|Year : 2021 | Volume
| Issue : 2 | Page : 42-48
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|
Prof. Can-Xia Xu
No. 138 Tongzipo Road, Changsha 410013, Hunan Province
Source of Support: None, Conflict of Interest: None
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. 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.,,,,
IBD has become a global disease, with accelerating incidence in newly industrialized continents such as Africa, Asia, and South America. According to previous studies, phenotypic variances exist between Caucasians with IBD and Asians. There is little research into distinct pathways of disease progression in Asian IBD populations.,, 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.
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|| |
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].
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.
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.
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.
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|
Click here to view
|Table 2: Univariate and multivariate analyses of risk factors for clinical relapse of Crohn's disease|
Click here to view
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|
Click here to view
|Table 3: Univariate and multivariate analyses of risk factors for clinical relapse of ulcerative colitis|
Click here to view
| 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., 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., 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,, while some studies indicate that male gender is associated with a higher risk of postoperative endoscopic recurrence. 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., 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. 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. 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.,
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., 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., 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. Mucin depletion and histological activity were shown to be independent predictive factors for clinical relapse in UC.,
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. 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.,
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. Compared with the use of an anti-TNF agent, prolonged GC therapy was associated with increased mortality in CD patients. 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.,, 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.
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.
| References|| |
Rosen MJ, Dhawan A, Saeed SA. Inflammatory bowel disease in children and adolescents. JAMA Pediatr 2015;169:1053-60.
Reinink AR, Lee TC, Higgins PD. Endoscopic mucosal healing predicts favorable clinical outcomes in inflammatory bowel disease: A meta-analysis. Inflamm Bowel Dis 2016;22:1859-69.
Veloso FT. Clinical predictors of Crohn's disease course. Eur J Gastroenterol Hepatol 2016;28:1122-5.
Adler J, Rangwalla SC, Dwamena BA, Higgins PD. The prognostic power of the NOD2 genotype for complicated Crohn's disease: A meta-analysis. Am J Gastroenterol 2011;106:699-712.
Park S, Abdi T, Gentry M, Laine L. Histological disease activity as a predictor of clinical relapse among patients with ulcerative colitis: Systematic review and meta-analysis. Am J Gastroenterol 2016;111:1692-701.
Jia Y, Li C, Yang X, Dong Z, Huang K, Luo Y, et al
. CT Enterography score: A potential predictor for severity assessment of active ulcerative colitis. BMC Gastroenterol 2018;18:173.
Ng SC, Shi HY, Hamidi N, Underwood FE, Tang W, Benchimol EI, et al
. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st
century: A systematic review of population-based studies. Lancet 2017;390:2769-78.
Ng SC, Zeng Z, Niewiadomski O, Tang W, Bell S, Kamm MA, et al
. Early course of inflammatory bowel disease in a population-based inception cohort study from 8 countries in Asia and Australia. Gastroenterology 2016;150:86-95000.
Chow DK, Leong RW, Tsoi KK, Ng SS, Leung WK, Wu JC, et al
. Long-term follow-up of ulcerative colitis in the Chinese population. Am J Gastroenterol 2009;104:647-54.
Kim B, Park SJ, Hong SP, Kim TI, Kim WH, Cheon JH. Proximal disease extension and related predicting factors in ulcerative proctitis. Scand J Gastroenterol 2014;49:177-83.
Qiu Y, Chen B, Li Y, Xiong S, Zhang S, He Y, et al
. Risk factors and long-term outcome of disease extent progression in Asian patients with ulcerative colitis: A retrospective cohort study. BMC Gastroenterol 2019;19:7.
Roda G, Chien NS, Kotze PG, Argollo M, Panaccione R, Spinelli A, et al
. Crohn's disease. Nat Rev Dis Primers 2020;6:22.
Charpentier C, Salleron J, Savoye G, Fumery M, Merle V, Laberenne JE, et al
. Natural history of elderly-onset inflammatory bowel disease: A population-based cohort study. Gut 2014;63:423-32.
Olén O, Askling J, Sachs MC, Frumento P, Neovius M, Smedby KE, et al
. Increased mortality of patients with childhood-onset inflammatory bowel diseases, compared with the general population. Gastroenterology 2019;156:614-22.
D'Haens G, Baert F, van Assche G, Caenepeel P, Vergauwe P, Tuynman H, et al
. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: An open randomised trial. Lancet 2008;371:660-7.
Peyrin-Biroulet L, Billioud V, D'Haens G, Panaccione R, Feagan B, Panés J, et al
. Development of the Paris definition of early Crohn's disease for disease-modification trials: Results of an international expert opinion process. Am J Gastroenterol 2012;107:1770-6.
Manser CN, Frei P, Grandinetti T, Biedermann L, Mwinyi J, Vavricka SR, et al
. Risk factors for repetitive ileocolic resection in patients with Crohn's disease: Results of an observational cohort study. Inflamm Bowel Dis 2014;20:1548-54.
Romberg-Camps MJ, Dagnelie PC, Kester AD, Hesselink-van de Kruijs MA, Cilissen M, Engels LG, et al
. Influence of phenotype at diagnosis and of other potential prognostic factors on the course of inflammatory bowel disease. Am J Gastroenterol 2009;104:371-83.
Auzolle C, Nancey S, Tran-Minh ML, Buisson A, Pariente B, Stefanescu C, et al
. Male gender, active smoking and previous intestinal resection are risk factors for post-operative endoscopic recurrence in Crohn's disease: Results from a prospective cohort study. Aliment Pharmacol Ther 2018;48:924-32.
Piovani D, Danese S, Peyrin-Biroulet L, Nikolopoulos GK, Lytras T, Bonovas S. Environmental risk factors for inflammatory bowel diseases: An umbrella review of meta-analyses. Gastroenterology 2019;157:647-59.e4.
Burisch J, Pedersen N, Cukovic-Cavka S, Turk N, Kaimakliotis I, Duricova D, et al
. Environmental factors in a population-based inception cohort of inflammatory bowel disease patients in Europe – An ECCO-EpiCom study. J Crohns Colitis 2014;8:607-16.
Beaugerie L, Massot N, Carbonnel F, Cattan S, Gendre JP, Cosnes J. Impact of cessation of smoking on the course of ulcerative colitis. Am J Gastroenterol 2001;96:2113-6.
Blackwell J, Saxena S, Alexakis C, Bottle A, Cecil E, Majeed A, et al
. The impact of smoking and smoking cessation on disease outcomes in ulcerative colitis: A nationwide population-based study. Aliment Pharmacol Ther 2019;50:556-67.
Hammer T, Lophaven SN, Nielsen KR, Petersen MS, Munkholm P, Weihe P, et al
. Dietary risk factors for inflammatory bowel diseases in a high-risk population: Results from the Faroese IBD study. United European Gastroenterol J 2019;7:924-32.
Jowett SL, Seal CJ, Pearce MS, Phillips E, Gregory W, Barton JR, et al
. Influence of dietary factors on the clinical course of ulcerative colitis: A prospective cohort study. Gut 2004;53:1479-84.
Shen J, Ran ZH, Zhang Y, Cai Q, Yin HM, Zhou XT, et al
. Biomarkers of altered coagulation and fibrinolysis as measures of disease activity in active inflammatory bowel disease: A gender-stratified, cohort analysis. Thromb Res 2009;123:604-11.
Alkim H, Ayaz S, Alkim C, Ulker A, Sahin B. Continuous active state of coagulation system in patients with nonthrombotic inflammatory bowel disease. Clin Appl Thromb Hemost 2011;17:600-4.
Biancone L, Armuzzi A, Scribano ML, D'Inca R, Castiglione F, Papi C, et al
. Inflammatory bowel disease phenotype as risk factor for cancer in a prospective multicentre nested case-control IG-IBD study. J Crohns Colitis 2016;10:913-24.
Torres J, Caprioli F, Katsanos KH, Lobatón T, Micic D, Zerôncio M, et al
. Predicting outcomes to optimize disease management in inflammatory bowel diseases. J Crohns Colitis 2016;10:1385-94.
Unger LW, Argeny S, Stift A, Yang Y, Karall A, Frelinger T, et al
. Mesenteric granulomas independently predict long-term risk of surgical recurrence in Crohn's disease. Colorectal Dis 2020;22:170-7.
Ponte A, Pinho R, Fernandes S, Rodrigues A, Alberto L, Silva JC, et al
. Impact of histological and endoscopic remissions on clinical recurrence and recurrence-free time in ulcerative colitis. Inflamm Bowel Dis 2017;23:2238-44.
Ozaki R, Kobayashi T, Okabayashi S, Nakano M, Morinaga S, Hara A, et al
. Histological risk factors to predict clinical relapse in ulcerative colitis with endoscopically normal mucosa. J Crohns Colitis 2018;12:1288-94.
Fiorino G, Morin M, Bonovas S, Bonifacio C, Spinelli A, Germain A, et al
. Prevalence of bowel damage assessed by cross-sectional imaging in early Crohn's disease and its impact on disease outcome. J Crohns Colitis 2017;11:274-80.
Campos C, Perrey A, Lambert C, Pereira B, Goutte M, Dubois A, et al
. Medical therapies for Stricturing Crohn's disease: Efficacy and cross-sectional imaging predictors of therapeutic failure. Dig Dis Sci 2017;62:1628-36.
Gao XH, Chouhan H, Liu GL, Lan N, Remer E, Stocchi L, et al
. Peripouch fat area measured on MRI image and its association with adverse pouch outcomes. Inflamm Bowel Dis 2018;24:806-17.
Targownik LE, Nugent Z, Singh H, Bernstein CN. Prevalence of and outcomes associated with corticosteroid prescription in inflammatory bowel disease. Inflamm Bowel Dis 2014;20:622-30.
Lewis JD, Scott FI, Brensinger CM, Roy JA, Osterman MT, Mamtani R, et al
. Increased mortality rates with prolonged corticosteroid therapy when compared with antitumor necrosis factor-α-directed therapy for inflammatory bowel disease. Am J Gastroenterol 2018;113:405-17.
Bruna-Barranco I, Lué A, Gargallo-Puyuelo CJ, Arroyo MT, Alfambra E, Montero J, et al
. Young age and tobacco use are predictors of lower medication adherence in inflammatory bowel disease. Eur J Gastroenterol Hepatol 2019;31:948-53.
Tae CH, Jung S, Moon HS, Seo JA, Song HK, Moon CM, et al
. Importance of patients' knowledge of their prescribed medication in improving treatment adherence in inflammatory bowel disease. J Clin Gastroenterol 2016;50:157-62.
van der Have M, Oldenburg B, Kaptein AA, Jansen JM, Scheffer RC, van Tuyl BA. Non-adherence to Anti-TNF therapy is associated with illness perceptions and clinical outcomes in outpatients with inflammatory bowel disease: Results from a prospective multicentre study. J Crohns Colitis 2016;10:549-55.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]