Change over time of bowel habit in irritable bowel syndrome: a prospective, observational, 1-year follow-up study (RITMO study)

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1 Alimentary Pharmacology & Therapeutics Change over time of bowel habit in irritable bowel syndrome: a prospective, observational, 1-year follow-up study (RITMO study) V. GARRIGUES*, F. MEARIN, X.BADÍAà, A.BALBOA, J.BENAVENT,A.CABALLERO, E. DOMÍNGUEZ**, M. DÍAZ-RUBIO,M.ROSETà, M.FIGUERASàà,M.CUCALAàà & RITMO GROUP 1 *Digestive Medicine Department, Hospital Universitari La Fe, Valencia, Spain; Institute of Functional and Motor Digestive Disorders, Centro Médico Teknon, Barcelona, Spain; àhealth Outcomes Research Europe, Barcelona, Spain; Centro de Atención Primaria Clinic, Barcelona, Spain; School of Medicine, Granada, Spain; **Gastroenterology Department, Hospital Universitario de Santiago de Compostela, Spain; Hospital Clínico de San Carlos, Madrid, Spain; àànovartis Farmacéutica, Barcelona, Spain Correspondence to: Dr V. Garrigues, Servicio de Medicina Digestiva, Hospital Universitario La Fe, Av Campanar 21, 469 Valencia, Spain. garrigues_vic@gva.es 1 RITMO group is made up of primary care doctors and gastroenterologists interested in the management of IBS. Publication data Submitted 11 August 26 First decision 21 August 26 Resubmitted 13 September 26 Resubmitted 25 October 26 Resubmitted 7 November 26 Accepted 7 November 26 SUMMARY Background Evolution of bowel habit in irritable bowel syndrome (IBS) is not well known. Aim To evaluate the change over time of bowel habit in IBS patients followed-up during 1 year. Methods Five hundred and seventeen patients with IBS were prospectively included in an observational study with five evaluations over a 1-year period. Symptoms were recorded daily in diary cards during four 4-week periods along the study. Bristol Stool Scale (BSS) was used to define bowel habit. Results Four-hundred patients completed the study. Rome II showed low moderate agreement (42%) with BSS to define bowel habit. Frequency of constipation and diarrhoea showed little changes throughout the study. Over 5% of the patients had the same bowel habit when each diary was compared with the next one. A third of patients maintained the same habit throughout the study. Most changes occurred from/to mixed or unsubtyped IBS. Only 14% of cases changed from constipation to diarrhoea or vice versa. This change was associated to female gender (OR: 2.65). Conclusions The frequency of constipation and diarrhoea remains relatively stable over time. Changes in IBS subtypes are common, but changes between constipation and diarrhoea are rare. Alternating IBS is more frequent in women. Aliment Pharmacol Ther 25, ª 27 The Authors 323 doi:1.1111/j x

2 324 V. GARRIGUES et al. INTRODUCTION Irritable bowel syndrome (IBS) is a common condition defined by abdominal pain/discomfort associated with a change in bowel habit and with characteristics of disordered defecation. 1 Rome II consensus defined two subtypes of IBS according to the predominant bowel habit, constipation (IBS-C) or diarrhoea (IBS- D). Some authors 2 considered that patients with symptoms of both constipation and diarrhoea should constitute an alternating subtype (IBS-A). However, the definition of this group is controversial. Recently, Drossman et al. 3 recommended that patients with constipation and diarrhoea at the same time should be considered as having mixed IBS (IBS-M), and IBS-A should be defined by the presence of at least one change between IBS-C and IBS-D over a prospective follow-up of 1 year. This recommendation has been assumed by Rome III consensus IBS subtyping scheme. 4 The natural history of IBS is defined by the chronic course of the disease with periods of symptom improvement and episodes of worsening. 5 Regarding the evolution of symptoms, the systematic review by Guilera et al. 6 concluded that, based on the results from five studies, 7 11 the clinical course of IBS is highly heterogeneous. Having a closer look at these and other studies, two issues are apparent: the frequency of symptoms is more stable than their severity, 11 and between-subject rather than within-subject variation could be the main source for heterogeneity. 1,12 Agreus et al. 13 showed that over a 1-year period, 5% of patients with IBS changed their symptom profile. However, the systematic review by El-Serag et al. 14 concluded that IBS is a stable diagnosis, and the review article by Janssen et al. 15 concluded that the nature of the complaints in IBS mostly remains the same although the severity varies. However, most of these studies included a small number of patients and/or had a short follow-up period, not longer than 3 months. As reported in several guidelines and review articles, 5, drug therapy in IBS should be aimed at the primary bowel symptom. Furthermore, new investigational drugs, such as 5-HT 3 antagonists and 5-HT 4 agonists, have been developed to treat specific bowel habit disorders, diarrhoea and constipation, respectively. 5, 16 In order to establish the most appropriate drug for an individual IBS patient and how long-term therapy should be prescribed by physicians, either continuously or on demand, it is important to know the variability of bowel habits in patients with IBS. In order to obtain information on the clinical course and bowel habit of IBS, we performed a prospective, observational study including over 5 patients with IBS, diagnosed according to Rome II criteria, who were followed-up during 1 year. The study had several aims and so many data, that we decided to communicate the results in different articles. In a previous article, 19 we reported the clinical course of the patients, in an attempt to determine factors that might predict clinical evolution of the disease. Severe basal symptoms and improvement at 3 months were related to better prognosis. In the present article, analysing the same group of patients with IBS, we evaluate the bowel habit, defined by Bristol Stool Scale (BSS), as recommended by Rome III criteria. 4 Our specific aims were to analyse (i) the percentage of time with constipation and diarrhoea, based on the shape/consistency of stools, and its variation along the study; (ii) the changes over time of IBS subtype according to the predominant bowel habit, defined by the shape/consistency of stools and (iii) the factors associated to IBS-A, defined by the presence of at least one change between IBS-C and IBS-D during the study. METHODS A multicentre, observational, prospective study was conducted in a cohort of IBS patients visiting Spanish primary care centres and gastroenterology clinics between December 2 and December 21. Patients The study group initially included 517 patients, 148 (29%) visiting primary care centres, and 369 (71%) gastroenterology clinics; 393 (76%) of them were women and mean age was 43 years (range: years). All patients were at least 18 years old and met Rome II criteria for IBS. 1 Patients with clinical evidence of organic or metabolic diseases that might affect bowel transit or cause abdominal pain, as well as those taking medication at the time of inclusion that could induce IBS-like symptoms, those with previous abdominal surgery, except for appendectomy or hernia repair and pregnant women were excluded. Recruitment was prospective and balanced to obtain approximately the same number of patients in all three IBS subtypes, which were assigned by investigators

3 VARIATIONOFBOWELHABITINIBS 325 using patient history. In each participating center, patients were consecutively included until a limit for each subtype was reached. According to Rome II supportive criteria, 1 at the baseline visit, 16 patients had IBS-C; 182 had IBS-D and 175, IBS-M. Eighteen per cent of patients had been diagnosed with IBS more than 1 years ago, 17% between 6 and 1 years, 38% between 1 and 5 years, 19% less than a year and in 8% it was a new diagnosis. Patients were managed according to the criteria of their attending physician following the daily clinical practice, and no investigational drug was given to any patient during the study. Patients gave their written informed consent to participate in the study after receiving a full explanation of its objectives and procedures. Data acquisition A complete description of the acquisition of data in the study is given elsewhere. 19 Briefly, over a 12-month follow-up period, patients completed five visits: at study inclusion (baseline) and at months 3, 6, 9 and 12. At baseline, the demographic data of the patients were obtained, along with a complete digestive and nondigestive history, and a complete physical examination was performed. Information on menstrual cycle was not gathered in the study. A diary was completed during four consecutive weeks in four different periods of the study: months 1, 4, 7 and 1. Patients recorded daily in paper diaries the presence of symptoms of diarrhoea or constipation, in terms of number of bowel movements, urgency, straining and shape/consistency of stools according to the BSS form, 2 which was made available to the patient including drawings and written descriptions. Data analysis and statistics First, the percentage of agreement among IBS subtype defined at baseline visit by Rome II supportive criteria and IBS subtype defined by BSS at first diary was calculated. This analysis was not defined as an aim of the study when it was designed and must be considered to be a post hoc objective. Frequency of constipation and diarrhoea Data recorded on diaries were evaluated to define the presence of constipation and diarrhoea, based on the shape/consistency of stools. Constipation was considered weekly for scores of 1 or 2 from the BSS for at least 25% of bowel movements; and diarrhoea was considered daily for scores 6 or 7 from the BSS for at least 25% of bowel movements. Scores of 3 through 5 were considered to be normal bowel pattern. Percentage of time with constipation and diarrhoea, during the four diary periods for the whole group of patients and for each subtype was compared by one-way analysis of variance (ANOVA). Within-subject variation during the study of these frequencies, was evaluated by ANOVA for repeated measures. Changes in IBS subtypes Data recorded on diaries were also evaluated to subtype IBS according to the predominant bowel habit, based on the shape/consistency of stools, as recommended by Rome III consensus. 4 For each diary period, patients with constipation for 1 week or more and without diarrhoea were classified as IBS-C, patients with diarrhoea and without constipation as IBS-D, patients with both constipation and diarrhoea as IBS- M, and those with neither constipation nor diarrhoea, as unsubtyped IBS (IBS-U). In order to increase the amount of information, changes in IBS subtypes were analysed in several ways. First, by calculating the agreement between each diary and the next one diary 1 vs. diary 2; diary 2 vs. diary 3; diary 3 vs. diary 4 and between first and last diaries. In this way, we evaluated the stability of each IBS subtype, in the whole group of patients, between two points of time, separated by 3 months or by 9 months. The degree of agreement was evaluated by the percentage of agreement and by Cohen s kappa coefficient with the corresponding 95% confidence interval (CI). Values for the kappa index greater than.8 indicate very good agreement, between.61 and.8 good agreement, between.41 and.6 moderate agreement, between.21 and.4 poor agreement and lower than.21 very poor agreement. 21 Secondly, data obtained from the diaries of patients with at least three valuable measures were analysed to establish the variation of IBS subtypes in different subgroups of patients defined by IBS subtype at diary 1, among two time points, from month 1 (diary 1) to months 4, 7 and 1. And third, patients with at least three valuable measures were also analysed to evaluate the changes in IBS subtypes throughout the whole study for each patient; calculating the number of patients

4 326 V. GARRIGUES et al. remaining in the same subtype during the entire study, and the number of patients shifting from one subtype to another. Factors associated with IBS-A In addition, the association of IBS-A to gender, age, time of evolution of IBS and subtype of bowel habit in diary 1 was evaluated by logistic regression analysis, entering all the independent variables at a single time. RESULTS Of the 517 IBS patients initially included, six were excluded from the study. Four of them did not meet Rome II criteria for IBS; one was diagnosed of hypothyroidism; and in one patient ulcerative colitis was found at colonoscopy. Follow-up was incomplete in 111 patients. Of them, 76 were lost to follow-up, 3 patients withdrew from the study, two moved residence, two women got pregnant and one patient met with a car accident. Finally, 4 patients were analysed at 1-year follow-up. Data on age, gender and basal IBS subtype for patients who finished the study were similar to those for patients who did not. The number of valuable diaries was 479 at month 1, 445 at month 4, 41 at month 7 and 385 at month 1. Constipation predominant IBS and IBS-M were more frequent in women than in men (3% vs. 25% and 17% vs. 9%, respectively, in the first diary), and IBS-D was more frequent in men (51% vs. 33%). Data were similar in the other three diaries. We did not find any significant differences in the follow-up results in terms of who had seen and included the patient in the study (primary health physician or gastroenterologist); data not shown. At baseline, 39% of patients were taking some type of medication because of IBS symptoms. At the end of the study, the percentage of patients receiving drug treatment for IBS had decreased to 3%. No patient took narcotics during the study. The percentage of patients taking anxiolytics, antidepressants or non-narcotic analgesics at any time during the study was 12%, 5% and 3%, respectively. Table 1 shows the concordance among Rome II subtyping system, at baseline visit, and subtyping system based on BSS, at first diary period. Less than half of the patients were classified in the same subtype by both systems; however, a minority of the discrepancies (about 1% of the whole group of cases) occurred between constipation and diarrhoea. It is of note that Table 1. Concordance between Rome II supportive criteria at baseline visit and Bristol Stool Scale (BSS) at first diary to define predominant bowel habit in irritable bowel syndrome BSS (first diary) Rome II (baseline visit) Constipation Diarrhoea Mixed first diary period began on the day of the baseline visit. Frequency of constipation and diarrhoea Total Constipation Diarrhoea Mixed Unsubtyped Total Percentage of agreement: 42.4%. The frequency of constipation and diarrhoea throughout the four diary periods in the whole group of patients is shown in Figure 1. Constipation was present about a quarter of the days, and diarrhoea about 5% of the time. Considering patients as a group, no significant changes occurred in frequency of symptoms during the study. Figure 2 shows the evolution of frequency of constipation and diarrhoea during the study, separately for each of the four subtypes of patients, classified according to the predominant bowel habit in the first % Month 1 Month 4 Month 7 Month 1 Constipation Diarrhoea Figure 1. Evolution of the frequency of symptoms in the whole group of IBS patients. Each bar represents the percentage of days each symptom was present in the corresponding 4-week period.

5 VARIATIONOFBOWELHABITINIBS 327 % Constipation Month 1 Month 4 Month 7 Month 1 diary. For all groups of patients, the changes in frequency of symptoms were maximal from first to second diary, remaining relatively stable during the rest of the study. Significant differences were found between the first diary and the other three diaries in all subtypes, but no differences were found when comparing data from the second, third and fourth diaries, with each other. These data have been previously published in part. 19 The analysis of within-subject variation throughout the study showed a reduction in the percentage of days with constipation, but no diarrhoea, between the first and second diaries (Table 2). As shown in the table, this reduction was statistically significant, although of little clinical importance. The frequency of symptoms remained without significant changes for the rest of the study. % 12 6 IBS-C IBS-D IBS-M IBS-U Diarrhoea Month 1 Month 4 Month 7 Month 1 IBS-C IBS-D IBS-M IBS-U Figure 2. Evolution of the frequency of symptoms along the study separately for different subtypes of patients. Each bar represents the percentage of time each symptom was present in the corresponding diary for each group of patients. IBS-C, constipation predominant; IBS-D, diarrhoea predominant; IBS-M, mixed; IBS-U, unsubtyped. Changes in IBS subtypes First, switches from one IBS subtype to another were evaluated by analysing the agreement between each diary and the next one (Table 3). Kappa coefficient was about.4 (95% CI ranging from.35 to.5), which must be considered as low to moderate. Globally, 4% of patients changed their bowel habits from one diary to the next; changes from abnormal to normal bowel habit or vice versa ranged between 19% and 25%; changes from IBS-C or IBS-D to IBS-M or vice versa ranged from 13% to 17% and changes from IBS-C to IBS-D or vice versa ranged from 3% to 6%. Agreement between first and last diaries was slightly lower than agreement between each diary and the next, although distribution of changes was very similar. Secondly, over 5% of patients with at least three valuable diaries remained in the same subgroup when comparing bowel habits between month 1 (diary 1) and months 4, 7 and 1 (Figure 3). As shown, changes between IBS-C and IBS-D were uncommon, ranging from 6% to 12%. Thirdly, changes of IBS subtype during the whole study were analysed in patients with valuable information from, at least, three diaries (Table 4). A total of 415 patients (44 with three valuable diaries and 371 with four valuable diaries) were analysed. Globally, Table 2. Within-subjects variation for constipation and diarrhoea along the 1-year follow-up period n* Multivariate test Diary 1 (%) Pà Diary 2 (%) Pà Diary 3 (%) Pà Diary 4 (%) Constipation Diarrhoea Data expressed as percentage of days with symptoms. * Number of patients with valuable data, for each symptom in the four diaries. Statistical significance level when evaluating within-subjects variation in the four diaries (ANOVA for repeated measures). à Statistical significance level when evaluating within-subjects variation from one diary to the next.

6 328 V. GARRIGUES et al. IBS-C IBS-D IBS-M IBS-U Total Diary 2 (month 4) Diary 1 (month 1) IBS-C IBS-D IBS-M IBS-U Total Percentage of agreement: 58.% j ¼.41 95% CI: Diary 3 (month 7) Diary 2 (month 4) IBS-C IBS-D IBS-M IBS-U Total Percentage of agreement: 58.6% j ¼.43 95% CI: Diary 4 (month 1) Diary 3 (month 7) IBS-C IBS-D IBS-M IBS-U Total Percentage of agreement: 58.9% j ¼.43 95% CI:.36.5 Diary 4 (month 1) Diary 1 (month 1) IBS-C IBS-D IBS-M IBS-U Total Percentage of agreement: 54.7% j ¼.38 95% CI: Table 3. Changes of IBS subtypes from one diary to the next, and from the start to the end of study, based upon Bristol Stool Scale IBS-C, constipation predominant; IBS-D, diarrhoea predominant; IBS-M, mixed; IBS-U, unsubtyped. 34% of the patients did not change their bowel habit subtype during the study. A further 27% of cases had the same alteration of bowel habit with periods of normal bowel habit. Twenty five per cent of the patients moved from IBS-C or IBS-D to IBS-M or vice versa. Finally, 14% of the patients had at least one change between IBS-C and IBS-D during the study, constituting the so-called IBS-A. Factors associated with IBS-A Age and time of evolution of the disease were similar in IBS-A patients and the rest of patients; however, IBS-A was more frequent in women (15.6%) than in men (8%); and it was also more frequent in patients whose predominant bowel habit at diary 1 was diarrhoea (17.3%), constipation (16.9%) or mixed (11.5%) than in patients with normal bowel habit (2.6%). By logistic regression, gender and predominant bowel habit at diary 1, but not age and time of evolution, were associated with IBS-A (Table 5). DISCUSSION To our knowledge, this is the largest prospective study analysing the evolution of bowel symptoms and pattern in IBS during a period of 1 year. Major findings of our study were. (i) Frequency of constipation and diarrhoea shows few changes during a 1-year follow-up; (ii) bowel habits remain stable in one third

7 VARIATIONOFBOWELHABITINIBS IBS-C Month IBS-D Month Figure 3. Changes in bowel habit along the 4-week periods. Patients are distributed into four groups according to their bowel habit subtype during the first month (diary 1). IBS-C, constipation predominant; IBS-D, diarrhoea predominant; IBS-M, mixed; IBS-U, unsubtyped IBS-M Month IBS-U Month IBS-C IBS-D IBS-M IBS-U Table 4. Changes in IBS subtype throughout the study for the group of patients with at least three valuable 4-week diaries Type of change n (%) No changes 142 (34) Constipation 49 (12) Diarrhoea 63 (15) Mixed 5 (1) Unsubtyped 25 (6) Constipation or diarrhoea or mixed, unsubtyped 112 (27) Constipation, unsubtyped 36 (9) Diarrhoea, unsubtyped 72 (17) Mixed, unsubtyped 4 (1) Constipation or diarrhoea, mixed 14 (25) Constipation, mixed 38 (9) Diarrhoea, mixed 3 (7) Constipation, unsubtyped, mixed 15 (4) Diarrhoea, unsubtyped, mixed 21 (5) Constipation, diarrhoea (alternating IBS) 57 (14) Constipation, diarrhoea 19 (4) Constipation, diarrhoea, mixed 15 (4) Constipation, diarrhoea, unsubtyped 16 (4) Constipation, diarrhoea, mixed, unsubtyped 7 (2) of the patients during a 1-year period; (iii) about 5% of changes in bowel habits are from/to IBS-M or IBS- U; (iv) changes from IBS-C to IBS-D or vice versa (IBS-A) occur in 14% of cases and (v) IBS-A is significantly more frequent in women. Our study was designed to use Rome II consensus criteria to include patients and Rome II supportive criteria as subtyping system at the moment of inclusion to balance the number of patients with different bowel habits (IBS-C, IBS-D and IBS-M) included in the study. However, recent publications 3, 22 have suggested that Rome II subtyping system may not be adequate for defining the predominant bowel habit. Instead, the consistency of stools as shown in the BSS seems to be a more appropriate subtyping system; and, in fact, Rome III subtyping scheme is based on this scale. 4 According to this recent information, we have used data on stool shape/consistency from diaries to define

8 33 V. GARRIGUES et al. Total Number (%) with IBS-A Odds-ratio P-value Table 5. Predicting variables associated to alternating IBS Gender Male 1 8 (8.) Reference Female (15.6) 2.65 (1.13, 6.22).26 IBS subtype at diary 1 Unsubtyped 77 2 (2.6) Reference Constipation (16.8) 7.22 (1.62, 32.24).1 Diarrhoea (17.2) 8.54 (1.95, 37.51).5 Mixed 61 7 (11.5) 4.76 (.93, 24.25).6 IBS-A, alternating IBS. Odds-ratios are expressed with 95% confidence intervals. the presence of constipation and diarrhoea and to classify the predominant bowel habit of the patients during the study. In our study, the classification of IBS patients by bowel habit subtype according to objective data on shape/consistency of stools, as recorded in the first diary cards, evidenced a low-to-moderate agreement with classification by data from patients history based on Rome II subtyping system. Three sources of discrepancy could account for this finding: differences in the criteria to define constipation and diarrhoea; differences in the nature of the data obtained, subjective in Rome II criteria and objective in diary cards; and, finally, real changes in symptoms after inclusion in the study. Most discrepancies occurred in the IBS-M subtype, but disagreement regarding the classification of patients in constipation and diarrhoea groups was low, about 1%. The lack of agreement between subjective opinion and objective data from diaries is consistent with the findings from other authors 23,24 that patients recall may be faulty in the clinical practice in order to establish the predominant bowel habit. This must be taken into account when deciding on the most appropriate drug to be administered to an individual patient. In our opinion, classification of patients according to bowel symptom predominance should be performed better, based on diaries than on subjective criteria. The frequency of constipation and diarrhoea in this study, based on BSS, is lower than its frequency in the same series of patients, using Rome II supportive criteria as subtyping scheme. 19 As a group, patients had few changes in frequency of constipation and diarrhoea symptoms during the 1-year study period. This finding seems to be in disagreement with conclusions by Guilera et al. 6, who reported the existence of intermittent symptom and bowel pattern alternation in most studies analysed However, if we try to identify the sources for the heterogeneity found in these and other studies, two facts are apparent. First, between-subject is greater than within-subject variation. Thus, considering that the IBS subtype 1, 12 probably shows the largest contribution to betweensubject heterogeneity, 1 a greater homogeneity can be expected in patients with the same IBS subtype, as in our series. Additionally, within-subject variation of the frequency of constipation and diarrhoea in our study was not clinically significant and main changes were apparent between the first and second diaries. This suggests that some patients were included in the study when they visited their physician for symptom worsening and/or the inclusion in the study itself was the cause for the clinical improvement, and/or it was due to initial therapy effect in the minority of patients 8% seeing the doctor for the first time when included in the study. The same finding was described in the study by Drossman et al. 3, where pain severity and stool frequency and consistency improved between the first two measurements. Secondly, the nature and frequency of symptoms, which was the parameter tested 11, 15 in our study, are more stable than their severity. The agreement between the IBS subtype definition at the beginning diary 1 and at the end diary 4 of the study was lower than in the study by Mearin et al. 11, where data were also obtained from diary cards but separated by 2 months (percentage of agreement 61.2%; j ¼.48). The shorter duration of Mearin s study is likely to be the cause for the greater stability. In fact, our data were closer to those by Mearin when evaluating the agreement between each

9 VARIATIONOFBOWELHABITINIBS 331 diary and the next one, separated by 3 months. Despite time variations occurring in a significant number of patients over 4%, it must be highlighted that changes from IBS-C to IBS-D or vice versa occurred in a minority of patients (3 6%), and most changes occurred from/to IBS-M or IBS-U. The analysis of objective data obtained from all the diaries recorded throughout the study provided a lower percentage of agreement. Overall, a third of the patients had the same bowel habits over a 1-year period, and a further 27% had the same disorder in bowel habit alternating with a period of normal bowel habit. Only 14% had at least one change between IBS-C and IBS-D or vice versa (IBS-A), vs. 29% of patients presenting this switching in the study by Drossman et al. 3. Several factors could account for this discrepancy. First, population differences could exist based on geographical variations. Secondly, patients included in both the studies could be different; in fact, inclusion criteria were different as Drossman study included only women with IBS, who, according to our results, show a higher percentage of IBS-A subtype. Thirdly, the criteria employed to define bowel habits were also different in both studies. All these factors were identified as sources of heterogeneity in the systematic review by Guilera et al. 6. Fourthly, diaries were recorded for a longer time period in our study, 4 weeks, than in Drossman s study, 2 weeks. Finally, the greater frequency in symptoms recording in Drossman study vs. ours (6 vs. 4) could also explain in part its higher percentage of IBS-A. One interesting result in our study is the significant association of female gender with the IBS-A. To our knowledge, this finding has not been previously reported in IBS-A defined according to Drossman et al. 3 criteria. In a previous epidemiological study, Mearin et al. 25 reported that 8% of patients with IBS-A were women. However, in this article, alternating was defined by the simultaneous presence of constipation and diarrhoea, which corresponds to IBS-M subtype in our study. In order to analyse the results of this and other studies, we must keep in mind that changes in symptoms and in bowel habit subtype depend on several factors besides the natural history of the disease. The effect of drug therapy, administered in one third of our patients or other kinds of therapies and the effect of having a visit with the doctor in the context of an observational study are important factors here. The possible effect of menstrual cycle on bowel habit cannot be evaluated in our study, as information on menses was not gathered. In addition, differences in therapy strategies among different groups and different countries could be an explanation for differences in data. In conclusion, this 1-year follow-up observational study in a large number of patients with IBS has shown that the frequency of constipation and diarrhoea in different IBS subtypes remains relatively stable along time. Changes in IBS subtypes are frequent and occur mainly from/to IBS-M and IBS-U, but changes between constipation and diarrhoea are less common. IBS-A is more frequent in women. ACKNOWLEDGEMENT This study was supported by an unrestricted grant from Novartis Farmacéutica S.A., Spain. REFERENCES 1 Thompson WG, Longstreth GF, Drossman DA, Heaton KW, Irvine JE, Müllerlissner SA. Functional bowel disorders and functional abdominal pain. Gut 1999; 45 (Suppl.): II Talley NJ, Zinsmeister AR, Melton LJ. Irritable bowel syndrome in a community: symptom subgroups, risk factors and health care utilization. Am J Epidemiol 1995; 142: Drossman DA, Morris CB, Hu Y, et al. A prospective assessment of bowel habit in irritable bowel syndrome in women: defining an alternator. Gastroenterology 25; 128: Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology 26; 13: Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable bowel syndrome. Gastroenterology 22; 123: Guilera M, Balboa A, Mearin F. Bowel habit subtypes and temporal patterns in irritable bowel syndrome: systematic review. Am J Gastroenterol 25; 1: Heaton KW, Ghosh S, Braddon FEM. How bad are the symptoms and bowel dysfunction of patients with the irritable bowel syndrome? A prospective, controlled study with emphasis on stool form. Gut 1991; 32: Stevens JA, Wan CK, Blanchard EB. The short natural history of irritable bowel

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