Clinical outcomes and risk factors of secondary extraintestinal manifestation in ulcerative colitis: results of a multicenter and long-term follow-up retrospective study

Study population

All consecutive UC patients at the Department of Colorectal Surgery, Xin-Hua Hospital, Shanghai Jiao Tong University School of Medicine (Shanghai, China), and the Department of Gastroenterology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine (Shanghai, China) from June 1986 to December 2018 were enrolled in the study. Patients were identified and their clinical data was obtained from a prospectively maintained, institutional review board-approved database (Chinese Database System for IBD, CHASE-IBD). The Ethics Committee of Xin-hua Hospital approved this study (approval no. XHEC-D-2018-089).

Inclusion and exclusion criteria

Inclusion criteria were as follows: (1) positive diagnosis of UC; (2) age at diagnosis ≥18 years old; and (3) received a regular follow-up at our department. Exclusion criteria were as follows: (1) patients who were diagnosed with familial adenomatous polyposis or indeterminate colitis; (2) patients with poor compliance; and (3) patients with underlying disease, impaired general health, and/or lost to follow-up.

In this study, poor patient compliance refers to patients who refuse to receive regular follow-up and give feedback to the doctor. Underlying disease was mainly defined as the infectious factors caused of intestinal inflammation as well as colorectal cancer (CRC) or high-grade dysplasia. The impaired general health refers to serious and chronic diseases such as hypertension, diabetes, hyperthyroidism and heart failure, which lead to poor general conditions.

Data collection and clinical evaluation

The patient’s medical history, examination data, surgical information, and clinical outcomes were retrospectively collected from the hospital medical records, outpatient examination, and long-term regular follow-up. The collected data were as follows: sex, age at diagnosis, disease duration, relapse, EIM, gastrointestinal symptoms, weight loss, primary sclerosing cholangitis (PSC), disease extent according to the Montreal classification system (Silverberg et al., 2005), surgical history, familial history of IBD or CRC, complications, development of CRC, use of steroids and immunomodulators, and hemoglobin (Hb) and Albumin (Alb) measurements. Each patient will undergo routine and systematic imaging examinations, colonoscopy or biopsy, immunological examinations, etc. All these baseline characteristics were presented based on the most recent follow-up. Relevant data of EIM was collected during treatment. In addition, the use of mesalamine, biologics, steroids, and immunomodulators refer to current treatment or the previous treatment that was used until the latest follow-up (December 2018). UC was strictly diagnosed according to the established internationally accepted criteria proposed by Lennard-Jones (1989). The criteria excluded infectious factors caused of intestinal inflammation. The diagnosis of UC and EIM were based on clinical, radiological, endoscopic, and immunologic examination, and histologic findings. In this study, primary EIM refers to extraintestinal symptoms that occur before the onset of UC and are not related to UC. While secondary EIM refers to extraintestinal symptoms that occur in the course of UC that affect various organs in the body. It includes various clinical manifestations such as rash, oral aphthous ulcers, arthritis, glomerulonephritis, PSC, vasculitis, ankylosing spondylitis, and autoimmune hepatitis. Only when these extraintestinal symptoms appear in the course of UC, and after detailed radiological, immunologic and histologic examination, can be diagnosed as a secondary EIM. The rash in the text refers to the long-term persistent skin damage that occurs in the course of UC, while the transient rash that occurs after drug treatment is not taken into account. We defined refractory clinical symptoms as more than 5 stools per day accompanied by diarrhea and mucous, and bloody stools after regular medical treatment, including 5-aminosalicylic acids (5-ASA), corticosteroid, immunomodulators, and biologics. In this study, patients with “weight loss” refers to patients who lost more than five kg at the latest follow-up. Family history of other cancers refers to first, second or third degree relative of the patient had or is currently living with cancer except CRC. Mild anemia was defined as Hb value was less than 120 g/L but more than 90 g/L in male and less than 110 g/L but more than 90 g/L in female. Moderate anemia refers to Hb value between 60 and 90 g/L, and severe anemia was defined as Hb value <60 g/L both in male and female, respectively. Therefore, in this study, we modified the definition that Hb <90 g/L refers to moderate or severe anemia. Patients with Hb value <90 g/L has at least a moderate anemia even more serious anemia. Remission in this study refer to the relief of clinical symptoms including less than three times of stools per day, the disappearance of diarrhea, fever, abdominal bloating and distension, and stool with mucus, pus and blood. To evaluate the associations between EIM and clinical outcomes, we divided the patients into two groups with or without EIM. The complications refer to various clinical manifestations as well as the development of CRC. All complications were diagnosed based on clinical manifestations, laboratory results, and endoscopic and imaging findings. Intestinal obstruction, colon perforation and gastrointestinal bleeding were defined as the serious complications.

Statistical analysis

SPSS version 19.0 software (IBM Corp., Armonk, NY, USA) were used for the statistical analyses. Values and percentages, mean and standard deviations, or the median and interquartile range (IQR) were used to describe the different varieties of data, respectively. Chi-squared or Fisher’s exact test were used for categorical variables. Moreover, we choose the Wilcoxon’s rank-sum test as the statistical method for ranked variables. Multivariate logistic regression was performed in the variables with p-value <0.05 in the analysis of the risk factors of EIM in UC. Confidence intervals (CI) were set at 95%. All statistical tests were two-sided, with a p-value of <0.05 considered statistically significant.

Demographics and clinical characteristics

A total of 291 UC patients were enrolled at our institute, 20 patients were lost to follow-up and excluded; 271 eligible patients were ultimately included for the current research. A schematic flow diagram of the present study is shown in Fig. 1 and the patient demographics and clinical and laboratory characteristics are shown in Table 1. In the entire cohort, the median follow-up time was 13.0 years (IQR: 9.0–17.0 years) from June 1986 to December 2018. Among the 271 patients, 132 were males and patients had a median age at diagnosis of 42.0 years (IQR: 29.0–53.3 years) and a median disease duration of 7.0 years (IQR: 4.0–10.0 years). In the entire cohort, 31 patients (11.4%) were found to develop at least one EIM, of which eight patients (3.0%) developed multiple EIM. In addition, six patients (2.2%) had proctitis (E1), 140 (51.7%) had left-sided colitis (E2), and 125 (46.1%) had pancolitis (E3). In addition, in the total of 31 EIM patients, 14 were men. Median age at diagnosis and disease duration in EIM patients was 47.0 years (IQR: 44.0–55.0 years) and 14,0 years (IQR:6.0–17.0 years), respectively (Table 1).

Analysis of EIM in the present study

Table 2 showed the detailed EIM in UC patients. In the 23 patients with single EIM, nine patients developed arthritis, six had oral aphthous ulcers, four had rash, two experienced glomerulonephritis, one had PSC, and one had ankylosing spondylitis. For eight patients with multiple EIM, three patients had arthritis and oral aphthous ulcers, one had arthritis and rash, one had oral aphthous ulcers and rash, one had arthritis and iritis, one developed rash and vasculitis, and one experienced PSC and autoimmune hepatitis (Table 2). Therefore, this data indicated that the overall incidence rate of EIM of UC in Shanghai was 11.4%.

Analysis of complications in UC

In the entire cohort, 107 patients (39.5%) had complications during hospitalization or follow-up. The most common complication was inflammatory polyps, which occurred in 63 patients (23.2%). In addition, 28 (10.3%) experienced gastrointestinal bleeding, 21 (7.7%) demonstrated intestinal obstruction, and 6 (2.2%) had colon perforation. Intestinal obstruction, colon perforation and gastrointestinal bleeding were defined as the serious complications. Moreover, 11 patients (4.1%) went on display malignant transformation and were subsequently diagnosed with CRC. In EIM patients, eight patients (25.8%) developed colorectal stricture, 5 (16.1%) had intestinal obstruction, and 4 (12.9%) had CRC (Table 3).

Comparison of clinical outcomes between UC patients with and without EIM

Clinical outcomes including remission, serious complications (intestinal obstruction or perforation or bleeding), surgery, development of CRC, and death were analyzed in non-EIM group and EIM group. As shown in Table 4, remission was more common in the non-EIM group (n = 127, 52.9%) than in the EIM group (n = 8, 25.8%) (p = 0.004). Patients with EIM had a higher likelihood of developing serious complications than those in the non-EIM group (n = 10, 32.3% vs n = 40, 16.7%, p = 0.035). In addition, patients in the EIM group had a higher risk of developing CRC than those in the non-EIM group (n = 4, 12.9% vs n = 7, 2.9%, p = 0.030). There were no statistical differences between the two groups with regards to cure, disease activity, surgery, or death. Taken together, this result suggested that EIM was closely associated with clinical outcomes in UC.

Risk factors for the development of EIM

Based on the previous results, we determined which risk factors were associated with the development of EIM. The results of univariable analysis showed that the age at diagnosis (p = 0.011), disease duration (p = 0.013), refractory clinical symptoms (p < 0.001), and the presence of moderate or severe anemia (p = 0.024) were all significantly associated with the development of EIM. No significant differences were observed between the EIM group and the non-EIM group in terms of sex, relapse, weight loss, history of surgery, family history, extent of UC, use of steroids and immunomodulators, and the Alb level (Table 5). The results of multivariate logistic analysis demonstrated that a disease duration >5 years (odds ratio (OR), 3.721; 95% CI [1.209–11.456]; p = 0.022), an age at diagnosis >40 years (OR, 2.924, 95% CI [1.165–7.340]; p = 0.022) and refractory clinical symptoms (OR, 4.119; 95% CI [1.758–9.650]; p = 0.001) were associated with the development of EIM. In addition, moderate or severe anemia (OR, 2.592; 95% CI [1.047–6.413]; p = 0.039) was associated with the development of EIM (Table 6).