New kid on the block? Autoimmune pancreatitis

Best Practice & Research Clinical Gastroenterology 24 (2010) 361–378

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Best Practice & Research Clinical Gastroenterology

New kid on the block? Autoimmune pancreatitis David G. Forcione, William R. Brugge* Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA 02114, USA

Introduction Autoimmune pancreatitis (AIP) represents a unique subset of chronic pancreatitis with distinct clinical, morphologic, and histopathologic features that typically responds dramatically to corticosteroid treatment [1–3]. Since the term ‘autoimmune pancreatitis’ was coined fifteen years ago by Yoshida, both histopathologic and clinical classification systems have emerged and these have led to improvements in our overall knowledge and diagnostic accuracy for this condition [4]. In this review, we will discuss the history, pathogenesis, clinical spectrum, and management strategies of AIP. History The history of AIP dates back to 1961 when Sarles published a paper entitled, ‘Chronic inflammatory sclerosis of the pancreas: an autonomous pancreatic disease?’ [5]. In 1991, Kawaguchi described a case of lymphoplasmacytic sclerosing pancreatitis [6]. Yoshida coined the term ‘autoimmune pancreatitis’ in 1995 when he described a 68 year old woman who presented with obstructive jaundice and clinical findings of hypergammagobulinemia, a diffusely swollen pancreas on computed tomography, and fibrosis on needle biopsy [4]. The patient demonstrated rapid improvement and resolution of radiologic findings with corticosteroid therapy. ‘AIP’ as a term for the pancreatic disease entity was based on similarities to ‘autoimmune hepatitis’ in which there is often a similar rapid improvement with corticosteroids. In 1997, Ito reported on several cases of steroid responsive disease, reaffirming Yoshida’s description [7]. A major advance in the AIP literature came in 2001 when Hamano et al. demonstrated the utility of serum IgG4 as a specific marker for AIP [8]. In the last decade, two major classification systems (Asian Consensus Criteria and HISORt) have been developed. These classifications incorporate several key features including serology, radiology, pathology, and response to corticosteroids [9,10]. In the next decade, major advances are expected to be in understanding of specific pathogenetic mechanisms, in identification of better serologic markers, and perhaps controlled therapeutic trials of immunomodulatory therapy.

This item refers to issue: 10.1016/j.bpg.2010.04.001. * Corresponding author. E-mail address: [email protected] (W.R. Brugge). 1521-6918/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpg.2010.04.002

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Pathogenesis The precise pathogenetic mechanisms underlying the development of autoimmune pancreatitis remain uncertain. The characteristic clinical and serologic findings have led to interest in understanding the potential role of genetic, immunologic, and microbial factors which might predispose to autoimmune pancreatitis. Genetic studies thus far have focussed in on four important loci which have associated diverse polymorphisms in the human population: (1) major histocompatibility complex, (2) cytotoxic T lymphocyte-associated antigen-4, (3) TNF-a promoter, (4) Fc receptor-like genes. All of these share two important features: importance in immunologic function and the presence of diverse polymorphisms which reflect on variations in both geography and antigenic exposures. These may help to explain differences in disease phenotype across populations. Immunologic factors include both the humoral (complement, B cell function and autoantibodies) and cellular immune systems (T-cell function). The best developed of these factors is the association of elevated serum IgG4 as a diagnostic marker. Finally, there is growing interest in the potential relationship that may exist between microbial exposure and the development of autoimmune pancreatitis. Through mechanisms of molecular mimicry, exposure to Helicobacter pylori among predisposed individuals may lead to an immune response capable of eliciting multiorgan (pancreas, bile ducts, renal tubules, salivary glands) autoinflammation. Genetic factors Major histocompatibility complex The major histocompatibility complex (MHC) is a set of molecules displayed on cell surfaces that are responsible for lymphocyte recognition and ‘antigen presentation’ [11,12]. The major histocompatibility complex (also known as the HLA or human leukocyte antigens) is encoded by several genes located on human chromosome 6 and are further classified as Class I or Class II molecules. The best known association between HLA and autoimmune disease is that of celiac disease in which three markers, DR3, B8 and DQ2, have all been highly associated with celiac disease. The MHC molecules belong to a group of molecules known as the Immunoglobulin Supergene Family, which includes immunoglobulins, T-cell receptors, CD4, CD8, and others. Class I molecules present antigen to cytotoxic T-cells (CTLs) while class II molecules present antigen to helper T-cells (TH-cells). This specificity reflects on the type of antigen presented - class I molecules present ‘endogenous’ antigen while class II molecules present ‘exogenous’ antigens. Thus far, limited data (all from Asia) exist on the association between MHC and AIP. A Japanese study identified a specific HLA haplotype (DRB1*0405-DQB1*0401) in association with AIP [13]. The same group later reaffirmed this finding among 25 AIP patients and also identified an HLA Class I association with C3-2-11 microsatellite (allele 219; OR ¼ 2.96, P ¼ 0.0076) [14]. However, a Korean study failed to note any relationship between Class I or II MHC with AIP [15]. It is clear that additional studies need to be performed across different populations to validate linkage between phenotype and HLA haplotypes.. Cytotoxic T lymphocyte-associated antigen-4 Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is another important immunologic mediator [16]. CTLA-4 is a key negative regulator of the T-cell immune response, and its gene is highly polymorphic. Many positive associations between CTLA-4 single-nucleotide polymorphisms and various autoimmune diseases (autoimmune hepatitis, systemic lupus erythematosus, and autoimmune thyroiditis) have been identified [17–19]. Umemura http://www.ncbi.nlm.nih.gov/pubmed? term¼%22Umemura%20T%22%5BAuthor%5Devaluated five CTLA-4 polymorphisms, located at 1722, 658, and 318 in the promoter, þ49 in exon 1, and þ6230 in the 3’ untranslated region [20]. The study involved CTLA-4 genotyping in 59 patients with AIP and 102 healthy subjects as well as measure of serum sCTLA-4 levels (soluble CTLA-4) in 52 patients and 32 controls. Compared with healthy subjects, a significant increase in the þ6230 G/G genotype (64%vs 42%, odds ratio [OR] 2.48, P ¼ 0.011) in AIP

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patients. The þ6230A (haplotype 2) was associated with AIP resistance (OR 0.49, P ¼ 0.011). The þ49A/ A and þ6230A/A genotypes were associated with an enhanced risk of relapse (OR 5.45, P ¼ 0.038 and OR 12.66, P ¼ 0.022). Median serum sCTLA-4 levels were significantly higher in patients with AIP (8.9 ng/mL) compared with healthy subjects (2.9 ng/mL, P < 0.001). An additional study from Taiwan identified a CTLA-4 haplotype (318C/þ49A/CT60G) with AIP (OR 8.53; P ¼ 0.001) [21]. These findings suggest that AIP is associated with a genetic polymorphism in ctla-4 and is positively correlated with serum sctla-4 levels. Others (TNF-a promoter and Fc receptor-like genes) TNF-a is a critical humoral factor in driving the immune response and has been implicated in a number of autoimmune conditions, particularly Crohn’s disease and rheumatoid arthritis [22,23]. Polymorphisms in the TNF-a promoter have been evaluated in this regard. A Taiwanese group genotyped 46 patients with AIP, 78 patients with chronic calcific pancreatitis and 200 healthy controls. They identified a promoter (863A) polymorphism that correlated with extrapancreatic involvement of AIP [21]. A new family of genes called Fc receptor-like genes (FCRLs) has recently been identified [24]. In Japanese patients, FCRL3 polymorphisms have been shown to be associated with rheumatoid arthritis, autoimmune thyroid disease, and systemic lupus erythematosus. These polymorphisms regulate FCRL3 expression on B cells. FCRL3 expression on B cells has been observed in significant amounts and appears to augment autoantibody production in individuals with disease susceptible genotypes. Umemura evaluated polymorphisms in the FCRL3 locus in 59 patients with AIP, as compared to patients with chronic pancreatitis and with healthy controls [25]. They identified a positive association between the frequency of the 110A/A alleles and autoimmune pancreatitis compared with controls (p ¼ 0.012, odds ratio ¼ 7.45). Immunologic factors Humoral immune system The specific autoantigen of AIP has been long sought after since the initial reports of elevated serum IgG4 by Hamano et al. in 2001 [8]. An array of autoantibodies has been described in AIP, the commonest of which are anti-lactoferrin antibodies (ALF), anti-carbonic anhydrase antibodies (ACA, type II), ANA (antinuclear antibodies), and the rheumatoid factor (RF) [26–28]. Okazaki evaluated a panel of autoantibodies in 20 patients with AIP and found the following frequency: ANA in 75%, ALF in 75%, ACA-II in 55% and RF in 25% [28]. Smooth muscle antibodies were seen in 15%. Antilactoferrin antibodies or ACA-II were seen in 90% of patients, and both are seen in 35% of patients. These autoantibodies target antigens (lactoferrin and carbonic anhydrase type II) with cross reactivity across several tissue types including salivary glands, biliary epithelium, pancreatic tissue, and renal tubules. Given the wide distribution of these antigens, it is believed that these may in fact be pathogenetically linked to disease. Three additional putative autoantigens have emerged as potential targets: a-fodrin, pancreatic secretory trypsin inhibitor protein (PSTI), and amylase a-2A. a-Fodrin (also known as nonerythroid spectrin) is a ubiquitous cytoskeletal protein [29]. This heterodimeric actin-binding protein is usually found in mature cells at the cytoplasmic face of the plasma membrane. It appears to be important in maintaining cell polarity and shape in epithelial tissues. Initial reports demonstrated the presence of anti-a-fodrin antibodies to be very sensitive and specific (>90%) for the diagnosis of Sjogren’s syndrome (SS) [30]. Correlation of IgG and IgA antibodies against a-fodrin with the severity of eye involvement suggests that these autoantibodies may be considered activation markers of SS [31]. There is also limited data demonstrating the presence of high titres of anti-a-fodrin among patients with both AIP and SS [32]. PSTI antibodies (typically IgG1) have been reported in 30–40% of patients with AIP. This may represent a unique subset as nearly two-thirds of patients without anti-LF and anti-CA have PSTI autoantibodies [33]. A recent paper from Japan identified a high frequency of antibodies against amylase a-2A among patients with AIP. In this study, all 15 serum samples from patients with AIP

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recognized this protein whereas sera from 25 patients with chronic alcoholic pancreatitis and sera from 25 patients with pancreatic neoplasia did not. Interestingly, 88% (15/17) of patients with fulminant type 1 diabetes were positive for anti-amylase a-2A antibodies. These results suggest that an autoantibody against amylase a-2A is a novel diagnostic marker for both AIP and fulminant type 1 diabetes [34]. IgG4 is the rarest of the IgG subclasses, accounting for less than 6% of total IgG in the serum of normal subjects [35]. IgG4 is unique among the IgG subclasses in its inability to bind Clq complement and, therefore, activate the classic pathway of complement [35]. To date, a limited array of conditions have been associated with high serum IgG4, including some autoimmune dermatologic diseases (atopic dermatitis, pemphigus vulgaris, pemphigus foliaceus), and some parasitic diseases (Strongyloides, Trichinella, and Filiriasis) [36–38]. In 2001, Hamano evaluated 20 patients with sclerosing pancreatitis, 20 age- and sex-matched normal subjects, and 154 patients with pancreatic cancer, ordinary chronic pancreatitis, primary biliary cirrhosis, primary sclerosing cholangitis, or Sjögren’s syndrome [8]. In this landmark study, the median serum IgG4 concentration in the patients with sclerosing pancreatitis was 663 mg/dL as compared with 51 mg/dL in normal subjects (P < 0.001). The serum IgG4 concentrations in the other groups of patients were similar to those in the normal subjects. The use of a cutoff value for serum IgG4 concentrations of 135 mg/dL resulted in a high rate of accuracy (97%), sensitivity (95%), and specificity (97%) for the differentiation of sclerosing pancreatitis from pancreatic cancer. The respective values for the use of a cutoff value of 1883 mg/dL for serum IgG were 80%, 65%, and 81%. In addition, serum IgG4 appeared to correlate well with disease activity. This initial report concluded that elevated IgG4 levels were nearly pathognomonic of AIP. A number of additional studies have since confirmed the association between elevated serum IgG4 and AIP [39,40]. However, the very high sensitivity and predictive value has not been validated in patients in the non-Asian countries. Furthermore, up to 10% of patient with pancreatic adenocarcinoma, 6% of patients with chronic pancreatitis, and 5% of normal subjects have been found to have serum IgG4 in excess of 140 mg/dL [41,41a]. In the largest clinical series from the US (Mayo Clinic, University of Pittsburgh), the frequency of IGg4 elevation >140 mg/dL was 75% and 44%, respectively, with specificity reaching 93% [2,40–42]. Clearly from these data, several conclusions can be made: (1) a wide variability in the diagnostic utility of IgG4 exists with greater yield amongst patients from Japan compared to Western populations, (2) IgG4 may not be pathogenetically linked to AIP and may represent an immunologic ‘epiphenomena’, (3) the diagnostic yield of IgG4 increases with higher serum levels (>280 mg/dL), and (4) elevated IgG4 alone is not sensitive or specific enough from which to make or not make a diagnosis of AIP. The latest advance in serologic diagnosis of AIP comes from Italian investigators. Frulloni et al. identified another putative autoantigen: ubiquitin-protein ligase E3 component n-recognin 2 (UBR2), a protein with amino acid homology with the Helicobacter pylori plasminogen-binding protein [43]. This novel association is discussed in further detail below. The role of the complement system in mediating AIP remains poorly understood. There are reports of elevated serum immune complexes and reduced total complement levels (C3 and C4). Interestingly, these immune complexes have largely been IgG1. It is has been postulated that IgG4 may function to clear these IgG1 complexes or may serve to dampen the cellular response by binding to Fc receptors and preventing immune activation [44].

Cellular immune system In the last two decades, our knowledge of the variability in disease phenotype due to T-cell response has been developed. Compared to patients with alcohol or gallstone pancreatitis, increased peripheral blood and pancreatic T-cell densities have been noted in patients with AIP [45]. Some data support variations in specific helper T-cell populations (TH1 or TH2) [46]. The TH2 response, characterized by IL-4 secretion, seems to dominate over the TH1 Response (gIFN and IL-2 pathways) amongst patients with biliary tract involvement with AIP [47,48]. Whether this holds true for other subsets (i.e. extrapancreatobiliary disease) remains to be seen.

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Microbial exposure Molecular mimicry has long been considered a fundamental putative mechanism across many autoimmune conditions including inflammatory bowel disease, diabetes mellitus, and multiple sclerosis [49]. The central idea of molecular mimicry involves cross immunoreactivity between microbial antigens and endogeneous proteins. Data has demonstrated a potential link between Helicobacter pylori and AIP [50,51]. Note has been made of amino acid homology between human carbonic anhydrase II and the a-carbonic anhydrase of Helicobacter pylori [52]. Furthermore, this peptide appears homologous to the binding motif of the DRB1*0405 HLA molecule, raising the possibility that genetically predisposed individuals may harbor unique sensitivity to the development of AIP in the setting of Helicobacter pylori exposure. More recently, an Italian group evaluated serum from 35 patients with AIP and 70 patients with pancreatic cancer [43]. Serum was careened against a random peptide library. A specific peptide sequence was identified with high affinity to AIP sera. This peptide (known as peptide ‘AIP1–7’) was noted to have amino acid homology to the plasminogen-binding protein (PBP) of Helicobacter pylori and with ubiquitin-protein ligase E3 component n-recognin 2 (UBR2), an enzyme highly expressed in acinar cells of the human pancreas. The antibody test was positive in 33 of 35 patients with autoimmune pancreatitis (94%) and in 5 of 110 patients with pancreatic cancer (5%). This exciting development needs to be validated in larger populations but may pave the way for additional studies in novel antibody detection techniques and in furthering the idea of microbial exposure and antigenic mimicry as a pathogenetic mechanism in AIP. Clinicopathologic spectrum There is little data on the global incidence and prevalence of AIP. Virtually all of data regarding epidemiology comes from Japan. The estimated prevalence is 0.8/100,000 prevalence, and it is believed to account for 5–6% of all patients with chronic pancreatitis [53]. The prevalence in the United States is unknown. Data from a surgical series in which there 1808 pancreatic resections from 2003–2005, demonstrated a frequency of AIP of 2.4% [54]. A Mayo series of 245 pancreatic resections for benign indications found the frequency of AIP to be 11% [55]. The clinical spectrum of AIP has evolved since the initial description by Sarles in 1961 [4]. There is now growing data that two distinct subtypes (type I AIP and type II AIP) exist, each with a different clinical phenotype and histopathologic fingerprint [42,56–58]. Futhermore, the concept of an ‘IgG4related systemic disease’ has developed to encompass the vast array of extrapancreatic manifestations often seen in patients. In this regard, AIP is now considered the pancreatic manifestation of a systemic fibroinflammatory disease which affects not only the pancreas but other organs including the bile duct, salivary glands, retroperitoneum, lymph nodes, and others (kidneys, lungs) [59,60]. Type I AIP Type I AIP – clinical manifestations Type I is the classical form of AIP described in the initial series out of Japan. In Western series, the majority of patients are men (62–83%) and over the age of 50 (70%) and present with mild abdominal pain often in association with acute obstructive, jaundice [40,42,58]. A small subset of patients may present with acute pancreatitis, or chronic pancreatitis with features of exocrine insufficiency and pseudocysts [2,61]. Relapsing acute pancreatitis and abdominal pain seems to be uncommon in adults and may seen more often in pediatric cases of AIP [62,63]. Weight loss is seen in up to 40% of patients, and tends to develop over weeks to a few months, often raising concern for neoplasia [42]. As many as 50% will present with acute glucose intolerance, and this too appears to respond well to corticosteroid therapy [64]. Extrapancreatic manifestations are the hallmark of type I AIP, with over half of patients having some form of systemic involvement. The most common of these including mediastinal adenopathy, biliary tree (intra- and extrahepatic bile ducts and gallbladder), salivary and lacrimal involvement (Sjogren’s- like syndrome), thyroiditis (Hashimito’s and Riedel’s), and retroperitoneal

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fibroinflammatory masses [65–67]. Hamano reported on the frequency of these manifestations among 64 patients with AIP [68]. This group found hilar adenopathy in 80%, biliary tree involvement in 73%, sjogren’s- like syndrome in 39%, thyroiditis in 22% and retroperitoneal extension in 13%. The Sjogren’s like syndrome is somewhat unique in that it primarily affects women (AIP alone is Male>Female). It appears to be different than Sjogren’s syndrome (SS) in several aspects: not associated with rheumatoid arthritis or the classic SS-A or SS-B autoantibodies. As with AIP alone, it appears to respond well to corticosteroid therapy [69,70]. Well documented examples of other site of organ involvement include: kidneys (focal renal masses and tubulointerstitial nephritis), liver (focal masses), mediastinum (lymphadenopathy and pericarditis), lungs (focal masses and interstitial pneumonitis), aorta (aortitis) and eyes (orbital pseudotumors). Mucosal involvement of the ampulla and stomach has also been described [1–3,71–73]. In addition to these extrapancreatic manifestations, AIP has been found in association with a number of other conditions including myelodysplastic syndrome, SLE, and IBD [74–77]. All of the previously described autoantibodies may be seen in Type I AIP. Hypergammaglobulinemia with selective elevation in IgG4 is seen in the majority of patients from Japan, but only in 44–76% of patients from US surveys [40,42]. Serum IgG4, ANA, and RF are most often measured as part of the evaluation of patients suspected to have AIP. Although elevated in 90%, ALF and ACA-II antibodies are rarely part of the typical serologic screen. Approximately 20% of patients with AIP may have a CA 19-9 level in excess of 100 mg/dL, mostly due to the associated cholangiopathy [41,78]. Nonetheless, this may confuse the clinical picture and may make distinguishing malignancy even more challenging. Type I AIP – imaging All of the traditional forms of cross-sectional abdominal imaging (ultrasound, computed tomography, and magnetic resonance imaging) have been evaluated in AIP [79]. None alone are diagnostic of AIP, but in combination with the appropriate clinical and serologic setting, may provide for a high enough degree of suspicion to recommend initiation of a corticosteroid trial. Transabdominal ultrasound, the least sensitive and specific, may identify intra- and/or extrahepatic biliary dilation and a diffusely edematous pancreas. Multidetector, contrast-enhanced computed tomography (MD-CT) has become the gold standard for imaging in AIP, with an estimated overall diagnostic accuracy of 85% [80,81]. The key features include diffuse enlargement of the pancreas with loss of normal lobularity (giving an appearance referred to as the ‘sausage pancreas’) (Fig. 1). There may overall decreased enhancement of the pancreas with a surrounding ‘halo’ of peripheral rim enhancement on delayed phases of imaging. The latter, also known as the ‘saran wrap’ sign is indicative of a proteinacious edema around the pancreas. Pancreatic tail involution may be seen. The bile ducts may show wall enhancement due to the brisk inflammatory infiltrate, whereas the pancreatic duct is typically diffusely narrowed in the background of an often large, edematous pancreas. Segmental dilation of the pancreatic duct in association with a low density focal mass is distinctly uncommon, although may be seen in classic focal pancreatic pseudotumors. The suspicion for neoplasia clearly remains high in these cases, and many of these patients may go on to pancreatic resection to confirm the diagnosis. Uncommon findings which may be seen late in the phase of disease (post acute phase) may include pseudocysts, parenchymal atrophy and calcifications, and vascular involvement. In the study of 26 AIP patients from the University of Pitttsburgh, 23% of patients were found to have involvement of major peri-pancreatic vasculature, including encasement and thrombosis of splenic vessels, splenic infarction secondary to splenic vascular involvement, and occlusion of the confluence between superior mesenteric, portal, and splenic veins. Hypercoagulable workup in all of these patients was negative. Furthermore, vascular findings were more common in patients who had a mass in the pancreatic tail or diffuse pancreatic enlargement. splenic vein thrombosis. Some of these patients developed complications including upper gastrointestinal bleeding from varices or portal hypertensive gastropathy. MRI shares many of the key features of MD-CT [82,83]. In addition to an expanded pancreatic parenchyma and diffuse>segmental pancreatic ductal narrowing, the T1 signal intensity of the pancreas is reduced and the T2 signal intensity of the pancreas is increased, both consistent with inflammation.

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Fig. 1. Typical CT scan in AIP. Note the presence of an enlarged tail with surrounding edema.

Positron emission tomography with 18FDG has been formally evaluated in AIP in limited fashion. Matsubayashi evaluated 13 patients with AIP, with 11/13 being evaluated before and 3 months after steroid therapy [84]. In all 13 cases of AIP, a moderate to intense level of FDG accumulation was recognized in the pancreatic lesion before steroid therapy. Of 13 patients, 11 (84.6%) showed FDG accumulation in the multiple organs, such as mediastinal and other lymph nodes, salivary gland, biliary tract, prostate, and aortic wall. In 11 patients who underwent PET before and after steroid therapy, FDG accumulation was diminished in almost all systemic lesions, with a mean of maximum standardized uptake value in the pancreatic lesion from 5.12 to 2.69. Reduction in PET activity correlated well with clinical response and IgG4 levels. The authors concluded that whole-body 18FDG-PET may be useful for detecting AIP, associated extrapancreatic lesions and for monitoring disease activity. Lee examined the utility of 18F-FDG PET/CT for differentiation of autoimmune pancreatitis with atypical pancreatic imaging findings from pancreatic cancer [85]. In this study, 17 patients with autoimmune pancreatitis and atypical pancreatic imaging underwent integrated PET/CT. The PET/CT findings on the 17 patients with autoimmune pancreatitis were compared with those of 151 patients with known pancreatic cancer. 18F-FDG uptake by the pancreas was found in all patients with autoimmune pancreatitis and in 82% (124/151) of patients with pancreatic cancer. Diffuse uptake by the pancreas was significantly more frequent in patients with autoimmune pancreatitis (53% vs 3%, p < 0.001). FDG uptake by the salivary glands and kidneys was seen only in patients with autoimmune pancreatitis, the former reaching statistical significance (p ¼ 0.003). Follow-up PET/CT after steroid therapy was performed for eight patients with autoimmune pancreatitis. After steroid therapy, none of the patients had intense FDG uptake by the pancreas or extrapancreatic organs. Although not recommended as part of routine imaging, it appears that 18F-FDG PET/CT may prove useful in a subset of patient with atypical clinical and radiologic findings in regards to differentiating AIP from pancreatic neoplasia. Advances in endoscopic imaging techniques with endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS) have led to their routine use in the diagnosis and evaluation of most forms of pancreatobiliary disease. ERCP remains the gold standard modality for obtaining high quality direct ductal imaging and for sampling the ducts and/or ampulla. Classic

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findings include biliary strictures (single or multifocal, intra- and/or extrahepatic). The most common lesion is a smooth, short intrapancreatic portion extrahepatic bile duct stenosis [1–3,86]. However, cholangiographic findings may mimic those of PSC (primary sclerosing cholangitis) with diffuse multifocal biliary strictures, or those of frank malignancy (cholangiocarcinoma, pancreatic neoplasia). Direct pancreatic access and ductal imaging is critical in the endoscopic evaluation and may help differentiate AIP from pancreatic neoplasia. The most common finding at direct pancreatography is a diffusely narrowed main pancreatic duct. Closer examination often demonstrates a diffusely beaded duct. Focal segmental dilation is uncommon but may be seen in cases of pancreatic pseudotumors. Significant mucin extrusion is uncommon and should raise suspicion for pancreatic neoplasia. Because of the close relationship of the pancreas to the stomach and duodenum, EUS has emerged as the most accurate imaging modality for the diagnosis of pancreatic disease. It has become a central imaging test in patients with obstructive jaundice in which the main differential diagnosis is AIP vs malignancy. Direct sampling of the pancreas via EUS-guided fine-needle aspiration (FNA) or core biopsy has proven to be an important part of this evaluation and may be diagnostic enough to avoid surgery and initiate appropriate corticosteroid therapy in a subset of patients. Farrell described the EUS morphology of autoimmune pancreatitis in 14 patients. The three most common features included a diffuse hypoechoic expansion of the pancreas (57%), a focal mass (43%), and lymphadenopathy (43%). In 21% of patients, evidence of vascular encasement was found. A subset of patients may demonstrate thickening of the bile duct wall and peripheral rim like edema. The main pancreatic duct can be focally or diffusely compressed by the enlarged parenchyma in the diffuse form of autoimmune pancreatitis. On the contrary, upstream dilatation of the main pancreatic duct is possible in the focal form [88]. Cleary, overlap with findings typical of neoplasm (mass and vascular encasement) makes EUS morphology alone an imperfect modality for evaluating AIP. To further evaluate this, Hoki compared EUS features in patients with AIP (n ¼ 25) and pancreatic carcinoma (n ¼ 30) using the conventional parenchymal and ductal EUS criteria for chronic pancreatitis. They showed that few features of chronic pancreatitis can be seen in autoimmune pancreatitis. Frequencies of diffuse hypoechoic areas, diffuse enlargement, bile duct wall thickening (typically a homogenous thickening characterized by hyperechoic–hypoechoic–hyperechoic echotexture of the bile duct wall), and peripancreatic hypoechoic margins were significantly higher in AIP than in neoplasia. Many of these features resolved after steroid treatment. In regards to characteristic bile duct wall thickening, EUS was found to superior to ultrasonography and CT; this EUS finding was significantly more frequent in autoimmune pancreatitis than in pancreatic cancer (53% versus 6%) [89]. Recently, sonoelastography has been used to try to further help distinguish AIP from pancreatic neoplasia. Contemporary EUS image processors may now include this module to assess the elastic properties of the tissue. Sonoelastography has been used in the evaluation of benign and malignant lymph nodes and pancreatic disease and preliminary data are promising [90,91]. Dietrich performed a prospective evaluation of five patients with AIP to investigate the role of this new technique in the characterization of mass lesions caused by AIP, with histology as the gold standard [92]. All five patients with AIP demonstrated a characteristic stiff elastographic pattern not only of the mass lesion but also of the surrounding pancreatic parenchyma, which was not found in 17 patients with ductal adenocarcinoma and 10 healthy subjects. This preliminary data clearly shows promise for sonoelastography and further data utilizing this technique in larger patient cohorts are expected.

Type I AIP – pathology The majority of patients (80%) have pancreatic head involvement and the gland feels firm and rubbery (Fig. 2). The classic histologic features of type I AIP are those initially described for lymphoplasmacytic sclerosing pancreatitis (LPSP), including a dense periductal lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative endothelitis [93–95]. (Fig. 3) IgG4 immunostaining of tissue (pancreatic or extra-pancreatic organ) provides strong adjunctive evidence of AIP and is seen in the majority of patients with type I AIP even at times when serum levels may be within normal limits [72,73].

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Fig. 2. Gross pathology specimen of AIP in the head of the pancreas. Note the small narrowed pancreatic duct.

Clearly, histopathology of pancreatic or hepatobiliary specimens has remained the gold standard for the diagnosis of AIP. In recent years, efforts to identify the diagnosis pre-operatively have been evaluated in the form of endoscopic biopsy. Fine-needle aspiration via EUS guidance has been shown to have poor sensitivity and specificity. Deshpande evaluated 16 patients with AIP (11 of whom went onto surgery), 16 patients with chronic pancreatitis, and 19 patients with pancreas adenocarcinoma [96]. The EUS-FNA cytology was compared to final surgical pathology for measure of accuracy. None of the 16 AIP patients were correctly diagnosed pre-operatively on the basis of cytology. Half of patients demonstrated atypical cytology, 30% had nondiagostic specimens, and 20% were falsely positive for neoplasm including solid pseuodpapillary neoplasm, mucinous cystic neoplasm, and adenocarcinoma. In retrospect, the characteristic cytopathologic findings of stromal fragments with imbedded, high cellularity (>30 per 60 field) lymphoplasmacytic infiltrate, could be seen in 37.5% of AIP EUS-FNA specimens, and in 12.5% of carcinoma cases, and 0% of chronic pancreatitis cases. The authors concluded that the presence of stromal fragments of high cellularity with a lymphoid infiltrate in conjunction with clinical and radiology findings could potentially both establish a diagnosis of AIP and exclude carcinoma, thus preventing pancreatic resection. In an attempt to further improve upon the pre-operative diagnostic yield of EUS, authors from the Mayo Clinic demonstrated the utility of EUS-guided core biopsy of the pancreas using a Trucut biopsy (TCB) technique. Levy evaluated EUS-TCB in 3 patients with obstructive jaundice and suspected autoimmune pancreatitis [97]. In each case, a diagnosis of pancreatic cancer also was considered, and surgical resection was the planned therapy before the patient underwent EUS-TCB. Histologic review of the TCB specimens established the diagnosis of AIP in two patients and identified nonspecific changes of chronic pancreatitis in the third patient. EUS-guided FNA was performed in two of the 3 patients and failed to establish the diagnosis in either patient. Other than mild transient abdominal pain (n ¼ 1), no complications were identified. Mizuno compared the utility of EUS-FNA and TCB in fourteen patients with suspected AIP based on imaging studies [98]. Patients underwent both EUS-guided fine-needle aspiration (FNA) and EUS-TCB for diagnosis of AIP and exclusion of pancreatic cancer. Pathologically, AIP was defined as

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Fig. 3. (a–c) Histology of autoimmune pancreatitis. Note the presence of lympho-plasmacystic cellular infiltrates in the low, medium, and high power microscopy (a, b, c, respectively).

lymphoplasmacytic sclerosing pancreatitis (LPSP), and sub-divided into two types: definite LPSP (dLPSP) showing full spectrum of LPSP and probable LPSP (p-LPSP) without obliterative phlebitis or abundant (>10 cells/hpf) IgG4-positive plasmacytes infiltration. The authors reported that carcinoma was excluded in all patients. EUS-FNA was diagnostic of AIP in 3/8, normal in 1/8, and 4/8 were inconclusive. One of six with non-autoimmune pancreatitis was diagnosed as p-LPSP on EUS-FNA, one as idiopathic chronic pancreatitis (ICP) and four were inconclusive. By using EUS-TCB, all AIP patients were diagnosed as LPSP (4 d-LPSP and 4 p-LPSP). No complications were identified in any patient with either EUS-FNA or TCB. The experience with the TCB technique has been limited to centers with expertise in the use of Trucut pancreatic biopsy under EUS guidance. Despite the good outcomes in these studies, concern remains for the widespread adaption of this technique as it may be technically difficult to perform in

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the head of the pancreas (due to angulation of the scope in the first portion of the duodenum), and the true safety of this biopsy technique remains uncertain in larger patient populations (risk of pancreatitis, bleeding). Two additional endoscopic techniques have been described for the accurate pre-operative diagnosis: ampullary biopsy and intraductal bile duct biopsy. Alexander reported two case reports of patients correctly diagnosed with AIP using a endoscopic forcep at the time of ERCP in the evaluation of obstructive jaundice [99]. Endoscopic forcep biopsy of the bile duct stricture demonstrated a dense IgG4þ lymphoplasmacytic infiltrate and led to the initiation of corticosteroid therapy. Endoscopic forceps biopsy of the major duodenal papilla may also provide a diagnostic specimen. Kamiswama et al. (GIE 2008) compared papilla biopsy from 10 patients with AIP, 10 patients with pancreas adenocarcinoma, and 10 patients with papillitis [100]. In 80% of the AIP patients, there was involvement of the head of the pancreas. In this subset of patients, a significant (>10/high power field) IgG4þ infiltrate was found in all patients. Only 1/10 carcinoma patients had moderate (4–9/high power field), and none of the patients with papillitis demonstrated more than rare IgG4þ cells. The authors concluded that endoscopic major duodenal papilla biopsy may provide high diagnostic yield among patients with pancreatic head involvement with AIP. This technique is simple and may be done at the time of ERCP or EUS evaluation of patients with suspect AIP.

Type II AIP Much less is known about type II AIP, also referred to as idiopathic ductocentric pancreatitis [101]. From some Western studies, it appears to represent 37–45% of cases [94,102]. At the present time, histopathology remains the main differentiator of this type of AIP. The classic finding is an exuberant ductocentric granulocytic infiltration (known as the granulocyte-epithelial lesion or GEL) [103]. Obliterative endothelitis is not seen. Type II AIP does appear to have a different clinical phenotype than Type I AIP [104]. In contrast to type I patients, type II patients appears to be younger at presentation (4th decade) and there is equal predilection among men and women. IgG4 (both in serum and tissue) is less prevalent. Patients may present with obstructive jaundice or focal pancreatic duct strictures with or without a discrete mass. The classic extrapancreatic manifestations of type I AIP are usually not seen with the exception of an increased association with inflammatory bowel disease in up to 30% [102,104]. The true short and long term efficacy of corticosteroids in this group is not well documented as many of these patients will undergo surgical resection early in the disease presentation in order to confirm the diagnosis. Diagnostic criteria To improve on the pre-operative diagnostic accuracy of AIP and to facilitate uniform research criteria, investigators from Asia and the US have developed several classification schemes based upon the clinical and pathologic findings [105]. These have included the Japanese Pancreas Society (I and II), the South Korean classification system, and the HISORt criteria from the Mayo Clinic [106–109]. The Japanese Pancreas Society first put forth four diagnostic criterion in 2002, including (1) radiologic imaging showing diffuse enlargement of the pancreas and diffuse irregular narrowing of the main pancreatic duct (more than one-third the length of the entire pancreas); (2) laboratory data demonstrating abnormally elevated levels of serum gammaglobulin or IgG, or the presence of autoantibodies, and (3) histologic examination of the pancreas showing lymphoplasmacytic infiltration and fibrosis. The diagnosis of AIP is made when either all 3 criteria are present or criterion 1 together with either criterion 2 or criterion 3 is present. This was later revised in 2006 to include segmental pancreatic involvement (eliminating the crtiterion of more than one-third of the pancreas), elevation of the serum IgG4 level as a diagnostic factor and also stressed the need to exclude malignant diseases such as pancreatic or biliary cancers, before making the diagnosis of AIP. The Korean criteria (2006) stratified the strength of the evidence for AIP into ‘‘definite,’’ ‘‘probable,’’ and ‘‘possible.’’ In addition to the Japanese criteria, the Korean criteria include the patient’s response to corticosteroid therapy and the presence of extrapancreatic lesions as diagnostic criteria. Chari et al. (Mayo Clinic, 2006) developed the

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HISORt system. This classification scheme categorizes patients into one of three groups: A: diagnostic pathology, B: typical imaging and serology, and C: response to corticosteroids. At the present time, the two main classification systems are the Asian consensus criteria and the Mayo HISORt criteria [110,109]. The Asian Consensus Criteria were developed out of the Japan-Korea Symposium on Autoimmune Pancreatitis and involved three categories: imaging, serology, and pathology. I-1. Imaging studies of pancreatic parenchyma show a diffuse/segmental/focally enlarged gland, occasionally with a mass and/or a hypoattenuation rim. I-2. Imaging studies of pancreaticobiliary ducts show diffuse/segmental/focal pancreatic ductal narrowing, often with stenosis of the bile duct. (Both I-1 and I-2 are required for diagnosis). II. Elevated level of serum IgG or IgG4, and detection of autoantibodies. III. Common lymphoplasmacytic infiltration and fibrosis, with abundant IgG4-positive cell infiltration. AIP should be diagnosed when criterion I and one of the other two criteria are satisfied, or when histology shows the presence of lymphoplasmacytic sclerosing pancreatitis in the resected pancreas. A diagnostic trial of steroid therapy can be applied carefully by expert pancreatologists only in patients fulfilling criterion I alone with negative diagnostic workup results for pancreatobiliary cancer. Although the diagnostic criteria appear to merging towards uniformity, some major differences among the algorithms remain. Ductal imaging by ERCP is mandated by the Asian Consensus as compared to any form (ERCP or MRCP) of ductal imaging by HISORt. The HISORt criteria also allow for the use of core or endoscopic forcep biopsy to provide a diagnostic specimen whereas the Asian Consensus permits only surgical pathology. Response to corticosteroids has been included now in all of the diagnostic schemes. Clearly none of the currently published diagnostic schemas are able to identify all patients with AIP. In particular, some Type II AIP patients may not fulfil criterion for diagnosis. Good clinical judgment with short term follow-up remains central to correctly classifying patients, and there is a clear need to identify and develop better biomarkers that encompass all forms of AIP. Nonetheless, these algorithms serve as important frameworks for both clinical and research purposes for how to evaluate such patients who present with features suggestive of AIP. Treatment Oral corticosteroid therapy remains the mainstay of medical therapy of AIP and as noted above, a rapid response to therapy, has developed as a major criterion for the diagnosis of AIP [1–3]. (Fig. 4) Spontaneous remission has been documented but usually on a greater time interval as compared to those patients undergoing active corticosteroid therapy [111]. Unfortunately, there are few prospective, randomized trials evaluating different dosing regimens. Largely on the basis of case series from Asia, most authors recommend an initial starting dose of 30–50 mg (0.5–0.6 mg/kg/day) prednisone on given once daily for four weeks followed by a taper of 2.5–5 mg/week. Most patients demonstrate marked improvement in both imaging (particularly the appearance of distal bile duct strictures and the expanded pancreatic parenchyma on CT scan) and IgG4 levels within 2 weeks, with resolution in many at 4 weeks from initiation of therapy [112–115]. In fact, a poor response at 2 weeks should alert the clinician of an alternative diagnosis such as malignancy or non-AIP chronic pancreatitis. From 2004 to 2007, Moon consecutively evaluated 22 patients with atypical features of AIP. Patients were challenged to undergo 2 weeks of corticosteroid therapy (0.5 mg/ kg of oral prednisolone per day) [116]. After the 2-week steroid trial, steroid responsiveness was assessed based on a marked improvement of narrowing of the main pancreatic duct and a reduction of the pancreatic mass. The steroid trial was continued in the case of positive steroid responsiveness, whereas surgical exploration was conducted in the case of negative steroid responsiveness. The final diagnosis was made by surgical exploration or long term clinical and radiological follow-up. All patients (n ¼ 15) who responded to steroids were diagnosed as having AIP, whereas all patients (n ¼ 7) who did not show a response to steroids were confirmed as having pancreatic cancer. Complete resection was possible in all (6/6; 100%), except one individual who refused surgery. The authors concluded a 2-week corticosteroid trial and subsequent assessment of its response may be helpful in confirming the diagnosis of AIP without negative consequences for resectable pancreatic cancer. However, they advocated that a corticosteroid trial should be performed carefully and only by specialists in pancreatology. Although this diagnostic and therapeutic algorithm has been challenged,

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Fig. 4. Diagnostic and therapeutic algorithm for patients suspected of having AIP.

many expert centers incorporate this practice into the evaluation and management of atypical AIP patients [117,118]. In many Asian series, patients remain on low dose corticosteroids therapy for months and potentially indefinitely to prevent relapse. This has not been the case in the US experience where patients are tapered to off within 2–3 months [40,42]. Despite initial reports of uniform long term success with one time therapy with corticosteroids, relapse rates up 40% on withdrawal are now well documented [104,119]. Relapse patterns may be seen clinically (weight loss, glucose intolerance, jaundice), radiologically (recurrent bile duct strictures or pancreatic edema), or serologically (recurrent IgG4 elevation). It is known that those patients with IgG4-associated cholangiopathy (i.e. proximal extrahepatic and intrahepatic ducts), higher IgG4 levels, extrapancreatic manifestations, focal or Type II AIP pattern, and those who smoke have higher relapse rates [104,120]. At the present time, there is no consensus on how to manage AIP relapse. Most experts will reinitiate therapy with corticosteroids. On withdrawal, some advocate for include long term corticosteroid. However, based upon the collective experiences with other autoimmune conditions such as IBD, RA, and SLE, the associated risks of long term corticosteroid therapy (glucose intolerance, osteoporosis, cataracts, weight gain, skin fragility, psychomotor) will likely outweigh the benefit in most patients. There are few reports regarding the use of non-corticosteroid based immunomodulators in patients with relapsing AIP. Azathioprine, mycofenalate mofetil (cellcept), cytoxan, and ritixumab have all been reported. The largest experience is with azathioprine, dosed at 1–2.5 mg/kg/day. Church evaluated eleven AIP patients who were followed for relapse [113]. They were treated with corticosteroids for 2–3 months (0.5 mg/kg/day) and then a slow taper. At 18 months follow-up, 6/11 had relapsed on corticosteroid taper. Of 6 patients treated with azathioprine (1–2 mg/kg/day), four noted improvement. Ghazale evaluated 53 patients with AIP for relapse, thirty of whom were treated with corticosteroids, eighteen surgically managed, and five with observation only [120]. Fifty-three percent of the medically treated relapsed following steroid withdrawal, as did 44% of the surgically treated patients (median 38.5 months). Various salvage regimens including corticosteroids (all surgical patients), azathioprine (2–2.5 mg/kg/day), mycophenolate mofetil 750 mg bid, and cytoxan were used in these patients.

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Fifteen patients treated with steroids for relapse after steroid withdrawal responded. Of these, 7 patients were placed on additional immunomodulatory drugs and remain in steroid-free remission at a median follow-up period of 6 months. Sandanaykes performed a prospective study of 28 patients with AIP from 2004–2007 [121]. The majority of these patients (23/28) demonstrated evidence of IgG4associated cholangiopathy (IAC). They noted relapse or failure to wean steroids in 46% (13/28). Patients with IAC demonstrated the highest risk for relapse. All relapses were treated with corticosteroids, and 10/13 were also given azathioprine (2 mg/kg/day). Seven of thirteen patients remain in remission on monotherapy with azathioprine at a median follow-up of 14 months. Dramatic responses to parenteral rituximab in patients refractory to corticosteroids and other immunomodulators has raised interest in the role of targeted B cell therapy [123,124]. Another question that remains to be unanswered is how to manage and follow patients prospectively who have undergone surgical treatment. In published series, relapse rates have been noted to be from 30 to 44% [104,120]. The use of ‘adjuvant’ corticosteroid and/or immunomodulatory therapy remains controversial. In addition, there are no clear guidelines on how to follow patients once surgery has been performed and the diagnosis of AIP has been made. One potential scenario is to monitor IgG4 levels, and follow cross-sectional imaging for pancreatobiliary or extrapancreatic recurrence.

Prognosis The long term prognosis of most patients with AIP is excellent as the vast majority respond consistently to pharmacologic therapy. Nonetheless, many patients appear to require long term management. A small subset of patients will be diagnosed in the chronic phase of AIP (chronic pancreatitis with or without exocrine insufficiency) and may require specific therapies for complication of this including enzyme replacement and/or management of specific complications such as pseudocysts or vascular thrombosis. A developing concept is that of AIP-associated carcinogenesis. It is well known that the risk of pancreatic cancer is significantly increased in patients with chronic pancreatitis. There are now several case reports of adenocarcinoma of the pancreas developing in patients with previously diagnosed and treated AIP [125,126]. To further support this association, Kamisawa documented significant K-ras mutations in the pancreas of all patients with AIP, and many of the bile duct and gallbladder specimens. The frequency of K-ras correlated with IgG4-related fibroinflammation. The authors concluded that autoimmune pancreatitis may be a risk factor of pancreatobiliary cancer. Finally, it is well known that serum IgG4 levels are elevated in approximately 10% of patients with pancreas adenocarcinoma [41]. It is uncertain if the serology is an epiphenomenon or whether these patients have undiagnosed underlying AIP. Clearly, given the implications for long term follow-up and surveillance, this observation bears further study in larger populations.

Future directions We have come a long way in our overall understanding of autoimmune pancreatitis since the initial reports of AIP by Sarles in 1961 [5]. We now have well defined clinical and histopathologic criteria, and fewer patients are subjected to surgical resection for characterization. Despite this, considerable gaps remain in our knowledge of the underlying pathogenesis and natural history of this condition. Identification of specific biomarkers (in addition to IgG4), and enhanced use and performance of pre-operative imaging and biopsy techniques will improve our classification of patients who present with typical and atypical AIP. There is a strong need to define the management strategy of those who relapse, and specifically address the role of immunomodulators and biologic therapies. In addition to progress in the long term pharmacologic management of patients, we may need to survey patients with AIP for increased pancreatobiliary neoplastic risk as we do in other forms of chronic pancreatitis. Given the overall rarity of this condition, this will likely best be performed through an international, multicenter clinical database and tissue repository.

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Summary        

AIP is now considered an IgG4-related systemic disease. Maintain a high clinical suspicion for AIP. IgG4þ tissue aggressively sought. Diagnose the disease before surgery! Steroid therapy is effective. Close follow-up for misdiagnosis and relapse. Long term immunomodulatory therapy likely in at least 30%. Pancreatic cancer may be an evolving long term risk of patients with AIP.

Conflict of interest None. References [1] [2] [3] [4]

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