.607, P=0.03), growth delay (χ²=5.012, P=0.03), and clinical response but failed to achieve clinical remission after IFX induction therapy (χ²=13.224, P<0.001) may be risk factors for the development of secondary LOR in CD patients treated with IFX. However, combined treatment with IFX and immunomodulators for more than 6 months (χ²=4.377, P=0.04) may be a protective factor for developing secondary LOR in the patients (Table 2).

Multivariate analysis of factors influencing secondary LOR in CD patients treated with IFX

Variables with a P<0.05 by univariate analysis, including BMI Z-score ≤−1, growth delay, clinical response but failed to achieve clinical remission after IFX induction therapy, and combined treatment with IFX and immunomodulators for more than 6 months, were evaluated by multivariate Cox regression analysis. As shown in Table 3, clinical response but failure to achieve clinical remission after IFX induction therapy was an independent risk factor for secondary LOR to IFX (P=0.009). However, combined treatment with IFX and immunomodulators for over 6 months was an independent protective factor for the secondary LOR (P=0.03).

Stratified Kaplan-Meier analysis showed that the cumulative secondary LOR rate was significantly lower in patients receiving combined treatment with IFX and immunomodulators for more than 6 months than those receiving the combined therapy for no more than 6 months (P=0.03) (Figure 3A). Moreover, the cumulative secondary LOR rate was significantly higher in patients who developed a clinical response after IFX induction therapy than those who showed clinical remission (P=0.009) (Figure 3B).

Figure 3 Effects of various factors on cumulative secondary loss of response rate in CD patients treated with IFX. (A) Classification was based on the duration of combined treatment with IFX and immunomodulators. (B) Classification was based on the efficacy of IFX induction therapy at week 14. CD, Crohn’s disease; IFX, infliximab.

Discussion

The number of pediatric CD patients has increased steadily over the years. CD patients often have malnutrition, growth delay, perianal lesions, and extra-intestinal symptoms and tend to experience rapid disease progression, high surgery rates, and treatment difficulties. Anti-TNF-α monoclonal antibodies have been shown to have significant therapeutic benefits for pediatric CD patients. Treatment with anti-TNF-α monoclonal antibodies during the early stage of the disease can significantly reduce the incidence of intestinal stricture, surgery, perianal lesions, and other complications. Therefore, early treatment with biologics may help improve patient prognosis (12).

The clinical remission and response rates for IFX induction therapy in pediatric CD patients are 34–85% and 80–96%, respectively (13-15). Although IFX is recognized as an effective drug for the treatment of pediatric CD, 10–30% of CD patients show no response to IFX induction therapy, and approximately 23–60% develop secondary LOR to IFX. There are specific differences in the clinical response rate and clinical remission rate of IFX therapy in different studies, which may be related to the timing and dosage of IFX, disease severity, disease behavior, and TDM. A study in Israel showed that the secondary LOR rate for pediatric CD patients after 1, 3, and 5 years of anti-TNF-α treatment was 17%, 38%, and 49%, respectively (14). Secondary LOR remains a significant challenge during IFX therapy of CD patients. In the present study, the secondary LOR rate of CD patients was 26.1%, and the median time of secondary LOR to IFX was 16.2 (11.6, 29.2) months. Furthermore, Kaplan-Meier analysis revealed that the cumulative secondary LOR rates of 69 CD patients after 1, 2, and 3 years of IFX were 15.7%, 27.3%, and 30.9%, respectively, similar to previous studies (7,14).

In this study, results demonstrated that the IFX concentration at week 14 of treatment in the secondary LOR group was significantly lower than that in the responder group. This finding supports an association between drug concentration and secondary LOR.

The exact mechanism of the secondary LOR remains unknown. It may be related to immunogenic effects (presence of anti-drug antibodies), pharmacokinetic effects (low trough concentrations of drugs, absence of anti-drug antibodies), or pharmacodynamic effects (sufficient trough concentration of drugs). Therefore, clinical guidelines recommend that when secondary LOR occurs during IFX treatment in CD patients, it is advisable to follow TDM rather than empirical drug escalation or drug switching. If the trough concentration of IFX lies within the therapeutic window, switching to other biologics is recommended. In the case of a lower trough concentration of IFX than the therapeutic window concentration and undetected anti-drug antibodies or a low titer of anti-drug antibodies, the treatment regimen can be optimized by increasing the IFX dosage or shortening the IFX medication interval and/or combining IFX with immunomodulators, enabling the patient to regain response to the treatment. For an insufficient trough concentration of IFX and a high titer of anti-drug antibodies, switching to other anti-TNF-α drugs or biologics is recommended (5).

In the present study, 11 of 18 CD patients with secondary LOR underwent optimization of IFX, and 5 regained clinical response. Similarly, Ling et al. found that 54% of CD patients with secondary LOR to IFX regained clinical response through optimization of IFX (16). The underlying reason may be that these patients develop secondary LOR to IFX due to pharmacokinetic effects (e.g., low trough concentration of drugs and the absence of anti-drug antibodies) and can eventually regain clinical response through optimization of IFX.

Evidence suggests that the younger the onset age of pediatric CD patients, the more closely associated the pathogenesis is with genetic factors. Some VEO-CD patients harbor unique single gene mutations involving IL10, the IL10 receptor, FOXP3, XIAP, and TTC37 genes; these CD patients with single gene mutations have been reported even in older children (17). Our study identified two patients with monogenic disease who had an onset age greater than 6 years of age. One patient with an XIAP gene mutation was successfully treated with allogeneic hematopoietic stem cell transplantation, while the other patient with a FOXP3 gene mutation declined treatment and discontinued taking medication. Thus, the possibility of monogenic disease should be considered for CD patients with early onset, atypical clinical manifestations, or poor response to conventional drug therapy, including the LOR to IFX. In such cases, genetic testing needs to be carried out as soon as possible to achieve precise treatment and an improved prognosis.

Since IFX remains the leading biological agent for treating CD patients in China, there is a pressing requirement for a practical tool to predict the efficacy of IFX in clinical practice. Various clinical characteristics and laboratory biomarkers have been used to predict secondary LOR to IFX, such as BMI, disease duration, disease severity, lesion extent, serum gamma-globulin, serum ALB, inflammatory markers (e.g., CRP, ESR, and fecal calprotectin), and combined treatment with immunomodulators (18,19).

The present study identified clinical response but failed to achieve clinical remission after IFX induction therapy as an independent risk factor for secondary LOR to IFX in CD patients. Likewise, a retrospective cohort study of 248 pediatric CD patients by Dupont-Lucas et al. showed that the development of a clinical response to IFX induction therapy, without clinical remission, was a predictor for secondary LOR to IFX. Further, a subgroup of patients with this predictor was at increased risk for secondary LOR (13). These studies highlight the importance of the response to IFX induction therapy in maintenance treatment. Therefore, patients with partial responses to IFX induction therapy should be identified as early as possible so that IFX therapy may be optimized through early TDM to improve patient prognosis.

Further, combined treatment with IFX and immunomodulators for more than 6 months was an independent protective factor for the secondary LOR. Studies on the treatment of IFX combined with immunomodulators in pediatric CD patients are relatively few. A study by Hoelz et al. found that early combined treatment with IFX and immunomodulators significantly prolonged the duration of secondary LOR to IFX compared with IFX monotherapy or short-term combined treatment with IFX and immunomodulators (30 vs. 9 months, P=0.01) (20). Other studies have provided evidence that combined treatment with IFX and immunomodulators can reduce the incidence of secondary LOR, prolonging the durability of IFX therapy (21,22). These observations can be explained by the fact that compared with IFX monotherapy, combined treatment with IFX and immunomodulators leads to a higher trough concentration of IFX and a lower titer of anti-drug antibodies (23). Anti-drug antibodies can accelerate drug clearance and reduce the concentration of IFX in serum, thereby affecting the long-term efficacy of IFX. Therefore, the 2020 ECCO/ESPGHAN guidelines recommend that pediatric CD patients initiating IFX therapy be treated with IFX in combination with immunomodulators for 6 to 12 months (5). However, it remains unclear which immunosuppressant achieves the optimal effect when combined with IFX. A network meta-analysis and systematic review indicated that no statistically significant differences were observed between various IFX-containing combination therapies in terms of inducing and maintaining remission in CD (23). Thus, additional head-to-head trials are warranted to address this question.

This investigation is a single-center retrospective study with limitations such as its small sample size, short follow-up period, and the fact that only some patients underwent TDM. However, the present study did allow us to draw meaningful conclusions regarding real-world medication experience. More multicenter, prospective, large-sample studies are needed to identify the influencing factors associated with secondary LOR to IFX in pediatric CD patients.

Conclusions

The present study indicates that CD patients who developed clinical response but failed to achieve clinical remission after IFX induction therapy were at increased risk of secondary LOR to IFX. In contrast, patients who received combined treatment with IFX and immunomodulators for over 6 months had a reduced risk for secondary LOR to IFX. Early identification of patients at high risk for secondary LOR to IFX therapy can improve the prognosis for CD patients through early IFX dose optimization, combined treatment with IFX and immunomodulators, or switching from IFX to other biologics.

Acknowledgments

We would like to thank the entire staff of the Department of Gastroenterology, Beijing Children’s Hospital, Capital Medical University, and the National Center for Children’s Health.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-344/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-344/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-344/prf

Funding: This work was supported by research grants from the National Key R&D Program of China (No. 2023YFC2706503), Beijing Natural Science Foundation (No. J230009), and High-Level Public Health Technical Personnel Project (Academic leader-02-04).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-344/coif). All authors report that this work was supported by research grants from the National Key R&D Program of China (No. 2023YFC2706503), Beijing Natural Science Foundation (No. J230009), and High-Level Public Health Technical Personnel Project (Academic leader-02-04). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Ethics and Review Committee of the Beijing Children’s Hospital, Capital Medical University (No. 2025-E-125-R). Informed consent was obtained from the children’s parents.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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