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Autoimmune Pancreatitis
Introduction
Autoimmune pancreatitis (AIP), also referred to as nonalcoholic destructive pancreatitis and sclerosing pancreatitis, is a rare condition characterized histologically by chronic inflammation of the pancreas and clinically by various symptoms related to biliary and pancreatic pathologies.[1] Recurrent acute pancreatitis or painless jaundice should prompt an evaluation for autoimmune pancreatitis.[2] AIP can be a primary pancreatic disorder or a systemic autoimmune disease associated with other autoimmune conditions, such as immunoglobulin G subclass 4 (IgG4)–related diseases.[3][4] Autoimmune pancreatic disease is the only pancreatic condition treated effectively with corticosteroids.
Three types of AIP are clinically recognized:
- Type 1: IgG4-related pancreatitis, associated with a serum IgG4 concentration greater than twice the normal reference range in most affected individuals. Diagnostic findings include infiltration with greater than 10 IgG4-positive plasma cells per high-power field (HPF), a cartwheel pattern of fibrosis, lymphocytic and plasma cell inflammation of venules, and a histologic description of lymphoplasmacytic sclerosing pancreatitis. The most common clinical presentation of type 1 AIP is painless jaundice with laboratory studies suggesting biliary obstruction and hyperglycemia. Other cases present with abdominal pain or are discovered in asymptomatic individuals with a pancreatic mass, pancreatic duct stricturing, or an enlarged pancreas. Acute pancreatitis is an unusual presentation in type 1 AIP, but it can result in exocrine and endocrine pancreatic insufficiency.[5] The pancreas may be the only organ affected, or there may also be other organs involved with corresponding clinical presentations, including:
- Bile ducts (secondary sclerosing cholangitis)
- Retroperitoneal fibrosis
- Kidneys (tubulointerstitial nephritis)
- Lungs
- Submandibular and parotid glands (Sjögren disease)
- Sublingual glands (sclerosing sialadenitis)
- Orbits and lacrimal glands (IgG4-related dacryoadenitis and sialoadenitis, formerly Mikulicz disease)
- Joints (rheumatoid arthritis)
- Type 2: Histologically, this is idiopathic duct-centric pancreatitis with granulocytic epithelial lesions within the pancreatic duct, small numbers of IgG4–positive plasma cells (fewer than 10/HPF), and no extrapancreatic involvement. Type 2 AIP is often associated with inflammatory bowel disease and is twice as common in patients with ulcerative colitis or proctitis as in those with Crohn disease.[6] Unlike patients with type 1 AIP, about half of those with type 2 AIP present with abdominal pain or acute pancreatitis.
- Type 3: Immune checkpoint inhibitor-induced pancreatic injury is a type of progressive immune-mediated pancreatitis, an adverse effect of cancer treatment with immune checkpoint inhibitor drugs. The risk of this immune response is heightened when multiple immune checkpoint inhibitors are used.[7] Most patients with type 3 AIP are asymptomatic.
Etiology
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Etiology
The presence of lymphocytic infiltration on histologic examination demonstrates the autoimmune etiology of AIP. Various immune-mediated mechanisms could initiate the inflammatory response in this IgG4-related disease.[8] Potential initiating mechanisms include bacterial infection and molecular mimicry in the setting of genetic predisposition and autoimmunity. The IgG4 antibodies can cause tissue destruction locally and systemically, although the etiology of IgG4-related diseases remains poorly understood.[9] Subsequently, regulatory T cells mediate an immune reaction, and the shift of peripheral blood T lymphocytes toward a T helper 2 cell response causes the release of cytokines and interleukins, inducing inflammation and fibrosis.[8] In the case of type 3 AIP, immune checkpoint inhibitors are triggered by a nonspecific inflammatory T-cell (mainly CD8+) response.[10]
Epidemiology
Autoimmune pancreatitis is an uncommon cause of chronic and recurrent pancreatitis but is often underdiagnosed. Approximately 2% of all cases of chronic pancreatitis are attributed to autoimmune pancreatitis, and the prevalence is less than 1 per 100,000 population. Most initial reports in the literature are from Asian countries, including Japan, where the prevalence is higher. This increased prevalence may be due to greater recognition.[11][12] However, autoimmune pancreatitis is less prevalent in North America, South America, Europe, and Africa.[13] Type 1 AIP is the most common form in Asia, but type 2 is more prevalent in Europe and the United States.
Most epidemiologic data on AIP are based on small case series and estimates from study groups. Type 1 AIP is more common in men than in women, with a ratio of 3:1, and the average age of onset is 68.[14] Type 2 is equally prevalent in men and women, and the average age of diagnosis is about 30 years younger than that of type 1. Type 3 AIP develops during treatment with immune checkpoint inhibitor drugs.
Histopathology
Histopathologic examination is often necessary to distinguish autoimmune pancreatitis from pancreatic cancer.[15][16] The presence of lymphoproliferative inflammation suggests an autoimmune etiology of pancreatitis. Furthermore, biopsy specimens often demonstrate dense lymphoplasmacytic infiltrates, particularly in and around the pancreatic ducts, accompanied by associated fibrosis.[17] Fibrosis may resemble chronic obstructive pancreatitis, characterized by interlobular and intralobular fibrosis and acinar atrophy. Each type of AIP has distinctive features:
- Type 1 AIP: Sclerosing pancreatitis with the abundance of IgG4-positive cells along with periductal lymphoplasmacytic infiltration, acinar fibrosis, or obliterative phlebitis
- Type 2 AIP: Paucity of IgG4-positive cells in the pancreatic parenchyma and granulocytic epithelial lesions in the pancreatic duct, also known as idiopathic duct-centric pancreatitis [15]
- Type 3 AIP: Absence of characteristic histopathologic lesions found in type 1 and type 2 AIP, but occasional elevation of serum IgG4 concentrations [10]
History and Physical
Autoimmune pancreatitis can present with symptoms related to biliary or pancreatic disease. Patients may present with recurrent episodes of abdominal pain, with or without documented attacks of acute pancreatitis. Obstructive jaundice is common and is often accompanied by nonspecific symptoms such as nausea, vomiting, anorexia, or weight loss, depending on the degree of biliary or pancreatic stricture.[20] Type 2 AIP is associated with symptoms of inflammatory bowel disease.[21] Patients may also have a history of other IgG4-related organ system involvement, such as salivary glands, thyroid, or kidneys. A subset of patients, particularly those with type 3 AIP, is often asymptomatic. The physical examination findings are frequently normal, but some patients have jaundice or abdominal tenderness.
Evaluation
The diagnosis of AIP should be considered in patients with abdominal pain or painless jaundice, those with imaging studies that demonstrate a pancreatic mass, pancreatic enlargement, or pancreatic duct stricture, and in patients with other autoimmune diseases. The international consensus diagnostic criteria for type 1 and type 2 AIP include abnormal imaging studies of the pancreas and pancreatic duct, elevated serum IgG4 concentrations, involvement of other organs, a suggestive pancreatic biopsy specimen, and evidence of corticosteroid responsiveness.[22] Elevated serum lipase or amylase concentrations suggest acute pancreatitis. Abnormal liver function test results, such as an elevated alkaline phosphase or bilirubin concentration out of proportion to transaminase levels, would suggest obstruction. Other diagnostic studies may be indicated if there is evidence of involvement in other organs.
Imaging of the biliary and pancreatic structures can be performed with a computed tomography (CT) scan or, preferably, a magnetic resonance cholangiopancreatogram (MRCP), which also helps evaluate other potential diagnoses. These studies assess pancreatic size, texture, and enhancement with contrast, and MRCP can demonstrate biliary and pancreatic duct stricture.[23] AIP can be difficult to distinguish from pancreatic malignancy when a pancreatic mass is present; therefore, tissue biopsies are necessary for an accurate diagnosis. Endoscopic ultrasound of the pancreas (ERCP) is preferred due to its superior imaging quality, image-enhancing capabilities, and ability to biopsy tissue through fine-needle aspiration.[22][24] Radiographic findings are similar for the various types of API.
Laboratory Testing: IgG4 serum concentrations are elevated in approximately 50% of type 1 AIP cases and are generally in the normal reference range in types 2 and 3. Cancer antigen 19-9 blood tests are modestly elevated in some patients with AIP, but not to the levels seen in pancreatic ductal adenocarcinoma.
MRI/MRCP Findings: Decreased T1 signal intensity and minimally increased T2 intensity are demonstrated on MRI and MRCP. There is a high diffusion-weighted image and a low apparent diffusion coefficient signal, more evident than that seen in pancreatic cancer. MRCP imaging results may demonstrate multiple strictures throughout the biliary tree, with normal segments in between, similar to the appearance of primary sclerosing cholangitis or other cholangiopathies. The main pancreatic duct may pass through a mass representing an area of AIP with partial pancreatic duct obstruction. Still, dilation of the distal pancreatic duct is unusual, distinguishing it from pancreatic malignancy.[25]
CT Findings: If CT imaging findings are abnormal, the pancreas may be focally or diffusely enlarged, appearing like a "sausage-shaped" pancreas. There may also be a rectangular-shaped tail of the pancreas. Fat stranding may involve the peripancreatic tissue without affecting more distant structures such as the mesentery or surrounding fascia. A peripancreatic or capsule-like rim is often seen in type 1 AIP and less frequently in type 2 AIP.[26] The pancreatic duct or biliary tree may be dilated, and the uncinate process and head of the pancreas may contain an isodense or hypodense mass lesion. If other sites are involved in the autoimmune process, CT imaging may show peripancreatic or mediastinal lymphadenopathy or other abnormalities, depending on the involved structures.
ERCP Findings: This is normal in some cases, or it might show a pattern similar to that of primary sclerosing cholangitis with multiple strictures of the common bile ducts and the intrahepatic biliary tree. When affected, the pancreatic duct is typically irregular and partially stenosed.
Treatment / Management
In the absence of established guidelines, therapy must be individualized according to subtype and associated comorbidities.[27][28][29] Most individuals with type 1 AIP respond to corticosteroid therapy, with improvement of symptoms and a reduction in complications.[30] Spontaneous remission occurs in up to 25% of patients,[31] but corticosteroid therapy is indicated in the following clinical scenarios:(B2)
- Abdominal or back pain
- Obstructive jaundice or persistently elevated liver enzyme levels for >3 weeks in the setting of IgG4-related sclerosing cholangitis [30]
- A pancreatic mass persisting for >4 weeks
- Progressive pancreatic exocrine or endocrine failure
- Progressive lesions (either symptomatic or subclinical) in other organs affected by IgG4-related disease
Furthermore, a lack of response to corticosteroids could indicate an alternative diagnosis, such as pancreatic cancer.[32] Initial treatment is usually prednisone 0.6 to 0.8 mg/kg/d (commonly 20 to 40 mg/d) for 1 month, with assessment for response at 2 to 4 weeks. A response is defined by improvement in symptoms, normalization of IgG4 concentrations, and an improvement in radiographic findings. After 1 month of treatment, the dose is tapered by 5 mg/d weekly, down to a maintenance dose of 2.5 to 5 mg/d for 2 to 3 months. Risk factors for recurrence include type 1 AIP, elevated IgG4 concentration, jaundice, and involvement of other organs.[20][33] In patients at high risk for recurrence, low-dose maintenance prednisone is continued for 6 months to 3 years, or lifelong if necessary. Alternative options studied for the treatment of type 1 AIP relapse include resumption of prednisone or substituting or adding azathioprine (either of which is typically highly effective). Rituximab, 6-mercaptopurine, mycophenolate mofetil, cyclophosphamide, or cyclosporine have also been studied, but have a lower response rate.[34][35](A1)
Although corticosteroid therapy induces remission in as many as 99%,[36] relapse or steroid dependence can occur in up to one-third of patients, especially in IgG4-related AIP. These patients may require long-term steroids or steroid-sparing agents.[20][37] If there is no response to steroid treatment after 4 to 6 weeks, pancreatic cancer must be excluded. If the diagnosis of AIP is confirmed, an immunomodulator such as azathioprine can facilitate steroid tapering,[38], though it is not effective as monotherapy. Rituximab is a second-line therapy for type 1 AIP in patients with a contraindication to glucocorticoids or if a complete course of steroid therapy is not feasible.[39] Colchicine and various biologic therapies can be effective for both treatment and maintenance therapy, primarily in type 2 AIP.[28][40] Finally, plasmacytoid dendritic cells and signaling pathways mediated by type 1 interferon and interleukin-33 are targets for novel therapies.[41](B2)
Type 2 AIP has a remission rate of 82% and a low relapse rate of 9%.[36] Maintenance therapy is similar to that of type 1. Conversely, type 3 AIP is usually asymptomatic, and corticosteroid treatment is not beneficial. Because discontinuation of immune checkpoint inhibitor treatment could accelerate cancer growth, decisions about discontinuation should consider the severity of AIP and the need for further oncologic treatment.[10](B3)
Differential Diagnosis
Pancreatic cancer must be excluded before initiating treatment for AIP because it may be difficult to differentiate the two based solely on clinical presentation or imaging findings.[42] Histopathologic examination of endoscopic ultrasound-guided or surgical specimens is required before initiating treatment for AIP if the diagnosis is uncertain based on laboratory results and radiographic findings. Other differential diagnoses to consider include various causes of pancreatic or biliary ductal obstruction, such as acute or chronic pancreatitis, pancreatic cysts, pancreatic duct stones, choledocholithiasis, cholangiocarcinoma, and benign biliary strictures, including primary sclerosing cholangitis.
Prognosis
Autoimmune pancreatitis generally responds to corticosteroid treatment and has a favorable prognosis. Most cases attain remission and have a low rate of complications with steroid treatment. Cases of AIP associated with pancreatic malignancy are challenging to treat, have a poorer prognosis, and may require pancreatic resection.[43] In contrast, type 2 AIP has lower mortality and malignancy rates, and no specific follow-up is recommended after radiologic remission.[44] The prognosis of type 3 AIP is primarily contingent upon the underlying malignancy and the necessity of treatment with immune checkpoint inhibitor drugs.
Complications
Recurrent attacks of pancreatitis may occur in a relatively small number of individuals. Although pancreatic malignancy has been identified during surveillance, AIP is not a precursor of or a risk factor for pancreatic cancer.[45] In cases that do not respond to treatment or if concurrent malignancy is considered, surgical resection is an option. However, pancreatic surgery, such as a pancreatoduodenectomy, is associated with significant morbidity and mortality.[46] Long-standing AIP can result in endocrine and exocrine pancreatic insufficiency complicated by diabetes mellitus due to pancreatic atrophy, particularly in older individuals. Pancreatic calcifications and stones may also occur.
If AIP is inadequately treated, progression of biliary strictures may contribute to cholangitis, obstructive jaundice, bacterial sepsis, fibrosis, and ultimately, cirrhosis. Adverse effects related to long-term treatment with corticosteroids, steroid dependence, or other complications secondary to immunomodulatory medications used to treat AIP can arise. If other organs are involved, such as the kidneys, thyroid gland, salivary glands, lungs, retroperitoneum, and lacrimal glands, complications specific to those organs and structures may arise.
Deterrence and Patient Education
Patients with autoimmune pancreatitis should be educated about the available treatment options for their condition. Clinicians should emphasize he importance of medication adherence and the consequences of inadequate treatment. Education should include the potential adverse effects of long-term corticosteroid use, including adrenal insufficiency, osteoporosis, weight gain, osteonecrosis, hypertension, and hyperglycemia.
Enhancing Healthcare Team Outcomes
Autoimmune pancreatitis can present a diagnostic challenge because of a nonspecific presentation with symptoms of abdominal pain and recurrent episodes resembling acute pancreatitis. These symptoms can be reported to primary care or emergency medicine clinicians. Diagnosis requires an interprofessional approach with gastroenterologists for possible endoscopic intervention, radiologists for imaging evaluation, and rheumatologists to assess associated autoimmune conditions. Nursing professionals are also vital interprofessional team members, playing key roles in clinical monitoring and educating patients and their family members. After a thorough evaluation and exclusion of differential diagnoses such as pancreatic cancer, patients need continuous follow-up with clinicians to assess response to medical therapy. Care coordination in inpatient and outpatient settings remains critical to enhancing healthcare outcomes for the condition, minimizing morbidity, and improving quality of life.
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