Introduction
Infliximab (IFX) is a mainstay in the treatment of Crohn´s disease (CD) and ulcerative colitis (UC)1,2. However, some patients do not respond to IFX; others develop antibodies to IFX (ATI), resulting in loss of response (LOR) over time3,4. As second-line treatments for adults are not approved in pediatrics, current ECCO/ESPGHAN guidelines recommend combination therapy with an immunomodulator (IM) to improve response and prevent ATI development.2,5 Recent studies suggested that combination therapy is not superior to IFX monotherapy if proactive therapeutic drug monitoring (TDM) is performed6.
Aims & Methods
We investigated whether recommended early combination therapy has an additional benefit in a proactively managed pediatric IBD cohort. Medical records from 01/2013 to 12/2022 were retrospectively reviewed and children (3-18 years) with at least four doses of IFX, 3-60 months (m) follow-up and proactive TDM were included. Patients were grouped in either early (IMe: ≤3m since IFX start and duration of IM therapy >6m or until the end of observation) or late/never IM treatment (IMl/n: >3m since IFX start/no IM combination therapy). Kaplan-Meier analysis and log-rank test (significance level p<0.05) were used to analyze time to LOR with IFX discontinuation or time to ATI development. Hazard ratio (HR) applying Cox regression represents the relative risk of LOR occurring in IMl/n compared to IMe.
Results
Of 315 reviewed IBD children, 127 patients were included (43% girls, median age at IFX start: 14 years, 77 CD, 50 UC including 5 IBD-u) and IFX treatment of 2855 visits was analysed. Sixty patients received IMe (41 CD, 19 UC), 20 patients started IM >3m after IFX (13 CD, 7 UC) and 47 patients had IFX monotherapy (23 CD, 24 UC). Patient characteristics, previous therapies, IFX dosage and intervals were comparable between IMe and IMl/n groups (except E2 in UC). Proactive TDM was comparable in both IMe and IMl/n, i.e., duration from IFX start to first TL measurement (median of 6 weeks, p=0.9), median number of 4 TL measurements per follow-up year (p=0.6), and median TL of 10 and 11 μg/mL (p=0.6), respectively. Most patients (84%) had a median TL >5µg/ml over time. The median follow-up time was 29.6m for IMe and 25.5m for IMl/n.
IFX treatment persistence was 68% after 60m in the total cohort. LOR with IFX discontinuation was observed in 7 IMe and 15 IMl/n patients (p=0.2). Combining IFX infusions with IMe significantly delayed the occurrence of LOR with IFX discontinuation (median LOR free interval IMe 29.4m, IMl/n 8.6m, p=0.01). The IMl/n group was more likely to experience LOR than IMe after 1, 2, 3, 4, and 5 years (HR1=10.3, p1=0.01; HR2=4.1, p2=0.02; HR3=2.9, p3=0.03; HR4=2.9, p4=0.03; HR5=2.1, p5=0.09). IMl/n instead of IMe increased the risk for LOR, especially in UC patients (HR 7.5, p=0.04).
Low ATI >10AU/ml were found in 76/106 IFX-treated patients, while high ATI >100AU/ml were detected in 10/52 IMe and 15/54 IMl/n patients, p=0.2. There was no significant difference regarding median ATI level (both 12AU/ml, p=0.7) and ATI-free interval (9m vs 8m, p=0.65) in the groups. Only in CD patients, IMl/n showed a significantly higher risk of developing high ATI (HR 4.1, p=0.046) compared to IMe.
Conclusion
Proactive TDM resulted in high IFX treatment persistence in pediatric IBD. Early combination therapy of IM with IFX showed a significant benefit with improved IFX treatment persistence during the first four years of therapy. This effect was partly explained by preventing high-titer ATI in CD patients.
References
1. van Rheenen, P. F. et al. The Medical Management of Paediatric Crohn’s Disease: an ECCO-ESPGHAN Guideline Update. J. Crohns Colitis 15, 171–194 (2021).
2. Turner, D. et al. Management of Paediatric Ulcerative Colitis, Part 1 and 2: Ambulatory Care-An Evidence-based Guideline from European Crohn’s and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J. Pediatr. Gastroenterol. Nutr. 67, 257–291 (2018).
3. Adedokun, O. J. et al. Pharmacokinetics of infliximab in children with moderate-to-severe ulcerative colitis: results from a randomized, multicenter, open-label, phase study. Inflamm. Bowel Dis. 19, 2753–2762 (2013).
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5. van Rheenen, P. F. et al. The Medical Management of Paediatric Crohn’s Disease: an ECCO-ESPGHAN Guideline Update. J Crohns Colitis (2020) doi:10.1093/ecco-jcc/jjaa161.
6. Sandborn, W. J. et al. Treating beyond symptoms with a view to improving patient outcomes in inflammatory bowel diseases. J. Crohns Colitis 8, 927–935 (2014).