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Original article
Identification of inflammatory mediators in patients with Crohn's disease unresponsive to anti-TNFα therapy
  1. Raquel Franco Leal1,2,
  2. Núria Planell1,3,
  3. Radhika Kajekar4,5,
  4. Juan J Lozano3,
  5. Ingrid Ordás1,
  6. Isabella Dotti1,
  7. Miriam Esteller1,
  8. M Carme Masamunt1,
  9. Harsukh Parmar4,6,
  10. Elena Ricart1,
  11. Julián Panés1,
  12. Azucena Salas1
  1. 1Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain
  2. 2Postdoctoral CAPES fellow, Brazil
  3. 3Bioinformatics Platform, CIBERehd, Barcelona, Spain
  4. 4Hoffmann-La Roche, Nutley, New Jersey, USA
  5. 5Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
  6. 6EMD Serono Research & Development Institute, Boston, Massachusetts, USA
  1. Correspondence to Dr Azucena Salas, Center Esther Koplowitz, Rosselló 149-153, 3rd Floor, Barcelona 08036, Spain; asalas1{at}


Background Anti-tumour necrosis factor α (TNFα) therapy effectively induces and maintains remission in Crohn's disease (CD). Up to 40% of patients, however, fail to respond to anti-TNFα.

Objective To identify the mechanisms underlying the persistence of mucosal lesions in patients who fail to respond to anti-TNFα therapy.

Design An observational study based on whole-genome transcriptional analysis was carried out using intestinal biopsy specimens from patients with CD receiving (n=12) or not (n=10) anti-TNFα therapy. The transcriptional signature of responders was compared with that of non-responders after anti-TNFα therapy. Controls with non-inflammatory bowel disease (non-IBD) (n=17) were used for comparisons. Genes of interest were validated by real-time RT-PCR in an independent cohort of patients with CD receiving (n=17) or not (n=16) anti-TNFα and non-IBD controls (n=7).

Results We confirmed that response to anti-TNFα is accompanied by significant regulation of a large number of genes, including IL1B, S100A8, CXCL1, which correlated with endoscopic activity. Remarkably, patients who failed to respond to anti-TNFα showed a mixed signature, maintaining increased expression of IL1B, IL17A and S100A8, while showing significant modulation of other genes commonly upregulated in active CD, including IL6 and IL23p19.

Conclusions Our results show that anti-TNFα therapy significantly downregulates a subset of inflammatory genes even in patients who fail to achieve endoscopic remission, suggesting that these genes may not be dominant in driving inflammation in non-responders. On the other hand, we identified IL1B and IL17A as genes that remained altered in non-responders, pointing to potentially more relevant targets for modulating mucosal damage in refractory patients.


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