Systematic review with network meta-analysis: Risk of Herpes zoster with biological therapies and small molecules in inflammatory bowel disease.

BACKGROUND: Biologics and small molecules for inflammatory bowel disease (IBD) may increase infection risk. Herpes zoster causes acute and long-term symptoms, but vaccination is not recommended in patients with IBD, unless >50 years of age. AIMS: To examine risk of Herpes zoster infection with all licensed biologics and small molecules for IBD using network meta-analysis. METHODS: We searched the literature to 4th October 2022, for randomised controlled trials of these drugs in luminal Crohn's disease or ulcerative colitis reporting data on occurrence of Herpes zoster infection during follow-up. We used a frequentist approach and a random effects model, pooling data as relative risks (RRs) with 95% confidence intervals (CIs). RESULTS: We identified 25 trials (9935 patients). Only tofacitinib 10 mg b.d. (RR = 6.90; 95% CI 1.56-30.63, number needed to harm (NNH) = 97; 95% CI 19-1022) and upadacitinib 45 mg o.d. (RR = 7.89; 95% CI 1.04-59.59, NNH = 83; 95% CI 10-14,305) were significantly more likely to increase risk of Herpes zoster infection. Janus kinase inhibitors were the most likely drug class to increase risk of infection, and risk increased with higher doses (RR with lowest dose = 3.16; 95% CI 1.02-9.84, NNH = 265; 95% CI 65-28,610, RR with higher dose = 5.91; 95% CI 2.21-15.82, NNH = 117; 95% CI 39-473). CONCLUSIONS: In a network meta-analysis, the janus kinase inhibitor tofacitinib, and all janus kinase inhibitors considered as a class, were most likely to increase risk of Herpes zoster infection. Risk increased with higher doses.

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.

Systematic review and meta-analysis: efficacy of peppermint oil in irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is one of the most common disorders of gut-brain interaction, with a complex pathophysiology. Antispasmodics are prescribed as first-line therapy because of their action on gut dysmotility. In this regard, peppermint oil also has antispasmodic properties. AIM: To update our previous meta-analysis to assess efficacy and safety of peppermint oil, particularly as recent studies have cast doubt on its role in the treatment of IBS METHODS: We searched the medical literature up to 2nd April 2022 to identify randomised controlled trials (RCTs) of peppermint oil in IBS. Efficacy and safety were judged using dichotomous assessments of effect on global IBS symptoms or abdominal pain, and occurrence of any adverse event or of gastro-oesophageal reflux. Data were pooled using a random effects model, with efficacy and safety reported as pooled relative risks (RRs) with 95% confidence intervals (CIs). RESULTS: We identified 10 eligible RCTs (1030 patients). Peppermint oil was more efficacious than placebo for global IBS symptoms (RR of not improving = 0.65; 95% CI 0.43-0.98, number needed to treat [NNT] = 4; 95% CI 2.5-71), and abdominal pain (RR of abdominal pain not improving = 0.76; 95% CI 0.62-0.93, NNT = 7; 95% CI 4-24). Adverse event rates were significantly higher with peppermint oil (RR of any adverse event = 1.57; 95% CI 1.04-2.37). CONCLUSIONS: Peppermint oil was superior to placebo for the treatment of IBS, but adverse events were more frequent, and quality of evidence was very low. Adequately powered RCTs of peppermint oil as first-line treatment for IBS are needed.

British Society of Gastroenterology guidelines on the management of irritable bowel syndrome.

Irritable bowel syndrome (IBS) remains one of the most common gastrointestinal disorders seen by clinicians in both primary and secondary care. Since publication of the last British Society of Gastroenterology (BSG) guideline in 2007, substantial advances have been made in understanding its complex pathophysiology, resulting in its re-classification as a disorder of gut-brain interaction, rather than a functional gastrointestinal disorder. Moreover, there has been a considerable amount of new evidence published concerning the diagnosis, investigation and management of IBS. The primary aim of this guideline, commissioned by the BSG, is to review and summarise the current evidence to inform and guide clinical practice, by providing a practical framework for evidence-based management of patients. One of the strengths of this guideline is that the recommendations for treatment are based on evidence derived from a comprehensive search of the medical literature, which was used to inform an update of a series of trial-based and network meta-analyses assessing the efficacy of dietary, pharmacological and psychological therapies in treating IBS. Specific recommendations have been made according to the Grading of Recommendations Assessment, Development and Evaluation system, summarising both the strength of the recommendations and the overall quality of evidence. Finally, this guideline identifies novel treatments that are in development, as well as highlighting areas of unmet need for future research.

Efficacy of psychological therapies for irritable bowel syndrome: systematic review and network meta-analysis.

OBJECTIVES: National guidelines for the management of irritable bowel syndrome (IBS) recommend that psychological therapies should be considered, but their relative efficacy is unknown, because there have been few head-to-head trials. We performed a systematic review and network meta-analysis to try to resolve this uncertainty. DESIGN: We searched the medical literature through January 2020 for randomised controlled trials (RCTs) assessing efficacy of psychological therapies for adults with IBS, compared with each other, or a control intervention. Trials reported a dichotomous assessment of symptom status after completion of therapy. We pooled data using a random effects model. Efficacy was reported as a pooled relative risk (RR) of remaining symptomatic, with a 95% CI to summarise efficacy of each comparison tested, and ranked by therapy according to P score. RESULTS: We identified 41 eligible RCTs, containing 4072 participants. After completion of therapy, the psychological interventions with the largest numbers of trials, and patients recruited, demonstrating efficacy included self-administered or minimal contact cognitive behavioural therapy (CBT) (RR 0.61; 95% CI 0.45 to 0.83, P score 0.66), face-to-face CBT (RR 0.62; 95% CI 0.48 to 0.80, P score 0.65) and gut-directed hypnotherapy (RR 0.67; 95% CI 0.49 to 0.91, P score 0.57). After completion of therapy, among trials recruiting only patients with refractory symptoms, group CBT and gut-directed hypnotherapy were more efficacious than either education and/or support or routine care, and CBT via the telephone, contingency management, CBT via the internet and dynamic psychotherapy were all superior to routine care. Risk of bias of trials was high, with evidence of funnel plot asymmetry; the efficacy of psychological therapies is therefore likely to have been overestimated. CONCLUSIONS: Several psychological therapies are efficacious for IBS, although none were superior to another. CBT-based interventions and gut-directed hypnotherapy had the largest evidence base and were the most efficacious long term. TRIAL REGISTRATION NUMBER: The study protocol was published on the PROSPERO international prospective register of systematic reviews (registration number CRD 42020163246).

Efficacy of soluble fibre, antispasmodic drugs, and gut-brain neuromodulators in irritable bowel syndrome: a systematic review and network meta-analysis.

BACKGROUND: Although novel therapies for irritable bowel syndrome (IBS) continue to be developed, many doctors rely on more established, traditional therapies as first-line or second-line treatment options. These therapies include soluble fibre (eg, ispaghula husk), antispasmodic drugs, peppermint oil, and gut-brain neuromodulators (including tricyclic antidepressants, selective serotonin reuptake inhibitors, or α-2-δ calcium channel subunit ligands). However, the relative efficacy of traditional treatments in patients with IBS is unclear because there have been few head-to-head randomised controlled trials (RCTs). We aimed to compare and rank the efficacy of traditional therapies in patients with IBS to help inform clinical decisions. METHODS: For this systematic review and network meta-analysis, we searched MEDLINE, Embase, Embase Classic, and the Cochrane Central Register of Controlled Trials from inception to week 2 of August 2019; ClinicalTrials.gov for unpublished trials or supplementary data published up to Aug 18, 2019; and gastroenterology conference proceedings for study abstracts published between 2001 and Aug 18, 2019. We included RCTs that compared any of these treatments with each other (head-to-head trials) or with placebo, in which the efficacy of soluble fibre, antispasmodic drugs, peppermint oil, or gut-brain neuromodulators was assessed in adults (aged at least 18 years) with IBS of any subtype after 4-12 weeks of treatment. Only RCTs reporting a dichotomous assessment of overall response to therapy, in terms of either improvement in global IBS symptoms or improvement in abdominal pain, were included. The efficacy and safety of all treatments were reported as a pooled relative risk (RR) with 95% CIs to summarise the effect of each comparison tested, and treatments were ranked according to their P-score. FINDINGS: Our search identified 5863 references, of which 81 were screened for eligibility. 51 RCTs with data from 4644 patients were eligible for inclusion in our analysis, but only 13 of these trials were at low risk of bias. Based on an endpoint of failure to achieve improvement in global IBS symptoms at 4-12 weeks, peppermint oil capsules were ranked first for efficacy (RR 0·63, 95% CI 0·48-0·83, P-score 0·84) and tricyclic antidepressants were ranked second (0·66, 0·53-0·83, P-score 0·77). For failure to achieve an improvement in global IBS symptoms at 4-12 weeks, there were no significant differences between active treatments after direct or indirect comparisons. For failure to achieve improvement in abdominal pain at 4-12 weeks, tricyclic antidepressants were ranked first for efficacy (0·53, 0·34-0·83, P-score 0·87); however, this result was based on data from only four RCTs involving 92 patients. For failure to achieve an improvement in abdominal pain, none of the active treatments showed superior efficacy upon indirect comparison. Tricyclic antidepressants were more likely than placebo to lead to adverse events (1·59, 1·26-2·06, P-score 0·16). INTERPRETATION: In this network meta-analysis of RCTs of soluble fibre, antispasmodic drugs, peppermint oil, and gut-brain neuromodulators for IBS, few of which were judged as being at a low risk of bias, peppermint oil was ranked first for efficacy when global symptoms were used as the outcome measure, and tricyclic antidepressants were ranked first for efficacy when abdominal pain was used as the outcome measure. However, because of the lack of methodological rigour of some RCTs analysed in our study, there is likely to be considerable uncertainty around these findings. In addition, because treatment duration in most included trials was 4-12 weeks, the long-term relative efficacy of these treatments is unknown. FUNDING: None.