Introduction

Crohn’s disease (CD) is a chronic inflammatory bowel disease common among young people in their late teens and early 20 s. In recent years, the number of CD patients in Asia, including Japan, has increased1,2. As of 2014, the number of CD patients in Japan was estimated to be 70,7003. Although the etiology of CD is currently unknown, it is considered to be a multifactorial disease caused by a combination of environmental and genetic factors. Many patients require intestinal surgery during the course of CD. The cumulative operative rate within 10 years of CD diagnosis is approximately 44–50%4. The recurrence rate of CD is high even after surgery, and controlling intestinal inflammation with medical therapy is important5 to prevent repeat surgeries and improve patients’ prognosis.

Antibody preparations against the inflammatory cytokine tumor necrosis factor alpha (TNFα), drugs such as Infliximab and Adalimumab, can be used in patients with CD8,9. In addition, Ustekinumab, an anti-IL-12/23p40 monoclonal antibody; Janus kinase (JAK) inhibitor; and Vedolizumab, monoclonal antibodies targeting α4β7 integrin heterodimers have been used to induce or maintain remission of CD10,11.

In patients with CD who have undergone ileal resection and have no residual disease, 1 year of maintenance therapy with infliximab started within 4 weeks postoperatively significantly reduces endoscopic recurrence at 1 year12. In the POCER study, which examined the usefulness of endoscopy in evaluating postoperative recurrence and the efficacy of intensified treatment when early mucosal lesions are detected, adalimumab-treated patients had significantly fewer recurrences than patients treated with thiopurine13. Planned adalimumab maintenance therapy after surgery has also been shown to be beneficial in Japanese patients with CD14. Thus, postoperative administration of anti-TNFα antibodies may be effective in preventing postoperative recurrence of CD. However, the efficacy of intensified treatment in cases in which the therapeutic effect is attenuated during preoperative maintenance therapy, called loss of response (LOR), is unknown. Few studies have analyzed the relationship between preoperative anti-TNFα antibody treatment history and postoperative recurrence. The purpose of the present study was to examine this relationship.

Patients and methods

Patients

One hundred and fourteen consecutive patients with CD who underwent surgical bowel resection and anastomosis for CD related inflammatory indications of other than malignancy from 2009 to 2021 were included in this study. All patients underwent treatment and follow-up at Osaka University Hospital.

Assessment of clinical features

Gender, age at surgery, age at diagnosis, BMI, surgical history, lesion location, blood test results, and CD treatment history were collected retrospectively from the patients’ records. The dosage of infliximab approved by the Japanese regulatory authorities for the treatment of CD is 5 mg per kg of body weight as a single intravenous infusion, administered again 2 weeks, 6 weeks, and 8 weeks after the initial dose. For adalimumab, 160 mg is injected subcutaneously for the first dose, 80 mg 2 weeks later, and 40 mg every 2 weeks thereafter. For patients with a diminished response to infliximab, doubling the dose, shortening the dosing interval to every 4–7 weeks, or switching to adalimumab are acceptable alternatives. For patients with a diminished response to adalimumab, the dose can be doubled or the treatment switched to infliximab.

The patients were divided into two groups to determine the relationship between preoperative use of anti-TNFα antibodies and postoperative recurrence. The TNFα Group was defined as patients who used anti-TNFα antibodies preoperatively, and the Non-TNFα Group was defined as patients who did not use anti-TNFα antibodies preoperatively. In addition, the TNFα Group was divided into two groups to evaluate the association between intensified treatment for preoperative anti-TNFα antibody attenuation and postoperative recurrence. The LOR Group consisted of patients who received double doses of anti-TNFα antibody, a shortened dosing regimen, or drug modification after weakening of the anti-TNFα antibody efficacy, whereas the Non-LOR Group consisted of patients who received a standard dose of anti-TNFα antibody before surgery (Fig. 1). In the introduction of biologics, anti-TNFα antibody were introduced first in all cases, and Ustekinumab, Vedolizumab and JAK inhibitors were not used prior to anti-TNFα antibody. The LOR for biologics is defined as a deviation from the state of remission after the introduction of biologics, i.e. IOIBD 0 or 1 and a state where both the erythrocyte sedimentation rate and CRP are within the institutional reference range, or when the attending physician judges that there has been a relapse based on endoscopic examination. Our department’s postoperative medical treatment policy was to not administer prophylactic anti-TNFα antibodies to the Non-TNFα Group and to resume the dose of anti-TNFα antibodies from before surgery in both the LOR and Non-LOR Groups, with treatment intensified according to the results of the first postoperative endoscopic examination.

Fig. 1
Fig. 1The alternative text for this image may have been generated using AI.
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Patient selection. Anti-TNFα, anti-tumor necrosis factor α; LOR, loss of response.

Postoperative follow-up and diagnosis of recurrence

After surgery, patients were followed up as outpatients once every 1–3 months. As a rule, lower endoscopy, ileal endoscopy, and double-balloon endoscopy were performed 6–12 months after surgery, even in the absence of symptoms. Thereafter, endoscopy was performed every 1–2 years. The Crohn’s Disease Activity Index (CDAI) was used to assess symptomatic recurrence, defined as CDAI ≥ 220. The Rutgeerts score (RS) was used to assess endoscopic recurrence, defined as RS ≥ i215,16.

Statistical analysis

Categorical data were compared using chi-squared or the Wilcoxon rank sum test. The Kaplan–Meier method and log rank test were used to compare endoscopic and symptomatic recurrence in the two groups and to calculate significant differences. P < 0.05 was considered significant. All statistical analyses were performed in JMP statistical software, package 14.0 (SAS Institute Inc., Cary, NC, USA).

Results

Patient characteristics

The characteristics of the 114 patients with CD who underwent surgical bowel resection and anastomosis for CD related inflammatory indications other than malignancy are provided in Table 1. The patients were mainly those who underwent initial surgery, and all patients who received biologics preoperatively were first treated with TNF agents; of those who received intensified biologic therapy before surgery after the TNF agents had diminished their efficacy, 11 patients switched to Ustekinumab and 2 patient switched to Vedolizumab. There were no cases of preoperative use of JAK inhibitors.

Table 1 Patient characteristics.
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Clinical features of the TNF groups

Anti-TNFα antibodies were used preoperatively in 74 patients. We found no differences between the TNFα and Non-TNFα Groups with respect to age at surgery, gender, BMI, preoperative CRP levels, preoperative CDAI, or corticosteroid use. However, there were significantly more cases of repeated surgery and preoperative albumin levels were significantly lower in the TNFα Group. Also, the number of patients using immunomodulatory drugs was significantly higher in the TNFα Group (Table 2).

Table 2 Patient characteristics according to TNFα treatment.
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Clinical features of the LOR groups

Of the 74 patients who used preoperative anti-TNFα antibodies, 43 received intensified treatment for decreased efficacy of the antibodies. We found no difference between the LOR and Non-LOR Groups in terms of age at surgery, gender, BMI, surgical history, preoperative albumin level, preoperative CRP level, preoperative CDAI, presence of immunomodulatory drugs or corticosteroid use (Table 3).

Table 3 Patient characteristics according to loss of response (LOR).
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Endoscopic and symptomatic relapse and recurrence

The median follow-up period was 84 months. Figure 2 shows the endoscopic and symptomatic recurrence-free periods and the time elapsed without requiring reoperation for 111 patients.

Fig. 2
Fig. 2The alternative text for this image may have been generated using AI.
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Postoperative endoscopic and symptomatic relapse-free duration and operation-free duration. RS, Rutgeerts score; CDAI, Crohn’s disease activity index.

The time to postoperative endoscopic recurrence was significantly shorter in the TNFα Group than the Non-TNFα Group (p = 0.0055; Fig. 3a). The time to postoperative symptomatic recurrence was not significantly different between the two groups (Fig. 3b). In addition, we found no predominant difference in time to postoperative endoscopic recurrence-free or time to symptomatic recurrence between the LOR and Non-LOR Groups (Fig. 4).

Fig. 3
Fig. 3The alternative text for this image may have been generated using AI.
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Endoscopic and symptomatic relapse-free duration based on preoperative anti-TNFα agent use. Anti-TNFα, anti-tumor necrosis factor α.

Fig. 4
Fig. 4The alternative text for this image may have been generated using AI.
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Endoscopic and symptomatic relapse-free duration based on the loss of response (LOR) after preoperative anti-TNFα with intensified treatment.

Discussion

The outcome of CD has improved dramatically with advances in medical therapy, especially biologic agents17. However, the emergence of a LOR to anti-TNFα antibodies has been problematic, with an attenuated therapeutic response reported to occur in approximately 37% of cases18. LOR is typically seen in 20% to 30% of patients, but approximately 10% of cases each year and nearly half of cases in 5 years have been reported to experience LOR19. The primary mechanism of LOR is thought to be a decrease in blood and tissue levels of anti-TNFα antibody. Anti-infliximab and anti-adalimumab antibodies have been reported as a possible cause20,21. As the main cause of LOR is a decrease in blood levels, the ACCENT I study increased the dose in 40 patients who initially responded but had lost efficacy by week 54. To avoid a decrease in efficacy during maintenance therapy, 5 mg/kg infliximab was increased to 10 mg/kg, which restored efficacy in 36 patients (90%)22.

In addition to evaluating clinical symptoms, endoscopic evaluation of postoperative recurrence is important23. After resection of the ileum, only 20% of CD patients are symptomatic 1 year postoperatively, but endoscopically recurrent lesions in the anastomotic ileum have been reported in 73% of cases24. Regarding recurrence after ileal resection and anastomosis, small aphthous ulcers appear on the ileal side of the anastomosis within the first postoperative year, and serpiginous ulcers and nodular thickening appear 1 to 3 years postoperatively. Anastomotic stenosis has been shown to occur within 3 to 10 years postoperatively25. The RS is used to evaluate postoperative endoscopy based on these observations. Symptomatic recurrence rates are low for i0 and i1 cases, but high for i2 to i4 cases.

In this study, we examined the preoperative anti-TNFα antibody treatment history and postoperative recurrence. As previously reported, endoscopic recurrence preceded symptomatic recurrence.

Preoperative serum albumin levels were significantly lower in the TNFα-treated group than the untreated group. Lower serum albumin levels are significantly correlated with increased clearance of infliximab, leading to a shorter half-life26. Low serum albumin levels also correlate with postoperative endoscopic recurrence in patients receiving preoperative anti-TNFα antibody therapy27, consistent with a significantly higher incidence of endoscopic recurrence in the TNFα Group than in the Non-TNFα Group. In addition to low serum albumin levels, male sex and high BMI are known factors that increase the clearance of anti-TNFα antibodies28.

One of the main causes of LOR is the appearance of antibodies to biological agents. Patients who develop LOR during preoperative anti-TNFα antibody therapy are considered to have emerging antibodies to anti-TNFα antibodies and are likely to relapse even with postoperative anti-TNFα antibody therapy.

This study has several limitations. First, it is a retrospective study conducted at a single institution with a small number of patients. Second, the timing of postoperative endoscopy in this study varied from patient to patient. Finally, this study did not measure antibody levels to biologics, a possible cause of LOR. Many new anti-TNFα antibodies have emerged to replace infliximab and adalimumab, as well as antibodies targeting cytokines and chemokines other than TNFα. Postoperative follow-up should consider the history of preoperative antibody therapy.

In conclusion, patients who received preoperative anti-TNFα antibody therapy had a shorter time to endoscopic recurrence than those who did not receive the therapy.