Autoimmune intraluminal neutrophils that infiltrate the small

Autoimmune pancreatitis (AIP) has been described as a chronic fibroinflammatory pancreatic disease that is corticosteroid-responsive when used as a management strategy. There are two well-described subtypes of AIP within the literature. Lymphoplasmacytic sclerosing pancreatitis (LPSP) belongs to the spectrum of immunoglobulin G-subclass-4 related disease with obstructive jaundice being the most common manifestation of the disease. LPSP also has several extrapancreatic pathologies associated with it, including lacrimal and salivary gland lesions, hilar lymphadenopathy and pulmonary lesions, sclerosing cholangitis, retroperitoneal fibrosis, and tubulointerstitial nephritis. Idiopathic duct-entric pancreatitis (IDCP) is a similar but distinct manifestation of AIP that mimics LPSP radiologically but presents usually with abdominal pain in the setting of acute pancreatitis associated with inflammatory bowel disease (IBD). IgG4 elevations in LPSP are typical while IDCP rarely occurs with IgG4 elevations. Histologically, there are some similarities while there are also some distinct differences between LPSP and IDCP. LPSP presents with lobular lymphoplasmacytic infiltrate obliterative phlebitis and storiform fibrosis while IDCP presents with granulocyte epithelial lesion (GEL), described as intraepithelial and intraluminal neutrophils that infiltrate the small and medium-sized ducts. Management of AIP typically consists of corticosteroid administration for 2-4 weeks followed by a steroid taper, which studies have shown reduces the relapse rate in patients being treated for AIP. If relapse occurs or steroids are not tolerated by the patient, Rituximab (RTX) has shown good efficacy when managing AIP patients who failed steroid therapy or cannot tolerate steroids. The long-term outcomes of AIP has been recently studied and some clinical manifestations after prolonged follow up found that some patients would go on to develop exocrine and endocrine dysfunction, particularly after stopping corticosteroid therapy. There has been much debate on whether AIP increases the risk of developing pancreatic malignancy or extrapancreatic malignancy. Most studies have come to the conclusion that the risk of developing a malignancy in patients with AIP is similar to the risk in the general population. However, one must be mindful that pancreatic malignancy can happen concurrently with AIP and should be ruled out prior to starting therapy.


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In 1961, Sarles et al the term idiopathic chronic pancreatitis in patients that presented with obstructive jaundice and hypergammaglobulinemia.1 In 1995, the term “autoimmune pancreatitis” was adapted to common literature, introduced by Yoshida et al.2 Today, Autoimmune pancreatitis (AIP) can be defined as a chronic fibroinflammatory steroid-responsive disease of the pancreas. Type I AIP refers to lymphoplasmacytic sclerosing pancreatitis (LPSP) that is more common among East Asians, typically characterized by IgG4-positive plasma cells in extrapancreatic organs, as described by Kamisawa. 3 Type II AIP refers to idiopathic duct-centric chronic pancreatitis (IDCP) typically seen in younger patients in a Western society like Europe and the US, characterized by the presence of granulocyte epithelial lesions proposed to lead to duct destruction. 4 AIP has also shown to have a strong association with inflammatory bowel disease (IBD), particularly with type II AIP versus Type I AIP that generally carries a worse prognosis and greater disease severity. 5 AIP has been used to describe these two separate disease entities that have various overlapping clinical and histological features. However, there are significant differences in the clinical course, diagnostic approach and management strategies that must be addressed to achieve improved clinical outcomes. Because of these two subtypes and their distinct features, it has been proposed to describe the two phenotypes as AIP referring to LPSP and IDCP as its own separate category as IDCP. The diagnostic challenge with AIP, particularly in the Western nations, is the apparent prevalence of IgG4-seronegative AIP along with extrapancreatic manifestations that could affect diagnostic accuracy. Another diagnostic hurdle is the similar presentations and mimicry of AIP to pancreatic neoplasm, which warrants urgent evaluation and diagnosis. The short-term prognosis of AIP is generally favorable as evidenced by radiological and clinical improvement after steroid therapy. However, there is limited data when it comes to long-term sequelae associated with AIP given the relatively recent discovery of high IgG4 serum levels in patients with AIP. In this article, we will examine the two different subtypes of AIP, their diagnostic criteria, and outline the treatment strategies recently employed for these diseases. We will reflect on the importance of early recognition of AIP and make the distinction between AIP and pancreatic cancer. We will also provide a comprehensive overview of the long-term outcomes of AIP including pancreatic stone formation, pancreatic exocrine/endocrine dysfunction, concurrent malignancy, and mortality rates.

Subtypes of Autoimmune Pancreatitis

Recent studies have elucidated to the fact that there are two main subtypes of AIP. Type 1 AIP, per Mackay in 1969, is defined by the presence of IgG4 autoantibodies, hypergammaglobulinemia, the deposition of immunoglobulins, and is steroid responsive.6  Type II AIP differs from its counterpart in that there are no serologic markers associated with Type II AIP.  However, there is a deposition of C3c and IgG within the basement membrane of pancreatic ducts and acini suggesting immune-mediated complex destruction of these structure in Type II AIP making the classification of type II AIP as a true AIP unclear.7





Clinical manifestations of LPSP


Patients with LPSP typically present at an older age compared to IDCP. In a multinational analysis of a total of 1064 patients from 23 different institutions found that the average age of diagnosis for LPSP is 61.4 (as compared to patients with IDCP who presented on average at the age of 39.9).8 Although painless obstructive jaundice is a similar presentation that can be found in both LPSP and IDCP, the most common clinical presentation in LPSP is obstructive jaundice. In a cohort study of 731 patients, 75% of patients with LPSP presented initially with jaundice compared to 47% of patients with IDCP. Patients with LPSP also were found to have more incidences of diffuse swelling of the pancreas compared to IDCP.9 Obstructive jaundice observed could be related to pancreatic swelling and subsequent biliary tree compression or proximal extrahepatic and intrahepatic biliary stricture, which can also be associated with IgG4-mediated colangitis.10 LPSP can also present in a variety of extrapancreatic lesions, including lacrimal and salivary gland lesions, hilar lymphadenopathy and pulmonary lesions, sclerosing cholangitis, retroperitoneal fibrosis, and tubulointerstitial nephritis.11-13 LPSP seems to be the pancreatic manifestation of IgG4-related disease, characterized by swelling of the pancreas, elevated serum IgG4 levels, and extrapancreatic lesions associated with the infiltration of IgG4+ plasma cells.14


Serology of LPSP

IgG4 + plasma cells have been studied extensively and may play a role in the pathogenesis of LPSP. In a cohort study from Mayo Clinic of 45 patients with LPSP, patients with a serum IgG4 level >140mg/dl had a sensitivity of 76% and specificity of 93% in diagnosing LPSP.15 The median IgG4 level in patients with LPSP in a cohort study of 20 patients with sclerosing pancreatitis was 663 mg/dL as compared to normal patients who had median IgG4 levels of 51 mg/dL.16 IgG4 titers, however, can be nonspecific and can be elevated in pancreatic cancer as well.17 Therefore, serology alone should not be routinely used to diagnosis LPSP.

Radiology of LPSP

Contrast-enhanced computed tomography (CECT) is the optimal imaging study to assess parenchymal changes within the pancreas as well as to exclude malignancy. Magnetic resonance cholangiopancreatography (MRCP) or endoscopic cholangiography (ERCP) are useful in assessing the biliary and pancreatic duct abnormalities that can arise from LPSP. Diffuse parenchymal enlargement is a characteristic radiologic finding seen in patients with LPSP described as “sausage-shaped” with featureless and effaced normal lobular architecture of the pancreas.18 For focal LPSP that presents with a homogeneous enhancement of the lesion in the delayed phase (likely due to retention of contrast), MRCP or EUS may show the main pancreatic duct penetrating through the mass lesion, called a positive duct penetrating sign. Long (>1/3 duct length) segment involvement or focal narrowing of the pancreatic duct and multiple strictures in the affected segment without significant upstream dilatation (<5 mm) and side branches originating from the strictured segment and the duct-penetrating sign are hallmark findings of LPSP on MRCP/ERCP.19 Perfusion abnormalities can be studied in conjunction with morphological features typical in LPSP and the involved areas of the pancreas usually demonstrate decreased enhancement in the pancreatic phase with gradually increasing enhancement in the delayed phase.20 Histology The histological hallmark for LPSP is lobular lymphoplasmacytic infiltrate obliterative phlebitis and storiform fibrosis.21 Histological evidence of periductal lymphoplasmacytic infiltrate without granulocytic infiltration and at least two additional histological features such as obliterative phlebitis, storiform fibrosis, and abundant IgG4-positive cells (>10 cells/HPF) is a widely accepted diagnostic marker for LPSP.17 IgG4 immunostaining can be used as supportive evidence for the diagnosis. However, it is non-specific and can be found in several other conditions, such as pancreatic malignancy and pancreatitis. 


Clinical Presentation of IDCP

The most common clinical presentation in these patients is acute pancreatitis, occurring in 1/3 to nearly 2/3 of patients with IDCP.22-23 Other common clinical features of IDCP also include painless obstructive jaundice, focal pancreatic mass, and symptomatic pancreatic duct stricture formation.24 IDCP typically affects younger patients with a mean age at diagnosis being 39.9 years (compared to 61.4 years in Type I AIP) as proposed by one of the largest case series on AIP.25 In a case series of 43 patients at Mayo Clinic diagnosed with IDCP, the median age for patients diagnosed with IDCP was 31 years of age and about half of the patients were found to be women.26 For IDCP, there appears to be no difference in prevalence among men and women with a nearly equal male-female ratio.25 IDCP is more common amongst European and US populations, accounting for 20-40% of AIP cases in Europe and the US.27 Several reports have also concluded that there is a significant association with inflammatory bowel disease (IBD), particularly ulcerative colitis (UC) where there is an increased risk of developing UC compared to the general population.28 Among Western countries, the prevalence of AIP-UC is between 30-35% and Eastern countries like Japan and Korea report a prevalence rate of 16% and 5.8% respectively.5 When AIP and IBD occur concurrently, the disease severity is more severe and the prognosis is poorer compared to patients with IBD alone. In a retrospective study comparing patients who underwent a colonoscopy showed more extensive colitis in patients diagnosed with AIP-UC compared to the UC only group with 66.7% of patients from the AIP-US group underwent surgery due to refractory colitis.29

Serological Markers of IDCP

Features of LPSP serologic markers such as elevated IgG4 level and multiorgan involvement are not present in IDCP, making diagnosis difficult unless histological features are examined and tested for.30

Radiological Features of IDCP

The presence of a distinct focal mass on radiographic imaging is the most common feature of IDCP, found in up to one-third of patients with IDCP. Another common radiographic finding is diffuse pancreatic enlargement, particularly in the absence of peripancreatic fat stranding which can be useful in distinguishing between other etiologies of acute pancreatitis. Little is known about perfusion abnormalities and pancreatic duct changes given the relative rarity of the condition compared to LPSP and therefore would require further investigation to differentiate the two subtypes radiologically.24

Histological manifestations of IDCP

There are similar histological patterns that are shared between LPSP and IDCP, including periductal lymphoplasmacytic infiltrate and storiform fibrosis.12 However, the hallmark histologic feature of IDCP not seen in LPSP is the granulocyte epithelial lesion (GEL), described as intraepithelial and intraluminal neutrophils that infiltrate the small and medium-sized ducts, can form microabscesses, and is often associated with duct destruction.19,1 IDCP also usually has none or very few (<10 cells/HPF) IgG4-positive plasma cells, although this can widely vary and is not as reliable in diagnosing IDCP definitively.17 Because IDCP lacks serologic markers and systemic involvement like its counterpart, it is imperative to make a definitive diagnosis through histology. Management and therapy for AIP Corticosteroid therapy is the gold standard for therapy for AIP. The standard dosing is typically .6-1mg/kg for 2 to 4 weeks with a taper of 5mg/day every week thereafter. Resolution of symptoms is typically seen after steroid treatment and response to treatment is usually followed by resolution of symptoms, liver function tests, IgG4 levels, and repeat CT or MRI.16 Early steroid initiation in patients with suspected AIP is warranted given that more unfavorable events occurred in patients who did not undergo corticosteroid therapy such as obstructive jaundice, pseudocyst, hydronephrosis, interstitial nephritis, and sclerogenic changes of extrapancreatic bile ducts compared to patients treated with corticosteroids (70% v 32%, respectively).17 In Japan, to establish a corticosteroid regimen, a multicenter study of 459 patients were treated with .6mg/kg of prednisolone and 98% of patients in the treatment group saw remission as compared to 74% who were not treated with steroids. 82% of the patients in the treatment arm were also kept on maintenance therapy and the relapse rate was found to be lower than in patients who did not initiate maintenance dosing.18 A large multinational study of more than 1000 patients (978 patients with LPSP and 86 patients with IDCP) found that 99% of patients with LPSP and 92% with IDCP went into remission after treatment with corticosteroids. On discontinuation of steroids, however, relapse occurred in up to 31% of patients with LPSP and 9% in patients with IDCP.1 In a Japanese study of 510 patients coming from 22 centers in Japan, patients who underwent maintenance corticosteroid therapy with a mean duration of 43.1 months had significantly lower relapse rates compared to patients who had their steroid treatment discontinued at 30.3% v 45.2%, respectively.19 (Low-dose maintenance steroid treatment could reduce the relapse rate in patients with type 1 autoimmune pancreatitis: a long-term Japanese multicenter analysis of 510 patients)  Rituximab (RTX) can also induce remission for AIP. Rituximab is a chimeric monoclonal antibody against CD20 antigen on B cells and is used for patients with relapsing disease or if corticosteroids are contraindicated. The two regimens widely used for induction include 375mg/m2 once weekly for 4 weeks or 1000 mg, 2 doses given 2 weeks apart.20 There is still limited data on using rituximab as a first-line agent for treating AIP. However, RTX has shown promise in managing patients with RTX despite not receiving concomitant glucocorticoid therapy in an open-label pilot study of 30 patients.21 Other immunomodulators that have been used to manage AIP include azathioprine, 6-mercaptopurine, cyclosporine, and cyclophosphamide). However, no large-scale studies have been performed and will need further investigation before using it as a viable treatment strategy for patients who have failed steroid therapy or who cannot tolerate steroid treatment.16 Long-term outcomes of AIP One relatively complication associated with LPSP is pancreatic stone formation. Interestingly enough, no cases of pancreatic stones were found to be in patients with IDCP.  In a multinational study, 7% of LPSP patients had on follow up pancreatic stones, which was more common in patients that had at least one episode of relapse.1 Hirano et al. Found in their study that ethanol consumption of greater than 50 grams per day was at increased risk of developing pancreatic stones, thought to be due to pancreatic juice alterations in the setting of alcohol consumption.22 In another study of 63 patients who were followed for at least 3 years who have AIP, pancreatic head swelling and Wirsungs and Santorini's pancreatic duct narrowing was found more often in patients with stone formation.23 In a study at Kyushu University of 21 patients that were diagnosed with AIP, 17 (81%) of patients were found to have pancreatic exocrine dysfunction while 14 (66.7%) were found to have pancreatic endocrine dysfunction at diagnosis.24 Another study of 44 patients with AIP saw that 34% of those patients had exocrine dysfunction and 39% of those patients had endocrine dysfunction.25 Risk factors that may contribute to the development of endocrine insufficiency include longer follow up period and older age of onset of AIP.26 Pancreatic atrophy has also been described as a long-term sequelae of AIP and in patients with pancreatic atrophy, there were high incidences of new onset Type 2 Diabetes mellitus or worsening diabetes in patients who underwent steroid therapy.25, 27 It is unclear if there is a higher incidence of pancreatic and nonpancreatic cancer in patients with AIP. However, in LPSP, IgG4 concentrations can be persistently elevated even after steroid therapy, which could suggest continued pancreatic inflammation, which can lead to carcinogenesis within the pancreas, similar to the chronic inflammatory processes of chronic hepatitis B and C leading to liver cancer, colon cancer in patients with inflammatory bowel disease, and chronic pancreatitis patients leading to pancreatic cancer.28-30 In a multicenter, retrospective cohort study of 108 patients with AIP, of the 108 patients, 15 patients (13.9%) were found to have 18 cancers at the median follow up time of 3.3 years with the highest risk of developing cancer to occur during the first year from diagnosis, suggesting that some patients may be developing a paraneoplastic syndrome.33 However, in the terms of increased risk of developing pancreatic cancer, in a long-term study of 107 patients with AIP, no incidences of pancreatic cancer were observed.26 Some studies have also suggested that the cancer risk before and after the diagnosis of AIP is similar to that of the general population.31,34 Therefore, there needs to be further investigation of the inherent cancer risk in patients with AIP with larger scale studies that can provide adequate evidence. What is also important to be aware of is that AIP and pancreatic cancer can both co-exist and it is crucial to exclude pancreatic cancer prior to initiating therapy for AIP.35 Conclusion AIP is a chronic fibroinflammatory disease of the pancreas that requires histological, radiographic, and serological investigation to confirm the diagnosis. Typically, AIP is steroid responsive. However, the relapse rate is not insignificant and may require 2nd line treatment with immunomodulators, particularly RTX which is quite effective in inducing relapse in patients intolerant of steroids or have failed corticosteroid therapy. LPSP and IDCP are distinct diseases with several similarities such as some radiographic and histological features and several differences such as elevated IgG4 in LPSP (compared to IDCP where no elevation is usually present). IBD is typically associated with IDCP and can, therefore, aid in the diagnosis of the subtypes of AIP if radiographically it remains unclear. AIP can have long-term outcomes like exocrine and endocrine insufficiency and pancreatic stone formation. Although there have been studies that indicate that there may be an increased risk of malignancy in patients with AIP, several other studies indicate otherwise and see that the malignancy risk is similar in these patients as compared to the general population. Given that pancreatic malignancy can mimic AIP and can even coexist, it is prudent to rule out malignancy prior to starting therapy for AIP.