Harms with placebo in trials of biological therapies and small molecules as maintenance therapy in inflammatory bowel disease: a systematic review and meta-analysis.

BACKGROUND: Randomised placebo-controlled trials for the induction of inflammatory bowel disease (IBD) remission involve potential harms to those receiving placebo. Whether these harms are also apparent with placebo during maintenance of remission trials in IBD is unclear. We aimed to examine the potential harms associated with receiving placebo in trials of licensed biologics and small molecules for maintenance of remission of ulcerative colitis and luminal Crohn's disease in a meta-analysis. METHODS: We performed a systematic review and meta-analysis. We searched several medical literature databases including MEDLINE (from Jan 1, 1946, to May 31, 2024), Embase and Embase Classic (Jan 1, 1947, to May 31, 2024), and the Cochrane Central Register of Controlled Trials from database inception to May 31, 2024, for randomised placebo-controlled trials of licensed biologics and small molecules for maintenance of remission in adults with IBD reporting data on adverse events over a period of 20 weeks or more. There were no language restrictions or prespecified exclusion criteria. We extracted summary data and pooled data using a random-effects model for any treatment-emergent adverse event, drug-related adverse event, infection, worsening of IBD activity, withdrawal due to adverse events, serious adverse events, serious infection, serious worsening of IBD activity, or venous thromboembolic events, reporting relative risks (RRs) for placebo versus active drug with 95% CIs for each outcomes. The protocol for this meta-analysis was registered with PROSPERO (CRD42024542624). FINDINGS: Our search identified 10 826 citations, of which 45 trials including 16 562 patients (10 319 [62·3%] receiving active drug and 6243 [37·7%] placebo) were eligible. The risks of any treatment-emergent adverse event (7297/9546 [76·4%] patients on active drug vs 4415/5850 [75·5%] on placebo; RR 1·01, 95% CI 0·99-1·04; I2 =47%), serious infection (260/10 242 [2·5%] vs 155/6149 [2·5%]; 0·97, 0·79-1·19; I2 =0%), or venous thromboembolic event (12/4729 [0·3%] vs 9/2691 [0·3%]; 0·72, 0·31-1·66; I2 =0%) were not significantly lower with active drug than placebo. The risks of any infection (3208/8038 [39·9%] vs 1713/4809 [35·6%]; 1·14, 1·05-1·23; I2 =60%) or any drug-related adverse event (1094/2997 [36·5%] vs 609/1950 [31·2%]; 1·24, 1·02-1·50; I2 =75%) were higher with active drug than placebo. However, the risks of any worsening of IBD activity (1038/8090 [12·8%] vs 1181/5191 [22·8%]; 0·58, 0·52-0·64; I2 =40%), any withdrawal due to adverse events (610/10 282 [5·9%] vs 561/6207 [9·0%]; 0·71, 0·60-0·84; I2 =43%), any serious adverse events (1066/10 292 [10·4%] vs 742/6198 [12·0%]; 0·85, 0·77-0·94; I2 =17%), or any serious worsening of IBD activity (101/5707 [1·8%] vs 143/3640 [3·9%]; 0·55, 0·42-0·71; I2 =0%) were lower with active drug than placebo. 21 randomised controlled trials were judged as low risk of bias across all domains. INTERPRETATION: In maintenance of remission trials in IBD, placebo was associated with some clinically significant potential harms. Patients should be counselled about these before participating in clinical trials and consideration given to alternative designs to test novel drugs in IBD. FUNDING: None.

Harms with placebo in trials of biological therapies and small molecules as induction therapy in inflammatory bowel disease: a systematic review and meta-analysis.

BACKGROUND: Randomised placebo-controlled trials are the gold standard to assess novel drugs in ulcerative colitis and Crohn's disease. However, there might be risks associated with receiving placebo. We aimed to examine the harms associated with receiving placebo in trials of licensed biologics and small molecules for the induction of remission in ulcerative colitis and luminal Crohn's disease in a meta-analysis. METHODS: We performed a systematic review and meta-analysis. We searched MEDLINE, Embase, Embase Classic, and the Cochrane Central Register of Controlled Trials from database inception to May 30, 2024, for randomised placebo-controlled trials of licensed biologics and small molecules for induction of remission in adults (≥18 years) with moderately to severely active ulcerative colitis or luminal Crohn's disease reporting data on adverse events over a minimum treatment period of 4 weeks. There were no prespecified study exclusion criteria. We extracted summary data and pooled data using a random-effects model for any treatment-emergent adverse event, any drug-related adverse event, infection, worsening of inflammatory bowel disease (IBD) activity, withdrawal due to adverse events, serious adverse events, serious infection, serious worsening of IBD activity, or venous thromboembolic events (VTEs), reporting relative risks (RRs) with 95% CIs. The protocol for this meta-analysis was registered with PROSPERO (CRD42024527341). FINDINGS: The search identified 10 826 citations, of which 47 trials including 20 987 patients (14 267 [68·0%] receiving active drug and 6720 [32·0%] receiving placebo) were eligible. The risk of any treatment-emergent adverse event was no different with active drug than with placebo (7660/14 267 [53·7%] patients on active drug vs 3758/6720 [55·9%] on placebo; RR 0·97, 95% CI 0·94-1·00; I2 =36%). However, the risks of worsening of IBD activity (563/13 473 [4·2%] vs 530/6252 [8·5%]; 0·48, 0·40-0·59; I2 =54%), withdrawal due to adverse event (401/13 363 [3·0%] vs 299/6267 [4·8%]; 0·62, 0·48-0·79; I2 =46%), serious adverse event (682/14 267 [4·8%] vs 483/6720 [7·2%]; 0·69, 0·59-0·80; I2 =30%), serious infection (140/14 194 [1·0%] vs 91/6647 [1·4%]; 0·67, 0·50-0·89; I2 =0%), serious worsening of IBD activity (187/11 271 [1·7%] vs 189/5056 [3·7%]; 0·45, 0·34-0·60; I2 =27%), or VTEs (13/7542 [0·2%] vs 12/2981 [0·4%]; 0·45, 0·21-0·94; I2 =0%) were all significantly lower with active drug than placebo. Numbers needed to treat with active drug to avoid these potentially serious adverse events ranged from 23 for worsening of IBD activity to 452 for VTEs. 27 randomised controlled trials were judged as low risk of bias across all domains. INTERPRETATION: Patients with moderately to severely active IBD receiving placebo are more likely to experience significant worsening of IBD activity and some serious adverse events, which might relate to a reduction in risk of these events with active drug. Patients should be counselled about these potential harms, and alternative trial designs to mitigate these harms should be considered. FUNDING: None.

A systematic review of yoga for the treatment of gastrointestinal disorders.

BACKGROUND: Several studies have reviewed yoga for the treatment of disorders of gut-brain interaction (DGBI) with most demonstrating a benefit for symptom reduction; however, yoga has been studied beyond DGBI. PURPOSE: The aim of this systematic review is to provide a comprehensive summary of yoga as treatment for gastrointestinal conditions. METHOD: We conducted literature searches in PubMed and Embase and included yoga trials of adults with a diagnosis of a gastrointestinal disorders and diseases. RESULTS: We identified 1275 articles; 12 studies were eligible. Most studies compared yoga to controls, for patients with different GI conditions (irritable bowel syndrome, ulcerative colitis, chronic pancreatitis, and gastrointestinal cancer). The type, method, and duration of yoga used varied. Across IBS studies, most demonstrated that yoga improved IBS symptom severity, mood-related symptoms, and quality of life compared with controls. In one study of inflammatory bowel disease, yoga improved quality of life compared to controls. Two studies of gastrointestinal cancer demonstrated that yoga led to a reduction in sleep disturbance and mood symptoms. One study of chronic pancreatitis found that yoga led to improvements in quality of life, stress, mood changes, alcohol dependence, and appetite. Yoga was generally safe, and no serious adverse events were attributed to the intervention. CONCLUSION: In conclusion, yoga appears to be safe and has potential to improve functioning across a spectrum of gastrointestinal diseases; however, current studies are limited by heterogeneity and methodological weaknesses. Further research is needed to evaluate the impact of yoga on health outcomes for a broader range of gastrointestinal conditions.

Prevalence of Sexual Dysfunction In Inflammatory Bowel Disease: Systematic Review and Meta-Analysis.

BACKGROUND & AIM: Patients with inflammatory bowel disease (IBD) may experience symptoms of sexual dysfunction (SD). However, the magnitude of this problem remains uncertain. Therefore, we performed a systematic review and meta-analysis to assess the prevalence of SD in adult patients with IBD. METHODS: MEDLINE EMBASE, EMBASE Classic (from inception to 9th April 2024) were searched to identify observational studies reporting the prevalence of SD in adult patients with IBD based on validated screening instruments. Data were extracted, and pooled prevalence (PP), odds ratios (OR), and 95% confidence intervals (CIs) were calculated. RESULTS: Of 1017 citations evaluated, 18 articles fulfilled eligibility criteria, containing 2,694 patients with IBD recruited from 13 different countries. The PP of SD in IBD patients was 50.6% (95% CI=40.8%-60.5%; I2=96.3%) with an OR=2.94 (95% CI=1.99-4.35, I2=73.4) compared to healthy controls. When we considered UC or CD separately, the PP of SD was 64.8% (95% CI=45.1%-82.1%; I2=88.8%) in patients with UC, and 58.3% (95% CI=36.0%-79.0%; I2=95.3%) in patients with CD. In the subgroup analysis based on sex, the PP of SD was higher in females with IBD than in males (62.7% vs 34.0%; OR=3.99, 95% CI=2.80-5.68; I2=61.7%,). Furthermore, the PP of SD was higher in patients with active disease than patients with inactive disease (75.1% vs 34.2%; OR=9.65, 95% CI=1.02-91.33, I2=95.5%). CONCLUSION: We demonstrated high prevalence of SD in IBD patients, especially in women. Encouraging gastroenterologists to screen for, and treat, these disorders with a holistic approach might improve quality of life of patients with IBD.

Novel Irritable Bowel Syndrome Subgroups are Reproducible in the Global Adult Population.

BACKGROUND & AIMS: Current classification systems for irritable bowel syndrome (IBS) based on bowel habit do not consider psychological impact. We validated a classification model in a UK population with confirmed IBS, using latent class analysis, incorporating psychological factors. We applied this model in the Rome Foundation Global Epidemiological Survey (RFGES), assessing impact of IBS on the individual and the health care system, and examining reproducibility. METHODS: We applied our model to 2195 individuals in the RFGES with Rome IV-defined IBS. As described previously, we identified 7 clusters, based on gastrointestinal symptom severity and psychological burden. We assessed demographics, health care-seeking, symptom severity, and quality of life in each. We also used the RFGES to derive a new model, examining whether the broader concepts of our original model were replicated, in terms of breakdown and characteristics of identified clusters. RESULTS: All 7 clusters were identified. Those in clusters with highest psychological burden, and particularly cluster 6 with high overall gastrointestinal symptom severity, were more often female, exhibited higher levels of health care-seeking, were more likely to have undergone previous abdominal surgeries, and had higher symptom severity and lower quality of life (P < .001 for trend for all). When deriving a new model, the best solution consisted of 10 clusters, although at least 2 seemed to be duplicates, and almost all mapped on to the previous clusters. CONCLUSIONS: Even in the community, our original clusters derived from patients with physician-confirmed IBS identified groups of individuals with significantly higher rates of health care-seeking and abdominal surgery, more severe symptoms, and impairments in quality of life.

Effect of Brain-Gut Behavioral Treatments on Abdominal Pain in Irritable Bowel Syndrome: Systematic Review and Network Meta-Analysis.

BACKGROUND & AIMS: Some brain-gut behavioral treatments (BGBTs) are beneficial for global symptoms in irritable bowel syndrome (IBS). United States management guidelines suggest their use in patients with persistent abdominal pain, but their specific effect on this symptom has not been assessed systematically. METHODS: We searched the literature through December 16, 2023, for randomized controlled trials (RCTs) assessing efficacy of BGBTs for adults with IBS, compared with each other or a control intervention. Trials provided an assessment of abdominal pain resolution or improvement at treatment completion. We extracted data as intention-to-treat analyses, assuming dropouts to be treatment failures and reporting pooled relative risks (RRs) of abdominal pain not improving with 95% confidence intervals (CIs), ranking therapies according to the P score. RESULTS: We identified 42 eligible randomized controlled trials comprising 5220 participants. After treatment completion, the BGBTs with the largest numbers of trials and patients recruited demonstrating efficacy for abdominal pain, specifically, included self-guided/minimal contact cognitive behavioral therapy (CBT) (RR, 0.71; 95% CI, 0.54-0.95; P score, 0.58), face-to-face multicomponent behavioral therapy (RR, 0.72; 95% CI, 0.54-0.97; P score, 0.56), and face-to-face gut-directed hypnotherapy (RR, 0.77; 95% CI, 0.61-0.96; P score, 0.49). Among trials recruiting only patients with refractory global IBS symptoms, group CBT was more efficacious than routine care for abdominal pain, but no other significant differences were detected. No trials were low risk of bias across all domains, and there was evidence of funnel plot asymmetry. CONCLUSIONS: Several BGBTs, including self-guided/minimal contact CBT, face-to-face multicomponent behavioral therapy, and face-to-face gut-directed hypnotherapy may be efficacious for abdominal pain in IBS, although none was superior to another.

Irritable bowel syndrome: low dose antidepressant improves symptoms.

The studyFord AC, Wright-Hughes A, Alderson SL, et al. Amitriptyline at low-dose and titrated for irritable bowel syndrome as second-line treatment in primary care (ATLANTIS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2023;402:1773-85.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/irritable-bowel-syndrome-low-dose-antidepressant-improves-symptoms/.

Postprandial symptoms in disorders of gut-brain interaction and their potential as a treatment target.

Postprandial, or meal-related, symptoms, such as abdominal pain, early satiation, fullness or bloating, are often reported by patients with disorders of gut-brain interaction, including functional dyspepsia (FD) or irritable bowel syndrome (IBS). We propose that postprandial symptoms arise via a distinct pathophysiological process. A physiological or psychological insult, for example, acute enteric infection, leads to loss of tolerance to a previously tolerated oral food antigen. This enables interaction of both the microbiota and the food antigen itself with the immune system, causing a localised immunological response, with activation of eosinophils and mast cells, and release of inflammatory mediators, including histamine and cytokines. These have more widespread systemic effects, including triggering nociceptive nerves and altering mood. Dietary interventions, including a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols, elimination of potential food antigens or gluten, IgG food sensitivity diets or salicylate restriction may benefit some patients with IBS or FD. This could be because the restriction of these foods or dietary components modulates this pathophysiological process. Similarly, drugs including proton pump inhibitors, histamine-receptor antagonists, mast cell stabilisers or even tricyclic or tetracyclic antidepressants, which have anti-histaminergic actions, all of which are potential treatments for FD and IBS, act on one or more of these mechanisms. It seems unlikely that food antigens driving intestinal immune activation are the entire explanation for postprandial symptoms in FD and IBS. In others, fermentation of intestinal carbohydrates, with gas release altering reflex responses, adverse reactions to food chemicals, central mechanisms or nocebo effects may dominate. However, if the concept that postprandial symptoms arise from food antigens driving an immune response in the gastrointestinal tract in a subset of patients is correct, it is paradigm-shifting, because if the choice of treatment were based on one or more of these therapeutic targets, patient outcomes may be improved.

Chronic Visceral Pain: New Peripheral Mechanistic Insights and Resulting Treatments.

Chronic visceral pain is one of the most common reasons for patients with gastrointestinal disorders, such as inflammatory bowel disease or disorders of brain-gut interaction, to seek medical attention. It represents a substantial burden to patients and is associated with anxiety, depression, reductions in quality of life, and impaired social functioning, as well as increased direct and indirect health care costs to society. Unfortunately, the diagnosis and treatment of chronic visceral pain is difficult, in part because our understanding of the underlying pathophysiologic basis is incomplete. In this review, we highlight recent advances in peripheral pain signaling and specific physiologic and pathophysiologic preclinical mechanisms that result in the sensitization of peripheral pain pathways. We focus on preclinical mechanisms that have been translated into treatment approaches and summarize the current evidence base for directing treatment toward these mechanisms of chronic visceral pain derived from clinical trials. The effective management of chronic visceral pain remains of critical importance for the quality of life of suffers. A deeper understanding of peripheral pain mechanisms is necessary and may provide the basis for novel therapeutic interventions.

Assessing Diagnostic Performance of Modifications to the Rome IV Criteria for Irritable Bowel Syndrome.

The gold standard symptom-based criteria for diagnosis of irritable bowel syndrome (IBS) are the Rome IV criteria.1 These are more restrictive than their predecessor, Rome III, because the cardinal feature required to meet criteria for IBS was changed to presence of abdominal pain alone, rather than abdominal pain or discomfort.2 This change was made because discomfort was believed to be an ambiguous term, with no equivalent in some languages. In addition, symptom frequency required for the presence of abdominal pain was increased to 1 day per week from 2 to 3 days per month. This has led to reduced sensitivity for detecting IBS and a 50% decrease in the prevalence of the disorder in the community.3,4 In a cross-sectional survey applying both Rome IV and III criteria to people living with IBS, 89% of those with Rome III-defined IBS not meeting Rome IV criteria did not meet Rome IV criteria because of this change in pain frequency.5 Previous iterations of the Rome criteria have performed only modestly in predicting a diagnosis of IBS.6-8 However, in a validation study, the Rome IV criteria outperformed Rome III,9 largely because their more restrictive nature made them more specific than Rome III. We assessed whether modifications to the Rome IV criteria led to a better trade-off between sensitivity and specificity.

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

BACKGROUND: 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. METHODS: We collected demographic, gastrointestinal, and psychological symptoms, healthcare usage and direct healthcare costs, impact on work and activities of daily living, and quality of life data from individuals with Rome IV-defined IBS. KEY RESULTS: We recruited 752 people with Rome IV IBS. Individuals with IBS-D reported a poorer disease-specific quality of life than those with IBS-C or IBS-M (mean (SD) IBS-QOL 45.3 (23.0) for IBS-D, vs. 52.3 (19.9) for IBS-C, vs. 49.4 (22.0) for IBS-M, p = 0.005). Mean (SD) IBS-QOL scores were also lower amongst those who reported diarrhea (44.8 (22.3)) or urgency (44.6 (22.3)) as their most troublesome symptom, compared with those reporting abdominal pain (52.2 (22.9)), constipation (49.5 (21.8)), or abdominal bloating or distension (50.4 (21.3)). However, there were no differences in mean EQ-5D scores, IBS severity, levels of anxiety, depression, somatoform symptom-reporting, or gastrointestinal symptom-specific anxiety. Direct healthcare costs of IBS were similar across all subtypes and all most troublesome symptom groups, although some differences in work productivity and social leisure activities were detected. CONCLUSIONS AND INFERENCES: There appears to be limited variation in the characteristics of individuals with Rome IV IBS based on both stool subtypes and most troublesome symptom reported, suggesting that gastrointestinal symptoms alone have limited ability to predict disease impact and burden.

Natural history and impact of irritable bowel syndrome-type symptoms in inflammatory bowel disease during 12 months of longitudinal follow-up.

BACKGROUND: Little is known about the natural history and impact of irritable bowel syndrome (IBS)-type symptoms on psychological health and quality of life in inflammatory bowel disease (IBD). We aimed to address this in a 12-month longitudinal follow-up study of secondary care patients. METHODS: We collected demographic, Rome III IBS-type symptom, psychological, and quality of life data, with questionnaires at 3-month intervals, over 12 months of follow-up in patients with IBD in clinical remission at baseline. We assessed the natural history of Rome III IBS-type symptoms over the 12 months of the study and compared psychological and quality of life data between those reporting Rome III IBS-type symptoms at each of the points of follow-up with those not reporting such symptoms. KEY RESULTS: Among 206 patients with IBD in clinical remission at baseline (104 [50.5%] women, mean age 56.9 years [range 18-83 years], 79 [38.3%] Crohn's disease), 33 (16.0%) reported Rome III IBS-type symptoms at baseline and 72 (35.0%) reported Rome III IBS-type symptoms at one or more time points. Among the 33 patients with Rome III IBS-type symptoms at baseline, symptoms resolved in 6 (18.2%) patients, were present throughout in 6 (18.2%) patients, and fluctuated in the remaining 21 (63.6%) patients. Among the 39 patients with new onset of Rome III IBS-type symptoms after baseline, 24 (65.1%) had symptoms at one point in time only, 10 (25.6%) at two points, four (10.3%) at three points, and one (2.6%) at four points. At each point in time, reporting IBS-type symptoms was associated with significantly higher anxiety, depression, or somatoform symptom-reporting scores, and/or lower quality of life scores. CONCLUSIONS & INFERENCES: In this 12-month follow-up study, one-third of patients with IBD reported presence of Rome III IBS-type symptoms at any point in time. Reporting such symptoms was associated with significant impacts on psychological health and/or quality of life.

Novel Symptom Subgroups in Individuals With Irritable Bowel Syndrome Predict Disease Impact and Burden.

BACKGROUND & AIMS: Current classification systems based on bowel habit fail to capture the multidimensional nature of irritable bowel syndrome (IBS). We previously derived and validated a classification system, using latent class analysis, incorporating factors beyond bowel habit. We applied this in another cohort of people with IBS to assess its ability to capture the impact of IBS on the individual, the health care system, and society. METHODS: We collected demographic, symptom, and psychological health data from adults in the community self-identifying as having IBS, and meeting Rome IV criteria. We applied our latent class analysis model to identify the 7 subgroups (clusters) described previously, based on overall gastrointestinal symptom severity and psychological burden. We assessed quality of life, health care costs (£1 = $1.20), employment status, annual income, work productivity, and ability to perform work duties in each cluster. RESULTS: Of 1278 responders, 752 (58.8%) met Rome IV criteria. The 7-cluster model fit the data well. The patients in the 4 clusters with the highest psychological burden, and particularly those in cluster 6 with high overall gastrointestinal symptom severity and high psychological burden, showed lower educational levels, higher gastrointestinal symptom-specific anxiety, were more likely to have consulted a gastroenterologist, and used more drugs for IBS. IBS-related and generic quality of life were impaired significantly in these 4 clusters and significantly fewer individuals reported earning ≥£30,000 per year. Productivity and the ability to work, manage at home, engage in social and private leisure activities, and maintain close relationships all were impacted significantly, and IBS-related health care costs over the previous 12 months were highest in these 4 clusters. In those in cluster 6, costs were more than £1000 per person per year. CONCLUSIONS: Our clusters identify groups of individuals with significant impairments in quality of life, earning potential, and ability to work and function socially, who are high utilizers of health care.

Systematic Review and Meta-analysis: Efficacy of Mesalamine in Irritable Bowel Syndrome.

BACKGROUND & AIMS: Some patients with irritable bowel syndrome (IBS) demonstrate low-grade inflammation in the intestine. Mesalamine, which has anti-inflammatory effects, may be an efficacious treatment for IBS, but studies are conflicting. We conducted a systematic review and meta-analysis to assess efficacy and safety of mesalamine in IBS. METHODS: We searched the medical literature up to September 14, 2022, to identify randomized controlled trials (RCTs) of mesalamine in IBS. We judged efficacy and safety using dichotomous assessments of effect on global IBS symptoms, abdominal pain, bowel habit or stool frequency, and occurrence of any adverse event. We pooled data using a random effects model, with efficacy and safety reported as pooled relative risks (RRs) with 95% confidence intervals (CIs). RESULTS: We identified 8 eligible RCTs (820 patients). Mesalamine was more efficacious than placebo for global IBS symptoms (RR of global symptoms not improving, 0.86; 95% CI, 0.79-0.95; number needed to treat = 10; 95% CI, 6-27), but not for abdominal pain or bowel habit or stool frequency. Subgroup analyses demonstrated efficacy of mesalamine in IBS with diarrhea for global IBS symptoms (RR, 0.88; 95% CI, 0.79-0.99), but not patients with other predominant bowel habits or those with post-infection IBS. Adverse event rates were no higher with mesalamine (RR, 1.20; 95% CI, 0.89-1.63) but were reported in only 5 trials. CONCLUSIONS: Mesalamine may be modestly efficacious for global symptoms in IBS, particularly IBS with diarrhea, but quality of evidence was low. Adequately powered high quality RCTs of mesalamine in IBS are needed.