Bottom-up approach best for treating AIP

Autoimmune pancreatitis (AIP) is the pancreatic manifestation of a multiorgan syndrome called immunoglobulin 4-related disease (IgG4-RD), which can affect various organs, including the bile ducts, salivary glands, kidneys, lungs and lymph nodes. Although associated with specific histologic, clinical and morphologic findings, AIP remains difficult to distinguish from pancreatic cancer. Maintaining remission and treating recurrences have proved equally challenging.

Administration of an oral corticosteroid is the standard treatment for AIP. Most patients show marked improvement in clinical symptoms two to four weeks after starting corticosteroid therapy, but 30 to 50 percent have a relapse after stopping treatment or during treatment tapering.

"We've been treating AIP for 10 years. Early on, there was a question of how to treat patients after the initial presentation was treated," says Suresh T. Chari, M.D., a principal author of Mayo Clinic's AIP diagnostic criteria known as HISORt, a mnemonic for histology, imaging, serology, other organ involvement and response to steroid therapy.

"Our only guide was what the Japanese were doing, which was to put patients on small doses of steroids for two to three years," he says. "But long-term steroid treatment, especially for elderly people, is controversial. So we decided we would treat the initial presentation with a three-month course of tapering steroid therapy and monitor patients closely for relapses. We found that only about half the patients had a relapse. Those who did were treated with another three-month course of steroids or with a repeat course of steroids and an immunomodulator — either azathioprine or 6-mercaptopurine."

The corticosteroid-immunomodulator combination seemed promising for maintaining remission until patients began to have a relapse while taking it, too.

An unexpected discovery

Then, in 2006, a patient with AIP and IgG4-related sclerosing cholangitis who could not tolerate 6-mercaptopurine developed orbital symptoms.

Dr. Chari explains, "The ophthalmologist who saw our patient directed us to Thomas E. Witzig, M.D., who was treating orbital pseudolymphoma with rituximab. He suggested that we stain the pancreatic biopsies for CD20, and if there were abundant CD20-positive cells, the disease would respond to rituximab."

The disease did respond. Within a month, the patient's pancreatic and extrapancreatic symptoms disappeared, and his disease remained in remission for two years with maintenance rituximab therapy.

Rituximab, an anti-CD20 antibody targeted to B lymphocytes, is typically used to treat lymphomas, leukemias, transplant rejection and certain autoimmune disorders, including rheumatoid arthritis. This was the first time it had been used — albeit serendipitously — for AIP. Rituximab eventually proved effective for both induction and maintenance of remission in other AIP patients.

A retrospective comparison of 116 patients with type 1 AIP at Mayo Clinic found that during a median follow-up period of 47 months, 52 patients had 76 relapse episodes. Twenty-four patients were treated with a second course of corticosteroids and 27 patients with corticosteroids and an immunomodulator. Relapse-free survival until the second relapse was similar in both groups. Twelve patients who were steroid-intolerant or immunomodulator-resistant were treated with rituximab. Of these patients, 83 percent had complete remission, with no relapses on maintenance therapy.

Rituximab is not a cure for the disease and has its downsides:

  • It is expensive and not yet approved by the Food and Drug Administration for use for IgG4-RD.
  • Although the majority of patients tolerate it well, it has a long list of adverse effects, including potentially fatal progressive multifocal leukoencephalopathy.
  • About 40 percent of patients have a relapse if rituximab is used only for inducing remission without follow-up maintenance therapy.

"We treat AIP with a bottom-up approach, starting with the cheapest drug and working up to the most expensive," Dr. Chari says. "Rituximab costs an arm and a leg, so it's not appropriate to say that this is a first line drug for everybody. It is a lifesaver for some patients who are otherwise hard to treat, but I'm not a fan of using it for everybody. Future studies will help tailor the treatment to the individual needs of the patient."

He adds, "We're starting to see patients whose disease is harder to diagnose and harder to treat. I learn from previous patients and I see patterns that make sense, so I keep trying different things to see if they work. But medicine is just not that straightforward. Once we know for sure there is a path that others can follow, then we can point the way. In the meantime, we can only show where we came from and where we're going."