Identification of inflammatory mediators in patients with Crohn's disease unresponsive to anti-TNFα therapy.
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.


METHODS
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.
Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain Postdoctoral CAPES fellow, Brazil.
Raquel Franco
RF
Leal
Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain Bioinformatics Platform, CIBERehd, Barcelona, Spain.
Núria
N
Planell
Hoffmann-La Roche, Nutley, New Jersey, USA Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
Radhika
R
Kajekar
Bioinformatics Platform, CIBERehd, Barcelona, Spain.
Juan J
JJ
Lozano
Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain.
Ingrid
I
Ordás
Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain.
Isabella
I
Dotti
Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain.
Miriam
M
Esteller
Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain.
M Carme
MC
Masamunt
Hoffmann-La Roche, Nutley, New Jersey, USA EMD Serono Research & Development Institute, Boston, Massachusetts, USA.
Harsukh
H
Parmar
Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain.
Elena
E
Ricart
Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain.
Julián
J
Panés
Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain.
Azucena
A
Salas
D000068879:Adalimumab; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D003106:Colon / Q000378:metabolism; D003424:Crohn Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005260:Female; D005765:Gastrointestinal Agents / Q000627:therapeutic use*; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D000069285:Infliximab; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D015533:Transcriptional Activation; D017211:Treatment Failure; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D055815:Young Adult
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D005765:Gastrointestinal Agents; D018836:Inflammation Mediators; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab
CROHN'S DISEASE; IBD BASIC RESEARCH; INFLAMMATORY MEDIATORS; TNF-ALPHA