Crohn's Disease Etiology Questioned

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Crohn's Disease Etiology Questioned



By Jeff Minerd, MedPage Today Staff Writer

Reviewed by Rubeen K. Israni, M.D., Fellow, Renal-Electrolyte and

Hypertension Division, University of Pennsylvania School of Medicine

February 23, 2006



MedPage Today Action Points

Advise patients that treatment of Crohn's disease with Viagra,

interleukin 8, or other pro-inflammatory factors must be proved safe

and effective by large clinical trials.

Review



The digestive system.

LONDON, Feb. 23 - The exaggerated immune response that is considered

part and parcel of Crohn's disease may have been exaggerated,

reported investigators here.

In fact, Crohn's therapies aimed at reducing chronic inflammation may

be doing more harm than good, reported W. Segal, F.R.S., and

colleagues of University College London here in the February 25 issue

of The Lancet.

Not only that, they suggested that one aspect of this weak response-

sluggish blood flow in reaction to bacterial invaders-may be improved

by Viagra (sildenafil).

Compared with 13 healthy controls, 13 patients with Crohn's disease

produced abnormally low levels of neutrophils and the inflammatory

cytokine interleukin 8 in response to experimental wounds and

abrasions (with sandpaper) the researchers made at various sites on

the body.

Neutrophil production was 79% lower than normal in the rectum (P=.

0003) and 50% of normal in the skin (P<.0001). IL-8 levels were 63%

lower in the rectum (P=.003) and 45% lower in the skin (P<.0001), the

investigators reported.

To assess response to the presence of bacteria, the researchers

injected heat-killed Escherichia coli under the skin of study

participants. Healthy controls showed a vigorous inflammatory

response, characterized by redness, swelling, and increased blood flow.

While superficially similar, the responses of Crohn's patients were

characterized by sluggish increases in blood flow. Blood flow was

reduced by 77% compared with controls in patients with colonic

disease (P=.0003) and by 50% compared with controls in patients with

ileal disease (P=.01).

Oral administration of 50 mg of Viagra to Crohn's patients after the

bacterial injection markedly increased blood flow, bringing it up to

normal or near-normal in half of the individuals within 30 minutes,

the investigators said.

The researchers also tested three patients with ulcerative colitis,

but the responses of these patients were more similar to the control

participants than to the patients with Crohn's disease, suggesting

that ulcerative colitis has a different etiology than Crohn's, the

authors said.

The authors believe that in Crohn's disease, reduced or delayed

recruitment of neutrophils to sites at which bacteria penetrate the

intestinal wall might lead to the persistence of bacteria and other

organic debris in the tissue. The body may respond to this buildup of

bacteria by secreting inflammatory molecules, which accumulate and

lead to the chronic inflammation typical of Crohn's.

" Causation of Crohn's disease by failure of the acute inflammatory

response would fit very well with the so-called hygiene hypothesis,

in which the increased incidence of the disease has been attributed

to improved standards of sanitation, " the authors wrote, noting that

incidence of the disease rose greatly in the latter part of the 20th

century.

" These findings provide hope for the development of more effective

therapies for Crohn's disease, " the authors said. Current treatments

are immunosuppressive, but although they reduce symptoms by dampening

the proposed secondary inflammation, they might actually accentuate

the underlying immunodeficiency.

A more successful treatment approach might be to introduce IL-8 or

other proinflammatory stimuli directly into acute lesions, either by

direct enteral administration or through synthesis by genetically

modified gut organisms, they proposed.

" Agents that increase blood flow, such as long-acting

phosphodiesterase-5 inhibitors or other vasodilatatory or

proinflammatory drugs, might be useful in healing or preventing

lesions in Crohn's disease, " they concluded.



Primary source: The Lancet

Source reference:

Marks DJB et al. Defective acute inflammation on Crohn's disease: a

clinical investigation. The Lancet

http://www.medpagetoday.com/Gastroenterology/InflammatoryBowelDisease/

dh/2737