The use of drug monitoring of infliximab and adalimumab to optimize the treatment of inflammatory bowel diseases in children

Introduction. The effectiveness of the use of TNF inhibitors in patients with inflammatory bowel diseases (IBD) has been shown. 20–40% of patients are known to fail to respond to received therapy, and 10–30% of patients experience a loss of effect by the year of therapy. Objective is to evaluate the information content of therapeutic drug monitoring (TDM) for effective treatment with TNF blockers (infliximab — IFX, adalimumab — ADA) in IBD children.

Materials and methods. There were examined seventy four children on IFX therapy including 66 children on ADA therapy. The age of the children ranged from 3.4 to 18 years. Residual levels of IHF and ADA were determined using a lateral flow immunoassay. Statistical data processing was performed using the Statistica 10.0, SPSS 16 software. Differences between groups were assessed using the nonparametric Mann–Whitney U test.

Results. IFX levels (less than 3 µg/ml) were detected in 64% of cases, ADA (less than 5 µg/ml) in 21% of cases. The residual level of IFX and ADA in remission significantly exceeded the level of drugs in groups of children in exacerbation. An inverse relationship was observed between the residual level of IFX (r = –0.68, p = 0.000) and ADA (r = –0.31, p = 0.000) and the number of days after drug administration. Anti-IFX antibodies were found in 27.3% in the exacerbation group and in 5.8% in remission (p < 0.001). Antibodies to ADA in children with IBD were found in 4 patients with a low concentration of the drug (2.57 ± 0.45 µg/ml) in the serum in a state of exacerbation. In patients on anti-TNF therapy, empirical dose selection revealed a residual level lower than in children in whom dose adjustment was carried out taking into account the residual concentration of drugs.

Conclusion. The use of TDM TNF blockers in combination with the determination of antibodies to drugs can significantly increase the effectiveness of therapy in IBD children.

Contribution:
Radygina T.V., Illarionov A.S., Petrichuk S.V. — research concept and design of the study;
Radygina T.V., Illarionov A.S., Petrichuk S.V., Kuptsova D.G., Potapov A.S., Anushenko A.O., Kurbatova O.V. — collection and processing of material;
Radygina T.V. — text writing;
Potapov A.S., Fisenko A.P. — editing.
All co-authors — approval of the final version of the article, responsibility for the integrity of all parts of the article.

Ethics approval. The study protocol was approved by the local ethics committee. The patients’ parents gave written voluntary informed consent to participate in the study. 

Acknowledgment. The study was carried out on state assignment of the Ministry of Health of Russia, number АААА-А19-119013090093-2.

Conflict of interest. The authors declare no conflict of interest.

Received: September 16, 2022
Accepted: September 20, 2022
Published: October 31, 2022

1. Gorelov A.V., Kanner E.V. Inflammatory bowel diseases in children: peculiarities of the disease course and therapy. Meditsinskiy sovet. 2018; (2): 140–5. (In Russian) https://doi.org/10.21518/2079-701X-2018-2-140-145

2. Marcil V., Levy E., Amre D., Bitton A., Sant’Anna A., Szilagy A., et al. A Cross-Sectional Study on Malnutrition in Inflammatory Bowel Disease: Is There a Difference Based on Pediatric or Adult Age Grouping? Inflammatory bowel diseases. 2019; 25(8): 1428–41. https://doi.org/10.1093/ibd/izy4033

3. Wilson D.C., Russell R.K. Overview of paediatric IBD. Seminars in Pediatric Surgery. 2017; 6(26): 344–8. https://doi.org/10.1053/j.sempedsurg.2017.10.002

4. Healthcare for patients with inflammatory bowel disease in Russian Federation in 2015–2021: information from the Healthcare Expert Advisory Board of the Social Policy Committee of the Federation Council. Meditsinskie tekhnologii. Otsenka i vybor. 2021; (4): 9–15. (In Russian). https://doi.org/10.17116/medtech2021430419

5. Oliveira S.B., Monteiro I.M. Diagnosis and management of inflammatory bowel disease in children. BMJ. 2017; (357): j2083.

6. de Souza H.S., Fiocchi C. Immunopathogenesis of IBD: current state of the art. Nat. Rev. Gastroenterol. Hepatol. 2016; 13(1): 13–27. https://doi.org/10.1038/nrgastro.2015.186

7. Kestens C., van Oijen M., Mulder C., van Bodegraven A., Dijkstra G., de Jong, et al. Dutch Initiative on Crohn and Colitis (ICC). Adalimumab and infliximab are equally effective for Crohn’s disease in patients not previously treated with anti-tumor necrosis factor-α agents. Clinical gastroenterology and hepatology. 2013; 11(7): 826831.

8. van Rheenen P., Aloi M., Assa A., Bronsky J., Escher J., Fagerberg U., et al. The Medical Management of Paediatric Crohn’s Disease: an ECCO-ESPGHAN Guideline Update. J Crohns Colitis. 2020.jjaa161. https://doi.org/10.1093/ecco-jcc/jjaa161

9. Clinical recommendations. Ulcerative colitis [Klinicheskie rekomendatsii. Yazvennyy kolit]. 2021;87. (In Russian)

10. Clinical recommendations. Crohn’s disease [Klinicheskie rekomendatsii. Bolezn’ Krona]. 2020; 115 (In Russian)

11. Turner D., Ruemmele F., Orlanski-Meyer E., Griffiths A., de Carpi J., Bronsky J., et al. Management of Paediatric Ulcerative Colitis, Part 1. J Pediatr Gastroenterol Nutr. 2018; 67(2): 257-91.

12. Privitera G., Pugliese D., Rapaccini G., Gasbarrini A., Armuzzi A., Guidi L. Predictors and Early Markers of Response to Biological Therapies in Inflammatory Bowel Diseases. Journal of clinical medicine. 2021; 10(4): 853. https://doi.org/10.3390/jcm10040853

13. Lopetuso L., Gerardi V., PapaV., et al. Can we predict the efficacy of anti-TNF agents? Int. J. Mol. Sci. 2017; 18: 1973.

14. Ungar B., Levy I., Yavne Y., Yavzori M., Picard O., Fudim E., 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(4): 550-557.e2. https://doi.org/10.1016/j.cgh.2015.10.025

15. Joosse M., Samsom J., van der Woude C., Escher J., van Gelder T. The role of therapeutic drug monitoring of anti-tumor necrosis factor alpha agents in children and adolescents with inflammatory bowel disease. Inflamm Bowel Dis. 2015; 21(9): 2214-21. https://doi.org/10.1097/MIB.0000000000000420

16. Carman, N., Mack, D.R. & Benchimol, E.I. Therapeutic drug monitoring in pediatric inflammatory bowel disease. Curr Gastroenterol Rep. 2018; 20: article18. https://doi.org/10.1007/s11894-018-0623-z

17. Turner D., Ruemmele F., Orlanski-Meyer E., Griffiths A., de Carpi J., Bronsky J., et al. Management of paediatric ulcerative colitis, part 2. J. Pediatr. Gastroenterol. Nutr. 2018; 67(2): 292–310. https://doi.org/10.1097/MPG.0000000000002036

18. Ungar B., Mazor Y., Weisshof R., Yanai H., Ron Y., Goren I., et al. Induction infliximab levels among patients with acute severe ulcerative colitis compared with patients with moderately severe ulcerative colitis. Aliment. Pharmacol. Ther. 2016; 43: 1293–9. https://doi.org/10.1111/apt.13631

19. Illarionov A.S., Potapov A.S., Petrichuk S.V., Fisenko A.P., Radygina T.V., Kuptsova D.G., et al. The importance of monitoring the level of infliximab and antibodies to it in the blood serum to optimize the treatment of inflammatory bowel diseases in children. Voprosy practicheskoy pediatrii. 2021; 16(2): 14–21. (In Russian). https://doi.org/10.20953/1817-7646-2021-2-14-21

20. Illarionov A.S., Radygina T.V., Potapov A.S., Fisenko A.P., Kuptsova D.G., Petrichuk S.V., et al. Therapeutic drug monitoring of adalimumab in inflammatory bowel diseases in children. Voprosy detskoy dietologii. 2021; 19(3): 14–25. (In Russian). https://doi.org/10.20953/1727-5784-2021-3-14-25

21. van Rheenen P., Aloi M., Assa A., Bronsky J., Escher J., Fagerberg U., et al. The medical management of paediatric crohn’s disease: an ECCO-ESPGHAN Guideline Update. J Crohns Colitis. 2020;jjaa161. https://doi.org/10.1093/ecco-jcc/jjaa161

22. Carman N., Mack D.R., Benchimol E.I. Therapeutic drug monitoring in pediatric inflammatory bowel disease. Curr. Gastroenterol. Rep. 2018 Apr 5; 20(5): 18. https://doi.org/10.1007/s11894-018-0623-z

23. Seow C., Newman A., Irwin S., Steinhart A., Silverberg M., Greenberg G. Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut. 2010; 59: 49–54. https://doi.org/10.1136/gut.2009.183095

24. Zitomersky N.L., Atkinson B.J., Fournier K. Antibodies to infliximab are associated with lower infliximab levels and increased likelihood of surgery in pediatric IBD. Inflamm. Bowel. Dis. 2015; 21(2): 307–14. https://doi.org/10.1097/mib.0000000000000284

25. Singh N., Dubinsky M.C. Therapeutic drug monitoring in children and young adults with inflammatory bowel disease: a practical approach. Gastroenterol Hepatol (N.Y.). 2015; 11(1): 48–55.

26. Kolho K.L. Therapeutic drug monitoring and outcome of infliximab therapy in pediatric onset inflammatory bowel disease. Front Pediatr. 2021; 8: 623689. https://doi.org/10.3389/fped.2020.623689

27. Kapoor A and Crowley E. Advances in therapeutic drug monitoring in biologic therapies for pediatric inflammatory bowel disease. Front. Pediatr. 2021; 9: 661536. https://doi.org/10.3389/fped.2021.661536

28. Chavannes M., Gervais F., Verreault A., Deslandres C., Jantchou P. Assessment of the use of therapeutic drug monitoring of Adalimumab during maintenance therapy in children with inflammatory bowel disease. Journal of Crohn’s and Colitis. 2017; 11: 255–6. https://doi.org/10.1093/ecco-jcc/jjx002.477

29. Matar M., Shamir R., Turner D., Broide E., Weiss B., Ledder O., et al. Combination therapy of adalimumab with an immunomodulator is not more effective than adalimumab monotherapy in children with Crohn’s disease: a post hoc analysis of the PAILOT randomized controlled trial. Inflamm Bowel Dis. 2020; 26(11): 1627–35. https://doi.org/10.1093/ibd/izz294

30. Matar M., Shamir R., Lev-Zion R., Broide E. Weiss B., Ledder O., et al. The effect of adalimumab treatment on linear growth in children with Crohn disease: A Post-hoc analysis of the PAILOT randomized control trial. J Pediatr Gastroenterol Nutr. 2020; 71(2): 237–42. https://doi.org/10.1097/MPG.0000000000002728