Utility of irritable bowel syndrome subtypes and most troublesome symptom in predicting disease impact and burden

Little is known about the characteristics of individuals with irritable bowel syndrome (IBS) according to stool subtype or the most troublesome symptom reported by the individual, or whether these are useful in predicting the impact of IBS.


| INTRODUC TI ON
2][3] It is characterized by abdominal pain and altered stool form and/or frequency. 4The Rome criteria for IBS are the gold-standard diagnostic criteria for IBS. 5,6They are based on patient-reported symptoms and have undergone several revisions to improve their diagnostic performance, with the most recent being the Rome IV criteria. 4Because the pathophysiology of IBS is poorly understood, the treatment goal is to alleviate symptoms, rather than addressing the cause(s) of IBS.Individuals with IBS are grouped according to different stool subtypes using the Bristol stool form scale. 5 The four subtypes, defined by the Rome IV criteria, are IBS with constipation (IBS-C), diarrhea (IBS-D), mixed bowel habits (IBS-M), and unclassified (IBS-U).
Originally, subtyping was developed as a research tool for participant selection and description, but it is also used in clinical practice to guide need for investigation and treatment selection. 7ing IBS subtypes to direct therapy or recruit patients in clinical trials is not ideal because predominant stool type fluctuates, as demonstrated in longitudinal studies. 8,9Nevertheless, understanding the distinction between IBS subtypes is important as it constitutes the prevailing classification system employed routinely in clinical practice, research trials, drug licensing, and guideline development.1][12][13][14][15] Given the fluctuation of stool subtype and the fact that IBS is a heterogeneous disorder characterized by a multitude of symptoms, an alternative to subgrouping by stool form or frequency would be to ask patients what their most troublesome symptom is.However, there have been no studies examining the characteristics of individuals with IBS according to the most troublesome symptom reported.It is unclear whether subtyping IBS according to predominant stool form or frequency or most troublesome symptom reported is a useful way of predicting disease impact and burden.
We, therefore, conducted a cross-sectional study to examine the characteristics of individuals with Rome IV-defined IBS according to both IBS stool subtype and most troublesome symptom reported by the individual.We aimed to assess their utility in predicting the impact of IBS on individuals, in terms of quality of life and ability to carry out daily activities and work duties, and the healthcare system, in terms of healthcare usage and direct healthcare costs.

| Participants and setting
This study recruited individuals registered with ContactME-IBS, a UK national registry run by County Durham and Darlington NHS Foundation Trust, of over 4280 members with IBS who are interested in research. 16ContactME-IBS recruits individuals in the UK through advertisements in primary care, hospital clinics, pharmacies, or on social media.Those interested enroll by completing a short online questionnaire about their bowel symptoms and providing their contact details.Of the registrants, 2268 (53%) have seen their primary care physician with IBS and another 1455 (34%) have seen a gastroenterologist.8][19][20][21][22] All participants were contacted via electronic mailshot in July 2021, with non-responders receiving a reminder email in August 2021.There were no exclusion criteria apart from the inability to understand written English.Participants' responses were stored in an online database.Those who completed the questionnaire were given a chance to win one of three gift cards worth £200, £100, or £50.The study was approved by the University of Leeds research ethics committee in March 2021 (MREC 20-051).

| Demographic and symptom data
We collected demographic data, including age, sex, lifestyle factors such as tobacco and alcohol consumption, ethnicity, marital status, educational level, and annual income.We defined the presence of IBS using the Rome IV questionnaire, 23 assigning presence or absence of Rome IV-defined IBS among all individuals according to the scoring algorithm proposed for its use. 4 We categorized IBS subtype, as recommended, using the proportion of time stools were abnormal according to the Bristol stool form scale.All participants were also asked to identify their most troublesome symptom from a list of five possibilities, including abdominal pain, constipation, diarrhea,

What is known
• IBS is a chronic disorder characterized by a multitude of GI symptoms.
• IBS is classified according to stool form and frequency but subtypes in IBS lack stability over time.
• There is little research examining the characteristics of individuals with IBS based on their reported most troublesome symptom.

What is new here
• Few variations were observed in the characteristics of individuals with respect to both the subtype of IBS and the reported most troublesome symptom.
• Gastrointestinal symptoms alone have limited ability to predict disease impact and burden in IBS.
• Assessing patients with IBS using both gastrointestinal and psychological symptoms may allow clinicians and healthcare systems to better stratify individuals in terms of disease impact and burden.
abdominal bloating or distension, or fecal urgency.We asked participants about the duration of their IBS diagnosis and whether their IBS symptoms started after an acute enteric infection.

| IBS symptom severity
We assessed severity of symptoms using the IBS severity scoring system (IBS-SSS), 24 which measures presence, severity, and frequency of abdominal pain, presence and severity of abdominal distension, satisfaction with bowel habit, and degree to which IBS symptoms are affecting, or interfering with, the individual's life.The IBS-SSS carries a maximum score of 500 points, with <75 points indicating remission of symptoms; 75-174 points mild symptoms; 175-299 points moderate symptoms; 300-500 points severe symptoms.

| Gastrointestinal symptom-specific anxiety
We used the visceral sensitivity index (VSI), 28 which measures gastrointestinal symptom-specific anxiety.Replies to each of the 15 items are provided on a 6-point scale from "strongly disagree" (score 0) to "strongly agree" (score 5).We divided these data into equally sized tertiles, as there are no validated cutoffs to define low, medium, or high levels of gastrointestinal symptom-specific anxiety.

| IBS-specific and generic health-related quality of life
We used the irritable bowel syndrome quality of life (IBS-QOL), a validated IBS-specific questionnaire, to measure health-related quality of life in individuals with IBS. 29,30The IBS-QOL consists of 34 items, each ranked on a 5-point Likert scale ranging from 0 to 4, with a total possible score of 0-136 and lower scores indicating better quality of life.The 34 items are based on the following eight variables: dysphoria, interference with activity, body image, health worry, food avoidance, social reactions, sexual activity, and relationships.As in the original validation studies, scores were transformed to a 0 to 100-point scale with zero indicating worst quality of life and 100 indicating best quality of life. 29,30We divided these data into equally sized tertiles as, again, there are no validated cutoffs to define low, medium, or high levels of quality of life.We also used the EQ-5D-5L instrument, 31 one of the three versions of the EuroQOL, 32 a generic health-related quality of life questionnaire, used widely throughout health care.The EQ-5D-5L consists of five items covering different aspects of health: mobility, self-care, ability to carry out usual activities, pain/discomfort, and anxiety/depression.Each item has five levels of responses, allowing for a total of 3125 possible health states.We mapped each health state to obtain a utility score for a UK population using a crosswalk calculator. 33

| IBS-related resource use
We collected data on healthcare usage related to a person's IBS over the 12 months prior to recruitment to the study.We asked participants to report any appointments with healthcare professionals (general practitioners (GPs), gastroenterologists, specialist nurses, dietitians, or psychologists), including the number of appointments, number of investigations (blood tests, stool tests, endoscopies, abdominal ultrasounds, computed tomography (CT) scans, magnetic resonance imaging (MRI) scans, hydrogen breath tests, or 23-seleno-25-homo-tauro-cholic acid (SeHCAT) scans), number of unplanned emergency department attendances or inpatient admissions (including length of stay), and over the counter and prescribed medication usage (in months).We applied costs for GP appointments from Unit Costs of Health and Social Care 2020, 34 and appointments, investigations, and unplanned inpatient days in secondary care using the NHS's 2019/20 National Cost Collection Data. 35We assumed that all the appointments for IBS were follow-up appointments, which cost less than a new patient appointment.We applied the lowest price for a 1-month supply of each IBS-related medication using the online version of the British National Formulary. 36

| Impact of IBS on productivity and ability to work
We used the work productivity and activity impairment questionnaire for irritable bowel syndrome (WPAI:IBS), 37 which is a validated questionnaire to assess the level of work productivity loss in people with IBS who are employed, as well as activity impairment in their activities of daily living.The WPAI:IBS consists of six questions related to current employment status, hours of work missed due to IBS, hours of work missed due to other reasons, hours actually worked, the degree to which IBS has affected work productivity whilst working, and the degree to which IBS has affected other activities of daily living in the last 7 days.The WPAI:IBS measures four domains: absenteeism, which is the percentage of work hours missed because of IBS; presenteeism, which is the percentage of impairment experienced whilst working because of IBS; overall work impairment, which is the percentage of work productivity loss; and activity impairment, which is the percentage impairment in activities of daily living.[41][42] The five domains are scored on a 9-point scale from "not at all" (score 0) to "very severely" (score 8).

| Statistical analysis
All participants who met Rome IV criteria for IBS were included in the analysis.We dichotomized the presence (score ≥4 ("definitely" impacting)) or absence (score <4) of an impact of IBS on home management activities, social leisure activities, private leisure activities, or maintaining close relationships.We compared the characteristics of participants according to IBS stool subtypes and most troublesome symptom reported.Categorical variables such as sex, IBS subtype, IBS symptom severity, presence or absence of abnormal anxiety or depression scores, level of somatoform symptom reporting, level of gastrointestinal symptom-specific anxiety, and level of IBS-related quality of life were compared using a χ 2 test.Data such as age, healthcare costs related to IBS, and scores for absenteeism, presenteeism, overall work impairment, or activity impairment were compared between groups using an independent samples t-test or Mann-Whitney U-test.Because of multiple comparisons, a twotailed p-value of <0.01 was considered statistically significant for all analyses.We performed all analyses using SPSS for Windows (version 27.0 SPSS, Chicago, IL).

| Characteristics of individuals according to IBS subtypes
We examined the characteristics of individuals with Rome IV IBS according to IBS subtypes (Table 1).A significantly higher proportion of those with IBS-C were female (95.6% with IBS-C, vs. 82.0%with IBS-D, vs. 88.7% with IBS-M, p < 0.001), and a significantly higher proportion of those with IBS-D reported onset of IBS after an acute enteric infection (7.4% with IBS-C, vs. 16.7% with IBS-D, vs. 9.6% with IBS-M, p = 0.005).There was no significant difference in age, ethnicity, marital status, smoking or alcohol use, level of education, annual income, or the proportion of individuals seeing a GP or gastroenterologist for their IBS in the 12 months prior to study recruitment according to subtype.There were significant differences in the most troublesome symptom reported according to subtype (p < 0.001 for trend), with the most prevalent troublesome symptom being abdominal bloating or distension for those with IBS-C and IBS-M (36.8% and 36.9%,respectively), and urgency for those with IBS-D (36.9%) (Figure 1).
There was no difference in IBS severity, levels of anxiety, depression, somatoform symptom-reporting, gastrointestinal symptomspecific anxiety, or direct healthcare cost of IBS according to stool subtype.Levels of absenteeism, presenteeism, overall work impairment, or activity impairment were also similar across subtypes.A higher proportion of those with IBS-D (63.1%), compared with those with IBS-C (51.5%) or IBS-M (51.5%), reported that IBS affected their social leisure activities (p = 0.007) but there was no difference in impairment in home management, private leisure activities, or close relationships.There was a statistically significant difference in mean IBS-QOL scores among individuals with different IBS subtypes (52.3   (standard deviation (SD) 19.9) for IBS-C, vs. 45.3 (SD 23.0) for IBS-D and 49.4 (SD 22.0) for IBS-M, p = 0.005) and a higher proportion of participants with IBS-D (37.9%), compared with those with IBS-C (20.6%) or IBS-M (30.6%) were in the lowest tertile of IBS-specific quality of life (p = 0.003).However, there was no significant difference in mean EQ-5D scores according to IBS subtype.

| Characteristics of individuals according to most troublesome symptom
We then examined the characteristics of individuals with Rome IV IBS according to the most troublesome symptom reported (Table 2).
There were no differences in sex, ethnicity, marital status, smoking, alcohol use, level of education, or annual income according to most troublesome symptom reported.A significantly higher proportion of patients who reported diarrhea as their most troublesome symptom had IBS after an acute enteric infection (p < 0.001).There were significant differences in the proportion of individuals meeting criteria for the different IBS subtypes according to most troublesome symptom reported (p < 0.001 for trend).(Figure 2).3) for urgency, p = 0.003), but no significant difference in mean EQ-5D scores.Finally, a higher proportion of those who reported diarrhea or urgency as their most troublesome symptom were in the lowest tertile of IBS-specific quality of life (p = 0.007).

| DISCUSS ION
We recruited over 700 individuals with Rome IV IBS and examined their characteristics according to both IBS subtype and the most troublesome symptom reported.Individuals with IBS-D, compared

TA B L E 2 (Continued)
with those with IBS-C or IBS-M, and those who reported diarrhea or urgency, as opposed to abdominal pain, constipation, or bloating or distension, as their most troublesome symptom had lower diseasespecific quality of life.However, there was no difference in generic health-related quality of life according to different IBS subtypes or most troublesome symptom reported.Interestingly, there were also no significant differences in symptom severity, levels of anxiety, depression, somatoform symptom-reporting, gastrointestinal symptom-specific anxiety, or direct healthcare costs of IBS according to either IBS subtype or most troublesome symptom reported.
In addition, there was no difference in work productivity or impairment in most areas of daily living among those with different IBS subtypes.Conversely, those who reported abdominal pain as their most troublesome symptom had higher levels of presenteeism and reported greater impact of their IBS on home management whilst those with diarrhea or urgency reported greater impact on social leisure activities.
Our study recruited individuals with IBS who met Rome IV criteria.It included a large, diverse sample of individuals, who are likely to be representative of people with IBS living in the UK.This is because it consisted of participants who had various healthcare experiences, including those who had never sought medical attention, those who had visited a primary care physician, and those who had consulted a gastroenterologist.It also included individuals from different age groups, educational backgrounds, income levels, and relationship statuses, representing people from all walks of life.We used validated questionnaires and obtained near-complete data for variables of interest because of the use of mandatory fields in our online questionnaire.
We recruited individuals with self-reported IBS from a UK national registry, expanding beyond the traditional recruitment from primary, secondary, or tertiary care settings.These individuals may differ from people in the community.As an example, over 40% of participants had reached university or postgraduate level of education, which is higher than the UK average of 34% in the 2021 census. 435][46][47][48] However, IBS has a higher prevalence compared with these conditions, and national guidelines in the UK advocate for the consideration or exclusion of these conditions during the diagnostic process for IBS. 49,50Moreover, nearly 90% of the individuals registered with ContactME-IBS had sought medical attention from their primary care physician or gastroenterologist for their IBS symptoms.Furthermore, nearly 80% of the study participants reported a minimum IBS duration of 5 years, and all participants were enrolled in a specialized IBS research registry.
Considering these factors, it is reasonable to assume that most of the study participants genuinely had IBS.The study sample consisted of UK residents, predominantly of white ethnicity, which may limit generalizability to populations outside the UK or individuals from other ethnic backgrounds.The proportion of individuals with constipation may be under-represented in our study, with only 18% meeting criteria for IBS-C, compared with previous reports of a similar prevalence of IBS-C, IBS-D, and IBS-M in the general population, 51,52 which may have affected our results.In addition, only nine of the 752 individuals met criteria for IBS-U, and we excluded this group in our analysis to preserve the ability to find meaningful differences among the other IBS subtypes.This is not unique to our study and in fact, most previous studies have only compared characteristics of individuals with IBS-C and IBS-D. 10,14,15I G U R E 2 Prevalence of IBS subtype according to most troublesome symptom.

IBS-C IBS-D IBS-M
To the best of our knowledge, this is the first study to examine the impact of IBS according to both stool subtype and most troublesome symptom reported.We not only assessed gastrointestinal symptoms but also examined psychological symptoms and healthcare usage and costs, as well as impact of IBS on work and activities of daily living.Our results demonstrating a higher proportion of females with IBS-C, compared with IBS-D and IBS-M, is similar to a large meta-analysis reporting the results of population-based studies on prevalence of IBS according to sex. 531][12][13] Nevertheless, there are some similarities between the results of these studies and our own.Two large cross-sectional studies recruiting individuals with Rome III-defined IBS reported no significant differences in symptom severity among those with IBS-C, IBS-D, or IBS-M. 11,12][13][14]54 However, other than Ray de Castro et al., who reported similar levels of somatoform symptom-reporting among subtypes, 12 albeit using a non-validated questionnaire, to our knowledge no previous studies have examined the spectrum of psychological comorbidities including anxiety, depression, somatoform symptom-reporting, and gastrointestinal symptom-specific anxiety, according to IBS subtype.Although there are conflicting results on impact of different IBS subtypes on activities of daily living, 11,15 results of one prior cross-sectional survey were consistent with our findings, showing no influence of IBS subtypes on work productivity outcomes. 15Our results do, however, suggest that those who report abdominal pain as their most troublesome symptom experience more impairment at work compared with other symptoms of IBS.This is in line with a recent study demonstrating that painful disorders of gut-brain interaction are associated with higher levels of impairment at work. 55nally, our results demonstrating similar generic health-related quality of life among different IBS subtypes are similar to previous studies. 10,12,14However, to our knowledge, this is the first study to also examine characteristics of individuals with IBS according to the most troublesome symptom reported.
The results from our study are important.Those with IBS-D, compared with IBS-C or IBS-M, and those who rated diarrhea or urgency, compared with abdominal pain, constipation, or bloating or distension, as their most troublesome symptom, had lower IBS-QOL scores.This suggests that, in terms of gastrointestinal symptoms, it is diarrhea or urgency, rather than abdominal pain or abdominal bloating or distension, which impact more on diseasespecific quality of life.Urgency also had a particularly notable effect on social engagement and leisure activities.This may be because those with IBS-D or those who report urgency as their most troublesome symptom are more likely to experience fecal incontinence. 20However, generic health-related quality of life, although reduced in IBS, and to a level comparable with other chronic diseases, 22 was similar across all IBS subtypes and most troublesome symptom reported.The additional finding that IBS subtypes or most troublesome symptom are poor discriminants of the presence or absence of psychological comorbidities, impact of IBS on work and activities of daily living, healthcare usage, and direct healthcare cost of IBS question the ability of differences in gastrointestinal symptoms alone to predict disease impact and burden.This is perhaps not unexpected given that the symptoms of IBS are known to fluctuate over time.
In contrast, we have previously demonstrated that a novel classification system for IBS, derived using latent class analysis, that groups patients according to both gastrointestinal and psychological symptoms, 56,57 can identify those with substantial impairment in ability to work, activities of daily living, generic health-related quality of life, and who are higher utilizers of healthcare.Given the multifaceted symptom profile of people with IBS, the modest efficacy of gut-specific medications, 58,59 the lack of availability of licensed medications for those with IBS-M or IBS-U, and the fact that brain-gut behavioral therapies, such as cognitive behavioral therapy or gutdirected hypnotherapy, 60 assessing patients with IBS using both gastrointestinal and psychological symptoms may allow clinicians and healthcare systems to better stratify individuals in terms of disease impact and burden.
In summary, this study, which enrolled individuals with Rome IV IBS, found few differences in the characteristics of individuals according to IBS subtype or most troublesome symptom.Severity of IBS, levels of anxiety, depression, somatoform symptom-reporting, or gastrointestinal symptom-specific anxiety, and generic healthrelated quality of life were similar irrespective of IBS subtype or most troublesome symptom reported.Individuals with IBS-D, compared with those with IBS-C or IBS-M, reported greater impairment in their social leisure activities.Participants who reported abdominal pain as their most troublesome symptom had higher levels of presenteeism and reported greater impact of their IBS on their home management, whereas those with diarrhea or urgency reported greater impact on social leisure activities.Clinicians should be sympathetic to the fact that diarrhea, urgency, and abdominal pain are key symptoms that impact on quality of life and social functioning.Although neither IBS subtype nor most troublesome symptom appeared to predict disease impact and burden, these classification systems are still useful for recruiting patients into trials of candidate drugs and to direct therapy in routine practice.Future studies should focus on whether gastrointestinal symptoms alone can predict disease impact and burden in longitudinal studies.

AUTH O R CO NTR I B UTI O N S
MK, FAS, CEN, CJB, VCG, and ACF conceived and drafted the study.
VCG and CEN collected all data.VCG, CJB, and ACF analyzed and interpreted the data.MK and FAS drafted the manuscript.All authors have approved the final draft of the manuscript.

ACK N OWLED G M ENTS
We are grateful to the patients who gave their time freely to answer our questionnaire.
Most troublesome symptom reported was not associated with IBS severity, levels of anxiety, depression, somatoform symptom-reporting, gastrointestinal symptom-specific anxiety, or direct healthcare cost of IBS.Levels of presenteeism were significantly higher among those reporting abdominal pain as the most TA B L E 1 Characteristics of individuals with Rome IV IBS according to IBS subtype.

1 2
Prevalence of most troublesome symptom according to IBS subtype.Characteristics of individuals with Rome IV IBS according to most troublesome symptom.
Independent samples t-test for continuous data, and Mann-Whitney U-test for all four dimensions of work productivity and activity impairment: irritable bowel syndrome.
*p-value for Pearson χ 2 for the comparison of categorical data.