Chronic pancreatitis (CP) is characterized by persistent inflammation of the pancreas leading to fibrosis and organ dysfunction.1 Clinical features of CP are highly variable and include minimal or no symptoms to debilitating pain, episode(s) of acute pancreatitis (AP), endocrine and/or exocrine insufficiency, local and/or systemic complications and pancreatic cancer. While there are known causes, in many cases the etiology remains elusive. Chronic pancreatitis profoundly affects quality of life commensurate with many severe chronic medical conditions and cancers.2 The estimated prevalence of CP ranges from 50 to 92 per 100,000 in the U.S. adult population.3,4

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Most published studies on the progression of CP are old, originate mostly from non-U.S. centers, and consist predominantly of males with alcoholic CP.5–11 The only large longitudinal study in the US was conducted in patients treated at the Mayo Clinic, Rochester, Minn from 1976–1982.12 While these data provide insights into disease progression, predicting clinical course in individual patients remains difficult. Moreover, longitudinal data in patients with early-stage disease when definitive morphological changes of CP are not evident on cross-sectional imaging are needed.

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In the past two decades, the etiologic profile of CP has broadened13–15 and there is growing recognition that CP represents a disease continuum.16,17 Improvements in radiologic and endoscopic imaging techniques have enabled better recognition of subtle morphological and functional changes in the pancreas,18 but validated criteria for diagnosis of early-stage CP are lacking. Magnetic Resonance Cholangiopancreatography (MRCP) is transforming from qualitative to quantitative technique, focusing on detection of pancreatic fibrosis in addition to the traditional ductal imaging.19,20 Endoscopic collection of pancreas fluid coupled with molecular analysis of this proximal biofluid has broadened the possibility of pancreas disease biomarker discovery and validation.21 The clinical significance of pancreatogenic (type 3c) diabetes is beginning to be recognized.22,23 While CP increases the risk of osteoporosis and fractures,24–26 the underlying mechanisms are yet to be elucidated. Finally, a new mechanistic definition and conceptual framework to conduct research on the pathophysiology and evolution of CP and to potentially interrupt disease progression has been proposed, and awaits validation.1,27

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Current management of CP is limited to symptomatic treatment of its clinical manifestations. Although animal models provide insights into pathogenesis,28 these have not translated into curative treatments or prevention of progression. Major limitations include the inability to obtain histology at early stages of disease and lack of prospective well-characterized study populations with clinical and electronic health record (EHR) linkage. Of these, the latter is a feasible goal, and can provide a platform to not only understand disease progression, but also conduct studies of early diagnosis, prediction and prognosis, and ultimately new diagnostic and therapeutic approaches.

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The Adult CP Working Group of the Consortium for the Study Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC)29 was tasked by its Steering Committee to design a longitudinal study of CP, which led to the conception and development of the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies (PROCEED). In addition to addressing the primary objectives of the CPDPC, PROCEED will provide a platform for multiple translational and mechanistic studies.

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Hypothesis and Objectives
The overarching goal of PROCEED is prospective ascertainment and follow-up of a well-phenotyped study population at different stages of CP to accurately define its progression and associated complications. Furthermore, collection of biological samples from study subjects at predefined intervals will provide a platform to develop biomarkers of early diagnosis and prediction of disease progression, understand disease mechanisms, and discover genetic and other factors affecting susceptibility and progression.

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PROCEED has four primary objectives – to:

1. Establish a model longitudinal research cohort of adult subjects for the study of CP and its complications.

2. Estimate the risk of progression from suspected to definite CP, and the risk of new-onset diabetes or exocrine pancreatic dysfunction in definite CP, and study how the risks are influenced by patient characteristics and conditions.

3. Test the predictive capability of candidate biomarkers for the diagnosis and prognosis of CP.

4. Develop a platform for conducting biomarker, genetic and mechanistic studies using clinical information and longitudinal biospecimens.

 

Through recruitment of subjects across clinical centers that span the U.S., and collection of data through standardized forms and common data elements, PROCEED will offer an opportunity to understand the similarities and variation during progression of CP across the nation. The cohort and linked biospecimens will provide the opportunity to address several secondary objectives through cross-sectional and longitudinal studies. PROCEED will, by nature, foster collaboration for generation of future hypotheses and new standards of care for pancreatitis. Transitioning some subjects from the pediatric (INternational Study Group of Pediatric Pancreatitis: In search for a cuRE [INSPPIRE-2])30 to adult (PROCEED) cohort once they age is underway.