Clinical Course and Prognosis of Isolated Terminal Ileal Ulcers

Background: Isolated terminal ileal ulcers (ITIUs) may be a clue to hidden intestinal diseases. However, there are no specific guidelines for ITIUs. Methods: We retrospectively screened subjects undergoing colonoscopy at The First Affiliated Hospital, Zhejiang University from March 2014 to July 2019, and included patients with ITIUs in the study. Some patients underwent further examination of the entire small intestine. Subsequently, patients with undetermined ITIUs received empiric therapy or observational follow-up. At least one year after baseline colonoscopy, telephone follow-up was performed to collect prognostic information. Results: A total of 120 (0.3%) patients undergoing colonoscopy in our center were found with ITIUs. Fourteen patients underwent further examination of the entire small intestine, six of whom were found with additional small bowel ulcers, but it did not significantly help the diagnosis. We obtained follow-up information from 41 undiagnosed patients. Over an average follow-up of 35.4 months, there was no significant difference in the prognosis of patients receiving empiric therapy or observational follow-up. The clinical and endoscopic outcomes improved or remain unchanged in most patients. In logistic regression analysis, gender, age, chief complaint, number of ulcers, and follow-up strategy had no significant impact on prognosis. Conclusion: Patients with nonspecific ITIUs usually improve without any therapy, and observational follow-up may be a reasonable strategy.


Introduction
The terminal ileum is 30-40 cm of the ileum at the distal end of the small intestine and terminates at the ileocecal sphincter.It is a common site for small bowel diseases, such as Crohn's disease (CD), 1 intestinal tuberculosis 2,3 and lymphoma, 4 as well as adenocarcinoma, druginduced enteropathy and Behcet's disease, 5 which can manifest as small ulcers in the terminal ileum.Although isolated terminal ileal ulcers (ITIUs) are only occasionally observed during colonoscopy, they are likely a clue to these diseases and should be given more attention.
7][8] Although terminal ileal intubation can be difficult, some techniques are available when standard maneuvers fail. 9It has been shown that terminal ileal intubation and biopsy can improve the diagnosis of terminal ileum lesions, especially for patients with abdominal pain. 10However, there are no specific guidelines for the diagnosis and management of ITIU as it is usually occult, asymptomatic or with nonspecific symptoms, and lacks evidence for early diagnosis.
In this study, we screened patients with ITIUs by colonoscopy and collected their histopathological findings.In addition, we followed the patients and analyzed the clinical course and prognosis of ITIUs.

Study Design and Population
We retrospectively screened subjects who underwent colonoscopy at The First Affiliated Hospital, College of Medicine, Zhejiang University from March 2014 to July 2019, and included the patients with ITIUs (only ulcers in the terminal ileum, no lesions in the colon or ileocecal valve). 5It was not appropriate or possible to involve patients or the public in the design, or conduct, or reporting, or dissemination plans of our research.Informed consent was obtained from all patients for inclusion in the study.All authors had access to the study data and reviewed and approved the final manuscript.
Patients who met the following criteria were excluded: (1) history of related chronic intestinal disease at baseline, including inflammatory bowel disease (IBD), intestinal tuberculosis, lymphoma, colorectal cancer and Behcet's disease; (2) endoscopic diagnosis (including histopathological evidence) of the above diseases; (3) history of colorectal surgery; (4) recent (within 6 months) use of non-steroidal anti-inflammatory drugs, corticosteroids or immunosuppressants; (5) oral or genital ulcers suggesting Behcet's disease.
Eligible patients may undergo some helpful laboratory tests for diagnosis, and some of them underwent further examination of the entire small intestine, including small Prognosis of terminal ileal ulcers bowel capsule endoscopy (SBCE), computed tomographic enterography (CTE), and double-balloon enteroscopy (DBE).Except for patients who were successfully diagnosed, the undiagnosed patients received follow-up management, that is, empiric therapy or observational follow-up.At least one year after the baseline colonoscopy, telephone follow-up was performed for patients with undiagnosed ITIUs to collect prognostic information about their clinical symptoms and colonoscopic reexamination.

Data Collection
We recorded the patients' gender, age, clinical symptoms, and the endoscopic features and histopathological results of ITIUs.For patients with follow-up information, data on further examination and follow-up management (empiric therapy or observational follow-up) were also collected, most importantly including the prognosis vis-a-vis clinical symptoms and endoscopic findings.

Statistical Analysis
All data were analyzed using SPSS 23.0 (IBM Inc., Chicago, IL).Continuous variables were expressed as mean ± standard deviation, and the differences between two groups were compared using Student's t test (based on normal distribution and homogeneity of variances); categorical variables were expressed as number (percentage), and the differences between two groups were compared using chi-square test or Fisher's exact test as appropriate (if no more than 20% of cells with a theoretical frequency T < 5 and no cells with a T < 1, chi-square test was used; otherwise Fisher's exact test was used).Logistic regression analysis was performed to assess whether potential influencing factors, including gender, age, chief complaint, number of ulcers, and follow-up strategy affect the clinical or endoscopic prognosis of ITIUs.A P value < 0.05 was considered statistically significant.

Results
Among the 48 000 individuals who underwent colonoscopy in the First Affiliated Hospital, College of Medicine, Zhejiang University from March 2014 to July 2019, a total of 120 patients were found with ITIUs, with a detection rate of 0.3%.Of these patients, nine had a history of potentially related bowel disease (including five IBDs, two intestinal tuberculosis and two colorectal cancers), one was diagnosed with lymphoma based on typical histopathological evidence, and one was suspected as Behcet's disease due to simultaneous oral ulcers.Excluding the patients with explainable ITIUs, we followed 109 eligible patients with undetermined ITIUs at baseline.The flowchart of follow-up is shown in Figure 1.

Further Examination and Diagnosis
Shortly after colonoscopy, 14 patients underwent further SBCE, CTE, or DBE to examine the entire small intestine.Eight (57%) of them only had terminal ileal ulcers, while the other (43%) were found to have additional small bowel ulcers, two of whom were diagnosed with CD.In addition, 95 patients did not undergo these examinations, with or without some helpful laboratory tests, 11 (12%) of whom received a definite diagnosis, including 10 cases of CD and one case of ulcerative colitis (UC).There was no significant difference in the diagnostic rate between patients with or without further examination (14% vs. 12%, P = 0.673; Table 2).Finally, a total of 13 patients were diagnosed with a definite disease, including 12 CDs and one UC.difference in prognosis between empiric therapy or observational follow-up.Most patients in both groups had improved clinical symptoms and endoscopic findings, or remained unchanged.In summary, ITIUs usually improve or limit themselves even without any therapy.As previously reported, ITIUs are occasionally observed in asymptomatic individuals, and most could resolve without empiric therapy.Even if the ulcer persists, it rarely progresses or causes any symptoms. 5In our study, we found that even in symptomatic individuals, ITIUs were sporadic, and most of them improved or self-limited without any therapy.Altogether, ITIUs may be a relatively benign

Follow-up Management and Prognosis
Thereafter, the remaining 96 undiagnosed patients received follow-up management, in the form of either empiric therapy (including 5-ASA, probiotics or 5-ASA plus probiotics) or observational follow-up.We obtained the follow-up information on clinical symptoms and colonoscopic re-examination in 41 patients at least one year after the baseline colonoscopy.As shown in Table 3, over an average follow-up of 35.4 months, there was no significant difference in the prognosis of patients receiving empiric therapy or observational follow-up.The clinical symptoms and endoscopic findings improved or remain unchanged in most patients of the two groups.Only one patient progressed from a single ulcer to multiple small ulcers during observational follow-up.In logistic regression analysis, gender, age, chief complaint, number of ulcers, and follow-up strategy had no significant effect on clinical or endoscopic prognosis (Table 4).

Discussion
In our study, 0.3% of patients who underwent colonoscopy in our center were found to have ITIUs.Among them, 11.9% were diagnosed with IBDs, and there was no difference in the diagnostic rate between patients with or without further examination of the entire small intestine.Subsequently, for undiagnosed patients, there was no Prognosis of terminal ileal ulcers natural history with no serious events and do not necessarily require empiric therapy or frequent colonoscopy.The cause of ulcers in the terminal ileum is not entirely clear.It may be related to bacterial colonization, infection and induction of immune response in the terminal ileum, leading to mucosal damage.It has been reported to be one of the earliest manifestations of certain diseases, such as CD.Patients with aphthous ulcers may develop typical CD later. 11However, Courville et al found that despite the chronic characteristics of ileal biopsy, isolated asymptomatic ileitis did not progress to overt CD over long-term follow-up. 12In our study, after baseline colonoscopy or further examinations (with or without helpful laboratory tests), patients with a successful diagnosis were most likely to be CDs, and there was no difference in the diagnostic rate between patients with and without small intestine examinations.No new CD patients were found during follow-up.These findings indicate that there are rarely missed diagnoses based on the available diagnostic methods, and small intestine examinations have a limited role in diagnosis, but may be helpful for severity assessment.
There were some limitations in our study.First, due to the low detection rate (0.3%) of terminal ileal ulcers, only 109 eligible patients were included in this study, and the follow-up information was incomplete.Second, although the patients were diagnosed as ITIUs by colonoscopy, only a few patients underwent further examination of the entire small intestine.In this study, 6 of the 14 patients who underwent further examination were found to have additional small bowel ulcers, but its role in diagnosis seemed to be limited.Third, the study population came from a single center, and we followed up for an average of 3 years.In future studies, prospective multicenter studies with long-term follow-up are needed, as disease progression may vary between populations and take a long time.
In summary, patients with ITIUs usually improve without any therapy, and even if the ulcer persists, it rarely progresses.These findings suggest that for patients with undetermined ITIUs based on routine diagnostic methods, we may choose observational follow-up rather than empiric therapy.However, we still recommend further diagnosis and intervention for patients at high risk of certain diseases.Of course, prospective multicenter studies with long-term follow-up are needed in the future.

Conclusion
Patients with ITIUs usually experience natural improvement without treatment, and they seldom deteriorate even if the ulcer persists.These findings suggest that opting for observational follow-up, rather than empirical therapy, may be a reasonable approach for patients with ITIUs when a definitive diagnosis cannot be achieved through conventional diagnostic methods.

Table 1 .
Baseline Characteristics of Patient with Isolated Terminal Ileal Ulcers

Table 2 .
Diagnostic Rate of Further Examination in Patient with Isolated Terminal Ileal Ulcers *Further examinations include small bowel capsule endoscopy (SBCE), computed tomographic enterography (CTE), and double-balloon enteroscopy (DBE) to examine the entire small intestine.