“Despite attempts of many workers to clarify matters, its (interstitial cystitis) etiology remains obscure” [3].

IC/BPS remains an enigmatic syndrome. Although considerable effort has been expended over the past several decades to identify infectious and non-infectious causes for this syndrome none have emerged as leading candidates. Thus, the clinical diagnosis of IC/BPS remains mainly based on excluding known illnesses and conditions-the so-called “confusable diseases”. This lack of precision in making a diagnosis undoubtedly leads to heterogeneity of patients and difficulty in matching the right patient with the right treatment. Thus, it is not surprising to observe use of multiple treatments in many patients and subsequent failed response to therapy. Importantly, the disappointing findings from many randomized clinical trials may be the result of study designs involving such broad groups of patients with diverse causes of their symptoms.

We believe we are now embarking on a period of substantial discovery that will delineate pathophysiological factors underlying IC/BPS. Studies utilizing state-of-the-art technology to assess the urinary microbiome, [4], metabolome [5] and proteome [6] hold great promise to better understand biological factors that contribute to initiating disease and those that exacerbate established disease (e.g., precipitate symptom worsening). Non-biological factors, including psychosocial characteristics will likely add important insights [7]. Combining the findings from these various approaches, as well as genetic studies [8], will require application of sophisticated statistical techniques to complex data sets from large and well-designed studies of IC/BPS patients.

“The diagnosis of BPS is thus made on the basis of exclusion of confusable diseases and confirmation by the recognition of the presence of the specific combination of symptoms and signs of BPS” [9].

As noted previously, IC/BPS remains primarily a diagnosis based on exclusion of other diseases and illnesses. The landmark 1988 publication of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Consensus Criteria for the Diagnosis of Interstitial Cystitis (“the NIDDK Diagnostic Criteria”) was an important first step to standardize the type of patients with IC enrolled in clinical research studies [10]. Subsequently it was recognized that applying these criteria was challenging. A report by Hanno and colleagues from the NIDDK-sponsored Interstitial Cystitis Database (ICDB) Study noted that upon applying these criteria more than 60% of patients traditionally classified by researchers as “definitely” or “likely” to have IC [11] would not have been included in this first ever major prospective study of IC. This observation and others resulted in a broadening of the NIDDK criteria for future research studies and ultimately to an expansion of the clinical spectrum of patients enrolled in clinical research studies of IC and the evolution of new terminology. As an example, the NIDDK Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network describes IC/BPS patients (along with patients with chronic prostatitis/chronic pelvic pain syndrome [CP/CPPS]) under the new broader term Urologic Chronic Pelvic Pain Syndrome (UCPPS) [12, 13]. While not directly improving upon the diagnosis of IC/BPS this broadened designation has permitted a more comprehensive, less “bladder-centered” view of this syndrome. This idea that IC/BPS may involve systemic contributors has promoted the growing research trend toward more diverse, multi-disciplinary studies. At the forefront of this trend, the MAPP Research Network (http://​www.​mappnetwork.​org/​) is conducting highly integrated studies designed to identify underlying biological and non-biological factors contributing to IC/BPS development and progression and to aid in the classification of clinically relevant patient sub-groups. This involves a comprehensive examination of the urologic and non-urologic systems through epidemiological, neurological, and molecular approaches, as well as studies of animal models selected to mimic the human condition. The goal is to inform the next generation of clinical research studies, especially randomized clinical trials, and ultimately improve patient care through new insights.