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.

Implications for sequencing of biologic therapy and choice of second anti-TNF in patients with inflammatory bowel disease: results from the IMmunogenicity to Second Anti-TNF therapy (IMSAT) therapeutic drug monitoring study.

BACKGROUND: Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD). AIM: To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence METHODS: We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF agent, defined at any timepoint as an anti-TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab. RESULTS: In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27-3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46-4.80, p < 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38-2.17, p < 0.001) and 1.99 (95%CI 1.34-2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39-4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure. CONCLUSION: Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure.

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.

When Your Pregnancy Echoes Your Illness: Transition to Motherhood With Inflammatory Bowel Disease.

Our aim is to provide an understanding of the experience of women with inflammatory bowel disease (IBD) who have made the transition to motherhood. A total of 22 mothers with IBD were recruited from around the United Kingdom. Semi-structured interviews were conducted and analyzed using thematic analysis. The central concept- Blurred Lines-offers a novel frame for understanding the transition to motherhood with IBD through identifying parallels between having IBD and becoming, and being, a mother. Parallels clustered into three main themes: Need for Readiness, Lifestyle Changes, and Monitoring Personal and Physical Development. Hence, women with IBD are in some ways well prepared for the challenges of motherhood even though, as a group, they tend to restrict their reproductive choices. We recommend health professionals initiate conversations about reproduction early and provide a multidisciplinary approach to pregnancy and IBD in which women have confidence that their ongoing treatment will be integrated successfully with their maternity care.