Simeng Lin, ECCO’23: Primary non-response to anti-TNF treatment in Crohn’s disease – an analysis of the PANTS study

The Personalised Anti-TNF Therapy in Crohn’s disease (PANTS) study was a UK-wide study that looked at anti-TNF treatment failure in Crohn’s disease. touchIMMUNOLOGY were delighted to speak with Simeng Lin (University of Exeter Medical School, Exeter, UK) to discuss the association between DNA methylation and primary non-response to anti-TNF treatment and the impact this will have on a personalized treatment approach in Crohn’s disease.

The abstract ‘Understanding the molecular mechanisms of anti-TNF treatment failure: Whole blood DNA methylation changes associated with primary non-response to anti-TNF treatment in patients with Crohn’s disease.’ (Abstract number: DOP88) was presented at ECCO 2023, March 1-4, 2023.

Questions

1. What was the rationale for investigating whole blood DNA methylation changes as a biomarker for primary non-response to anti-TNF treatment in Crohn’s disease (CD)? (0:18)
2. What was the methodology of your study? (1:02)
3. What were the findings and what impact will they have on a personalized treatment approach to CD? (1:53)

Disclosures: Simeng Lin discloses receiving honoraria from Pfizer unrelated to this video.

Support: Interview and filming supported by Touch Medical Media Ltd. Interview conducted by Victoria Jones.

Filmed in coverage of the European Crohn´s and Colitis Organisation Annual Meeting 2023.

Click here for more content on inflammatory bowel disease and read more here.

Transcript

What was the rationale for investigating whole blood DNA methylation changes as a biomarker for primary non-response to anti-TNF treatment in Crohn’s disease (CD)? (0:18)

Because anti-TNF drug concentration at week 14 was the only modifiable factor we found to be associated with primary non-response in the PANTS study, we wanted to identify markers at baseline of individuals who subsequently have low drug concentrations, who may benefit from dose optimization at the outset of therapy. So in this regard, DNA methylation from whole blood has previously been identified as effective biomarkers to predict response to other immunosuppressive therapies in patients with rheumatoid arthritis.

What was the methodology of your study? (1:02)

Using whole blood samples from the PANTS study. We sub-selected 200 patients each who experience primary non-response at week 14 and subsequent non-remission at week 54, compared to the other extreme who experienced response at week 14 and remission at 54 with an equal split of infliximab and adalimumab treated patients. We used whole blood samples from four time points across one year. So that includes baseline and longitudinal samples and profiled them using the Illumina EPIC array, which has over 800 of 50,000 CPG sites, which are areas where DNA methylation commonly occurs.

What were the findings and what impact will they have on a personalized treatment approach to CD? (1:53)

We found three main findings. The first being following anti-TNF treatment, over time, we found almost 5,000 differentially methylated probes annotated to more than 2000 genes. Pathway analysis suggested that these were in biological processes related to the immune system – perhaps unsurprisingly. The second finding we found was that using baseline DNA methylation values, we performed an epigenome wide analysis to identify DNA methylation associated with anti-TNF drug concentration at week 14 and found 323 differentially methylated probes that were associated with anti-TNF drug concentration at week 14. The third point being we subsequently performed an epigenome wide analysis of primary non-response and found that 20 differentially methylated probes were associated with both anti-TNF drug concentration at week 14, as well as primary non-response. And there was a strong correlation of effect size. Now the effect size of these findings, however, were only modest in our study, and we recommend validation in an independent cohort. But we believe that this shows the utility of DNA methylation to predict drug concentration at week 14.

So I think the idea that we can use DNA methylation to predict drug concentration at week 14 might allow us to predict who might need dose optimization at the outset of therapy or perhaps even drug sequencing as I eluded to the point at the beginning where there are quite a lot of new therapeutic options. So that might help to personalize therapy a bit. But the note of caution is that we do need to validate these findings in an independent cohort.

Subtitles and transcript are autogenerated.