Rituximab helps manage immunomodulator-refractory AIP patients

Autoimmune pancreatitis (AIP) is the pancreatic manifestation of a multiorgan syndrome called immunoglobulin G4-related disease (IgG4-RD). It's characterized by increased IgG4 antibodies in serum and affected tissues, and unlike other pancreatic diseases, a positive response to corticosteroid therapy. Although high-dose steroids are the standard treatment for inducing remission in AIP, no strategy for maintaining remission is universally accepted. Yet proper management is critical because up to 50 percent of patients relapse after stopping treatment or during treatment tapering.

"The biggest change in the last few years is that the patients we are seeing now are more difficult to treat; they are not the typical cases we used to see when we first started describing autoimmune pancreatitis," says Suresh T. Chari. M.D., a gastroenterologist at Mayo Clinic's campus in Rochester, Minnesota, and a principal author of Mayo Clinic's AIP diagnostic criteria. "In part, this is a measure of success because the disease is now being diagnosed, but it also reflects the difficulty of managing relapses."

At Mayo Clinic, the initial treatment for AIP is a four-week course of high-dose steroids followed by a taper over the course of eight weeks. Not all patients experience a relapse, so long-term immunosuppression isn't considered necessary in every case. But those who are at high risk of relapse because of multiple organ involvement have the option of maintenance therapy with a steroid-sparing immunomodulator — typically azathioprine or 6-mercaptopurine, according to Rahul Pannala, M.D., a gastroenterologist at Mayo Clinic's campus in Arizona.

In Mayo Clinic's experience, however, up to half of patients are unable to taper off steroids or are intolerant or refractory to immunomodulators. For these patients, rituximab, a chimeric monoclonal anti-CD20 antibody, is a promising alternative.

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 experienced complete remission, with no relapses on maintenance therapy. The study appeared in the November 2013 issue of Gut.

Rituximab and AIP

With the exception of high-dose steroids, rituximab, which was first licensed for CD20-positive B-cell non-Hodgkin's lymphoma, is the only agent known to induce disease remission in AIP as monotherapy. But it is not a cure and cost is a major issue, although Dr. Chari observes that tests to exclude cancer in repeatedly relapsing patients are equally expensive.

Still, rituximab is mainly reserved for patients who cannot tolerate steroids or are refractory to immunomodulators. It is not recommended as a first line therapy except in patients with IgG4-related sclerosing cholangitis, which can rapidly progress to secondary biliary cirrhosis.

"These patients need to be treated longer than just a few months, and we are treating them upfront with rituximab. As long as we keep them under surveillance for relapses, they do well. There are some infusion reactions, which we manage with certain interventions during the infusion, as well as some issues with immune suppression, but no major complications," Dr. Chari explains.

No medications for AIP, including rituximab, have been approved by the Food and Drug Administration. "We have to appeal for almost every patient, but no patient of ours has ever been refused treatment," Dr. Chari says. "Still, rituximab is expensive, and it's not appropriate to say this is a first line drug for everybody. It is a lifesaver for some patients who are hard to treat, though the optimal duration of treatment remains to be determined. For many who achieve remission, the disease may not come back, and they may not be served by long-term therapy. Future studies will help tailor the treatment to the unique needs of each patient."

For more information

Hart PA, et al. Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: The Mayo Clinic experience. Gut. 2013;62:1607.