Interstitial cystitis/bladder pain syndrome: The evolving landscape, animal models and future perspectives.

Interstitial cystitis/bladder pain syndrome is a debilitating condition of unknown etiology characterized by persistent pelvic pain with lower urinary tract symptoms and comprises a wide variety of potentially clinically useful phenotypes with different possible etiologies. Current clinicopathological and genomic evidence suggests that interstitial cystitis/bladder pain syndrome should be categorized by the presence or absence of Hunner lesions, rather than by clinical phenotyping based on symptomatology. The Hunner lesion subtype is a distinct inflammatory disease with proven bladder etiology characterized by epithelial denudation and enhanced immune responses frequently accompanied by clonal expansion of infiltrating B cells, with potential engagement of infection. Meanwhile, the non-Hunner lesion subtype is a non-inflammatory disorder with little evidence of bladder etiology. It is potentially associated with urothelial malfunction and neurophysiological dysfunction, and frequently presents with somatic and/or psychological symptoms, that commonly result in central nervous sensitization. Animal models of autoimmune cystitis and neurogenic sensitization might serve as disease models for the Hunner lesion and non-Hunner lesion subtypes, respectively. Here, we revisit the taxonomy of interstitial cystitis/bladder pain syndrome according to current research, and discuss its potential pathophysiology and representative animal models. Categorization of interstitial cystitis/bladder pain syndrome based on cystoscopy is mandatory to design optimized treatment and research strategies for each subtype. A tailored approach that specifically targets the characteristic inflammation and epithelial denudation for the Hunner lesion subtype, or the urothelial malfunction, sensitized/altered nervous system and psychosocial problems for the non-Hunner lesion subtype, is essential for better clinical management and research progress in this complex condition.

Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment.

PURPOSE: The purpose of this amendment is to provide an updated clinical framework for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome based upon data received since the publication of original guideline in 2011. MATERIALS AND METHODS: A systematic literature review 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. This initial review yielded an evidence base of 86 treatment articles after application of inclusion/exclusion criteria. The AUA update literature review process, in which an additional systematic review is conducted periodically to maintain guideline currency with newly published relevant literature, was conducted in July 2013. This review identified an additional 31 articles, which were added to the evidence base of this Guideline. RESULTS: Newly incorporated literature describing the treatment of IC/BPS was integrated into the Guideline with additional treatment information provided as Clinical Principles and Expert Opinions when insufficient evidence existed. The diagnostic portion of the Guideline remains unchanged from the original publication and is still based on Expert Opinions and Clinical Principles. CONCLUSIONS: The management of IC/BPS continues to evolve as can be seen by an expanding literature on the topic. This document constitutes a clinical strategy and is not intended to be interpreted rigidly. The most effective approach for a particular patient is best determined by the individual clinician and patient. As the science relevant to IC/BPS evolves and improves, the strategies presented will require amendment to remain consistent with the highest standards of care.

AUA guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome.

PURPOSE: To provide a clinical framework for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome. MATERIALS AND METHODS: A 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 interstitial cystitis/bladder pain syndrome. Insufficient evidence-based data were retrieved regarding diagnosis and, therefore, this portion of the Guideline is based on Clinical Principles and Expert Opinion statements. The review yielded an evidence base of 86 treatment articles after application of inclusion/exclusion criteria. These publications were used to create the majority of the treatment portion of the Guideline. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high), B (moderate) or C (low). Additional treatment information is provided as Clinical Principles and Expert Opinion when insufficient evidence existed. See text and algorithm for definitions, and detailed diagnostic management, and treatment frameworks. RESULTS: The evidence-based guideline statements are provided for diagnosis and overall management of interstitial cystitis/bladder pain syndrome as well as for various treatments. The panel identified first through sixth line treatments as well as developed guideline statements on treatments that should not be offered. CONCLUSIONS: Interstitial cystitis/bladder pain syndrome is best identified and managed through use of a logical algorithm such as is presented in this Guideline. In the algorithm the panel identifies an overall management strategy for the interstitial cystitis/bladder pain syndrome patient. Diagnosis and treatment methodologies can be expected to change as the evidence base grows in the future.

Early termination of a trial of mycophenolate mofetil for treatment of interstitial cystitis/painful bladder syndrome: lessons learned.

PURPOSE: We evaluated the efficacy and tolerability of mycophenolate mofetil in patients with treatment refractory interstitial cystitis/painful bladder syndrome. MATERIALS AND METHODS: A total of 210 patients with interstitial cystitis/painful bladder syndrome were to be randomized into a multicenter, placebo controlled trial using a 2:1 randomization. Participants in whom at least 3 interstitial cystitis/painful bladder syndrome specific treatments had failed and who had at least moderately severe symptoms were enrolled in a 12-week treatment study. The primary study end point was the global response assessment. Secondary end points were general and disease specific symptom questionnaires, and voiding diaries. RESULTS: Only 58 subjects were randomized before a black box warning regarding mycophenolate mofetil safety was issued by the manufacturer in October 2007. The trial was halted, and interim analysis was performed and presented to an independent data and safety monitoring board. Six of the 39 subjects (15%) randomized at study cessation were considered responders for mycophenolate mofetil compared to 3 of 19 controls (16%, p=0.67). Secondary outcome measures reflected more improvement in controls. CONCLUSIONS: In a randomized, placebo controlled trial that was prematurely halted mycophenolate mofetil showed efficacy similar to that of placebo to treat symptoms of refractory interstitial cystitis/painful bladder syndrome. The results of this limited study cannot be used to confirm or refute the hypothesis that immunosuppressive therapy may be beneficial to at least a subgroup of patients with interstitial cystitis/painful bladder syndrome. Despite study termination lessons can be gleaned to inform future investigations.

Current Understanding and Future Perspectives of Interstitial Cystitis/Bladder Pain Syndrome.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic disease characterized by suprapubic pain and lower urinary tract symptoms. Perhaps because of the heterogeneous nature of this disease and its multifactorial etiology, clinical trials in allinclusive populations of IC/BPS patients without phenotyping in the last decade have mainly failed to discover new therapeutic modalities of IC/BPS. Thus, phenotyping IC/BPS, aimed at identifying bladder-centric and/or bladder-beyond pathologies, including cystoscopic observation of Hunner or non-Hunner lesions of the bladder mucosa, is particularly important for the future of IC/BPS management. Based on recent discussions at international conferences, including the International Consultation on IC, Japan, it has been proposed that Hunner-lesion IC should be separated from other non-Hunner IC/BPS because of its distinct inflammatory profiles and epithelial denudation compared with non-Hunner IC/BPS. However, there are still no standard criteria for the diagnosis of Hunner lesions other than typical lesions, while conventional cystoscopic observations may miss atypical or small Hunner lesions. Furthermore, diagnosis of the bladder-centric phenotype of IC/BPS requires confirmation that identified mucosal lesions are truly a cause of bladder pain in IC/BPS patients. This review article discusses the current status of IC/BPS pathophysiology and diagnosis, as well as future directions of the proper diagnosis of bladder-centric IC/BPS, in which pathophysiological mechanisms other than those in inflammatory pathways, such as angiogenic and immunogenic abnormalities, could also be involved in both Hunner-lesion IC and non-Hunner IC/BPS. It is hoped that this new paradigm in the pathophysiological evaluation and diagnosis of IC/BPS could lead to pathology-based phenotyping and new treatments for this heterogeneous disease.

Effect of amitriptyline on symptoms in treatment naïve patients with interstitial cystitis/painful bladder syndrome.

PURPOSE: Amitriptyline is frequently used to treat patients with interstitial cystitis/painful bladder syndrome. The evidence to support this practice is derived mainly from a small, single site clinical trial and case reports. MATERIALS AND METHODS: We conducted a multicenter, randomized, double-blind, placebo controlled clinical trial of amitriptyline in subjects with interstitial cystitis/painful bladder syndrome who were naïve to therapy. Study participants in both treatment arms received a standardized education and behavioral modification program. The drug dose was increased during a 6-week period from 10 up to 75 mg once daily. The primary outcome was a patient reported global response assessment of symptom improvement evaluated after 12 weeks of treatment. RESULTS: A total of 271 subjects were randomized and 231 (85%) provided a global response assessment at 12 weeks of followup. Study participants were primarily women (83%) and white (74%), with a median age of 38 years. In an intent to treat analysis (271) the rate of response of subjects reporting moderate or marked improvement from baseline in the amitriptyline and placebo groups was 55% and 45%, respectively (p = 0.12). Of the subgroup of subjects (207) who achieved a drug dose of at least 50 mg, a significantly higher response rate was observed in the amitriptyline group (66%) compared to placebo (47%) (p = 0.01). CONCLUSIONS: When all randomized subjects were considered, amitriptyline plus an education and behavioral modification program did not significantly improve symptoms in treatment naïve patients with interstitial cystitis/painful bladder syndrome. However, amitriptyline may be beneficial in persons who can achieve a daily dose of 50 mg or greater, although this subgroup comparison was not specified in advance.

Bladder pain syndrome/interstitial cystitis: a sense of urgency.

A classic triad of symptoms (bladder pain, urinary frequency, and urgency) has served to define bladder pain syndrome/painful bladder syndrome/interstitial cystitis (BPS/PBS/IC) syndrome. BPS/PBS/IC is a distinct condition and it is likely that the urgency experienced by these patients differs from that experienced by those with overactive bladder syndrome. It is unclear how best to define urgency in the BPS/PBS/IC setting. Differences in the other primary symptoms associated with these conditions probably influence how urgency is perceived. Advances in research into the pathophysiology of urgency and underlying disease processes will help to optimize both the diagnosis and treatment of BPS/PBS/IC.

The relationship of common medical conditions and medication use with symptoms of painful bladder syndrome: results from the Boston area community health survey.

PURPOSE: The etiology of painful bladder syndrome is currently unknown. We investigated the relationship between medical factors and symptoms suggestive of painful bladder syndrome in a population based random sample. MATERIALS AND METHODS: Data were collected from the Boston Area Community Health Survey, an epidemiological study conducted from 2002 to 2005 in a racially and ethnically diverse population (30 to 79 years old) from Boston, Massachusetts. The operational definition of painful bladder syndrome was symptom based. Those reporting pain increasing as the bladder fills and/or pain relieved by urination (fairly often/usually/almost always) for 3+ months were considered to have symptoms suggestive of painful bladder syndrome. We used multivariate logistic regression to estimate odds ratios and 95% confidence intervals (adjusted for demographics, anthropometric and other factors) for the association of comorbidities, surgery and medication use with painful bladder syndrome symptoms. RESULTS: The prevalence of painful bladder syndrome symptoms was 1.3% in men and 2.6% in women. In men only depression was associated in a multivariate model (OR 4.96; 95% CI 1.65, 14.92). In women associations were observed for depression (OR 3.35; 95% CI 1.93, 5.81), history of urinary tract infections (OR 2.17; 95% CI 1.49, 4.96), chronic yeast infections (OR 3.11; 95% CI 1.29, 7.51), hysterectomy (OR 2.82; 95% CI 1.20, 6.62), calcium channel blockers (OR 4.59; 95% CI 2.71, 9.72) and cardiac glycosides (OR 10.28; 95% CI 1.46, 72.35), while thyroid medications and statins were inversely associated (OR 0.13; 95% CI 0.03, 0.47 and OR 0.24; 95% CI 0.08, 0.76; respectively). CONCLUSIONS: Gynecologic factors and certain medications may be associated with the painful bladder syndrome in women. Our results for medications suggest potentially modifiable risk factors.

Prevalence and psychosocial correlates of symptoms suggestive of painful bladder syndrome: results from the Boston area community health survey.

PURPOSE: We estimated the prevalence of symptoms suggestive of painful bladder syndrome defined as pain increasing as the bladder fills and/or pain relieved by urination for at least 3 months, and its association with sociodemographics (gender, age, race/ethnicity and socioeconomic status), lifestyle (smoking, alcohol consumption, physical activity) and psychosocial variables (sexual, physical, emotional abuse experienced as a child or as an adult, worry, trouble paying for basics, depression). MATERIALS AND METHODS: The data used come from the Boston Area Community Health Survey, an epidemiological study of 5,506 randomly selected adults 30 to 79 years old of 3 race/ethnic groups (black, Hispanic, white). RESULTS: The overall prevalence of symptoms suggestive of painful bladder syndrome was 2% (1.3% in men and 2.6% in women) with increased prevalence in middle-aged adults and those of lower socioeconomic status. Symptoms suggestive of painful bladder syndrome were more common in those who experienced abuse, in those who were worried about someone close to them and in those who were having trouble paying for basics. This pattern held even after adjusting for depression. CONCLUSIONS: Painful bladder syndrome is associated with a number of lifestyle and psychosocial correlates. This suggests that the treatment of patients with painful bladder syndrome (physical symptoms) may benefit from a multifaceted approach of combining medical, psychological and cognitive treatment.

Re-imagining interstitial cystitis.

Since the postulation of an "antiproliferative factor" in 1998 and a description, six years later, of this putative central protein in the etiologic pathway of the painful bladder syndrome/interstitial cystitis, there have been no dramatic breakthroughs in the field. Although much potentially exciting work is in progress with regard to epidemiology, etiology, and clinical treatment, many clinicians and researchers have used this hiatus to take another look at what exactly is being studied and how the syndrome should be approached. This article explores some of the current "hot-button" issues of definition and nomenclature that have formed the basis of many international meetings in the last 5 years.

Idiopathic partial thrombosis of the corpus cavernosum.

We report the case of an idiopathic partial segmental thrombosis of the left corpus cavernosum. The diagnosis was made by physical examination and radiological imaging. The patient was treated conservatively with aspirin, and follow-up imaging at 3 and 7 months revealed mild persistent thrombosis. Erectile function was maintained at 1 year follow-up.

Interstitial cystitis-epidemiology, diagnostic criteria, clinical markers.

Knowledge of the epidemiology of interstitial cystitis (IC), the burden of the disease in the population, and the identification of possible risk factors remains largely fragmentary. The most reliable information comes from the few population-based studies that have appeared in the literature over the past 25 years, but two major issues urgently need to be addressed by appropriate epidemiologic studies: although studies find that only 10% of IC occurs in men, the hallmark symptoms of chronic prostatitis-pelvic pain, voiding dysfunction, and pain associated with sexual activity-overlap with those in men who carry the IC diagnosis. In addition, it is not known whether children suffer from the condition. The definition of IC is grounded in the symptomatology of pelvic pain and urinary frequency of a chronic nature and unexplained by any known urologic or other system pathology, but undue reliance on cystoscopic criteria has undoubtedly led to significant underdiagnosis. Efforts to identify clinical markers for diagnosis of IC are continuing and may lead the way to ascertaining the etiology and pathophysiology of IC.

Targets for therapy of the painful bladder.

Interstitial cystitis is an elusive disorder. Without a defining etiology and distinctive pathophysiology, diagnosis is made on an exclusionary basis. Treatment strategies for the disease vary, as do estimates of its prevalence. Nevertheless, advances are being made in understanding this disease. Basic research is helping to define rational treatment approaches for interstitial cystitis, and new therapies based on the findings of such research are being developed. This article reviews the theories of the etiology of interstitial cystitis and reviews the evidence for clinical effectiveness of various treatments.

Intravesical nitric oxide production discriminates between classic and nonulcer interstitial cystitis.

PURPOSE: Interstitial cystitis (IC) is one of the most bothersome conditions in urological practice. There are 2 subtypes, classic and nonulcer IC, with similar symptoms but different outcomes with respect to clinical course and response to treatment. Histologically there are fundamental differences between the 2 subtypes, classic IC presenting a severe abnormality of the urothelium and characteristic inflammatory cell infiltrates while inflammation is scant in nonulcer IC. Regulation of urinary nitric oxide synthase activity has been proposed to be of importance for immunological responses in IC. We present evidence of a profound difference between the 2 subtypes concerning nitric oxide production, mirroring the differences in inflammatory response in IC. MATERIALS AND METHODS: A total of 17 patients with both subtypes and active disease as well as patients with disease in remission were included in the study, all diagnosed according to National Institute for Diabetes and Digestive and Kidney Diseases criteria. Luminal nitric oxide was measured in the bladder of patients using a chemiluminescence nitric oxide analyzer. RESULTS: All patients with classic IC had high levels of NO. None of the other patients had any significant increase in NO levels in the bladder. The NO level in patients with classic IC was not related to symptoms but rather to the assignment to this specific subgroup of IC. The highest levels of NO were found in patients in the initial phase of classic IC. CONCLUSIONS: The difference in NO evaporation between classic and nonulcer IC allows for subtyping of cases meeting National Institute for Diabetes and Digestive and Kidney Diseases criteria without performing cystoscopy. The findings in the present series together with previous findings clearly demonstrate that the 2 subtypes of IC represent separate entities. This separation further emphasizes the need to subtype all cases included in all scientific matters, ensuring that the 2 subtypes are evaluated separately in clinical studies.