Y-ECCO Literature Review: Michael De Gregorio
Michael De Gregorio
Higher anti-tumour necrosis factor levels are associated with perianal fistula healing and fistula closure in Crohn’s Disease
Plevris N, Jenkinson PW, Arnott ID, Jones GR, Lees CW
Eur J Gastroenterol Hepatol 2020;32(1):32–37. DOI: 10.1097/MEG.0000000000001561
Michael De Gregorio
© Michael De Gregorio
Perianal fistulising Crohn’s Disease is a challenging phenotype affecting more than 20% of patients diagnosed with Crohn’s Disease. It is associated with debilitating symptoms and significant morbidity, with subsequent reduced quality of life and increased disease-related work disability.
Currently treatment remains challenging, incorporating surgical and medical management; the latter is driven largely by biologic agents, specifically anti-tumour necrosis factor (TNF) agents such as adalimumab (ADA) and infliximab (IFX). Whilst ADA and IFX have proven efficacy in inducing and maintaining fistula healing and closure, a significant proportion of patients fail to respond or lose response over time. Increasing evidence suggests that this is in part due to sub-therapeutic drug levels, with or without the presence of antibodies to anti-TNF agents (ATA), with higher target drug levels required for fistula healing compared to mucosal healing in Crohn’s Disease. However, data evaluating the correlation between anti-TNF levels and perianal fistula outcomes, particularly with ADA, remain limited.
The aim of this study was to assess the association between anti-TNF levels and perianal fistula healing and closure with maintenance ADA and IFX therapy.
This was a retrospective cross-sectional study conducted at Western General Hospital, Edinburgh, UK. The study included patients >16 years old who had been diagnosed with perianal fistulising Crohn’s Disease and had been receiving IFX or ADA maintenance therapy for ≥24 weeks, with ≥1 externally draining perianal fistula at therapy initiation and with drug and ATA levels measured within 4 weeks of perianal fistula assessment. ADA drug and ATA levels were measured at any time between doses, whereas IFX drug and ATA levels were measured at trough. Patients with uncontrolled perianal sepsis or defunctioning colostomies were excluded.
The primary outcome was association of anti-TNF levels with perianal fistula healing, defined as no drainage either spontaneously or on palpation in the absence of seton drainage. The secondary outcome was association of anti-TNF levels with perianal fistula closure, defined as absence of any external fistula opening.
A total of 64 patients fulfilled the inclusion criteria, of whom 35 and 29 received ADA and IFX, respectively.
Perianal fistula healing occurred in 60.0% and 62.1% of patients receiving ADA and IFX therapy, respectively. Fistula healing was associated with a significantly higher median ADA level (12.6 vs 2.7 μg/mL, p<0.01) and median trough IFX level (8.1 vs 3.2 µg/mL, p<0.01) compared to those without healing. A positive correlation between anti-TNF drug levels and fistula healing was evident on ROC analyses, with an optimal ADA level of >6.8 μg/mL (100% sensitivity, 78.6% specificity) and trough IFX level of >7.1 µg/mL (77.8% sensitivity, 100% specificity).
Perianal fistula closure occurred in 42.9% and 44.8% of patients receiving ADA and IFX therapy, respectively. Fistula closure was associated with a significantly higher median ADA level (14.8 vs 5.7 μg/mL, p<0.01) and median trough IFX level (8.2 vs 3.2 µg/mL, p<0.01) compared to those without closure. There was a positive correlation between anti-TNF drug levels and fistula closure on ROC analyses, with an optimal ADA level of >9.8 μg/mL (93.3% sensitivity, 75.0% specificity) and trough IFX level of >7.1 µg/mL (64.0% sensitivity, 100% specificity).
Higher drug level quartiles were associated with a significantly higher proportion of fistula healing and closure for both ADA and IFX. Furthermore, fistula healing was associated with significantly lower incidences of ATA for both anti-TNF therapies (ADA ATA incidence 4.8% vs 42.9%, p<0.01; IFX ATA incidence 11.1% vs 63.6%, p<0.01) compared to those without healing. Fistula closure had only numerically lower incidences of ATA (ADA ATA incidence 6.7% vs 30.0%, p=0.09; IFX ATA incidence 15.4% vs 43.8%, p=0.10) compared to those without closure.
Although these findings were not novel, they support growing evidence relating to the integral role of maintenance anti-TNF levels with regard to perianal fistula outcomes. Retrospective data published by Yarur et al. identified significantly higher IFX trough levels in patients with fistula healing and closure, with incremental gains at higher drug level quartiles . A target IFX level of ≥10.1 µg/mL was recommended to achieve fistula healing. Published data regarding ADA levels and perianal fistula outcomes is more limited. In a retrospective study by Gu et al., patients achieving fistula healing had significantly higher ADA levels, with an optimal level of ≥7.05 μg/mL . Similarly, in a retrospective cohort analysed by Strik et al., higher ADA levels were significantly associated with fistula closure, with an optimal ADA level of ≥5.9 μg/mL .
Due to the nature of the study, only association and not causality could be determined. Additionally, the study outcomes were based on clinical assessment, which is inherently subjective and may entail bias. Greater objectivity would have been achieved through utilisation of radiological healing as an endpoint, with magnetic resonance imaging allowing greater sensitivity and specificity. The dosing regimens for anti-TNF agents within the patient cohort also varied. Although beyond the aims of the study, an exploratory analysis evaluating whether dosing regimens correlated with drug levels and fistula outcomes would have been clinically beneficial. Finally, heterogeneity existed in the timing of ADA level measurements. This needs to be considered when interpreting findings and extending them to recommended therapeutic targets; however, the authors state that this will have had minimal confounding effects due to an achieved steady state of the drug.
This study identified that higher maintenance anti-TNF drug levels are associated with fistula healing and closure. This finding was evident for both ADA and IFX therapy. The study identified optimal maintenance anti-TNF levels, with an optimal ADA level of >6.8 µg/mL and >9.8 µg/mL for fistula healing and closure, respectively, and an optimal trough IFX level >7.1 µg/mL for both fistula healing and closure. Furthermore, it was shown that higher anti-TNF drug level quartiles were significantly associated with incremental improvements in the proportion of patients achieving fistula healing and closure.
The findings support the growing evidence that higher target anti-TNF drug levels are required for improved fistula outcomes compared to mucosal healing. This highlights the need for prospective studies to evaluate causality and provide high-powered evidence to optimise guidelines, ensuring greater response rates and improved patient outcomes.
- Yarur AJ, Kanagala V, Stein DJ, et al. Higher infliximab trough levels are associated with perianal fistula healing in patients with Crohn’s disease. Aliment Pharmacol Ther. 2017;45:933–40. DOI: 10.1111/apt.13970
- Gu B, Venkatesh K, Williams AJ, et al. P586 Higher infliximab and adalimumab trough levels are associated with fistula healing in patients with fistulising perianal Crohn’s disease. J Crohns Colitis. 2020;14(Supp 1):S490–1. DOI: 10.1093/ecco-jcc/jjz203.714
- Strik AS, Löwenberg M, Buskens CJ, et al. Higher anti-TNF serum levels are associated with perianal fistula closure in Crohn’s disease patients. Scand J Gastroenterol. 2019;54:453–8. DOI: 10.1080/00365521.2019.1600014