Final Report, ECCO Grant for Neil Chanchlani

Neil Chanchlani, ECCO Grant Awardee

Intestinal epithelial cell stress modulates enteric fibroblastic and neuronal profiles in Inflammatory Bowel Disease

Neil Chanchlani 
© Neil Chanchlani

Background & aim of research

Multiple patient, disease and pharmacokinetic (including anti-TNF drug and antibody concentrations) factors, as well as a limited number of proteomic markers, have been implicated in anti-TNF treatment failure. However, their relative effects and interactions have not been fully explored. We aimed to replicate previously postulated serological markers and to identify novel inflammatory and immune response proteomic markers related to anti-TNF treatment failure in patients with active luminal Crohn’s Disease.

Methodology used in the research

As part of the multi-omic profiling project of Personalised Anti-TNF Therapy in Crohn's Disease study (PANTS), thyroid function tests, 25-hydroxyvitamin D concentration measurements and serological testing (ASCA, ANCA and anti-OmpC) were performed in stored samples from biologic-naive patients immediately prior to treatment with infliximab or adalimumab.

The Olink proteomic high-throughout inflammatory and immune response panels, simultaneously analysing 180 unique proteins, including Oncostatin-M and triggering receptor expressed on myeloid cells (TREM-1), were run in one discovery and two in-house replication cohorts from PANTS using broad and strict treatment response criteria.

Multivariable logistic regression analyses were performed to identify factors independently associated with primary non-response (PNR) and remission at week 54. Sensitivity analyses, stratifying results by anti-TNF drug and antibody concentrations, were undertaken.

Main findings/results of the research

In 549 infliximab- and 448 adalimumab-treated patients, the free triiodothyronine-to-thyroxine ratio was independently associated with PNR at week 14 (OR 0.51, 95%CI 0.31–0.85, p=0.009) but not with non-remission or changes in faecal calprotectin concentrations at week 54 [1]. In 659 infliximab- and 448 adalimumab-treated patients, pretreatment vitamin D status did not predict PNR (infliximab p=0.89, adalimumab p=0.18) or non-remission at week 54 (infliximab p=0.13, adalimumab p=0.58) [2].

In our discovery cohort of 480 anti-TNF treated patients who underwent proteomic analysis, we identified elevated baseline serum levels of fibroblast growth factor 21 and interleukin-10 receptor subunit α as proteins of interest that are associated with PNR [3]. However, these findings were not replicated in either replication cohort (broad n=529, strict n=128), which may have been due to cohort imbalance, pre-analytical variation or lack of endoscopic or mucosal definition of treatment response [4]. Pretreatment oncostatin-M and TREM-1 were not associated with anti-TNF treatment failure in PANTS.

Preliminary conditional analysis of serological data suggests that presence of ANCA prior to anti-TNF treatment may be associated with the development of anti-TNF antibodies [5]. However, further network analyses are currently underway to better understand this effect and its interactions.

Published and presented data arising from this grant

  1. Lin S, Chanchlani N, Carbery I, et al.; PANTS consortium. Understanding anti-TNF treatment failure: Does serum triiodothyronine-to-thyroxine (T3/T4) ratio predict therapeutic outcome to anti-TNF therapies in biologic-naïve patients with active luminal Crohn's disease? Aliment Pharmacol Ther 2022;56:783–93.
  2. Chanchlani N, Lin S, Smith R, et al. Pretreatment vitamin D concentrations do not predict therapeutic outcome to anti-TNF therapies in biologic-naïve patients with active luminal Crohn's disease. Crohns Colitis 2023;360: May 15;5(3):otad026. doi: 10.1093/crocol/otad026.
  3. Lin S, Chanchlani N, Invergo BM, et al. Understanding the molecular mechanisms of anti-TNF treatment failure in patients with Crohn’s disease: A pilot serum proteomic analysis of the PANTS cohort. J Crohns Colitis 2020;14(Suppl 1):S067–8.
  4. Chanchlani N, Lin S. Understanding the mechanisms of anti-TNF treatment failure in patients with Crohn’s disease: A proteomic analysis of the PANTS cohort. 8th Y-ECCO Basic Science Workshop. February 2022. Vienna, Austria.
  5. Dube S, Li D, Haritunians T, et al. Serological differences in an inflammatory bowel disease (IBD) trans-ancestry cohort highlighting population heterogeneity. Gastroenterology 2023;164:S-254. https://doi.org/10.1016/S0016-5085(23)01572-X.

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