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| ORIGINAL ARTICLE |
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| Year : 2021 | Volume
: 5
| Issue : 2 | Page : 42-48 |
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Predictors of clinical relapse in patients with new-onset inflammatory bowel disease: A retrospective single-center study
Hao Wu, Delin Tian, Hao Cai, Renjie Gong, Kaixiao Kun, Can-Xia Xu
Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha, China
| Date of Submission | 08-Dec-2020 |
| Date of Acceptance | 16-Mar-2021 |
| Date of Web Publication | 23-Jul-2021 |
Correspondence Address:
Prof. Can-Xia Xu
No. 138 Tongzipo Road, Changsha 410013, Hunan Province
China
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/LJMS.LJMS_106_20
Background and Aims: Inflammatory bowel disease (IBD) usually follows a pattern of more or less frequent relapses of alterable duration, interspersed with periods of remission. Various clinical predictors have been broadly studied, but the research study populations reported are mostly from Western countries. Methods: From January 2013 to December 2018, 106 new-onset Crohn's disease (CD) patients and 76 new-onset ulcerative colitis (UC) patients were followed up for a median of 12 months or until relapse. The predictors of clinical relapse were analyzed according to demographic, clinical, histological, endoscopic, and imaging variables. Results: In multivariate analysis, predictors of relapse were age of onset <35 years (hazard ratio [HR] = 5.236; 95% confidence interval [CI] 1.252–22.222; P = 0.023) in CD patients and poor medication adherence (HR = 2.070; 95% CI 1.018–4.202; P = 0.044) in UC patients. Conclusion: Younger age of onset and poor medication adherence increases the risk of clinical relapse in CD and UC, respectively.
Keywords: Age of onset, inflammatory bowel disease, medication adherence, relapse
How to cite this article:
Wu H, Tian D, Cai H, Gong R, Kun K, Xu CX. Predictors of clinical relapse in patients with new-onset inflammatory bowel disease: A retrospective single-center study. Libyan J Med Sci 2021;5:42-8 |
How to cite this URL:
Wu H, Tian D, Cai H, Gong R, Kun K, Xu CX. Predictors of clinical relapse in patients with new-onset inflammatory bowel disease: A retrospective single-center study. Libyan J Med Sci [serial online] 2021 [cited 2023 Mar 27];5:42-8. Available from: https://www.ljmsonline.com/text.asp?2021/5/2/42/322196 |
| Introduction | |  |
Inflammatory bowel disease (IBD) includes Crohn's disease (CD) and ulcerative colitis (UC), chronic diseases that generally last throughout life. The treatment goals in IBD are to alleviate symptoms, maintain symptom remission, promote endoscopic healing, achieve histological healing and improve long-term quality of life.[1] IBD follows a pattern, with variable numbers of relapses of variable duration, interspersed with remission periods. Some patients experience long-lasting remission under treatment, while others face far-reaching negative consequences. There is much research into clinical, histological, endoscopic, imaging, and genetic predictors of course-of-disease in IBD.[2],[3],[4],[5],[6]
IBD has become a global disease, with accelerating incidence in newly industrialized continents such as Africa, Asia, and South America.[7] According to previous studies, phenotypic variances exist between Caucasians with IBD and Asians.[8] There is little research into distinct pathways of disease progression in Asian IBD populations.[9],[10],[11] Identifying new-onset IBD patients at high risk of future relapse would be useful to determine the strategy for initial and maintenance medical treatments. Novel therapeutic strategies able to change the natural history of the disease are also required. In the immediate future, disease management will mostly rely on severity scoring that couples with prognostic factors and non-invasive close monitoring of disease activity to reduce the severity of complications.[12]
The goals of this study were to identify clinical predictors in new-onset Asian IBD patients that are helpful in targeting those who would benefit most from monitoring and prophylaxis.
| Methods | | |
Study population
From January 2013 to December 2018, 218 inpatients were diagnosed with CD and 123 inpatients were diagnosed with UC. Among these, we collected medical records of 122 patients initially treated for CD and 80 patients initially treated for UC. Finally, 106 patients with CD and 76 patients with UC that had complete medical records for clinical, histological, endoscopic, and imaging assessments, were included in the analysis [Figure 1].
Data collection
All clinical variables in the patients were obtained from the electronic medical record system. General clinical data collected in this study included age, age of onset, gender, smoking status, drinking status, and educational status. Laboratory results were collected on the first day after admission and included routine blood counts, erythrocyte sedimentation rate, C-reactive protein, and fibrinogen. The activity of the disease was assessed using the CD activity index (CDAI) for CD patients and the modified Mayo score for UC patients. The Montreal classification of disease extent and illness behaviors, endoscopic manifestations, computed tomography (CT) findings, pathological data, complications, and therapies were also obtained. Patients who stopped taking medications independently or with irregular medication were considered to be the poor medication adherence group. Complete medical records were reviewed by two independent investigators using standardized criteria. Where necessary, medical records were reviewed by the other members of the investigative team; divergent opinions were resolved by consensus.
Follow-up
All patients were followed up until February 2019. The median follow-up time was 12 months (interquartile range 6–24 months). The follow-up data mainly included clinical manifestations, endoscopic findings, laboratory examination, and medication adherence, to evaluate relapses of the disease. Clinical relapse was defined as an exacerbation of symptoms with a partial Mayo score ≥3 in UC patients and CDAI score ≥150 in CD patients, or modification of treatment accompanied by worsening of symptoms. All patients received the relevant follow-up. The overall remission period was recorded from clinical remission after therapy to the last date without relapse. To reduce follow-up bias, two researchers completed the work independently.
Statistical analysis
Data are presented as numbers and percentages or medians and interquartile range. Survival curves were constructed using the Kaplan–Meier method and statistical differences were calculated by the log-rank test. A criterion of P < 0.10 was used to identify candidate predictors. If a candidate factor at P < 0.10 was found by univariate analysis, further calculation using the multivariate Cox's model to eliminate nonsignificant variables was performed. All statistical analyses were performed using SPSS Statistics 25.0 software (IBM Corporation, Armonk, NY, United States). Survival curves were replotted with Graphpad prism 8.0 software (Graphpad Inc., La Jolla, United States). P < 0.05 was considered statistically significant, and variables pertaining to accuracy were calculated with 95% confidence intervals.
Ethical aspects
The study was approved by the Ethics Committee and performed in accordance with the Declaration of Helsinki and Good Clinical Practice. No written informed consent was obtained due to the retrospective nature of the study.
| Results | | |
Patient demographics and characteristics
The demographics and baseline clinical characteristics of the 106 CD patients and 76 UC patients are shown in [Table 1]. According to CDAI scores, there were 12 (11.32%) patients with CDAI scores of <150, 52 (49.06%) with CDAI scores of 150–220, 37 (34.91%) with CDAI 221–450 and 5 (4.71%) with CDAI >450. The endoscopic manifestations of CD patients indicated that 35 (33.02%) had polypoid lesions, 68 (64.15%) had segmental lesions and 16 (15.09%) had a cobblestone appearance. The CT findings of CD patients revealed that 90 (96.77%) had mural hyperenhancement, 92 (98.92%) had mural thickening, 32 (34.41%) had comb sign (vasa recta engorgement) and 31 (28.97%) had increased mesenteric fat attenuation. There were 14 (18.42%) UC patients with Mayo scores of 3–5, 37 (48.68%) with Mayo scores of 6–10 and 25 (32.90%) with Mayo scores of 11–12. The endoscopic manifestations of UC patients revealed that 28 (36.84%) had polypoid lesions and 66 (86.84%) had widespread erosion.
Effect of age of onset on the overall remission rate in Crohn's disease
At the end of follow-up, 36 (33.96%) CD patients had suffered clinical relapse on the basis of CDAI scores, under maintenance therapy. Kaplan–Meier analysis indicated that the incidence of clinical relapse in CD patients with age of onset <35 years was significantly higher (log-rank test, P = 0.023) than that in patients with age of onset ≥35 years [Figure 2]. The incidence of clinical relapse in CD patients with FIB >4 g/L (log-rank test, P = 0.027) was significantly lower than that in patients with FIB ≤4 g/L. Multivariate analysis demonstrated that age of onset <35 years was an independent risk factor for clinical relapse in CD patients [P = 0.023; [Table 2]]. | Figure 2: Effect of age of onset on overall remission rate in Crohn's disease
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 | Table 2: Univariate and multivariate analyses of risk factors for clinical relapse of Crohn's disease
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Effect of medication adherence on the overall remission rate in ulcerative colitis
In this cohort, 36 (47.37%) UC patients suffered clinical relapse according to Mayo scores, under maintenance therapy. Kaplan–Meier analysis revealed that the incidence of clinical relapse in UC patients with pancolitis was significantly higher (log-rank test, P = 0.025) than that in patients with nonpancolitis. The incidence of clinical relapse in UC patients under glucocorticoid (GC) therapy was significantly higher (log-rank test, P = 0.035) than that in patients without GC therapy and the incidence of clinical relapse in UC patients with good medication adherence was significantly lower (log-rank test, P = 0.027) than that in patients with poor medication adherence [Figure 3]. Subsequent multivariate analysis demonstrated that poor medication adherence was an independent risk factor for clinical relapse in UC patients [P = 0.044; [Table 3]]. | Figure 3: Effect of medication adherence on overall remission rate in ulcerative colitis
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 | Table 3: Univariate and multivariate analyses of risk factors for clinical relapse of ulcerative colitis
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| Discussion | | |
In this retrospective study, we identified younger age at onset and poor medication adherence as independent predictors for future clinical relapse in IBD. Age of onset <35 years CD patients have a higher risk of clinical relapse than the age of onset ≥35 years patients-the hazard ratio (HR) was 5.236 (95% confidence interval [CI], 1.252–22.222). There are various disease courses associated with a young age at diagnosis, such as disease recurrence, need for surgery, more frequent extensive disease, colorectal neoplasia, intestinal failure and increased mortality.[13],[14] In our study, age of onset is 3–4 years earlier than the age at diagnosis in IBD patients. Diagnostic delay is common in IBD, due to nonspecific clinical manifestations and variable phenotypes. Several studies have shown that initiation of more intensive treatment early in the course of the disease can result in better outcomes.[15],[16] We also analyzed gender, smoking, and drinking, but these were not found to predict clinical relapse. Gender differences as a prediction of disease course appear controversial. There is a body of research suggesting that gender is not a prognostic factor for disease course,[17],[18] while some studies indicate that male gender is associated with a higher risk of postoperative endoscopic recurrence.[19] In western countries, smoking has been identified as a modifiable risk factor for CD and is also strongly positively associated with CD onset and worse course of disease.[20],[21] Interestingly, there are a few small sample studies indicating that smoking has a protective effect in UC, emphasizing that severity of disease increases after smoking cessation.[22] This is refuted by a nationwide population-based study which established that smoking cessation is not associated with worsened disease course and UC patients should be counseled against smoking.[23] Even though alcohol intake may not increase the incidence of IBD, it is associated with a higher frequency of relapse and worsening of GI symptoms, including abdominal pain, reflux, and diarrhea, in IBD patients.[24],[25]
In addition, our study reports that fibrinogen (FIB) >4 g/L at diagnosis has a protective effect in CD relapse (HR 0.455, 95% CI 0.228–0.91); however, this protective effect was not confirmed by a multivariate analysis of risk factors. Growing evidence exists that IBD is characterized by a hypercoagulable state and prothrombotic conditions.[26],[27] Elevations in FIB levels are associated with an increased risk of thrombosis. FIB can also contribute to inflammation and is considered an acute phase reactant, increased in inflammatory conditions. Whether or not FIB levels at diagnosis could be prognostic factors for IBD is a question that requires further large-scale studies to address. We also analyzed white blood cell count, platelet count, hematocrit, erythrocyte sedimentation rate, and C-reactive protein at diagnosis, which were found not to predict clinical relapse.
Our study also collected endoscopic features in the analysis of clinical relapse in IBD. We identified that pancolitis UC patients have higher risk of clinical relapse than non-pancolitis patients (HR 2.191, 95% CI 1.104–4.349), which was not confirmed by a multivariate analysis of risk factors. There are several reports that extensive colitis is associated with an increased risk of colectomy and colon carcinoma, as well as future hospitalization.[28],[29] In our study, endoscopic features such as cobblestone appearance, segmental lesions, polypoid lesions, and widespread erosion failed to predict clinical relapse in IBD.
We also integrated microscopic features data into our analysis of IBD. Cryptolytic lesions were not associated with IBD clinical relapse and granulomas were not related to CD clinical relapse. There is a study reporting that mesenteric granulomas independently predict long-term risk of surgical recurrence in CD.[30] Mucin depletion and histological activity were shown to be independent predictive factors for clinical relapse in UC.[31],[32]
There were 34.41% and 28.97% of CD patients with comb sign and increased mesenteric fat attenuation, respectively, in our study. However, these CT findings were not associated with clinical relapse. According to our imaging study, having bowel damage at diagnosis is associated with worsened outcomes, including high rates of surgery and hospitalization.[33] Furthermore, comb sign is associated with short-term clinical failure in CD patients and accumulation of peripouch fat may be associated with poor outcomes in IBD patients.[34],[35]
Our data suggested that GC therapy at initiation increased the risk of clinical relapse in UC patients (HR 2.014, 95% CI 0.889–4.567), which was not confirmed by a multivariate analysis of risk factors. GC use in the first year of IBD is a strong predictor of subsequent surgery.[36] Compared with the use of an anti-TNF agent, prolonged GC therapy was associated with increased mortality in CD patients.[37] Thus, more aggressive treatment with biological therapies could profoundly change the natural history of the disease.
Poor medication adherence is an independent risk factor for clinical relapse in UC patients in our study (HR 2.07, 95% CI 1.018–4.202). Our finding is consistent with the great majority of research concerning adherence in IBD. Younger age, longer intervals between outpatient clinic visits, and limited knowledge of the prescribed medication are associated with nonadherence to treatment, which accordingly affects the risk of relapse and loss of response to therapy.[38],[39],[40] Thus, a tight monitoring strategy will result in decreased incidence of flares, decreased hospitalization, and improved quality of life.
There are several limitations to our present study. First, our results should be interpreted carefully due to the retrospective and single-center study design. Further long-term population-based studies are needed to reduce possible selection bias. Second, the endpoint of the study was clinical relapse, which is not precisely representative of disease activity compared to endoscopic or histological relapse. In the future, our group will attempt a prospective research study, which sets endoscopic and histological mucosal healing as the endpoint to further analyze prognostic factors in IBD.
| Conclusion | | |
Younger age of onset and poor medication adherence increases the risk of clinical relapse in CD and UC, respectively. There is a need to stratify IBD patients at the early stages of the disease on the basis of the risk of progression.
Acknowledgment
None.
Financial support and sponsorship
This research was supported by grants from the National Natural Science Foundation of China (No. 81570509).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]
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