yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the work of artificial intelligence, which forms the content of this project

Document related concepts

Pseudomonas aeruginosa wikipedia, lookup

M Ines Pinto-Sanchez, MD, MSc
Commentary on: Development of Celiac Disease Therapeutics: Report of the Third
Gastroenterology Regulatory Endpoints and Advancement of Therapeutics Workshop. By
Leffler D et al. Gastroenterology 2016.
The only currently available treatment for CD is lifelong adherence to a gluten-free diet (GFD),
which entails the avoidance any products containing even traces of wheat, rye, and barley. It is
well known that in celiac patients the lack of treatment may lead to anemia, osteoporotic
fractures and small-bowel lymphoma. Even though the risk of complications is predictable,
more than half of celiacs find difficulties following a strict GFD. Therefore, there is an unmet
medical need of alternative treatments options beyond GFD.
In this report, worldwide renowned experts in the field of celiac disease discussed at the third
Gastroenterology Regulatory Endpoints and Advancement of Therapeutics (GREAT 3)
workshop, how to define target populations for pharmacologic therapies, as well as measuring
clinical benefit in celiac disease trials to support marketing approval. Persistently symptomatic
and newly diagnosed patients, as well as children with CD who are affected by
neurodevelopmental or behavioral conditions may potentially benefit from a future
medication. There were 3 sessions in the workshop to discuss how to define clinical benefit in
clinical trials, as the definition may differ according to patients, physicians and the FDA. From
the perspective of celiac patients, they were more interested in therapies that protect against
gluten cross contamination, and that prevent them to develop symptoms while eating at home
or outside home. Gastroenterologists were looking not only on symptomatic improvement but
an expansion to other objective measures. There was consensus among patients and clinicians
at the workshop that diarrhea and abdominal pain will be central patient-reported outcomes
for research studies involving therapies. The FDA’s view usually includes survival within the
definition of clinical benefit, however, in celiac disease this is not a pragmatic end point.
Therefore, health-related quality of life was proposed as a measurement of clinical benefit.
There are many research studies ongoing investigating the effect of non-dietary therapies in
celiac disease, however, the efficacy of treatment will depend on how the outcome is
measured. There are many obstacles in clinical research, including the absence of a precedent
product approval for celiac disease, difficulties in defining target populations for pharmacologic
therapy, clinical end points, measurement tools, clinical and meaningful differences in
responder criteria, lowest effective dose, and translation to the pediatric population. Future
studies will benefit from collaboration between patients, physicians, industry and regulatory
Heather Galipeau, PhD
Comment on: Duodenal bacteria from patients with celiac disease and healthy subjects
distinctly affect gluten breakdown and immunogenicity. By Caminero et al.
Intestinal dysbiosis has been described in celiac disease, but a clear microbial signature, and the
pathophysiological significance is still unclear. Intestinal bacteria are able to degrade gluten invitro, which is highly resistant to degradation by human digestive enzymes. In the recently
published article by Caminero et al, the authors demonstrate that opportunistic pathogens and
commensal bacteria differentially participate in gluten metabolism in vivo, influencing the end
products of gluten metabolism and immunogenic potential of the generated peptides. Using
Pseudomonas aeruginosa, an opportunistic pathogen that was only isolated from the
duodenum of celiac disease patients, Caminero et al show that P. aeruginosa, through its
elastase activity, degrades gluten to produce immunogenic gluten peptides that can stimulate
gluten-specific T cells from HLA-DQ2.5 celiac disease patients. Moreover, these P. aeruginosadigested gluten peptides were able to translocate across the small intestinal barrier more
efficiently than those peptides digested by human proteases. On the other hand, Lactobacillus
spp, isolated from the duodenum of healthy controls, degraded gluten peptides produced by
both P. aeruginosa and human proteases to non-immunogenic gluten peptides. Thus, there are
distinct patterns in gluten breakdown products generated by the opportunistic pathogen P.
aeruginosa and Lactobacillus spp that are associated with increased or decreased
immunogenicity. The authors describe an important mechanism through which opportunistic
pathogens may modify the pool of gluten peptides in the small intestine, generating
immunogenic peptides that can translocate the intestinal barrier and increase susceptibility to
celiac disease in genetically susceptible individuals. Importantly, this microbe-gluten-host
interaction may apply to other opportunistic pathogens that are present in celiac disease
patients and may be a target for therapeutic interventions.