Prognostic value of systemic immune-inflammation index in patients with metastatic renal cell carcinoma treated with systemic therapy: a meta-analysis.

Objective: A novel systemic immune-inflammation index (SII), based on the neutrophils, lymphocytes, and platelet counts, is associated with the prognosis of several cancers, including non-metastatic renal cell carcinoma (RCC). In the present study, we evaluate the prognostic significance of SII in patients with metastatic RCC (mRCC) treated with systemic therapy. Method: Relevant studies were searched comprehensively from Web of Science, PubMed, Embase and the Cochrane Library up to January 2024. The pooled hazard ratio (HR) and 95% confidence interval (CI) were extracted from each study to evaluate the prognostic value of SII in patients with mRCC treated with tyrosine kinase inhibitor (TKI) or immune checkpoint inhibitor (ICI). Results: A total of 12 studies including 4,238 patients were included in the final analysis. High SII was significantly correlated to poor overall survival (OS, HR = 1.88; 95% CI 1.60-2.21; P < 0.001) and progression-free survival (PFS, HR = 1.66; 95% CI 1.39-1.99; P < 0.001). Stratified by therapy, high SII was also related to the poor OS (TKI: HR = 1.63, P < 0.001; ICI: HR = 2.27, P < 0.001) and PFS (TKI: HR = 1.67, P < 0.001; ICI: HR = 1.88, P = 0.002). Conclusion: In conclusion, high SII could serve as an unfavorable factor in patients with mRCC treated with systemic therapy. Stratified by therapies, the elevated SII was also associated with worse prognosis. Whereas, more prospective and large-scale studies are warranted to validate our findings. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024522831, identifier CRD42024522831.

Circulating and intestinal regulatory T cells in inflammatory bowel disease: A systemic review and meta-analysis.

Regulatory T cells (Tregs) play an important immunosuppressive role in inflammatory bowel disease (IBD). However, findings on the quantitative and functional changes of intestinal and circulating Tregs in patients with IBD are rather contradictory. We therefore conducted a meta-analysis on this issue. The pooled effect was assessed using the standardized mean difference (SMD) with a 95% confidence interval (CI), and subgroup analyses were performed to investigate heterogeneity. This analysis included 764 IBD (402 UC and 362 CD) patients and 341 healthy controls (HCs) pooled from 17 eligible studies. The percentage of circulating Tregs was significantly decreased in active IBD patients compared to HCs (SMD = -0.95, p < 0.001) and inactive IBD patients (SMD = -0.80, p < 0.001). There was no difference in the percentage of circulating Tregs between inactive IBD patients and HCs. The suppressive function of circulating Tregs was impaired in active IBD patients according to limited data (SMD = -0.75, p = 0.02). Besides, the percentage of intestinal Tregs was significantly higher in inflamed regions than in non-inflamed regions (SMD = 0.85, p < 0.001). Our study quantitatively summarized the quantitative and functional changes of Tregs and supported the therapeutic potential of Tregs in IBD. Moreover, additional research into the functions and characteristics of intestinal Tregs in IBD is needed.

Inflammatory bowel disease is a group of diseases in which the intestines are repeatedly inflamed. Regulatory T cells are a subset of immune cells that have been found to migrate from the blood and lymphoid tissues into the intestine to act as a suppressor of inflammation in inflammatory bowel disease. However, previous research on changes in the amount and function of regulatory T cells in the blood and intestine of patients with inflammatory bowel disease revealed inconsistent results. Therefore, we used a "meta-analysis" approach to integrate the results of previous studies to obtain an overall picture of Changes in regulatory T cell percentages and function. We found that patients with active inflammatory bowel disease had a lower proportion of blood regulatory T cells and a poorer ability to suppress inflammation compared to healthy individuals. In the intestine of patients with inflammatory bowel disease, a higher proportion of regulatory T cells are found in inflamed sites than in non-inflamed sites. However, compared to other intestinal inflammatory diseases, such as intestinal tuberculosis, patients with inflammatory bowel disease have a lower tendency of elevated proportions of intestinal regulatory T cells. In some ways, our study quantitatively summarized the conflicting results of the quantitative and functional changes of Tregs and supported the therapeutic potential of Tregs in IBD. Moreover, additional research into the functions and characteristics of intestinal Tregs in IBD is needed.

Predictors and optimal management of tumor necrosis factor antagonist nonresponse in inflammatory bowel disease: A literature review.

Tumor necrosis factor-α (TNF-α) antagonists, the first biologics approved for treating patients with inflammatory bowel disease (IBD), are effective for the induction and maintenance of remission and significantly improving prognosis. However, up to one-third of treated patients show primary nonresponse (PNR) to anti-TNF-α therapies, and 23%-50% of IBD patients experience loss of response (LOR) to these biologics during subsequent treatment. There is still no recognized predictor for evaluating the efficacy of anti-TNF drugs. This review summarizes the existing predictors of PNR and LOR to anti-TNF in IBD patients. Most predictors remain controversial, and only previous surgical history, disease manifestations, drug concentrations, antidrug antibodies, serum albumin, some biologic markers, and some genetic markers may be potentially predictive. In addition, we also discuss the next steps of treatment for patients with PNR or LOR to TNF antagonists. Therapeutic drug monitoring plays an important role in treatment selection. Dose escalation, combination therapy, switching to a different anti-TNF drug, or switching to a biologic with a different mechanism of action can be selected based on the concentration of the drug and/or antidrug antibodies.

Symptoms of anxiety and depression associated with steroid efficacy and clinical outcomes in patients with inflammatory bowel disease.

Background: Anxiety and depression symptoms are very common in patients with inflammatory bowel disease (IBD). We aimed to explore the impact of anxiety and depression on the efficacy of medications, as well as IBD-related poor outcomes. Method: This was a prospective longitudinal observational study. Hospital Anxiety and Depression Scale was used to assess anxiety and depression symptoms. Logistic regression analyses were used to assess the association between anxiety/depression and the response to different medications. Kaplan-Meier survival analysis and Cox regression model were applied to analyze the relationship between anxiety/depression and IBD-related poor outcomes, which were defined as urgent IBD-related hospitalization, IBD-related surgery, or death. Results: A total of 325 IBD patients were enrolled, 118 of whom were treated with corticosteroids, 88 with azathioprine/6-mercaptopurine (AZA/6-MP), and 147 with anti-TNF agents. Anxiety/depression symptoms were found to be significantly related to steroid resistance, but independent of AZA/6-MP and anti-TNF agents nonresponse. There was a significant association between anxiety/depression symptoms and IBD-related poor outcomes. Coexisting with anxiety/depression symptoms was an independent influencing factor of steroid resistance and IBD-related poor outcomes. Conclusion: IBD patients with anxiety/depression symptoms were at a higher risk of developing steroid resistance and IBD-related poor outcomes. Future studies are needed to explore whether interventions for anxiety and depression will improve their response to medications and change their prognosis.

Proton Pump Inhibitors Increase the Risk of Nonsteroidal Anti-inflammatory Drug-Related Small-Bowel Injury: A Systematic Review With Meta-analysis.

INTRODUCTION: Conflicting results exist on the association between proton-pump inhibitor (PPI) and nonsteroidal anti-inflammatory drug (NSAID)-related small-bowel damage. The aim of this study was to determine whether PPIs increased the risk of NSAID-related small-bowel damage by meta-analysis. METHODS: A systematic electronic search in PubMed, Embase, and Web of Science was conducted from the time the database was created until March 31, 2022, for studies reporting associations between PPI use and outcomes, including the endoscopy-verified prevalence of small-bowel injury, mean number of small-bowel injuries per patient, change in hemoglobin level, and risk of small-bowel bleeding in subjects taking NSAIDs. Meta-analytical calculations for odds ratio (OR) and mean difference (MD) were performed with the random-effects model and interpreted with 95% confidence intervals (CIs). RESULTS: Fourteen studies comprising 1996 subjects were included. Pooled analysis demonstrated that concomitant use of PPIs significantly increased the prevalence and number of endoscopy-verified small-bowel injuries (prevalence: OR = 3.00; 95% CI: 1.74-5.16; number: MD = 2.30; 95% CI: 0.61-3.99) and decreased hemoglobin levels (MD = -0.50 g/dL; 95% CI: 0.88 to -0.12) in NSAID users but did not change the risk of small-bowel bleeding (OR = 1.24; 95% CI: 0.80-1.92). Subgroup analysis demonstrated that PPIs significantly increased the prevalence of small-bowel injury in subjects taking nonselective NSAIDs (OR = 7.05; 95% CI: 4.70-10.59, 4 studies, I 2 = 0) and COX-2 inhibitors (OR = 4.00; 95% CI: 1.18-13.60, 1 study, no calculated I 2 ) when compared with COX-2 inhibitors alone. DISCUSSION: PPIs increased the risk of NSAID-related small-bowel damage, and the clinical significance of higher prevalence of small-bowel injuries should be studied in the future.

Effect of antidepressants on psychological comorbidities, disease activity, and quality of life in inflammatory bowel disease: a systematic review and meta-analysis.

Background: Patients with inflammatory bowel disease (IBD) are often accompanied by a more significant burden of depression or anxiety, and approximately one-third are prescribed antidepressants. However, previous studies on the efficacy of antidepressants in IBD have shown inconsistent results. Objectives: To evaluate the effect of antidepressants on depression, anxiety, disease activity, and quality of life (QoL) in IBD patients. Design: A systematic review and meta-analysis. Methods: We searched MEDLINE via Ovid, EMBASE via Ovid, the Cochrane Library, CINAHL, PsycINFO, Chinese CBM Database, China National Knowledge Infrastructure, VIP, and Wanfang Database from inception to 13th July 2022 without language restrictions. Results: In all, 13 studies containing 884 individuals were included. Compared with the control group, antidepressants were superior in reducing depression scores [standardized mean difference (SMD) = -0.791; 95% confidence interval (CI): -1.009 to -0.572; p < 0.001], anxiety scores (SMD = -0.877; 95% CI: -1.203 to -0.552; p < 0.001), and disease activity scores (SMD = -0.323; 95% CI: -0.500 to -0.145; p < 0.001). Antidepressants had a positive effect in reaching clinical remission [risk ratio (RR) = 1.383; 95% CI: 1.176-1.626; p < 0.001]. Higher physical QoL (SMD = 0.578; 95% CI: 0.025-1.130; p = 0.040), social QoL (SMD = 0.626; 95% CI: 0.073-1.180; p = 0.027), and Inflammatory Bowel Disease Questionnaire (SMD = 1.111; 95% CI: 0.710-1.512; p < 0.001) were found in the experimental group. No significant differences were observed in clinical response (RR = 1.014; 95% CI: 0.847-1.214; p = 0.881), psychological QoL (SMD = 0.399; 95% CI: -0.147 to 0.944; p = 0.152), and environmental QoL (SMD = 0.211; 95% CI: -0.331 to 0.753; p = 0.446). Conclusion: Antidepressants are effective for ameliorating depression, anxiety, disease activity, and QoL in IBD patients. Due to most studies having a small sample size, further well-designed studies are required.

Depression Exacerbates Dextran Sulfate Sodium-Induced Colitis via IRF5-Mediated Macrophage Polarization.

BACKGROUND AND AIMS: Patients with inflammatory bowel disease (IBD) and concurrent depression are predisposed to severer disease activity and a worse prognosis. Macrophage polarization toward the M1 phenotype may contribute to the exacerbation of IBD with comorbid depression. Moreover, interferon regulatory factor 5 (IRF5) is involved in the pathogenesis of IBD. The aim of this study was to explore the role of IRF5 in macrophage polarization in the impact of depression upon colitis. METHODS: Depressive-like behavior was induced by repeated forced swim stress. Colon length, disease activity index (DAI), colon morphology, histology, ultrastructure of epithelial barrier, lamina propria macrophage polarization, and expression of IRF5 were compared between DSS colitis rats with and without depressive-like behavior. IRF5 shRNA was constructed to affect the rat peritoneal macrophages polarization in vitro. After IRF5 shRNA lentivirus was introduced into colon by enema, the colitis severity, lamina propria macrophage polarization, and TNF-α, IL-1ß, and IL-10 of colon tissues were measured. RESULTS: The study found severer colonic inflammation in depressed versus non-depressed DSS-colitis rats. Depressed DSS-colitis rats exhibited smaller subepithelial macrophages size and reduced intracellular granule diversity compared with nondepressed DSS-colitis rats. Increased polarization toward the M1 phenotype, elevated expression of IRF5, and co-expression of IRF5 with CD86 were found in depressed versus nondepressed DSS-colitis rats. Lentivirus-mediated shRNA interference with IRF5 expression switched rat peritoneal macrophage polarization from the M1 to the M2 phenotype, downregulated TNF-α, IL-1ß expression to a greater extent in depressed versus nondepressed colitis rats. CONCLUSIONS: IRF5-mediated macrophage polarization may likely underlie the deterioration of DSS-induced colitis caused by depression.

Venlafaxine as an Adjuvant Therapy for Inflammatory Bowel Disease Patients With Anxious and Depressive Symptoms: A Randomized Controlled Trial.

Background and Aims: The effect of antidepressant therapy on Inflammatory Bowel Disease (IBD) remains controversial. This trial aimed to assess whether adding venlafaxine to standard therapy for IBD improved the quality of life (QoL), mental health, and disease activity of patients with IBD with anxious and depressive symptoms. Methods: A prospective, randomized, double-blind, and placebo-controlled clinical trial was conducted. Participants diagnosed with IBD with symptoms of anxiety or depression were randomly assigned to receive either venlafaxine 150 mg daily or equivalent placebo and followed for 6 months. Inflammatory Bowel Disease Questionnaire (IBDQ), Mayo score, Crohn's disease activity index (CDAI), Hospital Anxiety and Depression Scale (HADS), and blood examination were completed before the enrollment, during, and after the follow-up. Mixed linear models and univariate analyses were used to compare groups. Results: Forty-five patients with IBD were included, of whom 25 were randomized to receive venlafaxine. The mean age was 40.00 (SD = 13.12) years old and 25 (55.6%) were male. Venlafaxine showed a significant improvement on QoL (p < 0.001) and disease course (p = 0.035), a greater reduction in HADS (anxiety: p < 0.001, depression: p < 0.001), Mayo scores (p < 0.001), and CDAI (p = 0.006) after 6 months. Venlafaxine had no effect on IL-10 expression, endoscopic scores, relapse rate, and use rate of biologics and corticosteroids, but did reduce serum level of erythrocyte estimation rate (ESR; p = 0.003), C-reactive protein (CRP; p < 0.001) and tumor necrosis factor-α (TNF-α; p = 0.009). Conclusions: Venlafaxine has a significantly beneficial effect on QoL, IBD activity, and mental health in patients with IBD with comorbid anxious or depressive symptoms. (Chinese Clinical Trial Registry, ID: ChiCTR1900021496).

Systematic review with meta-analysis: effectiveness of hyperbaric oxygenation therapy for ulcerative colitis.

BACKGROUND AND AIMS: Hyperbaric oxygenation therapy has been used in the treatment of ulcerative colitis in the past few years. However, its efficacy still remains unclear. The aim of the study was to investigate the efficacy of hyperbaric oxygen combination therapy in patients with ulcerative colitis. METHODS: We conducted a comprehensive study search up to September 2020, from the online databases Embase, PubMed, Cochrane Library, China National Knowledge Infrastructure, WanFang and VIP. RESULTS: Thirteen studies comprising 780 patients were included. We found that compared with conventional therapy, hyperbaric oxygen combination therapy was superior in reaching clinical remission [risk ratio (RR)=1.62; 95% confidence interval (CI) 1.42 to 1.84; p < 0.001] and clinical response (RR=1.29; 95% CI 1.21 to 1.38; p < 0.001), with lower disease activity scores [standard mean difference (SMD)= -1.19; 95%CI -1.74 to -0.65; p < 0.001]. An obvious reduction of serum levels of tumor necrosis factor-α (SMD= -1.96; 95%CI -2.50 to -1.41; p < 0.001) and interleukin (IL)-6 (SMD= -2.49; 95% CI -2.84 to -2.15; p < 0.001), and elevation of IL-10 level (SMD=2.40; 95% CI 0.68 to 4.12; p = 0.006) were also observed. CONCLUSION: Hyperbaric oxygen combination therapy was effective in patients with ulcerative colitis, and has potential as a complementary method for its treatment.

Adult-onset citrullinaemia type II with liver cirrhosis: A rare cause of hyperammonaemia.

Adult-onset citrullinaemia type II (CTLN2) is a rare disease in Chinese patients. As a subtype of citrin deficiency (CD), it is an autosomal recessive disease related to the SLC25A13 mutation on chromosome 7q21.3. In this study, we report a case of CTLN2 presenting with paroxysmal altered consciousness and refractory hyperammonaemia. The diagnosis was finally confirmed by gene analysis. The patient recovered after liver transplantation. It can be learned from this case that CD should be considered in patients with refractory hyperammonaemia and paroxysmal mental disorder without a history of liver disease.

Symptoms of anxiety/depression is associated with more aggressive inflammatory bowel disease.

Studies have demonstrated that inflammatory bowel disease (IBD) patients are at an increased risk of developing anxiety and/or depression. IBD patients with depression/anxiety have higher rates of hospitalization and increased disease severity than those without. So far, there is a paucity of data concerning the impact of anxiety/depression on Chinese IBD patients. The aim of this study was to find out the prevalence of symptoms of anxiety/depression in Chinese IBD population and its impact on IBD-related features. This is a cross-sectional study from the southwest China IBD referral center. Eligible participants were divided into those with symptoms of anxiety/depression and those without based on the Hospital Anxiety and Depression Scale (HADS). Demographic data and disease duration, IBD-related surgery, tobacco use, extra-intestinal manifestations, disease activity scores, endoscopic evaluation, laboratory data and current medication use were compared between two groups. A total of 341 IBD patients [221 Crohn's disease (CD) and 120 ulcerative colitis (UC)] were included. The prevalence of symptoms of anxiety/depression in IBD was 33.1%. CD patients with symptoms of anxiety/depression tended to have higher scores of simple endoscopic scores for Crohn's disease (SES-CD) (p = 0.0005). UC patients with symptoms of anxiety/depression had a significantly higher Mayo score (p = 0.0017) and ulcerative colitis endoscopic index of severity (UCEIS) (p < 0.0001) than their non-anxiety/depression counterparts. CD-related surgery (p = 0.012) and Crohn's disease activity index (CDAI) (p < 0.0001) were identified as independent risk factors for symptoms of anxiety/depression in CD, while corticosteroid use (p = 0.036) as an independent risk factor for symptoms of anxiety/depression in UC. This study helps our understanding of the prevalence of symptoms of anxiety/depression in IBD patients and its impact on IBD course and reminds us to pay more attention on IBD management with anxiety/depression.

Crohn's Disease Patients with Depression Exhibit Alterations in Monocyte/Macrophage Phenotype and Increased Proinflammatory Cytokine Production.

BACKGROUND: Crohn's disease (CD) is strongly associated with depression, but the mechanisms underlying this relationship are not fully understood. Recently, neuroimmunological studies have demonstrated that proinflammatory monocytes/macrophages play a key role in the pathogenesis of depression. The present study investigates monocyte/macrophage phenotypes and plasma cytokine levels in CD. METHODS: Eligible CD patients were divided into nondepressed and depressed groups according to Hospital Anxiety and Depression Scale for depression (HADS-D). The Harvey-Bradshaw index (HBI), the Simple Endoscopic Score for Crohn's disease (SES-CD), and the Global Histological Disease Activity Score (GHAS) were compared between the 2 groups. Immunohistochemistry was performed to quantify the expression of CD68, inducible nitic oxide synthase (iNOS), and CD163 in colon mucosa. Enzyme-linked Immunosorbent Assay was used to detect plasma levels of M1 macrophage-secreted cytokines (tumor necrosis factor [TNF]-α, -interleukin 6 [IL-6], IL-1ß) and M2 cytokines (transforming growth factor [TGF]-ß1, IL-10, C-C motif chemokine ligand 22, [CCL22]). Flow cytometry was utilized to determine peripheral blood monocyte subsets. RESULTS: Depressed CD patients (n = 91) presented higher HBI, -SES-CD, GHAS than the nondepressed patients (n = 42). Intermediate (CD14++CD16+) and nonclassical monocytes (CD14+CD16++) percentages, integrated optical density (IOD) of iNOS+ cells representing M1 macrophages, and plasma levels of TNF-α, IL-6, IL-1ß were increased while -classical monocyte (CD14++CD16-) percentage, IOD of CD163+ cells representing M2 macrophages, and IL-10 plasma levels were decreased in depressed versus nondepressed CD patients. Plasma levels of TNF-α, IL-6, IL-1ß correlated with HADS-D scores. CONCLUSION: Monocytes subpopulation disequilibrium toward intermediate and nonclassic phenotypes and macrophage polarization toward M1 phenotype with increased proinflammatory cytokine release are more likely to be found in CD patients with depressive symptoms.

Prognostic value of the pretreatment systemic immune-inflammation index (SII) in patients with non-small cell lung cancer: a meta-analysis.

BACKGROUND: The objective of this study is to explore the association between the pretreatment systemic immune-inflammation index (SII) and prognosis in non-small cell lung cancer (NSCLC) patients. METHODS: A systemic literature search of PubMed, EMBASE, the Web of Science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, VIP and SinoMed databases was performed from January 1, 1966 to April 15, 2019, to identify potential studies that assessed the prognostic role of the pretreatment SII in NSCLC. The hazard ratio (HR) and 95% confidence interval (CI) were combined to evaluate the correlation of the pretreatment SII with overall survival (OS), disease-free survival (DFS), progression-free survival (PFS) and cancer-specific survival (CSS) in NSCLC patients. RESULTS: A total of 9 studies involving 2,441 patients were eventually included. An elevated pretreatment SII indicated significantly poorer OS (HR =1.88, 95% CI: 1.50-2.36; P<0.001) with high heterogeneity (I2=60.6%, P=0.019), DFS/PFS (HR =2.50, 95% CI: 1.20-5.20; P=0.014) with high heterogeneity (I2=58.2%, P=0.092) and CSS (HR =1.852, 95% CI: 1.185-2.915; P=0.007). Subgroup analyses further verified the above results. In addition, compared with the neutrophil to lymphocyte ratio (NLR) and the platelet to lymphocyte ratio (PLR), the SII showed a much higher prognostic value in NSCLC. CONCLUSIONS: The pretreatment SII may serve as a useful prognostic indicator in NSCLC and contribute to prognosis evaluation and treatment strategy formulation. However, more well-designed studies are warranted to verify our findings.