Meeting On Frontiers In Painful Bladder Syndrome, Interstitial Cystitis - Report On The NIDDK International Frontiers In PBS/IC Symposium
UroToday.com - The recently concluded NIDDK meeting on Frontiers in Painful Bladder Syndrome / Interstitial Cystitis was extremely successful and well-received. It was chaired by Deborah Erickson, Professor of Urology at the University of Kentucky. Many interesting "state of the art" presentations and research posters were presented, covering both basic science and clinical topics.
Perhaps the presentations that drew the most controversy were from the session given by the European Society for the Study of Interstitial Cystitis (ESSIC).
Dr. Arndt van Ophoven from M?nster, Germany reviewed the diagnosis and standard investigations for PBS/IC. (Eur Urol, 45:662-669, 2004) ESSIC recommends a medical history and physical examination, urinalysis and culture, voiding diary, O'Leary-Sant symptom score, and International Prostate Symptom Score. Urodynamics are recommended if bladder outlet obstruction in the male is in the differential diagnosis. A modified potassium sensitivity test with a 2M KCl solution is optional if one believes the data that it helps select patients appropriate for hyaluronic acid bladder irrigations. (J Urol, 170:807-809, 2003). This correspondent does not believe the data is compelling given the failure to show any benefit of hyaluronic acid in two large multicenter, placebo-controlled American trials with 40mg per 40cc and 200mg per 40cc formulations.
Dr. Magnus Fall from Göteborg, Sweden discussed the role of cystoscopy, considered an optional test by ESSIC. It is indicated to rule out the presence of "confusable diseases", but Dr. Fall believes it is extremely valuable in diagnosis. He believes the "Hunner's ulcer" is more common than the literature suggests, and that with a high index of suspicion and a willingness to perform cystoscopy under anesthesia, one can identify these lesions at a higher frequency than the 10% suggested in the literature. He also voiced the opinion that cystoscopy is worthwhile for categorization of patients and comparisons among groups. With cystoscopy no longer viewed as a routine part of the uncomplicated painful bladder investigation in the United States, further discussion of these comments is to be expected in future meetings.
Dr. Kirsten Bouchelouche discussed the ESSIC recommendations for biopsy with regard to technique and handling. Large forceps should be used to obtain at least 3 biopsies from the 2 lateral walls and dome in addition to sites with lesions. Tissue should include detrusor muscle and be examined by H&E and connective tissue stains. Naphtolesterase is recommended for mast cell counting. Less than 20 mast cells/mm2 shows a lack of detrusor mastocytosis, between 20 and 28 is a gray zone, and greater than 28 mast cells/mm2 denotes detrusor mastocytosis. ESSIC is promoting this for information gathering purposes at this point, and evidence of the importance of pathology in diagnosis or treatment continues to be lacking in the view of most American investigators.
Finally, Dr. Andrew Baranowski and Dr. J?rgen Nordling introduced a discussion about a new taxonomy for chronic pelvic pain syndromes (J. Urol., 175:1989-1990, 2006) and a new definition for the newly coined "Bladder Pain Syndrome" or "BPS" which ESSIC proposed to replace the designation of Painful Bladder Syndrome (PBS). Both terms are indefinitely linked to interstitial cystitis (BPS/IC and PBS/IC), but the long-term goal is to eliminate the term "IC". The rational is that interstitial cystitis is a misnomer, as the disorder is often not interstitial and not inflammatory. The more general pain term is more descriptive of the reality. A new paradigm, looking at interstitial cystitis as representing one of a number of chronic pain syndromes such as prostate pain syndrome, vulvar pain syndrome, testicular pain syndrome, etc., would potentially be more productive in terms of research focus and even clinical treatment focus. The ESSIC definition of bladder pain syndrome / interstitial cystitis is: pain related to the urinary bladder accompanied by at least one other urinary symptom (i.e. daytime or night-time frequency) in the absence of confusable disease. Dr. Joop van de Merwe presented an elegant classification grid whereby one can fit a patient within a category depending upon whether they underwent diagnostic cystoscopy and / or bladder biopsy, and incorporating the results of each of these investigations if performed.
Needless to say, the ESSIC presentations engendered heated debate by the patient organizations, who were present and vocal during the meeting, and among clinicians and researchers from around the United States. A major point of discussion was the definition of urgency, and problems engendered by the current International Continence Society definition, "sudden compelling desire to pass urine which is difficult to defer". This definition fails to clearly distinguish the urgency of overactive bladder from the urgency of interstitial cystitis. A fear of leakage would seem to typify the former, and an increasing discomfort or painful sensation would seem to be responsible in the latter condition. Mr. Paul Abrams took note of the discussion, and it is hoped that future consultations, perhaps at the International Continence Society meeting in New Zealand this month, and in future meetings in Europe and Asia in the next 2 years including the next International Consultation on Incontinence will bring this problem to a suitable solution. I think that this portion of the meeting served a very useful purpose as it brought into an open, international forum many ideas that have been circulating for the last few years and which will require further discussion and eventual resolution if patients are to be best served.
Other Highlights
Dr. Karen Berkley discussed cross-system viscero-visceral interactions and their implications for PBS/IC. She noted that ectopic endometrial growths in both experimental rats and in women develop their own sensory and sympathetic nerve supply. The activity of many neurons in the spinal cord and brain show convergent influences, and their activity can be increased or decreased by stimulation of organs in different bodily locations and systems. Most of the effects are influenced by reproductive status. Together, these findings suggest that the central nervous system provides a dynamic, hormonally modulated substrate by which pathology in one organ can influence the appearance and severity of symptoms and signs of pathology of other nearby and remote organs. Some of the symptoms and signs of PBS/IC may represent a manifestation of this central process.
Dr. Pedro Vera is investigating the role of macrophage migration inhibitory factor (MIF) in pelvic viscera inflammation using animal models, in vitro models, and analysis of human samples from patients with pelvic viscera inflammation. MMF is a pluripotent cytokine that functions as a key regulator of inflammation, cell proliferation, cell differentiation, and apoptosis. It is able to control the "set point" and magnitude of the inflammatory response. He reported studies that lead him to the hypothesis that increased luminal MMF maintains and/or increases pelvic visceral inflammation by interacting with cell-surface receptors (CD74) that activate pro-inflammatory mediators.
Dr. J. Curtis Nickel discussed sexual functioning in painful bladder syndrome / interstitial cystitis. He reported the first evaluation of sexual functioning as a predictor of quality of life in a large cohort of patients suffering from long-term moderate-severe PBS/IC. The patients came from the NIH clinical trial of intravesical Bacillus Calmette-Guerin. The MOS Sexual Functioning Scale was administered to 217 women with PBS/IC to assess libido, arousal, orgasmic, and enjoyment issues associated with sex. Sexual functioning was significantly impaired in this cohort of treatment refractory IC patients and predicted both mental and physical quality of life. This was the first study to identify sexual functioning as an important predictor of physical quality of life and as the only strong predictor of mental quality of life in patients suffering from severe IC. Dr. Nickel also presented data suggesting that as IC symptoms improve, sexual functioning will also improve.
Poster Presentations
Four poster presentations were honored at the meeting.
Intira Coowanitwong and colleagues from the University of Maryland noted that bladder epithelial cell explants from IC patients have been shown to produce significantly less heparin-binding epidermal growth factor-like growth factor (HB-EGF) and proliferate at significantly slower rates than explants from normal controls. The rate of IC cell proliferation can be normalized by recombinant human HB-EGF, suggesting it maybe useful as a treatment for IC. In an experimental rat model, they found that higher bladder exposure after intravenous compared to intravesical administration strongly suggested that a systemic route of administration can be utilized to deliver recombinant human HB-EGF for disease involving urinary bladder tissue. A relatively high concentration of recombinant human HB-EGF in bladder tissue following intravenous dosing also suggests that this growth factor may be particularly important for bladder cell physiology. The lack of toxicity attributable to the recombinant human HB-EGF after 28 days at high concentrations provides additional evidence for its potential therapeutic use.
Jayoung Kim and a group from Harvard and the University of Maryland looked for the mechanism of action of antiproliferative factor (APF). Using cell culture techniques, they discovered that APF increased levels of the transcription factor p53, andd its effector, p21Cip1/WAF1, while a purified mock APF preparation had no effect. These are the first findings demonstrating that APF regulates the checkpoint control mechanism and that p53 mediates the glycopeptide's growth suppressive effects. The observations implicate the network of p53 target genes in urothelial defects associated with IC.
Yu Zeng and associates from Kagawa University in Japan and the University of Pittsburgh and Shiga Medical University in Japan studied gene expression of uroplakins in urothelial biopsy specimens obtained from patients and normal healthy volunteers. The results indicate that aberrant expression of uroplakin III and III-delta4 is peculiar to non-ulcer IC. Uroplakin III-delta4 messenger RNA is a promising marker to identify non-ulcer IC patients.
Robert Caiazzo and a group from Harvard reported on identification of autoantibodies as biomarkers of interstitial cystitis using the "reverse capture" autoantibody microarray. They are able to profile antigen-autoantibody reactivities between normal and diseased patients (Proteomics 6:3199-3209, 2006). In this study they tested the feasibility of their technique to identify potential biomarkers of IC. They were able to consistently detect differential autoantibody profiles between IC patients and controls, and demonstrated at least 25 antigens that may be used as biomarkers of IC. Overall, autoantibody expression for any single significant autoantigen was greater in IC patients than in the control pool on 73% of the microarray slides.
This summary touches on only a very few of the many insightful and interesting presentations covering basic science and clinical science that were presented at this superb meeting.
Reviewed by UroToday.com Contributing Editor Philip Hanno, MD, MPH
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