Autoimmune Pancreatitis
- Acute Pancreatitis
- Recurrent Acute Pancreatitis
- Chronic Pancreatitis
- Autoimmune Pancreatitis
- Familial Chylomicronemia Syndrome
- Pediatric Pancreatitis
What is Autoimmune Pancreatitis?
Autoimmune Pancreatitis (AIP) is a rare and chronic form of recurrent acute and chronic pancreatitis where the body’s immune system mistakenly attacks the pancreas.
Watch Dr. Yasmin Hernandez-Barco from Massachusetts General Hospital and Harvard Medical School explain the different types of Autoimmune Pancreatitis (Type 1, Type 2, and Type 3), how AIP is diagnosed, and treatment options, including the new FDA-approved therapy for IgG4-related AIP.
An estimated 2-5% of all chronic pancreatitis cases are due to AIP. This can lead to potential long-term complications like pancreatic insufficiency and diabetes. AIP is categorized into two types:
Type 1 AIP
Type 1 AIP is a pancreatic manifestation of IgG4-related disease (IgG4-RD) and can affect multiple organs
Type 2 AIP
Type 2 AIP is pancreas-isolated and is not associated with IgG4-RD.
Type 1 Autoimmune Pancreatitis
Type 1 autoimmune pancreatitis is part of a systemic disease known as IgG4-related disease (IgG4-RD), where the immune system attacks multiple organs, including the pancreas. To better understand Type 1 AIP, it’s helpful first to learn about IgG4 and its role in this condition.
What is IgG4?
IgG4 is a specific type of antibody in the immunoglobulin G (IgG) family, made by the immune system to fight off bacteria, viruses, and allergens. IgG4 usually forms when the body is repeatedly exposed to certain triggers (known as antigens).
Unlike other types of IgG, IgG4 has some unique traits:
- Anti-inflammatory Properties: IgG4 helps reduce inflammation and encourages the immune system to tolerate harmless substances like allergens, preventing an overreaction.
- Association with Disease: High IgG4 levels are linked to IgG4-related disease, a chronic inflammatory condition where immune cells that produce IgG4 build up in organs, causing inflammation and damage.
What is IgG4-Related Disease (IgG4-RD)?
IgG4-RD is characterized by elevated levels of IgG4 and chronic inflammation that can affect multiple organs in the body. The immune system’s response to various triggers causes inflammation and damage that can involve up to 11 organs. The most commonly affected organs include the pancreas and the salivary glands. While IgG4-RD can initially involve just one or two organs, it can recur and involve other organs over time.
What Happens at the Cellular Level?
In a healthy immune system, B cells and T cells work together to defend the body against harmful invaders like bacteria and viruses. B cells identify invaders and, with help from T cells, produce antibodies to neutralize the threat. Once the job is done, the immune system usually pulls back to avoid damaging healthy tissue.
But in Type 1 Autoimmune Pancreatitis, this system goes off course.
For reasons that researchers are still studying, possibly due to genetic factors, environmental exposures, or a reaction to certain self-antigens, some B cells begin to mistake the pancreas for a threat. These B cells latch onto harmless proteins in the pancreas (called self-antigens) and get activated, often with help from a type of T cell called a follicular helper T cell (Tfh).
Instead of stopping the response, the immune system amplifies it:
- B cells turn into plasma cells and plasmablasts and begin producing large amounts of a specific antibody called IgG4.
- These plasma cells infiltrate the pancreas, leading to visible swelling and immune cell buildup.
- B cells interact with T cells, including cytotoxic types, release signaling molecules (cytokines), which promote chronic inflammation and fibrosis (scarring).
Instead of resolving the issue, the immune system continues to respond to its own pancreas, producing antibodies, recruiting immune cells, and sending inflammatory signals, which over time causes the pancreas to swell, stiffen, and function poorly.
Even though IgG4 antibodies are involved, they likely aren’t the main cause of damage. Instead, it’s the miscommunication between immune cells, and their overreaction, that leads to the disease.
What Causes IgG4-Related Disease?
Doctors and researchers don’t know exactly what causes IgG4-Related Disease (IgG4-RD), including Type 1 Autoimmune Pancreatitis. But they are studying several possible causes that may help explain why it happens.
The Body Attacking Itself (Self-Antigens)
Sometimes the immune system mistakenly attacks the body’s own proteins. These proteins are called self-antigens. In people with IgG4-RD, the immune system may react to certain proteins that it should normally ignore. Some of the proteins being studied include:
- Lactoferrin
- Carbonic anhydrase II
- Pancreatic secretory trypsin inhibitor
Exposure to Chemicals at Work
Being exposed to certain chemicals or particles at work may raise the risk of IgG4-RD. These include:
- Asbestos
- Mineral dust
- Vapors, dust, gases, and fumes
Workplace Chemicals: exposure to certain chemicals like asbestos, mineral dust, and vapors-dust-gases-fumes has been associated with a greater risk of developing IgG4-RD.
Infections from Bacteria
Researchers have looked at whether a common stomach bacteria called H. pylori might trigger IgG4-RD. So far, studies haven’t proven a clear link.
Genetics
Your genes might also play a role. Two parts of the genetic code, called FCGR2B and HLA regions, are being studied to see if they make some people more likely to get IgG4-RD
Key Features of Type 1 Autoimmune Pancreatitis (IgG4 Related Disease)
- Association with high levels of IgG4. Up to 30% of people with IgG4-RD will have a normal IgG4 level and a positive IgG4 level does not confirm the disease.
- Response to Steroid Treatment
- Presentation: Pancreas is often swollen or enlarged, which can look like pancreatic cancer/mass on scans. Other organs may also be affected.
- Recurrence: Relapse can occur after treatment.
- Demographics: Up 3 times more common in men than women and typically presents later in life, 45+ with the average age of diagnosis at 63
Symptoms
Many individuals with IgG4-RD might not display symptoms for months or even years after the condition begins.
Common symptoms of IgG4-RD include:
- Fatigue
- Weight loss
- Headaches
- Cranial nerve dysfunction
- Bulging eyes(proptosis)
- Facial or neck bulges
- Inflammatory thyroid tissue
- Vasculitis (inflammation of the blood vessel walls)
- Shortness of breath
- Urinary blockages
- Enlarged kidneys
- Abdominal pain
- Painless jaundice (yellowing of the skin or eyes)
Sometimes, IgG4-RD may appear as a mass or lump in various organs, including the pancreas, salivary glands, lungs, kidneys, and thyroid gland. These masses can be mistaken for cancer. However, IgG4-RD is a different condition, and accurate diagnosis is crucial to ensure appropriate treatment.
Type 2 Autoimmune Pancreatitis
Type 2 AIP is an even rarer form of pancreatitis. Unlike Type 1 AIP, which is associated with IgG4-related disease and can affect multiple organs, Type 2 AIP typically only affects the pancreas and does not typically involve elevated IgG4 levels.
Key Features of Type 2 AIP include:
- Association with Inflammatory Bowel Disease (IBD): Type 2 AIP is sometimes linked to IBD, such as Crohn’s disease or ulcerative colitis. About 30% of patients with Type 2 AIP also have IBD, though newer studies suggest this association may be as high as 80%.
- Demographics: Type 2 AIP typically affects younger individuals and appears equally in men and women.
- Recurrence: Type 2 AIP rarely recurs after treatment with steroids, distinguishing it from Type 1 AIP, which often relapses.
- Presentation: About 50% of patients with Type 2 AIP present as having acute pancreatitis (AP), but imaging features can be distinct making it a unique presentation compared to other forms of pancreatitis.
Symptoms of Autoimmune Pancreatitis
Symptoms of AIP can vary, but often include:
- Acute pancreatitis
- Painless jaundice (yellowing of the skin and eyes) is the most common sign of Type 1 AIP → can mimic pancreatic cancer and should be carefully evaluated
- Upper stomach pain / nonspecific abdominal pain
- Unintended weight loss
- Diabetes
- Fatigue
- Enlarged pancreas visible on imaging studies
- Diarrhea
These symptoms are caused by the pancreas not working properly. Jaundice is caused by the compression of the nearby drainage system of the liver (known as bile ducts). Notably, not many patients with autoimmune pancreatitis experience abdominal pain. Extreme abdominal pain is a main symptom of acute and chronic pancreatitis.
Risk Factors for Autoimmune Pancreatitis
The exact cause of autoimmune pancreatitis is unclear, but it is thought to stem from an abnormal immune response. Even so, certain risk factors have been identified.
- Genetics: A family history of autoimmune diseases or specific genetic markers may predispose individuals to AIP, such as CFTR
- Autoimmune conditions: People with other autoimmune disorders, such as inflammatory bowel disease (IBD) or systemic conditions like Sjögren’s syndrome, are at a higher risk of developing AIP.
- Environmental triggers: Exposure to certain infections, allergens, or other environmental factors may provoke an immune response, potentially leading to autoimmune pancreatitis.
While more research is needed, these factors help us understand what might trigger AIP. They give clues about how the condition develops and could lead to better ways to diagnose and treat it.
Diagnosing Autoimmune Pancreatitis
Diagnosing AIP can be tricky and requires a multi-faceted approach. The symptoms and imaging findings of AIP can be similar to those of pancreatic cancer, meaning that doctors will have to rule that out as a possibility. While there isn’t a single test that can definitively confirm AIP, a combination of imaging studies, blood tests, a pancreatic biopsy, and a steroid response test helps make an accurate diagnosis.
Here is an outline of the diagnostic process:
- Imaging: Doctors use CT scans, MRI, or endoscopic ultrasound (EUS) to look at the pancreas.
- These studies help identify classic imaging of AIP, which include diffuse enlargement of the pancreas (sometimes described as a “sausage-shaped” appearance) or a “halo-sign,” which is common in AIP. They can also reveal a narrowing of the pancreatic duct or bile ducts, which may resemble the presentation of cancer.
- Blood tests: Elevated levels of IgG4 are often seen in Type 1 AIP. While high IgG4 levels can suggest an IgG4-related disease, they can also occur due to other conditions and one cannot over-rely on a positive IgG4 level to make the diagnosis. People with Type 2 AIP do not have elevated levels of IgG4 so it is harder to diagnose using a blood test.
- Pancreatic biopsy: A biopsy is not typically needed for confirmation. Pancreas biopsy is typically performed to rule out pancreatic cancer. A pancreas biopsy involves collecting a tissue sample from the pancreas and examining it under a microscope. The biopsy is done via endoscopic ultrasound (EUS), which allows a physician to insert a flexible tube through the stomach or intestines to obtain a sample.
- Steroid response test: Doctors will prescribe a short-term dose of steroids and will then test to see if it lowers IgG4 levels and improves imaging findings.
Treatments for Autoimmune Pancreatitis
While autoimmune pancreatitis is treatable, the primary goal is managing inflammation, preventing relapses, and addressing symptoms.
Steroid Therapy (Type 1 and Type 2 AIP)
Steroids are considered the first-line treatment for AIP without other organ involvement. Patients usually begin with a high dose of 40 mg per day for four weeks, followed by a tapering schedule, reducing the dose by 5 mg per week over a 12-week period. Since long-term steroid use can lead to serious side effects, it is crucial to minimize exposure while effectively managing symptoms.
While both types of AIP respond well to steroids, Type 1 AIP often recurs if not managed with a more comprehensive treatment strategy. Relapses are more common in patients with Type 1 AIP compared to those with Type 2 AIP, with recurrence rates of 37.5% and 15.9%, respectively.
The most significant risk factors for relapse include:
- Biliary involvement
- Multiorgan involvement including: Involvement of retroperitoneal fibrosis, chronic periaortitis, autoimmune hypophysitis, sclerosing cholangitis, and Riedel’s thyroiditis.
- Elevated IgG4 levels
- Elevated IgE levels
When left untreated, IgG4-related disease (including AIP) can lead to irreversible fibrosis and tissue damage, ultimately resulting in end organ damage. In cases of repeated relapses, AIP may lead to severe fibrosis with calcification or stones, resembling chronic pancreatitis. Moreover, patients with late-stage AIP may not respond to glucocorticoids. As such, early diagnosis and appropriate treatment are critical.
Management of Relapse
Unfortunately, about 30-50% of patients may experience a relapse within the first 3 years of diagnosis. If relapse occurs, steroids may be needed for retreatment. Other immunosuppressive drugs may be considered, but they are generally less predictable and effective than biologic therapy. However, they may be considered in certain cases. It is important to have an open discussion with your doctor about any current medications or treatments and to review any changes before starting new therapies.
Rituximab (for Type 1 AIP)
Rituximab is a targeted therapy used to induce remission and prevent relapse in Type 1 AIP.
Rituximab works by specifically targeting a protein, called CD20, on B-cells, which are central to the IgG4-related immune responses. The treatment is typically given in two infusions, with regular follow-up to monitor for relapse. Unlike steroids, which suppress the entire immune system, Rituximab targets a specific cell type, reducing systemic immune suppression.
UPLIZNA (for Type 1 AIP)
On April 3, 2025, the FDA approved Uplizna® (inebilizumab-cdon) as the first and only approved treatment for Immunoglobulin G4-related disease (IgG4-RD), the condition behind Type 1 Autoimmune Pancreatitis (AIP). Uplizna is administered as an infusion once every 6 months after two starting doses given two weeks apart. During clinical trials, only 10% of AIP patients given Uplizna had one flare compared to 60% in the placebo group. Overall, Uplizna has been shown to reduce the risk of flares and may help many patients stay in remission without steroids.
Uplizna works by targeting a protein called CD19 on the surface of B cells and then depleting them. CD19 appears earlier than CD20 (the target for Rituximab) during early stages of B-cell growth and stays later potentially making it a more effective target.
Additional Supportive Treatments
Other treatments may include pain management and the treatment of related conditions like exocrine pancreatic insufficiency and diabetes. It is essential to work closely with your healthcare provider to tailor a treatment plan that suits your specific needs.
Complications of Autoimmune Pancreatitis
If left untreated, AIP can lead to severe complications, including:
- Bile duct obstruction and cirrhosis
- Pancreatic insufficiency
- Diabetes
- Chronic pancreatitis
- Higher risk of pancreatic cancer: Evidence is mixed about whether or not autoimmune pancreatitis increases a person’s risk for a cancer, such as pancreatic cancer. There have not been any rigorous studies that give a definitive answer.
Other Resources
Watch Dr. Yasmin Hernandez-Barco from Massachusetts General Hospital and Harvard Medical School explain autoimmune pancreatitis symptoms, diagnosis, treatment, and more.
The IgG4ward Foundation offers valuable resources for those affected by Type 1 AIP, providing education, support, and community outreach.
Is My Pancreatitis Autoimmune?
Autoimmune Pancreatitis vs Acute Pancreatitis
Acute pancreatitis (AP) is a sudden episode of inflammation in the pancreas, often triggered by gallstones, alcohol, or other factors. On the other hand, AIP is a chronic condition where the immune system causes inflammation. Although their symptoms may overlap, the underlying causes and treatments are quite different. Proper diagnosis is crucial to ensure the correct approach to treatment, as AIP requires different management than AP
Autoimmune Pancreatitis vs Chronic Pancreatitis
Chronic pancreatitis is a long-term inflammatory condition that causes irreversible damage and scarring of the pancreas. Factors like genetics, alcohol use, or other lifestyle choices typically trigger it. While autoimmune pancreatitis can resemble chronic pancreatitis, the root cause is different, AIP occurs when the immune system attacks the pancreas. Unlike chronic pancreatitis, AIP often responds well to steroid treatment, which helps reduce inflammation and manage the immune system’s activity.
Key Takeaways
- Autoimmune pancreatitis (AIP) is a rare, chronic condition where the immune system attacks the pancreas.
- There are two types of AIP, type 1 (IgG4-RD) or type 2
- Timely diagnosis and appropriate treatment are essential for managing symptoms and preventing complications.
- Steroids are the primary treatment, but relapse is common, and other therapies like Rituximab and Uplizna may be necessary for type 1.
