PERFUSE: Non-Interventional Cohort Study of Patients Receiving Infliximab Biosimilar SB2: Results in Pediatric Patients : Journal of Pediatric Gastroenterology and Nutrition

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Original Articles: Gastroenterology: Inflammatory Bowel Disease

PERFUSE: Non-Interventional Cohort Study of Patients Receiving Infliximab Biosimilar SB2: Results in Pediatric Patients

Martinez-Vinson, Christine MD*; Lemoine, Anaïs MD†; Bouhnik, Yoram MD, PhD‡; Braithwaite, Ben MScA, MIng§; Fohlen-Weill, Audrey PharmD‖; Addison, Janet MSc#

Author Information

From the *Service de Gastroentérologie et Nutrition Pédiatriques, Hôpital Universitaire Robert-Debré, Paris, France

the †Service de Nutrition et Gastroentérologie Pédiatriques, Hôpital Trousseau, APHP, Sorbonne Université, Paris, France

‡Paris IBD Center, Groupe Hospitalier Privé Ambroise Paré - Hartmann, Neuilly sur Seine, France

§Sanoïa e-Health Services, Gémenos, France

‖Biogen France SAS, Gastroenterology & Rhumatologie, Biosimilars, Paris, France

#Biogen IDEC, Clinical Research, Biosimilars, Maidenhead, UK.

Received July 27, 2022; accepted October 27, 2022.

C.M-Z. received consulting and/or speaker fees from AbbVie, MSD, Nestle, Biogen. A.L. received consulting and/or speaker fees from Mead Johnson, Modilac, Nestle, Nutricia. Y.B. received consulting and/or speaker fees from AbbVie, Biogaran, Biogen, Boehringer Ingelheim, CTMA, Ferring, Gilead, Hospira, ICON, Inception IBD, Janssen, Lilly, Mayoly Spindler, Merck, Merck Sharp & Dohme, Norgine, Pfizer, Robarts Clinical Trials, Roche, Sanofi, Shire, Takeda, UCB, Vifor Pharma. B.B. provided medical writing services for Biogen on behalf of Sanoïa e-Health Services. J.A. and A.F-W. are employees of and may hold options and/or stock in Biogen.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.jpgn.org).

Trial identification number: NCT03662919. URL: https://clinicaltrials.gov/ct2/show/NCT03662919

Sources of Funding: The authors acknowledge Sanoïa for data management services and writing and editorial support for this paper. Funding for this assistance was provided by Biogen International GmbH, Baar, Switzerland.

Address correspondence and reprint requests to Ben Braithwaite, MScA, MIng, Sanoïa e-Health Services Digital CRO, 188 avenue de la 2ème division blindée, 13 420 Aubagne, France (e-mail: [email protected]).

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Journal of Pediatric Gastroenterology and Nutrition 76(4):p 451-459, April 2023. | DOI: 10.1097/MPG.0000000000003683
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Abstract

What Is Known

  • Pediatric inflammatory bowel disease (IBD) is linked with growth failure in patients.
  • Infliximab (IFX) (originator or biosimilar) is a biologic used to treat pediatric Crohn disease and ulcerative colitis.
  • Most available real-life data on the use of biosimilar IFX in pediatric patients pertains to the induction period.

What Is New

  • SB2, an IFX biosimilar, allows effective disease control in both switched and naïve patients even after the induction period.
  • 12-month persistence on SB2 was in line with previous studies on originator IFX.
  • Patients treated with SB2 did not exhibit growth failure and were of a healthy weight.

The prevalence of inflammatory bowel disease (IBD) has sharply increased worldwide since the 1990s and around 1 in 5 cases occur before the age of 18 (1–4). Pediatric IBD is associated with higher disease activity, impacted growth rates, and higher rates of complications than adult IBD (5–8).

IBD treatments have evolved, particularly following the approval of anti-TNF molecules such as Infliximab (IFX) by the European Medicines Agency in 1999 for the treatment of Crohn disease (CD). Since then, the use of biologics and their equivalent biosimilars has kept increasing (9). In France, the first IFX biosimilar was approved in 2013, and SB2 was approved in 2016 (10,11), based on a phase I pharmacokinetic study and phase III equivalence study in patients with moderate to severe rheumatoid arthritis (12,13).

Studies from several European countries show the effectiveness of IFX biosimilars for the treatment of pediatric IBD, both in patients switching from the originator IFX and in naïve patients (14,15). Most present results after induction (generally 14–30 weeks). However, prospective real-life long-term data for biosimilars are scarce in comparison (16,17). Long-term real-life follow-up is valuable as many biologics and biosimilars require intensified initiation routines and increased dosing over time: secondary failure is one of the main reasons for treatment interruption (18,19).

The PERFUSE study (NCT03662919) is a non-interventional study designed to address the need for real-world evidence, involving patients routinely treated with SB2 in France. This paper describes the response to treatment and persistence on SB2 for up to 12 months in the pediatric IBD population of this large-scale study (126 of the 1358 total patients, see Figure 1, Supplemental Digital Content 1, https://links.lww.com/MPG/D33).

METHODS

Included Population

Patients included in the pediatric cohort of the PERFUSE study met all the following criteria: (i) diagnosis of CD or ulcerative colitis (UC), (ii) aged between 6 and 17 at treatment initiation, (iii) patient and their parents could understand the information provided and complete questionnaires in French, and (iv) initiated routine SB2 treatment between September 2017 and September 2019.

Patients meeting any of the following criteria were not included in the study: (i) patients treated with IFX for psoriasis, juvenile idiopathic arthritis, or suppurative hidradenitis, (ii) patients not subject to regular check-ups in the site that would include them or who are likely to change site during follow-up, and (iii) female patients who planned to get pregnant over the course of the follow-up period.

The pediatric population was subdivided into 2 groups for each diagnosis based on patients’ prior experience with originator IFX. This distinction is necessary as the expected results for naïve and switched patients are different.

Data Collection

Data were collected during routine visits over the course of 12 months after SB2 initiation, between 2018 and 2020. Patient characteristics were reported by the treating physician during the baseline visit: height, weight, birth year, sex, previous treatments, and concomitant treatments. Height and weight were tracked during each subsequent visit for pediatric patients. Disease activity was tracked at each visit using appropriate routinely used clinical disease scores: the Harvey-Bradshaw Index (HBI) for CD patients and the Pediatric Ulcerative Colitis Activity Index (PUCAI) for UC patients. These are recommended for assessing disease activity noninvasively due to their proven effectiveness in pediatric populations (20–22). Disease activity was also tracked using data from routine blood and stool analyses—C-reactive protein (CRP) concentration, calprotectin concentration, sedimentation rate, anti-drug antibody concentration, and trough level data were collected when available in patients’ files (23–25). Finally, persistence on SB2 was recorded by physicians during follow-up visits. Reasons for treatment discontinuation were reported by physicians as follows: primary failure (treatment failure observed within 14 weeks of initiating IFX), secondary failure (treatment failure observed more than 14 weeks after initiating IFX), patient decision, prolonged remission, and adverse events.

Pediatric patients who reached adulthood (their 18th birthday) during the study could continue in the adult cohort: they are included in this analysis, though height data was no longer routinely captured.

Statistical Analysis

Analysis was performed according to patients’ status at inclusion (naïve or switched) and diagnosis (CD and UC). Data are presented at two time points: M0 (baseline) and M12 (10–14 months after baseline). When no data was available at baseline, 6-month data is presented (M6) instead. Time series analysis was performed for all patients with available data at both time points by calculating the difference between the values for each time point. These data are presented using the mean value and a 95% confidence interval. Statistical significance is shown using a P value calculated with a paired t test: P < 0.05 is considered significant. For small populations which may not present Gaussian distributions around the mean, data are presented in the text using the median value and interquartile range (IQR) and significance is calculated using the Wilcoxon sign-rank test. Persistence was evaluated using a Kaplan Meier approach. Significance was calculated using a log-rank test. The number and frequency of the reasons for non-persistence are presented for each sub-group.

Disease activity scores were calculated and analyzed according to Harvey and Bradshaw (20) for the HBI, and Turner et al (26) for the PUCAI. Scores were also used to categorize disease activity at each time point (HBI: <5: remission, 5–7: low, 8–16: moderate, >16: high activity; PUCAI: <10: remission, 10–34: low, 35–64: moderate, >64 high activity).

Patients’ height and body mass index (BMI) growth were compared with the most recent French height growth chart and the WHO BMI growth chart respectively using z scores (27–29): the difference between patients’ heights and the national average was computed and then expressed using the national population’s standard deviation. z scores of ±2 indicate a statistically significant difference in height between the patient population and the overall French population at the same age. Significance is also expressed using a P value.

Ethical considerations

All necessary ethical considerations and measures were taken to ensure the protection of all participants: pediatric patients were only eligible for the study if they and their parents were able to understand and sign a non-opposition form. This being an observational study, non-opposition is sufficient (French Public Health Code, Article L1123-7).

The final amendment to the protocol for this study was approved by an independent ethics committee in France, in accordance with French regulations, on April 25, 2022.

This study is also listed on clinicaltrials.gov (NCT03662919) and was approved by the appropriate bodies in terms of the quality of the methodology, data security, and scientific merit.

RESULTS

Overall, 126 pediatric patients were included in 3 tertiary sites: 102 CD patients, (51 naïve and 51 switched) and 24 UC patients (9 naïve and 15 switched), see Table 1 for a detailed description.

TABLE 1. - Characteristics of the included population at baseline
CD (n = 102) UC (n = 24)
Naive (n = 51) Switched (n = 51) Naive (n = 9) Switched (n = 15)
Age, y, mean (SD) 13.4 (2.8) 15.0 (2.7) 12.4 (3.9) 12.5 (3.5)
Disease duration, y, mean (SD) 0.8 (0.9) 3.4 (2.0) 1.0 (1.3) 3.9 (2.8)
Previous exposure to infliximab, y, mean (SD) NA 2.1 (2.0)
n = 18		 NA 3.9 (3.0)
n = 7
Number of females, n (%) 21 (41.2) 23 (45.1) 4 (44.4) 7 (46.7)
Weight, kg, mean (SD) 45.6 (14.5) 54.6 (16.1) 38.6 (12.3) 46.8 (18.9)
Height, cm, mean (SD) 155.8 (17.4) 163.4 (14.6) 148.4 (17.2) 151.5 (19.1)
Height z score, mean [95% CI] 0.1 [−1.4; 1.6] 0.0 [−0.6; 0.7] −0.3 [−0.5; 0.0] −0.0 [−0.4; 0.3]
BMI z score, kg/m2,
CD: mean [95% CI]
UC: med [Q1; Q3]		 −0.5 [−0.9; −0.2] −0.4 [−0.7; 0.0] 0.4 [−0.9; 1.0] 0.3 [−0.7; 1.0]
Disease activity, n (%)
 Remission 26 (63.4) 45 (93.8) 0 (0.0) 10 (71.4)
 Low activity 8 (19.5) 2 (4.2) 2 (28.6) 4 (28.6)
 Moderate activity 7 (17.1) 1 (2.1) 2 (28.6) 0 (0.0)
 High activity 0 (0.0) 0 (0.0) 3 (42.8) 0 (0.0)
Prior medication (within 5 years of initiation), n (%)
 Immunosuppressors 13 (25.5) 24 (47.1) 3 (33.3) 9 (60.0)
 Corticoids 18 (35.3) 23 (45.1) 4 (22.2) 6 (40.0)
 5-ASA 9 (17.6) 12 (23.5) 3 (33.3) 5 (33.3)
 Adalimumab 0 (0.0) 2 (3.9) 2 (22.2) 0 (0.0)
 Golimumab 1 (2.0) 1 (2.0) 0 (0.0) 0 (0.0)
 Vedolizumab 0 (0.0) 1 (2.0) 0 (0.0) 0 (0.0)
 Ustekinumab 0 (0.0) 1 (2.0) 0 (0.0) 0 (0.0)
 Other 3 (5.9) 3 (5.9) 0 (0.0) 0 (0.0)
Concomitant medication, n (%)
 5-ASA (oral) 10 (19.6) 11 (21.6) 3 (33.3) 7 (46.7)
 5-ASA (topical) 2 (3.9) 1 (2.0) 4 (44.4) 4 (26.7)
 Azathioprine 23 (45.1) 22 (43.1) 2 (22.2) 1 (6.7)
 Methotrexate 0 (0.0) 1 (2.0) 0 (0.0) 1 (6.7)
 Budesonide 0 (0.0) 1 (2.0) 0 (0.0) 0 (0.0)
 Beclomethasone 1 (2.0) 0 (0.0) 0 (0.0) 0 (0.0)
 6-Mercaptopurine 1 (2.0) 0 (0.0) 0 (0.0) 0 (0.0)
 Other 33 (64.7) 40 (78.4) 4 (44.4) 8 (53.3)
5-ASA = 5-aminosalicylic acid; 95% CI = 95% confidence interval; BMI = body mass index; CD = Crohn disease; SD = standard deviation; UC = ulcerative colitis.

Response to Treatment

Naïve patients’ disease scores decreased significantly between baseline and M12 only for CD patients (HBI: −3.9 points, confidence interval (CI) = [−5.2; −2.7], n = 29, P < 0.01 and PUCAI: −20.0 points, IQR = [−20.0; −15.0], n = 3, P = 0.2) (Fig. 1A and B). CRP concentration significantly decreased only in the CD population (−10.9 mg/mL, CI = [−18.6; −3.1], n = 30, P < 0.01 and −1.2 mg/mL, IQR = [−59.0; 0.0], n = 3, P = 0.50 for CD and UC patients, respectively) (Fig. 1C and D). All naïve patients for whom we had disease activity measurements at M12 (CD: n = 29; 56.9% and UC: n = 3; 33.3%) were either in remission or presented low disease activity.

F1
FIGURE 1.:
Evolution of disease scores and biological assays. (A and B) The evolution of disease activity scores for patients with CD (HBI ranging from 0 to 18) and UC (PUCAI ranging from 0 to 85), respectively. (C and D) The evolution of measured CRP concentrations in mg/L for CD and UC patients, respectively. (E and F) The evolution of trough levels in µg/L for CD and UC patients, respectively. Values at baseline (M0), 6 months (M6), and 12 months (M12) are provided for naïve (blue) and switched (orange) patients. Data is presented using the mean and 95% CI for CD patients and median with IQR for UC patients. A colored star indicates a significant difference between baseline and M12 (P < 0.05). CD = Crohn disease; CI = confidence interval; CRP = C-reactive protein; HBI = Harvey-Bradshaw Index; IQR = interquartile range; PUCAI = Pediatric Ulcerative Colitis Activity Index; UC = ulcerative colitis.

Switched patients presented stable CRP levels between baseline and M12 (−3.8 mg/mL, CI = [−10.1; 2.5], n = 43, P > 0.1 and −0.2 mg/mL, IQR = [−2.1; 0.0], n = 13, P = 0.11 for CD and UC patients, respectively) (Fig. 1C and D). Disease activity also remained stable for UC patients (PUCAI: 0.0 points, IQR = [−7.5; 0.0], n = 12, P = 0.22) (Fig. 1B) and decreased significantly for CD patients (HBI: −0.8 points, CI = [−1.5; −0.1], n = 44, P = 0.02) (Fig. 1A). All switched patients for whom we had disease activity measurements at M12 (CD: n = 44; 86.3% and UC: n = 13; 86.7%) were either in remission or presented low disease activity.

Drug levels reached therapeutic levels by M6 for both naïve (7.1 µg/mL, CI = [3.5; 10.6], n = 23 and 11.1 µg/mL, IQR = [2.6; 19.7], n = 2 for CD and UC patients, respectively) and switched patients (10.7 µg/mL, CI = [7.1; 14.3], n = 43 and 12.6 µg/mL, IQR = [7.7; 15.0], n = 4 for CD and UC patients, respectively) and were maintained with no significant change between M6 and M12 for both naive (CD: n = 16, P = 0.08; UC: n = 2, P = 1.00) and switched patients (CD: n = 24, P = 0.26; UC: n = 4, P = 0.63) (Fig. 1E and F). Treatment intensification rates are presented in Table 1, Supplemental Digital Content 2, https://links.lww.com/MPG/D34.

Patient Growth

Only naïve CD patients’ height z score at baseline was significantly different from the general age-matched population: −0.4, CI = [−0.5; 0.0], n = 44, P < 0.05 and +0.2, IQR = [−1.3; 1.0], n = 14, P > 0.1 for naïve CD and UC patients, respectively; −0.0, CI = [−0.4; 0.3], n = 51, P > 0.1 and +0.3, IQR = [−1.3; 1.0], n = 6, P > 0.1 for switched CD and UC patients, respectively (Fig. 2A and B).

F2
FIGURE 2.:
Patient growth metrics: growth was measured using the height z score and ponderal growth was measured using BMI. (A and B) Distributions of height z scores for naïve (blue) and switched (orange) CD and UC patients at baseline and at 12 months. (C and D) Distributions of BMI for naïve (blue) and switched (orange) CD and UC patients at baseline and at 12 months. Significant differences (P < 0.05) between baseline and M12 are indicated with a star. BMI = body mass index; CD = Crohn disease; UC = ulcerative colitis.

During follow-up, height z score increased significantly for all populations except naïve UC patients (+0.5, CI = [0.3; 0.7], n = 29, P < 0.01 and +0.7, IQR = [0.6; 0.7], n = 2, P = 0.50 for naïve CD and UC patients, respectively; +0.4, CI = [0.3; 0.5], n = 36, P < 0.01 and +0.3 [0.0; 1.2], n = 13, P = 0.01 for switched CD and UC patients, respectively) (Fig. 2A and B).

Patient BMI z score increased significantly between baseline and M12 only for the naïve CD population (+0.5, CI = [0.2; 0.8], n = 29, P < 0.01 and −0.4, IQR = [−0.6; −0.2], n = 2, P = 0.50 for naïve CD and UC patients, respectively; −0.1, CI = [−0.4; 0.2], n = 36, P = 0.61 and −0.0, IQR = [−0.2; 0.2], n = 13, P = 0.74 for switched CD and UC patients, respectively). Change was observed mainly in patients with a low BMI at baseline (Fig. 2C and D).

Persistence and Safety

After 12 months, 31 out of 51 naïve CD patients (60.8%) were still treated using SB2, compared to 45 out of 51 switched CD patients (88.2%), and 3 out of 9 naïve UC patients (33.3%) were still treated compared to 13 out of 15 switched UC patients (86.7%) (Fig. 3A and B).

F3
FIGURE 3.:
Survival curves for participants based on a Kaplan Meier approach. (A) The survival curve for CD patients’ persistence on SB2 treatment. (B) The survival curve for UC patients’ persistence on SB2 treatment. Each step represents a patient who left the study and stopped SB2 treatment. Each star represents a censored patient for whom we have no data beyond that point. CD = Crohn disease; UC = ulcerative colitis.

Non-persistence of treatment was higher in naïve patients for both CD (P < 0.01) and UC (P < 0.01). Non-persistence was also significantly higher in naïve UC patients than in any other studied population (P < 0.05) (Fig. 3A and B).

Reasons for treatment discontinuation in naïve patients were primary failure (CD: n = 1, 4.3% and UC: n = 1, 14.3%), secondary failure (CD: n = 7, 30.4% and UC: n = 5, 71.4%), adverse events (CD: n = 11, 47.8% and UC: n = 1, 14.3%), prolonged remission (CD: n = 1, 4.3% and UC: n = 0), and patient decision (CD: n = 3, 13.0% and UC: n = 0).

Twelve of the 49 adverse events (24.5%) reported by naïve patients led to treatment discontinuation: nine (8 CD and 1 UC) were serious anaphylactic reactions to SB2 infusion and three (all CD) nonserious adverse events [development of psoriasis (n = 2) and persistent neutropenia (n = 1)].

Reasons for treatment discontinuation in switched patients were secondary failure (CD: n = 4, 44.4% and UC: n = 2, 66.7%), adverse events (CD: n = 3, 33.3% and UC: n = 0), and prolonged remission (CD: n = 2, 22.2% and UC: n = 1, 33.3%).

Three of the 10 adverse events (30%) reported by switched patients led to treatment discontinuation: 1 was a serious anaphylactic reaction to SB2 infusion and the other 2 were the development of psoriasis, and an undefined paradoxical side effect respectively.

Reasons for treatment discontinuation continued to be reported beyond the M12 window, with two discontinuations occurring beyond 14 months of study follow-up.

DISCUSSION

This study collected follow-up data from routine patient visits for 126 patients over a 12-month period. The relative size of the pediatric cohort within the PERFUSE study (126 of all 737 IBD patients) reflects the fact that 1 in 5 IBD diagnoses occur during childhood or adolescence (3). Most other real-world prospective studies in pediatrics focused either on IFX induction (up to 3 months of follow-up) or on the persistence of a smaller cohort (generally up to 60 patients) (19). With 102 CD patients, the CD cohort allows pertinent statistical analysis, even after a 12-month follow up. Conversely, the UC cohort (24 patients) is much smaller, possibly explaining some of the observed lack of statistical significance and differing safety and persistence profiles. That said, this reflects the relative prevalence of these pathologies: in France, pediatric CD is around 3 times more prevalent than pediatric UC (30).

Response to Treatment

Disease scores were low for all groups at M12: almost all patients for whom we have M12 data—both naïve and switched—were in remission and all had at most low disease activity, indicating that SB2 allows for effective disease control for both naïve and switched patients. This is in line with previous studies on IFX (originator and biosimilars): the first year of SB2 therapy is comparable to IFX and other biosimilars (31–34). Furthermore, no temporary loss of disease control is observed in switched patients and all patients reached and maintained therapeutic drug levels around or greater than 7 µg/mL, recommended for good control of inflammation (35).

Persistence and Safety

Persistence was high overall, especially in the switched population, in line with previous real-life studies of IFX in pediatric populations (33). Lower persistence is observed in naïve patients, as expected based on previous studies on biologics (36). Reasons for treatment discontinuation were mostly secondary failures and adverse events (more so for naïve patients who had a higher incidence of allergic reaction than switched patients). The incidence of allergic reactions was also higher in this pediatric cohort than in the adult cohort of the same study (37): younger patients, especially children, tend to have more allergic reactions than adults (38). Adverse event frequencies and types indicated a similar safety profile as those observed in other studies (38,39).

Adverse events were distinguished from primary and secondary failures as adverse events could occur even without increased disease activity. Primary failure was defined as “treatment failure occurring within 14 weeks of IFX initiation” and classification was left up to the treating physician. Though this leads us to report lower levels of primary failure than other studies using broader definitions, overall persistence in naïve patients over the course of the first 3 months is within the range observed in other pediatric IFX studies (between 60% and 90% persistence at 8–10 weeks, depending on the study) (40–42). The proportion of secondary nonresponders relative to the overall population size (UC: 55.6% and CD: 13.7%; UC: 13.3% and CD: 7.8%, for naïve and switched patients, respectively) was in line with other IFX studies (between 13% and 20% loss of response per patient year), except for naïve UC patients for whom it was higher (42,43). As for primary failures, certain adverse events may be considered as a loss of response in other studies due to different definitions, possibly explaining this study’s numerically lower rates.

Growth

Patients’ height z scores increased under SB2 for all populations except naïve UC patients. Baseline results indicate patients were not significantly shorter than the general population, suggesting that growth was not significantly impaired in the study population. Our results are coherent with previous studies which found varying rates of growth failure at diagnosis (7,44,45). As has been observed for originator IFX, growth failure in pediatric patients with IBD is not observed in patients under SB2 treatment (7,46). Furthermore, the BMI distribution tended to narrow with fewer underweight patients, indicating that some patients under SB2 experience restorative weight gain, in line with other anti-TNF studies (47). Weight gain does not appear excessive, with BMI in an acceptable range for French children and adolescents but should nevertheless be monitored.

Measures used in this study are appropriate to detect clinically relevant differences: the validated noninvasive disease scores for both UC and CD correlate well with other available options (22). The HBI is not as commonly used as the Pediatric Crohn’s Disease Activity Index for the evaluation of pediatric CD but it is validated for use in both adults and children allowing for simple transition from the pediatric to the adult cohort. For UC patients, the PUCAI was chosen for its ease of use, validity, and sensitivity.

Study Limitations

The PUCAI is limited, however, as it is not a patient-reported outcome and does not consider mucosal healing (48). Other, more complete, scores are available if more exhaustive information is needed. Design choices also imposed certain compromises. For instance, patient-reported outcomes are not considered as secondary outcome measures, and endoscopic healing data were not reported. This would have provided a better understanding of patient experience and of factors leading to treatment discontinuation. Furthermore, data collection relied on data availability during routine clinical visits: data for some biological assays used in other studies, such as calprotectin levels and antidrug antibody levels, were not dense enough to produce any meaningful analysis. Potentially, these investigations are not routinely conducted at French sites or are only evaluated when the physician deems it necessary. The differing densities of available data may offer insights into the care pathways of patients. Further investigation is needed at this time.

Pediatric patients who reached adulthood (18 years old) could integrate the adult cohort, which had different data collection processes: optional height reporting and UC activity evaluated using the Simple Clinical Colitis Activity Index (SCCAI). This led to some missing data points for patients who were 17 years old at treatment initiation. SCCAI scores could not be directly used, so PUCAI scores were calculated from patient files after the fact. This could be addressed by standardizing data collection processes over the whole cohort, which would come at the cost of modularity and possibly not using the most appropriate tools.

CONCLUSIONS

SB2 provides effective disease control for naïve patients and no loss of control occurs in switched patients. There is significant improvement in height z score after 1 year for naïve CD patients. Persistence and safety profiles were comparable to other IFX studies. The results for the UC population are less robust than those for the CD population due to the small population size, though this appears inevitable given the small number of pediatric UC patients in France.

REFERENCES

1. Ghione S, Sarter H, Fumery M, et al. Dramatic increase in incidence of ulcerative colitis and Crohn’s disease (1988–2011): a population-based study of French adolescents. Am J Gastroenterol 2018;113:265–72.
2. Alatab S, Sepanlou SG, Ikuta K, et al. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol 2020;5:17–30.
3. Däbritz J, Gerner P, Enninger A, Claßen M, Radke M. Inflammatory bowel disease in childhood and adolescence. Dtsch Arztebl Int 2017;114:331–8.
4. Kuenzig ME, Fung SG, Marderfeld L, et al. Twenty-first century trends in the global epidemiology of pediatric-onset inflammatory bowel disease: systematic review. Gastroenterology 2022;162:1147–1159.e4.
5. Lev-Tzion R, Turner D. Is pediatric IBD treatment different than in adults? Minerva Gastroenterol Dietol 2012;58:137–50.
6. Malham M, Jakobsen C, Vester-Andersen MK, et al. Paediatric onset inflammatory bowel disease is a distinct and aggressive phenotype—a comparative population-based study. GastroHep 2019;1:266–73.
7. Heuschkel R, Salvestrini C, Beattie RM, Hildebrand H, Walters T, Griffiths A. Guidelines for the management of growth failure in childhood inflammatory bowel disease. Inflamm Bowel Dis 2008;14:839–49.
8. Herzog D, Fournier N, Buehr P, et al. Prevalence of intestinal complications in inflammatory bowel disease: a comparison between paediatric-onset and adult-onset patients. Eur J Gastroenterol Hepatol 2017;29:926–31.
9. Park SH, Park JC, Lukas M, Kolar M, Loftus EV. Biosimilars: concept, current status, and future perspectives in inflammatory bowel diseases. Intest Res 2020;18:34–44.
10. Beck A, Reichert JM. Approval of the first biosimilar antibodies in Europe: a major landmark for the biopharmaceutical industry. MAbs 2013;5:621–3.
11. EMA. Flixabi [Internet]. European Medicines Agency; 2018. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/flixabi. Accessed February 01, 2022.
12. Shin D, Kim Y, Kim YS, Körnicke T, Fuhr R. A randomized, phase I pharmacokinetic study comparing SB2 and infliximab reference product (Remicade) in healthy subjects. BioDrugs 2015;29:381–8.
13. Choe JY, Prodanovic N, Niebrzydowski J, et al. A randomised, double-blind, phase III study comparing SB2, an infliximab biosimilar, to the infliximab reference product Remicade in patients with moderate to severe rheumatoid arthritis despite methotrexate therapy. Ann Rheum Dis 2017;76:58–64.
14. de Ridder L, Assa A, Bronsky J, et al. Use of biosimilars in pediatric inflammatory bowel disease: an updated position statement of the pediatric IBD porto group of ESPGHAN. J Pediatr Gastroenterol Nutr 2019;68:144–53.
15. Gervais L, McLean LL, Wilson ML, et al. Switching from originator to biosimilar infliximab in paediatric inflammatory bowel disease is feasible and uneventful. J Pediatr Gastroenterol Nutr 2018;67:745–8.
16. Jongsma MME, Vulto A, de Ridder L. The use of biosimilars in paediatric inflammatory bowel disease. Curr Opin Pediatr 2017;29:560–5.
17. Kang B, Lee Y, Lee K, Choi YO, Choe YH. Long-term outcomes after switching to CT-P13 in pediatric-onset inflammatory bowel disease: a single-center prospective observational study. Inflamm Bowel Dis 2018;24:607–16.
18. Eberl A, Huoponen S, Pahikkala T, Blom M, Arkkila P, Sipponen T. Switching maintenance infliximab therapy to biosimilar infliximab in inflammatory bowel disease patients. Scand J Gastroenterol 2017;52:1348–53.
19. Corica D, Romano C. Biological therapy in pediatric inflammatory bowel disease: a systematic review. J Clin Gastroenterol 2017;51:100–10.
20. Harvey RF, Bradshaw JM. A simple index of Crohn’s-disease activity. Lancet 1980;1:514.
21. Turner D, Otley AR, Mack D, et al. Development, validation, and evaluation of a pediatric ulcerative colitis activity index: a prospective multicenter study. Gastroenterology 2007;133:423–32.
22. Shaoul R, Day AS. An overview of tools to score severity in pediatric inflammatory bowel disease. Front Pediatr 2021;9:615216.
23. Vermeire S, Van Assche G, Rutgeerts P. Laboratory markers in IBD: useful, magic, or unnecessary toys? Gut 2006;55:426–31.
24. Chen P, Zhou G, Lin J, et al. Serum biomarkers for inflammatory bowel disease. Front Med 2020;7:123.
25. Cui G, Fan Q, Li Z, Goll R, Florholmen J. Evaluation of anti-TNF therapeutic response in patients with inflammatory bowel disease: current and novel biomarkers. EBioMedicine 2021;66:103329.
26. Turner D, Hyams J, Markowitz J, et al. Appraisal of the pediatric ulcerative colitis activity index (PUCAI). Inflamm Bowel Dis 2009;15:1218–23.
27. Heude B, Scherdel P, Werner A, et al. A big-data approach to producing descriptive anthropometric references: a feasibility and validation study of paediatric growth charts. Lancet Digit Health 2009;1:e413–23.
28. Scherdel P, Botton J, Rolland-Cachera MF, et al. Should the WHO growth charts be used in France? PLoS One 2015;10:e0120806.
29. de Onis M, et al. WHO Child Growth Standards: Growth Velocity Based on Weight, Length and Head Circumference. Geneva (CH): WHO Press; 2005.
30. Gower-Rousseau C, Fumery M, Savoye G, et al. Épidémiologie et histoire naturelle des maladies inflammatoires chroniques intestinales de l’enfant. Med Ther Pediatrie 2019;22:19–25.
31. Milassin A, Fábián A, Molnár T. Switching from infliximab to biosimilar in inflammatory bowel disease: overview of the literature and perspective. Therap Adv Gastroenterol 2019;12:1756284819842748.
32. Wynands J, Belbouab R, Candon S, et al. 12-month follow-up after successful infliximab therapy in pediatric crohn disease. J Pediatr Gastroenterol Nutr 2008;46:293–8.
33. Hyams J, Damaraju L, Blank M, et al. Induction and maintenance therapy with infliximab for children with moderate to severe ulcerative colitis. Clin Gastroenterol Hepatol 2012;10:391–9.e1.
34. Hyams J, Crandall W, Kugathasan S, et al. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children. Gastroenterology 2007;132:863–73; quiz 1165.
35. Drobne D, Kurent T, Golob S, et al. Success and safety of high infliximab trough levels in inflammatory bowel disease. Scand J Gastroenterol 2018;53:940–6.
36. Ebina K, Hirano T, Maeda Y, et al. Drug retention of 7 biologics and tofacitinib in biologics-naïve and biologics-switched patients with rheumatoid arthritis: the ANSWER cohort study. Arthritis Res Ther 2020;22:142.
37. Bouhnik Y, Fautrel B, Desjeux G, et al. P637 PERFUSE: a French non-interventional cohort study of infliximab-naïve and transitioned patients receiving infliximab biosimilar SB2; an interim analysis. Poster presented at ECCO 2020. 12–15 February 2020; 2020. Vienna, Austria.
38. Jongsma MME, Winter DA, Huynh HQ, et al. Infliximab in young paediatric IBD patients: it is all about the dosing. Eur J Pediatr 2020;179:1935–44.
39. Vilar P, de Carpi JM, Acuña CE, Masiques MAL. Infliximab in paediatric inflammatory bowel disease. J Crohns Colitis 2007;1:2–9.
40. Aardoom MA, Veereman G, de Ridder L. A review on the use of anti-TNF in children and adolescents with inflammatory bowel disease. Int J Mol Sci 2019;20:E2529.
41. Iijima H, Kobayashi T, Nagasaka M, et al. Management of primary nonresponders and partial responders to tumor necrosis factor-α inhibitor induction therapy among patients with Crohn’s disease. Inflamm Intest Dis 2020;5:78–83.
42. Roda G, Jharap B, Neeraj N, Colombel J-F. Loss of response to anti-TNFs: definition, epidemiology, and management. Clin Transl Gastroenterol 2016;7:e135.
43. Lee JS, Lee JH, Lee JH, et al. Efficacy of early treatment with infliximab in pediatric Crohn’s disease. World J Gastroenterol 2010;16:1776–81.
44. Ishige T. Growth failure in pediatric onset inflammatory bowel disease: mechanisms, epidemiology, and management. Transl Pediatr 2019;8:16–22.
45. Bamberger S, Vinson CM, Mohamed D, et al. Growth and adult height in patients with Crohn’s disease treated with anti-tumor necrosis factor α antibodies. PLoS One 2016;11:e0163126.
46. Jongsma MME, Aardoom MA, Cozijnsen MA, et al. First-line treatment with infliximab versus conventional treatment in children with newly diagnosed moderate-to-severe Crohn’s disease: an open-label multicentre randomised controlled trial. Gut 2022;71:34–42.
47. Mitchel E, Huang J, Zemel B, Baldassano R, Albenberg L, Denburg M. Excessive weight gain in pediatric inflammatory bowel disease patients on anti-TNF therapy. Inflamm Bowel Dis 2021;27:S19–S19.
48. Kerur B, Litman HJ, Stern JB, et al. Correlation of endoscopic disease severity with pediatric ulcerative colitis activity index score in children and young adults with ulcerative colitis. World J Gastroenterol 2017;23:3322–9.
Keywords:

inflammatory bowel disease; persistence; real-world evidence

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Copyright © 2022 The Author(s). Published by Wolters Kluwer on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.