Withdrawal of Immunomodulators or TNF Antagonists in Patients With Inflammatory Bowel Diseases in Remission on Combination Therapy: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Withdrawal of immunomodulators (IMMs) or tumor necrosis factor (TNF) antagonists in patients with inflammatory bowel diseases (IBDs) in remission on combination therapy is attractive. We evaluated the efficacy and safety of (1) IMM, or (2) TNF antagonist withdrawal in patients with IBD in sustained remission on combination therapy. METHODS: Through a systematic review till March 31, 2023, we identified randomized controlled trials (RCTs) that compared the efficacy and safety of IMM or TNF antagonist withdrawal vs continued combination therapy, in patients with IBD in sustained corticosteroid-free clinical remission for >6 months on combination therapy. Primary outcome was risk of relapse and serious adverse events at 12 months. We conducted meta-analysis to calculate relative risk (RR) and 95% confidence interval (CI) and used Grading of Recommendations Assessment, Development and Evaluation (GRADE) to appraise certainty of evidence. RESULTS: We identified 8 RCTs with 733 patients (77% with Crohn's disease, 91% on infliximab-based combination therapy). On meta-analysis of 5 RCTs, there was no difference in the risk of relapse between patients with IMM withdrawal (continued TNF antagonist monotherapy) vs continued combination therapy (16.8% vs 14.9%; RR, 1.15; 95% CI, 0.75-1.76) without heterogeneity (low certainty of evidence). TNF antagonist withdrawal (continued IMM monotherapy) was associated with 2.4-times higher risk of relapse compared with continuing combination therapy (31.5% vs 11.2%; RR, 2.35; 95% CI, 1.38-4.01), with minimal heterogeneity (low certainty of evidence). There was no difference in the risk of serious adverse events with IMM or TNF antagonist withdrawal vs continued combination therapy. CONCLUSIONS: In patients with IBD in sustained corticosteroid-free clinical remission for >6 months on combination therapy, de-escalation with TNF antagonist withdrawal, but not IMM withdrawal, was associated with an increased risk of relapse.

Fecal and Mucosa-Associated Intestinal Microbiota in Patients with Diarrhea-Predominant Irritable Bowel Syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) has been associated with changes in the intestinal microbiota. Only a few studies have explored differences in the mucosa-associated microbiota between IBS patients and healthy controls (HC). AIMS: To characterize and compare the microbiota in mucosal and fecal samples from carefully selected patients with IBS-D and HC. METHODS: The cohort was composed of 23 diarrhea-predominant IBS (IBS-D) patients and 24 HC. Fresh stool samples were collected from participants prior to the collection of colonic mucosal samples from an unprepped bowel. After DNA extraction, 16S rRNA genes were sequenced by 454 pyrosequencing and analyzed using the QIIME pipeline. RESULTS: The fecal microbiota (luminal niche) of IBS-D patients was found to have reduced enteric richness compared to HC (P < 0.05), whereas no differences were observed between the two groups within the mucosal microbiota. Within the luminal niche, the relative proportions of Faecalibacterium genus were found to be lower in IBS-D than in HC and the Dorea genus was higher in IBS-D. None of the taxa proportions were significantly different in IBS-D patients versus HC using an FDR of ≤ 0.1 when analyzing samples that appeared in > 25% samples of either niche. CONCLUSION: Fecal and mucosal microbiota of IBS-D patients and HC are very similar and are not sufficient to explain the reported altered physiology and symptomatology of IBS-D. Future studies should investigate intestinal microbiome-dependent functional activity in addition to the fecal and mucosal-associated microbial composition.

Sex and disease-related alterations of anterior insula functional connectivity in chronic abdominal pain.

Resting-state functional magnetic resonance imaging has been used to investigate intrinsic brain connectivity in healthy subjects and patients with chronic pain. Sex-related differences in the frequency power distribution within the human insula (INS), a brain region involved in the integration of interoceptive, affective, and cognitive influences, have been reported. Here we aimed to test sex and disease-related alterations in the intrinsic functional connectivity of the dorsal anterior INS. The anterior INS is engaged during goal-directed tasks and modulates the default mode and executive control networks. By comparing functional connectivity of the dorsal anterior INS in age-matched female and male healthy subjects and patients with irritable bowel syndrome (IBS), a common chronic abdominal pain condition, we show evidence for sex and disease-related alterations in the functional connectivity of this region: (1) male patients compared with female patients had increased positive connectivity of the dorsal anterior INS bilaterally with the medial prefrontal cortex (PFC) and dorsal posterior INS; (2) female patients compared with male patients had greater negative connectivity of the left dorsal anterior INS with the left precuneus; (3) disease-related differences in the connectivity between the bilateral dorsal anterior INS and the dorsal medial PFC were observed in female subjects; and (4) clinical characteristics were significantly correlated to the insular connectivity with the dorsal medial PFC in male IBS subjects and with the precuneus in female IBS subjects. These findings are consistent with the INS playing an important role in modulating the intrinsic functional connectivity of major networks in the resting brain and show that this role is influenced by sex and diagnosis.

Neuropsychiatric symptoms and regional neocortical atrophy in mild cognitive impairment and Alzheimer's disease.

BACKGROUND: To assess the relationship between regional neocortical atrophy and psychotic symptoms in adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD). METHODS: Rates of change in regional neocortical atrophy as measured by longitudinal magnetic resonance imaging scans and the occurrence of psychotic symptoms and/or the long-term use of antipsychotic medications in 389 outpatients with MCI or AD in Alzheimer's Disease Neuroimaging Initiative. RESULTS: Atrophy rate of 3 specific neocortical regions, lateral frontal, lateral parietal, and anterior cingulate gyrus, was significantly associated with the onset of psychosis including delusions, agitation, wandering, and hallucinations and/or the need for chronic antipsychotic medications. Atrophy rate of the lateral frontal lobe correlated most significantly with onset of psychotic symptoms or need for chronic antipsychotic medications. CONCLUSIONS: Psychosis was associated with volume loss in specific regions of the lateral frontal and parietal lobes as well as anterior cingulate gyrus.