Max Schmulson

Design of treatment trials for functional gastrointestinal disorders.

This article summarizes recent progress and regulatory guidance on design of trials to assess the efficacy of new therapies for functional gastrointestinal disorders (FGIDs). The double-masked, placebo-controlled, parallel-group design remains the accepted standard for evaluating treatment efficacy. A control group is essential, and a detailed description of the randomization process and concealed allocation method must be included in the study report. The control will most often be placebo, but for therapeutic procedures and for behavioral treatment trials, respectively, a sham procedure and control intervention with similar expectation of benefit, but lacking the treatment principle, are recommended. Investigators should be aware of, and attempt to minimize, expectancy effects (placebo, nocebo, precebo). The primary analysis should be based on the proportion of patients in each treatment arm who satisfy a treatment responder definition or a prespecified clinically meaningful change in a patient-reported outcome measure. Data analysis should use the intention-to-treat principle. Reporting of results should follow the Consolidated Standards for Reporting Trials guidelines and include secondary outcome measures to support or explain the primary outcome and an analysis of harms data. Trials should be registered in a public location before initiation and results should be published regardless of outcome.This document summarizes recent progress and regulatory guidance on design of trials to assess efficacy of new therapies for functional gastrointestinal disorders (FGIDs). The double-masked, placebo controlled parallel-group design remains the accepted standard for evaluating treatment efficacy. A control group is essential, and a detailed description of the randomization process and concealed allocation method must be included in the study report. The control will most often be placebo, but for therapeutic procedures and for behavioral treatment trials, respectively a sham procedure and control intervention with similar expectation of benefit but lacking the treatment principle are recommended. Investigators should be aware of and attempt to minimize expectancy effects (placebo, nocebo, precebo). The primary analysis should be based on the proportion of patients in each treatment arm who satisfy a treatment responder definition, or a prespecified clinically meaningful change in a patient-reported outcome measure. Data analysis should use the intention-to-treat principle. Reporting of results should follow the Consolidated Standards for Reporting Trials guidelines and include secondary outcome measures to support or explain the primary outcome and an analysis of harms data. Trials should be registered in a public location prior to initiation, and results should be published regardless of outcome.

Gender-related differences in IBS symptoms.

OBJECTIVE:Women are more likely than men to report irritable bowel syndrome (IBS) symptoms as well as chronic visceral and musculoskeletal pain. The study tests the general hypothesis that female IBS patients differ from their male counterparts in symptoms related to the viscera and musculoskeletal system, and that these differences are related to the menstrual cycle.METHODS:Seven hundred fourteen Rome positive IBS patients were evaluated for GI and extracolonic symptoms, psychological symptoms (SCL-90R), and quality of life (QOL) (SF-36). In addition, 54 postmenopausal women were compared with 61 premenopausal women and 54 age-matched males, all with IBS.RESULTS:Male and female subjects reported similar GI levels of symptom severity and psychological problems. Abdominal distension associated with a sensation of bloating was more commonly reported by female patients, as were symptoms of constipation. Female patients more often reported nausea, alterations of taste and smell, and unpleasant sensations on the tongue, muscle stiffness in the morning, greater food sensitivity, and side effects from medications. Forty percent of female patients reported menstrual cycle–related worsening of symptoms, but few symptom differences were found between pre- and postmenopausal women, making it unlikely that most of the gender differences observed are directly tied to the menstrual cycle.CONCLUSIONS:Female patients report higher levels of a variety of intestinal and nonintestinal sensory symptoms despite similar levels of IBS severity, abdominal pain, psychological symptoms, and illness impact. The apparent differences in sensitivity to nonpainful visceral sensations, medications, and food may represent altered sensory processes, autonomic responses, and/or cognitive hypervigilance.

Frequency of Functional Bowel Disorders among Healthy Volunteers in Mexico City

Background: The frequency of functional bowel disorders (FBD) in Mexico using the Rome II criteria is unknown. Methods: The Rome II Modular Questionnaire (RII-MQ) was translated into Spanish in coordination with the Rome Committee and their Latin American program. Volunteers were recruited by advertisement in Mexico City, and administered the RII-MQ. Results:The study population consisted of 324 healthy volunteers, with a mean age of 35.7; 66% were female. The most prevalent disorders were heartburn 35%, irritable bowel syndrome (IBS) 35%, functional bloating 21%, proctalgia fugax 21%, and functional constipation 19%. Based on gender, IBS-C was 4 times more frequent in females than males (19 vs. 4.6%) and functional bloating 3 times more frequent (10 vs. 3.7%). Differences according to occupation included a higher prevalence of ulcer-like dyspepsia (p = 0.04), IBS-C (p = 0.018) and proctalgia fugax (p = 0.034) among students. Conclusions: This is the first study to use RII-MQ to determine the prevalence of FBD in urban Mexico. The prevalence of IBS was significant and is related to a number of factors, including the stress of living in an overpopulated city. Selection bias is likely operative. A community-based study is warranted.

Cytokine imbalance in irritable bowel syndrome: a systematic review and meta-analysis

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder of unknown etiology; although infection and inflammation have recently been considered as important etiologic agents. A recent meta‐analysis showed correlations between cytokine [interleukin‐10 (IL‐10) and tumor necrosis factor (TNF)] gene polymorphisms and IBS; however, it is still unknown whether patients with IBS have different cytokine profiles compared to healthy population.

The global prevalence of IBS in adults remains elusive due to the heterogeneity of studies: a Rome Foundation working team literature review

Objectives The global prevalence of IBS is difficult to ascertain, particularly in light of the heterogeneity of published epidemiological studies. The aim was to conduct a literature review, by experts from around the world, of community-based studies on IBS prevalence. Design Searches were conducted using predetermined search terms and eligibility criteria, including papers in all languages. Pooled prevalence rates were calculated by combining separate population survey prevalence estimates to generate an overall combined meta-prevalence estimate. The heterogeneity of studies was assessed. Results 1451 papers were returned and 83, including 288 103 participants in 41 countries, met inclusion criteria. The mean prevalence among individual countries ranged from 1.1% in France and Iran to 35.5% in Mexico. There was significant variance in pooled regional prevalence rates ranging from 17.5% (95% CI 16.9% to 18.2%) in Latin America, 9.6% (9.5% to 9.8%) in Asia, 7.1% (8.0% to 8.3%) in North America/Europe/Australia/New Zealand, to 5.8% (5.6% to 6.0%) in the Middle East and Africa. There was a significant degree of heterogeneity with the percentage of residual variation due to heterogeneity at 99.9%. Conclusions The main finding is the extent of methodological variance in the studies reviewed and the degree of heterogeneity among them. Based on this, we concluded that publication of a single pooled global prevalence rate, which is easily calculated, would not be appropriate or contributory. Furthermore, we believe that future studies should focus on regional and cross-cultural differences that are more likely to shed light on pathophysiology.

The Epidemiology of Functional Gastrointestinal Disorders in Mexico: A Population-Based Study

Aims. The frequency of functional gastrointestinal disorders (FGIDs) in the general population of Mexico is unknown. Methods. To determine the prevalence of FGIDs, associated depression, and health care utilization, a population-based sampling strategy was used to select 500 households in the State of Tlaxcala, in central Mexico. Household interviews were conducted by two trained physicians using the Rome II Modular Questionnaire, a health-care and medication used questionnaire and the CES-D depression scale. Results. The most common FGIDs were IBS: 16.0% (95% CI: 12.9–19.5); functional bloating: 10.8% (8.2–13.9); unspecified functional bowel disorder: 10.6% (8.0–13.6); and functional constipation (FC): 7.4% (5.3–10.1). Uninvestigated heartburn was common: 19.6% (16.2–23.4). All FGIDs were equally prevalent among both genders, except for IBS (P = 0.001), IBS-C (P < 0.001), IBS-A/M (P = 0.049), and FC (P = 0.039) which were more frequent in women. Subjects with FGIDs reported higher frequencies of medical visits: 34.6 versus 16.8%; use of medications: 40.7 versus 21.6%; (both P < 0.001); and reported depression: 26.7 versus 6.7%, (P < 0.001). Conclusion. In this first population-based study of FGIDs in Mexico, heartburn, IBS, functional distension, and FC were common. Only IBS, IBS-C, IBS-A/M, and FC were more frequent in women. Finally, FGIDs in Mexico had an increased burden of health care utilization and depression.

Hydrogen and Methane-Based Breath Testing in Gastrointestinal Disorders: The North American Consensus

Objectives:Breath tests (BTs) are important for the diagnosis of carbohydrate maldigestion syndromes and small intestinal bacterial overgrowth (SIBO). However, standardization is lacking regarding indications for testing, test methodology and interpretation of results. A consensus meeting of experts was convened to develop guidelines for clinicians and research.Methods:Pre-meeting survey questions encompassing five domains; indications, preparation, performance, interpretation of results, and knowledge gaps, were sent to 17 clinician-scientists, and 10 attended a live meeting. Using an evidence-based approach, 28 statements were finalized and voted on anonymously by a working group of specialists.Results:Consensus was reached on 26 statements encompassing all five domains. Consensus doses for lactulose, glucose, fructose and lactose BT were 10, 75, 25 and 25 g, respectively. Glucose and lactulose BTs remain the least invasive alternatives to diagnose SIBO. BT is useful in the diagnosis of carbohydrate maldigestion, methane-associated constipation, and evaluation of bloating/gas but not in the assessment of oro-cecal transit. A rise in hydrogen of ≥20 p.p.m. by 90 min during glucose or lactulose BT for SIBO was considered positive. Methane levels ≥10 p.p.m. was considered methane-positive. SIBO should be excluded prior to BT for carbohydrate malabsorption to avoid false positives. A rise in hydrogen of ≥20 p.p.m. from baseline during BT was considered positive for maldigestion.Conclusions:BT is a useful, inexpensive, simple and safe diagnostic test in the evaluation of common gastroenterology problems. These consensus statements should help to standardize the indications, preparation, performance and interpretation of BT in clinical practice and research.

From cytokines to toll-like receptors and beyond - current knowledge and future research needs in irritable bowel syndrome.

The irritable bowel syndrome (IBS) is a complex disorder in which psychosocial, cultural and biological factors, interact. Recent knowledge in the pathophysiology of IBS, seem to combine issues such as a low grade inflammation or immune activation and dysbiosis that can trigger or exacerbate IBS. On the other hand, stress mediated through the hypothalamic-pituitary-adrenal axis can produce motility abnormalities that can modify the microbiota as well, with the subsequent immune activation in the mucosa and stimulation of nerve terminals, generating symptoms of IBS. Also, we speculate that, stress, dysbiosis or an underlying genetic predisposition, may increase the epithelial permeability leading to a contact between pathogens-associated molecular patterns and toll-like receptors in the deeper layers of the gut, developing a host immunity response and IBS generation. We believe that the role of toll-like receptors in IBS and elucidating the communication processes between the immune and the nervous system, warrant future research.

Lower Serum IL-10 Is an Independent Predictor of IBS Among Volunteers in Mexico

OBJECTIVES:Studies suggest that altered immune activation, manifested by an imbalance in anti- and pro-inflammatory cytokine levels, exists in a subgroup of irritable bowel syndrome (IBS) patients. However, similar studies have not been conducted in Latin populations. The objective of this study was to measure serum levels of interleukin (IL)-10 and tumor necrosis factor (TNF)-α in subjects fulfilling symptom criteria for IBS and controls.METHODS:Volunteers (n=178) from a university population in Mexico City, participated in the study. Of the sample, 34.8% met Rome II criteria for IBS and 65.2% were designated as controls. Serum cytokines were measured by enzyme-linked immunoabsorbent assay. Analysis of covariance models were used to test main effects between gender, IBS symptoms, and bowel habit subtype to explain the cytokine serum levels. Statistical models were tested using body mass index as a covariate.RESULTS:IL-10 levels were significantly lower in IBS vs. controls (mean (95% confidence interval): 15.6 (14.8, 16.3) vs. 18.6 (17.9, 19.4) pg/ml, P<0.001), while TNF-α levels were higher in IBS (20.9 (19.1, 23.0) vs. 17.9 (16.7, 19.3) pg/ml, P=0.010). IBS and female gender were independent predictors for IL-10 (P<0.05). In contrast, female gender was an independent predictor for TNF-α. In addition, women with IBS-D had the lowest IL-10 (P<0.001) and highest TNF-α (P=0.021) vs. other subtypes.CONCLUSIONS:The lower serum IL-10 in our subjects fulfilling IBS Rome II symptom criteria suggests an altered immune regulation. Further studies are needed to elucidate if a lower serum IL-10 may be useful as a biomarker for IBS in the Mexican population, especially for women with IBS-D.

What is new in Rome IV

Functional gastrointestinal disorders (FGIDs) are diagnosed and classified using the Rome criteria; the criteria may change over time as new scientific data emerge. The Rome IV was released in May 2016. The aim is to review the main changes in Rome IV. FGIDs are now called disorders of gut-brain interaction (DGBI). Rome IV has a multicultural rather than a Western-culture focus. There are new chapters including multicultural, age-gender-women’s health, intestinal microenvironment, biopsychosocial, and centrally mediated disorders. New disorders have been included although not truly FGIDs, but fit the new definition of DGBI including opioid-induced gastrointestinal hyperalgesia, opioid-induced constipation, and cannabinoid hyperemesis. Also, new FGIDs based on available evidence including reflux hypersensitivity and centrally mediated abdominal pain syndrome. Using a normative survey to determine the frequency of normal bowel symptoms in the general population changes in the time frame for diagnosis were introduced. For irritable bowel syndrome (IBS) only pain is required and discomfort was eliminated because it is non-specific, having different meanings in different languages. Pain is now related to bowel movements rather than just improving with bowel movements (ie, can get worse with bowel movement). Functional bowel disorders (functional diarrhea, functional constipation, IBS with predominant diarrhea [IBS-D], IBS with predominant constipation [IBS-C], and IBS with mixed bowel habits) are considered to be on a continuum rather than as independent entities. Clinical applications such as diagnostic algorithms and the Multidimensional Clinical Profile have been updated. The new Rome IV iteration is evidence-based, multicultural oriented and with clinical applications. As new evidence become available, future updates are expected.