Autoimmune

Pancreatitis

Dimitrios P Bogdanos Professor of Immunopathology

When to suspect How to confirm

How/when to treat

2008-2013 I have received in the past Lecture Honoraria, Consultation Fees, Expert

Panel Fees, Accommodation/Travel Expenses Coverage

INOVA, EUROIMMUN, Generic Assays, FALK, BIORAD,

(King’s College Hospital Charitable Trust) Part of travel/accommodation expenses are covered by the Organizers

I do not have shares or any other relevant financial or other relationship with a commercial organization that could influence the content of my

presentation

ALL FEES OR HONORIA SUPPORT MY FELLOWS’S RESEARCH INITIATIVES/CONFERENCE TRAVEL EXPENSES

Disclosure statement

EUROPE AID Biorad CyBio Diarect Euclone EUROIMMUN Generic Assays InnoVision Invitrogen- MabTech Mardx Meridian LS Menarini Miltenyi Molecular Probes PeproTech Pharmacia Roche

I have received diagnostic reagents free of charge and/ or participated in collaborative projects

AMERICA Gilead INOVA IMCCO Virusys

JAPAN MBL

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Autoimmune Pancreatitis: Current Status

pubmed - autoimmune pancreatitis pubmed - autoimmune pancreatitis

year count

2013 152

2012 196

2011 174

2010 164

2009 166

2008 154

2007 125

2006 96

2005 97

2004 60

2003 49

2002 36

2001 37

2000 23

1999 17

1998 11

1997 14

1996 11

1995 11

1994 5

1993 12

1992 8

1991 1

1990 5

1989 3

1988 12

1987 4

1986 8

1985 7

1984 8

1983 4

1982 2

1981 2

1980 4

1979 1

1978 4

1977 1

1976 2

1975 1

1974 1

1973 4

1972 4

1971 1

1970 3

1969 2

1968 2

1967 5

1966 2

Autoimmune Pancreatitis: Current Status

Figure 1 Key historical events in chronic pancreatitis.

Anil K. Rustgi

A Historical Perspective on Clinical Advances in Pancreatic Diseases

Gastroenterology Volume 144, Issue 6 2013 1249 - 1251

http://dx.doi.org/10.1053/j.gastro.2013.03.010

Chronic pancreatitis is a progressive inflammatory disease of the pancreas with irreversible damage of pancreatic tissue exocrine and endocrine insufficiency

Incidence of Chronic Pancreatitis

Switzerland 1.2/100 000/year

Poland 4.0/100 000/year

Germany 7.4/100 000/year

Czech Rep. 7.9/100 000/year

Hungary 8.0/100 000/year

Denmark 10.0/100 000/year

Sweden 10.0/100 000/year

Finland 23.0/100 000/year

United States 5.7-7.6/100 000/year

-oxic-metabolic -diopathic -enetic -utoimmune -ecurrent acute pancreatitis -bstructive

Etemed, Whitcomb, 2001

TIGARO Classification

T I GAR O

Tigar-O Classification System

Genetic

Hereditary pancreatitis

Cationic trypsinogen

PRSS1

PRSS2

CFTR mutations

SPINK1 mutations

Autoimmune

Autoimmune pancreatitis

Inflammatory bowel disease

Primary biliary cirrhosis

Year Reference Reported findings

1961 Sarles et al10

Reported a form of idiopathic chronic pancreatitis associated with

hypergammaglobulinaemia; suspected an autoimmune

mechanism

1991 Kawaguchi et al11 Described the histopathological pattern of what was later called

type 1 AIP (‘lymphoplasmacytic sclerosing pancreatitis (LPSP)’)

1995 Yoshida et al3 Coined the term ‘autoimmune pancreatitis’. Described all the major

clinical features of what was later called type 1 AIP

2001 Hamano et al12 Reported that elevated serum IgG4 levels were highly specific and

sensitive for the diagnosis of AIP

2002 Japan Pancreas

Society (JPS)13 First JPS diagnostic criteria for AIP

2003 Kamisawa et al14

Proposed that AIP was a systemic disease based on the findings

that the pancreas and other involved organs have abundant

infiltration with IgG4+ve plasma cells

2003 Notohara et al15

Reported two histological patterns in patients with ‘idiopathic

chronic pancreatitis with lymphoplasmacytic infiltration

sometimes called autoimmune pancreatitis’ (a) LPSP and

(b) idiopathic duct centric pancreatitis (IDCP)

2004 Kamisawa et al16 Japanese experience of steroid therapy in AIP

2006 Chari et al17 HISORt criteria for AIP published

2006 Kim et al18 Korean criteria for AIP published

2008 Ghazale et al19 First report of use of azathioprine in AIP

2008 Topazian et al20 First report of use of rituximab in AIP

2008 Moon et al21 Steroid trial to distinguish AIP from pancreatic cancer

2009 Chari et al22 Revised HISORt criteria

2010 Chari et al9 International consensus on classification of AIP into type 1 and

type 2

2011 Shimosegawa et

al23 International consensus diagnostic criteria

2012 Hart et al24 Proposed an algorithm for managing AIP using steroids,

immunomodulators and rituximab

HISORt CRITERIAS OF AIP Category Criteria

A. Histology 1. Diagnostic (any one): a) Pancreatic histology showing periductal lymphoplasmacytic infiltrate with obliterative hlebitis (LPSP) b) Lymphoplasmacytic infiltrate with abundant (>10 cells/hpf) IgG4 positive cells in the pancreas 2. Supportive (any one) a) Lymphoplasmacytic infiltrate with abundant (>10 cells/hpf) IgG4 positive cells in involved extra-pancreatic organ b) Lymphoplasmacytic infiltrate with fibrosis in the pancreas

B. Imaging Typical imaging features: 1. CT/MR: diffusely enlarged gland with delayed (rim) endhancement 2. ERCP: Diffusely irregular, attenuated main pancreatic duct

Atypical Imaging Features: Pancreatitis, focal pancreatic mass, focal pancreatic duct stricture, pancreatic atrophy, pancreatic calcification

C. Serology Elevated serum IgG4 level (normal 8-140 mg/dl)

D. Other Organ involvement

Hilar/intrahepatic biliary strictures, persistent distal biliary stricture, Parotid/lacrimal gland involvement, Mediastinal lymphadenopathy, Retroperitoneal fibrosis

E. Response to steroid therapy

Resolution/marked improvement of pancreatic/extrapancreatic manifestation with steroid therapy

Definition

Chronic pancreatitis caused by autoimmune inflammatory process

Lymphocyte infiltration

Fibrosis of pancreas

Organ dysfunction

Epidemiology

Rare

Increase in number of reported cases past 10 years

Prevalence and incidence not yet determined—possibly between 5-6% of all cases of chronic pancreatitis

May have increased prevalence in Japan

Twice as common in men as in women

Most patients are > 50 years old

The annual number of Japanese patients with type 1 Autoimmune Pancreatitis (AIP) is 0.71 per 100,000, which accounts for 2% of patients with chronic pancreatitis

Nishimori J Gastroenterol 2007

Incidence of autoimmune pancreatitis

Japan 21/451 4,6% Yoshida et al. Dig.Dis.Sci. 1995

Korea 17/315 5,4% Kim et al. Am.J.Gastroenterol. 2004

Italy 23/383 6,0% Parson et al. Pancreas 2003

Czech Rep. 9/185 4,8% Dite et al Best Practice and Res Clin. Gastroent., 2008

Sex ang age onset of autoimmune pancreatitis

Nishimori I. et al., Gastroent., 2007

Clinical Features

Unusual to present w/ severe abdominal pain

Usually mild, acute recurrent pancreatitis

Abdominal pain, weight loss, jaundice, obstructive pattern of LFTs

Biliary and pancreatic duct strictures

Pancreatic mass—can be confused with pancreatic carcinoma or lymphoma

Features of other autoimmune diseases

Clinical Features

Kamisawa et al Gut 2013

AUTOIMMUNE PANCREATITIS

23,0% FOCAL FORM (LIKE MALIGNANT LESION)

DIFFUSE FORM 77,0% (LIKE ACUTE PANCREATITIS)

Physical Examination

Imaging

MRI: sausage-shaped enlargement of pancreas, minimal fat stranding, peripheral rim of hypoattenuation “halo”

Similar lesions seen on CT

Can also see focal pancreatic involvement, usually in the head of pancreas

Imaging

EUS: diffusely hypoechoic, enlarged pancreas

ERCP: narrowed main and dorsal pancreatic duct, diffuse, irregular narrowing of duct, focal stricture of duct, irregular narrowing of intrahepatic ducts, lesion in pancreatic head can be seen

May not be able to distinguish between malignancy and autoimmune pancreatitis based on these results

CT Scan

CT scan of a patient with autoimmune pancreatitis. The head of the pancreas is enlarged (long arrow) and the common bile (small arrow) is dilated

Pancreatic Head Mass CT scan

showing low

attenuation, ill-defined

lesion in the pancreatic head with enhancing

mural thickening

at the gallbladder

fundus

ERCP

Endoscopic retrograde cholangio- pancreatography in a patient with autoimmune pancreatitis. The left panel shows a stricture in the common bile duct due to the surrounding enlarged pancreas. The right panel shows a stent that has been inserted across the narrowed segment

Endoscopic ultrasonographic image showing fine-needle aspiration of a hypoechoic mass

(arrow) in the head of the pancreas.

LAW R et al. Cleveland Clinic Journal of Medicine

2009;76:607-615

Dual-phase helical computed tomography shows focal enlargement of the pancreatic tail

(arrow) in a patient with autoimmune pancreatitis

LAW R et al. Cleveland Clinic Journal of Medicine

2009;76:607-615

©2009 by Cleveland Clinic

Gross Specimen: The real thing

Surgical specimen in a patient who underwent resection for autoimmune pancreatitis

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

David G. Forcione , William R. Brugge

New kid on the block? Autoimmune pancreatitis

Best Practice & Research Clinical Gastroenterology Volume 24, Issue 4 2010 361 - 378

http://dx.doi.org/10.1016/j.bpg.2010.04.002

Pathology

Diffusely indurated and firm pancreas on gross exam

Focal mass can be found in a subset of patients

Collar-like periductal infiltrate composed of lymphocytes and plasma cells

Can also involve gallbladder, bile ducts, kidney, lung, and salivary glands with dense lymphocytic infiltrate

Histology of autoimmune pancreatitis

DG Forcione Res Clin Gastroenterol 2010

Note the presence of lympho-plasmacystic cellular infiltrates

Autoimmune pancreatitis with intense and destructive fibroinflammatory replacement of

normal pancreatic parenchyma.

LAW R et al. Cleveland Clinic Journal of Medicine

2009;76:607-615

IgG4 immunohistochemistry in autoimmune pancreatitis showing more than 30 stained plasma cells (brown cells)

per 400X high-power field (dimethylaminoazobenzine chromagen and hematoxylin counterstain).

LAW R et al. Cleveland Clinic Journal of Medicine

2009;76:607-615

IgG4: serological marker as

well as histological marker

Nat Clin Pract Gastroenterol Hepatol

Overview of published series on the use of serological markers for the diagnosis of autoimmune pancreatitis

Scattergram of IgG4 values for patients with autoimmune pancreatitis and related diseases. PBC primary biliary cirrhosis, PSC primary sclerosing cholangitis

Kawa et al., Gastroent., 2007

Antibodies in patients with AIP

%

Okazaki et al. J. Gastroent. 2001

Zen J Hepatol 2013

Zen J Hepatol 2013

Treatment

Can respond dramatically to corticosteroids—optimal dose and duration not yet established

Possible approach: prednisone 40 mg daily for 4-6 weeks, followed by taper of 5 mg/week

Patients usually followed immunologically and by CT scan while on therapy

Recurrence of autoimmune pancreatitis

Takayama et al (Amer.J.Gastroent. 2004) 42(11) 26%

Wakabyashi et al.(Pancreas 2005) 36( 6) 17%

Zamboni et al. Wirchow Arch. 2004) 22( 5) 23%

Kim et al. (A.J. Gastroent. 2004) 17( 1) 6%

Ramisawa et al. (J.Gastroenterol. 2007) 32( 2) 6%

COMPARISON OF SUBJECTS WITH AIP AND PANCREATIC CANCER

AIP (N=45) Pacreatic Cancer

(N=135)

P Value

Gender, % male 37/45 (82%) 79/135 (59%) 0,004

Mean age ± SEM 59,6 ± 2,5 67,3 ± 1,1 0,001

% ≥ age 50 yr 34/45 (76%) 125/135 (93%) 0,002

CA 19-9 > 100 3/33 (9%) 91/126 (71%) <0,001

Mean value of S.

IgG4 (range) 550 ± 98,6 (3-

2,890)

69,5 ± 9,4 (3-1,140) <0,001

% with serum IgG4 >

140mg/dL 34/45 (76%) 13/135 (10%) <0,001

% with serum IgG4 >

280 mg/dL 24/45 (53%) 2/135 (1%) <0,001

Multivariate Analyses

of Factors predicting

AIP

Odds Ratio Confidence Interval P Value

IgG4 > 140 mg/dL 37,4 10,6-173,5 <0,001

CA19-9 < 37 11,7 3,70-46,2 <0,001

Ghazele A. et al. 2007

Usefulness of IgG4 in differentiating between pancreatic cancer and autoimmune pancreatitis

Kawa et al., Gastroent., 2007

AUTOIMMUNE PANCREATITIS VS PANCREATIC CANCER - RADIOLOGIC IMAGING

Autoimmune

pancreatitis

Pancreatic

cancer

Complete cutoff of main

pancreatic duct

Uncommon Common

Ductal stricture Multiple Localized (Single)

Upstream duct dilatation Mild Marked

Duct in the mass Present Absent

Diffuse swelling of the pancreas Almost always Rare

Double duct sign Common Common

Kim et al., 2004

Take Home Points

Autoimmune pancreatitis should be considered in patients with refractory pancreatitis without other identifiable etiology

Can present with mass that can be confused with pancreatic carcinoma or lymphoma--patients have been taken for Whipple procedure for this!

Typically responds very well to steroids