Crohn’s disease (CD) is a chronic inflammatory bowel disease whose etiology remains unclear. Deep and refractory ulcers frequently develop in the small intestine in CD patients, often causing severe complications, including abdominal abscesses and ileus. Open surgery is sometimes required to relieve the patient’s conditions, including ileus due to severe stricture, refractory abscesses, and fistulas, which lead to a deterioration of the general condition and quality of life in the patients, as well as severe intestinal bleeding [
The present retrospective study investigated factors affecting the interval from the time of diagnosis to the first surgery, including patient demographics, type of disease, and treatment procedures, in CD patients with no history of abdominal surgery.
Written informed consent was obtained from all identified patients, and the study was approved by the institutional review board of Asahikawa Medical University. The clinical records of 104 patients who were diagnosed as having CD at Asahikawa Medical University between February 1982 and October 2011 were retrospectively investigated. The diagnosis of CD was made based on the combination of the clinical course and the colonoscopy, double balloon endoscopy, small bowel enterolysis, and histological findings. Typical lesions of CD, including longitudinal ulcers and a cobblestone appearance in the small and/or large intestine, were observed on endoscopy in all patients. Intestinal strictures, fistula formation, and abdominal abscesses were also observed in the patients. These findings were also referenced for the diagnosis of CD. Data regarding patient demographics, treatments, and operative findings were collected by A.S., who did not participate in the diagnosis, medical examination, or treatment of the patients. The onset of the disease was defined as the time of appearance of symptoms caused by CD. The date of disease onset was used to divide the patients into two groups, those treated before 2001 and those treated after 2002, because infliximab became clinically available in Japan in 2002. Patients who received infliximab four or more times, corticosteroids as remission induction therapy, or immunomodulators for one or more months were classified as belonging to the infliximab-positive, corticosteroid-positive, or immunomodulator-positive groups, respectively. These agents were administered in patients resistant to 5-aminosalicylate treatment and/or those who requested these drugs.
The abdominal surgeries performed in this study included intestinal resection, strictureplasty, colostomy, and ileostomy. The demographic and treatment-related factors were retrospectively compared with the cumulative nonoperative rate until the first surgery. In the patients who did not undergo surgery, the interval from diagnosis to the end of the study was defined as the nonoperative time (March 2012). In the patients who underwent either single or multiple surgeries, the interval from diagnosis to the first surgery was defined as the nonoperative time.
The Kaplan-Meier method was used to test the cumulative nonoperative rates and the data related to each factor were statistically analyzed using the log-rank test. A Cox proportional hazards model was used to calculate the hazard ratios of the factors identified to estimate the frequency of surgery. A
Seventy-one male and 33 female patients were included in this study. Sixty-seven (64%) patients exhibited lesions in both the small and large intestines (ileocolitis type), 28 (27%) patients had lesions in the small intestine only (ileitis type), and nine (9%) patients had lesions in the large intestine only (colitis type). The age at disease onset ranged from 10 to 66 years, with a median of 22 years. The date of disease onset was before 2001 in 74 patients and after 2002 in 30 patients. Corticosteroids, immunomodulators, and infliximab were administered in 33 (32%), 37 (36%), and 39 (38%) of the patients before the first surgery, respectively. A total of 16 of the 74 patients who had disease onset before 2001 and 23 of the 30 patients who had disease onset after 2002 took infliximab. Sixty-nine patients (66%) underwent one or more surgeries (Table
Patient demographics and treatments (104 cases).
Number of patients |
|
---|---|
Sex | |
Male | 71 (68%) |
Female | 33 (32%) |
Type of disease | |
Ileitis | 28 (27%) |
Ileocolitis | 67 (64%) |
Colitis | 9 (9%) |
The age of onset | |
Median | 22 |
Range | 10–66 |
The history of corticosteroid use until the first operation | |
(+) | 33 (32%) |
(−) | 71 (68%) |
The history of immunomodulator use until the first operation | |
(+) | 37 (36%) |
(−) | 67 (64%) |
The history of infliximab use until the first operation | |
(+) | 39 (38%) |
(−) | 65 (62%) |
The history of enteral nutrition | |
(+) | 96 (92%) |
(−) | 8 (8%) |
Bowel surgery | |
(+) | 69 (66%) |
(−) | 35 (34%) |
Surgical procedures performed in 69 patients with Crohn’s disease (total: 134 operations).
Total of 134 operations | |
---|---|
Bowel resection | 76 |
Strictureplasty | 10 |
Colostomy or ileostomy | 6 |
Bowel resection and strictureplasty | 27 |
Bowel resection and colostomy (or ileostomy) | 13 |
Strictureplasty and colostomy (or ileostomy) | 1 |
Bowel resection and strictureplasty and colostomy (or ileostomy) | 1 |
The cumulative nonoperative rate among all 104 patients is shown in Figure
Factors associated with the nonoperative rate until the first surgery (univariate analysis).
Number of patients |
50% nonoperation time (months) |
| |
---|---|---|---|
Sex | |||
Male | 71 | 84 | <0.05 |
Female | 33 | 142 | |
Type of disease | |||
Ileitis/ileocolitis | 95 | 98 | <0.05 |
Colitis | 9 | Undefined | |
The age of onset | |||
Less than 20 | 39 | 117 | N.S. |
20 or more | 65 | 98 | |
The date of onset | |||
Before 2001 | 74 | 107 | N.S |
After 2002 | 30 | Undefined | |
Corticosteroid | |||
(+) | 33 | 126 | <0.05 |
(−) | 71 | 91 | |
Immunomodulator | |||
(+) | 37 | 169 | <0.05 |
(−) | 67 | 84 | |
Infliximab | |||
(+) | 39 | 256 | <0.05 |
(−) | 65 | 78 |
Undefined: nonoperation time is greater than 50% at the last time point. N.S.: not significant.
Factors associated with the nonoperative rate until the first surgery (multivariate analysis).
Hazard ratio | 95% CI | ||
---|---|---|---|
Sex | Female | 0.605 | 0.339–1.081 |
Type of disease | Colitis | 0.086 | 0.011–0.657 |
Corticosteroid | (+) | 0.912 | 0.519–1.604 |
Immunomodulator | (+) | 1.057 | 0.569–1.966 |
Infliximab | (+) | 0.256 | 0.122–0.540 |
The cumulative nonoperative rate among all 104 patients. The nonoperative rate was inversely proportional to the duration of the disease.
The results of a univariate analysis of the cumulative nonoperative rate based on the presence or absence of infliximab treatment. The univariate analysis revealed that the administration of infliximab is a factor estimated to improve the cumulative nonoperative rate.
The present study showed that the administration of infliximab extends the duration until the first surgery in CD patients who have not previously undergone abdominal surgery. This suggests that the administration of infliximab is useful in CD patients with no experience with abdominal surgery. While the usefulness of biological drugs for inducing and maintaining remission of CD and extending the duration from the first to the second surgery has been established [
Although the present study demonstrated the efficacy of infliximab treatment, the period of disease onset may have influenced the duration from disease onset to the first surgery. After 2002, the availability of infliximab treatment is not the only factor that changed from the previous era. The types and characteristics of microorganisms causing infectious colitis and the eating habits and lifestyle factors affecting the pathology of inflammatory diseases have been changed over the past two decades in Japan. Therefore, the present study investigated the influence of the date of disease onset on the duration until the first surgery, the results of which showed that the date of disease onset is not a significant factor affecting the duration until the first surgery in CD patients. An evaluation of the Nationwide Inpatient Sample conducted in the US concluded that, during the period of adoption of infliximab as a novel CD treatment, the overall rate of bowel resection either remained relatively stable or moderately decreased [
In this study, while the univariate analysis revealed that the administration of corticosteroids and immunomodulators affected the duration until the first surgery, the multivariate analysis did not identify these treatments to be independent factors. Therefore, these therapies are not very useful for treating CD patients with no history of abdominal surgery in comparison to the administration of infliximab. The administration of corticosteroids has been shown to be effective for inducing remission in patients with CD [
In summary, the results of the present study suggest that infliximab treatment has the potential to extend the duration until the first surgery. This implies that the administration of infliximab in CD patients with no history of abdominal surgery, even in CD patients with no experience with abdominal surgery, can improve the outcomes, including the cumulative nonoperative rate. Further randomized, controlled trials are needed to establish the appropriate timing of the initiation of infliximab treatment and determine the optimal dose, schedule, and duration of the administration of these biological drugs.
The authors declare that they have no conflict of interests.
Aki Sakatani and Mikihiro Fujiya contributed equally to this study.