Crohn’s disease (CD) is an inflammatory bowel disease that is characterized by the development of chronic lesions throughout the gastrointestinal tract due to a systemic inflammatory reaction. If inappropriately treated, strictures and fistulas can cause irreversible intestinal damage and may even require surgery, such as bowel resection and stoma formation (1, 2). However, the advent of anti-tumor necrosis factor (anti-TNF) agents, including infliximab (IFX) and adalimumab, as treatments of CD has allowed the rapid achievement and maintenance of remission in patients of all ages, including pediatric patients (3–6). This treatment has thus improved the quality of life of patients with CD. Moreover, current treatment strategies have evolved to include the administration of biologics, including anti-TNF alpha, in the early inflammatory phase of the disease before complications develop (7–9).

Beyond simple clinical remission, the treatment of CD aims to achieve deep remission. Deep remission is an evolving concept that lacks a widely mutual definition; however, it is generally considered a state of clinical remission (symptom control) with evidence of endoscopic healing (EH) (10). More recently, the concept of transmural healing (TH) is emerging. TH is evaluated by measuring bowel wall thickness and signal intensity using a noninvasive measurement tool, ultrasonography, or magnetic resonance enterography (MRE). Recently, some studies have compared EH and TH, with all suggesting that TH could be a potential treatment endpoint in CD (11–14).

IFX is an anti-TNF alpha drug used for CD treatment, for which the therapeutic trough level (TL) range (≥3 µg/mL) has been discussed in several studies (15–17). Recently, attempts to proactively evaluate TLs are undertaken to guide clinical decision-making regarding dose intensification (18, 19). Moreover, clinicians have demonstrated a relationship between IFX TL and EH, suggesting that EH occurs at concentrations of 5 µg/mL or higher in pediatric patients with CD (20). A previous study in adult CD recommended maintaining an IFX concentration of 6–10 µg/mL to reach EH (21). In the aforementioned studies, the association between EH and IFX TL has been demonstrated; however, data regarding the association between IFX TL and TH are limited. Therefore, we aimed to investigate whether IFX TLs were associated with TH in pediatric patients with CD at 1-year IFX treatment.

This study prospectively evaluated whether IFX TLs were associated with TH in pediatric patients with CD. As several recent studies have argued that TH is a promising new treatment target in CD, evaluating the relationship between IFX TLs and TH is necessary to develop new therapeutic approaches.

Consistent with previous studies, we observed a significant difference in IFX TLs between the two groups of patients with and without EH (20, 21, 30, 31); however, no difference in IFX TLs was observed between the two groups of patients with and without TH ( Figure 2 ). Consequently, the authors considered TH as a deeper target for remission than EH, as patients with TH may be a subgroup of patients with EH. Unlike ulcerative colitis (UC), patients with CD exhibit deep ulcers rather than superficial ulcers; therefore, although the surface of the ulcer is healed, some inflammatory responses inside the mucosa or bowel wall (e.g., increase in blood flow and recruitment of immune cells) may yet remain.

IFX, an anti-TNF alpha agent, blocks the cytokine downstream of the inflammation process of CD; however, it does not inhibit a series of reactions that increase blood flow, recruit inflammatory cells (monocytes and macrophages), and differentiate T helper cells, which are upstream of the inflammatory process (32–34). Considering this mechanism, IFX treatment alone may prevent direct mucosal injury but not all inflammatory signaling pathways. This presents the possibility that EH can be achieved but TH cannot be achieved. In this regard, treatments other than IFX may be required to reach TH.

An additional point to consider is whether an IFX TL above the known therapeutic range is needed to obtain an association between TH and IFX TLs. This is because past studies have reported that higher IFX TL concentrations are required to treat fistulizing perianal lesions, and recent studies have evaluated the need for high-dose IFX treatment before LOR develops (35–37). However, evidence for higher IFX concentrations and doses to achieve TH remain insufficient to date. To verify this, additional studies are needed.

The third possible reason that IFX TLs were not associated with TH is that the 1-year treatment period set in this study may be relatively short to achieve TH. In 2013, Van Assche et al. reported the results of MRE up to 6 months following IFX treatment, and only 13% of patients showed normalization of MRE findings, leading them to conclude that the 6-month treatment period was insufficient for observing the treatment effect (38). However, according to the study of Castiglione et al. in 2016, the TH rate evaluated at 2 years following IFX treatment increased to 23% (39).

The fourth reason is minor but may nevertheless affect the outcome. There is no standardized definition of TH to date. In 2021, Geyl et al. compiled 17 papers that evaluated TH in a systematic review (40); the method for defining TH in each study was summarized, showing that all studies used bowel wall thickening, MaRIA score, or SES-CD. Similar to our study, most studies defined TH using bowel wall thickness; however, the standard for thickness varied, with some studies setting the upper limit as 3 mm and others as 7 mm (12, 41–51). Compared with other studies, our study’s TH definition was relatively strict. These stringent criteria may have resulted in an underestimation of the number of patients who reached TH, which may have prevented us from obtaining statistically significant results.

The results of the logistic regression analysis ( Tables 3 , 4 ) support the aforementioned results. As mucosal defects result in a loss of albumin due to leakage, a high albumin level can be used as a predictor of TH ( Table 3 ). Furthermore, as the SES-CD represents EH, and EH can be observed as a preceding remission of TH, patients who reach EH may have a higher probability of reaching TH. Therefore, the SES-CD can be used as a predictor of TH. As shown in the results of the correlation between EH and IFX TLs, a high IFX TL could predict EH in the logistic regression analysis ( Table 4 ). Moreover, logistic regression analysis showed that achieving EH is difficult since the period from the time of diagnosis to the use of IFX increases. Consistently, previous studies have reported that rapid application of biologics results in a high remission rate (52–54).

The strength of this study is that it is the first to evaluate the relationship between IFX TLs and TH in pediatric patients with CD. Even when expanding this scope to include studies in adults, only one study has evaluated the association between IFX TLs and TH to date. This paper was published very recently, in 2022 (55), and evaluated TH using ultrasonography, not MRE, and suggested that lower maintenance IFX TLs are associated with sonographic parameters of inflammation in UC and CD. Similar to our study, this paper also states that further studies are required to determine whether targeting higher IFX TLs can increase sonographic TH. The primary limitation of this study is that only 13 patients reached TH, which was too low to reach statistical significance. However, the total number of patients, 56, was relatively large for a prospective study with pediatric patients. Furthermore, this study is the first to evaluate the relationship between IFX TLs and TH in pediatric patients.

The results of our analysis showed that higher IFX TLs were associated with EH but not with TH in pediatric patients with CD treated with IFX. TH should be considered a concept of deeper remission than EH, and higher TLs than conventional therapeutic IFX TLs or long-term treatment may be required to reach TH. The results of this study may serve as a basis for further studies investigating long-term TH and proactive dosing based on therapeutic drug monitoring, which may clarify whether an association between IFX TLs and TH exists.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

This study was approved by the Institutional Review Board of Kyungpook National University Chilgok Hospital. Written informed consent to participate in this study was provided by the participant’ legal guardian/next of kin.

SYC contributed in the analysis and interpretation of data, drafting of the initial manuscript, and critical revision for important intellectual content. YK contributed in the analysis and interpretation of data, and drafting of the initial manuscript. SJC contributed in acquisition of data, and drafting of the initial manuscript. SL contributed in in the analysis and interpretation of data, and critical revision for important intellectual content. B-HC contributed in acquisition, analysis and interpretation of data, and critical revision for important intellectual content. BK contributed in the conception and design of the study, acquisition, analysis and interpretation of data, statistical analysis, and critical revision for important intellectual content. All authors contributed to the article and approved the submitted version.