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RA, Inflammatory Bowel Overlap Still a Clinical Challenge


 

FORT LAUDERDALE, FLA. — Despite greater understanding of genetic influences and phenotypic manifestations, and the availability of multiple immunomodulatory medications, inflammatory bowel disease continues to pose significant clinical challenges.

Why is IBD of particular interest to rheumatologists? According to Dr. Sunanda Kane, there appear to be several shared mechanisms for inflammation, and there are certainly patients with “overlap” syndromes who have significant rheumatologic abnormalities along with intestinal inflammation.

Trying to understand the common threads—rather than focusing on the differences—of both conditions will ultimately help more patients, she said.

There is mounting evidence of a genetic link between rheumatoid arthritis and inflammatory bowel disease. The STAT4 polymorphism has been found to be associated with increased susceptibility to IBD and rheumatoid arthritis (Arthritis Rheum. 2008;58;9:2598–602).

Further research suggests a link between Th17 cells and interleukin-23. Th17 cells have been implicated in the pathogenesis of rheumatoid arthritis. These cells are found in high numbers in joints with RA-induced inflammatory destruction. Their production is dependent on growth factor IL-23. Findings from animal models show that IL-23 also plays a role in gut inflammation, and loss of IL-23 was associated with a loss of inflammation. Although it remains to be seen whether gut inflammation is totally dependent on Th17, it seems clear that IL-23 plays a significant role there (Ann. Rheum. Diseases 2008;67[suppl. 3]:iii26–9)

“Classically, in inflammatory bowel disease we talk about ulcerative colitis and Crohn's disease, but sometimes there is so much overlap it's hard to tell the difference,” said Dr. Kane of the Mayo Clinic, Rochester, Minn. “We don't fully understand what causes Crohn's and colitis, but we do know that the normal gut is always mildly inflamed. It has to be, because this is what 'tastes' the environment and determines what's friend and what's foe,” she said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

Genetic studies revealed genes that predispose to an inability to downregulate gut inflammation, such as the NOD2/CARD15 gene, located at chromosome 16q12.

This gene's product is similar to disease-resistance proteins in plants, and is related to immune response to bacteria. Mutations in this gene are associated with Crohn's disease through abnormal activation of downstream inflammatory cell signaling, she explained.

Diet, smoking, and stress all can contribute to worsening of disease, as can the use of antibiotics—particularly penicillin and the other “-illins”—and non-steroidal anti-inflammatory drugs, she said.

“There is a 30% increased risk of disease flare with regular NSAID use in IBD, so when patients have extraintestinal manifestations or concomitant rheumatologic conditions, we gastroenterologists really have to partner with the rheumatologists to make sure they use drugs other than NSAIDs,” she said.

Treatment also remains challenging, despite the availability of immunomodulating drugs. Infliximab, adalimumab, and certolizumab have been used successfully, but etanercept and onercept have not been superior to placebo, and ulcerative colitis has worsened in patients treated with rituximab for other conditions.

Dr. Kane is a consultant for and receives research support from Elan Pharmaceuticals Inc., Procter & Gamble Co., Shire Pharmaceuticals Group, and UCB Pharma Inc. SDEF and this news organization are owned by Elsevier.

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