Treatment of refractory patients with autoimmune liver diseases - PowerPoint Presentation

1. Treatment of refractory patients with autoimmune liver diseasesIskren KotzevMedical University, VarnaЛечение на рефрактерни пациенти с автоимунни чернодробни болести

2. Primary biliary cholangitisAASLD PRACTICE GUIDELINESPBC 2009EASL - 2017

3. Standart therapyUDCATreatment leading to a cure is not avaiable (Strassbourg,2004)UDCA is the only approved treatment for patients with PBC Improvement in liver biochemistriesDelayed histologic progressionDelayed development of oesophageal varices Prolong transplant free survivalUDCA at a dose of 13-15 mg/kg is proven benefitZein, C.O. and K.D. Lindor, Latest and emerging therapies for primary biliary cirrhosis and primary sclerosing cholangitis. Curr Gastroenterol Rep, 2010. 12(1): p. 13-22.Corpechot, C., et al., Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology, 2008. 48(3): p. 871-7.Steven Flamm,, Raoul Poupon, Up todate, Oct 15, 2015

4. Probability of response (defined as the absence of treatment failure) to UDCA in PBCPoupon RE, Poupon R, Balkau B, and the UDCA-PBC Study Group, N Engl J Med 1994; 330:1342.

5. UDCA slows disease progression in PBCPoupon RE, Poupon R, Balkau B, and the UDCA-PBC Study Group, N Engl J Med 1994; 330:1342.

6. Survival depends on response to therapyvan der Meer AJ, et al. Hepatology 2017;66:149-1185.

7. Criteria for biochemical response to UDCA in PBC Various risk scores have been validated to access the response of UDCA in patients with PBC: CriteriaAfterAdequate biochemical response to UDCARochesterAngulo et al. (1999)6 monthsALP < 2х ULN and Mayo score < 4.5BarcelonaPares et al. (2006)1 year↓serum ALP > 40% or normalisationParis ICorpechot et al. (2008)1 yearALP ≤ 3 x ULN, AST ≤ 2 x ULN and serum albumin ≤ 1mg/dlRotterdamKuiper et al. (2009)1 yearNormalisation of abnormal ser. bilirubin and/or ser. albumin TоrontoKumagi et al. (2010)2 yearsALP < 1.67 x ULNParis IICorpechot et al. (2011)1 yearALP and AST < 1.5 x ULN, serum bilirubin <1mg/dl

8. Criteria for biochemical response to UDCA in PBCCriteriaAfterAdequate biochemical response to UDCABiochemical + APRI (2014)1 yearBiochemical response (Barcelona, Paris-I/II, or Toronto) + APRI UK-PBC Risk Score (2015)1 yearAlbumin, Thr, Bilirubin, AP, AST(ALT) GLOBE Score (2015)1 yearAge, Bilirubin, AP, albumin, Thr EhimeAzemoto el al. (2011)6 months↓ GGT > 70% or normalisation Early biochemical response 6 monthsBarcelona, Paris-I, or Toronto criteria

9. About 40% of patients have a suboptimal response to UDCA and subsequently need additional therapyPares A, et al. Gastroenterology 2006;130:715-720.Corpechot C, et al. Hepatology 2008;48:871-877.Kuiper EM, et al. Gastroenterology 2009;136:1281-1287Corpechot C, et al. Journal of hepatology 2011;55:1361-1367.Kumagi T, et al. The American journal of gastroenterology 2010;105:2186-2194

10. EASL Clinical Practice GuidelineEASL Clinical Practice Guideline

11. Treatment of refractory patients (non-responders)OCA (FXR-аgonist) – approvedFibrates (PPAR-α аgonists) - off-labelBudesonid – off-label

12. Obeticholic acid (OCA) [farnesoid X receptor (FXR) agonist] OCA (Ocaliva) is a semi-synthetic bile acid analogue which has the chemical structure 6α-ethyl-chenodeoxycholic acidOCA is a derivative of the primary human bile acid chenodeoxycholic acid (CDCA)It is a ligand for the farnesoid X receptor, which plays a role in bile acid homeostasis

13. Obeticholic acid (OCA) [farnesoid X receptor (FXR) agonist] FXR is expressed in liver,intestine, adrenal glands and kidneys and has an important role in the enterohepatic circulation of bile acidsOCA is a more potent agonist of the receptor (approximately 100-fold higher potency) than CDCAFXR reduces bile acid synthesis by acting on the enzyme cholesterol 7a hydroxylase and also by down-regulating the expression of the Na-taurocholate cotransporting peptideSilveira, M.G. and K.D. Lindor, Obeticholic acid and budesonide for the treatment of primary biliary cirrhosis. Expert Opin Pharmacother, 2014. 15(3): p. 365-72.Parés, A., Treatment of primary biliary cirrhosis: Is there more to offer than ursodeoxycholic acid? Clinical Liver Disease, 2014. 3(2): p. 29-33.

14. Obeticholic acid (OCA) [farnesoid X receptor (FXR) agonist] Induces hydroxylation and conjugation of the bile acidsReduces hepatocellular penetration of bile acidsPruritus is the most common side effects and seen at high dose Silveira, M.G. and K.D. Lindor, Obeticholic acid and budesonide for the treatment of primary biliary cirrhosis. Expert Opin Pharmacother, 2014. 15(3): p. 365-72.Parés, A., Treatment of primary biliary cirrhosis: Is there more to offer than ursodeoxycholic acid? Clinical Liver Disease, 2014. 3(2): p. 29-33.

15. OCAObeticholic acid appears to be effective in reducing AP, GGT and TAOCA in patients with PBC have demonstrated marked biochemical improvement when administered in combination with UDCA and aloneObeticholic acid has not been demonstrated to improve survivalSilveira, M.G. and K.D. Lindor, Obeticholic acid and budesonide for the treatment of primary biliary cirrhosis. Expert Opin Pharmacother, 2014. 15(3): p. 365-72.Parés, A., Treatment of primary biliary cirrhosis: Is there more to offer than ursodeoxycholic acid? Clinical Liver Disease, 2014. 3(2): p. 29-33.

16. OCA - studiesOngoing phase 4 study COBALT – assessing clinical outcomeClinical Trials.gov Identifier: NCT02308111

17. OCA – responce: POISE Study (up to >60%)Nevens F, et al The New England journal of medicine 2016;375:631-643.

18. OCA – еffect on ALP: POISE StudyNevens F, et al The New England journal of medicine 2016;375:631-643.

19. OCA – еffect on bilirubin: POISE StudyNevens F, et al The New England journal of medicine 2016;375:631-643.

20. Еffects of OCA according POISE-studySignificant reduction of AP, ALT, AST, GGT, bilirubin Significant reduction of inflammatory markersNo changes in the liver stiffnessSignificant reduction of bile acids levelsPruritus – dosing adjustment Nevens F, et al The New England journal of medicine 2016;375:631-643.

21. OCA is approvedCombination OCA+UDCA for refractory PBC patients, treated at least 1 year and with inadequate response OCA-monotherapy for PBC patients, not tolerated UDCAOCA has antifibrotic property and decreases portal pressureAli AH, et al. Expert opinion on pharmacotherapy 2016;17:1809-1815

22. FibratesCombine therapy Fenofibrate/Bezafibrate + UDCA leeds to significant biochemical improvement among refractory patients with PBC Cheung AC, et al. Hepatology 2014;60:345A-346A.Grigorian AY, et al. Clinics and research in hepatology and gastroenterology 2015;39:296-306Yin Q, et al. Drug design, development and therapy 2015;9:5407-5419.Zhang Y, et al. Hepatology research 2015;45:48-58Freissmuth C, Ket al. Journal of hepatology 2016;64:S434-S435.Harms MH, et al. Hepatology 2016;64:108-109ANo influence to survival, free of transplantation The effects of Beza- and Fenofibrate are similar Harms MH, et al. Hepatology 2016;64:108-109A.Cheung AC, et al. Hepatology 2014;60:345A-346A.

23. Fibrates – BEZURSO Study (phase 3)BZF + UDCA – well tolerated, normalizes biochemical prognostic markers, decreases pruritus and prevents of the progression of the liver stiffness among PBC patients with nonadequate response to UDCA Corpechot C, et al. Journal of hepatology 2017;66:S89

24. BudesonideUDCA + MMF + Budesonide improves: Biochemical markers Histology activity FibrosisRabahi N, et al. Gastroenterologie clinique et biologique 2010;34:283-287.

25. Other drugs (CS & IS)Other drugs have been tested, but none have been found as single agents to be of benefit:CorticosteroidsChlorambucil Cyclosporine AzathioprineMethotrexate Mycophenolate mofetil Penicillamine ThalidomideMalotilate MolchicineLindor, K.D., et al., Primary biliary cirrhosis. Hepatology, 2009. 50(1): p. 291-308.

26. Normalization of liver biopsy after 6 years treatment with methotrexate for PBCKaplan M, DeLellis R, Wolfe H. Ann Intern Med 1997; 126:682

27. Experimental (antiviral) therapySuggestion - beta retrovirus might be involved in the pathogenesis of PBC There is a good biochemical response seen in patient taking lamivudine and zidovudine but complete biochemical normalisation was not observedThe study did not showed any correlation with virus and biochemical response and as a result, treatment is not recommended in PBCMason, A.L., et al., Clinical Trial: Randomized controlled trial of zidovudine and lamivudine for patients with primary biliary cirrhosis stabilized on ursodiol. Aliment Pharmacol Ther, 2008.

28. Experimental (future?) therapiesPilot studies and randomized controlled trials have evaluated various agents in PBC:Mesenchymal stem cells (replace host immune system)Rituximab (B-cells depletion)Moexipril - ACE inhibitor (antifibrotic)Abatacept (T-cells inhibition)Microbiome (of PBC differs from healthy subjects)www.clinicaltrials.gov;2017

29. Liver transplantationSurvival rate (%)Liver transplantation is the treatment for patients with decompensated liver cirrhosis after 5 years after 8 years PBC (n = 1339) 76 % 71 %Alcohol cirrhosis (n = 2954) 69 % 62 %Viral hepatitis (cirrhosis) (n = 4631) 66 % 61 %U. Leuschner;Interdisziplinäres Facharztzentrum;2014

30. Autoimmune hepatitisEASL -2015AASLD PRACTICE GUIDELINESAutoimmune hepatitis 2010

31. Survival in classic autoimmune hepatitisRoberts SK, Therneau TM, Czaja AJ. Gastroenterology 1996; 110:848

32. 0 1 2 3 4 5 6 7 8 9 10 Time [Years after start of therapy]100 80 60 40 20 0Treatment with steroidsSurvival rate [%]PlaceboSteroidsModified after Kirk et al.(1980)

33. Standart treatmentPredniso(lo)ne (0,5-1mg/kg – 60 mg→40 →30 →20 and less (for maintenance)Steroid side effects: hirsutism, diabetes, osteopenia, facies lunataAfter 12 months – in 44% After 24 months – in 80%Prednisolone(30→20→15→10)+Azathioprine (EU-1-2 mg/kg/day; USA-50 mg/day)Steroid side effects: in 10%Azathioprine side effects: pancreatitis, nausea, leukopenia, rashes and cholestatic hepatitis – in 15%6-MercaptopurineBudesonide?Manns, M.P., et al., Diagnosis and management of autoimmune hepatitis. Hepatology,2010. 51(6): p. 2193-2213.

34. EASL Clinical Practice GuidelineEASL - Тhеrapeutic strategy in AIH

35. Response to therapy90% - within first 2 weeks - improvment in Ig & liver enzymesRemission - up to 75%Treatment failure - 10%Suboptimal responseRelapse Relapsed AIH – ↑3xULN of transaminasesMore potent treatment (alternative treatment):Mycophenolate mofetilTacrolimus Manns, M.P., et al., Diagnosis and management of autoimmune hepatitis. Hepatology,2010. 51(6): p. 2193-2213.

36. Second line therapyAutoimmune hepatitis

37. Role of BudesonideInstead of Predniso(lo)nInductionRemissionAproved for AIH in 23 European and 13 Non-European countriesBudesonide should not be given to cirrhotic patients due toPortal hypertension and loss of ‘’topical effects’’M. Manns, AIH. AASLD; 2017

38. MMF (Mycophenolate mofetil)MMF inhibits T- and B-Ly proliferationTeratogenicMMF – good alternative for patients with intolerance to AZA, or with limited efficacy in refractory patientsHennes EM, et al. Am J Gastroenterol 2008;103:3063–3070.Sharzehi K, et al. Can J Gastroenterol 2010;24:588–592Efe C, et al. Clinical gastroenterology and hepatology 2017 doi: 10.1016/j.cgh.2017.06.001

39. 6-ThioguanineЕffective and well tolerated in AIH patients, who are non-responders or non-tolerated to conventional thiopurins (AZA или 6-MP)van den Brand FF, et al. Journal of hepatology 2017;66:S353-S3546-mercaptopurine metabolism

40. Cacineurin inhibitors (Cyclosporin A и Tacrolimus)Blocks selectively lymphocytes proliferationМultiple small studies support their effcasy and tolerabilityAl Taii H, et al. Scandinavian journal of gastroenterology 2016:1-5.Efe C, et al. Hepatology 2015;62:368A.Sherman KE, et al. J Hepatol 1994;21:1040–1047.Fernandes NF, et al. Am J Gastroenterol 1999;94:241–248Aqel BA, et al. J Clin Gastroenterol 2004;38:805–809Larsen FS, et al. World J Gastroenterol 2007;13:3232–3236Tannous MM, et al. Aliment Pharmacol Ther 2011;34:405–407Efe C, et al. Clinical gastroenterology and hepatology 2017 doi: 10.1016/j.cgh.2017.06.001

41. Cyclosporin AInhibits T cell function via Interleukin 2 geneExpirience with Cyclosporin A in AIH is limitedStrasbourg, 2008

42. TacrolimusMacrolide antibiotic Main side effect - renal toxicityCyclosporin A и Tacrolimus can be used as a rescue therapy for difficult to treat AIH patientsEfe C, et al. Clinical gastroenterology and hepatology 2017 doi: 10.1016/j.cgh.2017.06.001

43. Second line therapy for treatment failures: Alternative drugsDoseSide effectCyclosporin A3-5mg/kgHypertension, Renal insuff.Tacrolimus2x 3 mgHypertension, Renal insuff.Diabetes, NeuropathyMycophenolate Mofetil2x 750-1000 mgDiarrhea, Leukopenia6-Thioguanine20 mg/day6-Mercaptopurine1,5 mg/kgMethotrexate10 mg/weekCyclophosphamide1-1,5 mg/kgCystitis, LeukopeniaEverolimus2x 0,75-1,5 mgProteinuria, UlceraM. Manns, AIH. AASLD; 2017

44. Management of failures to SOCBiologicals:Anti TNFAnti CD 20 (Rituximab)Anti B cellM. Manns, AIH. AASLD; 2017

45. Anti-TNFα - InfliximabRecombinant humanized chimeric antibody against TNF-ɑ11 patients with refractory AIH – decrease of transaminases and immunoglobulinsBovensiepen CS, et al. Journal of hepatology 2017;66:S359.Weiler-Normann C, etl al. J Hepatol 2013;58:529–534Borman MA, et al. J Hepatol 2014;61:169–170.

46. RituximabAnti-CD 20 chimeric monoclonal antibodyActs via B cell depletionWell tolerated and no significant side effectsBiochemical response in patients with refractory or intolerant to other treatment (Burak et al.)

47. Rituximab for the treatment of patients with autoimmune hepatitis who are refractory or intolerant to standard therapyKelly W Burak, Mark G Swain, Tania Santodomino-Garzon, Samuel S Lee, Stefan J Urbanski, Alexander I Aspinall, Carla S Coffin, Robert P MyersRituximab, not yet approved for AIH by FDA, was safe, well tolerated and resulted in biochemical improvement in subjects with refractory AIH.We need more investigations of Rituximab or other anti B-cells agents as a treatment for AIH Can J Gastroenterol Vol 27 No 5 May 2013

48. Liver transplantationAutoimmune hepatitis is an acceptable reason for liver transplantation, with frequency of survival exceeding 75% at 5 and 10 years after transplantationVision of Prof. M. Manns (2017) – we don`t need more OLT for AIH!Miyake, Y., et al., Clinical characteristics of fulminant-type autoimmune hepatitis: an analysisof eleven cases. Aliment Pharmacol Ther, 2006. 23(9): p. 1347-53.Kanzler, S., et al., Duration of immunosuppressive therapy in autoimmune hepatitis. J Hepatol,2001. 34(2): p. 354-5.Yeoman, A.D., et al., Evaluation of risk factors in the development of hepatocellular carcinomain autoimmune hepatitis: Implications for follow-up and screening. Hepatology, 2008.48(3): p. 863-70.Survival after liver transplantation in the United States: a disease-specificanalysis of the UNOS database. Liver Transpl, 2004. 10(7): p. 886-97.

49. Using 2nd line therapy in real worldLiberal R, et al. Alimentary pharmacology & therapeutics 2017;45:723-732.

50. Summary First line SOCSteroids ± AZASecond line Budesonide instead of predniso(lo)nMMF, CyA, TAC, 6-thioguanine instead of AZAAnti TNF, anti CD20, anti CD3, anti B cellsCellular therapies: T regs transfer/IL2 Treg support

51. Primary sclerosing cholangitisAASLD PRACTICE GUIDELINESPrimary sclerosing cholangitis 2009EASL -2017

52. Standart therapyToday, there is no effective treatment Only treatment for end stage of PSC is OLTSometimes earlier, not fulfil MELD criteria

53. Drug therapyThere is no medical therapy with aproved benefit on survivalStandard doses of UDCA lead to improvements in biochemical abnormalities but not in histology, cholangiographic appearances, or survival No difference in fatigue, mortality, histologic progression or development of cholangiocarcinoma for standart (10-15 mg/kg/day) or high dose (17-23 mg/kg/day) UDCATriantos C. et al. Aliment Pharmacol Ther 2011;34(8):901-10Lindor KD, et al. Hepatology. 2009 Sep;50(3):808-14Imam MH, Sinakos E, Gossard AA, et al. High-dose ursodeoxycholic acid increases risk of adverse outcomes in patients with early stage primary sclerosing cholangitis. Aliment Pharmacol Ther 2011; 34:1185

54. AntibioticsThe rationale for antibiotic therapy in PSC is based upon studies in rodents with hepatobiliary disease (resembling PSC) and intestinal overgrowMetronidazole vs UDCA + MetronidazolImprovement of liver probs HistologyMayo risk scoreTendence to halt progression of ERCP-changesVancomycin / Metronidazole - improvement at least in 1: APBilirubinMayo PSC risk scorePruritusFatigueFarkkila M, et al.Hepatology. 2004;40(6):1379-86Tabibian JH, et al. Alimentary pharmacology & therapeutics 2013;37(6):604-12

55. Еndoscopic treatment

56. Еndoscopic treatmentFor patients with high-grade strictures, endoscopic dilation is beneficialSurvival is equal using balon dilation and stentingAt patients with intact papilla – the baloon dilation is the first method of choiseIntrabiliary instilation of Mytomycin C during ERCP?Ponsioen C, et al. J of Hepatol 2017;66:S1-S2ClinicalTrials.gov Identifier: NCT01688024

57. None of these therapies has been shown to halt disease progressionColchicine CholestyramineMycophenolate mofetilDocosahexaenoic acidHirschfield, G.M., et al., Primary sclerosing cholangitis. Lancet, 2013. 382(9904): p. 1587-99.Henriksen, E.K., E. Melum, and T.H. Karlsen, Update on primary sclerosing cholangitis genetics. Current opinion in gastroenterology, 2014. 30(3): p. 310-9.Karlsen, T.H. and K.M. Boberg, Update on primary sclerosing cholangitis. Journal of hepatology, 2013. 59(3): p. 571-82.

58. Glucocorticoids No studies have demonstrated a long-term benefit from glucocorticoid therapy (incl. Budesonide), either alone or in combination with other agentsAngulo P, Batts KP, Jorgensen RA, et al. Oral budesonide in the treatment of primary sclerosing cholangitis. Am J Gastroenterol 2000; 95:2333.

59. Cyclosporine and tacrolimusCyclosporine - decrease in ALPTacrolimus - bilirubin and ALP declined by over 50% and pruritus was improved without any significant change in ERCP findings or histology Kyokane K, Ichihara T, Horisawa M, et al. Successful treatment of primary sclerosing cholangitis with cyclosporine and corticosteroid. Hepatogastroenterology 1994; 41:449Van Thiel DH, Carroll P, Abu-Elmagd K, et al. Tacrolimus (FK 506), a treatment for primary sclerosing cholangitis: results of an open-label preliminary trial. Am J Gastroenterol 1995; 90:455.

60. Methotrexate, Azathioprine and 6-mercaptopurineMethotrexate —only in reduction in ALP, without any changes in histology, ERCP and liver function testsMethotrexate + UDCA - no benefit compared with treatment with UDCA aloneAzathioprine and 6-mercaptopurine — varying resultsKnox TA, Kaplan MM. Treatment of primary sclerosing cholangitis with oral methotrexate. Am J Gastroenterol 1991; 86:546.Knox TA, Kaplan MM. A double-blind controlled trial of oral-pulse methotrexate therapy in the treatment of primary sclerosing cholangitis. Gastroenterology 1994; 106:494.Lindor KD, Jorgensen RA, Anderson ML, et al. Ursodeoxycholic acid and methotrexate for primary sclerosing cholangitis: a pilot study. Am J Gastroenterol 1996; 91:511.Javett SL. Azathioprine in primary sclerosing cholangitif. Lancet 1971; 1:810.Wagner A. Azathioprine treatment in primary sclerosing cholangitis. Lancet 1971; 2:663.Kaplan MM. Medical approaches to primary sclerosing cholangitis. Semin Liver Dis 1991; 11:56.

61. Combination therapy AZA + prednisolone + UDCA - improvement in liver biochemical tests and liver histologyBudesonide + UDCA - no benefitPrednisone + UDCA - minor short-term effect UDCA + Metronidazole - histologic improvement in the preliminary report of a small randomized controlled trialFarkkila MA, Karkkainen P, Karvonen AL, et al. Combination of ursodeoxycholic acid (UDCA) and metronidazole (MTZ) in PSC: Reduction of inflammation in liver correlates with the decrease of the New Mayo Risk Score. Gastroenterology 2003; 124:A707.Färkkilä M, Karvonen AL, Nurmi H, et al. Metronidazole and ursodeoxycholic acid for primary sclerosing cholangitis: a randomized placebo-controlled trial. Hepatology 2004; 40:1379van Hoogstraten HJ, Vleggaar FP, Boland GJ, et al. Budesonide or prednisone in combination with ursodeoxycholic acid in primary sclerosing cholangitis: a randomized double-blind pilot study. Belgian-Dutch PSC Study Group. Am J Gastroenterol 2000; 95:2015

62. 24-norUDCA - promising

63. HCO3-HOOHCOO -PhospholipidsnorUDCABile acidsdetoxication and alternativetransport↑hydrophilityАntiproliferativeАntifibroticAntiinflammatory24-norUDCA - promisingPotent anti-cholestatic, anti-inflammatory and anti-fibrotic properties in a preclinical PSC mouse model24-norUDCA induces bile acid detoxification via hydroxylation, sulfation and glucuronidation, resulting in better water soluble and less toxic bile acid metabolitesMichael Trauner, Alan Hofmann, Peter Fickert; EP20110176271, 22. Juni 2016

64. 24-norUDCA (ALP)Phase II studynorUDCA reduces AP in 12 weeks Еffect of norUDCA on liver enzymes is dose-dependent Excellent safety (similar to PBO)Fickert P, et al. Journal of hepatology 2017;67:549-558.

65. 24-norUDCA (ALP, γGT, ALT, AST)Fickert P, et al. Journal of hepatology 2017;67:549-558.

66. FibratesSmall studies shows their efficasy in improvement of biochemical markersKita R, et al. The American journal of gastroenterology. 2002;97(7):1849-51.Mizuno S, et al.Journal of hepato-biliary-pancreatic sciences. 2015;22(10):766-70.Mizuno S, et al. Journal of gastroenterology 2010;45(7):758-62Chazouilleres O, et al. Hepatology 2010;52:488A. Dejman A, et al. vGastroenterology 2013;144:S1028-S1029.

67. Аntifibrotics - simtuzumabHumanized IgG4 monoclonal antibody against LOXL2No effect on prevention of fibrosis progression in patients with PSCMuir A, et al. Journal of hepatology 2017;66:S73

68. Probiotics Probiotics were studied in a randomized, placebo-controlled, crossover study of 14 patients with PSC There was no effect on symptoms (fatigue, pruritus, or stool frequency) or in laboratory parametersLaRusso NF, Shneider BL, Black D, et al. Primary sclerosing cholangitis: summary of a workshop. Hepatology 2006;44: 746–764Vleggaar FP, Monkelbaan JF, van Erpecum KJ. Probiotics in primary sclerosing cholangitis: a randomized placebo-controlled crossover pilot study. Eur J Gastroenterol Hepatol 2008; 20:688.

69. Penicillamine Randomized trial suggested no benefit on disease progression and more frequent side effectsIncreased hepatic copper stores in PSC are secondary to cholestasis rather than a primary event, perhaps explaining the lack of efficacy of penicillamineLaRusso NF, Wiesner RH, Ludwig J, et al. Prospective trial of penicillamine in primary sclerosing cholangitis. Gastroenterology 1988; 95:1036.Kowdley KV, Knox TA, Kaplan MM. Hepatic copper content is normal in early primary biliary cirrhosis and primary sclerosing cholangitis. Dig Dis Sci 1994; 39:2416.

70. OthersFMTNCT02424175Cenicriviroc Phase IICCR2/CCR5NCT02653625 BTT1023 Phase IIanti-Vap-1 NCT02239211OCAPhase IIFXRNCT02177136www.clnicaltrial.gov

71. Anti-TNF agentsAmong the anti-TNF drugs, etanercept was of no benefit in a pilot study of 10 patientsInfliximab was ineffective in a placebo-controlled, double-blind study in 24 patientsEpstein MP, Kaplan MM. A pilot study of etanercept in the treatment of primary sclerosing cholangitis. Dig Dis Sci 2004; 49:1.Hommes DW, Erkelens W, Ponsioen C, et al. A double-blind, placebo-controlled, randomized study of infliximab in primary sclerosing cholangitis. J Clin Gastroenterol 2008; 42:522.

72. Vedolizumab - promisingTreatment with vedolizumab, antiintegrin α4β7Selectively blocks gut lymphocyte traffickingMay improve or slow progression of inflammation and fibrosis of the biliary treeEksteen B, et al. Gastroenterology 2016;150:S1268.Westerveld D et al. BMJ case reports 2017;2017.Feagan BG, Rutgeerts P,Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013;369:699–710.doi:10.1056/NEJMoa1215734[CrossRef][Medline][Web of Science]Google Scholar

73. Liver transplantationLiver transplantation is successful for end-stage liver disease related to PSC and improves survivalThe most dreaded complication of PSC is cholangiocarcinoma (10-20%), CRC 10X risk for PSC+UC, pancreatic cancer -14x riskRazumilava N, Gores GJ, Lindor KD. Cancer surveillance in patients with primary sclerosing cholangitis. Hepatology 2011; 54:1842

74. PBC, AIH, PSCThe treatment of refractory patients with these diseases in XXI century remains a challenge

75. Acknowledgments!