Understanding and Management of Autoimmune Pancreatitis

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ACHAIKI IATRIKI | 2025; 44(2):67–70

Editorial

Ploutarchos Pastras, Ioanna Aggeletopoulou, Christos Triantos

Division of Gastroenterology, Department of Internal Medicine, University of Patras, Patras, Greece

Received: 08 Jan 2025; Accepted: 10 Mar 2025

Corresponding author: Christos Triantos, Associate Professor in Internal Medicine and Gastroenterology. E-mail: chtriantos@upatras.gr

Key words: Autoimmune pancreatitis, subtypes; therapy, new treatment options

 

Introduction

Autoimmune pancreatitis (AIP) is a chronic, benign inflammatory disease of the pancreas, characterized by autoimmune mechanisms. Unlike other pancreatic diseases, AIP responds dramatically to glucocorticoid therapy [1]. Although it is considered rare, it accounts for approximately 2% of chronic pancreatitis cases [2].

The clinical presentation of AIP varies widely, ranging from asymptomatic cases to symptoms such as obstructive jaundice, weight loss, chronic abdominal pain, fever, and acute pancreatitis episodes. AIP can present as a diffuse pancreatic process, which is pathognomonic, or as a focal pancreatic mass that can mimic pancreatic cancer. Histological confirmation may be necessary, with findings typically including pancreatic lymphoplasmacytic infiltration and fibrosis.

Diagnosing autoimmune pancreatitis is based on clinical features, serological markers, imaging findings from computed tomography (CT) or magnetic resonance imaging (MRI), and the classification of AIP type. Endoscopic ultrasound (EUS) with pancreatic biopsy is often crucial to rule out pancreatic cancer [3] and may also assist in determining the AIP subtype.

AIP is classified into two types: type I (lymphoplasmacytic sclerosing pancreatitis) and type II (idiopathic duct-centric pancreatitis) [1]. Each subtype differs in clinical presentation, histological features, and associated systemic involvement, necessitating tailored diagnostic and therapeutic approaches.

Autoimmune Pancreatitis Subtypes

Type I AIP (Lymphoplasmacytic Sclerosing Pancreatitis – LPSP)

Type I AIP is the most common subtype, accounting for approximately 80% of AIP cases. It is observed more frequently in Asia, particularly Japan, but its distribution is global. The mean age of onset is 60–70 years, and males are three times more likely to be affected than females. Clinically, type I AIP most often presents with painless obstructive jaundice (75%) and, less frequently, with abdominal pain. Imaging findings may include a diffuse pancreatic process or a focal pancreatic mass [4]. The hallmark feature is an elevated level of immunoglobulin G4 (IgG4)-positive plasma cells in the blood (≥2 times the upper limit of normal) and within the pancreatic parenchyma. Type I AIP is histologically defined as lymphoplasmacytic sclerosing pancreatitis (LPSP), according to the International Consensus Diagnostic Criteria (ICDC) [5]. This subtype often involves other organs beyond the pancreas and may present either as an isolated condition or as part of IgG4-related disease (IgG4-RD). Unlike type II AIP, type I has no association with inflammatory bowel disease (IBD). Relapses occur in up to 60% of cases following corticosteroid therapy [4].

Type II AIP (Idiopathic Duct-Centric Pancreatitis – IDCP)

Type II AIP is more prevalent in Europe and the United States compared to Asia, but it represents a minority of cases (approximately 20% of AIP patients). The mean age of onset is 40–50 years, and there is no significant gender predominance.

Patients with type II AIP commonly present with either obstructive jaundice or symptoms of acute pancreatitis at similar rates. Imaging frequently reveals a focal pancreatic mass (85%). Histologically, type II AIP is characterized as idiopathic duct-centric pancreatitis (IDCP), which features granulocyte epithelial lesions (GELs). Unlike type I, blood IgG4 levels are typically normal, and pancreatic tissue has very few IgG4-positive plasma cells. Type II AIP does not involve other organs but is strongly associated with IBD. Relapse is rare, occurring in less than 10% of cases [4].

Table 1 provides an overview of the key characteristics, prevalence, demographic trends, clinical features, and relapse rates associated with the different subtypes of AIP, highlighting the distinctions between type I and type II.

Other recorded disorders

Two additional disorders have been reported in the literature without being the primary classification of autoimmune pancreatitis. More specifically, AIP Not Otherwise Specified (AIP-NOS) refers to cases of AIP that do not meet the criteria for either type I or type II AIP. These patients typically lack elevated serum IgG4 levels, other organ involvement, IBD association, or histological confirmation. Evidence suggests that AIP-NOS shares similar clinical features with type II AIP, and a significant proportion of these patients are reclassified as type II AIP upon further follow-up [6].

Furthermore, Immune Checkpoint Inhibitor-Induced Pancreatic Injury is a recently described disorder, associated with immune-related adverse events caused by immune checkpoint inhibitors (ICIs). This iatrogenic pancreatic injury occurs due to a nonspecific immune response triggered by regulatory checkpoint blockade in patients undergoing treatment for advanced malignancies [7]. That condition typically manifests four–six months after initiating ICI therapy. While asymptomatic elevation of pancreatic enzymes (e.g., lipase) is the most common finding, a minority of patients may develop symptoms of chronic pancreatitis. Diagnosis relies on excluding alternative causes of pancreatitis and establishing a temporal correlation with ICI exposure, as radiological findings are often absent. Disorder is usually seronegative, and it lacks pathognomonic histopathological lesions [7].

Therapeutic Management and Follow-Up of Autoimmune Pancreatitis

It is not necessary to initiate treatment for all patients with AIP immediately. The decision to begin therapy is guided by specific clinical indications. Patients presenting with obstructive jaundice, abdominal pain, back pain, or other symptoms involving the pancreas or extrapancreatic organs (e.g., jaundice due to bile duct strictures in overlapping IgG4-related disease) should receive prompt treatment.

Additionally, asymptomatic patients with persistent pancreatic masses on imaging, irreversible pancreatic exocrine or endocrine dysfunction, persistent abnormalities in liver function tests, or progressive subclinical lesions in vital organs associated with (overlapping) IgG4-related disease should also be treated.

Conversely, patients without these characteristics typically do not require initial therapy. This approach is supported by evidence showing recurrence rates without a definitive cure in 25–55% of AIP cases [8].

The primary treatment for AIP patients with clinical indications is prednisone at an initial dose of 40 mg per day for four–six weeks. After this induction period, repeat clinical evaluation and imaging studies (e.g., CT or MRI) are performed. Patients who demonstrate clinical and radiological improvement undergo a gradual tapering of prednisone over two months until discontinuation. Most patients with AIP (80–99%) respond to this initial corticosteroid therapy.

In cases where patients fail to respond to corticosteroids, it is crucial to re-evaluate the diagnosis and exclude other conditions in the differential diagnosis [8]. For patients with contraindications to corticosteroid use, treatment with rituximab should be initiated or continued. Additionally, for certain AIP populations with co-existing IgG4-sclerosing cholangitis (IgG4-SC) as part of IgG4-RD, biliary stenting may be warranted depending on individual risk factors [9].

Follow-Up Care

After completing primary treatment, AIP patients should be monitored regularly by a physician. The suggested follow-up schedule includes clinical and serological evaluations every six months and radiological examinations initially at 4–6 weeks post-treatment, followed by a six-month interval thereafter [10].

Patients do not require maintenance therapy during follow-up, unless they experience a relapse or are considered at high risk for relapse. High-risk relapse characteristics include [8]:

  1. Type I AIP with diffuse pancreatic enlargement.
  2. Involvement of two or more extra-pancreatic organs or proximal IgG4-SC before treatment.
  3. Delayed radiologic remission with corticosteroid therapy.
  4. Persistently elevated serum IgG4 levels (>2 times the upper limit of normal) after treatment.

Maintenance Therapy

Patients experiencing relapse or identified as high risk for relapse require maintenance therapy during follow-up. The choice of maintenance therapy depends on the presence or absence of IgG4-RD:

In AIP without IgG4-RD:

Azathioprine: 2 mg/kg per day (first-line therapy).

Alternative options:

Prednisone: 2.5–10 mg per day for one–three years or indefinitely.
Mycophenolate mofetil: 750 mg twice daily.

In AIP with IgG4-RD:

Rituximab: 1 g IV on days 0 and 14 (maintenance therapy) [11].

It is important to recognize the increased risk of diabetes mellitus in AIP patients due to extensive pancreatic parenchymal atrophy. Proactive management of this risk should be considered during follow-up [12].

Potential New Treatment Options

Recent studies have explored the pathophysiology of AIP to identify new potential treatment options. Eotaxin, a chemokine involved in the recruitment of inflammatory cells, has emerged as a promising therapeutic target, and efforts to develop targeted anti-eotaxin therapies are ongoing [13]. Regarding type II AIP, a case series has reported that colchicine may be an effective treatment option due to its ability to inhibit neutrophils and reduce the formation of pathognomonic granulocytic epithelial lesions [14]. Additionally, some patients with type II AIP and coexisting IBD have responded effectively to ustekinumab, a monoclonal antibody targeting interleukin-12 and interleukin-23 [15]. For type I AIP, several targeted therapies have been proposed, including inhibitors of B-cell activating factors such as ianalumab and inebilizumab (anti-CD19), as well as agents targeting other pathways, including simtuzumab (anti-LOX2), abatacept (anti-CD80/86), elotuzumab (anti-SLAMF7), and daratumumab (anti-CD38) [16]. More specifically, a recent study published in the New England Journal of Medicine (N.E.J.M.) with 135 IgG4-related disease (IgG4-RD) participants showed that inebilizumab reduced the risk of flares and increased the likelihood of flare-free complete remission at one year [17].

Furthermore, therapies like anifrolumab and sifalimumab (anti-IFN-I), as well as etokimab (anti-IL-33), which have been successfully used in systemic lupus erythematosus, have been suggested for type I AIP. These therapies target interferon-I and interleukin-33, which are known to drive chronic inflammation and fibrosis in this subtype [18]. The role of the gut microbiome in AIP pathogenesis has also been highlighted, particularly in type I AIP. Studies in mice have shown that gut sterilization reduces the accumulation of pathognomonic plasmacytoid dendritic cells in the pancreas, suggesting that modulation of the gut microbiome could be a potential therapeutic strategy. Future approaches may include probiotics, prebiotics, symbiotics, or fecal microbiota transplantation as prophylactic or adjunctive treatments to mitigate pancreatic inflammation and fibrosis [19].

Conclusion

Response to corticosteroids is a hallmark characteristic of AIP. Most patients achieve remission through induction or maintenance therapy, and relapse rates remain relatively low. While some studies are exploring and proposing novel therapies for different AIP subtypes, the majority of current clinical trials are focused on improving diagnostic methods. This emphasis reflects the greater challenge physicians face in accurately diagnosing AIP in daily clinical practice. Among potential new treatment options, inebilizumab is a promising choice because the participants it tested included patients with AIP.

These trends suggest that research priorities in AIP are shifting toward a deeper understanding of its pathophysiology to facilitate the development of more precise and effective diagnostic tools. A better comprehension of the underlying mechanisms could not only improve diagnostic accuracy but also pave the way for identifying novel therapeutic approaches that enhance treatment outcomes for AIP patients.

Conflict of interest disclosure

None to declare.

Declaration of funding sources

None to declare.

Author contributions

PP was responsible for the literature review analysis; PP and IA were responsible for drafting the manuscript; CT was responsible for the revision of the manuscript for important intellectual content; all authors provided final approval for the version to be submitted.

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