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Gut doi:10.1136/gutjnl-2012-304154
  • Letter

Secukinumab failure in Crohn's disease: the yeast connection?

  1. Daniel Poulain2,3
  1. 1Clinique des Maladies de l'Appareil Digestif, Hôpital Huriez, CHRU de Lille, Lille, France
  2. 2Inserm U995, Université Lille Nord de France, Lille, France
  3. 3Laboratoire de Parasitologie- Mycologie, Centre de Biologie Pathologie, CHRU de Lille, Lille, France
  1. Correspondence to Professor Jean Frédéric Colombel, Clinique des Maladies de l'Appareil Digestif, Hôpital Huriez, CHRU, 2 Avenue Oscar Lambret, Lille Cedex 59037, France; Jean-Frederic.COLOMBEL{at}CHRU-LILLE.FR
  • Received 13 November 2012
  • Revised 13 November 2012
  • Accepted 14 November 2012
  • Published Online First 11 December 2012

We read with great interest the article by Hueber et al1 reporting on the dramatic failure of secukinumab, an anti-IL17A monoclonal antibody, in Crohn's disease (CD). This multicentre phase IIa study compared secukinumab with placebo in 59 patients with established moderate to severe CD. The study was prematurely stopped because the prespecified criterion for futility was met; for the first time to our knowledge in the history of recent CD trials, a statistical significant difference of mean Crohn's Disease Activity Index (CDAI) (between weeks 4 and 10) was observed in favour of placebo. Of the seven serious adverse events suspected to be drug related, five were worsening of CD, four on secukinumab. The study, thus, clearly showed that pharmacological blockade of IL-17A does not improve CD, but that it could also worsen the disease in some patients. Strikingly, a recent phase II trial of AMG 827, a human anti-IL17 receptor antibody also resulted in a disproportionate number of cases of worsening CD in subjects with active CD, and no evidence of meaningful efficacy.2 In an accompanying editorial referring to the secukinumab trial, T Raine and A Kaser provided several explanations for this failure, including problems in the trial design and at a more fundamental level, the complexity of Th17 biology. We would like to propose another hypothesis which is related to the potential role that Candida albicans may play in CD, and the major role of IL-17 in yeast immunity.3

This hypothesis has primarily emerged from our work on ASCA (anti-Saccharomyces cerevisiae antibodies) which is still the most sensitive serological marker of CD (see review paper ref. 3). In a series of studies following the original description of ASCA, we demonstrated that in contrast with the iniquitous yeast S cerevisiae, not adapted for surviving in the digestive tract, C albicans was an immunogen for ASCA, that other CD serological markers named anti-laminaribioside carbohydrate antibody and anti-chitobioside carbohydrate antibody against glucans and antichitin (which are yeast cell wall polysaccharides as well as mannnan) were also generated by C albicans pathogenic development and, finally, that in families with CD, patients and also their first-degree relatives were colonised by C albicans in association with the presence of ASCA, suggesting a genetic defect in C albicans sensing. These data were supported by experimental evidence, that a moderate chemically induced colitis in mice, triggered the thriving of C albicans which, in turn, dramatically increased intestinal inflammation and generated ASCA. More recently, the potential role of the fungal flora (mycobiome) in inflammatory bowel disease (IBD) was further suspected by the observation that mice lacking dectin-1 had an increased susceptibility to colitis, and that in humans, a polymorphism in the human gene for dectin-1 (CLEC7A) was linked to a severe form of ulcerative colitis.4 Dectin-1 is a c-type lectin among pathogen recognition receptors dedicated to fungal sensing. Its binding to fungal glucans strongly induces Th17 response. Dectin-1 is also a major upstream player in the regulation of the balance between Th1, Th2, TReg, Th17 and indoleamine 2,3-dioxygenase responses needed to avoid major host damage during C albicans infection.

In summary, we propose that the worsening of CD in both the secukinumab and AMG287 trial could have been linked to C albicans thriving in the gut induced by loss of control by IL17. The observation that four patients in the secukinumab trial displayed mucocutaneous candidosis (a so-far rare event during trials with biologic agents in IBD) reinforces this hypothesis.5 Further work is needed to elucidate the role of the mycobiome in CD and the molecular interplay between yeast antigens and inflammation in the gut.

Footnotes

  • Contributors JFC, BS, TJ and DP collectively participated in the drafting of the manuscript, and discussed the scientific contents of the final version.

  • Funding The study was supported by the European Community's Seventh Framework Program (FP7-2007-2013) under grant agreement No. HEALTHF2-2010-260338 ‘ALLFUN’.

  • Competing interests None.

  • Provenance and peer review Not commissioned; internally peer reviewed.

References


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