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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 24  |  Issue : 1  |  Page : 94-100

Causes, frequencies, and predictors of relapse in patients with ulcerative colitis on long-term follow-up in a tertiary care hospital of Northern India


1 Department of Medicine and Gasteroenterology, Command Hospital (NC), Udampur, Jammu and Kashmir, India
2 ECHS Polyclinic, Udampur, Jammu and Kashmir, India
3 Department of Hospital Administration, AFMC, Pune, Maharashtra, India
4 Department of Medicine, AFMC, Pune, Maharastrhtra, India
5 Department of Pathology, 151 Base Hospital, Guwahati, Assam, India
6 Department of Gatrointestinal Surgeon, Command Hospital (NC), Udampur, Jammu and Kashmir, India
7 Department of ENT, Command Hospital(Eastern Command), Kolkata, West Bengal, India

Date of Submission08-Dec-2020
Date of Decision06-Feb-2021
Date of Acceptance31-Mar-2021
Date of Web Publication26-Mar-2022

Correspondence Address:
Lt Col (Dr). Santosh Kumar Singh
Department of Medicine, AFMC, Pune, Maharasthra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jmms.jmms_182_20

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  Abstract 


Context: Ulcerative colitis (UC) initially thought to be a disease of developed world is equally common in India. Surprisingly, there are very scant data from India. The study was undertaken to find the frequency of relapse and to determine factors predictor of relapse in Indian population. Subjects and Methods: This study was conducted at a tertiary care center of New Delhi for a period of 1 year. Patients were included if they had a diagnosis of UC based on accepted historical, endoscopic, histological, and/or radiologic criteria. Detailed past/present history, baseline clinical examination, dietary details, and psychological analysis using shortened Depression Anxiety Stress Scale score, biochemical tests, inflammatory markers, endoscopic, and histopathological analysis were done at baseline and regular intervals. The outcome was clinical relapse or continued remission. Results: Out of 86 patients screened, 50 patients were included in the study according to inclusion criteria and were followed up. The frequency of relapse was 32%. Univariate analysis showed higher relapse frequency, frequency of steroid received in past, patients on immunomodulator therapy, presence of acute or chronic inflammatory cells on histology, and disease activity at baseline as predictors of relapse. There was no significant difference between anxiety, stress, and depression relapsers and those who maintained remission. On multivariate analysis, disease activity at baseline was the only independent predictor of relapse. Conclusions: Stringent control of disease activity with mucosal healing should be the aim, as mucosal healing is the only predictor for prolonged remission.

Keywords: Predictors, relapse, remission, ulcerative colitis


How to cite this article:
Jain R, Singh V, Naik A K, Singh SK, Chakrabarty BK, Ranjan P, Kumar P. Causes, frequencies, and predictors of relapse in patients with ulcerative colitis on long-term follow-up in a tertiary care hospital of Northern India. J Mar Med Soc 2022;24:94-100

How to cite this URL:
Jain R, Singh V, Naik A K, Singh SK, Chakrabarty BK, Ranjan P, Kumar P. Causes, frequencies, and predictors of relapse in patients with ulcerative colitis on long-term follow-up in a tertiary care hospital of Northern India. J Mar Med Soc [serial online] 2022 [cited 2022 Jul 4];24:94-100. Available from: https://www.marinemedicalsociety.in/text.asp?2022/24/1/94/339534




  Introduction Top


The clinical course of the disease varies greatly among patients with ulcerative colitis (UC). The course of UC is characterized by flares that alternate with periods of remission (80% patients); a minority of patients have continuous activity. Severity of disease and management response has been highly variable and is hard to forecast. Flare of symptoms may vary from minimal symptoms without systemic involvement to fatal life-threatening fulminant colitis requiring colectomy.[1] The duration of relapse-free periods varies greatly from patient to patient. More than 50% of patients present with mild-to-moderate disease at their first attack, and 10% of patients have severe disease at presentation. Following the initial flare during follow-up, 50% of patients have clinical remission or mild course of disease, 57% of patients have a chronic intermittent disease, and 18% of patients have chronic continuous activity. Up to 20%–30% of patients have extensive disease ultimately requiring colectomy.[2] Even after extensive advancements in the field of medical therapeutics and years after the first diagnosis of UC, 90% of patients still do not get complete remission; however, relapse nature, frequency, and disease activity in the prior timeline envisages the succeeding disease activity. The probability of remaining in remission for 1 year after a relapse has been estimated at 30%.[3] After being in remission for 1 year, the risk of relapse decreases to 20% for the following year. Few patients (1%) with UC have only one attack, followed by a relapse-free course, and it is likely that, in these cases, acute self-limiting colitis was misdiagnosed as UC.

Studies looking at relapse rates suggested 1-year relapse rates ranging from 58% to 89% in patients receiving placebo. With medication, yearly relapse rates are reduced to 12%–50%. To date, no factors have been identified as being reliable predictors of relapse in UC.[4]

Initial studies looking at factors related to relapse implicated emotional stress, upper respiratory tract infection (URTI), bacterial and viral infections, drug ingestion, smoking, and diarrheal episodes as possible triggers for disease activity. It has also been found that colitis relapse may have been associated seasonal variation. However, much of the data were uncontrolled, retrospective, and not subsequently validated. In the past two decades, few prospective studies have identified factors that predict an increased likelihood of relapse. Relapse was more likely to occur with higher relapse frequency, less time since last relapse, or a higher total number of previous relapses, at least in women.[5]

Numerous studies have scrutinized the connotation between dietary factors and onset of UC, but only a few have methodically studied the relationship between dietary habit and relapse nature of UC. A high intake of dairy products or low dietary fiber intake may be associated with relapse, but the strongest evidence for a dietary factor is that sulfur and sulfate may be implicated in relapse of colitis. Similarly, the impact of life events in recurrence of UC is unclear.[6]

Hence, there is a paucity of literature, which has comprehensively investigated all possible factors that could trigger a relapse in a cohort of UC patients in remission on long-term follow-up. Such information can be important, in altering the natural history by intervention or modification of the factors. The aim of this study was to determine the relapse rate in UC patients in remission and to identify factors that may influence the risk of relapse.


  Subjects and Methods Top


This was an observational study conducted at a tertiary care center of northern India for a period of 1 year on patients with UC in clinical remission attending gastroenterology clinic with subgroup analysis of relapse positive and no-relapse cohort. Consecutive patients seen in the outpatient department or contacted by mail were screened for eligibility. Patients were included if they had a diagnosis of UC based on accepted historical, endoscopic, histological, and/or radiologic criteria[7] and had been in clinical remission for at least 1 month. Of the 86 patients with UC who attended gastroenterology OPD, only 50 patients were in clinical remission. These fifty patients comprised the study population. Most of patients are from middle class salaried and were well built and nourished. The clearance from the hospital ethical committee was taken before initiation of the study. Informed consent was taken from all enrolled patients.

Patients with coexisting and serious cardiopulmonary, hepatic, renal, neurologic, psychiatric, and rheumatologic disease were not included in this study. Patients who were on mesalamine or azathioprine/6-mercaptopurine therapies if their medication dose has been altered within 30 days or within 3 months, respectively, before study entry; then they were also excluded from our study. If the patient with chronic active disease found to be on steroids or they were detected with clinically and endoscopically active disease as assessed by UC activity Index >03 and endoscopic Grade >1, then those patients were not included in the study population.[8]

Patients were seen at baseline and every 3 months for a total of 1 year if they remained in remission or for a shorter period if they had a relapse.

On entry to the study, a clinical history was taken and physical examination and colonoscopic examination with rectal biopsy specimens taken between 10 and 15 cm from the anal verge. Baseline parameters which included current stool frequency, disease extent, disease duration, presentation at onset, medication history, previous history of relapses, time from last relapse, duration of remission, use of nonsteroidal anti-inflammatory drugs (NSAIDs) or other drugs, comorbid illnesses, history of URTI, travel in last 4 weeks, extraintestinal manifestations, past history of antitubercular therapy, appendectomy, smoking, and alcohol intake were recorded. Blood was drawn for complete blood count (CBC), liver function tests (LFTs), and renal function tests (RFTs), erythrocyte sedimentation rate (ESR) and qualitative C-reactive protein (CRP) test. A dietary survey was done using food frequency questionnaire. Psychological survey was done using a shortened version of Depression Anxiety Stress Scale (DASS) which is a 21-item self-report questionnaire designed to measure the severity of a range of symptoms common to depression, anxiety, and stress.[9] Patients remained on their maintenance medications at stable dose throughout the study and compliance to medication was assessed.

During the study period, the patient came for 3 follow-up visit at 6, 9, and 12 months. At every follow-up visit, clinical activity was assessed by modified UC Disease Activity Index (UCDAI) score. Compliance to medication was assessed by the physician at every 3 months [Figure 1].
Figure 1: Study participant flow chart

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Patients were asked to contact with the treating clinician within 7 days if they were having any symptoms suggestive of flare of disease. UCDAI was recorded, and a flexible sigmoidoscopy/colonoscopy was performed if flare symptoms lasted for at least 7 days. Mucosal biopsies were taken for assessing histological activity and cytomegalovirus (CMV) immunohistochemistry. Stool test was done to rule out the presence of Clostridium difficile. CBC, LFTs, RFTs, ESR, and CRP were done. Food frequency questionnaire form and DASS psychological scale questionnaire were documented and analyzed subsequently. Compliance with maintenance medications was verified, and information regarding factors that may affect disease relapse and any other factor which patient felt important was obtained.

Primary end point of the study was set to disease relapse where “Relapse of disease” was defined as worsening of bowel function plus rectal bleeding with an endoscopic grade of 2, 3, or 4 for duration more than 7 days.[10]

All statistical analyses were performed with the aid of the SPSS 20.0 software Statistical Package for Social Sciences (SPSS) version 20 (IBM Corp., Armonk, NY, USA). Normally distributed continuous variables were expressed as mean (standard deviation) and the continuous variables with skewed distribution were expressed as median (range). The parameters between relapser and nonrelapser were compared by the Chi-square tests, Fisher's exact test when appropriate. For comparison of DASS scores in relapsers at base line and at the time of relapse, Wilcoxon signed rank test was used. Univariate analysis was performed to compare those who remained in remission, and those not, using independent t-test for continuous variables, and Chi-square test or Fisher's exact test for categorical variables, wherever applicable. Multivariate Cox Regression analysis was then performed to determine the contribution of each factor. Statistical significance will be inferred for P = 0.05.


  Results Top


Baseline information and characteristics for all fifty enrolled patients are tabulated in [Table 1]. Of the 50 patients, 16 patients had clinical as well as endoscopic relapse during the follow-up period. The median time to relapse was 14 (interquartile range: 6–24) months (mean time: 28.43 ± 48.14 months). The group who stayed in remission and those who relapsed were comparable for age, sex, maintenance drug treatment, drug compliance, disease duration, and disease extent [Table 2]. The relapsers had significantly higher relapse frequency (P ≤ 0.001) and higher frequency of steroid administration in past (P ≤ 0.001). Relapsers were more frequently put on immunomodulators afterward (P = 0.044). The relapsers also had a late age of disease onset (P = 0.08) although the difference was showing only a trend toward statistical significance. Qualitative CRP was positive in three relapsers and in only two patients in remission group. The hematological and biochemical parameters were comparable between patients in remission and relapsers [Table 2]. In this study, we could not find any evidence of infective pathology at the time of relapse. Out of 16 patients who relapsed, tests for C. difficile and CMV could be done in 12 patients. None of the patients had colonic biopsy positive for immunohistochemistry for CMV. None of these patients had stool sample positive for C. difficile. Dietary composition as assessed by Food frequency questionnaire was comparable in both groups.
Table 1: Characteristics of ulcerative colitis cohort (n=50)

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Table 2: A comparison of clinical haematological , biochemical , baseline histopathological parameters characteristics of ulcerative colitis patients in remission and relapsers

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Microscopic abnormalities were common in colonic biopsy specimens of patients even though they were in clinical remission. Chronic inflammatory infiltrate was seen in 62.5% (n = 10) of patients who relapsed as compared to 17.6% (n = 6) of patients who did not relapse. The presence of acute inflammatory infiltrate and chronic inflammatory cells in colonic biopsy at baseline was significantly associated with relapse (P = 0.015, 0.002, respectively) [Table 2]. There was no significant difference between anxiety, stress, and depression in those who relapsed and those who maintained remission. However, when the DASS scores of patients at the time of relapse were compared to their own baseline, a significant association between stress and depression was seen in these patients [Table 3].
Table 3: Comparison of depression anxiety stress scale scores in relapsers at base line and at time of relapse

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The major events in the past 4 weeks before regular follow-up visits of patients in remission were compared to relapsers. The events compared were a history of respiratory tract infection, history of analgesic use, and history of travel in the last 4 weeks. Analgesic use within 15 days before visit was significantly associated with relapse (P = 0.004) [Table 4]. Factors significantly associated with relapse on univariate analysis were a number of relapses, UC disease activity index score at baseline, frequency of steroid received, number of people taking immunomodulators, presence of acute inflammatory infiltrate, chronic inflammatory infiltrate on histopathology, and the use of analgesics 2 weeks before relapse. There was trend toward significance for relapse in age of onset, platelet count, ESR, the presence of crypt architectural abnormalities, and mucin depletion in histopathology. A multivariate Cox regression model for predicting relapse was determined. This model accounted for all variables which were statistically significant in univariate analysis. On multivariate analysis, only UC disease activity score (P = 0.02, odds ratio [95% confidence interval]: 2.58 [1.134–5.886]) was found to be statistically significant predictors of relapse.
Table 4: Major events within last 4 weeks in patients in remission and relapsers

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  Discussion Top


In view of lack of cure in UC, the aim of the treating clinician is to have a period of prolonged remission and prevent recurrent relapses. Various studies have postulated multiple factors which precipitate a relapse. However, most of these risk factors are nonmodifiable. Two modifiable risk factors which have been studied for prediction of relapse are dietary factors and stress.[11]

In this study, we observed the relapse rate was 32%. A similar relapse rate of 28%–38% has been shown by many studies.[4],[12] However, a study from India by Azad et al. showed a much higher relapse rate of 58% (15/26).[4] This higher relapse rate could be due to a small number of patients included in study and referral bias in chronic relapsing patients only reaching a tertiary referral center; however, different natural course in Indian subcontinent and poor drug compliance cannot be ruled out. Studies with a longer follow-up of 5–10 year have shown higher cumulative relapse rates of 67%–90%.[13],[14]

Nonadherence to prescribed therapy is found to be an important determining factor of relapse in various inflammatory bowel disease (IBD) patients. Bhatt et al. have shown that over 80% of patients with IBD were nonadherent to medical treatment;[15] forgetfulness was mentioned as the most common cause. In our study, although noncompliance was higher in patients who relapsed as compared to those who maintained remission (91% vs. 75%), there was no statistical significance. The importance for strict adherence to therapy can be brought about by the fact that, in our study, we had 8 patients who did not have any relapse since onset. Only one patient out of these who had prolong remission relapsed, which was also due to stopping of drug therapy 1 month before relapse.

The patients who relapsed had significantly a higher number of relapses in past despite 5 Aminosalicylic acid (ASA) therapy and had significantly higher frequency of steroid therapy in past and a higher number of patients on immunomodulator therapy. This finding is in concurrence with published reports stating that the pattern of disease in the previous year and higher number of relapses in the past are predictors of future relapse.[4] While one study had shown that higher relapse frequency was a predictor only in women, our study did not show such sex prelidiction.[4]

Immunomodulators are the current treatment of choice in patients who are steroid dependent or frequent relapsers as use of azathioprine decreases the relapse rate in such patients. This is likely the reason for significantly higher number of people on immunomodulators in our study. Meta-analysis of seven placebo-controlled trials concluded that the number needed to treat to prevent one recurrence with azathioprine or 6-mercaptopurine was 5, with an absolute risk reduction of 23%.[16] The need for higher/past immunosuppression reflects the disease severity pattern in the past and may thus predict relapse.

Our study also showed that, despite clinical remission, a significant number of patients had persistent microscopic activity. The presence of chronic inflammatory infiltrate and acute inflammatory infiltrate in colonic biopsy at baseline were significantly associated with relapse. The presence of mucin depletion and crypt architectural irregularities also showed trend toward significance. This finding is also in concordance with previous studies.[4],[17]

Our study showed the use of analgesics within 2 weeks before relapse to be significantly associated with relapse on univariate analysis. The use of analgesics was associated with a 3.8-fold higher risk of relapse. The safety of NSAIDs in patients with IBD remains unclear.[18] The possible principal mechanism for NSAIDs causing IBD relapse includes inhibition of cyclooxygenase, which leads to decreased prostaglandin synthesis which, in turn, results in an inability to maintain the mucosal defenses needed to prevent inflammation in the bowel. Although many workers have found NSAID as a significant cause of relapse, there are some studies where no such correlation was seen.[19]

On multivariate analysis, only independent predictor of relapse was disease activity as depicted by UCDAI score at baseline. The predominant difference was in mucosal appearance between those who maintained remission or who relapsed. This fact is also in accordance with the known literature that more active the disease is at baseline, higher are relapses and lesser are the remission rate.[19] UCDAI and Mayo Clinical score are the composite indexes of disease activity that include endoscopy and four point scoring scale for each variable (stool frequency, rectal bleeding, mucosal appearance, and physician rating of disease activity), thereby reducing physician and patient subjectivity in disease scoring. Various clinical trials (ACT I/II, ASCEND II, MEZAVANT, and PINCE) have used these scoring index to define their end point of remission.[20]

Although there is so much emphasis on achievement/maintenance of remission or prevention of relapse, surprisingly, there is no clear-cut definition of relapse or remission. Remission rates can vary by more than 2-fold depending on the definition of remission used for data analysis. It is only now becoming apparent that a stringent end point for remission such as defined in guidelines (clinical plus endoscopic remission) is related to longer duration of remission. Microscopic (histological) healing may be a better predictor than the macroscopic appearance (or clinical criteria) of time to relapse.[21] The combination of clinical, endoscopic, and histological remission has been reported to be associated with a 70% likelihood of remaining in steroid-free remission over the next 2½ years.[22] It appears that ideal definition of remission in UC should mean complete cessation of rectal bleeding, urgency and increased stool frequency, best confirmed by endoscopic mucosal healing, and histological inactivity.[23] The present study has followed up a cohort with clinical, biochemical, psychological, endoscopic, and dietary analysis and has identified the frequency of relapse and factors predictive of relapse in UC in remission. Mucosal healing should be the aim in all the studies and future data generated should be on therapies directed toward achieving mucosal healing.

The limitations of the present study include noninclusion of biomarkers such as fecal calprotectin or fecal lactoferrin in predicting relapse.[24] The follow-up duration was 12 months, a higher relapse may be seen over longer follow-up. There is various literature on newer endoscopy techniques such as identification of pit patterns on confocal endomicroscopy and endoscopic ultrasound in predicting the health of underlying mucosa and prediction of relapse.[25],[26] These findings are yet to be validated and were not included in our study.


  Conclusion Top


This study prospectively followed a cohort of UC with comprehensively looking into clinical factors, psychological factors, and dietary factors and their interactions if any leading to relapse. The implication of our study is that these data are the single large prospective data from Indian subcontinent, and it showed that various parameters of UC are comparable to Western population and aggressive therapy should be continued with mucosal healing being the aim.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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