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

Abstract

Interstitial cystitis/Bladder pain syndrome (IC/BPS) is a chronic, debilitating condition with the hallmark of pressure or pain perceived to be originating from the bladder. Prevalence estimates in the past decade suggest that IC/BPS may affect as many as 7% of women and 4% of men. This diagnosis was first publicly recorded in 1836 by Dr. Joseph Parrish, who documented a syndrome of chronic frequency, urgency, dysuria, and pelvic pain he called tic doloreux of the bladder”. Inherent in the term “tic doloreux” is the concept that no discernible etiology can be identified. Since then, tic doloreux of the bladder has evolved in terminology to interstitial cystitis (IC), bladder pain syndrome (BPS), and urologic chronic pelvic pain syndrome (UCPPS). Yet as the etiology of this syndrome of pain and lower urinary tract symptoms remains unclear, the diagnosis of IC/BPS largely remains a diagnosis of exclusion. Due to the lack of defining diagnostic criteria, patients with IC/BPS often exhibit pain with a widely variable constellation of accompanying genitourinary symptoms, such as nocturia, urgency, frequency, and dysuria, that overlap considerably with other urologic conditions, such as overactive bladder. Despite the wide spectrum of clinical presentations, IC/BPS is often studied, diagnosed, and treated as one entity. For decades, both clinical trials testing various therapies and basic science studies attempting to identify the underlying pathophysiology for IC/BPS have failed to provide definitive results advancing the field. It is becoming increasingly better accepted that these failures may derive from the reality that IC/BPS represents a heterogeneous group of clinical subtypes of pelvic pain resulting from different pathophysiologies. Better differentiation of distinct IC/BPS phenotypes is critical to improve our understanding and treatment of the condition. While the hypothesis that IC/BPS is made up of distinct phenotypes is commonly accepted, only the presence of Hunner lesions (bladder ulcers) on cystoscopic evaluation denotes a specific subgroup for which a change in treatment approach is recommended. While other classification systems for patients without Hunner lesions have been proposed, most require extensive clinical information, detailed physical exams, or even genetic or histopathologic results, which has limited their clinical utility. Our group recently evaluated symptomatic patterns in 145 women with IC/BPS without Hunner lesions using unsupervised machine learning (ML) approaches, revealing that patients with bladder pain could be categorized into 3 distinct phenotypes using only a limited set of patient-reported symptomatic questionnaires. These 3 unique symptom clusters included: 1) patients with myofascial pelvic pain (MFP) characterized by persistent pelvic discomfort and straining to void, urinary frequency and urgency, and a sensation of incomplete emptying, 2) a non-urologic pelvic pain (NUPP) group with urethral and vaginal pain not associated with voiding, and 3) patients with bladder-specific pain symptoms (BPS) worsened with bladder filling and relieved by bladder emptying. Importantly, these groups were associated with different responses to common IC/BPS therapies, correlating well with the presumed etiologies. This classification system was created on the basis of patient-reported symptoms alone, and did not require either physician assessment or exam, which could provide an objective classification system that could be used by providers of any specialty or skill level. As this was a single-center cohort, however, it is unclear if these symptomatic clusters could be reliably reproduced in other populations. The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network recruited a multi-center, national cohort of patients with IC/BPS to understand better the nature of the condition and its subgroups. As clinicians have noted that patients with widespread pain present and respond differently than those with localized pelvic pain, 3 different phenotypes based on pain distribution have previously been proposed for the MAPP cohort: local pain, intermediate pain, or widespread pain, using detailed body mapping of painful regions. We aimed to validate the findings of our prior pilot study in this larger, more geographically diverse patient cohort and determine the correlation of the pathophysiologic phenotype clusters defined in our pilot study with the widespreadness of pain described by body map phenotyping.