Acute Pancreatitis Research and the Role of CAPER — An Interview With Georgios Papachristou

The Pancreas and Biliary Center in the Division of Gastroenterology, Hepatology and Nutrition, home to some of the foremost pancreas researchers and clinicians in the world, specializes in the treatment and research of the full spectrum of pancreaticobiliary diseases. In this issue, the research work of one of its key members, Georgios Papachristou, MD, PhD, will be highlighted.

Dr. Papachristou, a professor of medicine in the Division, specializes in pancreaticobiliary diseases, particularly the study of acute pancreatitis and the practice of state-of-the-art endoscopic retrograde cholangio-pancreatography (ERCP), and endoscopic ultrasound (EUS). Dr. Papachristou’s research over the last 15 years has focused on acute pancreatitis. He leads a number of clinical trials investigating different aspects of acute pancreatitis. Dr. Papachristou also has been involved in the Collaborative Alliance for Pancreas Education and Research (CAPER) initiative. He recently concluded a two-year term as president and continues to serve on the CAPER board of directors.

You have a number of ongoing observational studies and clinical trials with respect to acute pancreatitis, one of which is the Pancreatitis-associated Risk of Organ Failure or PROOF Study. Can you give an overview of its aims and outcomes measures, and the possible clinical significance of the study in relation to treatment approaches?

“PROOF is an observational trial with several goals, the first of which is to assess the risk factors for severe acute pancreatitis. We also aim for the clinical data we are collecting to help validate risk factors and predictive scoring systems for severe disease states. In addition, the study has a translational aspect, which involves the collection of bio-samples for analysis of important acute pancreatitis markers, such as cytokines, free fatty acid levels, and the assessment of genetic predisposition for severe disease. PROOF has been an extremely successful study resulting in more than 25 original publications to date. The study has opened many doors for collaborative work with other groups around the country, which is vitally important to further advance the field.”

You also are currently running the APPRENTICE study, the Acute Pancreatitis Patient Registry To Examine Novel Therapies In Clinical Experiences. How does this study relate to PROOF, and what is its significance?

“About two and a half years ago, we realized that the creation of an international prospec -  tive registry of acute pancreatitis patients was needed. This international observational study has so far enrolled more than 1,700 patients from 22 centers in four continents. The goal is to use APPRENTICE in the near future as a platform for randomized trials. In 2018, we presented a few abstracts on early-phase clinical data, and we were invited to present our work at the American Pancreatic Association annual meeting in November 2018.”

For individuals who have acute pancreatitis, there can be significant and lasting long-term consequences. How are you approaching this from a research perspective in the Division?

“Acute pancreatitis can certainly have lasting effects. We know some of them, and others are still being investigated. We proposed a study in 2017 to follow patients for up to 12 months after discharge for a case of acute pancreatitis. This study, called Post-acute Pancreatitis Pancreatic Exocrine Insufficiency, will follow patients long- term to better understand what happens months after the injury, with a special emphasis on quality-of-life measures and development of exocrine insufficiency. This is an investigator-initiated with support from a biopharmaceutical company. We have recently expanded to a multicenter trial with Ohio State University, and Johns Hopkins University is joining the study as well.”

Acute pancreatitis is a worrisome issue. Can you encapsulate the problem and its consequences, which likely speak to why so much of your research is directed at acute pancreatitis?

“Acute pancreatitis is the third most common cause of GI-related hospital admissions in the United States. This translates to about 300,000 admissions per year. It’s a major health care burden, and its incidence is growing. We spend about $2 billion dealing with it every year in this country. That’s the big picture. For patients, it’s an acute illness, which puts them in great distress because of the associated abdominal pain. For a subgroup of patients, this disease can become extremely complicated with prolonged hospitalization and high rates of morbidity and mortality. Acute pancreatitis is a potentially lethal acute inflammatory disease and, unfortunately, we have no disease-specific medications to treat it, so we can only focus on adequate intravenous hydration and support of the patient rather than treating the disease itself. And, of course, it’s a disease that can persist in a subclinical manner with recurrences, which lead to a vicious circle of slow decline.”

A deeper understanding of acute pancreatitis really necessitates that you approach the condition from multiple directions. How else are you trying to combat the disease from a research perspective?

“We have one randomized trial open right now that is looking at the use of indomethacin suppositories to prevent severe acute pancreatitis. This is a pilot trial in which we are testing the use of this anti- inflammatory medication in cases of acute pancreatitis to see if we can control the disease better and to see if the medication can prevent complications and reduce the severity of the disease. Past work by others to prevent acute pancreatitis in patients undergoing a procedure called ERCP with indomethacin appears to not only prevent the development or the incidence of post-acute pancreatitis, but also to prevent severe pancreatitis. Therefore, we decided to expand the use of indomethacin in all patients with acute pancreatitis, not just patients undergoing ERCP. The advantage of indomethacin is that it can be administered rectally in those patients with nausea and vomiting. Importantly, it’s a very safe and tolerable medication for most people.”

The field likely won’t continue to advance without the infusion and training of new clinicians and researchers who dedicate their careers to understanding acute pancreatitis and the other myriad conditions on the gastroenterology spectrum. Can you highlight some of the educational and training programs in which you are currently involved?

“I am very much committed, and so is our entire Division and leadership, to cultivating an academic center that mentors young scientists in pancreatitis and other research. This commitment to teaching and training extends to my involvement with CAPER, whose mission is very closely aligned with my focus on mentoring young scientists.  CAPER helps to facilitate collaboration among pancreas researchers, and it supports scientifically rigorous multicenter investigations in pancreatic diseases. For example, our own APPRENTICE study was launched and initially supported through CAPER. CAPER also functions to educate and train health care providers in pancreatic diseases to foster a greater public health awareness of acute pancreatitis, while at the same time supporting providers through educational and training programs.

References and Further Reading

Below are references to clinical trials that are currently in progress, for which Dr. Papachristou serves as principal investigator and which are discussed in this article.

A Randomized Controlled Pilot Trial of Indo-methacin in Acute Pancreatitis. ClinicalTrials.gov Identifier: NCT02692391.

Post-ERCP Pancreatitis Severity Indication (PEPSI) Study. ClinicalTrials.gov Identifier: NCT03075592.

Acute Pancreatitis Patient Registry To Examine Novel Therapies in Clinical Experiences 2. ClinicalTrials.gov Identifier: NCT03075618.

Acute Pancreatitis Patient Registry To Examine Novel Therapies in Clinical Experiences (APPRENTICE). ClinicalTrials.gov Identifier: NCT03075618.

Post-Acute Pancreatitis Pancreatic Exocrine Insufficiency. ClinicalTrials.gov Identifier: NCT03063398.

PROOF: Pancreatitis-Associated Risk of Organ Failure. ClinicalTrials.gov Identifier: NCT03075605.

Stent vs. Indomethacin for Preventing Post ERCP Pancreatitis. ClinicalTrials.gov Identifier: NCT02476279.