Introduction The PANTS study highlights that secondary loss of response to anti-TNF treatment can be related to low drug levels¹ caused by development of anti-drug antibodies (ADA).² Early therapeutic drug monitoring (TDM) of anti-TNFs with dose optimisation is recommended.³

Aims The aim of this study is to have a real-life use of TDM, to understand the role of interventions on ADA and drug levels in a cohort of paediatric IBD patients that have developed ADA.

Subjects and Methods Paediatric IBD patients on Infliximab, who had TDM were identified from a prospectively held database. All tests that had presence of ADA were included. All TDM was done at the same lab (Exeter) using the same assay. Testing took place between July 2018 and March 2021. The response to TDM was assessed by using the electronic health record at Southampton Children’s Hospital.

We assessed the clinical response to the presence of ADA and the effectiveness of the changes on repeat TDM. The therapeutic interventions included were switching to Adalimumab, increased Infliximab dose, reduction in time between doses, increased immunomodulator (Azathioprine or 6-Mercaptopurine) dose or no change at all. The effectiveness of the intervention was assessed by median reduction in ADA and median increase in drug levels. Wilcoxon signed-rank test was performed looking for significant increase in drug level.

Results 20 patients had ADAs. Some of the patients required multiple interventions meaning that some patients were included in multiple analyses. Overall, 39 TDM tests were included over 20 patients. Patient characteristics at diagnosis according to Paris Classification are summarised in table 1. Median time between starting Infliximab after diagnosis was 6 months (IQR 2.75–8.5) and median time between first 1st TDM and starting Infliximab was 12.5 months (IQR 7–20.75).

Summary of interventions below and in table 2:

Patients with ADAs with normal Infliximab level did not require intervention in 9 cases and this did not significantly alter drug levels(p=ns).

Increased Infliximab dose in 9 cases led to a greater increase in median drug levels (4.1 p=0.01) than reduced time between doses in 4 cases (2.9 p=0.07). Both had a similar reduction in ADA. Complete resolution of ADA was seen in 3 cases after escalating anti-TNF dose.

Switching to Adalimumab was performed in response to 6 cases where ADAs were present, all had a very low drug level.

Increased immunomodulator dose done in 5 cases led to a reduction in ADA but no significant change in drug level(p=ns).

Conclusion The presence of ADA should always be assessed in the context of levels and interventions maybe considered if levels are low. In our small study, increasing Infliximab dose was more effective than reducing time between doses. Increasing immunomodulator dosage can be used as well. Switching to Adalimumab is an option and works well if drug level is very low, consideration should be given if there is a continued need for anti-TNF.

References

1. 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 May 2019;4(5):341–353. doi:10.1016/s2468-1253(19)30012-3

2. Roda G, Jharap B, Neeraj N, Colombel JF. Loss of Response to Anti-TNFs: Definition, Epidemiology, and Management. Clin Transl Gastroenterol Jan 7 2016;7(1):e135. doi:10.1038/ctg.2015.63

3. van Rheenen PF, Aloi M, Assa A, et al. The Medical Management of Paediatric Crohn’s Disease: an ECCO-ESPGHAN Guideline Update. J Crohns Colitis Oct 7 2020; doi:10.1093/ecco-jcc/jjaa161