Editors' ChoiceUlcerative Colitis

Quenching Flare-Ups

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Science Translational Medicine  23 Nov 2011:
Vol. 3, Issue 110, pp. 110ec188
DOI: 10.1126/scitranslmed.3003455

Physicians find it challenging to treat patients with ulcerative colitis (UC) who are unresponsive to standard immunosuppressive therapies. The recent demonstration that cytomegalovirus (CMV) may play a role in treatment-refractory patients may pave the way to new therapeutic strategies. Now, Roblin et al. study patients with acute UC flare-ups to assess the ability of CMV DNA load to predict resistance to immunosuppressive drugs.

CMV is a common and ubiquitous pathogen that often does not cause overt disease. The virus remains latent in tissues until replication is activated in immunosuppressed individuals. Treatment of UC patients with immunosuppressive steroids may spur CMV replication in intestinal colonic tissue, thus contributing to inflammation and tissue destruction in the gut. However, researchers have yet to detect the presence of CMV in gut tissue or to prove that the virus contributes to treatment-refractory disease.

Roblin and colleagues tackled this challenge by sampling tissue from 42 patients with moderate to severe UC who were undergoing treatment with steroids. Both inflamed and healthy colonic tissue was sampled from the same individuals and subjected to polymerase chain reaction to detect and quantitate CMV DNA. All of the patients (n = 26) who were negative for CMV DNA in their inflamed colonic tissue (that is, fewer than 10 copies per mg of CMV DNA) responded to one of three immune suppressive treatments (steroids, infliximab, or cyclosporine). Of the remaining 16 (of 42) patients who were positive for colonic CMV DNA, 6 responded to successive immunosuppressive treatments, 2 underwent emergent surgical removal of their colon, and 8 were also treated with the antiviral drug gangcyclovir.

A random sensitivity analysis was performed to explore the relationship between colonic-tissue CMV and response to treatment. This revealed that a higher viral load, >250 copies per mg, was predictive of resistance to the three immunosuppressive therapies with a sensitivity of 100% and specificity of 66.6%. No CMV DNA in colonic tissue was predictive of a positive response to therapy with a sensitivity of 100% and specificity of 50%. Of the eight patients who had colonic tissue CMV DNA with failure to respond to two lines of immunosuppressive medication and who were subsequently treated with antiviral medication, none had CMV at biopsy follow-up (≥30 days). Seven of these patients gained remission with standard immunosuppressive regimens. These findings suggest that the addition of antiviral drugs to the immunosuppressive treatment regimen of patients with UC may prolong the time before resistance to standard drugs develops. It will be important to test antivirals in a randomized controlled trial to discern whether CMV treatment changes clinical outcomes in inflammatory bowel disease.

X. Roblin et al., Cytomegalovirus load in inflamed intestinal tissue is predictive of resistance to immunosuppressive therapy in ulcerative colitis. Am. J. Gastroenterol. 106, 2001–2008 (2011). [Abstract]

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