Stephen Pandol, MD, and Elham Afghani, MD, on Treating Chronic Pancreatitis

In this video, Dr Pandol and Dr Afghani discuss current treatments for chronic pancreatitis and therapies now under investigation to add to the options for managing this challenging disease.

Stephen Pandol, MD, is a professor of medicine at UCLA and the director of Basic and Translational Pancreatic Research at Cedars-Sinai Medical Center in Los Angeles, California. Elham Afghani, MD, is gastroenterologist and assistant professor of medicine at the Johns Hopkins University School of Medicine in Baltimore, Maryland.

Dr. Elham Afghani:  Hi, My name is Dr. Elham Afghani from Johns Hopkins University. Today, we will be discussing a treatment for chronic pancreatitis. Joining us is Dr. Stephen Pandol who is professor of medicine at UCLA and the director of Basic and Translational Pancreatic Research at Cedars-Sinai Medical Center. Thank you for joining us, Dr. Pandol.

Dr. Stephen Pandol:  Thank you for having me, Dr. Afghani.

Dr. Afghani:  Can you give us a background on what we know of the current treatment for chronic pancreatitis?

Dr. Pandol:  The current treatments fall into a couple of categories, mostly symptomatic. The most common symptoms that patients have with chronic pancreatitis are pain. Pain management becomes very important. There are also issues of exocrine pancreatic insufficiency and diabetes that we can talk about later.

But pain is the major problem that most of the patients have, especially early on. The treatments are pain mitigation. Those can be several different things from nonsteroidal anti-inflammatories to narcotics and even visualization therapies. Also, as you know, there are interventional therapies. The intervention for removing stones or other manipulations that might help in opening up the ducts that sometimes can cause the pain. Finally, there's removal of the pancreas or other surgical procedures. That's very general, but that's the armamentarium we’ve got.

Dr. Afghani:  What have you found has been the best treatment for your patients with chronic pancreatitis as far as pain management?

Dr. Pandol:  I've found a couple of things. Obviously, I use nonsteroidal anti-inflammatories first. Often, I'll add agents like nortriptyline or Elavil that can have an additional beneficial effect. What I do is that I work closely with my interventional partners for potential evaluation for procedures that might help.

I do, interesting enough, have trials ongoing for new therapeutic interventions. Right now, I'm participating in a trial that I tried in the United States — and it didn't work, so we're trying it in India — to use statins, simvastatin in particular, and acetylcysteine. I can talk a little bit later about why I think those might be helpful.

Dr. Afghani:  How is the statin helpful in the treatment of chronic pancreatitis?

Dr. Pandol:  We found a couple of different things that gave us a hint. One is working with our colleagues at Kaiser Permanente in Southern California, specifically Bechien Wu. He found that those people in the Kaiser populations who took simvastatin and potentially other statins had decreased episodes of acute pancreatitis.

So we thought, "Oh, could a simvastatin prevent recurring acute pancreatitis which is part of the progression of chronic pancreatitis?" We started the trial in the United States with 4 centers. We had a problem with recruitment because we made the trial too complex. I carried that trial to India where there are much greater prevalence of the disease. That's where I'm studying it.

We have experimental animal models where we worked on the potential mechanism. The potential mechanism is related to the ability of simvastatin to augment the process of — we call it — autophagy. It's a process by which the cell will digest abnormal organelles. During pancreatitis, mitochondria start to dysfunction. That's, we think, both true in acute and recurrent acute pancreatitis. We found that simvastatin would augment eating up bad mitochondria.

The reason that's important is the mitochondria release molecules that can cause inflammation when the mitochondria aren't completely digested by these cells' autophagy process.

Both using epidemiologic data from Kaiser and the animal model data, we hypothesized that there would be a beneficial effect. I will say that like any disease in medicine will have probably some patients respond, some won't. Some will have partial responses. We'll probably have multimodal therapy at some point.

Dr. Afghani:  That's very interesting. Chronic pancreatitis, it's a fibroinflammatory syndrome of the pancreas. Many have just defined it as an irreversible tissue damage.

What I would think would be the best treatment for chronic pancreatitis as far as the pain, the exocrine/endocrine insufficiency, would be to reverse the inflammatory cascade and the fibrosis, so simvastatin being one of them, but also trying to reverse the fibrosis of chronic pancreatitis is another pathway. Do you have any thoughts on that?

Dr. Pandol:  You're exactly right. The fibroinflammatory response that you talked about is negated by a cell that gets activated in the pancreas called the stellate cell. It's similar to the stellate cell in the liver. When activated, it makes extracellular matrix proteins of fibrosis and secretes inflammatory cytokines

So in recurring acute and chronic pancreatitis, the stellate cells get activated. They start to lay down collagen into the other extracellular matrix proteins, but also they secrete cytokines that brings in an inflammatory response.

The inflammatory response, in. working with Aida Habtezion at Stanford, we found that macrophages that come into the pancreas are converted to what are called alternatively activated macrophages or often called type 2 macrophages. Those were recruited by the stellate cell cytokines and promoted better secretion of TGF-beta.

That's important because TGF-beta then activates stellate cells to make more cytokines to activate more macrophages so it proposed a feed-forward loop. My thought is that you would break the loop, and so agents that can inhibit the stellate cell activation would be really important. Also agents that might prevent the action of TGF-beta might be really important. I am thinking about interventions that would do that.

I will also tell you another interesting observation that was made by Jay Pasricha, whose one of your colleagues at Johns Hopkins who demonstrated TGF-beta was also the signal that mediates pain in pancreatitis. I think they're linked to the fibroinflammatory response and the pain through these cell types that I mentioned, the stellate cell and the inflammatory cell. The macrophage at least is one example. TGF-beta is a player that keeps them all going, including promoting the pain. I'm thinking about ways to attenuate that effect. And that would be to block stellate cell activation or block TGF-beta pathways. There are some possibilities. We are exploring those in the animal models, but human trials are not far off.

Dr. Afghani:  There's a couple of studies that have been attempted or done on small groups of patients and definitely on animals. One of them was on the camostat, which is an oral protease inhibitor. It was developed in Japan I believe in the early 2000s. It showed very promising results in small studies and definitely in animals in reversing the fibrosis of chronic pancreatitis.

I believe it also showed that there was improvement of the ductile function when compared to placebo. It's an ongoing trial. It's a phase 2 trial where they have enrolled the patients.

Dr. Pandol:  I think camostat and agents that work like it could also be beneficial. We know that trypsin activation is another process. It also happens inside of the tissue for the same reasons that I was mentioning about the mitochondria not being eaten up completely when trypsinogen, the proform of trypsin, is taken up by autophagic processes that can mediate some of the disease. The inflammatory response, for example. Agents like camostat that are protease inhibitors...They have used protease inhibitors for several years with success, especially giving them into the pancreatic circulation directly.

This is for acute pancreatitis by the way. We have not had as much, I would say, findings outside of Japan. But it is, for the reasons you said, there are several reasons why protease inhibitors could have benefit.

Dr. Afghani:  There is also another company, Theraly Fibrosis, which is a biotechnology company. It's working to develop and commercialize drugs to reverse fibrotic diseases including cirrhosis. Hopkins was involved with the development of this agent.

It's a recombinant inversion of the TRAIL protein which is intended to stop the fibrosis, the fibrotic pathways by acting on the activated fibroblasts in the fibrotic tissue. I think that, from my understanding of it, phase 1 has already been completed, the animal studies with promising results. They're preparing for phase 2. It's very similar to camostat.

Dr. Pandol: I think from what you’re saying and I'm saying is there's signals from the parenchymal cells that activate the fibroinflammatory response, but also the fibroinflammatory response can be directly targeted. It may depend upon the stage of the disease, how much fibrosis you have versus just inflammation, what agent might be more beneficial, and it may be combinations that ultimately are the most effective.

Dr. Afghani:  There's a lot of things to look forward to in the future. I think, with chronic pancreatitis treatment, we've come a long way in the last few years, and we're going pretty far. Thank you so much, Dr. Pandol, for joining us. Any last comments, or questions, or remarks?

Dr. Pandol:  A couple of things. One is patients are frustrated obviously when they have this disease. One of the things I hear from my patients, and it's a comment, is that they're often accused of being an alcoholic when they go to the emergency room or some doctors.

When in fact, we know some patients have alcoholism as a cause of pancreatitis. The majority of the ones I see, I don't think that's the case. We have to be maybe more cognizant and educate our medical colleagues that alcohol is not the only cause of chronic pancreatitis. It breaks the trust between patients and medical staff when we don't appreciate that.

Dr. Afghani:  Yes, that's a very, very good point. We are finding that there's other more common causes or often seen causes of chronic pancreatitis. So the more that we're studying chronic pancreatitis, the more we find out about it.

Dr. Pandol:  Agree.

Dr. Afghani:  Thank you so much for joining us.

Dr. Pandol:  You're welcome. Thank you for having me. Bye.