INTRODUCTION
Peyer's patches (PPs) are aggregates of lymphoid follicles, almost half of which are located in the distal 25 cm of the ileum. As gut-associated lymphoid tissue (GALT), PPs play a major role in activating immune responses against infection, as well as in maintaining oral tolerance against gut commensal microbes and food antigens.
1,2 Indeed, PPs are considered to be the major inductive site for the mucosal immune responses of GALT, because luminal antigens are taken up through M (microfold)-cells, which are located within PPs.
1 Taken together, this suggests that PPs are involved in the pathogenesis of gut immune diseases, such as IBD.
Specifically, IBD comprises two categories of diseases, UC and CD, both of which are intractable diseases of the digestive tract. Because gut flora or food antigens are involved in the pathogenesis of IBD,
3 and because the uptake of luminal antigens occurs within PPs, it has been speculated that immune responses within PPs play an important role in the onset and clinical course of UC. In CD, aphthoid lesions within PPs have been reported as the initial inflammatory lesions.
4 Nonetheless, the role of PPs in UC is not fully understood.
Colonoscopy is widely performed in patients with UC; it is useful in diagnosis, treatment decisions, and cancer surveillance.
5 However, little attention has been paid to PPs, because they cannot be readily seen using conventional endoscopy. On this note, we recently reported that PPs can be visualized using narrow-band imaging with magnifying endoscopy (NBI-ME); microstructurally, they appear as aggregates of domed structures, surrounded by villi.
6 We also reported that patients with IBD have structural and vascular alterations within the dome area, as well as in the surrounding villi.
6 However, the clinical significance of these alterations in patients with UC has not been well evaluated. In the present study, we aimed to evaluate the association between NBI-ME images of PPs and clinical course in patients with UC.
DISCUSSION
This is the first report showing that alterations in the villi of PPs, determined using NBI-ME, are associated with clinical relapse in patients with UC. Several trials have addressed endoscopy, including ME and chromoendoscopy, and shown that the technique is associated with improved assessment of disease activity in patients with UC.
11,12 For instance, Nishio et al.
11 reported that an irregular pit pattern, shown using ME and methylene blue staining in the rectal mucosa, is a predictor of relapse, while a study by a Spanish group found that neither chromoendoscopy nor NBI images obtained using rectosigmoidoscopy could predict clinical or endoscopic relapse.
12 In contrast to both these conflicting sets of data, the present study found that images of PPs obtained using NBI-ME can be used to reliably predict sustained clinical remission.
Only a few reports have addressed the endoscopic appearance of PPs in patients with UC. In one study that involved 18 such patients and used magnifying chromoendoscopy, Ishii et al.
13 reported that the dome of PPs is irregular, and that it is surrounded by sparse and atrophic villi. In the same study, the association between the endoscopic appearance of PPs and the clinical characteristics of UC, however, was not discussed. In our own study, we used the NBI technique, wherein the vascular network and surface texture of the mucosa can be promptly enhanced, without any additional equipment.
14,15 Using NBI-ME, we could show that the appearance of PPs may have predictive value for disease process in patients with UC. To further confirm this observation, a prospective study is on-going.
It is urgent that researchers develop biomarkers (ideally non-invasive) to predict the clinical course of UC.
16 Clinical characteristics, including young age at diagnosis, female gender, or extensive colitis (pancolitis), have been reported as predictors of recurrence in UC.
17 Although CRP levels do correlate with endoscopic disease activity and clinical relapse in patients with UC,
18 the sensitivity is poor for predicting relapse in patients with mild disease.
16 Similarly, fecal calprotectin has been shown to be correlated with the clinical activity of UC, and can be useful for predicting clinical relapse.
16 Indeed, fecal calprotectin can non-invasively detect the intestinal infiltration of neutrophils during mucosal inflammation, before patients become symptomatic. We did not measure fecal calprotectin in the current study, and we need to evaluate the correlation between fecal calprotectin and NBI-ME images in UC. Mucosal healing has been associated with a low risk of hospitalization
19 and future colectomy
20 in patients with UC. In this study, we compared patients who had Mayo endoscopic subscores of 0 or 1 with those who had Mayo subscores of 2 (
Table 2), because the majority of remissive patients in our cohort had a subscore of 0 or 1, and because a recent study demonstrated that patients with a Mayo endoscopic subscore of 1 had a higher recurrence rate than those with a subscore of 0.
21 In neither group (H- or L-type PPs) was there a significant difference between patients who had a Mayo endoscopic subscore of 0 or 1 and those who had a subscore of 2. Similarly, in our cohort of remissive patients, Mayo endoscopic subscore was not a significant predictor of relapse. In contrast, there was statistically significant difference rate between L-type and H-type PPs in terms of recurrence rate. Therefore, the appearance of PPs may be useful in predicting relapse before the patients concerned exhibit intestinal inflammation or elevated fecal calprotectin.
The cause of the alterations to PPs in UC has not been identified. Backwash ileitis is sometimes observed in UC patients who have severe pancolitis; this is caused by an incompetent Bauhin's valve.
22 However, as we analyzed remissive patients, it is unlikely that the PP alterations had been caused by spreading inflammation, such as backwash ileitis. Interestingly, patients with altered PPs had a significantly higher rate of peri-appendiceal inflammation. Peri-appendiceal lesions in the cecum have been considered distinct "skip lesions" of UC, and have been shown to have prognostic implications for the course of the disease.
23 In our study, however, the involvement of peri-appendiceal lesions had no predictive value for UC relapse (data not shown). On the same note, a recent report has suggested that cecal patches, the lymphoid clusters that exist in the appendix, also function as a major component of the GALT, similarly to PPs.
24 Therefore, we need to further clarify the role of the GALT in UC.
This study had several limitations. Firstly, it was a single-center study with a relatively small sample size. Moreover, we mainly evaluated patients in remission, and the number of patients with active disease was small. In addition, the influence of treatments for UC on the imaging was not analyzed sufficiently. Therefore, it will be necessary to carry out further investigation into PPs by using NBI-ME in patients with various disease types; long-term follow-up will also be required. To further clarify the role of PPs in UC, a multicenter study is currently underway.
In conclusion, using NBI-ME to observe PPs may be useful in predicting the clinical course of UC; specifically, UC patients with morphological PP alterations showed recurrence. Further studies are required to determine the relationship between the changes in PPs and the disease course of UC.