Infliximab trough level combined with inflammatory biomarkers predict long-term endoscopic outcomes in Crohn’s disease under infliximab therapy

Wan-Ting Cao,Rong Huang, Shan Liu,Yi-Hong Fan,Mao-Sheng Xu, Yi Xu,Hui Ni

Abstract

Key Words: Infliximab trough level; C-reactive protein; Fecal calprotectin; Crohn’s disease; Clinical remission; Long-term endoscopic outcomes

INTRODUCTION

Crohn’s disease (CD) is a persistently progressive disease with nonspecific inflammation characterized by disease scope involving the whole digestive tract and disease depth involving the whole intestinal wall. The accumulation damage of intestinal walls contributes to the occurrence of stenosis, fistula and even abscess, reducing the life quality. Therefore, recent clinical studies have consistently concluded that therapeutic strategies and targets play key roles in controlling CD progression. Setting different therapeutic targets will have different disease outcomes. Clinical response, focusing only on the improvement of clinical symptoms, can improve the quality of daily life but not affect long-term treatment outcomes. CD patients who do not achieve deep remission may be aggravated persistently,while achieving deep remission could reduce long-term hospitalization and surgery rates. Deep remission is mainly defined in previous studies as endoscopic remission or mucosal healing. Biologics,as an important step in the therapeutic strategy of CD, can effectively control the disease progression if conducted early and completely.

In consideration of the wide use of infliximab (IFX), precisely predicting the long-term endoscopic outcomes is stressed by more and more inflammatory bowel disease (IBD) physicians. Although the IFX trough level (ITL) has been proven to be closely related to the outcome of CD, ITL alone may be biased in predicting the outcome of CD. Monitoring inflammation biomarkers is one of the important links of IFX therapy, including C-reaction protein (CRP), fecal calprotectin (FCP),etc.High inflammatory load affects the pharmacokinetics of IFX, inducing secondary nonresponse by decreasing blood drug concentration. Currently, it is believed that inflammatory biomarkers are good predictors of disease activity,but there is still a lack of reliable evidence for predicting disease remission. Therefore, this study intends to evaluate long-term endoscopic outcomes of CD patients receiving IFX treatment by combining the blood drug concentration and inflammatory biomarkers.

MATERIALS AND METHODS

Study subjects design

A single-center retrospective research was implemented at the First Affiliated Hospital of Zhejiang Chinese Medical University. CD patients under IFX therapy from January 2012 to December 2020 were collected. One hundred and eighty-one CD patients underwent IFX treatment. One hundred and fiftyone CD patients underwent endoscopy as well as serum concentration monitoring at week 14 after the third dose of IFX induction therapy. Inclusion criteria: (1) Endoscopic remission at week 14 [Crohn’s disease endoscopic index of severity (CDEIS) score ≤ 2 points or Rutgeerts ≤ i1]; (2) Clinical remission after IFX induction therapy without corticosteroids more than 6 mo; and (3) Therapeutic strategy during maintenance stage was designed as IFX 5 mg/kg every 8 wk combined with azathioprine (AZA) 50 mg every day. Therapeutic strategic was modulated if CD patients were confronted with clinical relapse or secondary loss of response (LOR), and data analysis focused on the treatment course when patients received IFX 5 mg/kg and AZA therapy regularly. Secondary LOR was defined as a recurrence of the disease during IFX maintenance therapy. Two criteria were met to determine LOR: The recurrence of symptoms of IBD in clinical remission after induction therapy and symptoms caused by the inflammatory activity of IBD itself. Clinical relapse means Crohn’s disease activity index ＞ 150 points. Blood drug concentration monitoring and clinical, laboratory, endoscopic and imaging evaluation were implemented every 2 mo since the third dose of IFX induction therapy in all patients. The study was divided into two stages, step I study period defined as IFX maintenance therapy during week 14 to week 54 and step II study period defined as IFX maintenance therapy during week 54 to week 108.

Data collection

General data included age, sex, course, disease location, disease behavior, medication history and history of intestinal surgery. Laboratory indicators include white blood cell count, blood platelet count,CRP, erythrocyte sedimentation rate, serum albumin, FCP, ITL and anti-IFX antibody. Evaluation indicators of disease severity included Crohn’s disease activity index score on clinical severity, CDEIS score on endoscopic severity in CD patients without intestinal surgery and Rutgeerts score on endoscopic severity in CD patients with intestinal surgery.

Outcome definition

Endoscopic outcomes at week 54 and week 108 after IFX initial therapy were evaluated by specialist physicians on IBD under electronic colonoscopy. Endoscopic remission was defined as CDEIS score ≤ 2 or Rutgeerts score ≤ i1, and endoscopic activity was defined as CDEIS score ＞ 2 or Rutgeerts score ＞ i1.Survival outcomes during IFX maintenance therapy were concentrated on endoscopic relapse-free survival, defined as sustained endoscopic remission during step I study period or step II study period.

Statistical analysis

Descriptive statistical analysis was used to describe characteristics of CD patients. Number of cases(percentage) was used to describe categorial variable. mean ± SD was used to describe continuous variable. Nonparametric Mann-Whitney test was used to compare two groups in enumeration data or measurement data without normal distribution. Two-sample t test was used to compare two groups in measurement data with normal distribution. One-way analysis of variance was used to compare multigroup if data satisfied homogeneity of variance. Nonparametric Kruskal-Wallis test was used to compare multi-group if data not satisfied homogeneity of variance. SPSS 23.0 (Armonk, NY, United States) was used to analyze differences between groups. APvalue ＜ 0.05 was considered significant.

Receiver-operating characteristic (ROC) analysis was used to identify the best cut off level of ITL on predicting endoscopic remission as well as sensitivity, specificity, positive predictive value, negative predictive value, area under the curve and Youden Index. Univariate logistic regression analysis was used to identify the association between endoscopic activity and predictors. Log-rank test was used to identify the association between endoscopic relapse and predictors. GraphPad Prism9.0 (San Diego, CA,United States) was used to draw histograms and survival analysis curves and implement log-rank test.MedCalc19.0 was used to draw ROC curve and analyze the predictive value of indicators on endoscopic outcomes. APvalue ＜ 0.05 was considered significant.

RESULTS

Characteristics of study subjects

In total, the study cohort collected 112 CD patients achieving clinical remission after IFX induction therapy. In step I study, 19 CD patients were excluded due to data absence (n= 1, 5.26%) and endoscopic activity at week 14 (n= 18, 94.74%), while 93 CD patients with endoscopic remission at week 14 were included. In step II study, 58 CD patients were excluded due to course of therapy shorter than 2 years (n= 10, 17.24%), secondary non-response of IFX (n= 12, 20.69%), suspension of IFX therapy within 2 years for disease remission (n= 10, 17.24%) and endoscopic activity at week 54 (n= 26, 44.83%), while 54 CD patients with endoscopic remission at week 54 were included. These 12 patients did not satisfy indications of operation and received hormonotherapy as the primary choice to alleviate disease, for our center lacked other biological agents at that time. All CD patients under IFX maintenance therapy were combined with AZA (Figure 1). The dose of IFX was 5 mg/kg every 8 wk, and the dose of AZA was 50 mg every day. Characteristics of CD patients included in study are shown in Table 1.

Correlation between ITL, inflammatory biomarkers and endoscopic outcomes

In step I study, 67/93 CD patients (72.04%) sustained endoscopic remission at week 54 among.Multivariable regression analysis revealed that only ITL (OR = 0.666, 95%CI: 0.514-0.862,P= 0.002) and FCP (OR = 1.002, 95%CI: 1.001-1.004,P= 0.002) were independent risk of endoscopic activity at week 54(Table 2). Based on incremental gain analysis, an ITL range of 5.0-7.4 μg/mL was correlated with sustained endoscopic remission rate of more than 85% (Figure 2).

In step II study, 42/54 CD patients (77.78%) sustained endoscopic remission at week 108.Multivariable regression analysis revealed that only ITL (OR = 0.466, 95%CI: 0.247-0.877,P= 0.018) and CRP (OR = 1.590, 95%CI: 1.007-2.510,P= 0.047) were independent risks of endoscopic activity at week 108 (Table 2). Based on incremental gain analysis, an ITL range of 2.0-3.9 μg/mL was correlated with sustained endoscopic remission rate of more than 85% (Figure 2).

Predictive value of ITL and inflammatory biomarkers on endoscopic outcomes

In step I study, the ROC analysis demonstrated that the best cut off level of ITL and FCP at week 14 on predicting endoscopic relapse at week 54 was 5.60 μg/ml (AUC = 0.83, 95%CI: 0.73-0.90, P ＜ 0.001) and 238 μg/g (AUC = 0.82, 95%CI: 0.72-0.89, P ＜ 0.001) (Table 3 and Figure 3). CD patients with ITL ≤ 5.60 μg/ml and FCP ＞ 238 μg/g at week 14 had 82% probability of endoscopic relapse at week 54. However,CD patients with ITL ＞ 5.60 μg/ml and FCP ≤ 238 μg/g at week 14 had 98% probability of sustained endoscopic remission at week 54.

In step II study, the ROC analysis demonstrated that the best cut off level of ITL and CRP at week 54 on predicting endoscopic relapse at week 108 was 2.10 μg/mL (AUC = 0.85, 95%CI: 0.72-0.93,P＜ 0.001)and 3.00 mg/L (AUC = 0.73, 95%CI: 0.60-0.84,P= 0.012) (Table 3 and Figure 3). CD patients with ITL ≤2.10 μg/mL and CRP ＞ 3.00 mg/L at week 54 had 100% probability of endoscopic relapse at week 108.However, CD patients with ITL ＞ 2.10 μg/mL and CRP ≤ 3.00 mg/L at week 54 had 97% probability of sustained endoscopic remission at week 108.

Correlation between ITL, inflammatory biomarkers and endoscopic relapse-free survival

In step I study, 26/93 (27.96%) CD patients had experienced endoscopic relapse from week 14 to week 54 of IFX maintenance therapy. The estimated endoscopic relapse-free rate was 46/48 (95.83%) in CD patients with ITL ＞ 5.6 μg/ml and 21/45 (46.67%) in CD patients with ITL ≤ 5.6 μg/ml. The median time to endoscopic relapse of CD patients with ITL ≤ 5.6 μg/ml was 32.00 wk shorter than those with ITL ＞5.6 μg/ml [hazard ratio (HR) = 16.19, 95%CI: 7.44-35.22, P ＜ 0.0001] (Figure 4A). The estimated endoscopic relapse-free rate was 6/25 (24.00%) in CD patients with FCP ＞ 238 μg/g and 61/68 (89.71%)in CD patients with FCP ≤ 238 μg/g. The median time to endoscopic relapse of CD patients with FCP ＞238 μg/g was 21.00 wk shorter than those with FCP ≤ 238 μg/g (HR = 11.25, 95%CI: 4.26-29.73, P ＜0.0001) (Figure 4B).

Table 1 Clinical characteristics of Crohn‘s disease patients with endoscopic remission

In step II study, 12/54 (22.22%) CD patients had experienced endoscopic relapse from week 54 to week 108 of IFX maintenance therapy. The estimated endoscopic relapse-free rate was 38/41 (92.68%) in CD patients with ITL ＞ 2.1 μg/mL and 4/13 (30.77%) in CD patients with ITL ≤ 2.1 μg/mL. The median time to endoscopic relapse of CD patients with ITL ≤ 2.1 μg/mL was 40.00 w, shorter than those with ITL ＞ 2.1 μg/mL (HR = 13.14, 95%CI: 3.07-56.27,P＜ 0.0001) (Figure 4D). The estimated endoscopic relapse-free rate was 4/8 (50.00%) in CD patients with CRP ＞ 3.00 mg/L and 40/46 (86.96%) in CD patients with CRP ≤ 3.00 mg/L. The median time to endoscopic relapse of CD patients with CRP ＞ 3.00 mg/L was 50.00 wk shorter than those with CRP ≤ 3.00 mg/L (HR = 7.85, 95%CI: 1.31-46.85,P＜ 0.0001)(Figure 4C).

DISCUSSION

Several studies have confirmed that different ITLs brought about different outcomes of CD under IFX therapy (Table 4). Tanget al[1] discovered that CD patients achieving mucosal healing at week 14 of IFXtherapy with ITL ＞ 2.5 μg/mL at week 14 had 71% chance of mucosal healing at week 54, while patients with ITL ＜ 2.5 μg/mL had only 33% chance. ITL ≥ 3 μg/mL at the beginning of IFX maintenance therapy was confirmed as a predictor of sustained response to IFX in CD patients[2]. Recently a prospective study in Japan verified that CD patients with ITL ≥ 3 μg/mL at week 14 after IFX initial therapy had much better long-term clinical outcomes than patients with ITL ＜ 3 μg/mL, of which survival analysis indicated 100% probability of clinical remission at week 108 in the former and 33.3%probability in the latter[3]. A meta-analysis determined that ITL ＞ 2.0 μg/mL of IBD patients under IFX maintenance therapy contributes to better prognosis such as clinical remission or mucosal healing[4].Similarly, this study found that CD patients with ITL ＞ 5.6 μg/mL at week 14 had a large chance ofachieving sustained endoscopic remission during IFX maintenance therapy as well as CD patients with ITL ＞ 2.1 μg/mL at week 54. Borrenet al[5] implemented a multi-center retrospective study and concluded that low ITL in IBD patients during IFX maintenance therapy could not be a good predictor of clinical relapse in the next 2 years, suggesting that proactive therapeutic drug monitoring was not suitable in this group. However, this study discovered that CD patients with ITL ≤ 5.6 μg/mL at week 14 or ITL ≤ 2.1 μg/mL at week 54 were more likely to experience endoscopic relapse during the 1-year follow-up period.

Table 2 Predictive indicators of endoscopic relapse in Crohn's disease patients with endoscopic remission

Table 3 Predictive value of indicators on endoscopic relapse

Figure 1 Patients selected and outcome of infliximab therapy. CD: Crohn‘s disease; EA: Endoscopic activity; IFX: Infliximab.

Table 4 Previous research of infliximab trough level on deep remission in inflammatory bowel disease

Figure 2 Incremental gain analysis of sustained endoscopic remission rate in relation to infliximab trough level at week 14 and week 54.

According to previous studies, the challenge for IBD physicians is to frame the more suitable blood trough level of IFX to achieve better disease prognosis in clinical therapy. The elements associated with the blood trough level of IFX can be classified into three areas. Above all, the better the therapeutic goal desired by IBD physicians or patients, the higher the blood trough level of IFX is required. An observational study contraposing to CD patients with a history of intestinal surgery by Imaedaet al[6] verified that mucosal healing required higher ITLs as more than 4.0 μg/mL compared to those to achieve normalization of routine clinical markers. Papamichaelet al[7] considered that ITL surpassing 9.7 μg/mL indicated 80% probability of endoscopic remission in CD patients under IFX maintenance therapy, while ITL surpassing 2.2 μg/mL was associated only with biochemical remission. Recently, a prospective study verified that ITL ＞ 8.0 μg/mL was highly correlated with histological emission and sustained histological remission in IBD patients[8]. Perianal fistula, the most universal complications of CD patients, is another therapeutic goal. A retrospective cross-sectional study by Plevriset al[9]manifested that perianal fistula healing or closure is associated with higher ITLs as more than 7.1 μg/mL.

Secondly, each clinical study had different stages of IFX drug monitoring, especially during maintenance therapy. ITL continues to decrease as time passed during IFX maintenance therapy[10]. A cross-sectional study of IBD patients under IFX therapy with a fixed dose more than 6 mo found that IBD patients with ITL ≥ 3.4 μg/mL had a 73% chance of endoscopic mucosal healing[11]. Kanget al[12]showed that ITL ≥ 5 μg/mL during IFX maintenance therapy could identify mucosal healing in pediatric CD patients with 80% specificity. Fenget al[13] innovatively integrated ITL levels in different time stages to identify endoscopic mucosal healing in CD patients, indicating that patients with ITL ＞4.85 μg/mL at week 14 and ITL ＞ 2.85 μg/mL at week 30 had an 80% chance of achieving endoscopic mucosal healing. Based on incremental gain analysis in our study, sustained endoscopic remission rate at week 54 reached only 54.63% at an ITL range of 2.5 to 4.9 μg/mL at week 14 while corresponding numbers at week 108 was 89.47% at an ITL range of 2.0 to 3.9 μg/mL at week 54. Therefore, the study held the view that CD patients with endoscopic remission need higher ITL at the beginning of IFX maintenance therapy (≥ 5.6 μg/mL at week 14) than after IFX maintenance therapy over a half year (≥2.1 μg/mL at week 54). In addition, CD patients achieving endoscopic remission after IFX induction therapy and sustained endoscopic remission more than a half year may not need high ITL to maintain endoscopic remission.

Figure 3 Receiver operator characteristic curve of infliximab trough level and inflammatory biomarkers in predicting endoscopic outcomes. A: Receiver operator characteristic (ROC) curve of infliximab trough level at week 14 in predicting endoscopic remission of Crohn’s disease (CD) at week 54; B: ROC curve of fecal calprotectin at week 14 in predicting endoscopic remission of CD at week 54; C: ROC curve of infliximab trough level at week 54 in predicting endoscopic remission of CD at week 108; D: ROC of C-reactive protein at week 54 in predicting endoscopic remission of CD at week 108. ITL: Infliximab trough level; CRP: C-reactive protein; FCP: Fecal calprotectin; AUC: Area under the curve.

The third element is therapeutic optimization of IFX in IBD. Adverse IFX response as high ATI level or low ITL may occur in a few CD patients during IFX maintenance therapy. Several clinical studies held the view that severe inflammatory activity of CD patients could change pharmacokinetics of antitumor necrosis factor α biology[14-16]. Therapeutic optimization as increasing fixed dose from 5 mg/kg to 10 mg/kg or shortening injection interval form every 8 wk to 4-6 wk contributes to increase ITL and decrease ATI level. A study from Greece demonstrated that, for the initial measurement after therapeutic adjustment, ITL increased from 1.47 μg/mL to 8.50 μg/mL in patients with therapeutic optimization while ITL decreased from 5.65 μg/mL to 3.8μg/ml in patients without therapeutic optimization[10]. A multi-center randomized clinical trial conducted by Dreesenet al[17] showed that CD patients under IFX maintenance therapy as 5 mg/kg had high probability of no mucosal ulcer under endoscopy at week 54 with ITL more than 7.3mg/L, and CD patients under intensified dose IFX therapy as 10 mg/kg had 94% probability of no mucosal ulcer under endoscopy with ITL rising to more than 10.6 mg/L. Therefore, intensified therapy may contribute to mucosal healing in CD patients with ulceration if IFX injection dose is less than 10 mg/kg and ITL is less than 10.6 μg/mL. However, a few CD patients will accept combination therapy of IFX and immunosuppressant to boost the efficacy,especially AZA and mercaptopurine. AZA is a precursor of mercaptopurine, and two components ultimately produce thioguanine to exert clinical effect during metabolism. A study verified that thioguanine concentration more than 125 pmol/8 × 108red blood cells could enhance ITL to 8.3 μg/mL or more and decrease positive rate of ATI[18,19]. Hence, this study mainly included CD patients with sustained clinical remission more than 6 mo under fixed therapeutic strategy of IFX 5 mg/kg every 8 wk combined with AZA 50 mg every day. Retrospective records of CD patients included would suspend if therapy strategy changed, such as intensive therapy of IFX, conversion therapy of other biologics and combination therapy of surgery or other medications. The study design eliminated the influence of therapeutic adjustment on ITL.

Figure 4 Proportion without endoscopic relapse. A. Time since infliximab (IFX) therapy at week 14 [IFX trough level (ITL) ＞ 5.6 μg/mL vs ITL ≤ 5.6 μg/mL];B: Time to IFX therapy at week 14 (fecal calprotectin ≤ 238 μg/g vs fecal calprotectin ＞ 238 μg/g]; C: Time to IFX therapy at week 54 (C-reactive protein ≤ 3.0mg/L vs C-reactive protein ＞ 3.0 mg/L); D: Time to IFX therapy at week 54 (ITL ＞ 2.1 μg/mL vs ITL ≤ 2.1 μg/mL). ITL: Infliximab trough level; CRP: C-reactive protein; FCP:Fecal calprotectin; IFX: Infliximab.

The greatest strength of inflammatory biomarkers compared with blood trough level is that they are unaffected by time during different monitoring stages of biological therapy in IBD patients. This study showed that ITL ＞ 5.6 μg/mL combined with FCP ≤ 238 μg/g at week 14 moderately predicted sustained endoscopic remission during the 1-year follow-up period on CD patients with positive predictive value more than 95% as well as ITL ＞ 2.1 μg/mL combined with CRP ≤ 3.00 mg/L at week 54, superior to use ITL as the only predictor. FCP and CRP are considered as the most universal and typical biomarkers of inflammatory evaluation in IBD, also verified to be the independent risk factors of adverse endoscopic outcomes. The study confirmed that combining blood trough level with inflammatory biomarkers contributed to improving the accuracy of the prediction on endoscopic outcomes. A post hoc analysis from the CALM study manifested that CD patients with FCP ＜ 250 μg/g mostly achieved CDEIS ＜ 4 without deep ulceration, regardless of whether CRP ＜ 5 mg/L. However, among patients with CRP ＜ 5 mg/L but FCP ≥ 250 μg/g, only 16.7% achieved CDEIS ＜ 4 without deep ulceration[20]. The result indicated that the correlation between FCP normalization and endoscopic mucosal healing in CD patients was stronger than that of CRP normalization. A previous study verified that FCP is suitable for distinguishing mild endoscopic activity from endoscopic remission, while it is difficult to distinguish partial endoscopic remission from complete endoscopic remission[21]. Similar to blood trough level, the optimal cut off value of FCP for distinguishing endoscopic activity from endoscopic remission ranges from 71 μg/g to 250 μg/g with moderate diagnostic performance[22-27].The study identified that FCP ＞ 276 μg/g predicted endoscopic activity at week 54 of CD patients with clinical remission at week 14 moderately with 84.6% sensitivity and 92.1% specificity. Unlike FCP, the sensitivity of CRP to mild intestinal inflammation was low and the level of CRP increased much more dramatically in CD patients with moderate to severe inflammation. Therefore, the previous study preferred to utilize CRP to distinguish moderate to severe endoscopic activity from mild to moderate endoscopic activity rather than distinguish mild endoscopic activity from endoscopic remission. A Spanish study showed that FCP ＞ 155 μg/g in combination with CRP ＞ 6.7 mg/L could identify endoscopic activity with 82% specificity[27].

However, the study has shortcomings in some areas. Firstly, the retrospective single-center study with small sample, inferior to prospective multi-center with greater sample, comprised some confounding factors. More real-world studies and randomized controlled trials on guidance significance of ITL to therapeutic outcomes in IBD need to be conducted. Secondly, the study primarily concentrated on mucosal inflammation located in large intestine, ignoring small intestine due to the high cost and the incomplete scoring system of small intestinal evaluation accompanied by the poor compliance of patients and the laborious operation of endoscopists. Correlation between ITL and various small intestinal examinations including endoscopy or imageology may be the focus of the future study. Last but not least, definition of deep remission on CD has been tightened. Considering transmural inflammation of CD, endoscopy is confined to mucosal inflammation and macroscopical evaluation while imageology can accurately evaluate complete volume of intestinal wall and histopathological examination, which contributes to microscopical examination. Notwithstanding endoscopic remission considered as the main targets and histological remission considered as a novel target, the new concept of ‘disease clearance’, which includes clinical, endoscopic and microscopic remission, has drawn more and more attention from IBD physicians and may bring about a new upsurge of studies on IFX monitoring and new therapeutic targets[28].

CONCLUSION

In conclusion, during IFX maintenance treatment, low ITL, high CRP level and high FCP level were independent risk factors of long-term adverse endoscopy outcomes in CD patients with clinical remission. Combination of ITL, CRP and FCP contribute to long-term endoscopic prognosis monitoring.The best cut off values of ITL for predicting endoscopic activity within 1-year follow up were 5.60 μg/mL at week 14 and 2.10 μg/mL at week 54. In addition, ITL ≤ 5.60 μg/mL in combination with FCP＞ 238 μg/g at week 14 as well as ITL ≤ 2.10 μg/mL in combination with CRP ＞ 3.00 mg/L at week 54 increased the precision of prediction on endoscopic outcomes at week 54 and week 108, respectively.Therapeutic optimization is still recommended in CD patients achieving endoscopic remission,provided that low ITLs or high levels of inflammatory biomarkers, such as CRP or FCP, arise to prevent endoscopic recurrence as soon as possible.

ARTICLE HIGHLIGHTS

Research conclusions

The best cut off values of ITL for predicting endoscopic activity within 1-year follow up was 5.60 μg/mL at week 14 and 2.10 μg/mL at week 54. In addition, ITL ≤ 5.60 μg/mL in combination with FCP ＞ 238 μg/g at week 14 as well as ITL ≤ 2.10 μg/mL in combination with CRP ＞ 3.00 mg/L at week 54 increased the precision of prediction on endoscopic outcomes at week 54 and week 108, respectively.

Research perspectives

In view of the fact that conduction of intensive monitoring for biological management plays a vital role in precise treatment for CD patients, much larger and more stringent prospective studies are warranted to provide the best predictive models as acknowledged globally in allusion to long-term endoscopic outcomes of CD patients under IFX therapy.

ACKNOWLEDGEMENTS

The authors would like to thank Dr. Bin Lv, Full Professor and Chief Physician at the First Affiliated Hospital of Zhejiang Chinese Medical University, Department of Gastroenterology, for his help in revising this paper, and Shan Liu, at the First Affiliated Hospital of Zhejiang Chinese Medical University, Clinical Evaluation Center, for help with statistical analysis.

FOOTNOTES

Author contributions:Fan YH designed the research; Cao WT performed the research; Cao WT and Liu S analyzed the data; Cao WT, Huang R, Ni H and Xu MS wrote the paper; Xu Y supervised the paper; All authors have read and approve the final manuscript.

Supported byNational Natural Science Foundation of China, No. 81473506 and No. 81971600; Zhejiang TCM Science and Technology Project, No. 2019ZA056, No. 2021ZA057 and No. 2016ZA077.

Institutional review board statement:This study was reviewed and approved by the ethics committee of the First Affiliated Hospital of Zhejiang Chinese Medical University, No. 2021-KL-024-02.

Informed consent statement:All study participants, or their legal guardian, provided informed written consent prior to study enrollment.

Conflict-of-interest statement:The authors declare that they have no conflict of interest.

Data sharing statement:Some or all data, models, or code generated or used during the study are available from the corresponding author by request. People could contact the corresponding author to get the data which is not used for commercial purposes.

Open-Access:This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

Country/Territory of origin:China

ORCID number:Wan-Ting Cao 0000-0001-7277-4492; Rong Huang 0000-0002-8360-7777; Shan Liu 0000-0001-9139-3257;Yi-Hong Fan 0000-0001-8217-9793; Mao Sheng Xu 0000-0002-2396-1600; Yi Xu 0000-0002-3265-9534; Hui Ni 0000-0001-8973-8834.

S-Editor:Ma YJ

L-Editor:Filipodia

P-Editor:Cai YX