Extrapancreatic manifestations have been reported in up to 40 % of patients with type 1 AIP [41]. The most common extrapancreatic site in type 1 is the biliary tree. Chest (including mediastinal fibrosis), retroperitoneum (chronic periaortitis, retroperitoneal fibrosis), salivary glands, kidneys (tubulointerstitial nephritis) may be also affected, but the spectrum of IgG4-related disease is even larger [42]. IgG4-lymphoplasmacytic infiltrate is often found in affected organs. Involvement of the biliary tree in autoimmune pancreatitis, called or “IgG4 sclerosing cholangitis” (IgG4-SC), can be confused with primary sclerosing cholangitis or cholangiocarcinoma.

Although steroids are the treatment of choice in AIP, there is no consensus on the optimal dose and tapering schedule. Initial prednisone doses range from 0.5 mg/kg/day (as proposed by Asian studies) to 1 mg/kg/day (Italy, Germany) or 40 mg regardless of the weight (the USA, the UK). This dose should be kept for at least 2–4 weeks, then tapered by 5 mg/week [14]. The efficacy ranges from 95 to 100 % and is now considered as a standard induction therapy. The relapse rate after discontinuation of steroid treatment varies from 30 to 60 %; in such cases, most investigators recommend a second course of steroid therapy for induction followed by maintenance therapy with immunosuppressants (Europe, the USA) [43] or with low-dose steroids (Asia) [14]. Azathioprine is considered the most effective drug for maintenance therapy at a dose of 2–2.5 mg/kg/day. Other immunosuppressive drugs (methotrexate, mycophenolate mofetil) seem to be less effective. Rituximab, an anti-CD20 antibody able to deplete B cells, has been recently proposed [43, 44]. Although a hematologic regimen (4 weekly doses of 375 mg/m² followed by drug reinfusion every 2 months) has been proposed, we experienced a good clinical and morphological response with a rheumatologic regimen (two infusions of 1 g each at time 0 and 2 weeks, with repetition of the cycle to 6 months) (unpublished data). After the introduction of biologics, the problem of step-up vs. top-down therapy arises, similar to other diseases of the gastrointestinal tract (e.g., IBD). Based on our center experience on 231 AIP patients (at June 2015), of whom only 10 were treated with rituximab (while the remaining received mainly steroids), we suggest a step-up strategy, even for a cost-benefit assessment.

The natural history of AIP is still not clarified. Spontaneous remission can occur in patients with lower serum IgG4 levels and focal rather than diffuse enlargement of the pancreas. Steroids probably modified the natural history of the disease, particularly when the treatment is started in an early phase of the disease. Untreated AIP probably progresses from lymphoplasmacytic inflammation to extensive fibrosis that may result in permanent organ dysfunction and evolution toward an “ordinary” chronic pancreatitis [45]. Some studies have also suggested a slightly increased risk of malignancy (pancreatic, lung, colon, lymphoma) [46, 47].