Use of Urinary Biomarkers in Discriminating Interstitial Cystitis/Bladder Pain Syndrome from Male Lower Urinary Tract Dysfunctions.

To analyze the urinary biomarkers in men with lower urinary-tract symptoms (LUTS) and identify interstitial cystitis/bladder pain syndrome (IC/BPS) from the other lower urinary-tract dysfunctions (LUTDs) by the levels of characteristic urinary biomarkers. In total, 198 men with LUTS were prospectively enrolled and urine samples were collected before intervention or medical treatment. Videourodynamic studies were routinely performed and the LUTDs were diagnosed as having bladder-outlet obstruction (BOO) such as bladder-neck dysfunction, benign prostatic obstruction, or poor relaxation of external sphincter (PRES); and bladder dysfunction such as detrusor overactivity (DO), hypersensitive bladder (HSB), and IC/BPS. Patients suspicious of IC/BPS were further confirmed by cystoscopic hydrodistention under anesthesia. The urine samples were investigated for 11 urinary inflammatory biomarkers including eotaxin, IL-6, IL-8, CXCL10, MCP-1, MIP-1ß, RANTES, TNF-α, NGF, BDNF, and PGE2; and 3 oxidative stress biomarkers 8-OHdG, 8-isoprostane, and TAC. The urinary biomarker levels were analyzed between LUTD subgroups and IC/BPS patients. The results of this study revealed that among the patients, IC/BPS was diagnosed in 48, BOO in 66, DO in 25, HSB in 27, PRES in 15, and normal in 17. Patients with BOO had a higher detrusor pressure and BOO index than IC/BPS, whereas patients with IC/BPS, BOO, and DO had a smaller cystometric bladder capacity than the PRES and normal subgroups. Among the urinary biomarkers, patients with IC/BPS had significantly higher levels of eotaxin, MCP-1, TNF-α, 8-OHdG, and TAC than all other LUTD subgroups. By a combination of different characteristic urinary biomarkers, TNF-α, and eotaxin, either alone or in combination, had the highest sensitivity, specificity, positive predictive value, and negative predictive value to discriminate IC/BPS from patients of all other LUTD subgroups, BOO, DO, or HSB subgroups. Inflammatory biomarker MCP-1 and oxidative stress biomarkers 8-OHdG and TAC, although significantly higher in IC/BPS than normal and PRES subgroups, did not have a diagnostic value between male patients with IC/BPS and the BOO, DO, or HSB subgroups. The study concluded that using urinary TNF-α and eotaxin levels, either alone or in combination, can be used as biomarkers to discriminate patients with IC/BPS from the other LUTD subgroups in men with LUTS.

An urgent case for sensory urgency: A patient perspective.

Interstitial cystitis/bladder pain syndrome (IC/BPS) patients around the world are all too familiar with the immense stress and anxiety caused by an urgent and frequent need to void, leading to many patients with IC/BPS staying at home in social isolation since they are afraid that they will not find a public toilet when they urgently need it. It is therefore of great concern that for almost two decades the "sensory" type of urgency due to intolerable pain or unpleasant sensation as typically experienced by this group of patients has no longer been officially recognized, researched or treated as a symptom of IC/BPS. This official misrepresentation of IC/BPS symptoms needs to be addressed and rectified for the sake of patients and to ensure medical accuracy in research.

Clinical guidelines for interstitial cystitis/bladder pain syndrome.

The clinical guidelines for interstitial cystitis and related symptomatic conditions were revised by updating our previous guidelines. The current guidelines define interstitial cystitis/bladder pain syndrome as a condition with chronic pelvic pain, pressure or discomfort perceived to be related to the urinary bladder accompanied by other urinary symptoms, such as persistent urge to void or urinary frequency in the absence of confusable diseases. The characteristic symptom complex is collectively referred as hypersensitive bladder symptoms. Interstitial cystitis/bladder pain syndrome is divided into Hunner-type interstitial cystitis and bladder pain syndrome; Hunner-type interstitial cystitis and bladder pain syndrome represent interstitial cystitis/bladder pain syndrome with Hunner lesions and interstitial cystitis/bladder pain syndrome without Hunner lesions, respectively. So-called non-Hunner-type interstitial cystitis featured by glomerulations or bladder bleeding after distension is included in bladder pain syndrome. The symptoms are virtually indistinguishable between Hunner-type interstitial cystitis and bladder pain syndrome; however, Hunner-type interstitial cystitis and bladder pain syndrome should be considered as a separate entity of disorder. Histopathology totally differs between Hunner-type interstitial cystitis and bladder pain syndrome; Hunner-type interstitial cystitis is associated with severe inflammation of the urinary bladder accompanied by lymphoplasmacytic infiltration and urothelial denudation, whereas bladder pain syndrome shows little pathological changes in the bladder. Pathophysiology would also differ between Hunner-type interstitial cystitis and bladder pain syndrome, involving interaction of multiple factors, such as inflammation, autoimmunity, infection, exogenous substances, urothelial dysfunction, neural hyperactivity and extrabladder disorders. The patients should be treated differently based on the diagnosis of Hunner-type interstitial cystitis or bladder pain syndrome, which requires cystoscopy to determine the presence or absence Hunner lesions. Clinical studies are to be designed to analyze outcomes separately for Hunner-type interstitial cystitis and bladder pain syndrome.

Interstitial cystitis/bladder pain syndrome/hypersensitive bladder: Worldwide confusion! What has gone wrong and how can we put it right for the sake of the patients?

The international interstitial cystitis, bladder pain syndrome and hypersensitive bladder world is facing major problems. While healthcare is ultimately about making sick people feel better, this is still not happening for our patients who are not receiving the individually tailored treatment that they need. So, what has gone wrong, and why is there so much confusion everywhere? Since the first NIDDK research criteria were published over 30 years ago, there has been no major breakthrough either in treating the patients or even in truly understanding what bladder condition(s) we are dealing with. For the sake of the patients, it is imperative to take action now and make a fresh, determined start with meaningful, international, multi-stakeholder collaboration to determine how to proceed further to take the necessary decisions, solve the problems and achieve real global consensus and real progress to help the real patients with their real symptoms.

A standard for terminology in chronic pelvic pain syndromes: A report from the chronic pelvic pain working group of the international continence society.

AIMS: Terms used in the field of chronic pelvic pain (CPP) are poorly defined and often confusing. An International Continence Society (ICS) Standard for Terminology in chronic pelvic pain syndromes (CPPS) has been developed with the aim of improving diagnosis and treatment of patients affected by chronic pelvic pain syndromes. The standard aims to facilitate research, enhance therapy development and support healthcare delivery, for healthcare providers, and patients. This document looks at the whole person and all the domains (organ systems) in a systematic way. METHODS: A dedicated working group (WG) was instituted by the ICS Standardisation Steering Committee according to published procedures. The WG extracted information from existing relevant guidelines, consensus documents, and scientific publications. Medline and other databases were searched in relation to each chronic pelvic pain domain from 1980 to 2014. Existing ICS Standards for terminology were utilized where appropriate to ensure transparency, accessibility, flexibility, and evolution. Consensus was based on majority agreement. RESULTS: The multidisciplinary CPPS Standard reports updated consensus terminology in nine domains; lower urinary tract, female genital, male genital, gastrointestinal, musculoskeletal, neurological aspects, psychological aspects, sexual aspects, and comorbidities. Each is described in terms of symptoms, signs and further evaluation. CONCLUSION: The document presents preferred terms and definitions for symptoms, signs, and evaluation (diagnostic work-up) of female and male patients with chronic pelvic pain syndromes, serving as a platform for ongoing development in this field. Neurourol. Urodynam. 36:984-1008, 2017. © 2016 Wiley Periodicals, Inc.

Clinical guidelines for interstitial cystitis and hypersensitive bladder updated in 2015.

Clinical guidelines for interstitial cystitis and hypersensitive bladder have been updated as of 2015. The guidelines define interstitial cystitis by the presence of hypersensitive bladder symptoms (discomfort, pressure or pain in the bladder usually associated with urinary frequency and nocturia) and bladder pathology, after excluding other diseases explaining symptoms. Interstitial cystitis is further classified by bladder pathology; either Hunner type interstitial cystitis with Hunner lesions or non-Hunner type interstitial cystitis with mucosal bleeding after distension in the absence of Hunner lesions. Hypersensitive bladder refers to a condition, where hypersensitive bladder symptoms are present, but bladder pathology or other explainable diseases are unproven. Interstitial cystitis and hypersensitive bladder severely affect patients' quality of life as a result of disabling symptoms and/or comorbidities. Reported prevalence suggestive of these disorders varies greatly from 0.01% to >6%. Pathophysiology would be an interaction of multiple factors including urothelial dysfunction, inflammation, neural hyperactivity, exogenous substances and extrabladder disorders. Definite diagnosis of interstitial cystitis and hypersensitive bladder requires cystoscopy with or without hydrodistension. Most of the therapeutic options lack a high level of evidence, leaving a few as recommended therapeutic options.

Interstitial cystitis and the painful bladder: a brief history of nomenclature, definitions and criteria.

"Practically every author writing on this subject has suggested a new name which only adds to the confusion and multiplication" (Kretschmer H, 1922). Despite multiple names and many definitions and classifications over the past two centuries, the medical world is no closer to discovering the cause or causes of this enigmatic bladder disorder, currently known as interstitial cystitis, bladder pain syndrome or painful bladder syndrome and hypersensitive bladder. International consensus on nomenclature, definitions and diagnosis is now essential to ensure that studies are carried out on the same basis, thereby generating meaningful data that can be relied on for further use. In our electronic age, multiple names and definitions cause confusion for researchers, clinicians and patients, even leading to the patient's diagnosis being unrecognized by authorities, resulting in refusal to reimburse treatment or provide social benefits. As the key to the puzzle lies in the patients, with all their symptoms and comorbidities, and as patients are directly affected by changes in nomenclature and definitions, patient organization representatives should be given every opportunity to participate in discussions on guidelines, taxonomy, definitions and terminology.

Non-bladder conditions in female Taiwanese patients with interstitial cystitis/hypersensitive bladder syndrome.

OBJECTIVES: To detect non-bladder conditions in patients with interstitial cystitis/hypersensitive bladder syndrome. METHODS: A total of 122 female interstitial cystitis/hypersensitive bladder syndrome patients and a control group of 122 age-matched female patients with stress urinary incontinence completed screening questionnaires for irritable bowel syndrome, temporomandibular disorder, multiple chemical sensitivities, tension and migraine headache, localized myofascial pain disorder, and fibromyalgia. Interstitial cystitis/hypersensitive bladder syndrome patients also completed questionnaires on interstitial cystitis/hypersensitive bladder syndrome symptom severity, including the O'Leary-Sant symptom index, and the visual analog scale for pain and urgency. RESULTS: Interstitial cystitis/hypersensitive bladder syndrome patients were more likely to meet diagnostic criteria for irritable bowel syndrome than controls (37.5% vs 11.5%), and tension/migraine headache (38.7% vs 15.7%; all P < 0.001). The prevalence of temporomandibular disorder, multiple chemical sensitivities, localized myofascial pain disorders and fibromyalgia did not reach a statistical significant difference between the two groups. In the multivariate model, associations were also observed for irritable bowel syndrome (odds ratio 2.546; 95% confidence interval 1.136-5.704) and tension/migraine headache (odds ratio 2.684; 95% confidence interval 1.233-5.842). Patients with more comorbid conditions had more severe and bothersome interstitial cystitis/hypersensitive bladder syndrome symptoms as measured by the visual analog scale of pain (P = 0.008) and O'Leary-Sant bother index (P = 0.035). CONCLUSIONS: Interstitial cystitis/hypersensitive bladder syndrome patients are more likely to have multiple non-bladder conditions. These conditions correlate with the severity of interstitial cystitis/hypersensitive bladder syndrome symptoms.

Urine alkalization improves the problems of pain and sleep in hypersensitive bladder syndrome.

OBJECTIVE: To investigate the efficacy of urine alkalization therapy using citrates in patients with hypersensitive bladder syndrome. METHODS: A total of 76 patients with urinary frequency were assessed for their symptoms using a 2-day voiding diary as well as the urine pH at each voiding during the screening period. Their symptoms were also assessed by pain score, King's health questionnaire, and O'Leary-Sant symptom and problem index scores. Finally, 50 patients were evaluated for changes in symptoms after oral treatment with citrates for 2-4 weeks after the screening period. RESULTS: After the treatment, significant increases in the urine pH (from 5.8 ± 0.4 to 6.3 ± 0.4; increment of 0.5 ± 0.4; P < 0.01), and significant decreases in the number of micturitions per day (from 14.5 ± 6.5 to 13.5 ± 5.9; P = 0.02) and the number of episodes of pain/discomfort per day (from 7.8 ± 6.8 to 6.1 ± 7.1; P = 0.02) were observed. In the King's health questionnaire, the sleep/energy domain score was significantly improved (from 60.0 ± 25.0 to 50.3 ± 29.6; P < 0.01). In a subgroup analysis based on urine pH (urine pH <6.2 and ≥6.2), significant improvements in the voiding symptoms, the sleep/energy domain score and the O'Leary-Sant problem index were observed in the group with urine pH of ≥6.2. There were statistically significant differences between the subgroups in the volume per voiding, maximum volume per voiding and the problem index. In addition, the subgroup, in which patients had pain in the screening period, showed statistically significant improvements in the number of micturitions per day, episodes of pain/discomfort per day, the sleep/energy domain score and the problem index. CONCLUSIONS: Urine alkalization therapy is likely to be effective in the treatment for hypersensitive bladder syndrome.

Definition Change and Update of Clinical Guidelines for Interstitial Cystitis and Bladder Pain Syndrome.

The clinical guidelines for interstitial cystitis (IC) and bladder pain syndrome (BPS) have been revised by updating our previous guidelines. The symptoms of IC and BPS, collectively called as hypersensitive bladder (HSB) symptoms, are virtually indistinguishable between IC and BPS; however, IC and BPS should be considered as a separate entity of disorders. We define IC as a bladder disease with Hunner lesions, usually associated with HSB symptoms and bladder inflammation, and BPS as a condition with HSB symptoms in the absence of Hunner lesions and any confusable diseases. Pathophysiology totally differs between IC and BPS. IC involves immunological inflammation probably resulting from autoimmunity, while BPS is associated with the interaction of multiple factors such as neurogenic inflammation, exogenous substances, urothelial defects, psychological stress, and neural hyperactivity. Histopathology also differs between IC and BPS. IC is associated with severe inflammation of the whole bladder accompanied by plasma cell infiltration and urothelial denudation, while BPS shows little pathological changes. Management should begin with a differential diagnosis of IC or BPS, which would require cystoscopy to determine the presence or absence of Hunner lesions. The patients should be treated differently based on the diagnosis following the algorithm, although pain management would be common to IC and BPS. Clinical studies are also to be designed and analyzed separately for IC and BPS.

Clinical presentation, videourodynamic characteristics, and treatment outcome in men with interstitial cystitis-like lower urinary tract symptoms.

PURPOSE: In men, lower urinary tract symptoms (LUTS) similar to interstitial cystitis/bladder pain syndrome (IC/BPS) are difficult to diagnose, and treatment outcomes are poor. This study investigated clinical characteristics and videourodynamic study (VUDS) parameters, pathophysiology, and treatment outcomes in men with IC-like LUTS. METHODS: Men with frequency, urgency, dysuria, and bladder pain initially diagnosed as IC/BPS by ESSIC criteria were assessed to rule out other lower urinary tract diseases (LUTD) by voiding diary, digitorectal examination, urinalysis, VUDS, and cystoscopic hydrodistention. Subsequent treatments for LUTD and specific treatment for IC/BPS were based on VUDS and cystoscopic findings. Clinical VUDS characteristics and treatment outcomes were compared with those of women with IC/BPS. RESULTS: Seventy consecutive men (median age 54.5 years) were enrolled. The median maximum bladder capacity under cystoscopic hydrodistention was 650 mL (IQR 495-763) and glomerulation grade was 2 (1.0-2.0). The patients had moderate anxiety and depression severity; 49% had improved treatment outcomes. On VUDS, 42 (60%) patients had variable LUTD, including detrusor overactivity (n = 14), bladder neck dysfunction (n = 15), dysfunctional voiding (n = 3), and poor relaxation of the external sphincter (n = 24); also, 22 (31.4%) had a previous bladder outlet procedure. The self-reported treatment outcome was significantly better for patients with vs. without LUTD (p = 0.014). CONCLUSIONS: Men with IC-like LUTS diagnosed as IC/BPS may have bladder outlet dysfunction as well as bladder dysfunction, causing a hypersensitive and painful bladder. The IC-like symptoms in the patients with LUTD might, in part, originated from bladder outlet dysfunction rather than the bladder alone.

Therapeutic efficacy of mirabegron 25 mg monotherapy in patients with nocturia-predominant hypersensitive bladder.

OBJECTIVE: The objective of this study was to evaluate the efficacy of mirabegron 25 mg daily in patients with nocturia-predominant hypersensitive bladder (HSB). MATERIALS AND METHODS: This study prospectively investigated 219 consecutive patients with nocturia-predominant HSB and treated with mirabegron 25 mg daily from July 2015 to 2016. Patient with nocturia episode decreased by ≥1/night after treatment was considered successful. The subjective symptom score, such as International Prostate Symptom Score (IPSS), Quality of life index, Overactive Bladder Symptom Score (OABSS), Urgency Severity Scale, patient perception of bladder condition (PPBC), and nocturia episodes per night, was assessed before and 1 month after mirabegron treatment and between successful and failed groups. RESULTS: A total of 219 patients, including 51 women and 168 men, were enrolled. The mean age of the population was 72.3 ± 11.0 years. Totally, 58 (26.5%) of the patients had improvement in nocturia at 1 month after treatment. Among them, 14 (27.5%) women and 44 (26.2%) men had improvement in nocturia episodes after treatment (P = 0.858). Compared the clinical data between successful and failed group, the baseline symptom scores were more severe in successful group, including IPSS-storage subscore (4.84 ± 2.09 vs. 4.11 ± 2.19, P = 0.031), OABSS (3.21 ± 0.67 vs. 2.91 ± 1.00, P = 0.037), and nocturia episodes (3.81 ± 0.95 vs. 3.095 ± 1.32, P = 0.000). Multivariate analysis revealed only a higher nocturia episodes (P = 0.046) predict a successful treatment result. Mirabegron 25 mg daily significantly improved PPBC score along the 3 months' follow-up (P < 0.05), and postvoid residual volume did not increase after mirabegron treatment in overall patients. CONCLUSIONS: Mirabegron 25 mg daily treatment showed a limited therapeutic effect on nocturia-predominant HSB patients. The patients with higher OAB symptoms predict a successful result.

[Interstitial cystitis/bladder pain syndrome (IC/BPS)]. / Interstitielle Zystitis/Blasenschmerzsyndrom (IC/BPS).

As an orphan disease interstitial cystitis/bladder pain syndrome (IC/BPS) is a frequently underdiagnosed and inadequately treated disease of the urinary bladder, often after years of symptoms. Caused by an unknown etiology, a high variability of symptoms, a lack of biomarkers and a gradual onset, IC/BPS is a diagnosis by exclusion and poses a special challenge to doctors and patients. In addition to conventional and complementary medical treatment, oral medication, intravesical and transurethral procedures are available as treatment options. Due to the invasiveness or irreversibility, however, interventional surgical procedures should only be used after careful consideration or as a last resort. In order to find a suitable individualized treatment, a classification of the patients according to the severity and type of symptoms can be advantageous.

The Overactive Bladder Symptom Score, International Prostate Symptom Score-Storage Subscore, and Urgency Severity Score in Patients With Overactive Bladder and Hypersensitive Bladder: Which Scoring System is Best?

PURPOSE: To evaluate the correlations among the Overactive Bladder Symptom Score (OABSS), International Prostate Symptom Score-Storage Subscore (IPSS-S), and the modified Urgency Severity Scale (USS) in patients with overactive bladder (OAB) and hypersensitive bladder (HSB) and to identify the most useful diagnostic tool for classifying the severity of OAB. METHODS: We retrospectively reviewed the charts of consecutive patients with OAB who visited our urologic clinics for treatment. All patients underwent a detailed history, physical examination, urinalysis, uroflowmetry, and postvoid residual volume measurement, and completed a 3-day voiding diary. All patients answered the Chinese versions of the IPSS, OABSS, and USS, according to which they were classified as having wet or dry OAB based on whether their chief complaint was urgency urinary incontinence or urgency without incontinence. HSB was defined as a functional bladder capacity <350 mL and a USS of 0 or 1. RESULTS: The records of 325 OAB patients (99 women and 226 men) were reviewed. The OAB subgroups included HSB (n=31), OAB-dry (n=74), and OAB-wet (n=220). One-way analysis of variance showed significant differences among the OAB subgroups evaluated using each scoring system. Each scoring system was significantly correlated with the OAB subgroups. The Spearman rho was 0.983 for the USS, 0.651 for the OABSS, and 0.428 for the IPSS-S. CONCLUSIONS: The IPSS-S, OABSS, and USS showed good correlations with the OAB subgroups. Their ranking in terms of discriminant ability for classifying OAB severity as HSB, OAB-dry, and OAB-wet was USS>OABSS>IPSS-S. The simplest survey, the USS, with a single item scored from 0 to 4, had the strongest correlation with the OAB severity subgroups.

Patient-centred standardization in interstitial cystitis/bladder pain syndrome-a PLEA.

Standardization has an impact on all links in the healthcare chain and directly affects patients with regard to diagnosis, treatment, eligibility for reimbursement, social benefits and care. Furthermore, patients are also affected if research goes down inappropriate pathways due to inaccurate terminology and definitions. Complex healthcare coding and electronic medical record systems and global reliance on the internet and search machines mean that new terminology or changes now need in some way to be designed to last or to be updated in a way that will cause least disruption, while still allowing for evolution, since changes have far more ramifications today than they ever did in the past. Official recognition of a condition is vital, so coding must be correct and uniform across all authorities. Potential problems must be anticipated at an early stage in the process. In order to achieve global consensus, stakeholders from all parts of the world need to communicate and collaborate with all viewpoints taken into consideration. Patients and their advocacy groups should be involved in standardization processes to ensure that all aspects of a condition are covered, that no patients or symptoms are excluded and that there is no adverse impact on the patient in practical terms following implementation. The trend today is for patients to be more involved in healthcare and decision-making. We must ensure that standardisation and guidelines do not get left behind in this process of development either now or in the future. However, it is necessary to find some way of training patient representatives to enable them to participate fully in standardization and guidelines and also to encourage them to do so.

Upregulation of Angiotensin II Receptor and Connexin 43 in Increased Suburothelial Myofibroblasts in the Rat Inflammatory Bladder.

OBJECTIVES: Signaling pathways in suburothelial layer are involved in the bladder sensory response. The expression of angiotensin II type 1 (AT1) receptors and connexin 43 (Cx43) in suburothelial myofibroblasts was investigated in an acute bladder inflammation model. METHODS: Adult female Wistar rats underwent urethral catheterization and received 0.2 mL intravesical infusion of 0.4 M HCl to establish acute bladder inflammation model or 0.2 mL of sterile saline as control (n = 10 rats/group). Eight days after treatment, cystometry was performed. Suburothelial myofibroblasts were also collected and subjected to immunohistochemical staining to examine AT1 receptor and Cx43 expression. RESULTS: Eight days after treatment with HCl to induce acute bladder inflammation, the frequency and basal pressure of the bladder was significantly increased compared with those in control rats. The number of suburothelial myofibroblasts was significantly increased in acute bladder inflammation rats, as was the expression of AT1 receptor and Cx43. CONCLUSION: These results suggest that the increased number of suburothelial myofibroblasts, upregulation of AT1 receptor and Cx43 expression may be associated with the pathogenesis of hyperactivation of bladder sensory signaling pathways in acute inflammatory bladder.