Deborah R. Erickson

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.

The interstitial cystitis data base study: Concepts and preliminary baseline descriptive statistics

OBJECTIVES To describe the design, patient population, and data and specimen collection aspects of the interstitial Cystitis Data Base (ICDB) Study and to provide preliminary descriptive statistics and inferential results from an interim analysis. METHODS All 424 study participants successfully enrolled in the ICDB Study prior to December 31, 1995, were selected for an interim analysis and were classified into 1 of 3 symptom severity subgroups. Statistical tests for associations among these symptom severity subgroups and a broad range of baseline characteristics were conducted using Mantal-Haenszel procedures to adjust for variation among clinical centers. RESULTS ICDB Study patients are predominantly female (91.5%), white (91.0%), with an average age at enrollment of 44.3 years. Nearly 45% of these patients underwent a cystoscopy at baseline screening, among whom there was an overall prevalence of 10.5% for Hunners patch and 90% for glomerulations. Urodynamic evaluation for the entire 424 patients demonstrated that volumes at first sensation and at maximal capacity were inversely associated with symptom severity subgroups. A broad range of symptoms were analyzed, indicating that nearly 40% of patients reported urinating 15 times or more during awake hours, and more than 20% reported voiding at least 4 times per night. Almost half (47.9%) reported constant urgency and 23.6% reported having severe pain. Patients in the severe symptom subgroup reported greater limitations in selected quality-of-life indicators than those with less severe symptoms. CONCLUSIONS This interim analysis of the ICDB Study data was compared to previous epidemiologic studies of IC and provides an essential foundation for further analytic investigations of baseline associations and longitudinal trends.

A comparison of multiple urine markers for interstitial cystitis.

PURPOSE We measured several urine markers in 24-hour specimens from patients with interstitial cystitis and healthy controls. For each marker we determined whether the urine level was significantly different in interstitial cystitis and control cases, and whether the marker level correlated with the symptom score. MATERIALS AND METHODS Study participants included 36 female patients with interstitial cystitis and 36 age matched female volunteers. Multiple urine aliquots were obtained to measure the various markers. RESULTS Certain markers were significantly increased in interstitial cystitis, including anti-proliferative factor, epidermal growth factor, insulin-like growth factor (IGF) binding protein-3 and interleukin (IL)-6. Markers significantly decreased in interstitial cystitis were heparin-binding epidermal growth factor-like growth factor, cyclic guanosine monophosphate and methylhistamine. Other markers were not significantly different in the interstitial cystitis and control groups, including total glycosaminoglycans, epitectin, hyaluronic acid, IL-8, IL-1 and nitrates plus nitrites. IGF-1 was undetectable in 24-hour urine samples but spot voided samples from the same interstitial cystitis population had IGF-1 levels similar to previously reported levels. The only significant association of marker with symptom score was a positive correlation of IL-6 with nocturia. For all markers the conclusions were the same whether the marker was normalized to creatinine or to 24 hours. CONCLUSIONS This study confirmed several previously reported urine alterations in interstitial cystitis, including increased anti-proliferative factor, epidermal growth factor, IGF binding protein-3 and IL-6, and decreased heparin-binding epidermal growth factor-like growth factor and cyclic guanosine monophosphate. Of all markers studied anti-proliferative factor had the least overlap in the interstitial cystitis and control groups, and so it is the most likely candidate to become a diagnostic test.

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.

Sensitivity and specificity of antiproliferative factor, heparin-binding epidermal growth factor–like growth factor, and epidermal growth factor as urine markers for interstitial cystitis ☆

We previously determined that the urine of interstitial cystitis (IC) patients specifically contains a factor (antiproliferative factor [APF]) that inhibits primary bladder epithelial cell proliferation, and that it has significantly decreased levels of heparin-binding epidermal growth factor-like growth factor (HB-EGF) and increased levels of epidermal growth factor (EGF) compared with urine from asymptomatic controls and patients with bacterial cystitis. We sought to confirm the specificity of these findings for IC using a larger patient population, including control patients with a variety of urogenital disorders. Clean catch urine specimens were collected from 219 symptomatic IC patients, 113 asymptomatic controls without bladder disease, and 211 patients with various urogenital diseases including acute bacterial cystitis, vulvovaginitis, chronic nonbacterial prostatitis, overactive bladder, hematuria, stress incontinence, neurogenic bladder, benign prostatic hyperplasia, bladder or pelvic pain without voiding symptoms, bladder cancer, prostate cancer, or miscellaneous diagnoses including anatomic disorders. APF activity was determined by (3)H-thymidine incorporation into primary normal adult human bladder epithelial cells. HB-EGF and EGF levels were determined by enzyme-linked immunosorbent assay. APF activity was present significantly more often in IC than control urine specimens (P <0.005 for IC vs any control group; sensitivity = 94%, specificity = 95%, P <10(-82) for IC vs all controls). HB-EGF levels were also significantly lower and EGF levels significantly higher in IC urine than in specimens from controls (P <10(-84) and P <10(-36), respectively). These findings confirm the utility of APF, HB-EGF, and EGF as markers for IC. Understanding the reasons for altered levels of these markers may lead to understanding the pathogenesis of this disorder.

Inflammatory cell types and clinical features of interstitial cystitis.

PURPOSE We tested whether the types of inflammatory cells seen on bladder biopsies were associated with other clinical features and urinary markers of interstitial cystitis. MATERIALS AND METHODS Bladder biopsies from 30 interstitial cystitis patients were evaluated by immunohistochemical staining for T cells, B cells, macrophages and human leukocyte antigen-DR positive cells. These findings were tested for associations with clinical features and urinary markers of interstitial cystitis using alpha = 0.01 because multiple tests were performed. RESULTS Overall severity of inflammation was significantly associated with age at symptom onset, symptom relief after bladder distention and urinary interleukin-6 levels. Patients with severe inflammation had trends toward smaller bladder capacity under anesthesia, increased bladder vascularity and mucosal cracks, lower urinary MUC-1 glycoprotein levels and absence of bloating as a symptom. B cell staining was significantly associated with severe inflammation, symptom relief after distention and absence of bloating as a symptom. T cell staining was significantly associated with severe inflammation and age at symptom onset. Human leukocyte antigen-DR staining had trends with symptoms, including presence of bloating, constant urge to void and absence of burning. Macrophage staining did not associate with any features tested at the alpha = 0.05 level. CONCLUSIONS Interstitial cystitis patients with severe inflammation have different age, treatment response and urinary marker levels than those with mild inflammation. These findings suggest that the 2 patient groups have different underlying pathophysiologies. The significant associations for T and B cell staining were similar to those for overall inflammation.

Urine markers of interstitial cystitis.

This article describes the current state of the art with regard to urine markers of interstitial cystitis (IC), and describes the areas that need continuing research. Articles referenced in MEDLINE that describe urine alterations in IC were reviewed. Additional articles were identified by cross-referencing. The different marker alterations were tabulated. The relevant articles were discussed, considering different purposes for urine markers including: (1) diagnosing IC; (2) confirming a specific pathophysiology for IC; and (3) predicting or following response to a specific treatment. Currently, 2 markers (glycoprotein-51 and antiproliferative factor [APF]) clearly separate IC and control subjects, with minimal overlap. Markers that correlate with specific bladder biopsy features include 1,4-methylimidazole acetic acid and eosinophil cationic protein (ECP), which correlate with mast cell density, and interleukin (IL)-6, which correlates with mononuclear inflammation. Markers that changed after treatment were as follows: (1) nitric oxide synthase and cyclic guanosine monophosphate increased with oral L-arginine; (2) ECP decreased with subcutaneous heparin; (3) prostaglandin E(2) and kallikrein decreased after bladder distention; (4) neutrophil chemotactic activity decreased after dimethyl sulfoxide; (5) IL-2 inhibitor decreased after oral nifedipine; (6) IL-2, IL-6, and IL-8 decreased after bacille Calmette-Guérin (BCG) vaccine; and (7) APF and heparin-binding epidermal growth factor changed to or toward normal levels after bladder distention or sacral nerve stimulation. A larger number of urine alterations have been reported, and a few are being pursued further by correlating with bladder biopsy findings or treatment responses. Further research is needed.

Urine Markers Do Not Predict Biopsy Findings or Presence of Bladder Ulcers in Interstitial Cystitis/Painful Bladder Syndrome

PURPOSE We tested for associations between urine markers, bladder biopsy features and bladder ulcers in interstitial cystitis/painful bladder syndrome. MATERIALS AND METHODS Subjects were 72 patients with interstitial cystitis/painful bladder syndrome undergoing bladder distention and biopsy. Urine was collected before the procedure. Urine marker levels were correlated with biopsy and cystoscopic findings. Patients with no previous interstitial cystitis/painful bladder syndrome treatments (47) were analyzed separately from previously treated patients (25). RESULTS For untreated patients urine interleukin-6 and cyclic guanosine monophosphate were associated with urothelial epidermal growth factor receptor staining (for interleukin-6 r = 0.29; 95% CI 0.07, 0.51; p = 0.01 and for cyclic guanosine monophosphate r = 0.34; 95% CI 0.13, 0.55; p = 0.002). Urine interleukin-8 was negatively associated with urothelial heparin-binding epidermal growth factor-like growth factor staining (r = -0.34; 95% CI -0.55, -0.12; p = 0.002) and positively associated with lamina propria mast cell count (r = 0.29; 95% CI 0.06, 0.52; p = 0.01). The latter association also was seen in treated patients (r = 0.46; 95% CI 0.20, 0.73; p <0.001). None of the urine markers was significantly different for ulcer vs nonulcer groups. All of the patients with ulcer had extensive inflammation on bladder biopsy including severe mononuclear cell infiltration, moderate or strong interleukin-6 staining in the urothelium and lamina propria, and leukocyte common antigen staining in more than 10% of the lamina propria. However, these features also were seen in 24% to 76% of the patients without ulcer. CONCLUSIONS Overall urine markers did not associate robustly with biopsy findings. The strongest association was a positive association between urine interleukin-8 levels and bladder mast cell count. Patients with ulcer consistently had bladder inflammation but the cystoscopic finding of ulcers was not a sensitive indicator of inflammation on bladder biopsy.

INCREASED URINARY HYALURONIC ACID AND INTERSTITIAL CYSTITIS

PURPOSE We compared urinary levels of hyaluronic acid in patients who met the National Institute for Diabetes, and Digestive and Kidney Diseases criteria for interstitial cystitis and in age matched healthy female controls. MATERIALS AND METHODS Urinary hyaluronic acid was measured by solid phase radiometric assay using hyaluronic acid binding protein. Hyaluronic acid and symptom scores were compared in interstitial cystitis patients who gave multiple urine samples during treatment. Since hyaluronic acid changed with treatment in some patients, 17 samples from untreated interstitial cystitis patients were selected and compared with 17 control samples. RESULTS Mean plus or minus standard deviation urinary hyaluronic acid concentrations were similar in the 2 groups (interstitial cystitis group 574 +/- 496, controls 512 +/- 324 ng./ml., p = 0.77). When normalized to creatinine urinary hyaluronic acid was significantly higher in interstitial cystitis patients (interstitial cystitis group 674 +/- 220, controls 446 +/- 220 ng./mg. creatinine, p = 0.0019). Urinary creatinine concentrations did not differ significantly (interstitial cystitis group 842 +/- 715, controls 1,162 +/- 516 mg./l., p = 0.12). CONCLUSIONS Urinary hyaluronic acid was higher in interstitial cystitis patients than healthy controls. Since bladder hyaluronic acid is below the epithelium, this finding may indicate leakage across the epithelium into the urine in interstitial cystitis patients.

Interstitial cystitis: update on etiologies and therapeutic options.

Interstitial cystitis (IC) is a syndrome of pelvic and/or perineal pain, urinary urgency, and frequency. It is now agreed that IC is a multifactorial syndrome, not a single condition. A variety of etiologies for IC have been proposed, but none has been definitively proven. Since the etiologies for IC remain unknown, the current treatments are empiric. This article will review the major theories of etiology for IC and discuss the current treatment options with relevance to the proposed etiologies. No single treatment is effective for all IC patients. Therefore, the approach is to try different treatments, alone or in combination, until symptom relief is satisfactory. In some cases, none of the empiric IC treatments are successful. These patients require adjunctive pain management, and a small minority of IC patients resort to surgery if all other options fail.