1. Autoimmune pancreatitis Petr Dítě Dept. of Hepatogastroenterology Univ. Hospital Brno – Czech Republic

2. Incidence of Chronic Pancreatitis Switzerland1.2/100 000/year Poland 4.0/100 000/year Germany7.4/100 000/year Czech Rep.7.9/100 000/year Hungary8.0/100 000/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

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

4. -oxic-metabolic -diopathic -enetic -utoimmune -ecurrent acute pancreatitis -bstructive Etemed, Whitcomb, 2001 TIGARO C lassification TIGAROTIGARO

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

6. Autoimmune pancreatitis 1961H. SarlesChronic inflammatory sclerosis of the pancreas (Patients with jaundice, painful crises, hyperglobulinemia, no dilatation of pancreatic duct, lymphatic infiltration) 1975 R. Waldram et al Chronic pancreatitis, sclerosing cholangitis and sicca sy in two siblings 1978 S. Nakano et alVanishing tumor of the abdomen in patient with Sjögren´s sy 1995 K. YoshidaConcept of autoimmune pancreatitis 2001B. Etemed, D. Whitcomb TIGARO classification

7. Epidemiology of autoimmune pancreatitis Japan21/4514,6% Yoshida et al. Dig.Dis.Sci. 1995 Korea17/3155,4% Kim et al. Am.J.Gastroenterol. 2004 Italy23/3836,0%Parson et al. Pancreas 2003 Czech Rep. 9/1854,8%Dite et al Best Practice and Res. Clin. Gastroent., 2008

8. Sex ang age onset of autoimmune pancreatitis Nishimori I. et al., Gastroent., 2007

9. Antibodies in patients with AIP % Okazaki et al. J. Gastroent. 2001

10. HISORt CRITERIAS OF AIP CategoryCriteria 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

11. CLINICAL DIAGNOSTIC CRITERIA FOR AIP 2006 1. 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 resonance 2. 2. High serum γ-globulin, IgG, or IgG4, or the presence of autoantibodies such as antinuclear antibodies and rheumatoid factor 3. 3. 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.

12. AUTOIMMUNE PANCREATITIS - SUBTYPES TYP 1 – LYMPHOPLASMATIC SCLEROSING PANCREATITIS – LPSP - PERIDUCTAL LYMPHOPLASMATIC INFILTRATE - HIGH AMMOUNT IgG4 - POSITIVE PLASMA CELLS - SWIRLING FIBROSIS - OBLITERATIVE VENULITIS TYP 2 – IDIOPATHIC DUCT-CENTRIC PANCREATITIS – IDCP (“non-alcoholic duct destructive pancreatitis“) - DUCTAL EPITHELIAL GRANULOCYTIC INFILTRATION DUCTAL DAMAGE OBLITERATION

13. COMPARISON OF TYPE 1 AND TYPE 2 AIP Type 1 AIPType 2 AIP Mean ageSixth decadeFourth decade Gender distributionPredominantly maleEqual Histological patternLymphoplasmacytic sclerosing pancreatitis Duct-destructive pancreatitis Histological hallmarks Periductal lymphoplasmacytic infiltrate Swirling fibrosis Obliterative venulitis Lymphoplasmacyic infiltrate Granulocyte epithelial lesion with partial/complete duct obstruction IgG4 cells on immunostaining Moderate-severe (98%)Moderate (40%) in one study Serum IgG4 levelsElevatedNormal Other organ involvement Chronic sclerosing sialadenitis, IgG4-associated cholangitis, retroperitoneal fibrosis, IgG4- associated tubulointerstitial nephritis Inflammatory bowel disease AIP,autoimmune pancreatitis, IgG4, immunoglobulin G4

14. 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 fibrosis with complications (e.g., ureteral obstruction) Acute Post-acute/late Obstructive jaundice Pancreatitis Steatorrhea Persistent mass Steatorrhea Calcification, atrophy Park, D.H. 2009

15. AUTOIMMUNE PANCREATITIS 23,0% FOCAL FORM (LIKE MALIGNANT LESION) 23,0% FOCAL FORM (LIKE MALIGNANT LESION) DIFFUSE FORM 77,0% (LIKE ACUTE PANCREATITIS) DIFFUSE FORM 77,0% (LIKE ACUTE PANCREATITIS)

21. 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

22. Usefulness of IgG4 in differentiating between pancreatic cancer and autoimmune pancreatitis Kawa et al., Gastroent., 2007

23. Abundant IgG4 – bearing plasma cell infiltration in patients with autoimmune pancreatitis and gastric ulcer 23 pts with AIP and 230 control patients examined by EGD23 pts with AIP and 230 control patients examined by EGD In 8 pts with autoimmune pancreatitis gastric ulcer was found (34.8%). In control group during EGD was gastric ulcer found in 31 pts (13.3%) = p.0007In 8 pts with autoimmune pancreatitis gastric ulcer was found (34.8%). In control group during EGD was gastric ulcer found in 31 pts (13.3%) = p.0007 Conclusion: AIP is closely associated with gastric ulcer with abundant IgG4-bearing plasma cell infiltrationConclusion: AIP is closely associated with gastric ulcer with abundant IgG4-bearing plasma cell infiltration Shinji, A. et al. Gastrointest. Endosc. 2004

24. SET OF PATIENTS WITH AUTOIMMUNE PANCREATITIS (N = 10) GenderAgeOthers autoimmune disease Male36sclerosing cholangitis Male43 Sj ö gren sy Male53Sjögren sy, sick – sinus sy Female 54Sjögren sy, autoim. hepatitis Male56autoimmune hepatitis Male32autoimmune hepatitis Female55primary biliary cirrhosis Male51IBD Male46xxx Female33xxx Female58IgG4 pos. mastitis, sialoadenitis Female52Sicca syndrom Male49IgG4 pos. sclerosing cholangitis Dítě,P. al 2010 One patient died during hospitalization – pancreatic cancer

25. Review of AIP cases with systemic extrapancreatic lesions Western countries (n=172) Japan (n=132) Sjögren´s syndrome1324P<0.01 IBD UC145NS CD40NS Total185P<0.05 Retroperitoneal fibrosis 98NS Thyroid disease41NS Autoimmune hepatitis 02NS Malignant lymphoma20NS 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 2005

26. 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

27. 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

28. Steroid therapy in patients with AIP Initial doses30 – 40 mg per day for 2 – 4 weeksInitial doses30 – 40 mg per day for 2 – 4 weeks The steroid therapy could be stopped after the period of 6 – 12 months.The steroid therapy could be stopped after the period of 6 – 12 months. Monitoring of laboratory and clinical symptoms are essential.Monitoring of laboratory and clinical symptoms are essential. When AIP still appears after steroid therapy --- re-evaluation should be carried out taking pancreatic CARCINOMA into consideration!When AIP still appears after steroid therapy --- re-evaluation should be carried out taking pancreatic CARCINOMA into consideration! J.Jpn.Pacreas Soc., 2002 J.Jpn.Pacreas Soc., 2002

29. THERAPEUTIC OPTIONS IN PATIENTS WITH AIP A) A)MAYO CLINIC – 11 WEEKS STEROIDS WITH TAPPERING DOSE 5 mg / WEEK B) B)KIM – 1 mg/kg FOR 4 WEEKS AND TAPPERING THE DOSE 5 mg/WEEK C) C)FRULLONI – 0,5 mg/kg FOR 4 WEEKS AND TAPPERING THE DOSE 5 mg/WEEK UNEFFECTIVE THERAPY – PANCREATIC CANCER

31. Long-term follow up study treating patients with AIP 23 patients with AIP Pancreatoduode nectomy (N=6) Choledocho duodenostomy (N=4) Supportive therapy (N=3) Steroids (N=10) Steroid therapy 60 mg/day1 pts 40 mg/day1 ptsDuration from 21 – 37 months 30 mg/day7 pts 5 mg/day1 pts Dose was tappered by 2.5 – 5.0 mg every two weeks Maintenance therapy: 5mg daily Follow up period – 4 years 6 monts Kamisawa et al. Pancreatology 2005

32. Long term therapy patients with AIP - prognosis GroupPrognosis (month) Pancreatoduodenectomy (N=6) Died - pulmonary cancer (12) - hepatic failure (48) - pneumonia (12) Alive - 12 and 82 months Unclear - 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

33. AIP – ENDOCRINE AND EXOCRINE FUNCTION AFTER STEROID THERAPY 21 CASES AIP WITH STEROID THERAPY 10 CASES WITH EXOCRINE INSUFICIENCY - -NORMALIZATION8 - -NO CHANGE2 11 CASES WITH DIABETES MELLITUS - -IMPROVEMENT5 - -AGGRAVATION3 - -NO CHANGE3 Ito et al. 2007

34. 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%

35. 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

36. AUTOIMMUNE PANCREATITIS VS PANCREATIC CANCER - RADIOLOGIC IMAGING Autoimmune pancreatitis Pancreatic cancer Complete cutoff of main pancreatic duct UncommonCommon Ductal strictureMultipleLocalized (Single) Upstream duct dilatationMildMarked Duct in the massPresentAbsent Diffuse swelling of the pancreasAlmost alwaysRare Double duct signCommon Kim et al., 2004

37. Usefulness of IgG4 in differentiating between pancreatic cancer and autoimmune pancreatitis Kawa et al., Gastroent., 2007

38. COMPARISON OF SUBJECTS WITH AIP AND PANCREATIC CANCER AIP (N=45)Pacreatic Cancer (N=135) P Value Gender, % male37/45 (82%)79/135 (59%)0,004 Mean age ± SEM59,6 ± 2,567,3 ± 1,10,001 % ≥ age 50 yr34/45 (76%)125/135 (93%)0,002 CA 19-9 > 1003/33 (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 RatioConfidence IntervalP Value IgG4 > 140 mg/dL37,410,6-173,5<0,001 CA19-9 < 3711,73,70-46,2<0,001 Ghazele A. et al. 2007

39. CONCLUSION AND PRACTICE POINTS 1) 1)AIP IS NOT FREQUENT DISEASE IN EUROPE, MORE FREQUENT IN ASIA. 2) 2)CLINICAL SYMPTOMS ARE USUALLY MILD (MOSTLY ABDOMINAL “DISCOMFORT“ WITHOUT PAIN ATTACKS) 3) 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) 4)PRESENCE NON-SPECIFIC ANTIBODIES IN BLOOD SERUM AND INCREASED LEVEL OF IgG AND IgG4 IN SERUM AND TISSUE 5) 5)ASSOCIATION WITH OTHER AUTOIMMUNE DISEASE-TYP1 AIP 6) 6)PANCREATIC CALCIFICATIONS AND/OR CYSTOIDS ARE NOT FREQUENT 7) 7)THERAPY WITH STEROIDS IS EFFECTIVE 8) 8)IN DIF. DG DIAGNOSIS AIP VS PANCREATIC CANCER – EUS GUIDED BIOPSY IS FUNDAMENTAL PROCEDURE