Maintenance of clinical remission with biologics and small molecules in inflammatory bowel disease according to trial design: Meta-analysis.

BACKGROUND AND AIMS: Design of randomised controlled trials (RCTs) examining maintenance of clinical remission in inflammatory bowel disease (IBD) varies, with some trials re-randomising patients who have responded to active drug during induction to either active drug or placebo and others treating patients through with active drug or placebo from baseline. Whether this influences therapeutic gain of drug over placebo is unknown. METHODS: We searched the literature to January 2023 for maintenance of remission trials of biologics or small molecules versus placebo in IBD. We extracted maintenance of remission rates according to trial design; either trials re-randomising patients or trials treating patients through. We pooled data in a meta-analysis for all patients, and according to type of IBD. We calculated the number needed to treat (NNT), with a 95% confidence interval (CI), to assess therapeutic gain of active drug over placebo according to trial design. RESULTS: We identified 37 maintenance of remission trials (12,075 patients). Rates of maintenance of clinical remission were higher (41.9% with active drug, versus 20.3% with placebo), and NNT lowest (5; 95% CI 4-6), in trials re-randomising patients compared with those treating through (maintenance of remission rate 30.9% with active drug versus 14.6% with placebo, NNT = 7; 95% CI 5-9). Results were similar when trials were analysed according to IBD type but were more marked in ulcerative colitis RCTs (maintenance of remission rates in re-randomised trials 39.4% with active drug versus 17.8% with placebo, NNT = 5; 95% CI 3-7; treat-through trials 27.3% with active drug versus 11.9% with placebo, NNT = 7; 95% CI 5-11.5). CONCLUSION: Trials re-randomising patients had generally higher maintenance of remission rates, lower NNTs, and greater therapeutic gains over placebo.

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.

Impact of Opioid Use on the Natural History of Inflammatory Bowel Disease: Prospective Longitudinal Follow-up Study.

BACKGROUND: Opioid use is increasingly prevalent amongst patients with inflammatory bowel disease (IBD), but whether opioids have deleterious effects, or their use is merely linked with more severe disease, is unclear. We conducted a longitudinal follow-up study examining this issue. METHODS: Data on demographics, gastrointestinal and psychological symptoms, quality of life, and opioid use were recorded at baseline. Data on healthcare use and adverse disease outcomes were obtained from a review of electronic medical records at 12 months. Characteristics at baseline of those using opioids and those who were not were compared, in addition to occurrence of flare, prescription of glucocorticosteroids, treatment escalation, hospitalization, or intestinal resection during the 12 months of follow-up. RESULTS: Of 1029 eligible participants, 116 (11.3%) were taking opioids at baseline. Medium (odds ratio [OR], 4.67; 95% confidence interval [CI], 1.61-13.6) or high (OR, 8.03; 95% CI, 2.21-29.2) levels of somatoform symptom-reporting and use of antidepressants (OR, 2.54; 95% CI, 1.34-4.84) or glucocorticosteroids (OR, 6.63; 95% CI, 2.26-19.5; P < .01 for all analyses) were independently associated with opioid use. Following multivariate analysis, opioid users were significantly more likely to undergo intestinal resection (hazard ratio,  7.09; 95% CI, 1.63 to 30.9; P = .009), particularly when codeine or dihydrocodeine were excluded (hazard ratio, 42.9; 95% CI, 3.36 to 548; P = .004). CONCLUSIONS: Opioid use in IBD is associated with psychological comorbidity and increased risk of intestinal resection, particularly in stronger formulations. Future studies should stratify the risk of individual opioids, so that robust prescribing algorithms can be developed and assess whether addressing psychological factors in routine IBD care could be an effective opioid avoidance strategy.

Of the 1029 patients with IBD in this study, opioid use exceeded 10% and was associated with psychological comorbidity and an increased risk of intestinal resection during longitudinal follow-up, particularly when more potent formulations were used.

Novel symptom clusters predict disease impact and healthcare utilisation in inflammatory bowel disease: Prospective longitudinal follow-up study.

BACKGROUND: Predicting adverse disease outcomes and high-volume users of healthcare amongst patients with inflammatory bowel disease (IBD) is difficult. AIMS: The aim of this study is to use latent class analysis to create novel clusters of patients and to assess whether these predict outcomes during 6.5 years of longitudinal follow-up. METHODS: Baseline demographic features, disease activity indices, anxiety, depression, and somatoform symptom-reporting scores were recorded for 692 adults. Faecal calprotectin (FC) was analysed at baseline in 348 (50.3%) patients (<250 mcg/g defined biochemical remission). Using baseline gastrointestinal and psychological symptoms, latent class analysis identified specific patient clusters. Rates of glucocorticosteroid prescription or flare, escalation, hospitalisation, or intestinal resection were compared between clusters using multivariate Cox regression. RESULTS: A three-cluster model was the optimum solution; 132 (19.1%) patients had below-average gastrointestinal and psychological symptoms (cluster 1), 352 (50.9%) had average levels of gastrointestinal and psychological symptoms (cluster 2), and 208 (30.1%) had the highest levels of both gastrointestinal and psychological symptoms (cluster 3). Compared with cluster 1, cluster 3 had significantly increased risk of flare or glucocorticosteroid prescription (hazard ratio (HR): 2.13; 95% confidence interval (CI): 1.46-3.10), escalation (HR: 1.92; 95% CI: 1.34-2.76), a composite of escalation, hospitalisation, or intestinal resection (HR: 2.05; 95% CI: 1.45-2.88), or any of the endpoints of interest (HR: 2.06; 95% CI: 1.45-2.93). Healthcare utilisation was highest in cluster 3. CONCLUSIONS: Novel model-based clusters identify patients with IBD at higher risk of adverse disease outcomes who are high-volume users of healthcare.

Efficacy of psychological therapies in people with inflammatory bowel disease: a systematic review and meta-analysis.

BACKGROUND: There is increasing evidence for an influence of the gut-brain axis on the natural history of inflammatory bowel disease (IBD). Psychological therapies could, therefore, have beneficial effects in individuals with IBD, but data are conflicting. We aimed to update our previous systematic review and meta-analysis to assess whether the inclusion of more randomised controlled trials (RCTs) showed any beneficial effects and whether these effects varied by treatment modality. METHODS: In this systematic review and meta-analysis, we searched MEDLINE, Embase, Embase Classic, PsychINFO, and the Cochrane Central Register of Controlled Trials from Jan 1, 2016, to April 30, 2023, for RCTs published in any language recruiting individuals aged 16 years or older with IBD that compared psychological therapy with a control intervention or treatment as usual. We pooled dichotomous data to obtain relative risks (RR) with 95% CIs of inducing remission in people with active disease or of relapse in people with quiescent disease at final follow-up. We pooled continuous data to estimate standardised mean differences (SMD) with 95% CIs in disease activity indices, anxiety scores, depression scores, stress scores, and quality-of-life scores at completion of therapy and at final follow-up. We pooled all data using a random-effects model. Trials were analysed separately according to whether they recruited people with clinically active IBD or predominantly individuals whose disease was quiescent. We conducted subgroup analyses by mode of therapy and according to whether trials recruited selected groups of people with IBD. We used the Cochrane risk of bias tool to assess bias at the study level and assessed funnel plots using the Egger test. We assessed heterogeneity using the I2 statistic. FINDINGS: The updated literature search identified a total of 469 new records, 11 of which met eligibility criteria. 14 studies were included from our previous meta-analysis published in 2017. In total, 25 RCTs were eligible for this meta-analysis, all of which were at high risk of bias. Only four RCTs recruited patients with active IBD; there were insufficient data for meta-analysis of remission, disease activity indices, depression scores, and stress scores. In patients with active IBD, psychological therapy had no benefit compared with control for anxiety scores at completion of therapy (two RCTs; 79 people; SMD -1·04, 95% CI -2·46 to 0·39), but did have significant benefit for quality-of-life scores at completion of therapy (four RCTs; 309 people; 0·68, 0·09 to 1·26), although heterogeneity between studies was high (I2=82%). In individuals with quiescent IBD, RR of relapse of disease activity was not reduced with psychological therapy (ten RCTs; 861 people; RR 0·83, 95% CI 0·62 to 1·12), with moderate heterogeneity (I2=60%), and the funnel plot suggested evidence of publication bias or other small study effects (Egger test p=0·046). For people with quiescent IBD at completion of therapy, there was no difference in disease activity indices between psychological therapy and control (13 RCTs; 1015 people; SMD -0·01, 95% CI -0·13 to 0·12; I2=0%). Anxiety scores (13 RCTs; 1088 people; -0·23, -0·36 to -0·09; 18%), depression scores (15 RCTs; 1189 people; -0·26, -0·38 to -0·15; 2%), and stress scores (11 RCTs; 813 people; -0·22, -0·42 to -0·03; 47%) were significantly lower, and quality-of-life scores (16 RCTs; 1080 people; 0·31, 0·16 to 0·46; 30%) were significantly higher, with psychological therapy versus control at treatment completion. Statistically significant benefits persisted up to final follow-up for depression scores (12 RCTs; 856 people; -0·16, -0·30 to -0·03; 0%). Effects were strongest in RCTs of third-wave therapies and in RCTs that recruited people with impaired psychological health, fatigue, or reduced quality of life at baseline. INTERPRETATION: Psychological therapies have beneficial, short-term effects on anxiety, depression, stress, and quality-of-life scores, but not on disease activity. Further RCTs in selected groups are needed to establish the place for such therapies in IBD care. FUNDING: None.

A Diagnosis of Irritable Bowel Syndrome Using Rome IV Criteria and Limited Investigations is Durable in Secondary Care.

BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is a positive diagnosis, made using symptom-based criteria and limited, judicious, investigation. However, this may lead to uncertainty on the part of clinicians regarding potential for a missed diagnosis of organic gastrointestinal disease. Few studies have examined durability of a diagnosis of IBS, and none have used the current gold standard to diagnose IBS, the Rome IV criteria. METHODS: We collected complete symptom data from 373 well-characterized adults meeting Rome IV criteria for IBS referred to a single UK clinic between September 2016 and March 2020. All patients underwent relatively standardized work-up to exclude relevant organic disease before diagnosis. We followed these individuals up to December 2022, assessing rates of rereferral, reinvestigation, and missed organic gastrointestinal disease. RESULTS: During a mean follow-up of 4.2 years per patient (total follow-up in all patients, 1565 years), 62 (16.6%) patients were rereferred. Of these, 35 (56.5%) were rereferred for IBS and 27 (43.5%) for other gastrointestinal symptoms. Among the 35 rereferred with IBS this was caused by a change in symptoms in only 5 (14.3%). Reinvestigation was undertaken in 21 (60.0%) of 35 rereferred with IBS and 22 (81.5%) of 27 rereferred with other symptoms (P = .12). Only 4 (9.3% of those reinvestigated and 1.1% of the entire cohort) new cases of relevant organic disease, which may have been responsible for IBS symptoms at baseline, were identified (1 case of chronic calcific pancreatitis among those rereferred with IBS and 1 case each of inflammatory bowel disease-unclassified, moderate bile acid diarrhea, and small bowel obstruction among those rereferred with other gastrointestinal symptoms). CONCLUSIONS: Despite rereferral for gastrointestinal symptoms among 1 in 6 patients overall, with almost 10% rereferred with ongoing IBS symptoms, and substantial reinvestigation rates, missed organic gastrointestinal disease occurred in only 1%. A diagnosis of Rome IV IBS after limited investigation is safe and durable.

Impact of Baseline Disease Activity and Trial Duration on Efficacy of Biologics in Active Crohn's Disease: Meta-analysis.

BACKGROUND: Timings of assessment of efficacy and criteria used to define Crohn's disease (CD) activity at baseline may affect therapeutic gain of active drug over placebo in induction of remission trials in CD, but these issues have not been assessed systematically. We examined these issues in a meta-analysis. METHODS: We searched the literature to June 2022 for randomized controlled trials of biologics vs placebo in active CD. We extracted clinical remission and response rates according to criteria used to define CD activity and time point of assessment, pooling them in a meta-analysis for all patients according to previous biologic exposure. We calculated the number needed to treat (NNT), with a 95% confidence interval (CI) to assess therapeutic gain of active drug over placebo according to these characteristics of trial design. RESULTS: We identified 20 induction of remission trials (6754 patients). Rates of clinical remission were highest (42.6% with active drug vs 21.0% with placebo) and NNT lowest (5; 95% CI, 3-7.5) in trials using clinical and endoscopic activity to define active CD. Rates of remission were lower (26.5% with active drug, vs 18.6% with placebo) and NNT highest (12; 95% CI, 6-61) in trials using clinical activity alone. Results were similar according to previous biologic exposure. Time point of assessment seemed to have less of an effect, although the NNT was lowest in trials assessing remission rates at 9 to 12 weeks (NNT = 5.5; 95% CI, 4-8). Again, results were similar according to previous biologic exposure. CONCLUSIONS: Both the criteria used to define CD activity at study entry and the time point used to confirm efficacy may be important in maximizing therapeutic gain of active drug over placebo.

In this systematic review and meta-analysis of randomized controlled trials of biologics vs placebo in active CD, both the criteria used to define CD activity at study entry and the time point used to confirm efficacy appeared to be important in maximizing therapeutic gain of active drug over placebo.

Characteristics and Effect of Anxiety and Depression Trajectories in Inflammatory Bowel Disease.

INTRODUCTION: Symptoms of common mental disorders, such as anxiety or depression, are associated with adverse clinical outcomes in inflammatory bowel disease (IBD). We report trajectories of these symptoms in IBD, patient characteristics associated with different trajectories, and effects on healthcare utilization and prognosis. METHODS: We collected demographic, symptom, psychological, and quality-of-life data, with questionnaires at 3-month intervals, over 12 months of follow-up. We collected healthcare utilization and IBD outcomes through notes review. We compared characteristics of those with persistently normal or improving anxiety or depression scores with those with persistently abnormal or worsening scores and the number of flares, glucocorticosteroid prescriptions, escalations of therapy, hospitalizations, or intestinal resections due to IBD activity. RESULTS: Among 771 and 777 patients, respectively, worsening or persistently abnormal anxiety or depression scores were associated with increased antidepressant (28.6% vs 12.3% anxiety, 35.8% vs 10.1% depression, P < 0.001) and opiate use (19.0% vs 7.8% anxiety, P = 0.001 and 34.0% vs 7.4% depression, P < 0.001), compared with those with persistently normal or improving scores. These individuals were also more likely to have been diagnosed with IBD in the last 12 months (16.3% vs 5.0% anxiety, P = 0.001, and 15.1% vs 5.5% depression, P = 0.006), to have clinically active disease at baseline (57.1% vs 26.6% anxiety and 71.7% vs 29.1% depression, P < 0.001) and lower quality-of-life scores ( P < 0.001). Individuals with worsening or persistently abnormal trajectories of anxiety or depression required significantly more outpatient appointments, radiological investigations, and endoscopic procedures for IBD-related symptoms. DISCUSSION: In this 12-month follow-up study, patients with IBD with worsening or persistently high anxiety or depression scores were higher utilizers of health care but were not at an increased risk of future adverse disease outcomes.

Efficacy of biological therapies and small molecules in induction and maintenance of remission in luminal Crohn's disease: systematic review and network meta-analysis.

OBJECTIVE: There are numerous biological therapies and small molecules licensed for luminal Crohn's disease (CD), but these are often studied in placebo-controlled trials, meaning relative efficacy is uncertain. We examined this in a network meta-analysis. DESIGN: We searched the literature to 1 July 2022, judging efficacy according to induction of clinical remission, clinical response and maintenance of clinical remission, and according to previous exposure or non-exposure to biologics. We used a random effects model and reported data as pooled relative risks (RRs) with 95% CIs, ranking drugs according to p-score. RESULTS: We identified 25 induction of remission trials (8720 patients). Based on failure to achieve clinical remission, infliximab 5 mg/kg ranked first versus placebo (RR=0.67, 95% CI 0.56 to 0.79, p-score 0.95), with risankizumab 600 mg second and upadacitinib 45 mg once daily third. However, risankizumab 600 mg ranked first for clinical remission in biologic-naïve (RR=0.66, 95% CI 0.52 to 0.85, p-score 0.78) and in biologic-exposed patients (RR=0.74, 95% CI 0.67 to 0.82, p-score 0.92). In 15 maintenance of remission trials (4016 patients), based on relapse of disease activity, upadacitinib 30 mg once daily ranked first (RR=0.61, 95% CI 0.52 to 0.72, p-score 0.93) with adalimumab 40 mg weekly second, and infliximab 10 mg/kg 8-weekly third. Adalimumab 40 mg weekly ranked first in biologic-naïve patients (RR=0.59, 95% CI 0.48 to 0.73, p-score 0.86), and vedolizumab 108 mg 2-weekly first in biologic-exposed (RR=0.70, 95% CI 0.57 to 0.86, p-score 0.82). CONCLUSION: In a network meta-analysis, infliximab 5 mg/kg ranked first for induction of clinical remission in all patients with luminal CD, but risankizumab 600 mg was first in biologic-naïve and biologic-exposed patients. Upadacitinib 30 mg once daily ranked first for maintenance of remission.

Natural history and impact of irritable bowel syndrome-type symptoms in inflammatory bowel disease during 6 years of longitudinal follow-up.

BACKGROUND: The long-term natural history and impact of irritable bowel syndrome (IBS)-type symptoms on outcomes in inflammatory bowel disease (IBD) are uncertain. AIM: To assess this in a longitudinal follow-up study of patients in secondary care METHODS: We assessed the natural history of IBS-type symptoms in IBD via Rome III criteria applied at baseline, and 2 and 6 years. We defined longitudinal disease activity as the need for glucocorticosteroids or flare, escalation, hospitalisation or intestinal resection. To assess healthcare utilisation, we recorded the number of outpatient clinic attendances and investigations. We also collected anxiety, depression and somatoform symptom scores and quality of life scores during follow-up. RESULTS: Among 125 individuals with Rome III data at all three time points, only 41 (32.8%) never reported IBS-type symptoms. Fifteen patients (12.0%) had IBS-type symptoms at baseline that resolved, 19 (15.2%) had fluctuating symptoms, 35 (28.0%) had new-onset symptoms, and 15 (12.0%) had persistent symptoms. Among more than 300 patients with IBD activity data, IBS-type symptoms were not associated with an increased likelihood of the need for glucocorticosteroids or flare, escalation, hospitalisation or intestinal resection. However, the mean numbers of outpatient appointments and endoscopic investigations were significantly higher among those with IBS-type symptoms. Anxiety, depression and somatoform symptom scores were significantly higher, and quality of life scores were significantly lower, in those reporting IBS-type symptoms at least once during the study. CONCLUSIONS: IBS-type symptoms affected more than two-thirds of patients with IBD during >6 years of follow-up and were associated with increased healthcare utilisation, and worse anxiety, depression, somatoform symptom and quality of life scores, but not adverse disease activity outcomes.

Relative Contribution of Disease Activity and Psychological Health to Prognosis of Inflammatory Bowel Disease During 6.5 Years of Longitudinal Follow-Up.

BACKGROUND & AIMS: Symptoms of common mental disorders, such as anxiety or depression, are common in inflammatory bowel disease (IBD) and may affect prognosis. However, unlike clinical or biochemical markers of disease activity, psychological health is not a recommended therapeutic target. We assessed relative contribution of poor psychological health and clinical or biochemical activity to prognosis. METHODS: Demographic features, IBD subtype, treatments, and anxiety and depression scores were recorded at baseline for 760 adults, with clinical activity determined using validated scoring systems. Fecal calprotectin was analyzed in 379 (49.9%) patients (≥250 µg/g used to define biochemical activity). Glucocorticosteroid prescription or flare, escalation, hospitalization, intestinal resection, or death were assessed during 6.5 years of follow-up. Occurrence was compared using multivariate Cox regression across 4 patient groups according to presence of disease remission or activity, with or without symptoms of a common mental disorder, at baseline. RESULTS: In total, 718 (94.5%) participants provided data. Compared with clinical remission without symptoms of a common mental disorder at baseline, need for glucocorticosteroid prescription or flare (hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.58-3.54), escalation (HR, 1.65; 95% CI, 1.14--2.40), and death (HR, 4.99; 95% CI, 1.80-13.88) were significantly higher in those with clinical activity and symptoms of a common mental disorder. Rates in those with clinical remission and symptoms of a common mental disorder at baseline or those with clinical activity without symptoms of a common mental disorder were not significantly higher. Similarly, with biochemical activity and symptoms of a common mental disorder, rates of glucocorticosteroid prescription or flare (HR, 2.48; 95% CI, 1.38-4.46), escalation (HR, 2.97; 95% CI, 1.74-5.06), hospitalization (HR, 3.10; 95% CI, 1.43-6.68), and death (HR, 6.26; 95% CI, 2.23-17.56) were significantly higher. CONCLUSIONS: Psychological factors are important determinants of poor prognostic outcomes in IBD and should be considered as a therapeutic target.

Prognosis of patients with Rome IV-defined versus physician-diagnosed irritable bowel syndrome: Longitudinal follow-up study.

INTRODUCTION: Little is known about the differences between patients diagnosed with irritable bowel syndrome (IBS) by a physician who meet the Rome IV criteria for IBS and those who do not. We conducted a longitudinal follow-up study examining this. METHODS: We collected complete gastrointestinal, extraintestinal, and psychological symptom data from 577 consecutive adult patients with suspected IBS in a single UK gastroenterology clinic. We compared baseline characteristics between patients who met Rome IV criteria for IBS, and those who had IBS according to a physician's diagnosis but who did not meet Rome IV criteria, as well as examining whether meeting Rome IV criteria at baseline influenced evolution of symptoms under therapy. KEY RESULTS: Of 455 patients diagnosed with IBS by a physician, 375 (82.4%) met Rome IV criteria and 80 (17.4%) did not. Those who met Rome IV criteria were more likely to report severe symptoms (67.6%, vs. 30.0%, p < 0.001) and that symptoms limited activities ≥50% of the time (63.0%, vs. 37.5%, p < 0.001). Patients with Rome IV IBS were more likely to have abnormal anxiety scores (50.8%, vs. 35.9%, p = 0.007) and higher levels of somatoform symptom-reporting (29.4%, vs. 12.5%, p < 0.001). Despite this, during longitudinal follow-up, there was no significant difference in mean number of appointments required subsequently, or IBS symptom severity. CONCLUSIONS AND INFERENCES: Although patients who met the Rome IV criteria had more severe symptoms at baseline and were more likely to exhibit psychological comorbidity, they did not appear to have a worse prognosis than those with physician-diagnosed IBS.

Bidirectional brain-gut axis effects influence mood and prognosis in IBD: a systematic review and meta-analysis.

OBJECTIVE: The role of the brain-gut axis is of increasing interest in IBD, as the link between common mental disorders and GI inflammation may be bidirectional. We performed a systematic review examining these issues. DESIGN: We searched EMBASE Classic and EMBASE, Medline, and APA PsychInfo (to 11 July 2021) for longitudinal follow-up studies examining effect of symptoms of anxiety or depression on subsequent adverse outcomes in IBD, or effect of active IBD on subsequent development of symptoms of anxiety or depression. We pooled relative risks (RRs) and HRs with 95% CIs for adverse outcomes (flare, escalation of therapy, hospitalisation, emergency department attendance, surgery or a composite of any of these) according to presence of symptoms of anxiety or depression at baseline, or RRs and HRs with 95% CIs for new onset of symptoms of anxiety or depression according to presence of active IBD at baseline. RESULTS: We included 12 separate studies, recruiting 9192 patients. All 12 studies examined brain-to-gut effects. Anxiety at baseline was associated with significantly higher risks of escalation of therapy (RR=1.68; 95% CI 1.18 to 2.40), hospitalisation (RR=1.72; 95% CI 1.01 to 2.95), emergency department attendance (RR=1.30; 95% CI 1.21 to 1.39), or a composite of any adverse outcome. Depression at baseline was associated with higher risks of flare (RR=1.60; 95% CI 1.21 to 2.12), escalation of therapy (RR=1.41; 95% CI 1.08 to 1.84), hospitalisation (RR=1.35; 95% CI 1.17 to 1.57), emergency department attendance (RR=1.38; 95% CI 1.22 to 1.56), surgery (RR=1.63; 95% CI 1.19 to 2.22) or a composite of any of these. Three studies examined gut-to-brain effects. Active disease at baseline was associated with future development of anxiety or depression (RR=2.24; 95% CI 1.25 to 4.01 and RR=1.49; 95% CI 1.11 to 1.98, respectively). CONCLUSION: Bidirectional effects of the brain-gut axis are present in IBD and may influence both the natural history of the disease and psychological health.

Prevalence and impact of Rome IV versus Rome III irritable bowel syndrome in patients with inflammatory bowel disease.

BACKGROUND: Irritable bowel syndrome (IBS)-type symptoms are common in inflammatory bowel disease (IBD), but few studies have examined the prevalence and impact of IBS-type symptoms in IBD according to Rome IV criteria. METHODS: We collected demographic, symptom (Rome III, Rome IV, and clinical disease activity indices), psychological (anxiety, depression, and somatization), and quality of life data from 973 IBD patients. Medical records were reviewed to document disease type, extent/location, behavior, medical therapy, and antidepressant or opioid use. We compared characteristics of individuals with no IBS-type symptoms, Rome III IBS-type symptoms, and Rome IV IBS-type symptoms. KEY RESULTS: In total, 302 (31.0%) patients met the Rome III criteria for IBS, and 172 (17.7%) met Rome IV criteria. Those with IBS-type symptoms were younger, more likely to be female, and had higher rates of antidepressant (p = 0.006) or opioid use (p = 0.001). Rome IV IBS-type symptoms were associated with symptoms of mood disorders, flare of disease activity, and lower quality of life scores (p < 0.001 for all analyses). Compared with Rome III criteria, those with Rome IV IBS-type symptoms had significantly higher rates of anxiety (p < 0.001), depression (p = 0.002), and somatization (p < 0.001), lower quality of life scores (p < 0.001) and were more likely to have CD (p = 0.011), with ileal distribution (p = 0.006). CONCLUSIONS AND INFERENCES: Rome IV IBS-type symptoms are associated with increased psychological co-morbidity, lower quality of life scores, and higher rates of antidepressant or opioid use. This is a cohort potentially at risk of adverse clinical outcomes and should be a focus for future research.

Efficacy of biological therapies and small molecules in moderate to severe ulcerative colitis: systematic review and network meta-analysis.

OBJECTIVE: Biological therapies and small molecules continue to be evaluated in moderate to severely active ulcerative colitis, but are often studied in placebo-controlled trials, meaning their relative efficacy and safety is unknown. We examined this in a network meta-analysis. DESIGN: We searched the literature to October 2021 to identify eligible trials. We judged efficacy using clinical remission, endoscopic improvement, or clinical response, and according to previous exposure or non-exposure to antitumour necrosis factor (TNF)-α therapy. We also assessed safety. We used a random effects model and reported data as pooled relative risks (RRs) with 95% CIs. Interventions were ranked according to their P-score. RESULTS: We identified 28 trials (12 504 patients). Based on failure to achieve clinical remission, upadacitinib 45 mg once daily ranked first versus placebo (RR 0.73; 95% CI 0.68 to 0.80, P-score 0.98), with infliximab 5 mg/kg and 10 mg/kg second and third, respectively. Upadacitinib ranked first for clinical remission in both patients naïve to anti-TNF-α drugs (RR 0.69; 95% CI 0.61 to 0.78, P-score 0.99) and previously exposed (RR 0.78; 95% CI 0.72 to 0.85, P-score 0.99). Upadacitinib was superior to almost all other drugs in these analyses. Based on failure to achieve endoscopic improvement infliximab 10 mg/kg ranked first (RR 0.61; 95% CI 0.51 to 0.72, P-score 0.97), with upadacitinib 45 mg once daily, second, and infliximab 5 mg/kg third. Upadacitinib was more likely to lead to adverse events, but serious adverse events were no more frequent, and withdrawals due to adverse events were significantly lower than with placebo. Infections were significantly more likely with tofacitinib than placebo (RR 1.41; 95% CI 1.03 to 1.91). CONCLUSION: In a network meta-analysis, upadacitinib 45 mg once daily ranked first for clinical remission in all patients, patients naïve to anti-TNF-α drugs and patients previously exposed. Infliximab 10 mg/kg ranked first for endoscopic improvement. Most drugs were safe and well tolerated.

Infliximab Therapeutic Drug Monitoring in Inflammatory Bowel Disease Virtual Biologics Clinic Leads to Durable Clinical Results.

BACKGROUND: Therapeutic drug monitoring (TDM) of infliximab (IFX) trough levels and anti-drug antibodies in conjunction with symptoms, disease history, and investigations can aid decision-making. This study evaluated 1-year outcomes of patients with decisions that were altered on the basis of TDM results, in order to investigate whether outcomes from TDM-based decisions to adjust or stop IFX treatment are durable. METHODS: We retrospectively collected clinical outcomes 12 months post treatment decisions based on proactive TDM. Patients whose initial treatment decisions were altered on the basis of TDM results were compared with those where the decision remained unchanged. Events of interest were inpatient admissions with active inflammatory bowel disease (IBD), further changes to biologic therapy, and IBD-related health-care costs. RESULTS: Of 189 patients, 54 (28%) had initial treatment decisions altered in the light of TDM results. The 135 patients whose initial decision was not altered in light of TDM results served as the comparator. There were no differences in hospitalization rates or subsequent biologic switches between the altered decision groups and the comparator group. IBD-related health-care costs were higher in those whose initial decision was altered (median GBP 7,912 vs. GBP 6,521; p < 0.0001) due to higher drug costs (median GBP 7,062 vs. GBP 6,012; p < 0.0001). CONCLUSION: Our study demonstrates good outcomes from changes to IFX treatment based on TDM. Patients with a decision to stop, switch, or continue with an adjusted IFX dose experienced comparable clinical outcomes but had higher drug-related expenditure than those whose treatment decision was not altered in light of TDM.

Longitudinal follow-up study: effect of psychological co-morbidity on the prognosis of inflammatory bowel disease.

BACKGROUND: Psychological co-morbidity is more common in patients with inflammatory bowel disease (IBD), compared with the general population, but little is known about the cumulative effect of increasing psychological burden on disease behaviour. AIMS: To examine the effect of psychological co-morbidity on inflammatory bowel disease in a longitudinal follow-up study. METHODS: We collected complete demographic, symptom and psychological co-morbidity data (anxiety, depression and somatisation scores) at baseline from adults with IBD in biochemical remission (faecal calprotectin <250 µg/g). Objective markers of disease activity, including glucocorticosteroid prescription or flare of disease activity, escalation of therapy, hospitalisation or intestinal resection, were reviewed ≥2 years of follow-up. We performed multivariate Cox regression, controlling for patient characteristics and follow-up duration, to examine cumulative effect of psychological co-morbidities on subsequent IBD behaviour. RESULTS: Among 218 participants, 48 (22.0%) had one, 13 (6.0%) two and nine (4.1%) three psychological co-morbidities at baseline. Following multivariate Cox regression analysis, glucocorticosteroid prescription or flare, and escalation of medical therapy were significantly higher among those with two (hazard ratio [HR] = 3.18; 95% confidence interval [CI] 1.44-7.02, and HR = 2.48; 95% CI 1.03-5.93, respectively) or three (HR = 3.53; 95% CI 1.26-9.92, and HR = 8.19; 95% CI 2.88-23.23, respectively) psychological co-morbidities. Occurrence of at least one endpoint of interest was significantly higher with increasing psychological co-morbidity (HR = 1.74; 95% CI 1.07-2.82 for one, HR = 2.47; 95% CI 1.12-5.46 for two and HR = 4.93; 95% CI 1.84-13.17 for three psychological co-morbidities). CONCLUSIONS: Individuals with IBD in biochemical remission experienced a worse disease course with increasing psychological co-morbidity at baseline.