UPK3A+ umbrella cell damage mediated by TLR3-NR2F6 triggers programmed destruction of urothelium in Hunner-type interstitial cystitis/painful bladder syndrome.

Urothelial damage and barrier dysfunction emerge as the foremost mechanisms in Hunner-type interstitial cystitis/bladder pain syndrome (HIC). Although treatments aimed at urothelial regeneration and repair have been employed, their therapeutic effectiveness remains limited due to the inadequate understanding of specific cell types involved in damage and the lack of specific molecular targets within these mechanisms. Therefore, we harnessed single-cell RNA sequencing to elucidate the heterogeneity and developmental trajectory of urothelial cells within HIC bladders. Through reclustering, we identified eight distinct clusters of urothelial cells. There was a significant reduction in UPK3A+ umbrella cells and a simultaneous increase in progenitor-like pluripotent cells (PPCs) within the HIC bladder. Pseudotime analysis of the urothelial cells in the HIC bladder revealed that cells faced challenges in differentiating into UPK3A+ umbrella cells, while PPCs exhibited substantial proliferation to compensate for the loss of UPK3A+ umbrella cells. The urothelium in HIC remains unrepaired, despite the substantial proliferation of PPCs. Thus, we propose that inhibiting the pivotal signaling pathways responsible for the injury to UPK3A+ umbrella cells is paramount for restoring the urothelial barrier and alleviating lower urinary tract symptoms in HIC patients. Subsequently, we identified key molecular pathways (TLR3 and NR2F6) associated with the injury of UPK3A+ umbrella cells in HIC urothelium. Finally, we conducted in vitro and in vivo experiments to confirm the potential of the TLR3-NR2F6 axis as a promising therapeutic target for HIC. These findings hold the potential to inhibit urothelial injury, providing promising clues for early diagnosis and functional bladder self-repair strategies for HIC patients. © 2024 The Pathological Society of Great Britain and Ireland.

APRIL/BAFF upregulation is associated with clonal B-cell expansion in Hunner-type interstitial cystitis.

Hunner-type interstitial cystitis (HIC) is a chronic inflammatory disease of the urinary bladder with an unknown etiology. We conducted comprehensive immunogenomic profiling of bladder specimens obtained by biopsy and cystectomy from 37 patients with HIC. Next-generation RNA sequencing demonstrated abundant plasma cell infiltration with frequent light chain restriction in HIC-affected bladder tissue. Subsequent analysis of the B-cell receptor repertoire revealed spatial and temporal expansion of B-cell clones. The extent of B-cell clonal expansion was significantly correlated with the gene expression levels of TNFSF13 and TNFSF13B, which encode APRIL and BAFF, respectively. These findings indicate that APRIL and BAFF are the key regulators of clonal B-cell expansion in HIC and might serve as therapeutic targets in this debilitating disease. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Urologic Chronic Pelvic Pain Syndrome Flares: A Comprehensive, Systematic Review and Meta-Analysis of the Peer-Reviewed Flare Literature.

PURPOSE: We sought to systematically review and summarize the peer-reviewed literature on urologic chronic pelvic pain syndrome flares, including their terminology, manifestation, perceived triggers, management and prevention strategies, impact on quality of life, and insights into pathophysiologic mechanisms, as a foundation for future empirical research. MATERIALS AND METHODS: We searched 6 medical databases for articles related to any aspect of symptom exacerbations for interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. A total of 1486 abstracts and 398 full-text articles were reviewed, and data were extracted by at least 2 individuals. RESULTS: Overall, we identified 59 articles, including 36 qualitative, cross-sectional, or case-control; 15 cohort-based; and 8 experimental articles. The majority of studies described North American patients with confirmed diagnoses. "Flare" was a commonly used term, but additional terminology (eg, exacerbation) was also used. Most flares involved significant increases in pain intensity, but less data were available on flare frequency and duration. Painful, frequent, long-lasting, and unpredictable flares were highly impactful, even over and above participants' nonflare symptoms. A large number of perceived triggers (eg, diet, stress) and management/prevention strategies (eg, analgesics, thermal therapy, rest) were proposed by participants, but few had empirical support. In addition, few studies explored underlying biologic mechanisms. CONCLUSIONS: Overall, we found that flares are painful and impactful, but otherwise poorly understood in terms of manifestation (frequency and duration), triggers, treatment, prevention, and pathophysiology. These summary findings provide a foundation for future flare-related research and highlight gaps that warrant additional empirical studies.

Elucidation of the pathophysiology of interstitial cystitis/bladder pain syndrome via experimental autoimmune cystitis rat model.

Although the cause of interstitial cystitis/painful bladder syndrome (IC/PBS) remains unknown, autoimmune involvement has been strongly suggested to be a contributing factor. To elucidate the pathophysiology of IC/PBS, we characterized the experimental autoimmune cystitis (EAC) in rats. Adult female Sprague-Dawley rats were divided into the EAC and control groups. The EAC rats were generated by administrating a homogenate of donor rat bladder tissue as a bladder antigen. The characteristics of the two groups were determined by evaluating pain behavior and conducting cystometry, histopathology, and molecular analyses. The EAC rats showed: 1) a decreased paw withdrawal threshold, 2) a reduced intercontraction interval on cystometry, 3) the irregular surfaces of the umbrella cells of epithelium throughout the bladder wall, 4) accumulation of stress granules in the bladder and vascular endothelium, 5)the increased expression of genes related to inflammation and ischemia at the mRNA and protein levels, 6) a significantly increased paw withdrawal threshold with pain treatment, and 7) the induction of glomerulation of the bladder wall, epithelium denudation, and lymphocyte infiltration in the interstitium by bladder distension. These results suggest that the EAC rats showed pain and frequent urination with the overexpression of inflammatory chemokines, reflecting clinical IC/BPS, and the bladder epithelium and vascular endothelium may be the primary sites of IC/BPS, and bladder injury, such as bladder distension, can cause progression from BPS to IC with Hunner lesions.NEW & NOTEWORTHY The experimental autoimmune cystitis model rats showed pain and frequent urination with the overexpression of inflammatory chemokines, reflecting clinical interstitial cystitis/painful bladder syndrome (IC/PBS), and the bladder epithelium and vascular endothelium may be the primary sites of IC/BPS, and bladder injury, such as bladder distension, can cause progression from BPS to IC with Hunner lesions.

Effectiveness of nonpharmacological conservative therapies for chronic pelvic pain in women: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the effectiveness of nonpharmacological conservative therapies for women with CPP. DATA SOURCES: A systematic search of electronic databases (Amed, CINAHL, PsycINFO, SportDiscuss, Medline, PubMed, Embase, and Cochrane Central Register of Controlled Trials) was performed in January 2023, and updated in December 2023. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials comparing a nonpharmacological conservative therapy to inert (eg, placebo, usual care) or nonconservative (eg, surgical, pharmacological) treatment were included. Conservative therapies of interest to this review were: multimodal physical therapy, predominantly psychological approaches, acupuncture, and other tissue-based monotherapies (eg, electrophysical agents, manual stretching). STUDY APPRAISAL AND SYNTHESIS METHODS: All study data were aggregated, and analyses of the included studies were performed. Effects on pain; sexual measures; psychological and physical function; health-related quality of life; symptom severity/bother; pelvic floor muscle function and morphometry; perceived improvement; and adverse events were analyzed. Meta-analyses (random effects model) were conducted using postintervention scores for data that included similar interventions and outcomes. Standardized mean differences were calculated. A narrative summary of findings that could not be included in the meta-analysis is provided. The quality of the evidence was assessed with the Physiotherapy Evidence Database scale and the certainty of evidence with Grading of Recommendations, Assessment, Development, and Evaluations criteria. RESULTS: Of 5776 retrieved studies, 38 randomized controlled trials including 2168 women (mean age 35.1±8.6) were included. Meta-analyses revealed that multimodal physical therapy resulted in lower pain intensity compared to inert or nonconservative treatments in both the short (standardized mean difference -1.69, 95% confidence interval -2.54, -0.85; high certainty) and intermediate-terms (standardized mean difference -1.82, 95% confidence interval -3.13, -0.52; moderate certainty), while predominantly psychological approaches resulted in no difference in pain intensity (standardized mean difference -0.18, 95% confidence interval -0.56, 0.20; moderate certainty) and a slight difference in sexual function (standardized mean difference -0.28, 95% confidence interval -0.52, -0.04; moderate certainty). The level of evidence regarding the meta-analysis of the effects of acupuncture on pain intensity (standardized mean difference 1.08, 95% confidence interval -1.38, 3.54, nonstatistically significant results in favor of control treatment) precluded any statement of certainty. A limited number of trials investigated individual tissue-based monotherapies, providing a restricted body of evidence. CONCLUSION: This systematic review with meta-analysis revealed that multimodal physical therapy is effective in women with chronic pelvic pain with a high certainty of evidence.

Bladder instillations vs onabotulinumtoxinA injection for interstitial cystitis/bladder pain syndrome: a randomized clinical trial.

BACKGROUND: Interstitial cystitis (IC)/bladder pain syndrome (BPS) is an unpleasant sensation related to the bladder with lower urinary tract symptoms lasting more than 6 weeks, unrelated to an otherwise identifiable cause. The etiology is likely multifactorial including urothelial abnormalities, neurogenic pain upregulation, and potentially bladder and vaginal microbiome alterations. Despite treatment effectiveness of both bladder instillations and intradetrusor onabotulinumtoxinA injection for this condition, a head-to-head comparison has not been performed. OBJECTIVE: To compare the efficacy of bladder instillations and intradetrusor onabotulinumtoxinA injection for treatment of IC/BPS. STUDY DESIGN: Patients with O'Leary-Sant (OLS) questionnaire scores of ≥6, meeting clinical criteria for IC/BPS, and desiring procedural management were randomized to bladder instillations or intradetrusor onabotulinumtoxinA injection. The primary outcome was the difference in OLS scores at 2 months posttreatment between groups. Secondary outcomes included evaluation of sexual function, physical/mental health status, pain, patient satisfaction, treatment perception, retreatment, and adverse event rates. RESULTS: Forty-seven patients were analyzed with 22 randomized to bladder instillations and 25 to onabotulinumtoxinA injection. There were no differences in demographic and clinical characteristics between groups. From baseline to 2 months posttreatment, there was a decrease in OLS subscales in all patients (Interstitial Cystitis Symptom Index [ICSI] -6.3 (confidence interval [CI] -8.54, -3.95), P<.0001; Interstitial Cystitis Problem Index [ICPI] -5.9 (CI -8.18, -3.57), P<.0001). At 2 months posttreatment, patients in the onabotulinumtoxinA group had significantly lower OLS scores compared to those in the bladder instillation group (ICSI 6.3±4.5 [onabotulinumtoxinA] vs 9.6±4.2 [instillation], P=.008; ICPI 5.9±5.1 [onabotulinumtoxinA] vs 8.3±4.0 [instillation], P=.048). The difference in OLS scores between groups did not persist at 6 to 9 months posttreatment. There were no statistically significant differences between baseline and posttreatment time points for the remaining questionnaires. Eight percent of patients who received onabotulinumtoxinA injection experienced urinary retention requiring self-catheterization. Patients who underwent onabotulinumtoxinA injection were significantly less likely to receive retreatment within 6 to 9 months compared to patients who received bladder instillations (relative risk 13.6; 95% CI, 1.92-96.6; P=.0002). There were no differences between groups regarding patient satisfaction, perception of treatment convenience, or willingness to undergo retreatment. CONCLUSION: Both onabotulinumtoxinA injection and bladder instillations are safe, effective treatments for patients with IC/BPS, with significant clinical improvement demonstrated at 2 months posttreatment. Our findings suggest that intradetrusor onabotulinumtoxinA injection is a more effective procedural treatment for this condition than bladder instillation therapy and associated with decreased rates of retreatment.

Classification systems for chronic pelvic pain in males: a systematic review.

OBJECTIVE: To systematically review the classification systems for male chronic pelvic pain (CPP). METHODS: The Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica dataBASE (EMBASE), and Web of Science were searched. Any publication, with no restriction to publication date, was eligible. Publications had to propose a classification system for CPP in males or provide additional information of a system that had been identified. Systems were assessed with an adapted Critical Appraisal of Classification Systems tool. RESULTS: A total of 33 relevant publications were identified, with 22 proposing an original classification system. Systems aimed to: (i) diagnose CPP and/or differentially diagnose CPP from other conditions, (ii) differentially diagnose subtypes within CPP, or (iii) identify features that could inform underlying mechanisms and/or treatment selection. Conditions referred to as chronic prostatitis/chronic pelvic pain syndrome and interstitial cystitis/bladder pain syndrome were most represented. Clinical signs/symptoms, pathoanatomical investigations, and presumed pain mechanisms were used for classification. Quality of systems was low to moderate, implying limitations to consider for their interpretation. CONCLUSIONS: Many classification systems for CPP in males exist. Careful consideration of their intended purpose is required. Future work should examine whether outcomes for patients are improved when decisions are guided by their use.

Multi-omics analyses uncover metabolic signatures and gene expression profiles of interstitial cystitis/bladder pain syndrome.

BACKGROUND AND OBJECTIVE: We explore molecular and metabolic pathways involved in interstitial cystitis (IC) with integrating multi-omics analysis for identifying potential diagnostic and therapeutic targets. METHODS: Mouse models of IC/bladder pain syndrome (BPS) were established by intraperitoneal injection of cyclophosphamide and bladder tissue samples were collected for metabolomics and transcriptome analysis. RESULTS: We found a total of 82 and 145 differential metabolites in positive ion modes and negative ion modes, respectively. Glycerophospholipid metabolism, choline metabolism in cancer, and nucleotide metabolism pathways were significantly enriched in the IC/BPS group. Transcriptome analysis demonstrated that 1069 upregulated genes and 1087 downregulated genes were detected. Importantly, the stronger enrichment for cell cycle pathway was observed in IC/BPS than that in normal bladder tissue, which may be involved in the process of bladder remodeling. Moreover, the inflammatory response and inflammatory factors related pathways were enriched in the IC/BPS group. CONCLUSIONS: Our findings provide critical directions for further exploration of the molecular pathology underlying IC/BPS.

The effects of a galectin-3 inhibitor on bladder pain syndrome in mice with cyclophosphamide-induced cystitis.

AIMS: To explore the effect of blocking galectin-3 in the bladder pain syndrome associated with interstitial cystitis. METHODS: A galectin-3 inhibitor was used to treat mice with cyclophosphamide-induced cystitis. The expression of galectin-3 in bladder tissues and urine was examined by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), respectively. Suprapubic-pelvic pain, bladder voiding, bladder pain-like nociceptive behavior, and referred hyperalgesia were assessed. The weights of the bladders were also measured, and inflammatory cell infiltration and inflammatory cytokine levels were examined by histopathological evaluation. The inflammatory cytokines interleukin 1ß (IL-1ß), nerve growth factor (NGF), IL-6, and tumor necrosis factor α (TNF-α) were measured by ELISA. RESULTS: Increases in galectin-3 levels, inflammation, bladder weight, and bladder pain-related symptoms were observed in bladders with cyclophosphamide-induced cystitis. Administration of the galectin-3 inhibitor significantly mitigated bladder pain-related symptoms and inflammatory response. In response to the 500 µM dose of the galectin-3 inhibitor, nociceptive behaviors, nociceptive score, and bladder-to-body weight ratios were reduced by 65.1%, 65.3%, and 40.3%, respectively, while 500 µM Gal-3 inhibitor increased pelvic pain threshold by 86.7%. Moreover, galectin-3 inhibitor treatment inhibited the inflammation. Compared to untreated CYP-induced mice, there were significant changes in the levels of IL-1ß (41.72 ± 2.05 vs. 18.91 ± 2.26 pg/mg tissues), NGF (9.64 ± 0.38 vs. 1.88 ± 0.05 pg/mg tissues), IL-6 (42.67 + 1.51 vs. 21.26 + 2.78 pg/mg tissues, and TNF-α (22.02 ± 1.08 vs. 10.70 ± 0.80 pg/mg tissues) in response to the highest dose of the Gal-3 inhibitor subgroup (500 µM), and 500 µM Gal-3 inhibitor reduced mast cell infiltration ratios by 71.8%. CONCLUSIONS: The galectin-3 inhibitor relieved pelvic pain, urinary symptoms, and bladder inflammation in mice with cyclophosphamide-induced cystitis. Thus, galectin-3 inhibitors may be novel agents in interstitial cystitis treatment.

The efficacy and safety of monoclonal antibody therapies for interstitial cystitis/bladder pain syndrome: A meta-analysis of randomized controlled trials.

OBJECTIVES: This study aimed to assess the efficacy and safety of monoclonal antibody therapies (MATs) for interstitial cystitis/bladder pain syndrome (IC/BPS). METHODS: A systematic search was conducted across databases including PubMed, Embase, clinicalTrial.gov, and the Cochrane Library Central Register of Controlled Trials. Randomized controlled trials (RCTs) comparing MATs versus placebo were included. Primary outcomes comprised the Global Response Assessment (GRA) scale and the O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI). Additional analyses encompassed mean daily frequency of voids, the O'Leary-Sant Interstitial Cystitis Problem Index, pain scores, and complications. Statistical analyses were performed using Review Manager 5.3. RESULTS: Five high-quality RCTs, comprising 263 patients with IC/BPS, were ultimately selected. MATs were generally effective in treating IC/BPS. Patients receiving MATs exhibited a higher satisfaction rate (odds ratio [OR]: 2.7, confidence interval [CI]: 1.31-5.58, p = 0.007) and lower ICSI scores (mean difference [MD]: -1.44, CI: -2.36 to -0.52, p = 0.002). Moreover, MAT recipients experienced reduced pain (MD: -0.53, CI: -0.79 to -0.26, p < 0.0001) and decreased frequency of urination (MD: -1.91, CI: -2.55 to -1.27, p < 0.00001). Importantly, there were no disparities regarding complication incidence in the MAT and control groups. CONCLUSIONS: The current findings indicate that MATs are effective and safe for treating IC/BPS. Nonetheless, future RCTs with larger sample sizes and long-term follow-up are warranted.

A systematic and comprehensive review of the role of microbiota in urinary chronic pelvic pain syndrome.

BACKGROUND: Many genitourinary tract disorders could be attributed partly to the microbiota. This study sought to conduct a systematic review of the role of the microbiota in urinary chronic pelvic pain syndrome (UCPPS). METHODS: We searched Embase, Scopus, Web of Science, and PubMed with no time, language, or study type restrictions until December 1, 2023. The JBI Appraisal Tool was used to assess the quality of the studies. Study selection followed the PRISMA statement. Studies addressing microbiome variations among patients suffering from interstitial cystitis/bladder pain syndrome (IC/BPS) or chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and a control group were considered eligible. RESULTS: A total of 21 studies (1 UCPPS, 12 IC/BPS, and 8 CP/CPPS) comprising 1125 patients were enrolled in our final data synthesis. It has been shown that the reduced diversity and discrepant composition of the gut microbiota may partly be attributed to the UCPPS pathogenesis. In terms of urine microbiota, some operational taxonomic units were shown to be elevated, while others became less abundant. Furthermore, various bacteria and fungi are linked to specific clinical features. Few investigations denied UCPPS as a dysbiotic condition. CONCLUSIONS: Urinary and intestinal microbiota appear to be linked with UCPPS, comprising IC/BPS and CP/CPPS. However, given the substantial disparity of published studies, a battery of prospective trials is required to corroborate these findings.

Validation of a simple body map to measure widespread pain in urologic chronic pelvic pain syndrome: A MAPP Research Network study.

PURPOSE: In patients with urologic chronic pelvic pain syndrome (UCPPS), the presence of widespread pain appears to identify a distinct phenotype, with a different symptom trajectory and potentially different response to treatment than patients with pelvic pain only. MATERIALS AND METHODS: A 76-site body map was administered four times, at weekly intervals, to 568 male and female UCPPS participants in the MAPP Network protocol. The 76 sites were classified into 13 regions (1 pelvic region and 12 nonpelvic regions). The degree of widespread pain was scored from 0 to 12 based on the number of reported nonpelvic pain regions. This continuous body map score was regressed over other measures of widespread pain, with UCPPS symptom severity, and with psychosocial variables to measure level of association. These models were repeated using an updated body map score (0-12) that incorporated a threshold of pain ≥ 4 at each site. RESULTS: Body map scores showed limited variability over the 4 weekly assessments, indicating that a single baseline assessment was sufficient. The widespread pain score correlated highly with other measures of widespread pain and correlated with worsened UCPPS symptom severity and psychosocial functioning. Incorporating a pain severity threshold ≥4 resulted in only marginal increases in these correlations. CONCLUSIONS: These results support the use of this 13-region body map in the baseline clinical assessment of UCPPS patients. It provides reliable data about the presence of widespread pain and does not require measurement of pain severity, making it relatively simple to use for clinical purposes.

Anti-inflammatory effects of resveratrol in treating interstitial cystitis/bladder pain syndrome: a multi-faceted approach integrating network pharmacology, molecular docking, and experimental validation.

This study aims to investigate the anti-inflammatory effects of Resveratrol (RES) in the treatment of Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) by integrating network pharmacology, molecular docking, and experimental validation. Potential targets of RES were identified using DrugBank and SwissTargetPrediction, while IC/BPS-related targets were obtained from DisGeNET and Genecards. Molecular docking was performed using UCSF Chimera and SwissDock to validate the binding affinity of RES to key targets. Experimental validation involved treating TNF-α induced urothelial cells with RES, followed by assessments using RT-qPCR, ELISA, and Western blotting. A total of 86 drug targets and 211 disease targets were analyzed, leading to the identification of 8 key therapeutic targets for RES in IC/BPS treatment. Molecular docking revealed a strong affinity of RES for ESR2, with notable interactions also observed with SHBG, PTGS2, PPARG, KIT, PI3KCA, and AKT1. In vitro experiments confirmed that RES significantly alleviated the inflammatory response in TNF-α-induced urothelial cells, normalizing the expression levels of ESR2, SHBG, PPARG, and AKT1. RES can modulate critical pathways involving ESR2, SHBG, PPARG, and AKT1, highlighting its potential as a therapeutic agent for IC/BPS. This study provides a theoretical foundation for the clinical application of RES in treating IC/BPS.

Cytokines in Bladder Pain Syndrome: A Review of the Literature.

INTRODUCTION AND HYPOTHESIS: Bladder pain syndrome (BPS) is poorly understood with both the aetiology and pathophysiology being unknown. Symptoms overlap with other disorders, such as overactive bladder (OAB) and chronic pelvic pain disorders such as endometriosis, making a consensus on how to diagnosis and manage patients challenging. The development of biomarkers for BPS may be the key to understanding more about its pathophysiology, as well as aiding diagnosis, subclassification, and discovering new drug targets for its management. As inflammation is widely understood to hold a central role in BPS, the evaluation of cytokines has gained interest. This article summarises the current literature and understanding of urinary, serum, and bladder tissue cytokines found elevated in patients with bladder pain syndrome. METHODS: literature search using Pub Med with the keywords "bladder pain syndrome", "painful bladder syndrome", "bladder pain", "Interstitial cystitis" AND "cytokines" or "inflammation". This study was except from institutional approval. RESULTS: Thirty-six cytokines have been identified as being statistically significantly elevated in either the serum, urine, or bladder tissue of patients with bladder pain syndrome in the 22 studies identified in this review of the literature. These cytokines include those from the interleukin group (n = 14), the CXC chemokine group (n = 5), and the C-C chemokine group (n = 7). CONCLUSIONS: CXCL-1, CXCL-8, CXCL-9, CXCL-10, CXCL-11 from the CXC chemokine group, and CCL2, CCL4, CCL5, CCL7, and CCL11 from the C-C chemokine group have been found to be significantly elevated in patients with bladder pain in the literature. Many of these analytes also have supporting evidence for their roles in bladder pain from animal models and studies in other chronic inflammatory conditions. It is likely that a single cytokine will not serve as an adequate biomarker of disease in bladder pain syndrome for either diagnosis or disease severity. Instead, panels of inflammatory mediators may reveal more about the different pathways of inflammation leading to similar presentations of bladder pain in patients.

Evaluation of Central Sensitisation in Bladder Pain Syndrome: A Systematic Review.

INTRODUCTION AND HYPOTHESIS: Bladder pain syndrome (BPS) is a debilitating condition characterised by exaggerated bladder sensations and altered bladder function. It is still unknown whether the condition is a peripheral sensory problem or due to abnormal central sensory processing as seen in central sensitisation. This systematic review, which followed a published and Prospective Register of Systematic Reviews-registered protocol (CRD42021229962), is aimed at establishing the scope of central sensitisation in patients with BPS to aid optimal management and treatment. METHODS: Four databases were searched, and appraisal of the identified studies was conducted by two independent reviewers based on eligibility criteria: patients with BPS being investigated for central sensitisation with or without comparison of controls, English-language articles, full text and publication in a peer-reviewed journal. The Methodological Index for non-Randomised Studies was used to determine study quality. We identified 763 papers in total, with 15 studies included in the final analysis. All studies were observational and had a low risk of bias. Measures included in the evaluation of CS were questionnaires, urodynamics, and quantitative sensory testing methods. RESULTS: There was evidence of central sensitisation in patients with BPS in all papers evaluated (15 out of 15). In addition, more significant central sensitisation correlated with severe disease presentation (3 out of 3 papers) and concomitant chronic pain conditions (5 out of 5 papers). CONCLUSIONS: Central sensitisation plays an integral role in BPS patient pathology. Many secondary measures are used to evaluate this condition. Stratification of patients based on their pathology (peripheral, central or a combination of the two) will aid in implementing an individualised management strategy.

Therapeutic Effects of AF219 on Interstitial Cystitis/Bladder Pain Syndrome Induced by Cyclophosphamide or Water Avoidance Stress in Rats.

INTRODUCTION AND HYPOTHESIS: To evaluate the effect of AF219, a P2X3 receptor antagonist, in animal models of interstitial cystitis/bladder pain syndrome (IC/BPS) induced by cyclophosphamide (CYP) or water avoidance stress (WAS). METHODS: Thirty-two adult female Wistar albino rats were used in each IC/BPS model. Assessment of nociception and anxiety and severity of inflammation in the bladder were assessed by behavioral experiments and histopathological examinations respectively. The contraction responses of the bladder were evaluated in vitro and protein levels of P2X3, P2X7, Trk-A, TRPV1, and TRPA1 were analyzed by Western blot. RESULTS: The IC/BPS groups had shorter response times to noxious stimuli, exhibited more anxiety-like behavior, had higher inflammation-based histological scores, and showed greater increased contraction responses to carbachol, adenosine triphosphate, and electrical field stimulation in in vitro bladder strips than controls for both models (p < 0.05). The improvements in behavioral and bladder contraction responses and inflammation scores in the IC/BPS + AF219 groups were similar to control findings (p > 0.05). Exposure to WAS or CYP increased P2X3 expression in the bladder compared with the controls (p < 0.05). Apart from TRPA1, the levels of P2X7, Trk-A, and TRPV1 were also higher in the IC/BPS groups than in the controls (p < 0.05). No significant differences were observed between IC/BPS + AF219 and controls regarding P2X3, P2X7, Trk-A, and TRPV1 in the WAS model (p > 0.05). Moreover, P2X3 and P2X7 levels were significantly lower in IC/BPS + AF219 than in the AF219-untreated WAS model (p < 0.05). CONCLUSIONS: These findings suggest that P2X3 receptors play a significant role in bladder functional responses, nociception, and also the pathogenesis of IC/BPS. AF219 may be a promising therapeutic strategy for IC/BPS. Comparing AF219 with current IC/BPS treatment agents in future studies may yield valuable insights into its efficacy.

Validation of Distinct Bladder Pain Phenotypes Utilizing the MAPP Research Network Cohort.

INTRODUCTION AND HYPOTHESIS: As interstitial cystitis/bladder pain syndrome (IC/BPS) likely represents multiple pathophysiologies, we sought to validate three clinical phenotypes of IC/BPS patients in a large, multi-center cohort using unsupervised machine learning (ML) analysis. METHODS: Using the female Genitourinary Pain Index and O'Leary-Sant Indices, k-means unsupervised clustering was utilized to define symptomatic phenotypes in 130 premenopausal IC/BPS participants recruited through the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) research network. Patient-reported symptoms were directly compared between MAPP ML-derived phenotypic clusters to previously defined phenotypes from a single center (SC) cohort. RESULTS: Unsupervised ML categorized IC/BPS participants into three phenotypes with distinct pain and urinary symptom patterns: myofascial pain, non-urologic pelvic pain, and bladder-specific pain. Defining characteristics included presence of myofascial pain or trigger points on examination for myofascial pain patients (p = 0.003) and bladder pain/burning for bladder-specific pain patients (p < 0.001). The three phenotypes were derived using only 11 features (fGUPI subscales and ICSI/ICPI items), in contrast to 49 items required previously. Despite substantial reduction in classification features, unsupervised ML independently generated similar symptomatic clusters in the MAPP cohort with equivalent symptomatic patterns and physical examination findings as the SC cohort. CONCLUSIONS: The reproducible identification of IC/BPS phenotypes, distinguishing bladder-specific pain from myofascial and genital pain, using independent ML analysis of a multicenter database suggests these phenotypes reflect true pathophysiologic differences in IC/BPS patients.

Chemokine receptor 7 contributes to T- and B-cell filtering in ageing bladder, cystitis and bladder cancer.

BACKGROUND: Research has suggested significant correlations among ageing, immune microenvironment, inflammation and tumours. However, the relationships among ageing, immune microenvironment, cystitis and bladder urothelial carcinoma (BLCA) in the bladder have rarely been reported. METHODS: Bladder single-cell and transcriptomic data from young and old mice were used for immune landscape analysis. Transcriptome, single-cell and The Cancer Genome Atlas Program datasets of BLCA and interstitial cystitis/bladder pain syndrome (IC/BPS) were used to analyse immune cell infiltration and molecular expression. Bladder tissues from mice, IC/BPS and BLCA were collected to validate the results. RESULTS: Eight types of immune cells (macrophages, B-cells, dendritic cells, T-cells, monocytes, natural killer cells, γδ T-cells and ILC2) were identified in the bladder of mice. Aged mice bladder tissues had a significantly higher number of T-cells, γδ T-cells, ILC2 and B-cells than those in the young group (P < 0.05). Three types of T-cells (NK T-cells, γδ T-cells and naïve T-cells) and three types of B-cells (follicular B-cells, plasma and memory B-cells) were identified in aged mice bladder. Chemokine receptor 7 (CCR7) is highly expressed in aged bladder, IC/BPS and BLCA (P < 0.05). CCR7 is likely to be involved in T- and B-cell infiltration in aged bladder, IC/BPS and BLCA. Interestingly, the high CCR7 expression on BLCA cell membranes was a prognostic protective factor. CONCLUSIONS: In this study, we characterised the expression profiles of immune cells in bladder tissues of aged and young mice and demonstrated that CCR7-mediated T- and B-cell filtration contributes to the development of bladder ageing, IC/BPS and BLCA.

Management Strategies for Patients with Non-Infectious Cystitis: A Review of the Literature.

PURPOSE OF REVIEW: The management of noninfectious cystitis continues to evolve as new treatments continue to be developed and investigated. This review aims to synthesize the most recent data regarding management strategies for noninfectious cystitis focused on non-ulcerative, ulcerative, eosinophilic, and ketamine-induced cystitis. RECENT FINDINGS: Several novel treatments have shown promise as management options including combination antihistamine therapy, phosphodiesterase 5 inhibitors, alpha lipoic acid supplements, and onabotulinumtoxin A. Recent studies have also found pentosan polysulfate sodium to have adverse ophthalmologic effects. For patients with ulcerative cystitis, recent research has shown that fulguration with or without triamcinolone injections should not be delayed. The treatment of noninfectious cystitis should be patient specific based on factors including etiology and symptom profile. Multimodal regimens are often the most effective. Treatment should be started with conservative options and escalated as necessary to oral treatments, intravesical options, or procedural management.

Hypertension and urologic chronic pelvic pain syndrome: An analysis of MAPP-I data.

BACKGROUND: Urologic chronic pelvic pain syndrome (UCPPS), which includes interstitial cystitis/bladder pain syndrome (IC/BPS) and chronic prostatitis (CP/CPPS), is associated with increased voiding frequency, nocturia, and chronic pelvic pain. The cause of these diseases is unknown and likely involves many different mechanisms. Dysregulated renin-angiotensin-aldosterone-system (RAAS) signaling is a potential pathologic mechanism for IC/BPS and CP/CPPS. Many angiotensin receptor downstream signaling factors, including oxidative stress, fibrosis, mast cell recruitment, and increased inflammatory mediators, are present in the bladders of IC/BPS patients and prostates of CP/CPPS patients. Therefore, we aimed to test the hypothesis that UCPPS patients have dysregulated angiotensin signaling, resulting in increased hypertension compared to controls. Secondly, we evaluated symptom severity in patients with and without hypertension and antihypertensive medication use. METHODS: Data from UCPPS patients (n = 424), fibromyalgia or irritable bowel syndrome (positive controls, n = 200), and healthy controls (n = 415) were obtained from the NIDDK Multidisciplinary Approach to the Study of Chronic Pelvic Pain I (MAPP-I). Diagnosis of hypertension, current antihypertensive medications, pain severity, and urinary symptom severity were analyzed using chi-square test and t-test. RESULTS: The combination of diagnosis and antihypertensive medications use was highest in the UCPPS group (n = 74, 18%), followed by positive (n = 34, 17%) and healthy controls (n = 48, 12%, p = 0.04). There were no differences in symptom severity based on hypertension in UCPPS and CP/CPPS; however, IC/BPS had worse ICSI (p = 0.031), AUA-SI (p = 0.04), and BPI pain severity (0.02). Patients (n = 7) with a hypertension diagnosis not on antihypertensive medications reported the greatest severity of pain and urinary symptoms. CONCLUSION: This pattern of findings suggests that there may be a relationship between hypertension and UCPPS. Treating hypertension among these patients may result in reduced pain and symptom severity. Further investigation on the relationship between hypertension, antihypertensive medication use, and UCPPS and the role of angiotensin signaling in UCPPS conditions is needed.