P399 Higher anti-tumour necrosis factor-alpha drug levels are associated with improved radiological outcomes in patients with perianal fistulising Crohn’s disease: A retrospective multi-centre study

Abstract Background Higher anti-tumour necrosis factor-α (TNF) drug levels are associated with improved clinical fistula healing and closure in perianal fistulising Crohn’s disease (pfCD). It is hypothesised that higher drug levels will lead to improved healing on magnetic resonance imaging (MRI); but this is yet to be established. This study evaluated the association between anti-TNF drug levels and radiological outcomes in pfCD. Methods A multi-centre retrospective study (FISCAL), across 10 ANZ Inflammatory Bowel Disease Consortium sites. Patients with pfCD on stable maintenance dosing of infliximab or adalimumab, with drug levels within 6-months of a pelvic MRI from 2010 to 2020 were included. Patients receiving perianal fistula surgery between drug level and MRI were excluded. MRI disease activity was scored using the Van Assche Index (VAI), with an inflammatory sub-score (VAIinfl) derived from the VAI indices: hyperintensity on T2-weighted images, collections >3mm diameter, and rectal wall involvement. Primary endpoint was radiological healing (VAIinfl≤6). Secondary endpoint was radiological remission (VAIinfl=0). Drug level tertiles were correlated to changes in VAIinfl scores. ROC analyses were used to identify optimal target drug levels. Results Of 193 patients (infliximab, n=117; adalimumab, n=76), radiological healing was achieved in 47.0 and 44.7% and radiological remission in 17.1 and 15.8% of patients receiving infliximab and adalimumab, respectively. Patients with radiological healing had higher median drug levels compared to those with radiologically active disease (infliximab 6.0 vs 3.9µg/mL, P=0.03; adalimumab 9.1 vs 6.2µg/mL, P=0.02). Patients with radiological remission had higher median drug levels compared to those with radiologically active disease (infliximab 7.4 vs 3.9µg/mL, P<0.01; adalimumab 9.8 vs 6.2µg/mL, P=0.07). There was a significant incremental reduction in median VAIinfl with higher anti-TNF drug level tertiles, shown in Figure 1. By ROC analyses, the optimal trough infliximab levels for radiological healing and remission were 4.0µg/mL (sensitivity 69.1%, specificity 45.2%, AUC 0.62, P=0.03) and 6.5µg/mL (sensitivity 60.0%, specificity 72.2%, AUC 0.67, P=0.02), respectively. The optimal adalimumab levels for radiological healing and remission were 7.2µg/mL (sensitivity 67.6%, specificity 59.5%, AUC 0.65, P=0.03) and 9.7µg/mL (sensitivity 58.0%, specificity 70.0%, AUC 0.62, P=0.20), respectively. Conclusion In the largest study of its kind, higher anti-TNF drug levels were associated with improved MRI parameters as per the VAI in patients with pfCD; with an incremental improvement in MRI outcomes at higher anti-TNF drug level tertiles for both infliximab and adalimumab. Replication in prospective studies are awaited.

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Association of Faecal Calprotectin Level and Combined Endoscopic and Radiological Healing in Patients With Crohn’s Disease Receiving Anti-tumour Necrosis Factor Therapy

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjaa042 ◽

2020 ◽

Vol 14 (9) ◽

pp. 1231-1240

Author(s):

Soo Min Noh ◽

Eun Hye Oh ◽

Seong Ho Park ◽

Jung Bok Lee ◽

Jin Yong Kim ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Tumour Necrosis Factor ◽

Tumour Necrosis ◽

C Reactive Protein ◽

Faecal Calprotectin ◽

Reactive Protein ◽

Calprotectin Level ◽

Radiological Healing ◽

Necrosis Factor

Abstract Background and Aims Combined endoscopic and radiological healing, or deep healing, is associated with favourable outcomes in patients with Crohn’s disease; thus, a non-invasive biomarker for predicting deep healing would be invaluable. We evaluated the usefulness of faecal calprotectin for predicting deep healing in patients with Crohn’s disease receiving anti-tumour necrosis factor [TNF] therapy. Methods We analysed the records of patients with Crohn’s disease who received anti-tumour necrosis factor therapy and underwent endoscopic evaluation, radiological evaluation, and faecal calprotectin measurement within a period of 3 months between August 2017 and November 2018. Results of endoscopic and radiological studies were independently reviewed by two gastrointestinal endoscopists and a gastrointestinal radiologist, respectively. Serum C-reactive protein and albumin were also measured. Results Out of 268 patients analysed, 77 [28.7%] had deep healing, 36 [13.4%] had endoscopic healing only, 36 [13.4%] had radiological healing only, and 119 [44.4%] had neither. The median duration of anti-TNF treatment was 40.0 months. The deep healing group had the lowest median faecal calprotectin level [56.5 mg/kg] among the four groups [p <0.001]. The faecal calprotectin cutoff level of 81.1 mg/kg showed a sensitivity of 0.623 and a specificity of 0.817 in predicting deep healing (area under the receiver operating characteristic curve [AUROC], 0.767; 95% confidence interval, 0.702–0.832). Adding serum C-reactive protein and serum albumin to faecal calprotectin further increased the AUROC to 0.805 [95% confidence interval, 0.752–0.858]. Conclusions Faecal calprotectin, when combined with serum C-reactive protein and albumin, showed acceptable performance in predicting deep healing in patients with Crohn’s disease.

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Faculty Opinions recommendation of Impact of azathioprine and tumour necrosis factor antagonists on the need for surgery in newly diagnosed Crohn's disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.11291956.12290054 ◽

2011 ◽

Author(s):

Barney Hawthorne

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Tumour Necrosis Factor ◽

Tumour Necrosis ◽

Newly Diagnosed ◽

Necrosis Factor

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Randomised controlled trial of CDP571 antibody to tumour necrosis factor-α in Crohn's disease

The Lancet ◽

10.1016/s0140-6736(97)80083-9 ◽

1997 ◽

Vol 349 (9051) ◽

pp. 521-524 ◽

Cited By ~ 279

Author(s):

WA Stack ◽

SD Mann ◽

AJ Roy ◽

P Heath ◽

M Sopwith ◽

...

Keyword(s):

Crohn’S Disease ◽

Randomised Controlled Trial ◽

Crohn's Disease ◽

Tumour Necrosis Factor ◽

Tumour Necrosis ◽

Controlled Trial ◽

Tumour Necrosis Factor Α ◽

Randomised Controlled ◽

Factor Α ◽

Necrosis Factor

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P183. Loss of anti-tumour necrosis factor (TNF) drugs into faeces and its impact on anti-TNF serum levels and clinical response in Crohn’s disease patients

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjw019.302 ◽

2016 ◽

Vol 10 (suppl 1) ◽

pp. S183-S184

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Clinical Response ◽

Tumour Necrosis Factor ◽

Tumour Necrosis ◽

Serum Levels ◽

Necrosis Factor

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CD4+ Tissue-resident Memory T Cells Expand and Are a Major Source of Mucosal Tumour Necrosis Factor α in Active Crohn’s Disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz010 ◽

2019 ◽

Vol 13 (7) ◽

pp. 905-915 ◽

Cited By ~ 9

Author(s):

Shrinivas Bishu ◽

Mohammed El Zaatari ◽

Atsushi Hayashi ◽

Guoqing Hou ◽

Nicole Bowers ◽

...

Keyword(s):

T Cells ◽

Crohn’S Disease ◽

T Cell ◽

Crohn's Disease ◽

Tumour Necrosis Factor ◽

Tumour Necrosis ◽

Ex Vivo ◽

Factor Α ◽

And Control ◽

Necrosis Factor

Abstract Background and Aims Tumour necrosis factor [TNF]α- and IL-17A-producing T cells are implicated in Crohn’s disease [CD]. Tissue-resident memory T [TRM] cells are tissue-restricted T cells that are regulated by PR zinc finger domain 1 [PRDM1], which has been implicated in pathogenic Th17 cell responses. TRM cells provide host defence but their role in CD is unknown. We thus examined CD4+ TRM cells in CD. Methods Colon samples were prospectively collected at endoscopy or surgery in CD and control subjects. Flow cytometry and ex vivo assays were performed to characterise CD4+ TRM cells. Results CD4+ TRM cells are the most abundant memory T cell population and are the major T cell source of mucosal TNFα in CD. CD4+ TRM cells are expanded in CD and more avidly produce IL-17A and TNFα relative to control cells. There was a unique population of TNFα+IL-17A+ CD4+ TRM cells in CD which are largely absent in controls. PRDM1 was highly expressed by CD4+ TRM cells but not by other effector T cells. Suppression of PRDM1 was associated with impaired induction of IL17A and TNFA by CD4+ TRM cells Conclusions CD4+ TRM cells are expanded in CD and are a major source of TNFα, suggesting that they are important in CD. PRDM1 is expressed by TRM cells and may regulate their function. Collectively, this argues for prospective studies tracking CD4+ TRM cells over the disease course.

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