Autoimmune pancreatitisAutoimmune pancreatitis

Petr DítěPetr Dítě

Dept.Dept. of of Hepatogastroenterology HepatogastroenterologyUniv. Hospital Brno – Czech RepublicUniv. Hospital Brno – Czech Republic

Incidence of Chronic PancreatitisSwitzerland 1.2/100 000/yearPoland 4.0/100 000/yearGermany 7.4/100 000/yearCzech Rep. 7.9/100 000/yearHungary 8.0/100 000/yearDenmark 10.0/100 000/yearSweden 10.0/100 000/yearFinland 23.0/100 000/yearUnited States 5.7-7.6/100 000/year

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

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

Etemed, Whitcomb, 2001

TIGARO Classification

TI GARO

AUTOIMMUNE PANCREATITIS - chronic pancreatitis with distinct clinical, serological, histological and imaging features and it is involved in hyper- IgG4 group of diseases.

Autoimmune pancreatitisAutoimmune pancreatitis19611961 H. SarlesH. Sarles Chronic inflammatory sclerosis Chronic inflammatory sclerosis of of

the pancreasthe pancreas(Patients with jaundice, painful crises, hyperglobulinemia, no (Patients with jaundice, painful crises, hyperglobulinemia, no

dilatation of pancreatic duct, lymphatic infiltration)dilatation of pancreatic duct, lymphatic infiltration)

19751975 R. Waldram et al R. Waldram et al Chronic pancreatitis, sclerosing Chronic pancreatitis, sclerosing cholangitis and cholangitis and sicca sy sicca sy in two siblingsin two siblings

19781978 S. Nakano et alS. Nakano et al Vanishing tumor of the abdomen Vanishing tumor of the abdomen in in patient with Sjögren´s sypatient with Sjögren´s sy

19951995 K. YoshidaK. Yoshida Concept of autoimmune pancreatitisConcept of autoimmune pancreatitis

20012001 B. Etemed, D. Whitcomb B. Etemed, D. Whitcomb TIGARO classificationTIGARO classification

Epidemiology of autoimmune Epidemiology of autoimmune pancreatitispancreatitis

JapanJapan 21/45121/4514,6% 4,6% Yoshida et al. Yoshida et al. Dig.Dis.Sci. 1995Dig.Dis.Sci. 1995

KoreaKorea 17/31517/3155,4% 5,4% Kim et al. Kim et al. Am.J.Gastroenterol. 2004Am.J.Gastroenterol. 2004

ItalyItaly 23/38323/3836,0%6,0% Parson et al. Parson et al. Pancreas 2003Pancreas 2003

Czech Rep. Czech Rep. 9/1859/185 4,8%4,8% Dite et al Best Practice Dite et al Best Practice and Res. and Res. Clin. Gastroent., 2008Clin. Gastroent., 2008

Sex ang age onset of autoimmune pancreatitis

Nishimori I. et al., Gastroent., 2007

Antibodies in patients with AIPAntibodies in patients with AIP

%

Okazaki et al.J. Gastroent. 2001

HISORt CRITERIAS OF AIPCategory CriteriaA. 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 pancreas2. 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) endhancement2. 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

CLINICAL DIAGNOSTIC CRITERIA FOR AIP 2006

1. Diffuse or segmental narrowing of the MPD with irregular wall and diffuse or localized enlargement of the pancreas by imaging studies, such as abdominal US, CT, and magnetic resonance2. High serum γ-globulin, IgG, or IgG4, or the presence of autoantibodies such as antinuclear antibodies and rheumatoid factor3. Marked interlobular fibrosis and prominent infiltration of lymphocytes and plasma cells in the periductal area, occasionally with lymphoid follicles in the pancreas

Diagnosis of AIP is established when criterion 1 and criterion 2 and/or 3 are fulfilled. However, it is necessary to exclude malignant diseases.

AUTOIMMUNE PANCREATITIS - SUBTYPESTYP 1 – LYMPHOPLASMATIC SCLEROSING PANCREATITIS – LPSP - PERIDUCTAL LYMPHOPLASMATIC INFILTRATE - HIGH AMMOUNT IgG4 - POSITIVE PLASMA CELLS - SWIRLING FIBROSIS - OBLITERATIVE VENULITISTYP 2 – IDIOPATHIC DUCT-CENTRIC PANCREATITIS – IDCP

(“non-alcoholic duct destructive pancreatitis“) - DUCTAL EPITHELIAL GRANULOCYTIC INFILTRATION

DUCTAL DAMAGE

OBLITERATION

COMPARISON OF TYPE 1 AND TYPE 2 AIPType 1 AIP Type 2 AIP

Mean age Sixth decade Fourth decade

Gender distribution Predominantly male Equal

Histological pattern Lymphoplasmacytic sclerosing pancreatitis

Duct-destructive pancreatitis

Histological hallmarks Periductal lymphoplasmacytic infiltrateSwirling fibrosisObliterative venulitis

Lymphoplasmacyic infiltrateGranulocyte epithelial lesion with partial/complete duct obstruction

IgG4 cells on immunostaining

Moderate-severe (98%) Moderate (40%) in one study

Serum IgG4 levels Elevated Normal

Other organ involvement Chronic sclerosing sialadenitis, IgG4-associated cholangitis, retroperitoneal fibrosis, IgG4-associated tubulointerstitial nephritis

Inflammatory bowel disease

AIP,autoimmune pancreatitis, IgG4, immunoglobulin G4

CLINICAL PRESENTATIONS OF TYPE 1 AUTOIMMUNE PACREATITIS

Clinical presentations of type I AIP

Pancreatic Predominantly extra-pancreatic

Biliary stricture, sclerosing cholangitis

Interstitial nephritis,

renal failure

Retroperitoneal fibrosiswith complications

(e.g., ureteral obstruction)

Acute Post-acute/late

Obstructive jaundice

Pancreatitis

Steatorrhea

Persistent mass

Steatorrhea

Calcification,atrophy

Park, D.H. 2009

AUTOIMMUNE PANCREATITIS

23,0% FOCAL FORM(LIKE MALIGNANT LESION)

DIFFUSE FORM 77,0%(LIKE ACUTE 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

Usefulness of IgG4 in differentiating between pancreatic cancer and autoimmune pancreatitis

Kawa et al., Gastroent., 2007

Abundant IgG4 – bearing plasma cell infiltration Abundant IgG4 – bearing plasma cell infiltration in patients with autoimmune pancreatitis and in patients with autoimmune pancreatitis and

gastric ulcergastric ulcer

• 23 pts with AIP and 230 control patients examined 23 pts with AIP and 230 control patients examined by EGDby EGD

• In 8 pts with autoimmune pancreatitis gastric ulcer In 8 pts with autoimmune pancreatitis gastric ulcer was found (34.8%). In control group during EGD was found (34.8%). In control group during EGD was gastric ulcer found in 31 pts (13.3%) = p.0007was gastric ulcer found in 31 pts (13.3%) = p.0007

• Conclusion: AIP is closely associated with gastric Conclusion: AIP is closely associated with gastric ulcer with abundant IgG4-bearing plasma cell ulcer with abundant IgG4-bearing plasma cell infiltrationinfiltration

Shinji, A. et al.Gastrointest. Endosc. 2004

SET OF PATIENTS WITH AUTOIMMUNE PANCREATITIS(N = 10)

Gender Age Others autoimmune disease

Male 36 sclerosing cholangitis

Male 43 Sjögren sy

Male 53 Sjögren sy, sick – sinus syFemale 54 Sjögren sy, autoim. hepatitis

Male 56 autoimmune hepatitis

Male 32 autoimmune hepatitis

Female 55 primary biliary cirrhosis

Male 51 IBD

Male 46 xxx

Female 33 xxx

Female 58 IgG4 pos. mastitis, sialoadenitis

Female 52 Sicca syndrom

Male 49 IgG4 pos. sclerosing cholangitis

Dítě,P. al 2010One patient died during hospitalization – pancreatic cancer

Review of AIP cases with systemic extrapancreatic lesionsReview of AIP cases with systemic extrapancreatic lesions

Western countries(n=172)

Japan (n=132)

Sjögren´s syndrome 13 24 P<0.01

IBD

UC 14 5 NS

CD 4 0 NS

Total 18 5 P<0.05

Retroperitoneal fibrosis 9 8 NS

Thyroid disease 4 1 NS

Autoimmune hepatitis 0 2 NS

Malignant lymphoma 2 0 NS

IBD imflammatory bowel disease,UC ulcerative colitis, CD Crohn´s disease, ITP idiopathic trombocytopenic purpura, RA rheumatoid arthritis, SLE systematic lupus erythematosus

Ohara et al, Pancreas 2005Ohara et al, Pancreas 2005

AUTOIMMUNE PANCREATITIS IN PATIENTS WITH “IDIOPATHIC CHRONIC PANCREATITIS“

66 PATIENTS WITH IDIOPATHIC CHRONIC PANCREATITIS /ICP/AUTOIMMUNE DISEASE WAS PRESENT IN 10 PATIENTS (UC 5 pts, PSC 2 pst, Sjögren sy 1 pts, Hashimoto´s thyroiditis 1 pts, Graves disease 1 pts)POSITIVITY OF BIOCHEMICAL AND CLINICAL PARAMETRES – IN 40%CONCLUSION: CLINICAL OR BIOCHEMICAL AUTOIMMUNE STIGMATA ARE PRESENT IN 40% pts WITH ICP, AUTOIMMUNE MECHANISMS MAY BE FREQUENT IN ICP.

Uzan,K.N. et al. Clin Gastroent. Hepatol. 2005

CHRONIC PANCREATITIS IN CHILDREN – AUTOIMMUNE ETIOLOGY?

In the set of 31 children (age 3-18 years) • markers of AIP were found in 17 pts

(41,5%)• Genetic markers 10 pts

(32,5%)

Oracz G. et al, Clin Gastroent Hepat 2006

Steroid therapy in patients with AIPSteroid therapy in patients with AIP

• Initial dosesInitial doses 30 – 40 mg per 30 – 40 mg per day for 2 – 4 day for 2 – 4 weeksweeks• The steroid therapy could be stopped after the period The steroid therapy could be stopped after the period ofof

6 – 12 months.6 – 12 months.• Monitoring Monitoring of of laboratory and clinical symptoms laboratory and clinical symptoms

are essential. are essential.• When AIP still appears after steroid therapy --- re-evaluation When AIP still appears after steroid therapy --- re-evaluation

should be carried out taking pancreatic CARCINOMA into should be carried out taking pancreatic CARCINOMA into consideration!consideration!

J.Jpn.Pacreas Soc., 2002J.Jpn.Pacreas Soc., 2002

THERAPEUTIC OPTIONS IN PATIENTS WITH AIP

A) MAYO CLINIC – 11 WEEKS STEROIDS WITH TAPPERING DOSE 5 mg / WEEK

B) KIM – 1 mg/kg FOR 4 WEEKS AND TAPPERING THE DOSE 5 mg/WEEK

C) FRULLONI – 0,5 mg/kg FOR 4 WEEKS AND TAPPERING THE DOSE 5 mg/WEEK

UNEFFECTIVE THERAPY – PANCREATIC CANCER

Long-term follow up study treating patients with Long-term follow up study treating patients with AIPAIP

23 patients with AIP

Pancreatoduode nectomy (N=6)

Choledocho duodenostomy

(N=4)

Supportive therapy (N=3) Steroids (N=10)

Steroid therapy

60 mg/day 1 pts40 mg/day 1 pts Duration from 21 – 37 months30 mg/day 7 pts5 mg/day 1 pts

Dose was tappered by 2.5 – 5.0 mg every two weeksMaintenance therapy: 5mg dailyFollow up period – 4 years 6 monts

Kamisawa et al.Pancreatology 2005

Long term therapy patients with AIP - prognosisLong term therapy patients with AIP - prognosis

Group Prognosis (month)

Pancreatoduodenectomy (N=6)

Died - pulmonary cancer (12) - hepatic failure (48) - pneumonia (12)Alive - 12 and 82 monthsUnclear - 36 months

Palliative therapy(N=3)Died - pulmonary cancer (12) - renal failure (72)Alive - 240 months

Steroids (N=10) Died - esophageal cancer (12)Alive - 12, 12, 24, 36, 48, 48, 60, 72, 120

Kamisawa et al.Pancreatology 2005

AIP – ENDOCRINE AND EXOCRINE FUNCTION AFTER STEROID THERAPY

21 CASES AIP WITH STEROID THERAPY10 CASES WITH EXOCRINE INSUFICIENCY- NORMALIZATION 8- NO CHANGE 211 CASES WITH DIABETES MELLITUS- IMPROVEMENT 5- AGGRAVATION 3- NO CHANGE 3

Ito et al. 2007

Recurrence of autoimmune Recurrence of autoimmune pancreatitispancreatitis

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

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

Zamboni et al. Wirchow Arch. 2004)Zamboni et al. Wirchow Arch. 2004) 22( 5)22( 5) 23%23%Kim et al. (A.J. Gastroent. 2004)Kim et al. (A.J. Gastroent. 2004) 17( 1)17( 1)

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

6%6%

THE THERAPY OF AIP RECCURENCE

STEROID + AZATHIOPRINE 1mg/kg 2mg/kg FOR 11 WEEKS

Mycophenolate or Rituximab are not effective

S.CHari Abstr. DDW 2009

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

Usefulness of IgG4 in differentiating between pancreatic cancer and autoimmune pancreatitis

Kawa et al., Gastroent., 2007

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

Ghazele A. et al. 2007

CONCLUSION AND PRACTICE POINTS

1) AIP IS NOT FREQUENT DISEASE IN EUROPE, MORE FREQUENT IN ASIA.

2) CLINICAL SYMPTOMS ARE USUALLY MILD (MOSTLY ABDOMINAL “DISCOMFORT“ WITHOUT PAIN ATTACKS)

3) IN CT, EUS OR US-DIFFUSE ENLARGEMENT OF PANCREAS (sausage pancreas), IN NMR-CP OR ERCP IRREGULAR NARROWING OF THE MAIN PANCREATIC DUCT ARE TYPICAL

4) PRESENCE NON-SPECIFIC ANTIBODIES IN BLOOD SERUM AND INCREASED LEVEL OF IgG AND IgG4 IN SERUM AND TISSUE

5) ASSOCIATION WITH OTHER AUTOIMMUNE DISEASE-TYP1 AIP

6) PANCREATIC CALCIFICATIONS AND/OR CYSTOIDS ARE NOT FREQUENT

7) THERAPY WITH STEROIDS IS EFFECTIVE8) IN DIF. DG DIAGNOSIS AIP VS PANCREATIC CANCER – EUS

GUIDED BIOPSY IS FUNDAMENTAL PROCEDURE