JOP. J (Online) 2015 Jul 08; 16(4):326-334

REVIEW ARTICLE

Review Article: Diagnosis and Management of Igg4 Autoimmune

Ahmed Salem, Diaa Hamouda, Alyssa Parian

Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

ABSTRACT Autoimmune pancreatitis is a rare form of that has only recently been recognized as a separate type of pancreatitis

French Henry Sarles. in the last two decades. The histopathological features of this distinct form of pancreatitis was first described as early as 1961 when the

INTRODUCTION

Autoimmune pancreatitis (AIP) is a rare form of chronic [8] found intensely positive IgG4 cells in extrapancreatic pancreatitis that has only recently been recognized as organ systems in AIP patients. Thus, the concept of IgG4- a separate type of pancreatitis in the last two decades. diseaserelated systemicwhereas type disease 2 AIP emerged. appears Type to be 1 AIPa pancreas is now The histopathological features of this distinct form of considered to be a pancreatic manifestation IgG4-related

specificEPIDEMIOLOGY disorder. pancreatitis was first described as early as 1961 when pancreatitis associated with hypergammaglobulinemia. Up till now the true incidence of AIP is in the United the French Henry Sarles [1] described a type of sclerosing Subsequently, most of the early literature about AIP came States is unknown with reports limited to case series from Japan where the concept of Autoimmune Pancreatitis and descriptions of tertiary referrals. The estimated et al. many authors had reported a form of chronic pancreatitis (AIP)was first proposed in 1995 by Yoshida [2] after estimatedprevalence the in prevalence Japan, where of autoimmune AIP was first pancreatitis described, in AIP was widely accepted and AIP was differentiated from is 0.82 per 100,000 persons [9]. Japanese series have otherassociated types with of chronic Sjögren's-like pancreatitis. syndrome. An increasing The definition awareness of and further research of AIP has found it is a heterogeneous patients with chronic pancreatitis to be between 5% and disorder with variations in pathophysiology, genetic 6%. Several series in the United States have reported that 2% to 3% of pancreatic resections had evidence of thatautoimmune underwent pancreatitis pancreatic at pathologic resection analysisfor suspected [10-12]. predisposition and extra-pancreatic manifestations AIP was diagnosed in approximately 2%-6% of patients Asian and European observations were reported compared to chronic pancreatitis [3, 4]. form worldwide, accounting for almost all cases in Japan differently. Reports from Asia described a disease [13, 14].Type 1 AIP is the most common affecting elderly males with pancreatic histology showing and Korea and more than 80% of cases in Europe and the twiceUnited as States common [15, 16].in men Type as 1 AIPin women. has a peak It is incidence frequently in alymphoplasmacytic disease that affects sclerosing both genders pancreatitis equally (LPSP)with pancreatic [5], later the sixth or seventh decade of life [9, 16] and is at least histologycalled type characterized 1 AIP. Reports by fromgranulocytic Europe andepithelial US described lesions associated with sclerosing extra-pancreatic lesions such pancreatitis (IDCP) or type 2 AIP. 2as AIP sclerosing seems to cholangitis, affect a younger retroperitoneal subset of patients fibrosis with and (GEL) [6], later called idiopathic duct-centric chronic sclerosing sialadenitis [17, 19]. On the other hand, Type et al. a peak incidence typically about a decade younger than aIn critical 2001, milestone Hamano was reached [7] reported when increasedKamisawa serumet al. There also appears to be an association between type 2 levels of IgG4 in patients with AIP. Subsequently in 2004 those with type 1 AIP with no gender preponderance [16].

Received Accepted AIP and inflammatory bowel diseases especially ulcerative Keywords Pancreatitis; Pancreatic Neoplasms colitisCLINICAL [20-22]. PRESENTATION CorrespondenceMarch 16th, Ahmed 2014- Salem May 04th, 2015 Johns Hopkins University School of Medicine Department, USA Phone phase, The presentation the most common of AIP canclinical be variable presentation [23]. Itfor can both be E-mail [email protected] subtypesdivided into of AIPan acuteis obstructive and a sub-acute , phase. typically In the painless acute +1-410-733-2204

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Further evidence suggesting an autoimmune pathophysiology is the variety of against or with mild epigastric pain. The jaundice of type 1 typically carbonic anhydrase, antinuclear antibody, rheumatoid pancreatitishas a fluctuating such course as abdominal and spontaneous pain and resolution elevation has of factor, lactoferrin, trypsinogen and pancreatic secretory serumbeen reported pancreatic [13, enzymes 24]. Features greater suggestive than three of times acute upper limit of normal are more often observed in type 2 exclusive to AIP. Animal models of AIP have been limited, trypsin inhibitor [31, 46-48], although none of these are

AIP [15, 24-28]. Another key feature that can characterize but have suggested AIP may be T-cell mediated since type 1 AIP is other organ involvement (OOI) [21]. As agents that increase regulatory T-cell population and canpreviously be involved mentioned, prior, type concomitant, 1 AIP is considered or subsequent to be part to molecularactivity (sirolimus, mimicry rapamycin) in genetically had significantpredisposed benefits persons [4]. of systemic IgG4-related disease, therefore, other organs One proroposed mechanism for the pathogenesis of AIP is present with manifestations , such as biliary disease, DIAGNOSIS symptomspancreatic of involvement. Sjogren’s disease, Thus type lung 1 nodules, patients interstitial can also [31, 46]. An accurate diagnosis of AIP remains challenging. The and diffuse or focal lymphadenopathy among others nephritis, retroperitoneal fibrosis, orbital pseudotumors, AIPclinical is andmisdiagnosed radiographic as findingspancreatic of AIPcancer and pancreaticand only In the subacute phase, after initial treatment, AIP can [29, 30]. realizedmalignancy after have pathology a significant from Whipple overlap surgery and frequently returns present with pancreatic atrophy leading to steatorrhea More concerning though, is mistaking a diagnosis of pancreaticas lymphoplasmotic malignancy infiltrates for AIP and as nodelay sign in of diagnosis carcinoma. is patientsresembling with chronic AIP. Interestingly, pancreatitis glycemic [21]. Diabetes control improves mellitus likely to close the already narrow window of curative in(DM) a subset or impaired of AIP fastingpatients glucose following is seen the intreatment up to 50% with of

surgical options in these patients [50]. Many diagnostic corticosteroidPATHOPHYSIOLOGY therapy [31, 32]. different approaches of medical practice between East and criteria have evolved over the last 15 years and reflected The exact pathophysiology of AIP has yet to be fully West. The first sets of diagnostic criteria were established by the Japanese Pancreatic Society in 2002 and 2006 (JPS autoimmuneelucidated. It cause is an of inflammatory AIP has been and inferred fibrosing due diseaseto the 2002, 2006) [51, 52] and consisted of three main items: profoundmarked by response pancreatic to steroid lymphoplasmacytic therapy and the infiltrates. pancreatic An retrograde pancreatocholangiography), serology tests, characteristic radiographic findings (including endoscopic infiltrates of various types of immune cells, including CD4- and Europe histopathological diagnostic findingsERCP is used .IgG4 less was commonly added to due the serological evaluation in JPS 2006. In the United States thepositive pathogenesis T-cells, IgG4-producing of AIP has been plasma studied cells mainly (in type from 1 to the risk of pancreatitis, therefore a different diagnostic anAIP), immunological and granulocytes approach (in type and 2focused AIP)[21, mainly 33-35]. on Thus,type et al.. of the approach (HISORt ) was proposed by Chari Mayo Clinic in 2006 [53] . HISORt criteria (Figure 1) constitutes1 AIP. The the most smallest striking fraction observation of total is theIgG associationin plasma imaging and serology, other organ involvement, and between serum IgG4 and AIP [7]. In healthy subjects, IgG4 responseconsisted to of five cardinal therapy features and of newly AIP in introduced histology,

(usually less than 5%) [36, 37] and elevation in serum (Rt) as diagnostic parameters whereas ERCP was excluded IgG4 is seen in only a limited number of autoimmune asother a major organ factor. involvement (OOI) and response to steroid and parasitic diseases [37-41]. It has been demonstrated that IgG4 antibodies are unable to activate the classical the International Association of Pancreatology, the complement pathway and have limited binding to Fc- InternationalSubsequently inConsensus 2010 during Diagnostic the 14thCriteria Congress (ICDC) of gamma receptor [42]. This can be explained by the fact that IgG4 antibodiesare involved in a continuous process referred to as ‘Fab-arm exchange’ or “half antibody [21] were proposed in attempt to globally unify the AIP exchange” by swapping a heavy-light chain pair with a exceptiondiagnostic criteria.of steroid ICDC responsiveness were similar to considered the original optional HISORt heavy-light chain pair from another molecule . This results infive the cardinal ICDC criteria. features ICDC proposed also focused by Mayo on the clinic distinction with the in a bispecific (two different Fab arms),but functionally monovalent, IgG4 that is unable to bind antigensand criteria there are two levels of evidence according to ratherform immune than the complexescause of AIP. [43]. Some Therefore, studies even most suggested experts theirbetween diagnostic Type 1 reliability, and Type For 2 AIP, example, and for a four greater of the than five considered increased IgG4 levels to be an epiphenomenon typically rise after prolonged exposure to a particular that they may be protective [44, 45] since IgG4 levels pancreatic2-fold elevation ductal of and IgG4 parenchymal is considered appearances, a level 1 criteria; histology a caused by the stimulating antigen. lesser elevation level 2. Further specification is given for allergen and reduce the degree of chronic inflammation

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Figure 1

. HISORt criteria for the diagnosis of autoimmune pancreatitis

AIP can be confirmed with a variety of combinations of level negative56, 60-62]. should Hence,elevated not be assumed IgG4 to alone have typecannot 2 AIP. be Though,used to 1 and level 2 evidence, whereas by ICDC recommendations, make the diagnosis of AIP [62] and patients who are sero- a definitive diagnosis of Type 2 AIP requires histology. In late 2011, the Japanese Pancreatic Society released a elevated IgG4 cannot be used to make the diagnosis of indeterminaterevised criteria imaging (JPS 2011) evidence. [54] whichAn important were more goal similarof each diagnosisAIP, twice-the-upper-limit-of-normal especially when combined with elevation other features markedly of ofto these ICDC withdiagnostic a notable criteria difference was to ofavoid ERCP misdiagnosing classified as increased its specificity [55] and can be helpful to guide the pancreatic cancer which is much more common. clinicalAIP. IgG4 improvement. levels are frequently used to monitor AIP disease Serology activity as steroids cause a decline in IgG4 relative to the Given the presumed autoimmune etiology, numerous autoimmune antibodies have been reported to be elevated bindingOther antibodies protein peptides, have been carbonic associated anhydrase with AIP antigens, but are in AIP. Hamano et al. not diagnostic and include antibodies to anti-plasminogen- . was one of the first to report elevated et al. recommended lactoferrin, pancreatic secretory trypsin inhibitor, anti- serum IgG4 levels and IgG4-positive plasmacytic pancreatic plasminogen-binding peptide antibody (PSTI or SPINK) as infiltration in AIP patients [7]. Hamano to differentiate AIP from pancreatic cancer, which had an preliminarywell as rheumatoid strengths factor, of association antinuclear with antibody, these antibodies, and anti- a cut-off value of 135 mg/dL for serum IgG4 concentration nonesmooth of muscle these antibodybiomarkers [50, appears63]. Although to be there sensitive are some or accuracy of 97%, a sensitivity of 95% and specificity of 97%. More recent studies reveal a much lower sensitivity foldspecific the enoughupper limitto serve of normal as distinctive remains evidence the most of AIP.reliable For and specificity. A Mayo Clinic cohort study including 45 now, elevation of IgG4 serum levels to greater than two AIP patients and 465 controls used a cut-off value of 140 mg/dl for IgG4 serum levels which gave a sensitivity, andIMAGING reproducible indicator that a patient has AIP [64]. specificity and positive predictive value of 76%, 93% and Pancreatic imaging is essential in the diagnosis of AIP. It 36% respectively [55]. A meta-analysis of seven studies, can be subdivided into pancreatic parenchymal imaging evaluating the usefulness of serum IgG4 in diagnosing AIP, and pancreatic ductal imaging. Parenchymal imaging showed variation in sensitivity and specificity ranging by computed tomography (CT) or magnetic resonance typefrom 2 67–94% AIP most and often 89–100%, does not respectivelyhave an elevated [56]. Typeserum 1 imaging (MRI) is usually performed as part of initial work AIP almost always has an elevated serum IgG4, whereas up of obstructive jaundice. Though MRI and CT have comparative results, the lower cost and more availability IgG4 level. It is important to keep in mind that up to 5% of CT has made it rapidly the imaging modality of choice to of control subjects and 10% of patients with pancreatic diagnose AIP. Three different forms of the disease process cancer may have elevated IgG4 [55, 57, 58]. Notably, some can be seen diffuse, focal or multifocal disease, with the patients with type 1 AIP are seronegative for IgG4 [21]. diffuse form being the most common. The classic features IgG4 levels between 135 – 200 mg/dl should be interpreted of diffuse disease on a pancreas protocol abdominal CT with caution. Serum IgG4 levels were found to be elevated in cholangiocarcinoma and some had a more than 2-fold rise [59]. Also, CA 19-9 levels may be elevated in AIP [34, JOP. Journal of the Pancreas - http://www.serena.unina.it/index.php/jop - Vol. 16are No. 4 a – Jul diffusely 2015. [ISSN enlarged, 1590-8577] sausage-shaped pancreas with328 JOP. J Pancreas (Online) 2015 Jul 08; 16(4):326-334

pancreas, and delayed enhancement of the pancreas in the pancreas that are easily differentiated from changes featureless borders, a low-density rim surrounding the occurringAIP shows in well-definedother types of histopathological pancreatitis. Some changes of these in pattern is distinct from that of pancreatic cancer and is the late arterial phase [65, 66, 67]. This enhancement others are used to differentiate both groups. Common histologictypes are features common for findings both subtypes for type include 1 and type(periductal 2 and Peripancreaticapplied to contrast-enhanced stranding is usually EUS for minimal the differentiation in AIP, unlike of AIP and cancer by analyzing time-intensity curves [68, 69]. cellular stroma), which can positively differentiate it lymphoplasmacytic infiltrate and an inflammatory slightlyother forms hyperintense of pancreatitis on T2 [70].­weighted On MRI,images the and pancreas exhibits heterogeneouslyappears diffusely diminished hypointense enhancement on T1weighted­ during images, the early is twofrom clinical other typesphenotypes of chronic of AIP. pancreatitis Differentiated [3, 21, by 82, expert 83]. phase and delayed enhancement during the late phase of Other features serve as the basis for distinguishing the contrast enhancement . The rim is hypointense on both called lymphoplasmacytic sclerosing pancreatitis (LPSP). Itpathologists. is characterized The histopathological by a periductal pattern lymphoplasmacytic of type 1 AIP is

T1and­ T2 ­weighted images, and has delayed enhancement thanon contrast diffuse­enhanced disease andMRI manifests[71, 72]. Focal as a disease focal mass, also calledoften infiltrate, peculiar storiform fibrosis and obliterative within“mass-forming the pancreatic autoimmune head that pancreatitis” is typically is isoattenuating less common notphlebitis, all, of these and features abundant are IgG4present, immunostaining they substantiate (>10/ the high power field IgG4-positive cells [21]. When most, if pancreatic parenchyma making it indistinguishable from or hypoattenuating to the spared, non-enlarged segment of ofdiagnosis the features of type of LPSP1 AIP. and In thatthis context,the histologic it is important diagnosis toof AIP may involve the dorsal pancreas or the pancreatic tail point out that the presence of IgG4-positive cells is just one pancreatic cancer[ 11, 59, 73 ]. Sometimes however focal presence or absence of this one feature alone. Similar histologicaltype 1 AIP should features not might be made also orbe excluded seen in othersolely organson the estimates[33]. Multi-focal vary, it involvementis more common is also for type evident 2 autoimmune a can also pancreatitismimic multifocal to present pancreatic with focal cancer pancreatic [74]. Although involvement exact involvedThe histological in type 1hallmark AIP. of type 2 AIP is the presence of granulocytic epithelial lesions (GEL ) in pancreatic ducts, relativePancreatic to typeduct 1[13, imaging 75, 76]. with endoscopic retrograde pancreatography (ERP) can be a useful adjunct in the phlebitis is uncommon in type 2 AIP, and there are scant which can lead to duct destruction [6, 82, 84] .Obliterative abdominal features for AIP. ERCP features of AIP include thediagnosis presence of AIP, of especiallya long narrow in patients stricture with (more non-classic than one CT to no IgG4-positive cells. Although type 2 AIP also has third of the main pancreas duct), the lack of upstream bothstoriform forms fibrosis of AIP, andthere a is lymphoplasmacytic a conspicuous absence infiltrate, of dilation from the stricture, side branches arising from the intraductalthese features protein are lessplugs, prominent stones, andthan pseudocysts; in type 1 AIP. the In strictured portion of the duct, and multiple noncontiguous usual features of other types of chronic pancreatitis. Other Organ Involvement (Extra Pancreatic MRCP is a less invasive with fewer adverse events, but Manifestations) MRCPstrictures cannot longer completely than 3 cm replace in the ERCPdiffuse for form diagnosing of AIP [77]. AIP, since experts believe main pancreatic ductal narrowing

describedAs mentioned pattern above, of the Type multiple 1 AIPother is organs the involved pancreatic is mayEndoscopic best be ultrasound visualized with(EUS) ERCP classically [78, 79]. exhibits a diffusely manifestation of a multisystem disease. Thus, the well- hypoechoic gland. However, the greatest advantage of EUS common extrapancreatic site of involvement is the biliary an important clue to the diagnosis [3, 85-89]. The most cancer,is the ability but a core to obtain biopsy tissue. of the Tissuepancreas sampling is likely via to have fine- tree [85]. This condition has been termed IgG4-associated needle aspiration is sufficient for diagnosing pancreatic cholangitis (IAC), sometimes called IgG4 sclerosing IACcholangitis and primary (IgG4-SC) sclerosing and has cholangitis been reported (PSC) to occuris also in TCBall the needles features especially of LPSP andin pancreatic diagnose AIPhead [80]. lesions, Though is 20%-88% of cases of AIP [90]. A possible overlap between anthere accurate might beprocedure some technical for the limitationsdiagnosis offor AIP using and EUS- can serve as a rescue technique in cases of AIP lacking typical suggested by the finding that 9%-36% of patients with mayPSC have be able increased to distinguish serum IgG4 between levels, these compared two entities with less by provide histological diagnosis of AIP regardless imaging or than 1% in other liver diseases [60, 91]. Cholangiograms imaging or serological findings. Furthermore, EUS-TCB can diverticulum formation and a beaded appearance typical ofhighlighting PSC, compared the short with band-likethe longer, biliary segmental strictures, strictures with serologicalHistology findings [81]. The traditional ‘gold standard’ for the diagnosis of distal common bile duct are also more common in IAC autoimmune pancreatitis is characteristic histology. with pre-stenotic dilation found in IAC. Strictures of the

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mainstay treatment of AIP, although the relapse rate retroperitoneumOther affected organs (chronic include salivaryperiaortitis, glands(sialadenitis), idiopathic improve AIP symptoms, labs and radiographs, but also chest (including mediastinal fibrosis and adenopathy), possiblyis significant. prevent Steroids further havecomplications been shown such as not sclerosing only to retroperitoneal fibrosis), kidneys (tubulointerstitial reported,nephritis) such and asorbits aorta, (IgG4-associated prostate, breast, pseudolymphoma) meninges, thyroid, fromcholangitis, Kamisawa bile ductet al. stenosis and retroperitoneal fibrosis [30]. There are other organs that have been less frequently [97]. A large multicenter, Japanese, retrospective trial in 2009 identified 563 patients with topericardium the pancreas, and skinincluding [30]. Extrapancreaticmassive lymphoplasmacytic lesions have largeAIP and multinational found that analysis 98% responded of data toobtained steroid from therapy 23 been reported as showing pathological findings similar versus 74% that improved without [98]. Another recent infiltration and fibrosis, obliterating phlebitis, and presence institutions from 10 different countries and included of prominent IgG4 positive plasma cells [93]. These lesions 1064 patients meeting the ICDC diagnostic criteria for can be detected incidentally in cross-sectional images and either type 1 or type 2 AIP, showed that 99% of type 1 whole body imaging such as 18F-Fluoro-deoxyglucose varietyAIP patients of steroid and 92%regimens of type were 2 employed AIP patients for wentinduction into positron emission tomography (PET) [94, 95] and Gallium andclinical maintenance remission of withremission. steroid Most therapy experts [16]. use an A initial wide scintigraphyExtrapancreatic [96]. disease can be a useful factor in the diagnosis of AIP, distinguishing it from pancreatic cancer, weight-based (0.6 mg/kg/d) or fixed-dose (30-40 mg/d) provides collateral evidence for AIP, according to the IAP regimen [15, 16]. Currently, there is no consensus on the diagnosticand forms guidelines. part of the HISORt and ICDC criteria. It also improvement needed prior to initiating steroid taper, or definition of ‘clinical remission, the degree of radiological A Practical Approach to Diagnose AIP remission is an important issue in the treatment of AIP what constitutes ‘radiological remission’. Clearly defining There is no single diagnostic test for AIP and there is sincepatients who experience relapse during the course of steroid taper or while on steroid maintenance might complexity of the criteria used in the ICDC is necessary due represent a recrudescence of residual disease which is not tosignificant the protean variation disease inpresentations. clinical practice Applying worldwide. ICDC strictly The is necessary to avoid misdaignosing pancreatobiliary initiate a tapering regimen, most experts rely on objective yet in remission [99]. Due to a lack of consensus on when to malignancies and AIP diagnosis can’t be established without data such as radiologic evidence of a dramatic decrease in the pancreatic mass or other organ involvement, resolution clinician is primarily to exclude malignancy rather than to of the obstructive jaundice without biliary stenting, and establishexluding an maliganacy AIP diagnosis. first. As Thus, mentioned the responsibility above, pancreatic of the normalization of liver function tests. It is also important enlargement can be focal or diffuse based on pancreatic parenchymal imaging. When typical imaging (e.g., diffuse with treatment and should not be used as a criterion to pancreatic enlargement with delayed enhancement of the determineto keep in response mind that to changestherapy. inMoon serum et al. IgG4 have levels suggested vary parenchyma, with or without presence of a capsule sign)

isthat rising, two weeksthen the may diagnosis be sufficient of AIP to shoulddetermine be reconsidered the response AIPis present diagnosis. any non-ductalIn these patients imaging a collateraldiagnostic evidence steroid trial(i.e. and[60] furtherand if there efforts is noto ruleimprovement out pancreatic or if thecancer CA 19-9should level be andelevated core serumbiopsy IgG4 of pancreas OR presence are unnecessaryof OOI) will establish to support an the diagnosis. pursuedMultiple [3,tapering 73]. regimens have been also advocated. segmental enlargement particularly in the presence On the other hand, if the pancreatic imaging shows focal/ Asian centers use a maintenance strategy of low-dose diagnostic goal is to exclude pancreatic cancer, even if the purpose(2.5–5 mg/day) of maintenance prednisolone, therapy here which is to is prevent continued relapses for presenceof a low-density of clinical pancreatic (young age, mass other at organ imaging, involvement), the first anywhere from 6 months to 3 years [98, 100]. The main radiological (perfusion of the pancreatic mass suggestive which can be evident in up to 30% to 50% of AIP type 1 notpatients typically after use the maintenance first course steroids. of corticosteroid Based on The therapy Mayo of inflammation, no or mild dilation of the main pancreatic Clinic’s[16, 25]. experience, In contrast, more American than half and of patients European do notcenters relapse do areduct) suggestive and serological of AIP. (highTherefore, level ofpancreatic IgG4, presence biopsy ofis autoantibodies, low serum levels of Ca 19-9) findings Therefore, they suggested that maintenance therapy is not detecting pancreatic cancer. warrantedwithin 3 years in afterall patients induction since therapy risks with of long steroids term [25, steroid 101]. mandatory. EU-FNA provides a sensitive modality for TREATMENT AND RELAPSE Unlike other forms of pancreatitis, AIP is very responsive immunomodulatorsuse outweighs the benefits (IMs) [15].such A asrecent small series in bya to steroid therapy, therefore making therapy a component The Mayo Clinic attempted to employ steroid-sparing of the diagnostic criteria. For now, steroids remain the survival was similar to those treated with steroids. maintenance regimen in AIP patients, but the relapse-free

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A report from the Mayo Clinic outlining their experience Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, 7. Fukushima M, Nikaido T, et al. High serum IgG4 concentrations in treating relapsed type 1 AIP demonstrated that steroids patients with sclerosing pancreatitis. N Engl J Med 2001; 344: 732-738. 8. plus IM were equivalent to steroids alone [102]. This study [PMID: 11236777] also reported on 12 patients that received , an Kamisawa T, Funata N, Hayashi Y. Lymphoplasmacyticsclerosing anti-CD20 antibody,for treatment of refractory AIP or pancreatitis is a pancreatic lesion of IgG4-related systemic disease. Am J complete remission, one patient had a partial response and Surg Pathol 2004; 28: 1114. [PMID: 15252325] wassteroid/IM then found intolerance. to have Tencholangiocarcinoma, of the 12 patients and achieved the last 9. Nishimori I, Tamakoshi A and Otsuki M. Prevalence of autoimmune patient had a symptomatic improvement, but continued to pancreatitis in Japan from a nationwide survey in 2002. J GastroenterolKamisawa 2007; T, Takuma 42:6–8. K, [PMID:Egawa 17520216]N, Tsuruta K, Sasaki T. Autoimmune

A wide range of relapse rates after an initial course of 10. require steroid therapy [103]. pancreatitis and IgG4-related sclerosing disease. Nat Rev Gastroenterol Hepatol 2010; 7:401-409. [PMID: 20548323] be due to the heterogeneity of AIP, the lack of a uniform 11. Finkelberg DL, Sahani D, Deshpande V, Brugge WR. Autoimmune steroids have been reported [104]. This variation may pancreatitis.Gardner NTB, Engl Chari J Med ST. 2006; Autoimmune 355:2670-2676. pancreatitis. [PMID: Gastroenterol 17182992] Clin 12. steroiddefinition regimens. of disease Relapses relapse, are various generally study more designs, common short in NorthSmith Am 2008;CD, 37:439-460.Behrns KE, [PMID: van 18499030]Heerden JA, Sarr MG. Radical follow-up times, ethnic variability, and differences in pancreatoduodenectomy for misdiagnosed pancreatic mass. Br J Surg 13. type 1 AIP than in type 2 AIP. A large recent multinational 1994; 81:585-589. [PMID: 7911387] analysis reported relapses in 31% of patients with type histology,14. Yadav and D, Notaharanatural history K, Smyrk after TC, resection. Clain JE, Clin Pearson Gastroenterol RK, Farnell Hepatol MB, pancreatic1 AIP and involvement 9% of patients have with been type found 2 AIP to be after associated steroid Chari ST. Idiopathic tumefactive chronic pancreatitis: clinical profile, discontinuation [16]. Higher serum IgG4 levels and extra- 2003; 1:129-135. [PMID: 15017505] agree that an isolated serologic relapse (repeat elevation 15. Sah RP, Chari ST. Autoimmune pancreatitis: an update on with higher relapse rates [105]. Whereas most experts classification, diagnosis, natural history and management. Curr Gastroenterol Rep 2012; 14:95–105. [PMID: 22350841] weightin serum loss)or IgG4) doesradiological not necessitate relapse maintenance (enlarged pancreas, therapy, 16. Hart PA, Kamisawa T, Brugge WR. Long-term outcomes of presenceclinical relapse of new (obstructive duct strictures) jaundice, will often recurrence necessitate of OOI, a autoimmune pancreatitis: a multicentre, international analysis. Gut 2012;Kamisawa 11. [PMID: T, 23232048] Nakajima H, Egawa N, Funata N, Tsuruta K,

Treatment of relapse is usually achieved with the same 17. second course of corticosteroid therapy [90, 102, 106]. Okamoto A. IgG4-related sclerosing disease incorporating sclerosing initial dose of , though the Japanese consensus pancreatitis, cholangitis, sialadenitis and retroperitoneal fibrosis with lymphadenopathy. Pancreatology 2006; 6:132-137. [PMID: 16327291] 18. Kamisawa T, Matsukawa M, Ohkawa M. Autoimmune pancreatitis guideline recommend to a more gradual taper [102]. associated with retroperitoneal fibrosis. JOP 2005; 6:260-263. [PMID: 15883477] Conflicting Interest 19. Okazaki K, Uchida K, Koyabu M, Miyoshi H, Ikeura T, Takaoka M, IgG4 cholangiopathy-current concept, diagnosis, and pathogenesis. J Hepatol 2014; 61:690-5. [PMID: 24768756] The authors had no conflicts of interest 20. Okazaki K. Autoimmune pancreatitis: etiology, pathogenesis, clinical References findings and treatment. The Japanese experience. JOP 2005; 6:89–96. [PMID:Shimosegawa 15650291] T, Chari ST, Frulloni L et al. International consensus 21. 1. Sarles H, Sarles JC, Muratore R, Guien C. Chronic inflammatory diagnostic criteria for autoimmune pancreatitis: guidelines of the sclerosis of the pancreas-an autonomous pancreatic disease? Am J Dig International Association of Pancreatology. Pancreas 2011; 40:352–8. Dis2. 1961; 6:688–98. [PMID: 13746542] [PMID:22. 21412117] Chronic pancreatitis caused by an autoimmune abnormality. Proposal of K, Noma E, et al. Prevalence and Clinicopathological Features of Yoshida K, Toki F, Takeuchi T, Watanabe S, Shiratori K, Hayashi N. Ueki T, Kawamoto K, Otsuka Y, Minoda R, Maruo T, Matsumura the concept of autoimmune pancreatitis. Dig Dis Sci 1995; 40:1561-1568. Autoimmune Pancreatitis in Japanese Patients With Inflammatory Bowel [PMID:3. Chari 7628283] ST, Kloeppel G, Zhang L, Notohara K, Lerch MM, Disease.23. Frulloni Pancreas. L, Lunardi 2014 [Epub C, Simone ahead R, of print].Dolcino [PMID: M, Scattolini 25469544] C, Falconi Shimosegawa T. Histopathologic and clinical subtypes of autoimmune M, Benini L, et al. Identification of a novel antibody associated pancreatitis: the Honolulu consensus document. Pancreas 2010; 39: with autoimmune pancreatitis. N Engl J Med 2009; 361: 2135-2142. 549-554.Kamisawa [PMID: T, 20562576]Chari ST, Lerch MM, Kim MH, Gress TM, Shimosegawa [PMID:Sugumar 19940298] A. Diagnosis and management of autoimmune pancreatitis. 4. 24. T. Recent advances in autoimmune pancreatitis: type 1 and type 2. Gut GastroenterolSah RP, Chari Clin ST,North Pannala Am 2012; R, Sugumar 41:9-22. A, [PMID: Clain 22341247]JE, Levy MJ, Pearson 2013; 62:1373-1380. [PMID: 23749606] 25. 5. Notohara K, Burgart LJ, Yadov D, et al. Idiopathic chronic pancreatitis RK, et al. Differences in clinical pro fi le and relapse rate of type 1 versus with periductallymphoplasmacytic infiltration: clinicopathologic features type 2 autoimmune pancreatitis. Gastroenterology 2010; 139:140-148. of6. 35Zamboni cases. Am Z, JLu¨ttges SurgPathol J, Capelli 2003; P,27:1119Y1127. et al. Histopathological [PMID: 12883244] features of [PMID:26. Kamisawa 20353791] T, Chari ST, Giday SA, Kim MH, Chung JB, Lee KT, Werner J, diagnostic and clinical relevance in autoimmune pancreatitis: a study on Bergmann F, Lerch MM, et al. Clinical profile of autoimmune pancreatitis 53 resection specimens and 9 biopsy specimens. Virchows Arch 2004; and its histological subtypes: an international multicenter survey. 445:553Y563. [PMID: 15517359] Pancreas 2011; 40:352–8. [PMID: 21747310] JOP. Journal of the Pancreas - http://www.serena.unina.it/index.php/jop - Vol. 16 No. 4 – Jul 2015. [ISSN 1590-8577]

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