Secondary Analysis of Interstitial Cystitis/Bladder Pain Syndrome Patients Enrolled in a Recurrent Urinary Tract Infection Prevention Study Provides a Novel Paradigm for Etio-Pathogenesis and Practical Management of This Infection Phenotype

Abstract

Introduction: A subset of interstitial cystitis/bladder pain syndrome (IC/BPS) patients experience recurrent urinary tract infection (rUTI) associated with symptom flares. Recurrent UTI subjects with associated IC/BPS were enrolled in the first North American early clinical experience trial evaluating a new sublingual UTI preventative vaccine, MV140. It has been shown that women with rUTI develop an imbalance in the T helper 1 and 2 (Th2 over-expression) in the bladder mucosa. Our hypothesis-generating secondary analysis will suggest that this infection subcategory of IC/BPS patients develop a similar imbalance of Th1-Th2 response type to bacteria present in their urinary microbiome, leading to a bladder hypersensitivity that responds to mucosal immune modulation.

Methods: Female participants with ≥3 documented UTI/year underwent a 3-month vaccination treatment period with a 9-month efficacy period after completion of vaccine treatment (total 12 months). There were no exclusion criteria for subjects in relation to baseline urinary symptoms and/or discomfort/pain. Primary outcome was no UTI following vaccination. Secondary outcomes included change in UTI incidence, overall patient-reported subjective global assessment (SGA responder defined as moderately or markedly improved on 7-point scale), and safety.

Results: Sixteen subjects with IC/BPS-related symptoms and rUTI (mean age 47; range 23-74 years; mean number of UTI episodes in previous year 6.1 +/- 4.2) were eligible to be included in the Health Canada-approved MV140 vaccine study for prevention of rUTI. All subjects completed the 3-month vaccination period. One subject was lost to follow-up after their 6-month visit. Six subjects were UTI-free, while all 16 subjects had a reduction in UTI episodes compared to the year pre-vaccination. The total post-vaccination reduction in UTI episodes compared to pre-vaccination was 80% (0.1 UTI/subject/month from 0.5 UTI/subject/month, respectively). At 12 months, 13 subjects (81%) were SGA responders (moderately or markedly improved), and the responders reported a reduction in IC/BPS symptoms, with 8 subjects reporting significant or almost complete resolution of their specific long-term bladder discomfort/pain and bothersome urinary frequency or urgency. Four subjects reported mild and self-limited adverse events during vaccination period, but none were related to MV140 vaccine.

Conclusion: Sublingual MV140 vaccine in IC/BPS patients with rUTI not only achieved UTI-free or reduced UTI incidence status but also, after approximately 9 months post vaccination, resolution of patients' long-term treatment-refractory IC/BPS symptoms. This suggests some cases of IC/BPS may be etiologically based on Th2-driven hypersensitivity to bacteria within or entering the urinary microbiome that responds to a vaccine whose mechanism of action is to normalize or balance the bladder Th1/Th2 mucosal immune system.

Keywords: bladder pain syndrome; interstitial cystitis; recurrent urinary tract infection; urinary tract infection; vaccine; women’s health.

Figure 1

Typical course of an infrequently occurring UTI resulting from uropathogenic bacteria entering the bladder and overcoming the host defenses. The resulting inflammation, pain, and bladder irritability usually resolves with a standard course of an appropriate antibiotic.

Figure 2

Scenario believed to occur in susceptible females who develop rUTI. In these individuals epithelial damage may result in an increase in T helper 2 (Th2) response in the bladder mucosa, which may counteract Th1-mediated microbicidal action and lead to a cycle of recurrent UTI-like episodes.

Figure 3

The increased mucosal sensitivity that can occur with the imbalance of Th1:Th2 levels in the bladder mucosa may lead to increased bladder hypersensitivity and pain between rUTI episodes.

Figure 4

Mechanism by which MV140 decreases risk of rUTI from bacteria outside and inside the bladder microbiome by increasing Th1 and Th17 cells, which both downregulate the abnormal Th2 response and promote or mediate cellular immune responses.

Figure 5

Hypothesis is that restoring the immunological balance within the bladder mucosa in patients with IC/BPS and rUTI will result in eventual amelioration of the bladder mucosal hypersensitivity responsible for the development, propagation, and maintenance of the IC/BPS symptoms.