Hypothesis / aims of study
Efforts to research and treat interstitial cystitis/bladder pain syndrome (IC/BPS) are complicated by the broad heterogeneity within the disorder. Efforts to identify clinically meaningful IC/BPS subgroups have found that molecular profiling of bladder mucosal tissue from a modest number of IC/BPS patients and controls shows a separation of profiles based on anesthetic bladder capacity (BC) [1]. Patients with a low BC (which was defined empirically as BC ≤ 400cc) had a characteristic gene expression profile that was distinct from patients with a non-low BC (> 400cc), and controls. Further examination of clinical and demographic information utilizing a patient registry, using low BC as the benchmark, revealed a bladder-centric IC/BPS patient subgroup characterized by older age, higher symptom scores on validated questionnaires, higher prevalence of Hunner’s lesions (HL), and fewer non-urologic associated symptoms and syndromes [2]. With the understanding that the cutoff of BC ≤ 400cc to identify as ‘low BC’ was truly an estimate, we have undertaken an analysis of our large patient registry utilizing genetic expression data as well as demographic and clinical data to determine if an adjustment in this cutoff estimate is warranted.
Study design, materials and methods
IC/BPS patients scheduled to undergo therapeutic hydrodistention (HOD) were recruited to participate in our IRB-approved study. Following written informed consent, mucosal biopsies were collected at the time of HOD and stored for genomic analysis in our biobank. Clinical and demographic information, including BC, HL status, scores on validated IC/BPS symptom scores (O’Leary Sant Interstitial Cystitis Symptom & Problem Indices [ICSI/ICPI], and Pain & Urgency/Frequency [PUF] patient symptom scale), were collected for each patient. In addition, questionnaire data to determine the presence/absence of several common non-urologic associated symptoms (NUAS), subdivided into localized pelvic pain syndromes (PPS) and widespread neurologic, allergic, and systemic pain syndromes (NASP), were also prospectively collected. For this study, we initially analyzed whole genome gene expression array data from 48 mucosal biopsy samples (41 from IC/BPS patients; 7 from controls) to provide an updated assessment of patient stratification based on anesthetic BC. Next, we identified 491 individual recruited patients with complete demographic, clinical, and questionnaire data that were available for analysis. Characteristics of these 491 patients were compared between those having the current low BC cutoff (≤ 400cc) and the proposed new cutoff (≤ 500cc) utilizing independent samples t-test (continuous variables) and chi square tests (categorical variables), with a p<0.05 being considered significant.
Results
Unsupervised clustering and principal component analysis (PCA) of 48 whole genome data profiles identified three primary individual clusters: (1) IC/BPS patients with a BC between 200-500cc, (2) IC/BPS patients with a BC of 500-1500cc, and (3) controls (Figure 1). A statistical comparison of the demographic and clinical characteristics of these IC/BPS patient sub-groups showed that those with a bladder capacity ≤500cc were older, more likely to have Hunner’s lesions, had higher ICSI and ICPI scores, as well as frequency and nocturia sub scores (PUF) (p<0.05), were less likely to be female, and had a shorter length of diagnosis than those with a BC >500mL (p<0.05). This group also had a lower average number of NUAS, pelvic pain syndromes (PPS), and neurologic, immune, or systemic pain syndromes (NASP), including lower rates of endometriosis, pelvic floor muscle dysfunction, irritable bowel syndrome (IBS), chronic fatigue syndrome (CFS), fibromyalgia, migraines, depression, panic disorder, insomnia, and asthma. These findings, based on a low BC designation of ≤500cc, were closely aligned with the former low BC designation (≤400cc) findings (Table 1).
Interpretation of results
Molecular (gene expression) analysis can be used to highlight a statistically meaningful difference between IC/BPS patients that is based on anesthetic bladder capacity. Using this molecular information together with demographic and clinical data from a large cohort of IC/BPS patients, we have identified significant differences between these subgroups, with a low bladder capacity (i.e., bladder centric) phenotype having a high prevalence of Hunner’s lesions, as well as higher symptom scores and fewer non-urologic associated syndromes. Comparatively, the non-bladder centric phenotype has a low prevalence of Hunner’s lesions, moderately lower validated symptom scores, and higher numbers of combined non-urologic associated syndromes, including higher prevalence rates of many syndromes individually. These findings expand upon earlier data that posited a 400cc cut-off for low BC and supports that idea that the 400mL cutoff may be too low and may exclude patients with a true bladder-centric phenotype.