We evaluated bowel symptoms in patients with endoscopically quiescent UC by using PROs based on SF and RB derived from MCS and found that approximately one-third of patients complained of bowel symptoms mainly due to increased SF. The multivariate analysis revealed that female sex and greater extent of bowel damage (E2 or E3) were significant risk factors for increased SF and greater extent of bowel damage for SF + RB.
Monitoring disease activity in patients with UC is essential. MCS that includes SF, RB, MES, and PGA is most commonly used as the disease activity index. Because frequent endoscopic evaluation in patients with inactive UC is not usually performed, partial MCS is more commonly used during follow-up visits in the real-world setting. In general, PGA reflects patients’ impaired quality of life which is affected by abdominal pain, discomfort; however, due to the subjective aspects of PGA, it is difficult to consider MCS as an objective index of PRO. In contrast, SF and RB are symptom-based PROs that are usually considered clinical targets of remission  and are associated with endoscopic remission. Studies have reported that in some patients, these PROs did not exactly correlate with endoscopic findings, and up to one third of the patients with endoscopically and histologically inactive UC may experience increased SF . In the present study, we defined strict endoscopic remission as MES = 0, and 33% of the patients still complained of increased SF and/or RB, mostly due to increased SF (30%).
There have been some suggestions regarding PROs in patients with UC. Walmsley et al. suggested a simple clinical colitis activity index including bowel frequency (day and night), urgency, bloody stool, general well-being, and extracolonic features had good correlation with other complex indexes . Bewtra et al. indicated that SF, RB, and patient-reported general well-being accurately determined clinical disease activity . SF and RB can be used in routine clinical practice because they can easily derived from MCS. However, SF and RB in patients with endoscopically quiescent UC may present different patterns. Jharap et al. investigated the relationship between mucosal healing and PROs (SF + RB) in patients with UC who were treated with adalimumab or placebo, and reported that among the patients with MES = 0, the proportion of patients with SF ≥ 1 (71.2%) was higher than that of patients with RB ≥ 1 (12.8%) , which is consistent with our results (SF ≥ 1 vs. RB ≥ 1; 30% vs. 6.5%). This suggests that RB is more influenced by mucosal healing than SF, and other factors might be associated with increased SF in these patients. In addition, although 20% of patients with bowel symptoms showed RB ≥ 1 in this study, their rectal bleeding symptoms were not severe to occur anemia or require red blood cell transfusion.
One possible explanation is that these patients might still have low-grade inflammation in the bowel wall, which was insufficient to generate definite erythema, erosion or ulcers, but could provoke IBS-like symptoms. Low-grade inflammation may be associated with altered enteric nervous system and microbiota, similar to IBS. However, some discrepancies were reported between IBS-like symptoms and fecal calprotectin levels in patients with UC . In the present study, female sex was a significant risk factor of increased SF, which appears similar to IBS. In general, functional gastrointestinal disorders, including IBS, are more common in women than men [22, 23]. These gender difference is considered to be associated with the difference of visceral pain perception, autonomic function, and sex hormonal effect. Thus, patients with endoscopically quiescent UC but presenting bowel symptoms may share common features with IBS more than expected, and same management of IBS such as low FODMAP diet and usage of bowel movement drugs may be also helpful in these patients.
Previous disease extent can be another explanation. In the present study, the maximum extent of UC was analyzed, and it was found that E2 and E3 were more common in patients with bowel symptoms than in those without bowel symptoms (Table 2). Proximal disease extension of UC not only indicates the progression of UC but also a more damaged bowel. Long-term disease involvement of UC could lead to anatomical changes in the diseased bowel, which may be associated with impaired motility and absorptive function, similar to IBS . In multivariate analysis, previous E2 or E3 suggesting greater bowel damage was a significant risk factor of increased SF and SF + RB. Henriksen et al. conducted a long-term follow-up study for 20 years on the prevalence of IBS-like symptoms in patients with UC and reported that the overall prevalence of IBS-like symptoms was 27%, which was not significantly different than those among patients with ongoing inflammation and those without signs of inflammation (25–35%) . These IBS-like symptoms might be affected by previous long-term bowel damage during 20 years.
This study has some limitations. First, the retrospective nature of this study cannot eliminate selection bias. Our study was based on a tertiary center-based registry, and hence, we could not avoid referral bias. Our results may not reflect the general aspect of bowel symptoms in patients with inactive UC. In addition, some patients’ drug histories were incomplete, thus we could not provide concomitant medication for UC treatment or bowel movement (e.g., anti-diarrheal drugs, laxatives). Second, we did not assess histological findings of endoscopically quiescent UC. The presence of histologic bowel inflammation in the absence of endoscopic activity may be the cause of bowel symptoms . Fecal calprotectin levels, which correlate with mucosal activity, were not assessed in the majority of the enrolled patients. To overcome these limitations, we applied more strict criteria of endoscopic remission (MES = 0) than those applied in previous studies (MES = 0 or 1) [19, 25]. Third, we did not evaluate the relapse rate according to the patients’ bowel symptoms because we focused on temporal findings of bowel symptoms. In addition, MCS records bowel symptoms during previous 3 days by definition, thus it may not correctly reflect persistent bowel symptom. To minimize the ovelap of temporal worsening of symptoms such as infectious enteritis, we minimize the interval between the day of endoscopy and the nearest visit (median 8 days). Fourth, some patients (2.2%) underwent sigmoidoscopy only after endoscopic remission thus it is impossible to reveal possible residual inflammation in the proximal colon. However, these patients were in clinically stable state without evidence of disease aggravation, thus we included these patients.
In conclusion, even in patients with endoscopically quiescent UC, approximately one-third of the patients reported bowel symptoms, especially increased SF. These results might be associated with female sex and previous significant bowel damage. Physicians who treat IBD patients must know these phenomena and could suggest proper management of bowel symptoms in patients with long-standing UC.