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    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

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    Veterans Affairs Medical Center, Univ. California San Francisco
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    Robert S. Bresalier University of Texas M. D. Anderson Cancer Center, Houston, USA
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Effectiveness of Switching to Subcutaneous Infliximab in Ulcerative Colitis Patients Experiencing Intravenous Infliximab Failure

June Hwa Bae1 , Jung-Bin Park1 , Ji Eun Baek1 , Seung Wook Hong1 , Sang Hyoung Park1,2 , Dong-Hoon Yang1 , Byong Duk Ye1,2 , Jeong-Sik Byeon1 , Seung-Jae Myung1 , Suk-Kyun Yang1,2 , Sung Wook Hwang1,2

1Department of Gastroenterology and 2Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Correspondence to: Sung Wook Hwang
ORCID https://orcid.org/0000-0002-6981-7575
E-mail hsw903@gmail.com

Received: July 25, 2023; Revised: October 18, 2023; Accepted: November 27, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut Liver.

Published online June 5, 2024

Copyright © Gut and Liver.

Background/Aims: Studies on elective switching to the subcutaneous (SC) formulation of infliximab revealed comparable efficacy and safety and higher infliximab level than those exhibited by intravenous (IV) infliximab. However, no studies have reported on the effectiveness of SC switching in ulcerative colitis (UC) patients who experienced IV infliximab failure during maintenance treatment.
Methods: This retrospective study included UC patients who had been switched to SC infliximab because of IV infliximab failure, between January 2021 and January 2023. Group A was defined as having clinically and biochemically active UC (secondary loss of response), and group B consisted of patients with stable symptoms but biochemically active UC.
Results: Twenty-three patients met the inclusion criteria: 15 in group A and eight in group B. The serum infliximab levels significantly increased after SC switching in both groups. The electively switched group also exhibited increased infliximab levels after SC switching. Patients in group A showed improved partial Mayo score with a significant decrease in fecal calprotectin and C-reactive protein after switching. In group B, the fecal calprotectin level significantly decreased without clinical relapse after switching. A high proportion of patients (≥80%) in both groups achieved clinical and/or biochemical responses at the last follow-up. During the follow-up period, only two patients in group A discontinued SC infliximab, and only one complained of severe injection site reaction.
Conclusions: In UC patients who experience IV infliximab failure during maintenance treatment, switching to SC infliximab may be a promising option because of better efficacy and safety.

Keywords: Ulcerative colitis, Infliximab, Subcutaneous

Inflammatory bowel diseases (IBDs), which include Crohn’s disease (CD) and ulcerative colitis (UC), are chronic, immune-mediated, gastrointestinal disorders that exhibit a relapsing-remitting course.1,2 Newer drugs such as biologics and small molecules have been recently introduced,3 and this expansion of therapeutic options has reshaped the therapeutic strategy for IBD.4-7 Recent guidelines recommend the use of biologics and small molecules for the treatment of moderately to severely active UC and CD while emphasizing the importance of tight monitoring and a treat-to-target approach to achieve the treatment goals of IBD.3,8-10 Among the feasible treatment targets, C-reactive protein (CRP) and fecal calprotectin (FC), which are the most widely utilized biomarkers in clinical practice, were emphasized in the STRIDE-II guideline.8

Infliximab, a monoclonal antibody targeting tumor necrosis factor α, is one of the most commonly prescribed biologics with the highest efficacy for IBD patients.11-13 However, a significant proportion of IBD patients treated with intravenous (IV) infliximab experience nonresponse or loss of response (LOR), thus necessitating either a dose escalation of IV infliximab or switching to another biologic/small molecule agent.14-16 Unfortunately, in several countries, including South Korea, the healthcare system or insurance programs do not permit the dose escalation of IV infliximab in such cases (e.g., up to 10 mg/kg every 8 weeks or 5 mg/kg every 4 weeks). Recently, a new subcutaneous (SC) formulation of infliximab, namely, CT-P13 SC, has been developed,17 and it has shown comparable efficacy and safety with improved acceptability.12,18 Interestingly, pivotal studies have shown that switching from IV to SC formulation can lead to increased serum infliximab levels.12,13 This observation suggests that such a switch may serve as a promising option for UC patients who have failed to maintain response after the induction of IV infliximab. However, there is limited evidence available for patients with active UC who have experienced IV infliximab failure. Only one case series has been reported, involving four CD patients who experienced failure with IV infliximab.19

In this study, we assessed the clinical and biochemical responses after switching from IV to SC infliximab in UC patients who experienced a clinically and/or biochemically active disease during maintenance treatment of IV infliximab. Additionally, we investigated the pharmacokinetic profiles after SC switching in patients with active UC comparing them with those in patients with stable UC who underwent elective SC switching.

1. Patients and study design

The IBD registry has been prospectively maintained since 1997 at Asan Medical Center, which is a tertiary university hospital in Korea, and it has been previously described in detail.20 From the IBD registry, a total of 41 adult patients who had been switched from IV infliximab to SC infliximab (CT-P13) between January 2021 and January 2023 were retrospectively recruited (Fig. 1). Patients who had initially responded to IV infliximab induction but developed aggravated symptoms and/or worsening findings in FC or CRP during maintenance therapy leading to a switch from IV to SC infliximab were included in the analysis. (1) Group A was defined as patients who “required” dose escalation because of clinical relapse (defined as an increase in partial Mayo score of ≥2 points from the previous visits) and biochemical activity (defined as FC >200 μg/g and/or CRP >0.6 mg/dL) at baseline (secondary LOR). (2) Group B was defined as patients who did not show a significant difference in partial Mayo score from the previous visits (differences of 0 to 1 point) but were eligible for “considering” dose escalation because of biochemical activity (FC >200 μg/g and/or CRP >0.6 mg/dL) at baseline (biochemically active). To compare the pharmacokinetic profiles, an additional group (elective switching group) was included in the analysis; this group consisted of patients who electively switched to SC infliximab while on a stable IV maintenance treatment (partial Mayo score ≤2, FC ≤200 μg/g, and CRP ≤0.6 mg/dL). The exclusion criteria were as follows: (1) patients who switched to SC right after IV induction (no IV maintenance); (2) patients who switched back to IV after a single SC injection (single SC injection for long-term trip and poor acceptance of SC formulation); (3) patients with poor adherence who showed irregular injection; or (4) use of infliximab for concurrent ankylosing spondylitis other than UC.

Figure 1.Flowchart of the study. UC, ulcerative colitis; IV, intravenous; SC, subcutaneous.

All patients included in the analysis had a follow-up period of at least 6 months after SC switching, except for two individuals who were followed up for 4 months. The theoretical date of the next IV infusion was considered as “baseline,” and data were collected between 4 and 8 weeks (W4–W8), 12 and 16 weeks (W12–W16), and 24 and 28 weeks after the switch (W24–W28). If there were two measured values within one period, the data from the earlier time point were used. Follow-up data included the partial Mayo score, FC, CRP, and serum infliximab levels at each specified period. FC was measured using EliATM Calprotectin 2 (Phadia GmbH, Freiburg, Germany) on the Phadia 250 system (Thermo Fisher Scientific, Waltham, MA, USA). Fecal samples were refrigerated (2°C–8°C) when collected at home, and they were sent to the Department of Laboratory Medicine within 1 day of collection.21 We also documented the details of adverse events, infliximab discontinuation, and surgery. The Institutional Review Board of Asan Medical Center approved the study protocol (IRB number: 2023-0747). The informed consent was waived.

2. Infliximab treatment

Patients were switched from either originator IV infliximab (Remicade) or IV CT-P13 (Remsima) to SC infliximab (CT-P13). In accordance with the healthcare policy of Korea, dose escalation was not permitted with IV infliximab in UC patients, and all patients were on maintenance treatment with 5 mg/kg IV infliximab at 8-week intervals. All patients who switched to SC infliximab received 120 mg injections every other week. Dose escalation to 240 mg every other week or 120 mg weekly is not permitted. Initially, the SC injections were administered by a healthcare professional, and after receiving adequate training, they were self-administered starting from week 2. During each visit, physicians confirmed adherence to the SC injection schedule and assessed any potential side effects.

3. Drug level and ADA assay

An enzyme-linked immunoassay platform with RIDASCREEN IFX Monitoring (R-Biopharm AG, Darmstadt, Germany) and RIDASCREEN Anti-IFX Antibodies (R-Biopharm AG, Darmstadt, Germany) was used to quantitatively measure the serum infliximab levels and antibodies to infliximab, respectively.22 A predose sample to measure serum infliximab levels was collected at each visit while the physician verified the administration schedule. RIDASCREEN Anti-IFX Antibodies uses a drug-sensitive assay; therefore, it was only included in the analysis when the infliximab concentration in the serum sample was <1 μg/mL.22 Antibody values for infliximab <2.5 ng/mL were classified as undetected according to the manufacturer’s recommendations. For statistical analysis, serum infliximab levels below 0.1 μg/mL (undetectable) were imputed as 0.05 μg/mL, which is half of the lower limit of quantification.23

4. Efficacy outcomes

We evaluated the efficacy of switching to SC infliximab by analyzing the proportions of patients achieving clinical remission, clinical response, and biochemical response at the last follow-up. Clinical remission was defined as partial Mayo score ≤1 point. Clinical response was defined as a decrease from baseline in partial Mayo score ≥2 points, with an accompanying decrease in rectal bleeding subscore of ≥1 point or an absolute rectal bleeding subscore of 0 or 1.12 Biochemical response was defined as a ≥50% decrease in FC level from baseline.24

5. Statistical analysis

Categorical variables were summarized as frequency (%), and continuous variables were summarized as mean and standard deviation or median and interquartile range (IQR). We used the Wilcoxon signed rank test to assess the changes in pharmacokinetics, disease activity index, and biomarkers from baseline to each follow-up. A two-sided p-value <0.05 was considered statistically significant. All analysis was performed using IBM SPSS statistics 21.0 for Windows (IBP Corp., Armonk, NY, USA).

1. Baseline characteristics of the patients

Among the 41 recruited patients who had been switched from IV infliximab to SC infliximab, seven were excluded from this study (Fig. 1). Among the remaining 34 patients, 15 patients were categorized into group A (secondary LOR), and eight patients were categorized into group B (only biochemically active). The remaining 11 patients were on stable maintenance IV infliximab and were electively switched to SC infliximab (elective switching group).

Table 1 shows the baseline characteristics of groups A and B. In group A, seven patients (46.7%) were on concomitant immunomodulatory therapy, and six (40.0%) were on steroids. Three patients (20.0%) were exposed to other biologics before using infliximab. In group B, three patients (37.5%) were on concomitant immunomodulator therapy, and no patients were exposed to other biologics or on steroids at baseline.

Table 1. Baseline Characteristics of Patients Switched to Subcutaneous Infliximab

CharacteristicTotal (n=23)Group A (n=15)Group B (n=8)
Age at diagnosis, yr23.0 (20.0–31.0)22.0 (20.0–53.0)24.5 (17.5–28.8)
Age at baseline, yr34.0 (25.0–50.0)36.0 (25.0–61.0)32.5 (23.8–42.8)
Male sex16 (69.6)12 (80.0)4 (50.0)
Weight, kg76.2±19.176.9±19.974.9±18.6
Body mass index, kg/m226.3±5.926.3±6.526.4±4.9
Disease extent
Proctitis (E1)1 (4.3)01 (12.5)
Left-sided (E2)8 (34.8)6 (40.0)2 (25.0)
Pancolitis (E3)14 (60.9)9 (60.0)5 (62.5)
5-ASA use22 (95.7)14 (93.3)8 (100.0)
Immunomodulator use10 (43.5)7 (46.7)3 (37.5)
Thiopurine7 (30.4)6 (40.0)1 (12.5)
Methotrexate3 (13.0)1 (6.7)2 (25.0)
Steroid at baseline6 (26.1)6 (40.0)0
Other biologics exposure3 (13.0)3 (20.0)0
Infliximab trough level, μg/mL1.6 (0.2–4.3)1.6 (0.1–4.8)2.7 (0.6–4.2)
Partial Mayo score3.0 (2.0–4.0)4.0 (3.0–5.0)1.0 (0.3–2.0)
Fecal calprotectin, μg/g1,236 (417–4,180)2,044 (1,100–4,304)508 (229–1,020)
CRP, mg/dL0.37 (0.10–0.91)0.65 (0.29–1.24)0.15 (0.10–0.58)
Serum albumin, g/dL,4.0 (3.5–4.3)3.9 (3.4–4.3)4.0 (3.9–4.3)
Disease duration at baseline, yr8.0 (2.0–16.0)8.0 (4.0–15.0)12.0 (1.3–18.5)
Duration of IV IFX, wk55.3 (28.1–154.3)44.1 (28.1–154.3)63.8 (24.7–381.3)

Data are presented as median (interquartile range), number (%), or mean±SD. Group A was defined as a patient with clinically and biochemically active state at baseline, and group B was defined as a patient with only biochemically active state at baseline.

5-ASA, 5-aminosalicylate; CRP, C-reactive protein; IV, intravenous; IFX, infliximab.



2. Trends in serum infliximab levels, disease activity index, and biomarkers

Serum infliximab levels significantly increased in groups A and B throughout the study period (Table 2, Fig 2A). One patient in group B did not show an increase in infliximab level, and the patient was antidrug antibody (ADA) positive. Similarly, the elective switching group showed a significant increase in infliximab level, except in two patients (Table 2, Fig. 3). The two patients had undetectable infliximab levels both at baseline and during the follow-up periods. Notably, they were also ADA positive. In response to increased infliximab levels, there was a significant reduction in partial Mayo score, FC, and CRP from baseline to W24–W28 in group A (Fig. 2, Supplementary Table 1). In group B, FC showed a significant reduction. Supplementary Figs 1 and 2 show the changes in each value over the follow-up period for each individual.

Figure 2.(A) Trends in serum infliximab level among patients who switched to subcutaneous (SC) infliximab. (B) Trends in partial Mayo score among patients who switched to SC infliximab. (C) Trends in fecal calprotectin among patients who switched to SC infliximab. (D) Trends in C-reactive protein (CRP) among patients who switched to SC infliximab. Bars represent median and error bars represent interquartile range. Group A was defined as a patient with clinically and biochemically active state at baseline, and group B was defined as a patient with only biochemically active state at baseline. W4–W8, 4–8 weeks after switching; W12–W16, 12–16 weeks after switching; W24–W28, 24–28 weeks after switching. *p-value for side-by-side <0.05 compared to baseline; p-value for side-by-side <0.01 compared to baseline.

Figure 3.Trends in serum infliximab level in the elective switching group. Bars represent median and error bars represent interquartile range. W4–W8, 4–8 weeks after switching; W12–W16, 12–16 weeks after switching; W24–W28, 24–28 weeks after switching.

Table 2. Trends in Serum Infliximab Levels

BaselineW4–W8W12–W16W24–W28
Median (IQR)No.Median (IQR)No.Median (IQR)No.Median (IQR)No.
Serum infliximab level, μg/mL
Group A1.6 (0.1–4.8)1510.5 (5.5–13.7)1412.4 (8.6–21.2)1516.6 (11.0–22.9)14
Group B2.7 (0.6–4.2)814.4 (6.4–21.6)*718.0 (8.3–23.6)*720.0 (8.8–24.4)*7
Elective switching group3.4 (0.4–4.6)109.6 (4.9–15.3)*1012.0 (7.0–22.4)1112.6 (7.9–19.6)*10
Serum infliximab level according to concurrent IMM use, μg/mL
Combination with IMM1.6 (0.1–4.3)179.9 (2.9–14.2)1611.8 (8.1–20.0)1711.4 (11.2–20.1)14
No combination with IMM2.7 (0.6–4.7)1611.1 (7.6–20.4)1518.0 (8.4–23.3)1618.4 (8.7–23.8)17
Serum infliximab level according to baseline body weight, μg/mL
Body weight <80 kg2.6 (0.1–4.9)1710.5 (6.8–21.3)1614.8 (8.9–25.6)1718.8 (11.6–25.2)15
Body weight ≥80 kg1.6 (0.6–3.9)1610.8 (5.7–13.6)1513.1 (8.4–18.9)1611.2 (8.7–21.2)16

Group A was defined as a patient with clinically and biochemically active state at baseline, and group B was defined as a patient with only biochemically active state at baseline.

W4–W8, 4–8 weeks after switching; W12–W16, 12–16 weeks after switching; W24–W28, 24–28 weeks after switching; IQR, interquartile range; IMM, immunomodulators.

*p-value for side-by-side <0.05 compared to baseline; p-value for side-by-side <0.01 compared to baseline; Combination group was defined as patients who concurrently used immunomodulators.



3. Efficacy of switching to SC infliximab

The proportions of patients achieving clinical remission, clinical response, and biochemical response were assessed at the last follow-up (Fig. 4). In group A, 60% of patients (9 out of 15) achieved clinical remission, whereas 80% (12 out of 15 patients) achieved clinical response. In the case of clinical response, the median serum infliximab level between the response and nonresponse groups showed a numerical difference (1.6 [IQR, 0.3 to 4.1] μg/mL vs 0.1 [IQR, 0.1 to 4.8] μg/mL at baseline, 16.6 [IQR, 11.2 to 25.2] μg/mL vs 11.4 [IQR, 6.20 to 21.60] μg/mL at the last follow-up), although there was no statistical significance. Biochemical response was achieved in 80% of group A (12 out of 15 patients). In group B, 87.5% of patients (7 out of 8) achieved biochemical response, whereas clinical remission and response were not evaluated because of the low baseline partial Mayo scores.

Figure 4.Clinical remission/response and biochemical response rates at last follow-up. Clinical remission, a partial Mayo score of ≤1 point. Clinical response, a decrease from baseline in partial Mayo score of ≥2 points with an accompanying decrease in rectal bleeding subscore of ≥1 point or an absolute rectal bleeding subscore of 0 or 1. Biochemical response, ≥50% decrease in fecal calprotectin level from baseline. Clinical remission/response was not evaluated in group B because of the low baseline partial Mayo scores. Group A was defined as a patient with clinically and biochemically active state at baseline, and group B was defined as a patient with only biochemically active state at baseline.

4. Pharmacokinetics according to ADA, immunomodulator use, and body weight

Among the 34 patients, 13 patients had serum infliximab levels below 1 μg/mL at baseline. Among these 13 patients, ADA was measured in six patients. Three of six patients were ADA positive: one in group B and two in the elective switching group. Notably, all three patients showed an infliximab level <1 μg/mL at baseline and during all follow-up periods. However, the patient in group B remained on SC infliximab over the study period as FC decreased from 5,958 μg/g to 212 μg/g.

Regarding concurrent immunomodulator use, 17 out of 34 patients were receiving immunomodulators at baseline. All of them continued with immunomodulators for at least 4 months after SC switching. There were no patients who newly started immunomodulators during the follow-up period. Although there was a tendency for higher absolute values of infliximab levels in the monotherapy group in each follow-up period (Table 2), the difference between the two groups was not statistically significant (p=0.739). The combination group included all three ADA-positive patients, in whom the serum infliximab level remained <0.1 μg/mL throughout the follow-up period. Excluding these three patients, the infliximab levels in the combination group were a median of 14.6 (IQR, 10.1 to 21.7) μg/mL at W12–W16 and a median of 14.8 (IQR, 11.2 to 20.2) μg/mL at W24–W28.

Fig. 5 shows the baseline weight and serum infliximab level of each individual at the last follow-up. We divided patients into two groups: the ≥80 kg group (n=17) and the <80 kg group (n=17). During each follow-up period, there was no statistically significant difference between the two groups, but the group weighing <80 kg showed higher values (Table 2). Regarding the serum albumin level at baseline, there was no significant difference in the serum infliximab level during the follow-up (data not shown).

Figure 5.Scatter plot of serum infliximab level at the last follow-up versus body weight at baseline.

5. Treatment discontinuation and safety outcomes

In group A, two of 15 patients stopped treatment during the follow-up period (Fig. 1). The first patient discontinued SC infliximab because of lack of efficacy. After three other preceding biologics, he switched to SC infliximab following 7 months of IV infliximab. He showed a biochemical response, but his symptoms did not improve, and his serum infliximab level did not significantly increase (0.1 μg/mL at baseline to 6.2 μg/mL at W24–W48). Subsequently, he underwent surgery. The second patient discontinued SC treatment because of malignancy. He had experienced vedolizumab failure before infliximab. Seven months after receiving IV infliximab, he switched to SC infliximab. He initially achieved clinical and biochemical responses. However, approximately 6 months after switching, he was diagnosed with prostate cancer and stopped taking SC infliximab.

Localized injection site reactions (ISRs) occurred in five out of 34 patients. One of the five patients experienced severe ISR 3 months after SC switching, which led to the discontinuation of SC injection. The patient had previously experienced a moderate infusion reaction during the administration of IV infliximab. The patient opted for elective switching to SC infliximab to avoid infusion reactions before considering other biologics; however, severe ISR developed with SC infliximab. The remaining four patients had mild symptoms. Other adverse events, such as infections, systemic injection reactions, and delayed hypersensitivity reactions were not noted in this study.

To our knowledge, this is the first study to analyze the effectiveness of switching from IV to SC infliximab in UC patients experiencing IV infliximab failure while on maintenance treatment. We confirmed the significant increase of serum infliximab level after SC switching. In group A, we confirmed significant reductions in partial Mayo score, FC, and CRP after the use of SC infliximab. In group B, a significant decrease in FC was observed after SC switching. In terms of the safety and acceptability of SC infliximab, there was only one severe ISR, and only one patient refused to continue SC infliximab because of poor acceptability.

Schreiber et al.12 conducted the first pivotal study regarding SC infliximab switching in IBD patients. They demonstrated that the pharmacokinetics of SC infliximab was found to be noninferior to that of IV infliximab. It also revealed the efficacy of SC infliximab in maintaining clinical remission with safety and immunogenicity profiles comparable to IV infliximab. The retrospective, multicenter cohort study conducted by Smith et al.18 evaluated the effectiveness of elective switching to SC infliximab in 181 IBD patients, most of whom were in clinical remission during maintenance IV infliximab. The high persistence rates and low immunogenicity rates of SC infliximab were observed throughout this study period, with no significant change in clinical activity indices or biomarkers. The REMSWITCH study by Buisson et al.13 explored the pharmacokinetic profiles and risk of relapse during a 6-month follow-up period after switching from IV to SC infliximab in patients with IBD who were in remission and treated with various doses of IV infliximab. The elective SC change was deemed to be safe, well accepted, and carried a low risk of relapse, except for patients receiving IV dosage of 10 mg/kg/4 weeks.

To date, no study has explored the effectiveness of switching from IV to SC infliximab in UC patients who experienced an LOR during maintenance treatment. However, there was a case series exploring the effectiveness of switching to SC infliximab in four CD patients who experienced IV infliximab failure.19 Among them, three patients showed clinical response to maintenance treatment with SC infliximab, but one patient experienced primary nonresponse even after induction treatment with weekly SC infliximab. This study highlights the potential benefit of switching to SC infliximab in terms of efficacy and tolerability. However, the number of patients included was very limited, and the main reason for switching was severe hypersensitivity reaction and/or immunogenicity rather than secondary LOR, such as in the current study.19

SC infliximab differs in pharmacokinetics from IV infliximab. Administration via the IV route leads to early and rapid peak concentration followed by a steady decline to trough. Conversely, subcutaneously administered biologics have lower peak concentrations and smaller differences between peak and trough concentrations. Therefore, relatively stable drug concentrations are maintained between dosing intervals,25-27 and switching from IV to SC infliximab may be beneficial in selected cases. In the present study, serum infliximab levels significantly increased after SC switching, along with a decrease in clinical index and FC levels. These results can be attributed to the stable drug exposure according to the pharmacokinetics of SC infliximab. Interestingly, during the study period, there was a difference in the infliximab levels among the three groups. The serum infliximab levels at baseline were 1.6, 2.7, and 3.4 μg/mL in group A, group B, and the elective switching group, respectively. The lower level in groups A and B may reflect the extent of gut inflammation at baseline. This finding is consistent with previous studies that have reported a low drug concentration in association with anti-tumor necrosis factor treatment failure.28,29 Conversely, the level of serum infliximab during the follow-up period was slightly higher in groups A and B than in the elective switching group. The reason for this disparity was not clear in our data. The higher weight of the elective switching group may influence the infliximab level (76.9, 74.9, and 80.3 kg, respectively).

Immunologic mechanism in which anti-infliximab antibodies are produced as a result of a patient’s immune response to infliximab is considered one of the main causes of LOR.30,31 Unfortunately, in the current study, immunogenicity could not be accurately assessed because of the limited measurement of ADA, which was performed only in six patients. Three out of six patients showed positive ADA, and notably, all three patients had a serum infliximab level <0.1 μg/mL both at baseline and during the follow-up period. From this, we could presume that in the presence of ADA, infliximab levels may not increase even after switching to SC infliximab. However, one ADA-positive patient in group B showed a dramatic decrease of FC despite undetectable infliximab levels during the follow-up, suggesting that further well-designed studies are needed to confirm the effect of SC switching in ADA-positive patients.

In addition to ADA, concurrent immunomodulator use, body weight, and serum albumin level are the main factors affecting infliximab pharmacokinetics.32-37 Combination therapy with immunomodulators is associated with higher drug levels, lower immunogenicity, and subsequent better disease control compared to anti-tumor necrosis factor monotherapy.25,38 Owing to the retrospective design of our study, the concurrent use of immunomodulators was not controlled. The concurrent use of immunomodulators might reflect the disease course severity in our study. To determine whether the concurrent use of immunomodulators enhances the efficacy of SC infliximab, a well-controlled prospective study is warranted. Regarding body weight, patients weighing <80 kg had higher serum infliximab levels than those of patients weighing ≥80 kg, which was consistent with the previous study.37

In this study, 21 out of 23 patients maintained the usage of SC infliximab, indicating the high treatment persistence of SC infliximab. The two patients in group A who discontinued SC infliximab had previously failed with other biologics, but it remains unclear whether these previous biologics failures are related to the poor outcome of SC switching. The safety and acceptability of SC infliximab were good and consistent with the findings of previous studies.13,18 In the current study, only one out of 34 patients developed a severe ISR that required the discontinuation of SC injection. One patient refused SC injection because of poor acceptability. As noted in several studies, SC biologics have advantages that can increase acceptability, such as easier use and less medical visits, thus providing convenience to patients.39-41

Our study has several limitations. First, this study has a single-center, retrospective design. The sample size is relatively small, and there are some missing data. Specifically, the limited number of patients who underwent endoscopy posed constraints in evaluating gut inflammation. Nevertheless, previous studies have indicated a strong correlation between FC and endoscopic activity.42 In our study, we regard FC as a reliable indicator of gut inflammation. Second, since SC infliximab began to be covered by Korean reimbursement policy in 2021, the follow-up period in our study is relatively short. Third, our study included only UC patients on a standard dose of IV infliximab (5 mg/kg every 8 weeks). Considering the situation in Korea where IV infliximab dose escalation is not permitted in UC patients, we initially attempted SC switch in UC patients with suboptimal response to IV infliximab. Currently, a multicenter study including UC and CD patients with a 1-year follow-up period is underway. This study has strengths beyond its limitations. With the theoretical effectiveness of switching to SC infliximab, we were able to confirm the effectiveness of SC switching in UC patients who experienced IV infliximab failure while on maintenance treatment. In contrast to previous studies,13,18 dose escalation of SC infliximab (240 mg every other week or 120 mg weekly) was not permitted. Our results confirmed the effectiveness of switching from the IV standard dose to the SC standard dose. Additionally, despite the retrospective design, we incorporated both disease activity index and biomarkers at each visit in the analysis. This was possible because we had standardized the follow-up observation period in our clinical practice following the introduction of SC switching.

In conclusion, SC infliximab could be considered a promising treatment option for UC patients who had experienced failure with IV infliximab during maintenance treatment.

This work was supported by a grant from the Korean Gastroenterology Fund for Future Development and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (No. 2021R1A6A1A03040260).

We would like to thank the infusion nurses and administration staff at Asan Medical Center for their support to this study.

Study concept and design: J.H.B., S.W.H. Data acquisition: J.H.B., J.B.P., J.E.B., S.W.H., S.H.P., D.H.Y., S.W.H. Data analysis and interpretation: J.H.B., J.B.P., J.E.B., S.W.H., S.H.P., D.H.Y., S.W.H. Drafting of the manuscript: J.H.B., S.W.H. Critical revision of the manuscript for important intellectual content: J.H.B., S.W.H. Statistical analysis: J.H.B., J.B.P., J.E.B., S.W.H., S.H.P., D.H.Y., S.W.H. Obtained funding: S.W.H. Administrative, technical, or material support; study supervision: B.D.Y., J.S.B., S.J.M., S.K.Y. Approval of final manuscript: all authors.

All data, analytic methods, and study materials relevant to the study are included in the article or available upon request from the corresponding author, SWH.

  1. Torres J, Mehandru S, Colombel JF, Peyrin-Biroulet L. Crohn's disease. Lancet 2017;389:1741-1755.
    Pubmed CrossRef
  2. Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel JF. Ulcerative colitis. Lancet 2017;389:1756-1770.
    Pubmed CrossRef
  3. Baumgart DC, Le Berre C. Newer biologic and small-molecule therapies for inflammatory bowel disease. N Engl J Med 2021;385:1302-1315.
    Pubmed CrossRef
  4. Raine T, Bonovas S, Burisch J, et al. ECCO guidelines on therapeutics in ulcerative colitis: medical treatment. J Crohns Colitis 2022;16:2-17.
    Pubmed CrossRef
  5. Torres J, Bonovas S, Doherty G, et al. ECCO guidelines on therapeutics in Crohn's disease: medical treatment. J Crohns Colitis 2020;14:4-22.
    Pubmed CrossRef
  6. Feuerstein JD, Isaacs KL, Schneider Y, et al. AGA clinical practice guidelines on the management of moderate to severe ulcerative colitis. Gastroenterology 2020;158:1450-1461.
    Pubmed KoreaMed CrossRef
  7. Feuerstein JD, Ho EY, Shmidt E, et al. AGA clinical practice guidelines on the medical management of moderate to severe luminal and perianal fistulizing Crohn's disease. Gastroenterology 2021;160:2496-2508.
    Pubmed KoreaMed CrossRef
  8. Turner D, Ricciuto A, Lewis A, et al. STRIDE-II: an update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD. Gastroenterology 2021;160:1570-1583.
    Pubmed CrossRef
  9. Na SY, Choi CH, Song EM, et al. IBD Research Group of the Korean Association for the Study of Intestinal Diseases. Korean clinical practice guidelines on biologics and small molecules for moderate-to-severe ulcerative colitis. Intest Res 2023;21:61-87.
    Pubmed KoreaMed CrossRef
  10. Koh SJ, Hong SN, Park SK, et al. Korean clinical practice guidelines on biologics for moderate to severe Crohn's disease. Intest Res 2023;21:43-60.
    Pubmed KoreaMed CrossRef
  11. Parigi TL, D'Amico F, Peyrin-Biroulet L, Danese S. Evolution of infliximab biosimilar in inflammatory bowel disease: from intravenous to subcutaneous CT-P13. Expert Opin Biol Ther 2021;21:37-46.
    Pubmed CrossRef
  12. Schreiber S, Ben-Horin S, Leszczyszyn J, et al. Randomized controlled trial: subcutaneous vs intravenous infliximab CT-P13 maintenance in inflammatory bowel disease. Gastroenterology 2021;160:2340-2353.
    Pubmed CrossRef
  13. Buisson A, Nachury M, Reymond M, et al. Effectiveness of switching from intravenous to subcutaneous infliximab in patients with inflammatory bowel diseases: the REMSWITCH study. Clin Gastroenterol Hepatol 2023;21:2338-2346.
    Pubmed CrossRef
  14. Schultheiss JP, Mahmoud R, Louwers JM, et al. Loss of response to anti-TNFα agents depends on treatment duration in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2021;54:1298-1308.
    Pubmed KoreaMed CrossRef
  15. Yamamoto-Furusho JK, Al Harbi O, Armuzzi A, et al. Incidence of suboptimal response to tumor necrosis factor antagonist therapy in inflammatory bowel disease in newly industrialised countries: the EXPLORE study. Dig Liver Dis 2020;52:869-877.
    Pubmed CrossRef
  16. Otake H, Matsumoto S, Mashima H. Long-term clinical and real-world experience with Crohn's disease treated with anti-tumor necrosis factor-α antibodies. Intest Res 2022;20:464-474.
    Pubmed KoreaMed CrossRef
  17. Albshesh A, Ben-Horin S. CT-P13: a review on a biosimilar to infliximab in the treatment of inflammatory bowel disease. Expert Opin Biol Ther 2019;19:971-978.
    Pubmed CrossRef
  18. Smith PJ, Critchley L, Storey D, et al. Efficacy and safety of elective switching from intravenous to subcutaneous infliximab [CT-P13]: a multicentre cohort study. J Crohns Colitis 2022;16:1436-1446.
    Pubmed KoreaMed CrossRef
  19. Caron B, Fumery M, Netter P, Peyrin-Biroulet L. Letter: treatment with subcutaneous CT-P13 in Crohn's disease patients with intravenous infliximab failure. Aliment Pharmacol Ther 2022;55:508-509.
    Pubmed CrossRef
  20. Park SH, Yang SK, Park SK, et al. Long-term prognosis of Crohn's disease and its temporal change between 1981 and 2012: a hospital-based cohort study from Korea. Inflamm Bowel Dis 2014;20:488-494.
    Pubmed CrossRef
  21. Noh SM, Oh EH, Park SH, et al. Association of faecal calprotectin level and combined endoscopic and radiological healing in patients with Crohn's disease receiving anti-tumour necrosis factor therapy. J Crohns Colitis 2020;14:1231-1240.
    Pubmed CrossRef
  22. Bertin D, Serrero M, Grimaud JC, Desjeux A, Desplat-Jégo S. Monitoring of infliximab trough levels and anti-infliximab antibodies in inflammatory bowel diseases: a comparison of three commercially available ELISA kits. Cytokine 2020;126:154859.
    Pubmed CrossRef
  23. Herbers J, Miller R, Walther A, et al. How to deal with non-detectable and outlying values in biomarker research: best practices and recommendations for univariate imputation approaches. Compr Psychoneuroendocrinol 2021;7:100052.
    Pubmed KoreaMed CrossRef
  24. Zubin G, Peter L. Predicting endoscopic Crohn's disease activity before and after induction therapy in children: a comprehensive assessment of PCDAI, CRP, and fecal calprotectin. Inflamm Bowel Dis 2015;21:1386-1391.
    Pubmed KoreaMed CrossRef
  25. Little RD, Ward MG, Wright E, et al. Therapeutic drug monitoring of subcutaneous infliximab in inflammatory bowel disease: understanding pharmacokinetics and exposure response relationships in a new era of subcutaneous biologics. J Clin Med 2022;11:6173.
    Pubmed KoreaMed CrossRef
  26. Papamichael K, Rakowsky S, Rivera C, Cheifetz AS, Osterman MT. Association between serum infliximab trough concentrations during maintenance therapy and biochemical, endoscopic, and histologic remission in Crohn's disease. Inflamm Bowel Dis 2018;24:2266-2271.
    Pubmed KoreaMed CrossRef
  27. Ungar B, Levy I, Yavne Y, et al. Optimizing anti-TNF-α therapy: serum levels of infliximab and adalimumab are associated with mucosal healing in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol 2016;14:550-557.
    Pubmed CrossRef
  28. Kennedy NA, Heap GA, Green HD, et al. Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn's disease: a prospective, multicentre, cohort study. Lancet Gastroenterol Hepatol 2019;4:341-353.
    Pubmed CrossRef
  29. Seow CH, Newman A, Irwin SP, Steinhart AH, Silverberg MS, Greenberg GR. Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut 2010;59:49-54.
    Pubmed CrossRef
  30. Measurement of infliximab and anti-infliximab antibody levels can help distinguish maintenance versus loss of response. Gastroenterol Hepatol (N Y) 2012;8:131-134.
  31. Su CG, Lichtenstein GR. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. Gastroenterology 2003;125:1544-1546.
    Pubmed CrossRef
  32. Ternant D, Aubourg A, Magdelaine-Beuzelin C, et al. Infliximab pharmacokinetics in inflammatory bowel disease patients. Ther Drug Monit 2008;30:523-529.
    Pubmed CrossRef
  33. Adedokun OJ, Sandborn WJ, Feagan BG, et al. Association between serum concentration of infliximab and efficacy in adult patients with ulcerative colitis. Gastroenterology 2014;147:1296-1307.
    Pubmed CrossRef
  34. Fasanmade AA, Adedokun OJ, Ford J, et al. Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis. Eur J Clin Pharmacol 2009;65:1211-1228.
    Pubmed KoreaMed CrossRef
  35. Loftus EV Jr, Paul S, Roblin X. Therapeutic drug monitoring for subcutaneous infliximab? Too early to conclude. Clin Gastroenterol Hepatol 2023;21:2193-2194.
    Pubmed CrossRef
  36. Kumar P, Vuyyuru SK, Das P, et al. Serum albumin is the strongest predictor of anti-tumor necrosis factor nonresponse in inflammatory bowel disease in resource-constrained regions lacking therapeutic drug monitoring. Intest Res 2023;21:460-470.
    Pubmed KoreaMed CrossRef
  37. Hanzel J, Bukkems LH, Gecse KB, D'Haens GR, Mathôt RA. Population pharmacokinetics of subcutaneous infliximab CT-P13 in Crohn's disease and ulcerative colitis. Aliment Pharmacol Ther 2021;54:1309-1319.
    Pubmed KoreaMed CrossRef
  38. Remy C, Caron B, Gouynou C, et al. Inflammatory bowel disease patients' acceptance for switching from intravenous infliximab or vedolizumab to subcutaneous formulation: the Nancy experience. J Clin Med 2022;11:7296.
    Pubmed KoreaMed CrossRef
  39. Singh A, Mahajan R, Kedia S, et al. Use of thiopurines in inflammatory bowel disease: an update. Intest Res 2022;20:11-30.
    Pubmed KoreaMed CrossRef
  40. Kim ES, Kim KO, Jang BI, et al. Factors contributing to the preference of Korean patients with Crohn's disease when selecting an anti-tumor necrosis factor agent (CHOICE Study). Gut Liver 2016;10:391-398.
    Pubmed KoreaMed CrossRef
  41. Allen PB, Lindsay H, Tham TC. How do patients with inflammatory bowel disease want their biological therapy administered?. BMC Gastroenterol 2010;10:1.
    Pubmed KoreaMed CrossRef
  42. Hart L, Chavannes M, Kherad O, et al. Faecal calprotectin predicts endoscopic and histological activity in clinically quiescent ulcerative colitis. J Crohns Colitis 2020;14:46-52.
    Pubmed CrossRef

Article

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Gut and Liver

Published online June 5, 2024

Copyright © Gut and Liver.

Effectiveness of Switching to Subcutaneous Infliximab in Ulcerative Colitis Patients Experiencing Intravenous Infliximab Failure

June Hwa Bae1 , Jung-Bin Park1 , Ji Eun Baek1 , Seung Wook Hong1 , Sang Hyoung Park1,2 , Dong-Hoon Yang1 , Byong Duk Ye1,2 , Jeong-Sik Byeon1 , Seung-Jae Myung1 , Suk-Kyun Yang1,2 , Sung Wook Hwang1,2

1Department of Gastroenterology and 2Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Correspondence to:Sung Wook Hwang
ORCID https://orcid.org/0000-0002-6981-7575
E-mail hsw903@gmail.com

Received: July 25, 2023; Revised: October 18, 2023; Accepted: November 27, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background/Aims: Studies on elective switching to the subcutaneous (SC) formulation of infliximab revealed comparable efficacy and safety and higher infliximab level than those exhibited by intravenous (IV) infliximab. However, no studies have reported on the effectiveness of SC switching in ulcerative colitis (UC) patients who experienced IV infliximab failure during maintenance treatment.
Methods: This retrospective study included UC patients who had been switched to SC infliximab because of IV infliximab failure, between January 2021 and January 2023. Group A was defined as having clinically and biochemically active UC (secondary loss of response), and group B consisted of patients with stable symptoms but biochemically active UC.
Results: Twenty-three patients met the inclusion criteria: 15 in group A and eight in group B. The serum infliximab levels significantly increased after SC switching in both groups. The electively switched group also exhibited increased infliximab levels after SC switching. Patients in group A showed improved partial Mayo score with a significant decrease in fecal calprotectin and C-reactive protein after switching. In group B, the fecal calprotectin level significantly decreased without clinical relapse after switching. A high proportion of patients (≥80%) in both groups achieved clinical and/or biochemical responses at the last follow-up. During the follow-up period, only two patients in group A discontinued SC infliximab, and only one complained of severe injection site reaction.
Conclusions: In UC patients who experience IV infliximab failure during maintenance treatment, switching to SC infliximab may be a promising option because of better efficacy and safety.

Keywords: Ulcerative colitis, Infliximab, Subcutaneous

INTRODUCTION

Inflammatory bowel diseases (IBDs), which include Crohn’s disease (CD) and ulcerative colitis (UC), are chronic, immune-mediated, gastrointestinal disorders that exhibit a relapsing-remitting course.1,2 Newer drugs such as biologics and small molecules have been recently introduced,3 and this expansion of therapeutic options has reshaped the therapeutic strategy for IBD.4-7 Recent guidelines recommend the use of biologics and small molecules for the treatment of moderately to severely active UC and CD while emphasizing the importance of tight monitoring and a treat-to-target approach to achieve the treatment goals of IBD.3,8-10 Among the feasible treatment targets, C-reactive protein (CRP) and fecal calprotectin (FC), which are the most widely utilized biomarkers in clinical practice, were emphasized in the STRIDE-II guideline.8

Infliximab, a monoclonal antibody targeting tumor necrosis factor α, is one of the most commonly prescribed biologics with the highest efficacy for IBD patients.11-13 However, a significant proportion of IBD patients treated with intravenous (IV) infliximab experience nonresponse or loss of response (LOR), thus necessitating either a dose escalation of IV infliximab or switching to another biologic/small molecule agent.14-16 Unfortunately, in several countries, including South Korea, the healthcare system or insurance programs do not permit the dose escalation of IV infliximab in such cases (e.g., up to 10 mg/kg every 8 weeks or 5 mg/kg every 4 weeks). Recently, a new subcutaneous (SC) formulation of infliximab, namely, CT-P13 SC, has been developed,17 and it has shown comparable efficacy and safety with improved acceptability.12,18 Interestingly, pivotal studies have shown that switching from IV to SC formulation can lead to increased serum infliximab levels.12,13 This observation suggests that such a switch may serve as a promising option for UC patients who have failed to maintain response after the induction of IV infliximab. However, there is limited evidence available for patients with active UC who have experienced IV infliximab failure. Only one case series has been reported, involving four CD patients who experienced failure with IV infliximab.19

In this study, we assessed the clinical and biochemical responses after switching from IV to SC infliximab in UC patients who experienced a clinically and/or biochemically active disease during maintenance treatment of IV infliximab. Additionally, we investigated the pharmacokinetic profiles after SC switching in patients with active UC comparing them with those in patients with stable UC who underwent elective SC switching.

MATERIALS AND METHODS

1. Patients and study design

The IBD registry has been prospectively maintained since 1997 at Asan Medical Center, which is a tertiary university hospital in Korea, and it has been previously described in detail.20 From the IBD registry, a total of 41 adult patients who had been switched from IV infliximab to SC infliximab (CT-P13) between January 2021 and January 2023 were retrospectively recruited (Fig. 1). Patients who had initially responded to IV infliximab induction but developed aggravated symptoms and/or worsening findings in FC or CRP during maintenance therapy leading to a switch from IV to SC infliximab were included in the analysis. (1) Group A was defined as patients who “required” dose escalation because of clinical relapse (defined as an increase in partial Mayo score of ≥2 points from the previous visits) and biochemical activity (defined as FC >200 μg/g and/or CRP >0.6 mg/dL) at baseline (secondary LOR). (2) Group B was defined as patients who did not show a significant difference in partial Mayo score from the previous visits (differences of 0 to 1 point) but were eligible for “considering” dose escalation because of biochemical activity (FC >200 μg/g and/or CRP >0.6 mg/dL) at baseline (biochemically active). To compare the pharmacokinetic profiles, an additional group (elective switching group) was included in the analysis; this group consisted of patients who electively switched to SC infliximab while on a stable IV maintenance treatment (partial Mayo score ≤2, FC ≤200 μg/g, and CRP ≤0.6 mg/dL). The exclusion criteria were as follows: (1) patients who switched to SC right after IV induction (no IV maintenance); (2) patients who switched back to IV after a single SC injection (single SC injection for long-term trip and poor acceptance of SC formulation); (3) patients with poor adherence who showed irregular injection; or (4) use of infliximab for concurrent ankylosing spondylitis other than UC.

Figure 1. Flowchart of the study. UC, ulcerative colitis; IV, intravenous; SC, subcutaneous.

All patients included in the analysis had a follow-up period of at least 6 months after SC switching, except for two individuals who were followed up for 4 months. The theoretical date of the next IV infusion was considered as “baseline,” and data were collected between 4 and 8 weeks (W4–W8), 12 and 16 weeks (W12–W16), and 24 and 28 weeks after the switch (W24–W28). If there were two measured values within one period, the data from the earlier time point were used. Follow-up data included the partial Mayo score, FC, CRP, and serum infliximab levels at each specified period. FC was measured using EliATM Calprotectin 2 (Phadia GmbH, Freiburg, Germany) on the Phadia 250 system (Thermo Fisher Scientific, Waltham, MA, USA). Fecal samples were refrigerated (2°C–8°C) when collected at home, and they were sent to the Department of Laboratory Medicine within 1 day of collection.21 We also documented the details of adverse events, infliximab discontinuation, and surgery. The Institutional Review Board of Asan Medical Center approved the study protocol (IRB number: 2023-0747). The informed consent was waived.

2. Infliximab treatment

Patients were switched from either originator IV infliximab (Remicade) or IV CT-P13 (Remsima) to SC infliximab (CT-P13). In accordance with the healthcare policy of Korea, dose escalation was not permitted with IV infliximab in UC patients, and all patients were on maintenance treatment with 5 mg/kg IV infliximab at 8-week intervals. All patients who switched to SC infliximab received 120 mg injections every other week. Dose escalation to 240 mg every other week or 120 mg weekly is not permitted. Initially, the SC injections were administered by a healthcare professional, and after receiving adequate training, they were self-administered starting from week 2. During each visit, physicians confirmed adherence to the SC injection schedule and assessed any potential side effects.

3. Drug level and ADA assay

An enzyme-linked immunoassay platform with RIDASCREEN IFX Monitoring (R-Biopharm AG, Darmstadt, Germany) and RIDASCREEN Anti-IFX Antibodies (R-Biopharm AG, Darmstadt, Germany) was used to quantitatively measure the serum infliximab levels and antibodies to infliximab, respectively.22 A predose sample to measure serum infliximab levels was collected at each visit while the physician verified the administration schedule. RIDASCREEN Anti-IFX Antibodies uses a drug-sensitive assay; therefore, it was only included in the analysis when the infliximab concentration in the serum sample was <1 μg/mL.22 Antibody values for infliximab <2.5 ng/mL were classified as undetected according to the manufacturer’s recommendations. For statistical analysis, serum infliximab levels below 0.1 μg/mL (undetectable) were imputed as 0.05 μg/mL, which is half of the lower limit of quantification.23

4. Efficacy outcomes

We evaluated the efficacy of switching to SC infliximab by analyzing the proportions of patients achieving clinical remission, clinical response, and biochemical response at the last follow-up. Clinical remission was defined as partial Mayo score ≤1 point. Clinical response was defined as a decrease from baseline in partial Mayo score ≥2 points, with an accompanying decrease in rectal bleeding subscore of ≥1 point or an absolute rectal bleeding subscore of 0 or 1.12 Biochemical response was defined as a ≥50% decrease in FC level from baseline.24

5. Statistical analysis

Categorical variables were summarized as frequency (%), and continuous variables were summarized as mean and standard deviation or median and interquartile range (IQR). We used the Wilcoxon signed rank test to assess the changes in pharmacokinetics, disease activity index, and biomarkers from baseline to each follow-up. A two-sided p-value <0.05 was considered statistically significant. All analysis was performed using IBM SPSS statistics 21.0 for Windows (IBP Corp., Armonk, NY, USA).

RESULTS

1. Baseline characteristics of the patients

Among the 41 recruited patients who had been switched from IV infliximab to SC infliximab, seven were excluded from this study (Fig. 1). Among the remaining 34 patients, 15 patients were categorized into group A (secondary LOR), and eight patients were categorized into group B (only biochemically active). The remaining 11 patients were on stable maintenance IV infliximab and were electively switched to SC infliximab (elective switching group).

Table 1 shows the baseline characteristics of groups A and B. In group A, seven patients (46.7%) were on concomitant immunomodulatory therapy, and six (40.0%) were on steroids. Three patients (20.0%) were exposed to other biologics before using infliximab. In group B, three patients (37.5%) were on concomitant immunomodulator therapy, and no patients were exposed to other biologics or on steroids at baseline.

Table 1 . Baseline Characteristics of Patients Switched to Subcutaneous Infliximab.

CharacteristicTotal (n=23)Group A (n=15)Group B (n=8)
Age at diagnosis, yr23.0 (20.0–31.0)22.0 (20.0–53.0)24.5 (17.5–28.8)
Age at baseline, yr34.0 (25.0–50.0)36.0 (25.0–61.0)32.5 (23.8–42.8)
Male sex16 (69.6)12 (80.0)4 (50.0)
Weight, kg76.2±19.176.9±19.974.9±18.6
Body mass index, kg/m226.3±5.926.3±6.526.4±4.9
Disease extent
Proctitis (E1)1 (4.3)01 (12.5)
Left-sided (E2)8 (34.8)6 (40.0)2 (25.0)
Pancolitis (E3)14 (60.9)9 (60.0)5 (62.5)
5-ASA use22 (95.7)14 (93.3)8 (100.0)
Immunomodulator use10 (43.5)7 (46.7)3 (37.5)
Thiopurine7 (30.4)6 (40.0)1 (12.5)
Methotrexate3 (13.0)1 (6.7)2 (25.0)
Steroid at baseline6 (26.1)6 (40.0)0
Other biologics exposure3 (13.0)3 (20.0)0
Infliximab trough level, μg/mL1.6 (0.2–4.3)1.6 (0.1–4.8)2.7 (0.6–4.2)
Partial Mayo score3.0 (2.0–4.0)4.0 (3.0–5.0)1.0 (0.3–2.0)
Fecal calprotectin, μg/g1,236 (417–4,180)2,044 (1,100–4,304)508 (229–1,020)
CRP, mg/dL0.37 (0.10–0.91)0.65 (0.29–1.24)0.15 (0.10–0.58)
Serum albumin, g/dL,4.0 (3.5–4.3)3.9 (3.4–4.3)4.0 (3.9–4.3)
Disease duration at baseline, yr8.0 (2.0–16.0)8.0 (4.0–15.0)12.0 (1.3–18.5)
Duration of IV IFX, wk55.3 (28.1–154.3)44.1 (28.1–154.3)63.8 (24.7–381.3)

Data are presented as median (interquartile range), number (%), or mean±SD. Group A was defined as a patient with clinically and biochemically active state at baseline, and group B was defined as a patient with only biochemically active state at baseline..

5-ASA, 5-aminosalicylate; CRP, C-reactive protein; IV, intravenous; IFX, infliximab..



2. Trends in serum infliximab levels, disease activity index, and biomarkers

Serum infliximab levels significantly increased in groups A and B throughout the study period (Table 2, Fig 2A). One patient in group B did not show an increase in infliximab level, and the patient was antidrug antibody (ADA) positive. Similarly, the elective switching group showed a significant increase in infliximab level, except in two patients (Table 2, Fig. 3). The two patients had undetectable infliximab levels both at baseline and during the follow-up periods. Notably, they were also ADA positive. In response to increased infliximab levels, there was a significant reduction in partial Mayo score, FC, and CRP from baseline to W24–W28 in group A (Fig. 2, Supplementary Table 1). In group B, FC showed a significant reduction. Supplementary Figs 1 and 2 show the changes in each value over the follow-up period for each individual.

Figure 2. (A) Trends in serum infliximab level among patients who switched to subcutaneous (SC) infliximab. (B) Trends in partial Mayo score among patients who switched to SC infliximab. (C) Trends in fecal calprotectin among patients who switched to SC infliximab. (D) Trends in C-reactive protein (CRP) among patients who switched to SC infliximab. Bars represent median and error bars represent interquartile range. Group A was defined as a patient with clinically and biochemically active state at baseline, and group B was defined as a patient with only biochemically active state at baseline. W4–W8, 4–8 weeks after switching; W12–W16, 12–16 weeks after switching; W24–W28, 24–28 weeks after switching. *p-value for side-by-side <0.05 compared to baseline; p-value for side-by-side <0.01 compared to baseline.

Figure 3. Trends in serum infliximab level in the elective switching group. Bars represent median and error bars represent interquartile range. W4–W8, 4–8 weeks after switching; W12–W16, 12–16 weeks after switching; W24–W28, 24–28 weeks after switching.

Table 2 . Trends in Serum Infliximab Levels.

BaselineW4–W8W12–W16W24–W28
Median (IQR)No.Median (IQR)No.Median (IQR)No.Median (IQR)No.
Serum infliximab level, μg/mL
Group A1.6 (0.1–4.8)1510.5 (5.5–13.7)1412.4 (8.6–21.2)1516.6 (11.0–22.9)14
Group B2.7 (0.6–4.2)814.4 (6.4–21.6)*718.0 (8.3–23.6)*720.0 (8.8–24.4)*7
Elective switching group3.4 (0.4–4.6)109.6 (4.9–15.3)*1012.0 (7.0–22.4)1112.6 (7.9–19.6)*10
Serum infliximab level according to concurrent IMM use, μg/mL
Combination with IMM1.6 (0.1–4.3)179.9 (2.9–14.2)1611.8 (8.1–20.0)1711.4 (11.2–20.1)14
No combination with IMM2.7 (0.6–4.7)1611.1 (7.6–20.4)1518.0 (8.4–23.3)1618.4 (8.7–23.8)17
Serum infliximab level according to baseline body weight, μg/mL
Body weight <80 kg2.6 (0.1–4.9)1710.5 (6.8–21.3)1614.8 (8.9–25.6)1718.8 (11.6–25.2)15
Body weight ≥80 kg1.6 (0.6–3.9)1610.8 (5.7–13.6)1513.1 (8.4–18.9)1611.2 (8.7–21.2)16

Group A was defined as a patient with clinically and biochemically active state at baseline, and group B was defined as a patient with only biochemically active state at baseline..

W4–W8, 4–8 weeks after switching; W12–W16, 12–16 weeks after switching; W24–W28, 24–28 weeks after switching; IQR, interquartile range; IMM, immunomodulators..

*p-value for side-by-side <0.05 compared to baseline; p-value for side-by-side <0.01 compared to baseline; Combination group was defined as patients who concurrently used immunomodulators..



3. Efficacy of switching to SC infliximab

The proportions of patients achieving clinical remission, clinical response, and biochemical response were assessed at the last follow-up (Fig. 4). In group A, 60% of patients (9 out of 15) achieved clinical remission, whereas 80% (12 out of 15 patients) achieved clinical response. In the case of clinical response, the median serum infliximab level between the response and nonresponse groups showed a numerical difference (1.6 [IQR, 0.3 to 4.1] μg/mL vs 0.1 [IQR, 0.1 to 4.8] μg/mL at baseline, 16.6 [IQR, 11.2 to 25.2] μg/mL vs 11.4 [IQR, 6.20 to 21.60] μg/mL at the last follow-up), although there was no statistical significance. Biochemical response was achieved in 80% of group A (12 out of 15 patients). In group B, 87.5% of patients (7 out of 8) achieved biochemical response, whereas clinical remission and response were not evaluated because of the low baseline partial Mayo scores.

Figure 4. Clinical remission/response and biochemical response rates at last follow-up. Clinical remission, a partial Mayo score of ≤1 point. Clinical response, a decrease from baseline in partial Mayo score of ≥2 points with an accompanying decrease in rectal bleeding subscore of ≥1 point or an absolute rectal bleeding subscore of 0 or 1. Biochemical response, ≥50% decrease in fecal calprotectin level from baseline. Clinical remission/response was not evaluated in group B because of the low baseline partial Mayo scores. Group A was defined as a patient with clinically and biochemically active state at baseline, and group B was defined as a patient with only biochemically active state at baseline.

4. Pharmacokinetics according to ADA, immunomodulator use, and body weight

Among the 34 patients, 13 patients had serum infliximab levels below 1 μg/mL at baseline. Among these 13 patients, ADA was measured in six patients. Three of six patients were ADA positive: one in group B and two in the elective switching group. Notably, all three patients showed an infliximab level <1 μg/mL at baseline and during all follow-up periods. However, the patient in group B remained on SC infliximab over the study period as FC decreased from 5,958 μg/g to 212 μg/g.

Regarding concurrent immunomodulator use, 17 out of 34 patients were receiving immunomodulators at baseline. All of them continued with immunomodulators for at least 4 months after SC switching. There were no patients who newly started immunomodulators during the follow-up period. Although there was a tendency for higher absolute values of infliximab levels in the monotherapy group in each follow-up period (Table 2), the difference between the two groups was not statistically significant (p=0.739). The combination group included all three ADA-positive patients, in whom the serum infliximab level remained <0.1 μg/mL throughout the follow-up period. Excluding these three patients, the infliximab levels in the combination group were a median of 14.6 (IQR, 10.1 to 21.7) μg/mL at W12–W16 and a median of 14.8 (IQR, 11.2 to 20.2) μg/mL at W24–W28.

Fig. 5 shows the baseline weight and serum infliximab level of each individual at the last follow-up. We divided patients into two groups: the ≥80 kg group (n=17) and the <80 kg group (n=17). During each follow-up period, there was no statistically significant difference between the two groups, but the group weighing <80 kg showed higher values (Table 2). Regarding the serum albumin level at baseline, there was no significant difference in the serum infliximab level during the follow-up (data not shown).

Figure 5. Scatter plot of serum infliximab level at the last follow-up versus body weight at baseline.

5. Treatment discontinuation and safety outcomes

In group A, two of 15 patients stopped treatment during the follow-up period (Fig. 1). The first patient discontinued SC infliximab because of lack of efficacy. After three other preceding biologics, he switched to SC infliximab following 7 months of IV infliximab. He showed a biochemical response, but his symptoms did not improve, and his serum infliximab level did not significantly increase (0.1 μg/mL at baseline to 6.2 μg/mL at W24–W48). Subsequently, he underwent surgery. The second patient discontinued SC treatment because of malignancy. He had experienced vedolizumab failure before infliximab. Seven months after receiving IV infliximab, he switched to SC infliximab. He initially achieved clinical and biochemical responses. However, approximately 6 months after switching, he was diagnosed with prostate cancer and stopped taking SC infliximab.

Localized injection site reactions (ISRs) occurred in five out of 34 patients. One of the five patients experienced severe ISR 3 months after SC switching, which led to the discontinuation of SC injection. The patient had previously experienced a moderate infusion reaction during the administration of IV infliximab. The patient opted for elective switching to SC infliximab to avoid infusion reactions before considering other biologics; however, severe ISR developed with SC infliximab. The remaining four patients had mild symptoms. Other adverse events, such as infections, systemic injection reactions, and delayed hypersensitivity reactions were not noted in this study.

DISCUSSION

To our knowledge, this is the first study to analyze the effectiveness of switching from IV to SC infliximab in UC patients experiencing IV infliximab failure while on maintenance treatment. We confirmed the significant increase of serum infliximab level after SC switching. In group A, we confirmed significant reductions in partial Mayo score, FC, and CRP after the use of SC infliximab. In group B, a significant decrease in FC was observed after SC switching. In terms of the safety and acceptability of SC infliximab, there was only one severe ISR, and only one patient refused to continue SC infliximab because of poor acceptability.

Schreiber et al.12 conducted the first pivotal study regarding SC infliximab switching in IBD patients. They demonstrated that the pharmacokinetics of SC infliximab was found to be noninferior to that of IV infliximab. It also revealed the efficacy of SC infliximab in maintaining clinical remission with safety and immunogenicity profiles comparable to IV infliximab. The retrospective, multicenter cohort study conducted by Smith et al.18 evaluated the effectiveness of elective switching to SC infliximab in 181 IBD patients, most of whom were in clinical remission during maintenance IV infliximab. The high persistence rates and low immunogenicity rates of SC infliximab were observed throughout this study period, with no significant change in clinical activity indices or biomarkers. The REMSWITCH study by Buisson et al.13 explored the pharmacokinetic profiles and risk of relapse during a 6-month follow-up period after switching from IV to SC infliximab in patients with IBD who were in remission and treated with various doses of IV infliximab. The elective SC change was deemed to be safe, well accepted, and carried a low risk of relapse, except for patients receiving IV dosage of 10 mg/kg/4 weeks.

To date, no study has explored the effectiveness of switching from IV to SC infliximab in UC patients who experienced an LOR during maintenance treatment. However, there was a case series exploring the effectiveness of switching to SC infliximab in four CD patients who experienced IV infliximab failure.19 Among them, three patients showed clinical response to maintenance treatment with SC infliximab, but one patient experienced primary nonresponse even after induction treatment with weekly SC infliximab. This study highlights the potential benefit of switching to SC infliximab in terms of efficacy and tolerability. However, the number of patients included was very limited, and the main reason for switching was severe hypersensitivity reaction and/or immunogenicity rather than secondary LOR, such as in the current study.19

SC infliximab differs in pharmacokinetics from IV infliximab. Administration via the IV route leads to early and rapid peak concentration followed by a steady decline to trough. Conversely, subcutaneously administered biologics have lower peak concentrations and smaller differences between peak and trough concentrations. Therefore, relatively stable drug concentrations are maintained between dosing intervals,25-27 and switching from IV to SC infliximab may be beneficial in selected cases. In the present study, serum infliximab levels significantly increased after SC switching, along with a decrease in clinical index and FC levels. These results can be attributed to the stable drug exposure according to the pharmacokinetics of SC infliximab. Interestingly, during the study period, there was a difference in the infliximab levels among the three groups. The serum infliximab levels at baseline were 1.6, 2.7, and 3.4 μg/mL in group A, group B, and the elective switching group, respectively. The lower level in groups A and B may reflect the extent of gut inflammation at baseline. This finding is consistent with previous studies that have reported a low drug concentration in association with anti-tumor necrosis factor treatment failure.28,29 Conversely, the level of serum infliximab during the follow-up period was slightly higher in groups A and B than in the elective switching group. The reason for this disparity was not clear in our data. The higher weight of the elective switching group may influence the infliximab level (76.9, 74.9, and 80.3 kg, respectively).

Immunologic mechanism in which anti-infliximab antibodies are produced as a result of a patient’s immune response to infliximab is considered one of the main causes of LOR.30,31 Unfortunately, in the current study, immunogenicity could not be accurately assessed because of the limited measurement of ADA, which was performed only in six patients. Three out of six patients showed positive ADA, and notably, all three patients had a serum infliximab level <0.1 μg/mL both at baseline and during the follow-up period. From this, we could presume that in the presence of ADA, infliximab levels may not increase even after switching to SC infliximab. However, one ADA-positive patient in group B showed a dramatic decrease of FC despite undetectable infliximab levels during the follow-up, suggesting that further well-designed studies are needed to confirm the effect of SC switching in ADA-positive patients.

In addition to ADA, concurrent immunomodulator use, body weight, and serum albumin level are the main factors affecting infliximab pharmacokinetics.32-37 Combination therapy with immunomodulators is associated with higher drug levels, lower immunogenicity, and subsequent better disease control compared to anti-tumor necrosis factor monotherapy.25,38 Owing to the retrospective design of our study, the concurrent use of immunomodulators was not controlled. The concurrent use of immunomodulators might reflect the disease course severity in our study. To determine whether the concurrent use of immunomodulators enhances the efficacy of SC infliximab, a well-controlled prospective study is warranted. Regarding body weight, patients weighing <80 kg had higher serum infliximab levels than those of patients weighing ≥80 kg, which was consistent with the previous study.37

In this study, 21 out of 23 patients maintained the usage of SC infliximab, indicating the high treatment persistence of SC infliximab. The two patients in group A who discontinued SC infliximab had previously failed with other biologics, but it remains unclear whether these previous biologics failures are related to the poor outcome of SC switching. The safety and acceptability of SC infliximab were good and consistent with the findings of previous studies.13,18 In the current study, only one out of 34 patients developed a severe ISR that required the discontinuation of SC injection. One patient refused SC injection because of poor acceptability. As noted in several studies, SC biologics have advantages that can increase acceptability, such as easier use and less medical visits, thus providing convenience to patients.39-41

Our study has several limitations. First, this study has a single-center, retrospective design. The sample size is relatively small, and there are some missing data. Specifically, the limited number of patients who underwent endoscopy posed constraints in evaluating gut inflammation. Nevertheless, previous studies have indicated a strong correlation between FC and endoscopic activity.42 In our study, we regard FC as a reliable indicator of gut inflammation. Second, since SC infliximab began to be covered by Korean reimbursement policy in 2021, the follow-up period in our study is relatively short. Third, our study included only UC patients on a standard dose of IV infliximab (5 mg/kg every 8 weeks). Considering the situation in Korea where IV infliximab dose escalation is not permitted in UC patients, we initially attempted SC switch in UC patients with suboptimal response to IV infliximab. Currently, a multicenter study including UC and CD patients with a 1-year follow-up period is underway. This study has strengths beyond its limitations. With the theoretical effectiveness of switching to SC infliximab, we were able to confirm the effectiveness of SC switching in UC patients who experienced IV infliximab failure while on maintenance treatment. In contrast to previous studies,13,18 dose escalation of SC infliximab (240 mg every other week or 120 mg weekly) was not permitted. Our results confirmed the effectiveness of switching from the IV standard dose to the SC standard dose. Additionally, despite the retrospective design, we incorporated both disease activity index and biomarkers at each visit in the analysis. This was possible because we had standardized the follow-up observation period in our clinical practice following the introduction of SC switching.

In conclusion, SC infliximab could be considered a promising treatment option for UC patients who had experienced failure with IV infliximab during maintenance treatment.

ACKNOWLEDGEMENTS

This work was supported by a grant from the Korean Gastroenterology Fund for Future Development and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (No. 2021R1A6A1A03040260).

We would like to thank the infusion nurses and administration staff at Asan Medical Center for their support to this study.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS

Study concept and design: J.H.B., S.W.H. Data acquisition: J.H.B., J.B.P., J.E.B., S.W.H., S.H.P., D.H.Y., S.W.H. Data analysis and interpretation: J.H.B., J.B.P., J.E.B., S.W.H., S.H.P., D.H.Y., S.W.H. Drafting of the manuscript: J.H.B., S.W.H. Critical revision of the manuscript for important intellectual content: J.H.B., S.W.H. Statistical analysis: J.H.B., J.B.P., J.E.B., S.W.H., S.H.P., D.H.Y., S.W.H. Obtained funding: S.W.H. Administrative, technical, or material support; study supervision: B.D.Y., J.S.B., S.J.M., S.K.Y. Approval of final manuscript: all authors.

SUPPLEMENTARY MATERIALS

Supplementary materials can be accessed at https://doi.org/10.5009/gnl230291.

DATA AVAILABILITY STATEMENT

All data, analytic methods, and study materials relevant to the study are included in the article or available upon request from the corresponding author, SWH.

Fig 1.

Figure 1.Flowchart of the study. UC, ulcerative colitis; IV, intravenous; SC, subcutaneous.
Gut and Liver 2024; :

Fig 2.

Figure 2.(A) Trends in serum infliximab level among patients who switched to subcutaneous (SC) infliximab. (B) Trends in partial Mayo score among patients who switched to SC infliximab. (C) Trends in fecal calprotectin among patients who switched to SC infliximab. (D) Trends in C-reactive protein (CRP) among patients who switched to SC infliximab. Bars represent median and error bars represent interquartile range. Group A was defined as a patient with clinically and biochemically active state at baseline, and group B was defined as a patient with only biochemically active state at baseline. W4–W8, 4–8 weeks after switching; W12–W16, 12–16 weeks after switching; W24–W28, 24–28 weeks after switching. *p-value for side-by-side <0.05 compared to baseline; p-value for side-by-side <0.01 compared to baseline.
Gut and Liver 2024; :

Fig 3.

Figure 3.Trends in serum infliximab level in the elective switching group. Bars represent median and error bars represent interquartile range. W4–W8, 4–8 weeks after switching; W12–W16, 12–16 weeks after switching; W24–W28, 24–28 weeks after switching.
Gut and Liver 2024; :

Fig 4.

Figure 4.Clinical remission/response and biochemical response rates at last follow-up. Clinical remission, a partial Mayo score of ≤1 point. Clinical response, a decrease from baseline in partial Mayo score of ≥2 points with an accompanying decrease in rectal bleeding subscore of ≥1 point or an absolute rectal bleeding subscore of 0 or 1. Biochemical response, ≥50% decrease in fecal calprotectin level from baseline. Clinical remission/response was not evaluated in group B because of the low baseline partial Mayo scores. Group A was defined as a patient with clinically and biochemically active state at baseline, and group B was defined as a patient with only biochemically active state at baseline.
Gut and Liver 2024; :

Fig 5.

Figure 5.Scatter plot of serum infliximab level at the last follow-up versus body weight at baseline.
Gut and Liver 2024; :

Table 1 Baseline Characteristics of Patients Switched to Subcutaneous Infliximab

CharacteristicTotal (n=23)Group A (n=15)Group B (n=8)
Age at diagnosis, yr23.0 (20.0–31.0)22.0 (20.0–53.0)24.5 (17.5–28.8)
Age at baseline, yr34.0 (25.0–50.0)36.0 (25.0–61.0)32.5 (23.8–42.8)
Male sex16 (69.6)12 (80.0)4 (50.0)
Weight, kg76.2±19.176.9±19.974.9±18.6
Body mass index, kg/m226.3±5.926.3±6.526.4±4.9
Disease extent
Proctitis (E1)1 (4.3)01 (12.5)
Left-sided (E2)8 (34.8)6 (40.0)2 (25.0)
Pancolitis (E3)14 (60.9)9 (60.0)5 (62.5)
5-ASA use22 (95.7)14 (93.3)8 (100.0)
Immunomodulator use10 (43.5)7 (46.7)3 (37.5)
Thiopurine7 (30.4)6 (40.0)1 (12.5)
Methotrexate3 (13.0)1 (6.7)2 (25.0)
Steroid at baseline6 (26.1)6 (40.0)0
Other biologics exposure3 (13.0)3 (20.0)0
Infliximab trough level, μg/mL1.6 (0.2–4.3)1.6 (0.1–4.8)2.7 (0.6–4.2)
Partial Mayo score3.0 (2.0–4.0)4.0 (3.0–5.0)1.0 (0.3–2.0)
Fecal calprotectin, μg/g1,236 (417–4,180)2,044 (1,100–4,304)508 (229–1,020)
CRP, mg/dL0.37 (0.10–0.91)0.65 (0.29–1.24)0.15 (0.10–0.58)
Serum albumin, g/dL,4.0 (3.5–4.3)3.9 (3.4–4.3)4.0 (3.9–4.3)
Disease duration at baseline, yr8.0 (2.0–16.0)8.0 (4.0–15.0)12.0 (1.3–18.5)
Duration of IV IFX, wk55.3 (28.1–154.3)44.1 (28.1–154.3)63.8 (24.7–381.3)

Data are presented as median (interquartile range), number (%), or mean±SD. Group A was defined as a patient with clinically and biochemically active state at baseline, and group B was defined as a patient with only biochemically active state at baseline.

5-ASA, 5-aminosalicylate; CRP, C-reactive protein; IV, intravenous; IFX, infliximab.


Table 2 Trends in Serum Infliximab Levels

BaselineW4–W8W12–W16W24–W28
Median (IQR)No.Median (IQR)No.Median (IQR)No.Median (IQR)No.
Serum infliximab level, μg/mL
Group A1.6 (0.1–4.8)1510.5 (5.5–13.7)1412.4 (8.6–21.2)1516.6 (11.0–22.9)14
Group B2.7 (0.6–4.2)814.4 (6.4–21.6)*718.0 (8.3–23.6)*720.0 (8.8–24.4)*7
Elective switching group3.4 (0.4–4.6)109.6 (4.9–15.3)*1012.0 (7.0–22.4)1112.6 (7.9–19.6)*10
Serum infliximab level according to concurrent IMM use, μg/mL
Combination with IMM1.6 (0.1–4.3)179.9 (2.9–14.2)1611.8 (8.1–20.0)1711.4 (11.2–20.1)14
No combination with IMM2.7 (0.6–4.7)1611.1 (7.6–20.4)1518.0 (8.4–23.3)1618.4 (8.7–23.8)17
Serum infliximab level according to baseline body weight, μg/mL
Body weight <80 kg2.6 (0.1–4.9)1710.5 (6.8–21.3)1614.8 (8.9–25.6)1718.8 (11.6–25.2)15
Body weight ≥80 kg1.6 (0.6–3.9)1610.8 (5.7–13.6)1513.1 (8.4–18.9)1611.2 (8.7–21.2)16

Group A was defined as a patient with clinically and biochemically active state at baseline, and group B was defined as a patient with only biochemically active state at baseline.

W4–W8, 4–8 weeks after switching; W12–W16, 12–16 weeks after switching; W24–W28, 24–28 weeks after switching; IQR, interquartile range; IMM, immunomodulators.

*p-value for side-by-side <0.05 compared to baseline; p-value for side-by-side <0.01 compared to baseline; Combination group was defined as patients who concurrently used immunomodulators.


References

  1. Torres J, Mehandru S, Colombel JF, Peyrin-Biroulet L. Crohn's disease. Lancet 2017;389:1741-1755.
    Pubmed CrossRef
  2. Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel JF. Ulcerative colitis. Lancet 2017;389:1756-1770.
    Pubmed CrossRef
  3. Baumgart DC, Le Berre C. Newer biologic and small-molecule therapies for inflammatory bowel disease. N Engl J Med 2021;385:1302-1315.
    Pubmed CrossRef
  4. Raine T, Bonovas S, Burisch J, et al. ECCO guidelines on therapeutics in ulcerative colitis: medical treatment. J Crohns Colitis 2022;16:2-17.
    Pubmed CrossRef
  5. Torres J, Bonovas S, Doherty G, et al. ECCO guidelines on therapeutics in Crohn's disease: medical treatment. J Crohns Colitis 2020;14:4-22.
    Pubmed CrossRef
  6. Feuerstein JD, Isaacs KL, Schneider Y, et al. AGA clinical practice guidelines on the management of moderate to severe ulcerative colitis. Gastroenterology 2020;158:1450-1461.
    Pubmed KoreaMed CrossRef
  7. Feuerstein JD, Ho EY, Shmidt E, et al. AGA clinical practice guidelines on the medical management of moderate to severe luminal and perianal fistulizing Crohn's disease. Gastroenterology 2021;160:2496-2508.
    Pubmed KoreaMed CrossRef
  8. Turner D, Ricciuto A, Lewis A, et al. STRIDE-II: an update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD. Gastroenterology 2021;160:1570-1583.
    Pubmed CrossRef
  9. Na SY, Choi CH, Song EM, et al. IBD Research Group of the Korean Association for the Study of Intestinal Diseases. Korean clinical practice guidelines on biologics and small molecules for moderate-to-severe ulcerative colitis. Intest Res 2023;21:61-87.
    Pubmed KoreaMed CrossRef
  10. Koh SJ, Hong SN, Park SK, et al. Korean clinical practice guidelines on biologics for moderate to severe Crohn's disease. Intest Res 2023;21:43-60.
    Pubmed KoreaMed CrossRef
  11. Parigi TL, D'Amico F, Peyrin-Biroulet L, Danese S. Evolution of infliximab biosimilar in inflammatory bowel disease: from intravenous to subcutaneous CT-P13. Expert Opin Biol Ther 2021;21:37-46.
    Pubmed CrossRef
  12. Schreiber S, Ben-Horin S, Leszczyszyn J, et al. Randomized controlled trial: subcutaneous vs intravenous infliximab CT-P13 maintenance in inflammatory bowel disease. Gastroenterology 2021;160:2340-2353.
    Pubmed CrossRef
  13. Buisson A, Nachury M, Reymond M, et al. Effectiveness of switching from intravenous to subcutaneous infliximab in patients with inflammatory bowel diseases: the REMSWITCH study. Clin Gastroenterol Hepatol 2023;21:2338-2346.
    Pubmed CrossRef
  14. Schultheiss JP, Mahmoud R, Louwers JM, et al. Loss of response to anti-TNFα agents depends on treatment duration in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2021;54:1298-1308.
    Pubmed KoreaMed CrossRef
  15. Yamamoto-Furusho JK, Al Harbi O, Armuzzi A, et al. Incidence of suboptimal response to tumor necrosis factor antagonist therapy in inflammatory bowel disease in newly industrialised countries: the EXPLORE study. Dig Liver Dis 2020;52:869-877.
    Pubmed CrossRef
  16. Otake H, Matsumoto S, Mashima H. Long-term clinical and real-world experience with Crohn's disease treated with anti-tumor necrosis factor-α antibodies. Intest Res 2022;20:464-474.
    Pubmed KoreaMed CrossRef
  17. Albshesh A, Ben-Horin S. CT-P13: a review on a biosimilar to infliximab in the treatment of inflammatory bowel disease. Expert Opin Biol Ther 2019;19:971-978.
    Pubmed CrossRef
  18. Smith PJ, Critchley L, Storey D, et al. Efficacy and safety of elective switching from intravenous to subcutaneous infliximab [CT-P13]: a multicentre cohort study. J Crohns Colitis 2022;16:1436-1446.
    Pubmed KoreaMed CrossRef
  19. Caron B, Fumery M, Netter P, Peyrin-Biroulet L. Letter: treatment with subcutaneous CT-P13 in Crohn's disease patients with intravenous infliximab failure. Aliment Pharmacol Ther 2022;55:508-509.
    Pubmed CrossRef
  20. Park SH, Yang SK, Park SK, et al. Long-term prognosis of Crohn's disease and its temporal change between 1981 and 2012: a hospital-based cohort study from Korea. Inflamm Bowel Dis 2014;20:488-494.
    Pubmed CrossRef
  21. Noh SM, Oh EH, Park SH, et al. Association of faecal calprotectin level and combined endoscopic and radiological healing in patients with Crohn's disease receiving anti-tumour necrosis factor therapy. J Crohns Colitis 2020;14:1231-1240.
    Pubmed CrossRef
  22. Bertin D, Serrero M, Grimaud JC, Desjeux A, Desplat-Jégo S. Monitoring of infliximab trough levels and anti-infliximab antibodies in inflammatory bowel diseases: a comparison of three commercially available ELISA kits. Cytokine 2020;126:154859.
    Pubmed CrossRef
  23. Herbers J, Miller R, Walther A, et al. How to deal with non-detectable and outlying values in biomarker research: best practices and recommendations for univariate imputation approaches. Compr Psychoneuroendocrinol 2021;7:100052.
    Pubmed KoreaMed CrossRef
  24. Zubin G, Peter L. Predicting endoscopic Crohn's disease activity before and after induction therapy in children: a comprehensive assessment of PCDAI, CRP, and fecal calprotectin. Inflamm Bowel Dis 2015;21:1386-1391.
    Pubmed KoreaMed CrossRef
  25. Little RD, Ward MG, Wright E, et al. Therapeutic drug monitoring of subcutaneous infliximab in inflammatory bowel disease: understanding pharmacokinetics and exposure response relationships in a new era of subcutaneous biologics. J Clin Med 2022;11:6173.
    Pubmed KoreaMed CrossRef
  26. Papamichael K, Rakowsky S, Rivera C, Cheifetz AS, Osterman MT. Association between serum infliximab trough concentrations during maintenance therapy and biochemical, endoscopic, and histologic remission in Crohn's disease. Inflamm Bowel Dis 2018;24:2266-2271.
    Pubmed KoreaMed CrossRef
  27. Ungar B, Levy I, Yavne Y, et al. Optimizing anti-TNF-α therapy: serum levels of infliximab and adalimumab are associated with mucosal healing in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol 2016;14:550-557.
    Pubmed CrossRef
  28. Kennedy NA, Heap GA, Green HD, et al. Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn's disease: a prospective, multicentre, cohort study. Lancet Gastroenterol Hepatol 2019;4:341-353.
    Pubmed CrossRef
  29. Seow CH, Newman A, Irwin SP, Steinhart AH, Silverberg MS, Greenberg GR. Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut 2010;59:49-54.
    Pubmed CrossRef
  30. Measurement of infliximab and anti-infliximab antibody levels can help distinguish maintenance versus loss of response. Gastroenterol Hepatol (N Y) 2012;8:131-134.
  31. Su CG, Lichtenstein GR. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. Gastroenterology 2003;125:1544-1546.
    Pubmed CrossRef
  32. Ternant D, Aubourg A, Magdelaine-Beuzelin C, et al. Infliximab pharmacokinetics in inflammatory bowel disease patients. Ther Drug Monit 2008;30:523-529.
    Pubmed CrossRef
  33. Adedokun OJ, Sandborn WJ, Feagan BG, et al. Association between serum concentration of infliximab and efficacy in adult patients with ulcerative colitis. Gastroenterology 2014;147:1296-1307.
    Pubmed CrossRef
  34. Fasanmade AA, Adedokun OJ, Ford J, et al. Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis. Eur J Clin Pharmacol 2009;65:1211-1228.
    Pubmed KoreaMed CrossRef
  35. Loftus EV Jr, Paul S, Roblin X. Therapeutic drug monitoring for subcutaneous infliximab? Too early to conclude. Clin Gastroenterol Hepatol 2023;21:2193-2194.
    Pubmed CrossRef
  36. Kumar P, Vuyyuru SK, Das P, et al. Serum albumin is the strongest predictor of anti-tumor necrosis factor nonresponse in inflammatory bowel disease in resource-constrained regions lacking therapeutic drug monitoring. Intest Res 2023;21:460-470.
    Pubmed KoreaMed CrossRef
  37. Hanzel J, Bukkems LH, Gecse KB, D'Haens GR, Mathôt RA. Population pharmacokinetics of subcutaneous infliximab CT-P13 in Crohn's disease and ulcerative colitis. Aliment Pharmacol Ther 2021;54:1309-1319.
    Pubmed KoreaMed CrossRef
  38. Remy C, Caron B, Gouynou C, et al. Inflammatory bowel disease patients' acceptance for switching from intravenous infliximab or vedolizumab to subcutaneous formulation: the Nancy experience. J Clin Med 2022;11:7296.
    Pubmed KoreaMed CrossRef
  39. Singh A, Mahajan R, Kedia S, et al. Use of thiopurines in inflammatory bowel disease: an update. Intest Res 2022;20:11-30.
    Pubmed KoreaMed CrossRef
  40. Kim ES, Kim KO, Jang BI, et al. Factors contributing to the preference of Korean patients with Crohn's disease when selecting an anti-tumor necrosis factor agent (CHOICE Study). Gut Liver 2016;10:391-398.
    Pubmed KoreaMed CrossRef
  41. Allen PB, Lindsay H, Tham TC. How do patients with inflammatory bowel disease want their biological therapy administered?. BMC Gastroenterol 2010;10:1.
    Pubmed KoreaMed CrossRef
  42. Hart L, Chavannes M, Kherad O, et al. Faecal calprotectin predicts endoscopic and histological activity in clinically quiescent ulcerative colitis. J Crohns Colitis 2020;14:46-52.
    Pubmed CrossRef
Gut and Liver

Vol.18 No.3
May, 2024

pISSN 1976-2283
eISSN 2005-1212

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