Clinical spectrum of acute severe ulcerative colitis in the biologic era: a prospective cohort study from India
Article information
Abstract
Background/Aims
Acute severe ulcerative colitis (ASUC) is a time-critical situation requiring urgent intervention. Limited data exist on the evolving clinical spectrum of ASUC in the era of advanced therapies.
Methods
This prospective real-world observational cohort study included 145 adult patients hospitalized with ASUC between January 2020 and June 2024. ASUC was defined by the modified Truelove and Witts criteria. Demographics and disease characteristics, including disease severity, probable precipitating factors, and corticosteroid failure rates, were recorded.
Results
The median age of patients was 36 years (interquartile range, 26–48.5 years) with 63 females (43.4%). Most patients had left-sided colitis (53.1%). The median disease duration was 1 year (IQR, 0.5–3 years), with 91 patients (62.7%) presenting with ASUC within the first year of diagnosis of ulcerative colitis. One-third of the patients had previous exposure to biologics and small molecules. The most commonly reported probable precipitants of ASUC were poor compliance with treatment (n = 43, 29.6%), antibiotic use (n = 35, 24.1%), high perceived stress (n = 32, 22.1%), and Clostridioides difficile infection (n = 19, 13.1%). Forty patients (27.5%) were non-responders to intravenous corticosteroids (IVCS). Twenty-nine patients (20%) received medical rescue therapy (infliximab, n = 14 [48.27%], cyclosporine A, n = 6 [20.68%], and tofacitinib, n = 9 [31.03%]). Seven patients (4.82%; 4 after non-response to IVCS and 3 after non-response to medical rescue therapy) underwent colectomy.
Conclusions
In this cohort of ASUC patients, poor treatment compliance, antibiotic use, stress, and C. difficile infection were common precipitants of flare-ups. Nearly one-third of patients required medical rescue therapy, and a small proportion ultimately underwent colectomy.
INTRODUCTION
Acute severe ulcerative colitis (ASUC) is the most severe form of ulcerative colitis and necessitates urgent medical intervention. ASUC is associated with significant morbidity and mortality, and approximately 1 in 5 patients ultimately require colectomy [1]. Despite advancements in therapeutic strategies, including the use of immunosuppressants, biologics, and/or small molecules, the outcomes for ASUC have remained largely unchanged over recent decades [2]. This stagnation in outcomes highlights the need for a deeper understanding of the factors associated with disease behavior. While recent studies have primarily focused on the therapeutic interventions in ASUC, there is a notable lack of data on the clinical spectrum of the disease, warranting a comprehensive re-evaluation. Given the evolution in disease management and the widespread use of immunosuppressive agents and advanced therapies, it is expected that the clinical profile of ASUC has shifted over time. Therefore, revisiting the current disease spectrum is essential to understanding how these shifts may affect patient outcomes.
We aimed to evaluate the clinical profile of ASUC, including patient demographics, disease characteristics, potential triggers for disease exacerbation, responses to intravenous corticosteroids (IVCS), and the performance of the predictive indices.
METHODS
1. Study Design
This prospective real-world observational cohort study was conducted in patients with ASUC admitted to the Department of Gastroenterology at Dayanand Medical College and Hospital, India, between January 2020 and June 2024. The study was approved by the Institutional Ethics Committee of Dayanand Medical College and Hospital (DMCH/R&D/IEC/2020/23). Informed consent was obtained from all the participants.
2. Study Population
Consecutive adult patients ( ≥ 18 years of age) who were hospitalized due to ASUC were included. ASUC was defined by the modified Truelove and Witts (TW) criteria ( ≥ 6 stools with blood and at least one of the following: pulse >90 beats per minute, temperature >37.8°C, hemoglobin <10.5 g/dL, and C-reactive protein [CRP] >30 mg/L) [3]. Patients with severe ulcerative colitis (UC) not fulfilling the TW criteria, infectious or indeterminate colitis, toxic megacolon, and intestinal perforation, or massive hemorrhage requiring emergency colectomy, and those enrolled in the TACOS trial were excluded [4].
3. Data Collection
A structured questionnaire was developed to systematically capture comprehensive information relevant to the study. The sections of the questionnaire included demographics, disease activity, nutritional status, probable precipitants of acute exacerbation, treatment, and clinical outcomes.
1) Demographic Data and Clinical Profile
The patient demographics (including age and sex) and clinical characteristics (including age at diagnosis, disease duration and extent, disease activity, and previous treatment) were recorded at the time of hospitalization. The investigations, including hemogram, liver and renal function tests, CRP, and a limited unprepared flexible sigmoidoscopy with biopsy for histopathology, were performed in all patients within 24 hours of hospitalization.
2) Assessment of Disease Activity
The endoscopic disease severity was assessed by the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) [5]. The score (0–8) is calculated by the sum of 3 descriptors, including vascular pattern (scored 0–2), bleeding (scored 0–3), and erosions and ulcers (scored 0–3) assessed at the most severely affected area on flexible sigmoidoscopy. The number of additional TW criteria (including tachycardia, temperature, hemoglobin and CRP [1 point for each criterion]); admission model for intensification of therapy in acute severe colitis (ADMITASC; which includes albumin <2.5g/dL [1 point], CRP >100 mg/L [1 point], UCEIS ≥ 4 [1 point] or UCEIS ≥ 7 [2 points]); albumin, CRP, and endoscopy (ACE) index (including albumin <3 g/dL, CRP >50 mg/L and severe endoscopic lesions [1 point for each criterion]) and ASUC score (admission steroid use, serum albumin and endoscopic severity [1 point for each criterion]) were calculated for all patients [6-8].
3) Nutritional Assessment
All patients underwent nutritional screening and assessment at presentation. The malnutrition universal screening tool (MUST) was used to screen for malnutrition and a score ≥2 was taken as high risk of malnutrition. For nutritional assessment, anthropometric measurements including height, body weight, body mass index and handgrip strength (Jamar hydraulic hand dynamometer) were noted.
4) Precipitants of ASUC
For all patients, the probable precipitating factors for ASUC were recorded. Broadly, the precipitating factors were grouped into infectious and non-infectious causes. These factors were pre-defined and included presence or consumption of any of the following within 4 weeks preceding hospitalization:
(1) Infectious causes
• Enteric infections
- Stool routine examination and culture: All patients underwent stool routine examination and stool culture to identify potential infectious agents. Routine examination included microscopy for ova, cysts, and parasites, while culture targeted enteric pathogens.
- Clostridioides difficile infection (CDI): Stool samples were tested for glutamate dehydrogenase (GDH), toxin A, and toxin B using the Vitassay rapid kit. CDI was confirmed in cases with a positive GDH result accompanied by a positive result for either toxin A or toxin B. If GDH was positive but both toxin A and toxin B were negative, a stool polymerase chain reaction for CDI was performed. A positive polymerase chain reaction result was considered diagnostic for CDI.
- Cytomegalovirus: Histological evaluation included hematoxylin and eosin-stained biopsy samples to identify owl’s eye inclusion bodies, along with immunohistochemistry for all patients. The presence of cytomegalovirus was diagnosed upon identification of inclusion bodies or a positive immunohistochemistry result.
• Extra-enteric infections: For patients with suspected extraintestinal infections, relevant diagnostic investigations were conducted, including body fluid cultures and specific tests based on the suspected infectious etiology.
(2) Non-infectious causes
• Compliance to therapy: This was evaluated using the Medication Adherence Rating Scale (MARS-5). This scale includes five items scored from 1 to 5, with a total score range of 5–25. Non-compliance to therapy was defined as a MARS-5 score of ≤ 15, indicating suboptimal adherence to prescribed medications [9].
• Medication use: The use of drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs) and antibiotics, for at least 2 consecutive days, was recorded.
• Perceived stress: The perceived stress was assessed using the Perceived Stress Scale (PSS). A PSS score >13 was defined as moderate to high perceived stress [10].
• Recent travel: Any travel undertaken within the past 4 weeks was documented to evaluate potential exposure to new environmental factors, dietary changes, and unfamiliar pathogens.
• Acute unaccustomed physical activity/exercise: This was defined as physical activity that was new or significantly different from an individual’s usual routine. This involved a sudden increase in the intensity, duration, or type of exercise, which the body had not yet adapted to and could act as a physical stressor [11].
4. Treatment
All patients were treated with intravenous hydrocortisone (100 mg every 6 hours), in addition to correction of fluid and electrolyte balance, enteral nutrition, and prophylaxis against venous thromboembolism. Clinical assessments (including total number of stools with blood) were performed daily until discharge.
5. Outcomes
The assessed outcomes included characterization of clinical profile of patients presenting with ASUC and corticosteroid failure (defined as need for colectomy or use of rescue medical therapy such as infliximab, cyclosporine, or tofacitinib during the index hospitalization).
6. Statistical Analysis
Descriptive statistics were used to summarize patient demographics, baseline characteristics, and clinical profiles. Baseline data were reported as frequencies with percentages or median (interquartile range, IQR), as appropriate. The Kolmogorov-Smirnov test was applied to assess the normality of the data distribution. Multivariate logistic regression analysis was performed to identify independent predictors of response to IVCS during the index hospitalization. Variables with a P-value <0.10 in univariate analysis were included in the initial multivariate model. Backward elimination was employed to refine the model, sequentially removing variables with the highest P-values until only those with P<0.05 remained. The adjusted odds ratios and corresponding 95% confidence intervals were reported for the final model. All analyses were conducted using SPSS version 26.0 (IBM Corp., Armonk, NY, USA).
RESULTS
1. Patient and Disease Characteristics
A total of 145 patients (median age 36 years, IQR 26–48.5 years, 63 [43.44%] females) were included. The majority of patients had left-sided colitis (n =77, 53.10%), followed by pancolitis (n=52, 35.86%), and proctitis (n=16, 11.03%). The median disease duration was 1 year (IQR, 0.5–3 years), with most of the patients presenting with ASUC within the first year of diagnosis of UC. Eighteen patients (12.41%) had their index presentation of UC as ASUC (Table 1).
Baseline Patient and Disease Characteristics
2. Clinical Presentation
At the time of hospitalization, the majority of patients (n=130, 89.65%) had been symptomatic for ≥7 days. Along with experiencing 6 or more stools with blood per day, 71 patients (48.96%) had one, 51 patients (35.17%) had two, 17 patients had three (11.72%), and 6 patients (4.13%) had four additional TW criteria. The median UCEIS score was 5 (IQR, 4–6) and 33 patients (22.75%) had deep ulcers on endoscopic examination. The ADMIT-ASC score ≥3, ACE index of 3, and ASUC score ≥2 was observed in 16 (11.03%), 18 (12.41%), and 42 (28.96%) patients, respectively. The median levels of hemoglobin, albumin, and CRP were 9.90 g/dL (IQR, 8.55–11.60 g/dL), 3.22 g/L (IQR, 2.52–3.70 g/L), and 29.28 mg/L (IQR, 9.39–78.16 mg/L), respectively (Table 2). All patients underwent nutritional screening and assessment upon hospitalization. A MUST score of ≥2 was observed in 76 patients (52.41%). The median body mass index was 20.70 kg/m2 (IQR, 17.81–23.89 kg/m2) and median handgrip strength was 15 kg (IQR, 15–21.50 kg).
Characteristics of Current Episode of ASUC
3. Probable Precipitants of ASUC
The probable precipitants of ASUC were classified into infectious and non-infectious categories. Among infectious causes, CDI was observed in 19 patients (13.10%), and cytomegalovirus infection was detected in 8 patients (5.51%). Additionally, 2 patients (1.37%) had urinary tract infections. In the non-infectious category, poor compliance to prescribed treatment regimens was noted in 43 patients (29.65%). Recent consumption of NSAIDs and antibiotics within 4 weeks prior to hospitalization was reported by 15 patients (10.34%) and 35 patients (24.13%), respectively. Thirty-two patients (22.06%) reported experiencing symptoms indicative of high perceived stress within the 4-week period preceding their ASUC onset. Other identified precipitants included recent travel (30 patients, 20.68%) and engagement in intense, unaccustomed physical exercise (14 patients, 8.27%). Specifically, the acute exercises included unaccustomed dancing, lifting heavy weights in gyms, fields, or farms, and operating or driving a tractor on rough terrains, such as farm fields.
4. Corticosteroid Failure
Corticosteroid failure was seen in 40 patients (27.58%). On multivariate analysis, higher stool frequency at hospitalization, ACE index ≥2, and CDI were associated with non-response to corticosteroids (Supplementary Table 1). Twenty-nine patients (20%) received medical rescue therapy, with 14 (48.27%), 6 (20.68%), and 9 (31.03%) patients receiving infliximab, cyclosporine A, and tofacitinib, respectively. Four patients (13.79%) underwent colectomy for corticosteroid refractoriness and frank bleeding per rectum. Another 3 patients underwent colectomy after failure of the medical rescue therapy (infliximab, n=2; cyclosporine, n=1) (Fig. 1). Among the patients who received rescue therapy or underwent colectomy, 7 (24.13%) had an ADMIT-ASC score of ≥3, 5 (17.24%) had an ACE index of 3, and 6 (20.68%) had an ASUC score of ≥2. Three patients (2.06%) died during the index hospitalization, all due to post colectomy sepsis and multiorgan failure. The distribution of scores of predictive indices (ADMIT-ASC, ACE, and ASUC score) are summarized in Fig. 2.
Flow of patients.
The distribution of scores of predictive indices (ADMIT-ASC, ACE, and ASUC score), stratified according to the response or non-response to intravenous corticosteroids during index hospitalization. The numbers added as data labels, indicate the number of patients. ADMIT-ASC, admission model for intensification of therapy in acute severe colitis; ACE index, albumin, CRP, endoscopy index; ASUC, acute severe ulcerative colitis.
DISCUSSION
ASUC represents a medical emergency requiring prompt recognition, urgent hospitalization, and timely intervention to optimize patient outcomes. In this prospective analysis of 145 ASUC cases, the median age was 36 years, with a slight male predominance. Most patients presented with left-sided colitis. Although ASUC is frequently associated with pancolitis, our findings align with the disease patterns prevalent in India and recent studies reporting left-sided colitis as the most common disease location [12-14]. Pancolitis, characterized by extensive inflammation, is traditionally considered to present a greater disease burden compared to more localized forms of UC, such as left-sided colitis or proctitis [15]. However, in our study, two-thirds of patients had disease limited to the left colon. Interestingly, 11% of our patients had disease limited only to rectum. These findings suggest that disease severity is independent of disease extent, and even patients with limited disease, such as proctitis, are at risk of developing ASUC.
The majority of patients (60%) in our study had no prior history of hospitalizations for UC flares, despite two-thirds having received corticosteroids in the past. Additionally, 60% of patients were diagnosed with UC within 1 year of their presentation with ASUC, a figure double that reported in the earlier literature [16]. This suggests the potential existence of inherently severe subgroup, possibly driven by genetic and environmental predispositions, although the precise etiology remains elusive. Approximately one-third of the cohort had prior exposure to biologics and small molecules, reflecting the evolving ASUC treatment landscape and contemporary clinical practices [12,13,17-20].
The common precipitants of ASUC flares included poor treatment compliance (30%), the use of antibiotics (24%), high perceived stress (22%), travel (21%), NSAIDs (10%), and acute unaccustomed exercise (8%). Poor compliance to therapy was a major factor precipitating ASUC. Counseling patients on the importance of strict compliance to therapy is crucial, as it can prevent flares and reduce the risk of ASUC. The widespread and continuous use of over-the-counter antibiotics and NSAIDs may precipitate UC flares through mechanisms such as intestinal barrier disruption and gut microbial dysbiosis. Acute psychosocial stressors are known to exacerbate ASUC by inducing adrenal insufficiency, triggering systemic and mucosal proinflammatory responses, and impairing the healing phase of ASUC [21-23]. Acute exercise has variable effects on gut microbiota and metabolites. Studies indicate that acute exercise influences gut microbial metabolic activity, potentially affecting host health [24]. We hypothesize that acute unaccustomed exercise, via modulation of the gut microbial activity and variations in the abdominal pressures, may be a possible trigger of ASUC. CDI was present in 19 patients (13.10%). This prevalence is similar to the previous studies from the developed countries but higher than that previously reported from India. All patients with ASUC should, therefore, be evaluated for concomitant CDI [25-28].
One-fourth of the patients were non-responders to IVCS. Of these non-responders, 20% of the patients did not receive rescue therapy during the index hospitalization. Potential reasons for this include inhibitory costs, especially in the absence of universal healthcare insurance, requiring patients to pay out-of-pocket, and concerns about the increased risk of infections, particularly reactivation of tuberculosis associated with infliximab in countries like India with high burden of tuberculosis. While emerging data support the use of tofacitinib in ASUC and the availability of cost-effective generic formulations makes it an attractive option for rescue therapy, further experience is needed [29]. It is important to note that the study, spanning nearly 5 years, coincided with a significant transition in clinical practice. During the initial 2 years, patients requiring rescue therapy were primarily managed with infliximab or cyclosporine. In the latter half of the study, however, the introduction of generic tofacitinib in India led to its use as rescue therapy among non-responders, especially in cases where infliximab was unaffordable. Additionally, as reported, 7 patients did not receive any rescue therapy despite being non-responsive to IVCS. These cases occurred during the early years of the study when treatment options were limited due to the high cost of infliximab, contraindications to cyclosporine, or patients’ refusal to consent to colectomy. Nonetheless, these observations underscore the importance of policymakers addressing region-specific challenges, especially in resource-limited settings. Also, only approximately 5% of patients required a colectomy during the index admission. The mortality reported in the current study is higher than that reported in the contemporary literature [30]. Three patients died in the current study during index admission, all in the post colectomy period due to sepsis and multiorgan failure. However, the 30-day post colectomy mortality in emergency surgeries in UC has been reported in up to 5% of patients, consistent with the observations in the current study [29].
Interestingly, only 50% of the patients in our study had elevated CRP levels ( ≥30 mg/L); however, when the threshold was lowered to 12 mg/L, this proportion increased to 70% [31]. CRP-based indices like ADMIT-ASC and ACE have been demonstrated to predict non-response to IVCS. However, these scores need to be evaluated prospectively, especially in populations with lower CRP levels, where their performance is expected to be suboptimal [5,6]. This highlights the unmet need of either ethnicity specific predictors of response or possibly lower the current cutoff values of CRP to enhance the diagnostic accuracy of predictive indices [31-33].
A comparison of the ASUC spectrum in the present study with historical cohorts worldwide reveals stability in the demographic profile, including age at hospitalization and sex distribution, over time. Notably, the proportion of patients presenting with ASUC as an initial manifestation has decreased from approximately 25% to 12%, likely reflecting advancements in diagnostics and early disease management. With the introduction of immunosuppressants and later biologics, the therapeutic landscape of ASUC has evolved; patients are now often pre-exposed to these agents before development of ASUC. However, despite these developments, the proportion of patients requiring oral corticosteroids has remained unchanged over time. Also, the rate of non-response to IVCS has remained static and not improved, even with prior exposure to immunosuppressants and biologics. A significant shift, however, is observed in the reduced necessity for emergency colectomy. In earlier cohorts, colectomy rates were high due to limited therapeutic options, as steroids were the primary treatment modality, with biologics and other advanced therapies unavailable. The relatively low percentage of colectomy in the recent ASUC cohorts, compared to the historical cohorts, reflects a shift in the management paradigm, where rescue medical treatments have minimized the need for colectomy during initial hospitalizations [34]. Overall, the spectrum of ASUC has transitioned from a largely surgically managed condition to a medically manageable one, though it remains severe and necessitates immediate, aggressive intervention (Table 3) [25,34-43].
Comparative Analysis of Key Cohort Studies Reporting the Spectrum of ASUC
The strengths of the study include a comprehensive real-world assessment of the disease spectrum in patients with ASUC. To the authors’ knowledge, this is the first study focused on the disease spectrum in the era of biologics and small molecules, including evaluation of possible precipitants, in patients presenting with ASUC. The data were collected prospectively, adding robustness to the findings. However, recruitment of patients from a single-center limits the generalizability of the findings.
In conclusion, our study provides valuable insights into the spectrum of ASUC. Common precipitants, such as poor adherence to treatment, antibiotic and NSAID use, and acute stressors, were significant triggers for ASUC flares. Patient demographics, disease characteristics, prior corticosteroid use, clinical presentation, and response to IVCS have remained largely consistent across both the pre-biologic and biologic eras, suggesting an incomplete understanding of underlying disease mechanisms. However, with the introduction of biologics and small molecules as rescue therapies, the colectomy rate during index hospitalization has decreased over time.
Notes
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
Sood A is on the advisory board of Janssen Pharmaceuticals (Asia-Pacific) and received honorarium for speaker events from Pfizer India and Takeda India; an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. The remaining authors disclose no conflicts.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author, upon reasonable request.
Author Contributions
Conceptualization: Singh A, Midha V, Sood A. Data curation: Luthra M, Singh D, Jain D. Formal analysis: Bhardwaj A, Sharma R, Singh A. Investigation: Singh A, Luthra M, Bhardwaj A, Sharma R, Mahajan R. Methodology: Singh A, Mahajan R, Sood A. Project administration: Sood A, Midha V. Resources: Sood A, Singh A, Bhardwaj A. Software: Sharma R. Supervision: Midha V, Sood A. Validation: Sood A, Midha V, Singh A. Visualization: Singh A, Bhardwaj A, Sharma R, Luthra M. Writing - original draft: Singh A, Bhardwaj A, Mahajan R, Sharma R. Writing – review & editing: Sood A, Midha V, Singh A, Goyal O, Mehta V, Kaur K, Gupta YK. Approval of final manuscript: all authors.
Supplementary Material
Supplementary materials are available at the Intestinal Research website (https://www.irjournal.org).
Supplementary Table 1.
Predictors of Response to Intravenous Corticosteroids in the Current Cohort (n=145)