Scandinavian Journal of Gastroenterology. 2014; 49: 177–183
ORIGINAL ARTICLE
Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
Proximal disease extension and related predicting factors in ulcerative proctitis
BUN KIM, SOO JUNG PARK, SUNG PIL HONG, TAE IL KIM, WON HO KIM & JAE HEE CHEON Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
Abstract Objective. Ulcerative colitis usually involves the rectum, may extend in a proximal and continuous fashion to involve varying portions of the bowel. However, the risk factors predictive of proximal extension have yet to be determined. The aim of this study was to evaluate both the natural course of disease and the risk factors influencing the proximal disease extension in ulcerative proctitis. Material and methods. We retrospectively analyzed 98 patients with ulcerative proctitis at the time of diagnosis who were regularly followed and underwent sigmoidoscopy or colonoscopy between January 2000 and December 2007. Results. The mean duration of follow-up was 109.2 ± 49.5 months. A total of 27 (27.6%) patients experienced proximal disease extension. Mayo scores were significantly higher in the extension group compared with patients whose ulcerative proctitis did not extend proximally (p < 0.001). Corticosteroid use at initial diagnosis was also more frequent in the extension group (p = 0.026). In addition, chronic, continuous disease activation within 6 months of the initial diagnosis was significantly higher in the extension group (p < 0.001), as was disease relapse and the number of hospitalizations over the entire follow-up period (p < 0.001 and p = 0.002). According to multivariate analysis, disease extension after the initial diagnosis was associated with chronic disease activation, disease relapse and hospitalization (p = 0.030, p = 0.042 and p = 0.044, respectively). Conclusion. Increased severity of disease upon diagnosis of ulcerative proctitis was associated with a higher probability of proximal disease extension during the follow-up period. Moreover, those with disease extension were more likely to experience relapse and to be hospitalized, indicating poor prognosis.
Key Words: disease extension, proctitis, progression, ulcerative colitis
Introduction Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) of unknown etiology that mostly affects the young and middle aged. As a chronic disease, UC is commanding focus due to its implications for quality of life and social cost [1,2]. UC typically involves the rectum, may extend in a proximal and continuous fashion to involve varying portions of the bowel, and thereby, results in diverse clinical outcomes. The presentation of UC can range from quiescent disease to chronic refractory disease, leading to surgery or complications such as cancer or death [3,4]. Because of the potentially serious and
unpredictable course of UC, efforts to determine long-term clinical outcomes and factors predictive of relapse have been underway [5]. The ability to better identify early risk factors that influence the natural presentation of the disease is important for therapies and for providing good prognostic information. Often, UC initially presents in the rectum or anus, which, at this stage, can be classified as ulcerative proctitis. In the majority of patients presenting with proctitis, the disease remains stable with restricted colonic involvement. However, some patients with ulcerative proctitis might experience proximal disease extension into the colon. Patients with extensive
Correspondence: Jae Hee Cheon, MD PhD, Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea. Tel: +82 2 2228 1990. Fax: +82 2 393 6884. E-mail: [email protected]
(Received 3 October 2013; revised 12 November 2013; accepted 13 November 2013) ISSN 0036-5521 print/ISSN 1502-7708 online 2014 Informa Healthcare DOI: 10.3109/00365521.2013.867360
178
B. Kim et al.
Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
colitis have more frequent complications, extraintestinal manifestations and systemic symptoms, need more immunosuppressive and surgical therapies and have greater cancer risk [3]. Because disease extent progression directly influences severity of UC, identifying the risk factors predictive of proximal extension is essential. Therefore, in this study, we sought to observe the natural course of disease in patients with ulcerative proctitis, and also sought to explore the incidence of and the risk factors for proximal disease extension. Methods Patients Initially, a total of 457 patients who were diagnosed with UC after undergoing sigmoidoscopy or colonoscopy were recruited from January 2000 to December 2007. Patients were diagnosed and regularly followed for at least 1 year at Severance Hospital, Seoul, Korea. Among them, 354 were excluded because their disease involvement was proximal to the rectum at initial diagnosis. Additionally, five more were excluded due to having a follow-up period of less than 12 months. As a result, 98 total patients were included in this study. Study design This is a retrospective data analysis study based on medical records. Patient-related factors such as age, sex, smoking history, family history and comorbidities were investigated. Laboratory measures such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, hemoglobin level and the presence or absence of perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA) were collected as indicators of the presence of UC or as measures of UC activity level. Medications at diagnosis and surgical history were also investigated. Evaluation of proximal disease extension, chronic disease activation and prognosis The indications for endoscopy in UC at our clinic are as follows: 1) at initial diagnosis, 2) every 3 years as follow-up in asymptomatic patients regardless of disease duration, 3) every 1–3 years for the surveillance of dysplasia and colorectal cancer in patients with long-standing extensive UC (greater than 10 years in duration) and 4) at any time symptoms worsen or new symptoms occur. The assessment of disease extension during all colonoscopies was based on biopsies taken serially from the cecum, ascending colon, transverse colon, descending colon, sigmoid
colon and rectum. Patients were included in the study after completing a follow-up period of at least 1 year. The state of disease was characterized as “chronic active” when the disease continued to be active for at least 6 months or more despite adequate treatment according to a standardized treatment protocol [6], which include both persistent disease activation poorly responsive to therapy and poor drug adherence. To evaluate UC disease activity, the Mayo score and partial Mayo score were used [7–10]. The Mayo score consists of four components: stool frequency, rectal bleeding, endoscopy findings and the physician’s global assessment. Each component is assigned a score of 0–3 with the total score ranging from 0 to 12. A higher score indicates more severe disease. Clinical remission in UC is defined as a Mayo score of £3. The partial Mayo score consists of the three previously listed components of the Mayo score, but it excludes endoscopic findings. Therefore, the total score ranges from 0 to 9, and clinical remission in UC is defined as a partial Mayo score of £2. We also classified prognosis of ulcerative proctitis; indicators of poor prognosis were disease relapse, frequency of relapse and hospitalization due to UC. Statistical analysis Continuous variables were expressed as the mean ± standard deviation (SD). Baseline characteristics of the non-extension group and the extension group were compared using a Student’s t-test for continuous variables and a chi-square test (or Fisher’s exact test) for categorical variables. The Kaplan–Meier method was used to estimate the distribution of the time from diagnosis to proximal disease extension according to independent variables. We also used Cox proportional hazards modeling to control for multiple risk factors shown to influence disease extension in ulcerative proctitis by using univariate analysis to compute 95% confidence intervals (CIs). Results were considered statistically significant when p < 0.05. All statistical analyses were performed using SPSS version 18.0 (SPSS, Inc., Chicago, IL, USA). Results Patient characteristics A total of 98 patients with ulcerative proctitis were selected by reviewing medical records from our internal electronic database system. The baseline characteristics at diagnosis are as follows. The mean age was 38.1 ± 13.2 years, and 50% of the patients were male. Among them, 47 (45.9%) had a history of smoking, including former smokers (n = 37) and current smokers (n = 6).
Proximal disease extension in ulcerative proctitis
179
Table I. Comparison of baseline characteristics at diagnosis organized by proximal disease extension.
Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
Non-extension group n = 71
Extension group n = 27
p-Value
Age (mean, age) Sex male/female Smoking former/current Family history of IBD Mayo score (0 ~ 12) Partial Mayo score (0 ~ 9) Endoscopic score (0 ~ 3) Extraintestinal manifestations
37.7 34 21 6 3.9 2.8 1.1 25
± 12.5 (47.9%)/37 (52.1%) (32.3%)/3 (4.6%) (8.5%) ± 0.8 ± 0.7 ± 0.4 (35.2%)
38.9 15 10 1 4.7 3.4 1.4 11
± 15.3 (55.6%)/12 (44.4%) (40.0%)/3 (12.0%) (3.7%) ± 1.2 ± 0.9 ± 0.6 (40.7%)
0.699 0.498 0.125 0.670 0.001 0.001 0.012 0.275
Laboratory data ESR (mm/h) (n = 60) CRP (mg/l) (n = 57) Hb (g/dl) (n = 68) P-ANCA + (n = 67)
13.0 2.0 13.8 8
± 12.2 ± 1.6 ± 1.6 (17.4%)
16.1 7.6 14.0 7
± 13.4 ± 22.5 ± 1.4 (33.3%)
0.381 0.333 0.642 0.207
2 (7.4%) 2 (7.4%) 3 (11.1%)
1.000 0.666 0.681
Comorbidity Hypertension Diabetes Pulmonary disease Medications No treatment Topical 5-ASA therapy 5-ASA oral 5-ASA oral + topical 5-ASA + prednisolone topical 5-ASA + prednisolone oral ± topical Initial corticosteroid use
5 (7.0%) 4 (5.6%) 5 (7.0%)
0 25 6 33 1 6 7
(0.0%) (35.2%) (8.5%) (46.5%) (1.4%) (8.5%) (9.9%)
1 4 1 13 2 6 8
(3.7%) (14.8%) (3.7%) (48.1%) (7.4%) (22.2%) (29.6%)
0.045
0.026
Abbreviations: 5-ASA = 5-aminosalicylic acid; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; Hb = Hemoglobin; IBD = inflammatory bowel disease; P-ANCA = perinuclear anti-neutrophil cytoplasmic antibodies. Variables are expressed as mean ± SD or n (%).
Seven (7.1%) patients had a family history of IBD. The mean value of the Mayo score (0–12), partial Mayo score (0–9) and endoscopic score (0–3) at the time of diagnosis was 4.1 ± 0.9, 3.0 ± 0.8 and 1.2 ± 0.5, respectively. Extraintestinal symptoms including eye involvement (uveitis and episcleritis), skin involvement (erythema nodosum and pyoderma gangrenosum), arthritis, sclerosing cholangitis, lung disease and venous and arterial thromboembolism, were found in
36 patients (36.7%). The mean values of ESR, CRP level and hemoglobin level were 13.9 ± 12.5 mm/h, 3.6 ± 12.5 mg/l and 13.9 ± 1.5 mg/dl, respectively. PANCA was positive in 15 patients (22.4%). At initial diagnosis, the majority of patients who were on medication were using a combination of topical and systemic 5-aminosalicylic acids (5-ASA) (n = 46, 46.9%). The clinical characteristics measured during the follow-up period are as follows. The mean duration
Table II. Comparison of clinical characteristics during the follow-up period by proximal disease extension.
Surgical operation Appendectomy Total colectomy Chronic disease activation (‡6 months) Relapse (at least 1 attack) Frequency of relapse Duration of disease (month) Duration of follow-up (month) Duration until disease extension (month) Hospitalization due to UC relapse Duration until hospitalization (month) Abbreviation: UC = ulcerative colitis. Variables are expressed as mean ± SD or n (%).
Non-extension group n = 71
Extension group n = 27
8 (11.1%) 0 8 (11.3%) 18 (25.4%) 1.2 ± 0.4 116.6 ± 57.0 104.8 ± 50.0 1 (1.4%) 116
1 (3.7%) 1 (3.7%) 12 (46.2%) 23 (85.2%) 1.9 ± 1.0 129.8 ± 47.4 120.7 ± 47.0 52.8 ± 43.6 6 (22.2%) 46.0 ± 18.8
p-Value
ORIGINAL ARTICLE
Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
Proximal disease extension and related predicting factors in ulcerative proctitis
BUN KIM, SOO JUNG PARK, SUNG PIL HONG, TAE IL KIM, WON HO KIM & JAE HEE CHEON Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
Abstract Objective. Ulcerative colitis usually involves the rectum, may extend in a proximal and continuous fashion to involve varying portions of the bowel. However, the risk factors predictive of proximal extension have yet to be determined. The aim of this study was to evaluate both the natural course of disease and the risk factors influencing the proximal disease extension in ulcerative proctitis. Material and methods. We retrospectively analyzed 98 patients with ulcerative proctitis at the time of diagnosis who were regularly followed and underwent sigmoidoscopy or colonoscopy between January 2000 and December 2007. Results. The mean duration of follow-up was 109.2 ± 49.5 months. A total of 27 (27.6%) patients experienced proximal disease extension. Mayo scores were significantly higher in the extension group compared with patients whose ulcerative proctitis did not extend proximally (p < 0.001). Corticosteroid use at initial diagnosis was also more frequent in the extension group (p = 0.026). In addition, chronic, continuous disease activation within 6 months of the initial diagnosis was significantly higher in the extension group (p < 0.001), as was disease relapse and the number of hospitalizations over the entire follow-up period (p < 0.001 and p = 0.002). According to multivariate analysis, disease extension after the initial diagnosis was associated with chronic disease activation, disease relapse and hospitalization (p = 0.030, p = 0.042 and p = 0.044, respectively). Conclusion. Increased severity of disease upon diagnosis of ulcerative proctitis was associated with a higher probability of proximal disease extension during the follow-up period. Moreover, those with disease extension were more likely to experience relapse and to be hospitalized, indicating poor prognosis.
Key Words: disease extension, proctitis, progression, ulcerative colitis
Introduction Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) of unknown etiology that mostly affects the young and middle aged. As a chronic disease, UC is commanding focus due to its implications for quality of life and social cost [1,2]. UC typically involves the rectum, may extend in a proximal and continuous fashion to involve varying portions of the bowel, and thereby, results in diverse clinical outcomes. The presentation of UC can range from quiescent disease to chronic refractory disease, leading to surgery or complications such as cancer or death [3,4]. Because of the potentially serious and
unpredictable course of UC, efforts to determine long-term clinical outcomes and factors predictive of relapse have been underway [5]. The ability to better identify early risk factors that influence the natural presentation of the disease is important for therapies and for providing good prognostic information. Often, UC initially presents in the rectum or anus, which, at this stage, can be classified as ulcerative proctitis. In the majority of patients presenting with proctitis, the disease remains stable with restricted colonic involvement. However, some patients with ulcerative proctitis might experience proximal disease extension into the colon. Patients with extensive
Correspondence: Jae Hee Cheon, MD PhD, Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea. Tel: +82 2 2228 1990. Fax: +82 2 393 6884. E-mail: [email protected]
(Received 3 October 2013; revised 12 November 2013; accepted 13 November 2013) ISSN 0036-5521 print/ISSN 1502-7708 online 2014 Informa Healthcare DOI: 10.3109/00365521.2013.867360
178
B. Kim et al.
Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
colitis have more frequent complications, extraintestinal manifestations and systemic symptoms, need more immunosuppressive and surgical therapies and have greater cancer risk [3]. Because disease extent progression directly influences severity of UC, identifying the risk factors predictive of proximal extension is essential. Therefore, in this study, we sought to observe the natural course of disease in patients with ulcerative proctitis, and also sought to explore the incidence of and the risk factors for proximal disease extension. Methods Patients Initially, a total of 457 patients who were diagnosed with UC after undergoing sigmoidoscopy or colonoscopy were recruited from January 2000 to December 2007. Patients were diagnosed and regularly followed for at least 1 year at Severance Hospital, Seoul, Korea. Among them, 354 were excluded because their disease involvement was proximal to the rectum at initial diagnosis. Additionally, five more were excluded due to having a follow-up period of less than 12 months. As a result, 98 total patients were included in this study. Study design This is a retrospective data analysis study based on medical records. Patient-related factors such as age, sex, smoking history, family history and comorbidities were investigated. Laboratory measures such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, hemoglobin level and the presence or absence of perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA) were collected as indicators of the presence of UC or as measures of UC activity level. Medications at diagnosis and surgical history were also investigated. Evaluation of proximal disease extension, chronic disease activation and prognosis The indications for endoscopy in UC at our clinic are as follows: 1) at initial diagnosis, 2) every 3 years as follow-up in asymptomatic patients regardless of disease duration, 3) every 1–3 years for the surveillance of dysplasia and colorectal cancer in patients with long-standing extensive UC (greater than 10 years in duration) and 4) at any time symptoms worsen or new symptoms occur. The assessment of disease extension during all colonoscopies was based on biopsies taken serially from the cecum, ascending colon, transverse colon, descending colon, sigmoid
colon and rectum. Patients were included in the study after completing a follow-up period of at least 1 year. The state of disease was characterized as “chronic active” when the disease continued to be active for at least 6 months or more despite adequate treatment according to a standardized treatment protocol [6], which include both persistent disease activation poorly responsive to therapy and poor drug adherence. To evaluate UC disease activity, the Mayo score and partial Mayo score were used [7–10]. The Mayo score consists of four components: stool frequency, rectal bleeding, endoscopy findings and the physician’s global assessment. Each component is assigned a score of 0–3 with the total score ranging from 0 to 12. A higher score indicates more severe disease. Clinical remission in UC is defined as a Mayo score of £3. The partial Mayo score consists of the three previously listed components of the Mayo score, but it excludes endoscopic findings. Therefore, the total score ranges from 0 to 9, and clinical remission in UC is defined as a partial Mayo score of £2. We also classified prognosis of ulcerative proctitis; indicators of poor prognosis were disease relapse, frequency of relapse and hospitalization due to UC. Statistical analysis Continuous variables were expressed as the mean ± standard deviation (SD). Baseline characteristics of the non-extension group and the extension group were compared using a Student’s t-test for continuous variables and a chi-square test (or Fisher’s exact test) for categorical variables. The Kaplan–Meier method was used to estimate the distribution of the time from diagnosis to proximal disease extension according to independent variables. We also used Cox proportional hazards modeling to control for multiple risk factors shown to influence disease extension in ulcerative proctitis by using univariate analysis to compute 95% confidence intervals (CIs). Results were considered statistically significant when p < 0.05. All statistical analyses were performed using SPSS version 18.0 (SPSS, Inc., Chicago, IL, USA). Results Patient characteristics A total of 98 patients with ulcerative proctitis were selected by reviewing medical records from our internal electronic database system. The baseline characteristics at diagnosis are as follows. The mean age was 38.1 ± 13.2 years, and 50% of the patients were male. Among them, 47 (45.9%) had a history of smoking, including former smokers (n = 37) and current smokers (n = 6).
Proximal disease extension in ulcerative proctitis
179
Table I. Comparison of baseline characteristics at diagnosis organized by proximal disease extension.
Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 06/10/15 For personal use only.
Non-extension group n = 71
Extension group n = 27
p-Value
Age (mean, age) Sex male/female Smoking former/current Family history of IBD Mayo score (0 ~ 12) Partial Mayo score (0 ~ 9) Endoscopic score (0 ~ 3) Extraintestinal manifestations
37.7 34 21 6 3.9 2.8 1.1 25
± 12.5 (47.9%)/37 (52.1%) (32.3%)/3 (4.6%) (8.5%) ± 0.8 ± 0.7 ± 0.4 (35.2%)
38.9 15 10 1 4.7 3.4 1.4 11
± 15.3 (55.6%)/12 (44.4%) (40.0%)/3 (12.0%) (3.7%) ± 1.2 ± 0.9 ± 0.6 (40.7%)
0.699 0.498 0.125 0.670 0.001 0.001 0.012 0.275
Laboratory data ESR (mm/h) (n = 60) CRP (mg/l) (n = 57) Hb (g/dl) (n = 68) P-ANCA + (n = 67)
13.0 2.0 13.8 8
± 12.2 ± 1.6 ± 1.6 (17.4%)
16.1 7.6 14.0 7
± 13.4 ± 22.5 ± 1.4 (33.3%)
0.381 0.333 0.642 0.207
2 (7.4%) 2 (7.4%) 3 (11.1%)
1.000 0.666 0.681
Comorbidity Hypertension Diabetes Pulmonary disease Medications No treatment Topical 5-ASA therapy 5-ASA oral 5-ASA oral + topical 5-ASA + prednisolone topical 5-ASA + prednisolone oral ± topical Initial corticosteroid use
5 (7.0%) 4 (5.6%) 5 (7.0%)
0 25 6 33 1 6 7
(0.0%) (35.2%) (8.5%) (46.5%) (1.4%) (8.5%) (9.9%)
1 4 1 13 2 6 8
(3.7%) (14.8%) (3.7%) (48.1%) (7.4%) (22.2%) (29.6%)
0.045
0.026
Abbreviations: 5-ASA = 5-aminosalicylic acid; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; Hb = Hemoglobin; IBD = inflammatory bowel disease; P-ANCA = perinuclear anti-neutrophil cytoplasmic antibodies. Variables are expressed as mean ± SD or n (%).
Seven (7.1%) patients had a family history of IBD. The mean value of the Mayo score (0–12), partial Mayo score (0–9) and endoscopic score (0–3) at the time of diagnosis was 4.1 ± 0.9, 3.0 ± 0.8 and 1.2 ± 0.5, respectively. Extraintestinal symptoms including eye involvement (uveitis and episcleritis), skin involvement (erythema nodosum and pyoderma gangrenosum), arthritis, sclerosing cholangitis, lung disease and venous and arterial thromboembolism, were found in
36 patients (36.7%). The mean values of ESR, CRP level and hemoglobin level were 13.9 ± 12.5 mm/h, 3.6 ± 12.5 mg/l and 13.9 ± 1.5 mg/dl, respectively. PANCA was positive in 15 patients (22.4%). At initial diagnosis, the majority of patients who were on medication were using a combination of topical and systemic 5-aminosalicylic acids (5-ASA) (n = 46, 46.9%). The clinical characteristics measured during the follow-up period are as follows. The mean duration
Table II. Comparison of clinical characteristics during the follow-up period by proximal disease extension.
Surgical operation Appendectomy Total colectomy Chronic disease activation (‡6 months) Relapse (at least 1 attack) Frequency of relapse Duration of disease (month) Duration of follow-up (month) Duration until disease extension (month) Hospitalization due to UC relapse Duration until hospitalization (month) Abbreviation: UC = ulcerative colitis. Variables are expressed as mean ± SD or n (%).
Non-extension group n = 71
Extension group n = 27
8 (11.1%) 0 8 (11.3%) 18 (25.4%) 1.2 ± 0.4 116.6 ± 57.0 104.8 ± 50.0 1 (1.4%) 116
1 (3.7%) 1 (3.7%) 12 (46.2%) 23 (85.2%) 1.9 ± 1.0 129.8 ± 47.4 120.7 ± 47.0 52.8 ± 43.6 6 (22.2%) 46.0 ± 18.8
p-Value
