Background
Urologic chronic pelvic pain syndrome (UCPPS) encompasses two highly prevalent non-malignant urologic disorders, interstitial cystitis/bladder pain syndrome (IC/BPS) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). UCPPS is primarily characterized by chronic and often debilitating pain in the pelvic region and/or genitalia and typically a spectrum of defects in bladder and lower urinary tract function [
1,
2].
Numerous studies have been conducted over the past two decades to define the pathophysiology and natural history of UCPPS and to examine the efficacy of therapies. Many of those studies were supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the U.S. National Institutes of Health (NIH). The first NIDDK-sponsored pelvic pain clinical research network, the Interstitial Cystitis Database study (ICDB) was initiated in 1991 [
3]. This five-year prospective cohort study collected data on more than 600 persons and characterized them across demographic and clinical characteristics, including bladder biopsy [
4]. The Interstitial Cystitis Clinical Trials Group (ICCTG) was subsequently established to conduct randomized clinical trials beginning in 1996 [
5‐
9]. In 2003, this group became the Interstitial Cystitis Collaborative Research Network (ICCRN) and carried out additional randomized clinical trials [
10‐
12]. In 1998, the Chronic Prostatitis Cohort (CPC) study began to prospectively collect patient data to systematically examine the demographics, clinical characteristics and natural history of CP/CPPS [
13]. The NIDDK subsequently initiated the Chronic Prostatitis Collaborative Research Network (CPCRN) which performed clinical trials for CP/CPPS [
14‐
17]. Results from these clinical research studies failed to identify definitive risk factors or generally effective treatments, with the exception of a single study suggesting that myofascial physical therapy might be effective in IC/BPS [
18]. The NIDDK-supported Boston Area Community Health (BACH) Survey [
19‐
21] and the RAND IC Epidemiology (RICE) Study [
22,
23] provided estimates on the prevalence of IC-related symptoms for both men and women, as well as an expanded understanding of symptom morbidity. In addition to these clinical and epidemiological studies, many basic research efforts were developed to describe pathophysiology at the cellular level, including
in vivo studies of model systems. However, no consensus agreement has been achieved on an underlying etiology for UCPPS, though co-occurrence of UCPPS with other chronic non-urologic pain syndromes has been revealed [
24‐
30].
In light of the limitations of previous studies and results showing potential associations between UCPPS and other chronic pain conditions, the NIDDK proposes that the traditional bladder and prostate centered focus of UCPPS research be broadened to a systemic view of disease in which the interplay between the genitourinary system and other physiological systems (e.g., the central nervous system), is highlighted. In addition, it is suggested that studies of UCPPS would benefit from incorporating broad approaches involving a diversity of urologic and non-urologic disciplines to promote a more comprehensive characterization of patient phenotype.
These concepts, as well as recommendations solicited from the scientific community [
31], prompted the NIDDK to initiate a new research program for the study of UCPPS, the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. Since its inception in 2008, the MAPP Research Network has adopted a highly collaborative and integrated research strategy that incorporates new and novel approaches conducted by investigators representing traditional urologic disciplines and broad non-urologic expertise, including experts in pain research, neurobiology and neuroimaging, infectious disease, biomarker discovery, animal modeling, epidemiology, psychology, immunology, among many others. The overarching goal of the MAPP Research Network is to provide findings useful for designing future clinical trials and ultimately to improve clinical management for UCPPS patients. Importantly, the design and goals of the MAPP Network are complementary to other large phenotyping efforts for non-urologic pain conditions being conducted, such as the OPPERA study [
32].
The MAPP Research Network includes six Discovery Sites and several specialized sub-sites that conduct multiple, collaborative Trans-MAPP (i.e., across sites) studies, as well as a number of single-site studies, and two specialized Cores (see Acknowledgement for complete listing of MAPP Network Sites and affiliated personnel). The Data Coordination Core (DCC) serves as the central site for data acquisition and storage; provides bio-statistical analyses for all studies; and promotes network-wide quality assurance. The DCC also provides administrative support, including development and maintenance of a public website (
http://www.mappnetwork.org/). The Tissue Analysis and Technology Core (TATC) monitors biosample collection and provides sample banking, annotation, and distribution services.
The MAPP Research Network is currently conducting complementary basic, translational, and clinical science studies to investigate questions of significant clinical relevance and adopts the view that UCPPS potentially involves significant systemic contributions. The primary scientific protocol is a prospective observational study of the treated natural history UCPPS, the Trans-MAPP Epidemiology/Phenotyping (EP) Study. A full description of the central Trans-MAPP EP Study and the complement of urologic and non-urologic measures employed are described in the companion report by Landis et al. [
33]. In addition to the extensive phenotyping, the Trans-MAPP EP Study also provide a source of highly characterized participants for further phenotyping through other integrated network protocols. Assembled network working groups develop and conduct complementary Trans-MAPP studies that broadly address potential contributions of various physiological systems and hypotheses of underlying etiology, pathophysiology, risk, and relationships between UCPPS and commonly associated non-urologic syndromes. These include structural and functional assessments of the central nervous system; efforts to uncover potential contributions of infectious agents to etiology; discovery efforts to identify new biological markers; extensive characterizations of symptom variation (e.g., flares); and efforts to develop new and more informative patient reported outcome measures. The network is also engaged in collaborative research to establish and assess animal models validated for the presence of clinically-relevant phenotypes, thus allowing for improved translation between animal and human studies. The MAPP study will provide comprehensive, state-of-the-art phenotyping data which will set the standard for future UCPPS research. Results from the MAPP study can be integrated with other, more clinically focused phenotyping efforts (such as the UPOINT system [
34,
35]) to better define the ‘minimal data set’ required to provide optimal patient care for UCPPS patients.
Within the MAPP Research Network all clinical Trans-MAPP protocols and site-specific efforts, which primarily serve to pilot test ideas complementary to the collaborative protocols, are highly integrated through their use of shared patients and controls evaluated through standard phenotyping; common biological samples; and a standardized data collection, storage, and analysis strategy. In addition, neuroimaging study parameters are standardized across sites and scan data is centrally managed by the University of California at Los Angeles (UCLA) Center for Neurobiology of Stress (painrepository.org), in close collaboration with UCLA-Laboratory of Neuroimaging (LONI), which has extensive experience in the collection, storage and analysis of large multi-site MRI data sets (loni.usc.edu). In this way diverse findings across protocols may be integrated to allow a detailed characterization of a single UCPPS patient or patient sub-groups. Importantly, these efforts are also generating a unique national resource of highly detailed longitudinal clinical and epidemiological data associated with data from additional, integrated phenotyping studies and linked biological samples, for future use by the wider research community through the NIDDK Data and Sample Repositories (
http://www3.niddk.nih.gov/researchprograms/repositories/).
Appendix: MAPP Research Network Study Group
MAPP Network Executive Committee
J. Quentin Clemens, MD, FACS, MSci,
Network Chair, 2013-Philip Hanno, MD
Ziya Kirkali, MD
John W. Kusek, PhD
J. Richard Landis, PhD
M. Scott Lucia, MD
Chris Mullins, PhD
Michel A. Pontari, MD
Northwestern University Discovery Site
David J. Klumpp, PhD, Co-Director
Anthony J. Schaeffer, MD, Co-Director
Apkar (Vania) Apkarian, PhD
David Cella, PhD
Melissa A. Farmer, PhD
Colleen Fitzgerald, MD
Richard Gershon, PhD
James W. Griffith, PhD
Charles J. Heckman II, PhD
Mingchen Jiang, PhD
Laurie Keefer, PhD
Darlene S. Marko, RN, BSN, CCRC
Jean Michniewicz
Todd Parrish, PhD
Frank Tu, MD, MPH
University of California, Los Angeles Discovery Site and PAIN Neuroimaging Core
Emeran A. Mayer, MD, Co-Director
Larissa V. Rodríguez, MD, Co-Director
Jeffry Alger, PhD
Cody P. Ashe-McNalley
Ben Ellingson, PhD
Nuwanthi Heendeniya
Lisa Kilpatrick, PhD
Jason Kutch, PhD
Jennifer S. Labus, PhD
Bruce D. Naliboff, PhD
Fornessa Randal
Suzanne R. Smith, RN, NP
University of Iowa Discovery Site
Karl J. Kreder, MD, MBA, Director
Catherine S. Bradley, MD, MSCE
Mary Eno, RN, RA II
Kris Greiner, BA
Yi Luo, PhD, MD
Susan K. Lutgendorf, PhD
Michael A. O’Donnell, MD
Barbara Ziegler, BA
University of Michigan Discovery Site
Daniel J. Clauw, MD, Co-Director;
Network Chair, 2008-2013
J. Quentin Clemens, MD, FACS, MSci,
Co-Director; Network Chair, 2013-
Suzie As-Sanie, MD
Sandra Berry, MA
Megan E. Halvorson, BS, CCRP
Richard Harris, PhD
Steve Harte, PhD
Eric Ichesco, BS
Ann Oldendorf, MD
Katherine A. Scott, RN, BSN
David A. Williams, PhD
University of Washington, Seattle Discovery Site
Dedra Buchwald, MD, Director
Niloofar Afari, PhD, Univ. Of California, San Diego
John Krieger, MD
Jane Miller, MD
Stephanie Richey, BS
Susan O. Ross, RN, MN
Roberta Spiro, MS
TJ Sundsvold, MPH
Eric Strachan, PhD
Claire C. Yang, MD
Washington University, St. Louis Discovery Site
Gerald L. Andriole, MD, Co-Director
H. Henry Lai, MD, Co-Director
Rebecca L. Bristol, BA, BS, Coordinator
Graham Colditz, MD, DrPH
Georg Deutsch, PhD, Univ. of Alabama at Birmingham
Vivien C. Gardner, RN, BSN, Coordinator
Robert W. Gereau IV, PhD
Jeffrey P Henderson, MD, PhD
Barry A. Hong, PhD, FAACP
Thomas M. Hooton, MD, Univ of Miami
Timothy J. Ness, MD, PhD, Univ. of Alabama at Birmingham
Carol S. North, MD, MPE, Univ. Texas Southwestern
Theresa M. Spitznagle, PT, DPT, WCS
Siobhan Sutcliffe, PhD, ScM, MHS
University of Pennsylvania Data Coordinating Core (DCC)
J. Richard Landis, PhD, Core Director
Ted Barrell, BA
Philip Hanno, MD
Xiaoling Hou, MS
Tamara Howard, MPH
Michel A. Pontari, MD
Nancy Robinson, PhD
Alisa Stephens, PhD
Yanli Wang, MS
University of Colorado Denver Tissue Analysis & Technology Core (TATC)
M. Scott Lucia, MD, Core Director
Adrie van Bokhoven, PhD
Andrea A. Osypuk, BS
Robert Dayton, Jr
Karen R. Jonscher, PhD
Holly T. Sullivan, BS
R. Storey Wilson, MS
Additional Sites: Drexel University College of Medicine
Garth D.Ehrlich, PhD
Harvard Medical School/Boston Children’s Hospital
Marsha A. Moses, PhD, Director
Andrew C. Briscoe
David Briscoe, MD
Adam Curatolo, BA
John Froehlich, PhD
Richard S. Lee, MD
Monisha Sachdev, BS
Keith R. Solomon, PhD
Hanno Steen, PhD
Stanford University
Sean Mackey, MD, PhD, Director
Epifanio Bagarinao, PhD
Lauren C. Foster, BA
Emily Hubbard, BA
Kevin A. Johnson, PhD, RN
Katherine T. Martucci, PhD
Rebecca L. McCue, BA
Rachel R. Moericke, MA
Aneesha Nilakantan, BA
Noorulain Noor, BS
Queens University
J. Curtis Nickel, MD, FRCSC, Director
National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH)
Chris Mullins, PhD
John W. Kusek, PhD
Ziya Kirkali, MD
Tamara G. Bavendam, MD
Acknowledgements
The MAPP Research Network acknowledges support through NIH grants: U01 DK82315, U01 DK82316, U01 DK82325, U01 DK82333, U01 DK82342, U01 DK82344, U01 DK82345, and U01 DK82370. The NIDDK and MAPP Network investigators wish to thank the Interstitial Cystitis Association (ICA) and the Prostatitis Foundation (PF) for their assistance in study participant recruitment and other network efforts.
We thank the participants and staff from the following sites that participated in the study: Northwestern University; University of California, Los Angeles; University of Iowa; Washington University, St. Louis; University of Washington, Seattle; University of Michigan; University of Pennsylvania (Data Coordinating Core); University of Colorado Denver (Tissue Analysis & Technology Core); Stanford University; NIDDK.
This article outlines independent research commissioned by the National Institute for Health (NIH). The views expressed in this article are those of the author(s) and are not necessarily those of the NIH, the NIDDK, or the Department of Health and Human Services (DHHS).
Competing interests
JQ Clemens, C Mullins, JW Kusek, Z Kirkali, EA Mayer, LV Rodriguez, AJ Schaeffer, D Buchwald, and JR Landis declare no competing interests. DJ Klumpp declares ownership and equity interests in ProbioTx Inc, and Gold Coast Therapeutics Inc. KJ Kreder is a Consultant for Medtronic, Astellas, Symptelligence, and Tengion. GL Andriole is a Consultant for Augmenix, Bayer, Genomic Health, GlaxoSmithKline and Myriad Genetics and has received research grants from Johnson & Johnson, Medivation and Wilex. MS Lucia declares ownership of 3D Biopsy and has consulted for Myriad Genetics and Bayer Healthcare. DJ Clauw has received grants from Pfizer, Cerephex, Lilly, Merck, Nuvo and Furest, and Consulting Fees and Honoraria from Pfizer, Cerephex, Lilly, Merck, Nuvo, Furest, Tonix, Purdue, Therauance, and Johnson & Johnson.
Authors’ contributions
JQC wrote the initial draft manuscript. All authors read and approved the final manuscript.