Long-term durability of infliximab maintenance therapy incorporating plant-based diet in inflammatory bowel disease

Introduction

Background

Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by repetition of relapse leading to a disabling course or bowel surgery. The latter is particularly common in CD. Because teenagers and young adults are most frequently affected, relapse prevention and maintenance of remission is of paramount importance.

Biologics became available more than 25 years ago, and they revolutionized therapy in medicine including IBD (1). Biologics are indicated for cases unresponsive to conventional therapies in IBD. Biologics are effective for induction and maintenance of remission and reducing hospitalization and surgery in IBD (2-5). The use of biologics is increasing. In Europe, biologics are used in 69.7% of patients with CD and 43.5% of patients with UC (6). In addition, because early use of biologics is more effective than late use, there is a tendency toward earlier use of biologics after diagnosis from years to months (1,7).

Infliximab, anti-tumor necrotizing factor (TNF) α antibody, was the first biologic utilized in IBD (1). Among biologics, infliximab is most frequently used, followed by adalimumab, vedolizumab, and ustekinumab (6). Therefore, there are a lot of data on infliximab. Induction therapy with infliximab is standardized: three infusions (5 mg/kg) at 0, 2, and 6 weeks. Responders subsequently receive scheduled maintenance therapy every 8 weeks (1). This modality is the same for both CD and UC. However, there are limitations. A proportion of patients (10–40%) are primary nonresponders to infliximab (8), and secondary loss of response is seen in a considerable number of patients during the maintenance phase. The latter occurs in 30–46% of CD patients within 1 year, and the majority of these patients (50–70%) regain response with dose intensification, i.e., dose escalation and/or shortening the interval between infliximab infusions (9). Failure to regain a response leads to withdrawal of maintenance therapy.

Rationale and knowledge gap

Efficacy and adverse reactions are always a concern with the use of a new drug in a patient. Although there are new medications such as biologics and small molecules, no medication for definite induction in all patients is available. There is a barrier of primary nonresponders to biologics as described above (8). The net remission rates calculated based on remission rates in the induction and maintenance phases are less than 35% at around 1 year for biologics including infliximab, adalimumab, ustekinumab, and vedolizumab in CD (10). Therefore, doctors want to continue effective medication(s) as long as possible.

IBD tends to manifest in individuals with genetic predispositions, typically in affluent regions where environmental triggers are more prevalent. Although no universal environmental cause has been definitively established, our earlier studies point to a notable link between IBD and westernized dietary patterns (11,12). Westernized dietary patterns are commonly high in animal-derived fats and proteins, and low in carbohydrates. Increased consumption of sugar among carbohydrates is also characteristic of westernized dietary patterns (13). Therefore, we recommend that all patients with IBD, including those newly diagnosed, undergo hospitalization to experience a lacto-ovo-vegetarian plant-based diet (PBD) as a therapeutic alternative to conventional western eating habits (14). The total number of patients with CD and UC treated with our modality incorporating a plant-based diet between 2003 and 2020 were 70 and 170, respectively (14-18). This approach has demonstrated superior clinical outcomes compared to standard treatments during both active disease and remission phases in CD and UC (14-18). By integrating our clinical data with recent insights from epidemiological, nutritional, microbiological, immunological, and omics-based studies, we were the first to recommend PBD for IBD in the academic literature (19-21).

There are no reports in the literature of scheduled maintenance therapy in IBD with a modality incorporating PBD. There are no criteria for evaluating the efficacy of maintenance therapy with infliximab. Some researchers regarded the dose intensification as relapse (22). There are difference in criteria for the starting dose intensification among researchers: appearance of abnormal biomarker(s) with or without symptoms. The former is conventionally recognized as a relapse and the latter is not. As stated above, doctors and patients want to continue taking effective medication(s) as long as possible. Because biologic agents are pretty expensive, infliximab is immediately withdrawn upon judging it to be ineffective. From these, it seems appropriate that outcomes of infliximab maintenance therapy can be assessed based on the durability of maintenance therapy.

Objective

The aim of this single group study was to investigate the durability of scheduled maintenance therapy with infliximab incorporating PBD. This manuscript is presented in accordance with the TREND reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-162/rc).

Methods

Design and settings

We designed a single-group, non-randomized, open, non-control trial, which was conducted at Akita City in northern Japan. This city has a population of 315,000 individuals. Both Nakadori General Hospital and Akita City Hospital are tertiary care hospitals in Akita City. MC, the first author, worked for the former between 2003 and 2012 and has been working for the latter since 2013.

Protocols of this study were approved by the Ethical Committee of Nakadori General Hospital and by the Ethical Committee of Akita City Hospital (Protocol numbers: 19-2003, 12-2013, and 17-2014). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from all individual participants. The study started in 2008 for CD and 2011 for UC following the approval of infliximab for maintenance therapy in Japan.

Patients

Based on our assertion that IBD is a lifestyle disease mediated mainly by a westernized diet, all patients with IBD were advised to be admitted once to experience PBD and to learn how to combat this lifestyle disease. Because the majority of CD patients are destined for a clinical course of disability, and because glucocorticoid therapy for severe UC, the current standard first-line therapy, is unsatisfactory, we provided infliximab and a plant-based diet as first-line (IPF) therapy for these cases (15,17). Infliximab monotherapy without immunomodulators was used only in the induction phase and was not continued in the quiescent phase. The details and outcomes of IPF therapy have been described previously (15,17,18). Relapsed cases after successful induction with the IPF therapy were eligible for infliximab maintenance therapy (Table 1). Clinical remission with C-reactive protein (CRP) levels above the reference range (≤0.3 mg/dL until March 2013, ≤0.19 from April 2013 to March 2017, ≤0.14 after April 2017) even after a few months of the induction phase was judged as unstable remission. Patients with unstable remission and patients with a response but not remission were followed with infliximab maintenance therapy. Another indication for the maintenance therapy was UC patients with chronic continuous type or steroid dependency. Post-bowel surgery CD patients were included for prevention of relapse (23) (Table 1).

Protocol: scheduled infliximab maintenance therapy

Relapsed cases that were either symptomatic or asymptomatic after the IPF therapy were retreated with standard infliximab induction therapy and PBD before the initiation of scheduled infliximab maintenance therapy (Figure 1). Asymptomatic relapse means active inflammatory findings on endoscopy despite an absence of symptoms. Infliximab (5 mg/kg) was infused at weeks 0, 2, and 6 (24). Azathioprine was not co-administered, except for those already on the drug. In cases in the quiescent phase, the maintenance therapy was initiated without the reinduction therapy (Figure 1).

Figure 1 Schedule of infliximab maintenance therapy after or without induction therapy. The number of patients is 15 for the former and nine for the latter. During hospitalization (yellow paint), infliximab was infused, and a PBD was served. PBD, plant-based diet.

Scheduled maintenance therapy was provided every 8 weeks on an inpatient basis (2-day hospitalization) (Figures 1,2). There were several reasons for inpatient maintenance therapy rather than outpatient therapy in our study. First, it was for safety reasons. Since the introduction of infliximab, immediate adverse drug reactions, infusion reactions to infliximab, have been well known (24). With hospitalization, a swift response is possible for unexpected infusion reaction(s) (25). Second, inpatient therapy would be a starker reminder to patients of the grave clinical course than outpatient therapy. IBD has been designated an intractable disease in Japan, and patient medical fees are supported by the national insurance system. The monthly upper limit of copayment for high medical costs is anywhere from free to ¥20,000 depending on annual income (The Ministry of Health, Labour and Welfare, Japan) (26). Thereby, doctors can use biologics without serious concern for the patient’s economic burden. Patients with IBD and doctors are to appreciate our nation’s medical system for the great support for medical expenses including biologics. Third, responsible doctor (M.C.) can assess the condition of patients more accurately by meeting patients more than once. Fourth, the patient’s work colleagues, or the patient’s school would further understand the nature of IBD.

Figure 2 Infliximab maintenance therapy during hospitalization. PBD, plant-based diet.

On admission, vital signs and body weight were checked. On the first day, blood tests including complete blood count, erythrocyte sedimentation rate, CRP, total protein, serum albumin, and liver/kidney function tests were performed. A fecal immunochemical test for hemoglobin was also performed. On the second day, infliximab (5 mg/kg body weight) (24) was infused. During hospitalization, patients ate three meals before coronavirus disease 2019 (COVID-19) and four meals after COVID-19. Before COVID-19, patients were admitted at 2:00 p.m., while after COVID-19, patients were required to come in the morning for a COVID-19 test (Figure 2). The details of PBD have been described previously (14). Briefly, PBD comprised a lacto-ovo-vegetarian diet with fish once a week and meat once every 2 weeks (14). Protein, fat, and carbohydrates accounted for 16.1%±0.5%, 18.6%±1.4%, and 66.1%±1.6% of total calories, respectively. PBD contained 32.4±2.1 g of dietary fiber/2,000 kcal (soluble dietary fiber 6.8±0.7 g, insoluble dietary fiber 23.3±1.6 g) (14). About 30 kcal per kg standard body weight was provided. Patients were instructed to continue the diet after discharge.

Follow-up studies

The original scheduled maintenance therapy was continued for asymptomatic patients with normal CRP levels. When symptoms appeared with elevated CRP, intensification of infliximab therapy was initiated: an increase in dose most often from 5 to 7.5 mg/kg and/or decrease in infusion interval most often from 8 weeks to 6 weeks. Scheduled maintenance therapy was discontinued when the intensification failed to regain a response or turned out to be ineffective. Such patients had substantial difficulties in daily life. Change of medication, hospitalization or surgery was needed. The maintenance therapy was also discontinued if a significant adverse event occurred.

Four criteria for termination of infliximab maintenance therapy were set for favorable patients: asymptomatic with consecutive normal CRP and negative fecal immunochemical test for hemoglobin for at least for 2 years, in addition to absence of active findings on ileo-colonoscopy.

The duration of maintenance therapy was defined as the time between the first and the last scheduled infliximab infusions.

Food-frequency questionnaire and plant-based diet score (PBDS)

A questionnaire investigating dietary habits and lifestyle factors prior to disease onset was administered promptly after the patient’s initial admission, as previously outlined (27). The same questionnaire was re-administered during short-term (≤2 years) or long-term (>2 years) follow-up. PBDS for Japanese IBD patients was calculated from the questionnaire. They were designated as baseline PBDS, short-term PBDS, and long-term PBDS, respectively.

The procedure for calculating the PBDS has been outlined in an earlier publication (27). In brief, eight dietary items identified as protective against IBD (vegetables, fruits, pulses, potatoes, rice, miso soup, green tea, and plain yogurt) were assigned positive points (PBDS+), whereas eight items regarded as increasing IBD risk (meat, minced or processed meat, cheese/butter/margarine, sweets, sugar-sweetened beverages, alcohol, bread, and fish) contributed negative points (PBDS−). Consumption frequencies were scored as 5 points for daily intake, 3 points for 3–5 times per week, and 1 point for 1–2 times per week. The total PBDS was obtained by summing the positive and negative points, with possible scores ranging from −40 to +40. A higher PBDS reflected greater compliance with the PBD. During hospitalization, the PBDS achieved for the PBD was 35 (27).

Assessment of the efficacy of scheduled infliximab maintenance therapy incorporating PBD

The primary endpoint was the durability of infliximab scheduled maintenance therapy. The secondary end point was change over time in PBDS.

Safety evaluations

Safety evaluations comprised vital signs, patient-reported symptoms, observations from physician and nurse rounds, findings from physical examinations, and the results of blood tests at scheduled visits.

Statistical analysis

Demographic data were presented as mean ± standard deviation (SD) and/or median (interquartile range), as appropriate. Statistical comparison tests (the χ² test, Wilcoxon’s rank sum test) were performed between CD cases and UC cases. Changes over time in PBDS+, PBDS−, and overall scores in the same individuals were analyzed using the paired t-test. Kaplan-Meier analysis was employed to evaluate the continuation rate of infliximab maintenance therapy. Comparison of durability rates of infliximab maintenance therapy between CD patients and UC patients was assessed using the log rank test. All tests were two-sided, with significance defined as a P value ≤0.05. Statistical analyses were carried out using JMP 17 software (SAS Institute, Inc., Cary, NC, USA).

Results

Characteristics of patients

In CD, there were 11 relapsed cases after IPF therapy (15) (10 symptomatic and one asymptomatic relapse). There were five patients who had bowel surgery. One of those patients relapsed and was eligible for maintenance therapy. Prevention of relapse after surgery was indicated in the other four patients (23). These 16 CD cases were eligible for scheduled maintenance therapy (Figure 3). After IPF therapy for severe UC (17), there were two cases with unstable remission or response. These two cases were followed with infliximab maintenance therapy. Relapse occurred in four cases after remission with IPF therapy. There was one case each with chronic continuous type or steroid dependency. In UC, these eight cases were eligible for scheduled maintenance therapy (Figure 3). One of the eight cases was duplicated with an intermission of 20 months. The first infliximab maintenance therapy combined with azathioprine was terminated due to thrombocytopenia, as described below. Twenty months later, the second maintenance therapy with infliximab monotherapy was initiated without azathioprine. Altogether, 24 cases were included in the study (Figure 3). Fifteen of 24 cases received standard infliximab induction therapy with PBD during hospitalization for either 6 weeks (n=7) or 3 weeks (n=8). The remaining nine cases received maintenance therapy without standard induction therapy (Figures 1,3).

Figure 3 Indication for infliximab maintenance therapy. IPF therapy, infliximab and a plant-based diet as first-line therapy. CD, Crohn’s disease; PBD, plant-based diet; UC, ulcerative colitis.

The demographics of CD patients, UC patients, and all patients including the Montreal classification of IBD (28) are presented in Table 2. Males were predominant in both diseases. The mean age was younger in CD (26.1 years old) than UC (44.7 years old). The median disease duration from onset of symptoms to the first infliximab infusion of maintenance therapy was 51.5 months for CD and 79.0 months for UC. CRP levels at initiation of maintenance therapy were normal in 15 patients and abnormal in nine patients. Bowel surgery was performed previously in five CD patients. All patients were non-smokers. The immunosuppressant, azathioprine, was used in five patients (Table 2).

Efficacy

Primary endpoint: durability of scheduled infliximab maintenance therapy

The median follow-up period was longer in CD (83 months) than UC (45 months) (Table 2). There were four withdrawals from the maintenance therapy. Two patients with CD had lost response to therapy. One patient switched to adalimumab after 2 years, and the other patient underwent subtotal colectomy with ileostomy after 10 years. Two patients with UC withdrew due to side effects of medication. One patient had trouble breathing and experienced flushing during the 8th infliximab infusion (13 months after the first infusion). This patient remained in remission without scheduled maintenance therapy. The other patient withdrew after the 9th infusion (14 months after the first infusion) due to progressive thrombocytopenia. This patient was able to resume and continue infliximab monotherapy without azathioprine 20 months later.

Durability rates of the therapy at 1, 3, and 5 years in CD and UC were 100%, 93%, and 93%, and 100%, 75%, and 75%, respectively. There was no difference in durability rates between CD and UC. In total, the durability rates of the therapy were 100% at 1 year and 86% at 3 years, and thereafter at 5 and 10 years (Figure 4).

Figure 4 Kaplan-Meier curve for the durability of infliximab maintenance therapy.

We had only one case who was symptom free with consecutive normal CRP tests and negative fecal immunochemical tests for hemoglobin for more than 2 years. Endoscopy, however, showed small erosions in the terminal ileum. Therefore, the patient was advised to continue the therapy.

Secondary endpoints: change over time in PBDS

A questionnaire of dietary habits and lifestyle behaviors on the first admission was systematically obtained from all patients for the sake of dietary guidance. It was not obtained, however, in the follow up period in several patients. Mean (SD) baseline PBDS+, PBDS−, and PBDS in 23 patients were 19.9 (5.0), 11.4 (5.4), and 8.4 (7.1), respectively. Those in the short term after a median of 12 months of follow up in 11 patients were 34.5 (5.9), 1.7 (2.1), and 32.7 (6.7), respectively. Those in the long term after a median of 111 months (9 years and 3 months) of follow up in 15 patients were 27.9 (6.8), 7.0 (6.2), and 20.9 (9.2), respectively (Table 3). From the short to long term, PBDS+ decreased, while PBDS− increased, resulting in a decrease in PBDS (Table 3). All scores in the follow up period were significantly different compared to those at baseline according to the results of paired t-test: higher in PBDS+ and PBDS, and lower in PBDS− (Table 3, Figure 5).

Figure 5 Change overtime in PBDS. Green, yellow, and black columns show positive, negative, and final score for PBDS, respectively (mean ± SD). All three scores in the short (median duration after the first hospitalization provided by plant-based diet was 1 year) and long term (median duration 9 years and 3 months) were significantly different from those at baseline (*) (Table 3). PBDS, plant-based diet score; SD, standard deviation.

Safety

The side effects of medication in two patients resulted in withdrawal of maintenance therapy, as described above. Stopping the infliximab infusion was the only intervention necessary in one case. In the other case, thrombocytopenia resolved after withdrawal of infliximab and azathioprine. Thrombocytopenia did not occur after resumption of infliximab maintenance monotherapy without azathioprine. There were no serious adverse events in this study.

Discussion

Key findings

In this study, durability rates of infliximab maintenance therapy incorporating PBD at 1 year and 3 to 10 years were 100% and 86 %, respectively. This is the highest durability rate in literature.

Strengths and limitations

There are limitations with our small sample size. Assessment of the trough level of infliximab and antibody formation to infliximab are not routinely available in Japan. Nevertheless, our study showed a longer durability of infliximab maintenance therapy than others.

Comparison with similar researches

Data on maintenance therapy are primarily available for infliximab. Earlier studies on maintenance therapy with infliximab were heterogenous in their methods in induction and maintenance. Thereafter, a method was standardized: the standard induction therapy at 0, 2, and 6 weeks followed by maintenance therapy every 8 weeks (1). The present study followed this method. Although there is heterogeneity in indication and prior or concomitant medication, reports describing the durability of infliximab maintenance therapy in IBD at 5 years or more are presented in Table 4 (3,7,29-36). Durability rates at 5 years were 50–78% in most of the reports including reports from Japan (31,33), the same country as the present study. Two studies found a longer durability in CD than UC (7,32). Concurrent immunomodulators were reported to increase the durability rate at 5 years compared to monotherapy: 70% verses 22% (29) and 58% verses 37% (34) (Table 4). This is not consistent, however, because other studies showed high durability rates, 58–74%, with a low rate of concomitant use of immunomodulation of less than 30% (31,35,36). Smoking, a well-known risk factor for CD (11), was reported to decrease the durability of maintenance therapy (29). Enteral nutrition, which was quite common for adult CD in Japan before the use of biologics, was shown to increase the durability of infliximab maintenance therapy (37). This was used in 71% of patients in a Japanese study (33). In our study, an immunomodulator was used in 21% of patients, which is less than in other studies (Table 4). All smokers with either CD or UC were advised to stop smoking at the first admission to our hospital. Consequently, there were no smokers among our subjects. Enteral nutrition was used in 13% of patients with CD (2/16) in our study (Table 2).

Explanations of findings

How can the high durability rate in this study compared to that in other reports be explained? The factors described above cannot explain this. The other difference between ours and other reports is that maintenance therapy was executed on an inpatient basis in the former and on an outpatient basis in the latter. Inpatient maintenance therapy with infliximab compelled our patients to consume PBD. In this study, a half of patients (12/24) relapsed after IPF therapy and repeated the same induction therapy, followed by maintenance therapy. Repetition of PBD in the induction phase and periodic consumption of the PBD during maintenance therapy likely enhanced adherence to PBD. Their PBDS were significantly higher than those at base line even after a median of 9.3 years of follow up (Table 3; Figure 5). It is remarkable because improved outcomes with a trial healthy diet return to baseline within 1 year of follow up in many studies (38,39). Periodic meetings with nurses, nutritionists, pharmacists, and clerks during hospitalization might encourage patients to fight against the disease.

Implications and actions needed

A new issue is the timing of withdrawing maintenance therapy (40). Discontinuation of maintenance therapy with anti-TNF therapy frees the patient from worry over possible side effects of long-term use of medication. It also decreases the patient’s and national medical cost. However, unlike UC, the relapse rate after cessation in CD is remarkably high. About half of patients will relapse at about 5 years (40). Relapse even occurs in patients with complete deep remission, i.e., the concurrent remission in symptomatology, biomarkers, endoscopy, and histology (41). Therefore, at the moment, cessation of maintenance therapy is not recommended in CD (40,41). There were no patients who satisfied the four criteria for cessation of maintenance therapy in this study. Endoscopic findings of small erosions in the terminal ileum prevented cessation. Later, we learned that endoscopic remission was not necessarily required for long-term remission (18). Whether small lesion(s) such as aphtha and ulcers in patients with consistent normal biomarker(s) are determinant of future relapse warrants investigation.

Our series on the outcomes with a modality incorporating PBD in IBD is going to end. This study was the last one. Our outcomes exceeded those of the current standard therapy in both CD and UC in both the induction and quiescent phases (14-18,21). Twenty-one years ago, when PBD was provided to all patients with IBD, the first author (M.C.) was anxious for outcomes of PBD in IBD (14). Later, fundamental biomedical research has highlighted the relationship between dietary intake, gut microbiota and their metabolites, and disease processes. These findings indicate that westernized diets often promote inflammation, while PBDs are associated with anti-inflammatory properties (21). Now we realize that the current modality in IBD lacks countermeasures against an environmental factor(s) despite the widely appreciated recognition that IBD is triggered by an environmental factor(s) in wealthy societies. Our excellent outcomes are thought to be a result of the new therapeutic modality incorporating countermeasure against the most plausible environmental factor in IBD, i.e., a plant-based diet. Our outcomes strengthen our assertion that the ubiquitous environmental factor in IBD is our current westernized diet (11). We hope our observation is more widely appreciated so that patients with IBD can lead better lives.

Conclusions

Infliximab maintenance therapy incorporating plant-based diet yielded a high durability rate of 87% at 5 years in patients with IBD.

Acknowledgments

The authors thank Miki Yamada and Kimiko Yamada, registered dietitian, and other staff of the Dietary Division of Nakadori General Hospital and Akita City Hospital for providing plant-based diet and dietary guidance.

Footnote

Reporting Checklist: The authors have completed the TREND reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-162/rc

Data Sharing Statement: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-162/dss

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-162/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-162/coif). The authors have no 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. Protocols of this study were approved by the Ethical Committee of Nakadori General Hospital and by the Ethical Committee of Akita City Hospital (Protocol numbers: 19-2003, 12-2013, and 17-2014). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from all individual participants.

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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