Gastroenterol Clin N Am 37 (2008) 439–460

GASTROENTEROLOGY CLINICSOF NORTH AMERICA

Autoimmune Pancreatitis

Timothy B. Gardner, MD, Suresh T. Chari, MD*Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic, 200 First Street SW,Rochester, MN 55905, USA

Autoimmune pancreatitis (AIP) represents a unique subset of chronic in-flammatory pancreatic disease with distinct clinical, morphologic, andhistopathologic features that typically responds dramatically to steroid

treatment [1–3]. Named in 1995 by Yoshida and colleagues [4,5], the clinicalcharacteristics of the disease had been described as early as 1961. It took sev-eral decades for it to be accepted as a distinctive entity; in fact, as recently as2003, the American Pancreatic Association still debated its existence [6]. Inthe last 5 years, however, AIP has generated significant interest from cliniciansand researchers, resulting in a better understanding of its pathophysiology andclinical manifestations. Although still a rare disease, it is increasingly being rec-ognized and its existence is no longer in doubt.

This article details the full spectrum of AIP. It focuses on the history, defini-tion, and pathophysiology of this disease. Clinical, radiographic, and histologicfeatures are discussed as are the current diagnostic classification recommenda-tions. Finally, this article outlines current therapeutic approaches and suggestsfuture areas of study.

HISTORICAL MILESTONESAIP is a relatively newly characterized disease entity, with much of our knowl-edge gained in only the last decade. Sarles and colleagues [5] in 1961 were thefirst to describe an autoimmune phenomenon in relation to ‘‘sclerosis of thepancreas’’. Although treatment with immune-modulating therapy was not sug-gested at that time, this spurred interest in this entity over the next several de-cades. Several terms were then used to subsequently describe the disease,including ‘‘chronic sclerosing pancreatitis,’’ ‘‘lymphoplasmacytic sclerosingpancreatitis,’’ ‘‘nonalcoholic duct-destructive pancreatitis,’’ ‘‘sclerosing pancrea-titis,’’ ‘‘sclerosing pancreaticocholangitis,’’ and ‘‘autoimmune chronic pancrea-titis’’ [7–11].

In 1991, Kawaguchi and colleagues [12] described a variant of cholangitis ex-tensively involving the pancreas. This description was quickly followed by

*Corresponding author. Division of Gastroenterology and Hepatology, College of Medi-cine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail address: chari.suresh@mayo.edu (S.T. Chari).

0889-8553/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.doi:10.1016/j.gtc.2008.02.004 gastro.theclinics.com

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several other reports describing other organ involvement in patients who hadAIP [7,13–16]. Ito and colleagues [17] subsequently described the first threecases of AIP that were successfully treated with corticosteroids. In a seminalstudy published in 2001, Hamano and colleagues [10] reported that elevatedserum IgG4 levels were associated with sclerosing pancreatitis and that treat-ment with corticosteroid therapy successfully decreased these levels. The firstdiagnostic criteria were proposed by the Japanese Pancreas Society in 2001and subsequently modified in 2006 [18,19]. Chari and colleagues [1] in 2006proposed new diagnostic criteria, which included histologic, imaging, andserologic characteristics and other organ involvement and response tocorticosteroids.

DEFINITIONAIP has been defined as ‘‘the pancreatic manifestation of a systemic fibroinflam-matory disease which affects not only the pancreas but also various other or-gans including bile duct, salivary glands, the retroperitoneum and lymphnodes. Organs affected by AIP have a lymphoplasmacytic infiltrate rich inIgG4 positive cells and the inflammatory process responds to steroid therapy’’[1]. The systemic disease of which AIP is a manifestation has been called IgG4-related systemic disease (ISD) in recognition that all organs afflicted showa dense lymphoplasmacytic infiltrate rich in IgG4-positive cells [20]. The detec-tion of elevated serum IgG4 levels in 5% to 10% of subjects who do not haveAIP and tissue infiltration with IgG4-positive cells in more than 20% of pancre-atic cancer patients questions the pathogenic role of IgG4 in this systemic dis-order, however [21].

EPIDEMIOLOGYAlmost all data describing the epidemiology of AIP come from Japan. In 2002,Nishimori and colleagues [22] randomly surveyed Japanese hospitals on howmany patients they had who had pancreatitis in 2002 who fulfilled the diagnos-tic criteria for AIP as proposed by the Japan Pancreas Society. Based on thissurvey, the prevalence of patients who had AIP in Japan was estimated to be0.82 per 100,000. AIP was predominantly seen in men past middle age (olderthan 45 years). Other Japanese series have described the prevalence of diseasebetween 5% and 6% of all patients who have chronic pancreatitis [23,24].

The prevalence of AIP in the United States is unknown, because no exten-sive population-based studies have been performed. Because AIP often mimicspancreatic cancer in its initial presentation, the best estimates of prevalence ofAIP are in patients undergoing resection for presumed pancreatic cancer be-cause of obstructive jaundice or a pancreatic mass. In three recent studies, 43of 1808 (2.4%) pancreatic resections were reported to have lymphoplasmacyticsclerosing pancreatitis (LPSP) on histologic examination of the resected speci-men [8,25,26]. Another retrospective evaluation of 245 pathology specimensat the Mayo Clinic from patients who underwent resection for benign

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pancreatic disease revealed that 27 (11%) represented AIP with a ‘‘tumefactive’’presentation [27].

Males are nearly twice as likely as females to develop AIP and the averageage of onset is in the fifth decade [22]. In fact, 85% of patients are older than 50years of age. One study that has evaluated the clinical characteristics of youn-ger (less than 40 years old) patients who had AIP found that compared witholder patients, the young are more likely to present with features of abdominalpain and elevated amylase [28].

PATHOGENESISCurrently, the pathogenesis of AIP is unknown, although it almost certainly re-flects an immune-mediated process. Genetic susceptibility to AIP has beenlinked to both the HLA-DRB1*0405-DQB1*0401 in the class II and theABCF1 proximal to C3-2-11 telomeric of HLA-E in the class I regions [29].In addition, a recent report described the genetic association of Fc receptor-like 3 polymorphisms with AIP in Japanese patients [30].

The trigger for AIP remains elusive. It is hypothesized that HLA-DR anti-gens on the pancreatic ductal and acinar cells may serve as antigens recognizedby CD4þ producing interferon-c and CD8þ T lymphocytes, leading to subse-quent inflammation. Polymorphisms of the cytotoxic T lymphocyte-associatedantigen 4, a key negative regulator of the T-cell immune response, have beendemonstrated in patients who have AIP [31]. An etiologic role for antigenic Hel-icobacter pylori infection by way of molecular mimicry has also been proposed[32].

Like many immune-mediated diseases, AIP has been linked to many otherautoimmune conditions, such as Sjogren syndrome, retroperitoneal fibrosis,and primary sclerosing cholangitis (PSC) [3,33–38]. The work by Kamisawaand colleagues, however [39], has shown that these associated conditions arein fact manifestations of a new clinicopathological entity, IgG4-related systemicdisease (ISD) that is characterized by tissue infiltration with abundant IgG4-positive plasma cells. These associated conditions often mimic other well-known diseases. For example, unlike Sjogren syndrome, the salivary andlacrimal gland pathology associated with AIP, called chronic sclerosing sialade-nitis, is not associated with rheumatoid arthritis, is not usually associated withSSA and SSB antibodies, and responds to corticosteroids. In the past thiscondition has also been called Mikulicz disease [40] or Kuttner tumor [41]. Sim-ilarly, the biliary involvement in ISD has recently been termed IgG4-associatedcholangitis (IAC) [42] and may resemble cholangiocarcinoma or PSC [43].Other possible manifestations of ISD include Reidel thyroiditis and IgG4-asso-ciated nephritis [44]. Whether AIP is truly associated with any other distinctautoimmune disorder needs confirmation in case-control studies.

CLINICAL FEATURESMost patients who have AIP are male and older than 50 years [22,45,46]. Themale/female predominance is approximately 2:1 [47]. Female patients are more

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prevalent in the subset of AIP associated with parotid gland involvement, how-ever [35]. Although the age of onset is typically in the sixth decade, AIP hasbeen described in patients in their 30s [28]. Patients affected by AIP havebeen described in Eastern and Western first-world countries and in developingcountries. The authors have seen histologically proven AIP in many patientsfrom India and in Indian immigrants to the United States [23,48]. AIP hasalso been described as an incidental finding at autopsy [49].

AIP has diverse clinical presentations, which may be classified in relation toonset of disease as acute or late and by the organs affected as predominantlypancreatic or extrapancreatic presentations. The most common acute presenta-tion is with painless obstructive jaundice [15,47,50]. Very uncommonly pa-tients may present with typical acute pancreatitis. In the postacute phase AIPmay present or be incidentally discovered because of a persistent pancreaticmass, atrophic pancreas with or without calcification, or pancreatic steatorrhea.Although patients who have AIP may have radiologic evidence of pancreaticcalcification or atrophy, unlike in usual chronic pancreatitis it is painless.The pancreatic manifestations of AIP thus can mimic pancreatic cancer, acutepancreatitis, painless chronic pancreatitis, or unexplained pancreatic functionalinsufficiency.

The extrapancreatic manifestations are equally diverse and may be seensimultaneously with its pancreatic manifestations, may precede them, ormay occur many years later when the pancreatic disease may or may notbe symptomatic. The most common extrapancreatic organ involved is the bil-iary tree, wherein distal biliary involvement mimics pancreatic cancer–relatedstricture. More proximal involvement may trigger suspicion of cholangiocarci-noma or PSC. Other well-described manifestations include salivary glandinvolvement resembling Sjogren syndrome, mediastinal adenopathy resem-bling sarcoidosis, retroperitoneal fibrosis, and tubulointerstitial nephritis[16,44,51–53].

The acute presentation of AIP is with obstructive jaundice and it has re-ceived the most attention because it closely mimics the presentation of pancre-atic cancer. The inflamed gland can often have the appearance of a pancreatichead mass, suggesting pancreatic adenocarcinoma. In fact, before recognitionof AIP as a clinical entity, patients frequently underwent pancreatic resectionfor suspicion of pancreatic adenocarcinoma [6,27,46]. Current diagnostic crite-ria have significantly enhanced our ability to recognize AIP and the Japaneseand Korean diagnostic criteria are designed exclusively to diagnose AIP inthis setting and distinguish it from pancreatic cancer.

Jaundice is usually secondary to entrapment of the intrapancreatic bile ductin an inflamed gland [54–56]; however, a true IgG4-associated distal cholangi-tis is also seen on histology in some patients [57]. Although jaundice is themost common clinical symptom at presentation occurring in up to 80% of pa-tients, multiple other symptoms have been described, such as abdominal pain,back pain, recurrent vomiting, and weight loss [58,59]. Although described,acute or recurrent acute pancreatitis is a rare presenting complaint in AIP,

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and may be more common in younger patients [28]. Diabetes mellitus hasbeen reported at presentation in AIP and up to 50% of patients may presentwith glucose intolerance [6,60]. About half of patients treated with corticoste-roids have subsequent improvement in their glucose intolerance, and com-plete resolution of diabetes mellitus following treatment has been reported[61,62]. Virtually all patients who have AIP have narrowing of dorsal or ven-tral pancreatic ducts on pancreatography [63,64]. Idiopathic pancreatic steator-rhea should also prompt concern for AIP, especially in elderly males. Table 1summarizes the common, atypical, and rare clinical features encountered inAIP.

HISTOPATHOLOGYOn gross examination, the pancreas in AIP is often noted to be indurated andfirm [6]. Classically, the predominant histologic feature of AIP has been denseinfiltration of the periductal space with plasma cells and T lymphocytes. Asso-ciated with this infiltrate is acinar destruction, obliterative phlebitis involvingthe major and minor veins, and storiform or ‘‘whirling’’ fibrosis of the

Table 1Clinical features of autoimmune pancreatitis

Feature Typical (>50%)Less common(10%–50%) Rare (<10%)

Presenting complaint Obstructivejaundice

Abdominal pain,weight loss,diabetes,steatorrhea

Clinical acutepancreatitis,asymptomatic

Histology LPSP IDCP Extensive fibrosis,minimalinflammation

Pancreatic imaging Diffuselyenlarged glandwith delayedand rimenhancement,irregularnarrowedpancreatic duct

Parenchymalatrophy,intraductalcalcification

Pseudocyst

Serology Elevated serumIgG4 levels

Normal serumIgG4 levels

Other organinvolvement

Bile duct,kidneys,lymphadenopathy

Retroperitoneum,salivary gland

Mesenteritis,inflammatory boweldisease

Response to steroids Complete Incomplete Refractory to steroids

Abbreviation: IDCP, idiopathic duct-centric chronic pancreatitis.Data from Lara LP, Chari ST. Autoimmune pancreatitis. Curr Gastroenterol Rep 2005;7:101–6.

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pancreatic parenchyma, which can extend to contiguous peripancreatic soft tis-sue [47]. This constellation of histopathologic findings defines LPSP (Fig. 1)[12,65]. A less common histopathologic variant termed idiopathic duct-centricchronic pancreatitis is characterized by a neutrophilic infiltrate with occasionalmicroabscesses and rare obliterative phlebitis [9,27,47,66]. Nearly a third of pa-tients who have AIP develop pancreatic calcification and atrophy and the ap-pearance can resemble usual chronic calcific pancreatitis.

It is well accepted that AIP has a diagnostic pancreatic histology that distin-guishes it from usual chronic pancreatitis and pancreatic cancer. Additionally,the pancreas and other organs involved in AIP show abundant infiltration with

Fig. 1. Three examples of the predominant histologic features of LPSP in AIP. (A) Trucut biopsyof the pancreas demonstrating the dense infiltration of the periductal space with plasma cellsand T lymphocytes. (B) Obliterative phlebitis involving a major vein and storiform or ‘‘whirl-ing’’ fibrosis of the pancreatic parenchyma. (C) Abundant parenchyma infiltration withIgG4-positive plasma cells.

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IgG4-positive cells. Immunostaining pancreatic tissue for IgG4 positivity hasbeen shown to be a helpful adjunct in diagnosing AIP [67]. Pancreatic resectionspecimens show diagnostic histology in almost all patients who have AIP inwhom they are available. Histologic diagnosis of AIP requires preservationof tissue architecture, however, and hence fine-needle aspirates used to diag-nose pancreatic cancer are not suitable for diagnosing AIP. The use of endo-scopic ultrasound (EUS)–guided Trucut biopsy has emerged as an effectiveand safe tool for obtaining pancreatic biopsies in AIP [68,69]. When core biop-sies are obtained, the diagnostic sensitivity of pancreatic histology for AIP de-pends on the size of the tissue sample. For example, in a report from MayoClinic, only 7 of 16 (44%) subjects who underwent pancreatic core biopsyshowed the full spectrum of diagnostic changes of LPSP, and 15 of 16 (94%)patients had diagnostic IgG4 immunostaining [67]. The pancreas is often notuniformly involved by classic AIP features, however, and thus sampling errorcan occur [70], especially if visibly uninvolved areas are biopsied. In addition,staining of involved extrapancreatic tissues, such as the biliary tree, retroperi-toneum, and colon, has revealed IgG4 positivity in affected patients [71]. Atthis time, it is unclear whether pancreatic histology predicts disease severityor progression to endocrine or exocrine insufficiency.

IMAGING FEATURESCharacteristic cross-sectional and ultrasound imaging features have been welldescribed in AIP. Classically, the pancreatic parenchyma is diffusely enlarged,forming a sausage-shaped gland with featureless borders (Fig. 2) [1,58,72,73].Other classic features that may be present include delayed and prolonged

Fig. 2. Pancreas-phase CT scan from a patient who had untreated AIP demonstrating a dif-fusely enlarged (sausage-shaped) heterogenous pancreatic parenchyma. Note the relativelysmooth contour of the parenchymal border and the lack of an identifiable pancreatic duct.

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contrast enhancement, a rimlike capsule surrounding the gland on delayed en-hancement sequences (the hypoattenuation halo), a nondilated, ectatic pancre-atic duct, and the absence of peripancreatic fat hypoenhancement [47,74]. Ina recent study, dual-phase CT scans of 74 patients (25 AIP, 33 pancreatic ade-nocarcinoma, and 16 normal pancreas) were independently evaluated by threeradiologists blinded to clinical diagnosis [75]. Readers correctly identified 17 to19 of 25 AIPs (sensitivity 68%–76%) and overall accuracy was 81% to 85%. Theauthors concluded that dual-phase CT of the pancreas was moderately accuratein the diagnosis of AIP and in differentiating it from pancreatic carcinoma. Find-ings that were relatively specific for AIP included a diffusely enlarged pancreas,diffusely decreased pancreatic enhancement, and presence of a capsule-like rim,bile duct wall enhancement, and solid renal lesions.

MRI characteristically reveals enlargement of the pancreas with decreasedsignal intensity on T1-weighted MR images, increased signal intensity onT2-weighted MR images, and, occasionally, a hypointense capsule-like rim[76]. Magnetic resonance cholangiopancreatography (MRCP) is often helpfulin characterizing the pancreatic and bile ducts, although the narrowed segmentof the pancreatic duct is not well visualized. Narrowing of the anterior superiorpancreaticoduodenal artery, posterior superior pancreaticoduodenal artery,and transpancreatic artery on angiographic evaluation has also been describedin AIP patients [77].

Increasingly, endoscopic ultrasound has been used to evaluate patients forAIP [69,78,79]. Not only can the parenchyma and biliary and pancreatic ductsbe visualized, EUS also provides an opportunity to obtain Trucut biopsy sam-ples. Intraductal ultrasound can also be used to evaluate indeterminate biliarystrictures. Levy and colleagues [68] have reported on the diagnostic usefulnessof Trucut biopsy in three patients who had suspected pancreatic adenocarci-noma with planned surgical resection following indeterminate fine-needle aspi-ration. In two of the patients, AIP was diagnosed using Trucut biopsy; in theother chronic pancreatitis was diagnosed. In all patients, unnecessary surgerywas avoided.

Cholangiography has been shown to be an accurate method to differentiateAIP from primary sclerosing cholongitis (PSC). Nakazawa and colleagues [80]reported that bandlike stricture, beaded or pruned-tree appearance, and diver-ticulum-like formation were significantly more frequent in patients who hadPSC. In contrast, segmental stricture, long stricture with prestenotic dilatation,and stricture of the distal common bile duct were significantly more common insclerosing cholangitis with AIP. Increased uptake with whole-body (18)F-fluo-rodeoxyglucose positron emission tomography is seen in the pancreas and ex-trapancreatic lesions of patients who have AIP [81–83].

A characteristic feature of the acute presentation of AIP is that the pancreaticchanges improve, if not completely resolve, with corticosteroid treatment[1,84,85]. In our experience, failure of the pancreatic imaging to significantlyimprove after a 2- to 4-week course of corticosteroids should cast doubt onthe diagnosis of AIP (Fig. 3).

Fig. 3. Representative pancreatograms in the same patient obtained at ERCP demonstrating thepancreas pre (A) and post (B) treatment with 6 weeks of corticosteroids. Note the narrowed,ectatic pancreatic duct seen before treatment has completely normalized in appearance.

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SEROLOGYIncreased numbers of circulating immunoglobulins, specifically immunoglobu-lin subclass 4, are a hallmark of the disease [10,21,86]. In a landmark study,Hamano and colleagues [10] reported that serum IgG4 levels were highly(95%) sensitive and highly (97%) specific for AIP. In a recent study of 510 pa-tients from the United States [21] including 45 who had AIP, 135 who had pan-creatic cancer, 62 who had no pancreatic disease, and 268 who had otherpancreatic diseases, the sensitivity, specificity, and positive predictive valuesfor elevated serum IgG4 (>140 mg/dL) for diagnosis of AIP were 76%, 93%,and 36%, respectively. When using a cutoff of twice the upper limit of normalfor serum IgG4 (>280 mg/dL), the corresponding values were 53%, 99%, and75%, respectively [21]. In this study, 5% to 10% of non-AIP patient groups, in-cluding 10% of patients who had ductal adenocarcinoma, had elevated IgG4levels [21]. In addition, serum IgG4 levels, even in the presence of classic his-tologic findings of AIP, can be normal (Table 2) [58,87].

Elevated titers of many autoantibodies have been described in AIP. Autoan-tibodies against carbonic anhydrase II and IV and lactoferrin are detected inmost patients who have AIP [88–91]. Involvement of antinuclear and anti–smooth muscle antibodies has also been described [89,92]. Autoantibodies tothe pancreatic secretory trypsin inhibitor have been shown to be elevated innearly 50% of AIP patients compared with controls [93]. None of these autoan-tibodies have prediction characteristics that equal that of IgG4. Levels of totalIgG and gamma globulins are also increased in AIP. In our experience, how-ever, it is unusual to have elevated serum levels of IgG or gamma globulinswithout elevation of serum IgG4 levels. Although a combination of serumIgG4 levels and autoantibody titers of antinuclear antibodies and rheumatoid

Table 2IgG4 level in patients who have different diseases of the pancreas

AIPNormalpancreas

Pancreaticcancer

Benign pancreatictumor

Chronicpancreatitis

Numbera 45 62 135 64 79Mean IgG4 � SM 550 � 99 49 � 6 68 � 9 47 � 5 46 � 5Range 16–2890 3–263 3–1140 3–195 3–231Proportion

elevated >140 mg/dL76% 4.8% 9.6% 4.7% 6.3%

aBased on 510 patients referred to the Mayo Clinic for evaluation of pancreatic disease from January 2005through June 2006.

Data from Ghazale A, Chari ST, Smyrk TC, et al. Value of serum IgG4 in the diagnosis of autoimmunepancreatitis and in distinguishing it from pancreatic cancer. Am J Gastroenterol 2007;102(8):1646–53.

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factor modestly increases sensitivity, it also significantly reduces specificity.The authors do not routinely use autoantibody titers to diagnose AIP.

OTHER ORGAN INVOLVEMENTOther organs are often involved in AIP; their involvement may be diagnosedbefore, simultaneous with, or after the diagnosis of AIP. Biliary tract is in-volved in 60% to 100% of all patients presenting with AIP [1,51,55,59,63]and has recently been termed IAC [42]. IAC affects both intra- and extrahe-patic bile ducts, with the distal common bile duct being the most commonsite of involvement [94]. Biliary imaging may not necessarily reveal involve-ment, even when present microscopically [55,76]. Histologically, a lymphoplas-macytic infiltrate surrounds the bile ducts in a pattern similar to that seen in thepancreas and IgG4-positive staining is often present [42,47,95].

AIP coexisting with PSC has been described [96], although this is likely notprimary sclerosing cholangitis but IgG4-associated cholangitis. It has also beenshown that in a small proportion of patients who have aggressive PSC, serumIgG4 levels are elevated suggesting a possible role for corticosteroid therapy[47,95]. One should be cautious in diagnosing IAC simply based on elevatedserum IgG4 levels, however, because false-positive elevations may occur intrue PSC. IAC differs from PSC in that there is generally less intrahepatic in-volvement, the strictures can be transient under observation, the strictures areusually segmental, and patients are typically pANCA negative [47,97]. Inflam-matory bowel disease, which is present in 70% of PSC, is less common (6%) inIAC [98]. Analogous to the response seen in the inflammatory component ofpancreatic involvement, inflammation of the biliary tree typically responds tocorticosteroid treatment, although the specific response of each duct segmentis still being evaluated [99].

In addition to the biliary system, multiple other organs may be involved inISD [85]. Hamano and colleagues [51] reviewed the frequency, distribution,clinical characteristics, and pathology of five extrapancreatic lesions in 64

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patients who had AIP and found the most frequent extrapancreatic lesion washilar lymphadenopathy (80.4%), followed by extrapancreatic bile duct lesions(73.9%), lacrimal and salivary gland lesions (39.1%), hypothyroidism(22.2%), and retroperitoneal fibrosis (12.5%). No patients had all five typesof lesions. Patients who had hilar lymphadenopathy or lacrimal and salivarygland lesions were found to have significantly higher IgG4 levels than thosewho did not. Both intrinsic (tubulointestinal fibrosis) and extrinsic (hydroneph-rosis secondary to retroperitoneal fibrosis) renal disease have been associatedwith AIP, as has inflammatory pneumonitis and inflammatory pseudotumorof the liver [44,100–103]. Fig. 4 demonstrates some of the more common ex-trapancreatic manifestations associated with AIP.

Based on the significant degree of extrapancreatic disease and the associationwith IgG4 staining of tissues, the concept of an IgG4-related autoimmune dis-ease entity has been proposed by Kamisawa [39]. This distinct clinicopatho-logic disease process would encompass all IgG4 diseases, of which AIPwould be only one manifestation.

DIAGNOSTIC CRITERIAIn 1995 Yoshida and colleagues [19] reported a list of 12 features suggestive ofAIP, but stopped short of providing clinical criteria for its diagnosis. The firstdiagnostic criteria were proposed by the Japan Pancreas Society in 2002 andlater modified in 2006. These guidelines were developed to distinguish betweenAIP and pancreatic adenocarcinoma. To make the diagnosis of AIP based onthe Japanese guidelines, it is mandatory that findings on radiography be consis-tent with AIP. These findings include the presence of diffuse or segmental nar-rowing of the main pancreatic duct with irregular wall diagnosed by endoscopicretrograde pancreatogram and diffuse or localized enlargement of the pancreason abdominal ultrasonography, CT, or MRI. In addition, one of serologic(high serum c-globulin, IgG, or IgG4, or the presence of autoantibodies,

Fig. 4. Extrapancreatic manifestations of AIP demonstrated in a patient who had untreatedAIP. Retroperitoneal fibrosis (A, white arrow) and intrahepatic biliary dilatation secondary todiffuse inflammatory stricturing of the biliary system (B, white arrow) are shown.

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such as antinuclear antibodies and rheumatoid factor) or histologic (marked in-terlobular fibrosis and prominent infiltration of lymphocytes and plasma cellsin the periductal area, occasionally with lymphoid follicles in the pancreas) cri-teria are required to satisfy Japanese criteria for diagnosis of AIP. The Japanesecriteria do not take into account that AIP has unique histologic features, char-acteristic findings on IgG4 immunostaining of the organs involved, other organinvolvement, or response to steroids.

In 2006, Chari and colleagues [1] published an alternate set of guidelinesbased on the Mayo Clinic experience with AIP. These criteria, known bythe mnemonic HISORt, recognize characteristic features of AIP on pancreatichistology and imaging, serology, other organ involvement, and response to cor-ticosteroid therapy. Based on the HISORt criteria patients can be diagnosed asAIP if they fall into one of three groups: (A) diagnostic pancreatic histology orpresence of 10 or more IgG4-positive cells per high-power field (HPF) on im-munostain of lymphoplasmacytic infiltrate with storiform fibrosis; (B) typicalpancreatic imaging with elevated serum IgG4 �140 mg/dL, or (C) unexplainedpancreatic disease with negative workup for other pancreatic diseases, espe-cially malignancy, with elevated serum IgG4 levels �140 mg/dL or other organinvolvement confirmed by presence of abundant IgG4-positive cells, and reso-lution/marked improvement in pancreatic or extrapancreatic manifestationswith steroid therapy (Box 1). By including additional features, these criteriaidentify a wider spectrum of clinical presentations of AIP.

When the imaging features are typical and there is confirmatory serologic ev-idence of elevated levels of serum IgG4, the diagnosis of AIP is relatively easy. Itstill requires a radiologist familiar with the characteristic imaging features ofAIP, but that is a matter of education. In some patients, however, the radiologicfeatures are simply not diagnostic. In such patients a pancreatic biopsy can bea helpful adjunct to the diagnosis. The diagnostic gold standard for AIP is thepresence of LPSP with IgG4-positive immunostaining of pancreatic tissues[6,50]. The presence of the full spectrum of LPSP on histology requires core bi-opsy, however, because fine-needle aspiration is usually not sufficient to makethe diagnosis. Core biopsies can be obtained percutaneously with ultrasoundor CT guidance or by transmurally using EUS-guidance biopsy [68].

TREATMENTThe cornerstone of treatment of AIP is the use of corticosteroids with multipleauthors reporting dramatic response rates with prolonged therapy [1,10,104–106]. A word of caution, however, is that it is imperative to thoroughlyrule out other possible causes of pancreatic disease, most notably pancreaticmalignancy, before initiating corticosteroid therapy.

Although spontaneous remissions do occur in AIP, the use of corticosteroidsseems to hasten recovery and may prevent recurrences. There are several rea-sons, therefore, to initiate treatment of AIP with corticosteroids. For one, if thediagnosis remains in doubt and malignancy has been excluded, response to cor-ticosteroids can be a reasonable method of diagnosing AIP. The clinical

Box 1: Mayo Clinic HISORt criteria for the diagnosis of autoimmunepancreatitis

Diagnostic criteria

Histology

At least one of the following:

� Periductal lymphoplasmacytic infiltrate with obliterative phlebitis and storiform fibrosis

� Lymphoplasmacytic infiltrate with storiform fibrosis with abundant (�10 IgG4 cells/HPF)

Imaging

� Typical: diffusely enlarged gland with delayed rim enhancement, diffusely irregular,attenuated main pancreatic duct

� Other: focal pancreatic mass/enlargement, focal pancreatic ductal stricture, pancre-atic atrophy, calcification, pancreatitis

Serology

� Elevated serum IgG4 level (normal 8–140 mg/dL)

Other organ involvement

� Hilar/intrahepatic biliary strictures, persistent distal biliary stricture, parotid/lacrimalgland involvement, mediastinal lymphadenopathy, retroperitoneal fibrosis

Response to steroid therapy

� Resolution/marked improvement of pancreatic/extrapancreatic manifestation withcorticosteroid therapy

Diagnostic groupsa

Group A: diagnostic pancreatic histology

Presence of one or more of the following criteria:

� Specimen demonstrating the full spectrum of LPSP

� �10 IgG4 cells/HPF on immunostain of pancreatic lymphoplasmacytic infiltrate

Group B: typical imaging + serology

Presence of all of the following criteria:

� CT or MRI scan showing diffusely enlarged pancreas with delayed and rimenhancement

� Pancreatogram showing diffusely irregular pancreatic duct

� Elevated serum IgG4 levels

Group C: response to corticosteroids

Presence of all of the following criteria:

� Unexplained pancreatic disease after negative workup for other causes

� Elevated serum IgG4 or other organ involvement confirmed by presence of abundantIgG4-positive cells

� Resolution/marked improvement in pancreatic or extrapancreatic manifestations withcorticosteroid therapy

aPatients meeting criteria for one or more of the groups have AIP.Data from Chari ST, Smyrk TC, Levy MJ, et al. Diagnosis of autoimmune pancreatitis: the Mayo Clinic

experience. Clin Gastroenterol Hepatol 2006;4(8):1010–6.

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suspicion for AIP should be high before initiation of therapy, however, and pa-tients should be followed closely for any symptoms (eg, profound weight loss,anorexia, night sweats) more consistent with malignancy than AIP. Treatmentcan also be a means of reducing clinical symptoms from acute pancreatic (pan-creatic endocrine insufficiency, rarely acute pancreatitis) or extrapancreatic(jaundice from biliary strictures, sialadenitis) manifestations of disease[62,104,107–110]. In addition, there can sometimes be structural improvement,for example in the pancreatic duct, with corticosteroid therapy [56]. The degreeof structural response depends on the extent of fibrosis versus inflammation; pa-tients who have more inflammatory injury typically have a greater structural re-sponse and extensive fibrosis may not allow complete remission to occur [104].

The exact corticosteroid treatment protocol for patients who have AIP is notstandardized; however, most practitioners initiate therapy with between 30 and40 mg of prednisone daily. These doses are usually effective to induce remis-sion; it is unclear if starting at lower doses would be equally effective. Resolu-tion of symptoms is generally rapidly achieved within 2 to 3 weeks ofcorticosteroid initiation. It usually takes several weeks to months for evidenceof serologic (normalization of IgG4) or radiologic remission. Occasionally,because of fibrotic involvement of tissue, radiologic remission is not seen,especially in proximal biliary strictures resembling cholangiocarcinoma,intrahepatic strictures resembling PSC, and retroperitoneal fibrosis. Progres-sion toward normalization of serum IgG4 levels can be used to guide treatmentin these instances. Because histologic specimens are often difficult to obtain, wegenerally do not use histology as a marker for remission.

At the Mayo Clinic, we treat patients diagnosed with AIP with a prolongedsteroid taper. Patients are started on 40 mg/d of prednisone for 4 weeks. After4 weeks, their clinical response is gauged and repeat cross-sectional imagingand serologic evaluation are performed to check for response. If clinical, sero-logic, or radiographic response is documented, the prednisone dose is tapered 5mg/wk until gone. In patients in whom a biliary stent has been placed, this usu-ally can be removed at 6 to 8 weeks following initiation of therapy. IgG4 levelsare also followed and in patients who have AIP, a decrease in IgG4 (althoughnot necessarily normalization) should occur within 4 weeks of treatment initi-ation (Fig. 5).

Recently, in patients who present with jaundice because of biliary stricturingdisease who do not wish to undergo initial endoscopic retrograde cholongiopan-creatography with stent placement, we have occasionally treated with a largeinitial bolus of intravenous corticosteroids. Although our experience is limitedand at this time anecdotal, jaundice does seem to respond rapidly to this treat-ment, thus obviating the need for biliary stent placement. Further prospectivestudies are needed to determine if large initial doses of corticosteroids are aneffective alternative to initial biliary stent placement in newly diagnosed AIP.

Between 30% and 40% of patients have clinical or radiographic relapse fol-lowing treatment with prolonged corticosteroids requiring retreatment witha second prolonged course [1,43,84,107,111]. These relapses generally occur

Diagnosis of Autoimmune Pancreatitis

Start Prednisone 40 mg daily for 4 weeks

After four weeks, measure IgG4 and repeat imaging

Consider alternative diagnosis

Clinical response, decrease inIgG4 and/or improvement of

inflammation on imaging

No change in symptoms, IgG4level or improvement of

inflammation on imaging

Taper Prednisone 5 mg/weekuntil taper complete

Recheck IgG4 and imaging 4-6weeks following completion of

Prednisone taper

No symptoms, IgG4 andradiographic improvement

Clinical, biochemical orimaging relapse

Serial clinical follow-up (6months initially) and imaging

More than 1 relapse, initiatechronic suppressive

therapy*

Fig. 5. Algorithm for treatment of AIP. Recent data suggest that relapse following steroid with-drawal is likely in 70% of patients who have AIP who have proximal extrahepatic or intrahe-patic biliary strictures. Chronic immunosuppression is therefore recommended afterwithdrawal of first course of steroid. (Data from Ghazale A, Chari ST, Zhang L. Immunoglob-ulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology2008;134:706–15.)

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in the short term; data on long-term relapse are lacking. Relapse may be symp-tomatic, radiologic, serologic, or histologic. The presence of symptoms (recur-rent abdominal pain, weight loss, and so forth) is often a clue to relapse withinthe pancreas; only in the presence of symptoms is cross-sectional imaging re-peated. Serologic relapse alone can be seen in patients who do not have clinicalsymptoms or radiologic changes; whether or not this represents a subclinicaldisease relapse is unclear at this time. It is also unclear if certain types of organinvolvement are more prone to relapse than others. For example, Ghazale andcolleagues [43] found that in patients who had IAC treated with 11 weeks of

454 GARDNER & CHARI

corticosteroids, proximal biliary involvement (proximal extrahepatic and intra-hepatic biliary strictures) relapsed with a rate of 65% compared with a 25% re-lapse rate in those who had intrapancreatic stricturing of the distal common bileduct.

In a certain subset of patients who have relapse after a second prolongedcourse of steroids, either chronic prednisone therapy or use of another agent,such as azathioprine or 6-mercaptopurine, may be necessary. In Japan, it is of-ten standard of care to continue patients on a chronic low dose (2.5–10 mg/d)of prednisone indefinitely [104,107]. Although there are only case reports eval-uating the efficacy of long-term treatment of AIP with immunomodulating ther-apy, we have had favorable, although limited, experience with thesemedications [112]. As more experience is gained about the long-term pathogen-esis of AIP, recommendations on the use of chronic suppressive therapy needsto be developed. In addition, because there is such a high frequency of short-term relapse, whether maintenance therapy should be used in all patients, andwhat type of maintenance therapy should be used, remains to be established.

It is unclear at this time whether corticosteroid therapy alters the long-termnatural history of disease, prevents the development of future pancreatic or ex-trapancreatic involvement and organ dysfunction, or is adequate as a long-termsuppressive strategy.

MISDIAGNOSISIncreasingly, we are evaluating patients in whom AIP has been inaccuratelydiagnosed. The misdiagnosis occurs in the setting of patients who have otherunrelated conditions, such as pancreatic adenocarcinoma, being treatedinappropriately with corticosteroids. We have also seen several patients whohad functional abdominal pain complaints treated with prolonged courses ofhigh-dose corticosteroids without evidence of AIP. Conversely, multiple pa-tients have undergone therapies, such as pancreatic head resections or partialhepatectomy, without consideration of an autoimmune cause.

It is therefore important that AIP be considered in the differential diagnosisof patients who have chronic pancreatitis or biliary strictures. It is imperative,however, that a thorough evaluation be performed for other causes of disease,with histopathologic analysis if possible, before the initiation of corticosteroidtherapy. Once corticosteroid therapy has been initiated, patients should be fol-lowed closely for signs of worsening or refractory disease symptoms; it ishighly unusual for AIP not to quickly respond to appropriate corticosteroidtherapy. In addition, clinicians must be cognizant that AIP is a rare disease,and in patients who do not meet the Japanese Pancreas Society or Mayo HI-SORt guidelines, corticosteroid therapy is likely not advisable.

PROGNOSISThere are limited data about the long-term outcome of patients who have AIP.Hirano and colleagues [105] published the most comprehensive report on

455AUTOIMMUNE PANCREATITIS

prognosis when they evaluated 42 patients who had AIP, 19 of whom receivedcorticosteroid treatment at the time of diagnosis. In the 23 patients who didnot have corticosteroid treatment initially, 16 developed unfavorable events,including obstructive jaundice attributable to distal bile duct stenosis in 4,growing pseudocyst in 1, and sclerogenic changes of extrapancreatic bileduct in 9, over an average observation period of 25 months. After an averageobservation period of 23 months in the initial treatment group, 6 patients de-veloped unfavorable events consisting of interstitial pneumonia in 3 and re-currence of obstructive jaundice in 3. Their conclusions were that earlyintroduction of corticosteroids is important to prevent subsequent diseasecomplications.

Most patients treated with corticosteroids develop ‘‘burn out’’ of disease, ren-dering the pancreas usually somewhat atrophic following treatment [10,47].The degree of residual pancreatic exocrine or endocrine insufficiency is likelyrelated to the degree of gland fibrosis at the time of treatment [104].

At this time, given the relatively recent description and active investigation ofAIP, there are no data regarding the long-term mortality rate of patients whohave this disease. In addition, it has not been investigated whether life expec-tancy is altered by the course of this disease.

FUTURE DIRECTIONSThere are several lines of investigation that need to be addressed in regard toAIP. Continued work to determine the cause of this disease and its relationshipwith IgG4 is imperative. Specifically, the antigenic trigger of CD4 and CD8T-cell activation needs to be identified. Clinically, investigation should focuson the natural history of AIP with specific attention to the wide-ranging effectsof IgG4-related systemic disease. It is not currently known whether differentmanifestations of IgG4-related disease have unique or alternate prognoses.The role of corticosteroids, specifically their role in changing the natural historyof disease, needs to be investigated. In asymptomatic patients, it will be impor-tant to determine if treatment helps to prevent future organ dysfunction. Fur-thermore, the role of chronic suppressive therapy, either with corticosteroids oranother immune-modulating drug, in preventing relapse and affecting long-term prognosis is yet to be determined.

SUMMARYAIP is a unique subtype of recently identified chronic pancreatitis that is im-mune mediated and represents one manifestation of a systemic IgG4-relateddisease process. Although a rare condition, it is important to recognize becauseit responds often dramatically to immune system–modulating treatment. Diag-nosing AIP can sometimes be challenging, however, and it is imperative thatclinicians be cautious when considering this diagnosis in patients suspectedof having a pancreatic malignancy. As clinical experience with AIP increases,refinement of diagnostic criteria and development of standardized therapeuticprotocols should allow further optimization of care for our patients.

456 GARDNER & CHARI

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