Hunner Lesions Research Articles

The impact of Hunner lesion-type interstitial cystitis/bladder pain syndrome on health-related quality of life and the effects of transurethral ablation.

Interstitial cystitis/bladder pain syndrome (IC/BPS) has a negative impact on quality of life. We compared health-related quality of life (HRQoL) of patients with IC/BPS with patients having other diseases using the EuroQol five-dimension (EQ-5D) and evaluated whether the HRQoL is improved after surgery. We compared EQ-5D of patients with Hunner lesion type IC/BPS with patients who had other diseases that cause chronic and severe pain including arthritis and cancer from a cross-sectional analysis of responses to the 2012-2016 Korea National Health and Nutrition Examination Survey. Changes in EQ-5D after transurethral coagulation (TUC) or resection (TUR) were measured in the IC/BPS participants. Compared to the EQ-5D index of normal population, patients with arthritis, cancer and IC/BPS had -0.07 (95% CI -0.07, -0.06), -0.01 (95% CI -0.02, -0.01), and -0.21 (95% CI -0.23, -0.20) lower scores, respectively. Patients with IC/BPS were 35.9, 9.24, and 9.05 times more likely to have "extreme problem" in pain/discomfort, anxiety/depression, and usual activities EQ-5D domains, respectively, than patients without arthritis/cancer. After TUC or TUR, EQ-5D index was 0.90 in the TUC group and 0.92 in the TUR group. IC/BPS patients have worse HRQoL than healthy individuals. However, after surgical treatment, HRQoL is restored to a level close to normal.

A pilot study on oral cyclosporine A in association with fulguration for the treatment of interstitial cystitis with Hunner's lesions.

To evaluate the efficacy and safety of lesion fulguration in combination with cyclosporine A (CyA) as a maintenance therapy in patients with interstitial cystitis/bladder pain syndrome (IC/BPS) with Hunner's lesion (HL). Retrospective observational study of refractory patients with HL treated with daily 1.5 mg/kg or less of oral CyA following lesion fulguration. Pain severity, subjective improvement, urinary symptoms, and adverse events were used to assess long-term treatment efficiency and safety. Among the 22 patients, median follow-up under CyA was 27 months. Patients reported sustained significant reduction compared to pretreatment in pain (0/10 vs. 8/10; p < 0.001), urinary frequency per 24 h (9.5 vs. 20.8; p < 0.001), and nocturia (2.3 vs. 7.6; p < 0.001). Subjective improvement rate (SIR) and patient global impression of improvement were of 90% and 1 ("very much better"), respectively, including four patients who considered themselves cured (SIR: 100%). Three patients needed an additional procedure due to pain relapse. Minor increase in creatinine was observed and three patients developed or worsened their arterial hypertension. CyA dosage was decreased to 1.2 mg/kg or less for long-term relief (n = 8), creatinine increase (n = 5), and neutropenia (n = 1) with subsequent improvement in renal function without symptom deterioration. Oral CyA seems to allow a sustained long-term relief following HL fulguration by alleviating pain, decreasing urinary symptoms, and procuring great subjective improvement. The daily low dose of 1.5 mg/kg or less appears to have limited adverse events while preventing repeated procedures. Larger trials are warranted.

Prospective randomized controlled trial comparing fulguration versus fulguration and hydrodistension for Hunner-type interstitial cystitis/bladder pain syndrome.

In Hunner-type interstitial cystitis/bladder pain syndrome (IC/BPS), it is unclear whether suburothelial afferents underlying normal-appearing background areas contribute to symptom development. We examined whether adding hydrodistension (HD) to transurethral fulguration (TUF) of Hunner lesions, for the purpose of treating the background areas, is superior to TUF alone. This randomized controlled trial included 52 patients with Hunner-type IC/BPS allocated at a 1:1 (TUF:TUF+HD) ratio. HD was performed at 80 cmH2O for 8min before TUF in the TUF+HD group. Thirty-three patients remained until the end of the 6-month observational period. The primary endpoint was the visual analogue scale (VAS) pain score at 1month. Major secondary endpoints were the treatment-failure rate, VAS pain scores at ≥ 2months, and frequency-volume chart parameters. Both TUF and TUF+HD showed significant improvement in VAS pain score at 1month (95% confidence interval [CI]: - 1.62 to 0.16, P = 0.106). VAS pain scores were significantly lower in TUF+HD than TUF at 2 (95% CI: - 1.97 to - 0.28, P = 0.011), 4 (95% CI: - 2.83 to - 0.72, P = 0.002), and 6 (95% CI: - 3.11 to - 0.07, P = 0.040) months. Treatment-failure rate was higher in TUF (36.4%) than TUF+HD (17.4%), without significance (odds ratio: 2.714, 95% CI: 0.68 to 10.84, P = 0.189). Functional capacity and urgency were not significantly different between groups. The addition of HD to TUF tended to be superior to TUF monotherapy for controlling pain in Hunner-type IC/BPS. This indicates that not only Hunner lesions but also normal-appearing background areas may have a role in the pain of IC/BPS. ClinicalTrials.gov Identifier: NCT03987594, date of registration: 2019-06-17 (retrospectively registered).

A Prospective Observational Study of the Recurrence Characteristics of Hunner Lesion After Repeated Transurethral Ablation in Patients With Interstitial Cystitis/Bladder Pain Syndrome.

PurposeThe aim of this study was to investigate the rate and pattern of recurrence for patients with Hunner lesion (HL) type interstitial cystitis/bladder pain syndrome (IC/BPS) after transurethral ablation.MethodsThis prospective study included 210 patients with HL type IC/BPS. The primary outcomes were the recurrence rate according to 3 patterns of recurrence: pattern A (according to the relationship with the previous surgical site), pattern B (according to the bladder zone), and pattern C (according to the number of lesions). The secondary outcomes were recurrencefree time after treatment according to pattern A and pattern C.ResultsThe pattern A recurrence rate was 50.8% in the same site (A1), 6.7% at a new site (A2), and 42.5% at mixed sites (A3). The pattern B recurrence rate was 10.5% for the anterior wall, 59.0% for the posterior wall, 69.5% for the lateral wall, and 69.0% for the dome area. Multiple lesions recurred as multiple lesions in 75.8% of cases. The pattern C recurrence rate was 10.8% for C1 (single → single), 6.7% for C2 (single → multiple), 6.7% for C3 (multiple → single), and 75.8% for C4 (multiple → multiple). The recurrence-free time in pattern A was 13 months for A1, 12.5 months for A2, and 8 months for A3, with a significant difference between A1 and A3 (P=0.008). There was no significant difference in recurrence-free time in pattern C, either with single or multiple HLs.ConclusionsThe distinct recurrence characteristics of HLs was not predictable despite repeated ablations. Complete remission should not be expected because the whole bladder was to have the potential to develop the HLs even after repeated transurethral ablation.

Interstitial cystitis/bladder pain syndrome (IC/BPS): Single-center 20 year experience and treatment results in India.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is an enigmatic disease that is difficult to treat. Even among physicians, the prevalent belief is that patients do not improve over time. In this study, we retrospectively reviewed our experience and treatment results for patients diagnosed with IC/BPS at our clinic in India over the past 20 years. Three hundred and eightyIC/BPS patients diagnosed between January 2001 and December 2020 were included. Patients underwent cystoscopy and hydrodistension and were treated with oral drugs, intravesical instillations, and surgery as needed. FromJanuary 2021 to June 2021, all patients were contacted by telephone. The study had 380 participants, but only 231 could be contacted for analysis. Follow-up averaged 6.37 years and the median was 14 years. Eighteen percentshowed no improvement, 2% showed a slight improvement on Global Response Assessment (GRA) questionnaire and were considered nonresponders (NR). Yet, 67% reported notable improvements, and 13% moderate improvements, all of which make up 80% responders (R). In 11 patients who were operated on for ileocystoplasty, 9 showed significant improvements. In addition, three patients developed Urothelial Malignancy. Pregnancy did not affect the disease in any way. Long-term results have been encouraging for IC/BPS patients. Unfortunately, Hunner's lesions patients need a more intensive treatment regimen. Re-evaluation with cystoscopy is recommended in NR. In spite of good results of surgery in our series, it is best to perform surgery only as a last resort.

Diagnosis and Treatment of Interstitial Cystitis/Bladder Pain Syndrome.

This guideline provides direction to clinicians and patients regarding how to recognize interstitial cystitis/bladder pain syndrome (IC/BPS), conduct a valid diagnostic process, and approach treatment with the goals of maximizing symptom control and patient quality of life while minimizing adverse events and patient burden. An initial systematic review of the literature using the MEDLINE® database (search dates 1/1/83-7/22/09) was conducted to identify peer-reviewed publications relevant to the diagnosis and treatment of IC/BPS. The review yielded an evidence base of 86 treatment articles after application of inclusion/exclusion criteria. In July 2013, the Guideline underwent an Update Literature Review, a process in which an additional literature search is conducted and a systematic review is produced in order to maintain guideline currency with newly published literature. The 2013 review identified an additional 31 articles relevant to treatment. An Update Literature Review in 2022 (search dates: 06/2013-01/2021) identified 63 studies, 53 of which were added to the evidence base. In contrast to the prior versions, the 2022 updated Guideline no longer divides treatments into first-line through sixth-line tiers. Instead, treatment is categorized into behavioral/non-pharmacologic, oral medicines, bladder instillations, procedures, and major surgery. This approach reinforces that the clinical approach for IC/BPS needs to be individualized and based on the unique characteristics of each patient. In addition, new statements were written to provide guidance on cystoscopy for patients with Hunner lesions, shared decision-making, and potential adverse events from pentosan polysulfate. The supporting text on major surgery also has been completely revised. IC/BPS is a heterogeneous clinical syndrome. Even though patients present with similar symptoms of bladder/pelvic pain and pressure/discomfort associated with urinary frequency and strong urge to urinate, there are subgroups or phenotypes within IC/BPS. Except for patients with Hunner lesions, initial treatment should typically be nonsurgical. Concurrent, multi-modal therapies may be offered.

Comparing surgical interventions for interstitial cystitis: A systematic review.

The purpose of this review was to summarize and compare the efficacy among surgical interventions in terms of symptomatic relief in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). The review protocol was published on PROSPERO. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 checklist was followed. Following database search, a narrative synthesis was performed. Data pertaining symptom scores, pain levels, and voiding frequency following surgery were summarized by calculating percentage change in these parameters. Multiple surgical treatments were identified. These included injections of hyaluronic acid (HA), botulinum toxin A (Botox A), triamcinolone, resiniferatoxin (RTX), platelet-rich plasma, and 50% dimethyl sulfoxide (DMSO) solution, neuromodulation, hydrodistension (HD), resection/fulguration of Hunner lesions, resection of ilioinguinal and iliohypogastric nerves, reconstructive surgery, and cystectomy. This review found no evidence suggesting that HD and RTX injections can ameliorate IC/BPS symptoms. Current evidence suggests that sacral neuromodulation, cystectomy, and transurethral resection/fulguration of Hunner lesions could lead to symptomatic relief in IC/BPS. Further research into the efficacy of Botox A, triamcinolone, 50% DMSO solution, and HA instillations is required. However, the best treatment options cannot be reliably stated due to the low level of evidence of the studies identified. Further research should report outcomes for Hunner-type IC and BPS separately given their differing histopathological characteristics. Performing high-quality randomized controlled trials could be hindered by the low prevalence of the condition and a small proportion of patients progressing to surgery.

Reduction of Bladder Capacity Under Anesthesia Following Multiple Recurrences and Repeated Surgeries of Hunner Lesions in Patients With Interstitial Cystitis

PurposeTo investigate the influence of multiple recurrences and repeated surgeries of Hunner lesions on bladder capacity under general anesthesia in patients with interstitial cystitis (IC).MethodsWe retrospectively reviewed the clinical records of Hunner-type IC (HIC) patients who underwent transurethral fulguration or resection of Hunner lesions combined with hydrodistension by a single surgeon between 2011 and 2020. Recurrence was defined as reappearance of uncontrolled urinary symptoms in association with new Hunner lesions identified by cystoscopy. Recurrent Hunner lesions were then treated by transurethral surgeries. The recurrence-free rate, potential predictive factors of recurrence, and changes in bladder capacity under anesthesia were examined at each surgical procedure.ResultsA total of 92 surgeries were performed in 47 HIC patients, 23 (49%) of whom required multiple procedures (range, 1–5 times). The mean recurrence-free time after the first surgery was 21.7 months. The recurrence-free rate was 53% at 24 months, and decreased to 32% at 48 months. There were no significant differences in age, sex, bladder capacity under anesthesia at the first surgery, duration from symptom onset to the first surgery, O’Leary-Sant questionnaire including symptom and problem indexes, visual analogue scale pain score, and the number of comorbidities between the cases with or without recurrence. Bladder capacity under anesthesia was gradually decreased as the number of surgeries was increased, and bladder capacity at the fourth procedure was significantly decreased to 80% of the capacity at the first surgery.ConclusionsThese results suggest that multiple recurrences and repeated surgeries of Hunner lesions result in a reduction of bladder capacity under anesthesia in HIC patients although no predictive factors for recurrence of Hunner lesions were detected.

Identification of diagnostic serum biomarkers for Hunner-type interstitial cystitis.

Diagnosis of Hunner-type interstitial cystitis (HIC) relies on the ability to identify Hunner lesions endoscopically, which can lead to storage symptom misdiagnosis. Here, we examined serum biomarkers for HIC and verified their utility. Based on the previous definition of the Japanese guidelines, which did not distinguish HIC and non-HIC diseases, we searched for serum biomarkers in 25 patients with interstitial cystitis (IC) and 25 control participants using metabolomics during 2013-2014. In 2019, we conducted a validation study in HIC and control groups. Serum samples were analyzed using liquid chromatography-tandem mass spectrometry, and candidate biomarker concentrations were compared between the groups using Mann-Whitney test. Metabolomics targeted 678 metabolites and revealed that the levels of 14 lysolipids, seven γ-glutamyl amino acids, and two monoacylglycerols were significantly different between the IC and control groups. The following metabolites were selected from each metabolite category as candidates: 1-linoleoylglycerophosphocholine (1-linoleloyl-GPC [18:2]), γ-glutamylisoleucine (γ-Glu-Ile), and 1-arachidonylglycerol (1-AG). The serum concentrations of 1-linoleoyl-GPC (18:2) in the HIC and control groups were 27 920 ± 6261 and 40 360 ± 1514 ng/mL (P=0.0003), respectively. The serum concentrations of γ-Glu-Ile and 1-AG were not significantly different between the groups. When the cut-off value of 1-linoleoyl-GPC (18:2) was set at 28 400 ng/mL, the sensitivity and specificity were 68% and 84%, respectively. Serum 1-linoleoyl-GPC (18:2) is a candidate diagnostic biomarker for HIC. Additional studies on whether this biomarker can distinguish HIC from other diseases with high urination frequency are required for its clinical use.

Integrated Analysis of Microarray Studies to Identify Novel Diagnostic Markers in Bladder Pain Syndrome/Interstitial Cystitis with Hunner Lesion.

BackgroundThe aim of this study was to identify novel genetic features of Hunner’s lesion interstitial cystitis (HIC) via comprehensive analysis of the Gene Expression Omnibus (GEO) database.MethodsThe GSE11783 and GSE28242 datasets were downloaded from GEO for further analysis. Differentially expressed genes (DEGs) were identified and analyzed for functional annotation. The diagnostic markers for HIC were screened and validated using the least absolute shrinkage and selection operator (LASSO) logistic regression and support vector machine recursive feature elimination (SVM-RFE) algorithms. Finally, the cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm was adopted to investigate the correlation between immune cell infiltration and diagnostic markers in HIC.ResultsA total of 7837 DEGs were identified in GSE11783 and 1583 DEGs in GSE28242. Venn diagrams were used to obtain 16 overlapping upregulated and 67 overlapping downregulated DEGs separately. The LASSO logistic model and SVM-RFE algorithm were used to identify 6 genes including KRT20, SLFN11, CD86, ITGA4, PLAC8, and BTN3A3 from DEGs as diagnostic markers for HIC. Their diagnostic potential in HIC and bladder pain syndrome/interstitial cystitis (BPS/IC) were acceptable. PLAC8 exhibited the best diagnostic performance in BPS/IC with an area under the curve of 0.916. The results of immune infiltration involving GSE11783 revealed that the plasma cell ratio (p = 0.017), activated memory CD4+ T cells (p = 0.009), activated dendritic cells (p = 0.01), eosinophils (p = 0.004), and neutrophils (p = 0.03) were significantly higher in HIC than in normal samples, in contrast to resting mast cells (p = 0.022). A positive correlation existed between diagnostic markers and infiltrating immune cells.ConclusionKRT20, SLFN11, CD86, ITGA4, PLAC8, and BTN3A3 represent novel and potent diagnostic markers for HIC. They also exhibit certain diagnostic potential in BPS/IC. Immune cell infiltration might play a key role in the pathogenesis and progression of BPS/IC.

Immune cell profiles of patients with interstitial cystitis/bladder pain syndrome

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a disorder characterized by bladder pain upon filling which severely affects quality of life. Clinical presentation can vary. Local inflammatory events typify the clinical presentation of IC/BPS patients with Hunner lesions (IC/BPS-HL). It has previously been proposed that B cells are more prevalent in HL, but understanding their exact role in this environment requires a more complete immunological profile of HL. We characterized immunological dysfunction specifically in HL using immunohistochemistry. We detected significantly more plasma cells (50× increase, p < 0.0001), B cells (28× increase, p < 0.0001), T cells (3× increase, p < 0.0001), monocytes/macrophages (6× increase, p < 0.0001), granulocytes (4× increase, p < 0.0001), and natural killer cells (2× increase, p = 0.0249) in IC/BPS patients with HL than in unaffected controls (UC). Patients with IC/BPS-HL also had significantly elevated urinary levels of IL-6 (p = 0.0054), TNF-α (p = 0.0064) and IL-13 (p = 0.0304) compared to patients with IC/BPS without HL (IC/BPS-NHL). In contrast, IL-12p70 levels were significantly lower in the patients with HL than in those without these lesions (p = 0.0422). Different cytokines were elevated in the urine of IC/BPS patients with and without HL, indicating that different disease processes are active in IC/BPS patients with and without HL. Elevated levels of CD138+, CD20+, and CD3+ cells in HL are consistent B and T-cell involvement in disease processes within HL.

Supervised machine learning algorithm identified KRT20, BATF and TP63 as biologically relevant biomarkers for bladder biopsy specimens from interstitial cystitis/bladder pain syndrome patients.

This study was carried out to identify biomarkers that distinguish Hunner-type interstitial cystitis from non-Hunner-type interstitial cystitis patients. Total ribonucleic acid was purified from 212 punch biopsy specimens of 89 individuals who were diagnosed as interstitial cystitis/bladder pain syndrome. To examine the expression profile of patients' bladder specimens, 68 urothelial master transcription factors and nine known markers (E-cadherin, cytokeratins, uroplakins and sonic hedgehog) were selected. To classify the biopsy samples, principal component analysis was carried out. A decision tree algorithm was adopted to identify critical determinants, in which 102 and 116 bladder specimens were used for learning and validation, respectively. Principal component analysis segregated tissues from Hunner-type and non-Hunner-type interstitial cystitis specimens in principal component axes 2 and 4. Principal components 2 and 4 contained urothelial stem/progenitor transcription factors and cytokeratins, respectively. A decision tree identified KRT20, BATF and TP63 to classify non-Hunner-type and Hunner-type interstitial cystitis specimens. KRT20 was lower in tissues from Hunner-type compared with non-Hunner-type interstitial cystitis specimens (P < 0.001). TP63 was lower in Hunner's lesions compared with adjacent mucosa from Hunner-type interstitial cystitis patients (P < 0.001). Blinded validation using additional biopsy specimens verified that the decision tree showed fairly precise concordance with cystoscopic diagnosis. KRT20, BATF and TP63 were identified as biologically relevant biomarkers to classify tissues from interstitial cystitis/bladder pain syndrome specimens. The biologically explainable determinants could contribute to defining the elusive interstitial cystitis/bladder pain syndrome pathogenesis.

Voiding Function and Dysfunction, Bladder Physiology and Pharmacology, and Female Urology.

Voiding Function and Dysfunction, Bladder Physiology and Pharmacology, and Female Urology.

Pentosan polysulfate in patients with bladder pain syndrome/interstitial cystitis with Hunner's lesions or glomerulations: systematic review and meta-analysis.

Background:Bladder pain syndrome/interstitial cystitis (BPS/IC) is a persistent pain perceived in the urinary bladder region, accompanied by at least one symptom, such as pain worsening with bladder filling and daytime or nighttime urinary frequency without any proven infection or obvious pathology. The aim of this study is to evaluate the efficacy and safety of pentosan polysulfate (PPS) in patients with BPS/IC.Methods:Systematic search was performed by PRISMA checklist. Electronic databases, including PubMed and Cochrane library, were checked until 2021 using keywords: ‘pentosan polysulfate’, ‘pain syndrome’, ‘interstitial cystitis’, and bibliography of relevant papers was checked.Inclusion criteria:Patients with confirmed diagnosis of BPS/IC and cystoscopy criteria – Hunner’s lesions. Exclusion criteria included hypersensitivity, pregnancy, lactation, and oral therapy for BPS/IC in the period of 1 month before the study and abstracts or unpublished papers.Results:In total, 13 clinical trials were included in systematic review and 7 were included in meta-analysis. Studies evaluated the effectiveness and safety of oral PPS versus placebo or other treatment options. In the first meta-analysis, three studies compared oral PPS with placebo: [relative risk (RR) = 2.07, 95% confidence interval (CI): 1.37–3.13, p = 0.0006]. The second meta-analysis of two studies compared oral PPS with another treatment options (intravesical liposome and CyA): (RR = 0.44, 95% CI: 0.10–1.93, p = 0.28). The third meta-analysis of two studies included intravesical regimen of PPS compared with intravesical placebo: (RR = 1.09, 95% CI: 0.54–2.22, p = 0.80). The majority of studies do not report any particular serious side effects.Conclusion:PPS treatment has a statistically significant effect over placebo on the subjective improvement of patients with BPS/IC. There was no difference between PPS and other treatment options. Intravesical regimen of PPS had no significant impact on response rates. None of included studies reported severe side effects after intervention.

Evidence for Early Cyclosporine Treatment for Hunner Lesion Interstitial Cystitis

(Abstracted from Female Pelvic Med Reconstr Surg 2021; doi: 10.1097/SPV.0000000000001108) Hunner lesion interstitial cystitis (HLIC) is a form of interstitial cystitis/bladder pain syndrome (IC/BPS), occurring in 5%–57% of patients. HLIC is diagnosed by the presence of Hunner lesions on cystoscopy.

Urinary Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome and Its Impact on Therapeutic Outcome.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is defined as a chronic bladder disorder with suprapubic pain (pelvic pain) and pressure and/or discomfort related to bladder filling accompanied by lower urinary tract symptoms, such as urinary frequency and urgency without urinary tract infection (UTI) lasting for at least 6 weeks. IC/BPS presents significant bladder pain and frequency urgency symptoms with unknown etiology, and it is without a widely accepted standard in diagnosis. Patients’ pathological features through cystoscopy and histologic features of bladder biopsy determine the presence or absence of Hunner lesions. IC/PBS is categorized into Hunner (ulcerative) type IC/BPS (HIC/BPS) or non-Hunner (nonulcerative) type IC/BPS (NHIC/BPS). The pathophysiology of IC/BPS is composed of multiple possible factors, such as chronic inflammation, autoimmune disorders, neurogenic hyperactivity, urothelial defects, abnormal angiogenesis, oxidative stress, and exogenous urine substances, which play a crucial role in the pathophysiology of IC/BPS. Abnormal expressions of several urine and serum specimens, including growth factor, methylhistamine, glycoprotein, chemokine and cytokines, might be useful as biomarkers for IC/BPS diagnosis. Further studies to identify the key molecules in IC/BPS will help to improve the efficacy of treatment and identify biomarkers of the disease. In this review, we discuss the potential medical therapy and assessment of therapeutic outcome with urinary biomarkers for IC/BPS.

Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome with and without Hunner Lesion: A Review and Future Perspectives.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating urinary bladder condition that presents with a wide variety of clinical phenotypes. It is commonly characterized by persistent pelvic pain and lower urinary tract symptoms, such as urinary frequency and urgency. Current clinicopathological and genomic evidence has indicated that IC/BPS with Hunner lesions is a clinically relevant distinct subtype with proven bladder pathology of subepithelial chronic inflammatory changes that are characterized by enhanced local immune responses and epithelial denudation. However, other forms of IC/BPS lacking Hunner lesions are a symptom syndrome complex of non-inflammatory conditions with little evidence of bladder etiology, characterized by aberrant neural activity in neurotransmission systems which leads to central nervous sensitization with potential involvement of urothelial malfunction, or clinical presentation of somatic and/or psychological symptoms beyond the bladder. Given such distinct potential pathophysiology between IC/BPS subtypes, disease biomarkers of IC/BPS should be provided separately for subtypes with and without Hunner lesions. Tailored approaches that target characteristic immunological inflammatory processes and epithelial denudation for IC/BPS with Hunner lesions, or the sensitized/altered nervous system, urothelial malfunction, association with other functional somatic syndromes, and psychosocial problems for IC/BPS without Hunner lesions, are essential to identify optimal and reliable disease-specific IC/BPS biomarkers.

Possible role of intravenous administration of mesenchymal stem cells to alleviate interstitial cystitis/bladder pain syndrome in a Toll-like receptor-7 agonist-induced experimental animal model in rat

BackgroundInterstitial cystitis/bladder pain syndrome (IC/BPS) categorized with and without Hunner lesions is a condition that displays chronic pelvic pain related to the bladder with no efficacious treatment options. There are strong associations suggested between Hunner-type IC and autoimmune diseases. Recently, we established an animal model of Hunner-type IC using a Toll-like receptor-7 (TLR7) agonist. Intravenous infusion of mesenchymal stem cells (MSCs) can be used to treat injury via multimodal and orchestrated therapeutic mechanisms including anti-inflammatory effects. Here, we investigated whether infused MSCs elicit therapeutic efficacy associated with the TLR7-related anti-inflammatory pathway in our Hunner-type IC model.MethodsVoiding behaviors were monitored 24 h prior to the Loxoribine (LX), which is a TLR7 agonist instillation in order to establish a Hunner-type IC model (from − 24 to 0 h) in female Sprague–Dawley rats. LX was instilled transurethrally into the bladder. At 0 h, the initial freezing behavior test confirmed that no freezing behavior was observed in any of the animals. The LX-instilled animals were randomized. Randomized LX-instilled rats were intravenously infused with MSCs or with vehicle through the right external jugular vein. Sampling tissue for green fluorescent protein (GFP)-positive MSCs were carried out at 48 h. Second voiding behavior tests were monitored from 72 to 96 h. After the final evaluation of the freezing behavior test at 96 h after LX instillation (72 h after MSC or vehicle infusion), histological evaluation with H&E staining and quantitative real-time polymerase chain reaction (RT-PCR) to analyze the mRNA expression levels of inflammatory cytokines were performed.ResultsFreezing behavior was reduced in the MSC group, and voiding behavior in the MSC group did not deteriorate. Hematoxylin–eosin staining showed that mucosal edema, leukocyte infiltration, and hemorrhage were suppressed in the MSC group. The relative expression of interferon-β mRNA in the bladder of the MSC group was inhibited. Numerous GFP-positive MSCs were distributed mainly in the submucosal and mucosal layers of the inflammatory bladder wall.ConclusionIntravenous infusion of MSCs may have therapeutic efficacy in a LX-instilled Hunner-type IC rat model via a TLR7-related anti-inflammatory pathway.

Neuroinflammatory gene expression analysis reveals potential novel mediators and treatment targets in interstitial cystitis with Hunner lesions.

BackgroundWe sought to study differential neuroinflammatory gene expression in men with interstitial cystitis (IC) with Hunner lesions compared with asymptomatic controls using NanoString, which uses barcoded probes to measure hundreds of genes. IC is a heterogenous condition lacking reliable biomarkers, and a subset of patients exhibits Hunner lesions, implicating the bladder as an inflammatory pain generator.MethodsBlood, urine, and bladder biopsies were collected from 6 men with IC and Hunner lesions. 7 asymptomatic controls had blood and urine collected and 2 benign bladder biopsies were obtained from our tissue bank. RNA was isolated and analyzed with NanoString Human Neuroinflammation panel. Gene expression was considered significant if there was a >1.5-fold change and adjusted P value <0.05 compared with controls.ResultsMean patient age was 61.5 years with 8 years median symptom duration. In bladder tissue, while many cytokine and chemokine genes had higher expression as expected (e.g., TNF, CXCL10), other significant genes included TRPA1 (1098-fold increased, expressed in pain sensing neurons) and TNFRSF17 (735-fold, B-cell related). In urine, there was 114-fold increase in S1PR4, which mediates pain via TRP-dependent pathways. A patient on cyclosporine had lower inflammatory gene expression levels relative to other IC patients, but no difference in TRPA1.ConclusionsMen with IC and Hunner lesions have a diverse set of neuroinflammatory genes with differential expression compared to controls. We identified genes linked to neuropathic pain through the TRP pathway and this expression was not reduced by cyclosporine. These findings open a new direction for biomarker and therapeutic discovery.

Overexpression of HIF1α in Hunner Lesions of Interstitial Cystitis: Pathophysiological Implications.

The aim of our study was to elucidate biological changes in Hunner lesions, which underlie the pathophysiology of Hunner-type interstitial cystitis, by characterizing their whole transcriptome and immunopathological profiles. Paired bladder mucosal biopsies, 1 sample each from the Hunner lesion and nonlesion area, were obtained from 25 patients with Hunner-type interstitial cystitis. The samples were subjected to whole-transcriptome profiling; immunohistochemical quantification of CD3, CD4, CD8, CD20, CD138, mast cell tryptase, cytokeratin and HIF1α; and quantitative polymerase chain reaction for IFN-α, IFN-β, IFN-γ, TNF, TGF-β1, HIF1α, IL-2, IL-4, IL-6, IL-10 and IL-12A. The results were compared between the lesion and nonlesion areas. RNA sequencing identified 109 differentially expressed genes and 30 significantly enriched biological pathways in Hunner lesions. Up-regulated pathways (24) included HIF1α signaling pathway, PI3K-Akt signaling pathway, RAS signaling pathway and MAPK signaling pathway. By contrast, down-regulated pathways (6) included basal cell carcinoma and protein digestion and absorption. The mRNA levels of HIF1α, IFN-γ and IL-2, and the HIF1α protein level were significantly higher in lesion areas. Otherwise, there were no significant differences between the lesion and nonlesion samples in terms of mRNA levels of inflammatory cytokines or histological features such as lymphoplasmacytic and mast cell infiltration, epithelial denudation and CD4/CD8 T-lymphocyte ratio. Our findings demonstrate significant overexpression of HIF1α and up-regulation of its related biological pathways in Hunner lesions. The results indicate that ischemia, in conjunction with inflammation, plays a pathophysiological role in this subtype of interstitial cystitis/bladder pain syndrome, particularly in Hunner lesions.