TNF-alpha is an important pathogenic factor contributing to reactivation of cytomegalovirus in inflamed mucosa of colon in patients with ulcerative colitis: lesson from clinical experience.

To the Editor: In patients with inflammatory bowel disease (IBD), particularly those with refractory ulcerative colitis (UC), cytomegalovirus (CMV) is often reactivated because they are frequently treated with immunosuppressive agents. However, significance of CMV reactivation in inflamed mucosa of patients with UC still remains unclear. Indeed, some investigators suggested that CMV behaves in the intestine as a nonpathogenic bystander, and others reported that CMV has a crucial role in triggering the onset of inflammation, resulting in its complication. Therefore, when CMV is detected either by blood tests or by mucosal biopsy specimens in patients with severe IBD, clinicians are faced with a therapeutic dilemma: should antiviral therapy be initiated and the level of immunosuppression be reduced, with the risk of further worsening IBD, or should we increase the dose of immunosuppressive agents to suppress the IBD activity? We note with great interest the article by Criscuoli et al. In that article they reported that 2 patients with steroid-dependent moderate-to-severe UC treated with infliximab (IFX) for active disease in whom a clinical response with virus disappearance was obtained. These clinical data led us to expect a new possibility of IFX as treatment for UC patients with concomitant CMV infection. However, it is still controversial whether or not IFX is effective for all UC patients with concomitant CMV infection because Helbling et al reported widespread of CMV infection in refractory Crohn’s disease after antiTNF-a therapy. Recently, we also experienced 3 cases of refractory UC patients concomitant with reactivation of CMV in colonic mucosa who were treated with IFX. In all patients, polymerase chain reaction (PCR) analysis was positive for CMV-DNA in their colonic mucosa. One patient achieved clinical remission after a single infusion of IFX, while 2 patients required surgery despite 3 infusions of IFX. Interestingly, PCR analysis showed that the CMV-DNA in colonic mucosa of all patients was negative after IFX treatment. Both our and Criscuoli et al’s clinical series suggested that IFX could lead to a reduction of viral genome of CMV in colonic mucosa of patients with UC and be carried out without significant relapse of UC. Thus, these clinical experiences demonstrated a possible role of TNF-a in reactivation of CMV. Previously, it was reported that TNF-a plays an important role of reactivation of CMV in both monocytes and dendritic cells. In addition, a recent in vitro study showed CMV could force monocytes to acquire an M1 proinflammatory phenotype and differentiate into long-lived macrophages. Also, CMVinfected monocytes with M1 phenotype induce cytokine expression of IL-6, TNF-a, and IL-1b, which can contribute to increasing activated macrophages and permissive cells supporting active replication of CMV. In this regard, it would be theoretically reasonable that IFX could be administered to UC patients with concomitant CMV infection. However, in our case 2 patients finally required surgical treatment, although PCR analysis showed that CMV-DNA disappeared in their colonic mucosa. Our cases demonstrated that IFX alone is not necessarily useful for all UC patients with concomitant CMV infection, and reflects the complexity of the pathophysiology of patients with UC. Therefore, additional medical therapy such as cytapheresis might be considered for UC patients with concomitant CMV refractory to IFX. Is antiviral therapy not necessary as therapy for UC patients with concomitant CMV infection if we use IFX? We have reported that 10 (83.3%) of the 12 refractory UC patients with CMV-DNA positive in colonic mucosa receiving antiviral therapy went into remission. This clinical experience also strongly demonstrated the involvement of CMV in exacerbation of UC activity. Hommes et al proposed schematic representation of sequelae during bowel inflammation in CMV-seropositive patients, which is classified into 3 phases (initiation, reactivation, and consolidation phase). During the initiation phase, mucosal inflammatory responses induce expression of several cytokines and chemokines, which triggers the hosts’ latently infected cells and migration of monocytes and dendritic cells into inflamed mucosa. Next is the reactivation phase, in which latently infected monocytes differentiate into tissue macrophages and dendritic cells. At this phase, CMV reactivation was restricted to the inflamed bowel section. Finally, during the consolidation phase, active replication takes place predominantly in endothelial cells, and possibly is responsible for further aggravating the inflammatory response. Thus, with reference to the sequelae, optimal therapy for active UC with concomitant CMV infection might be changing according to the CMV reactivation status. In conclusion, blockade of TNFa as a therapeutic strategy for active UC with concomitant CMV infection might be acceptable; however, further CopyrightVC 2009 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.21047 Published online 27 July 2009 in Wiley InterScience (www.interscience.wiley.com).