Almanac of Clinical MedicineAlmanac of Clinical MedicineАльманах клинической медицины2072-05052587-9294Moscow Regional Research and Clinical Institute (MONIKI)88710.18786/2072-0505-2018-46-5-504-513POINT OF VIEWТОЧКА ЗРЕНИЯAlternative treatment regimens in autoimmune hepatitis: how justified is their choice?Альтернативные схемы терапии аутоиммунного гепатита: насколько обоснован их выбор?MatsievichM. V.МациевичМ. В.
Russian Federation

Mariya V. Matsievich - MD, PhD, Head of the Department of Gastroenterology.

57 Gilyarovskogo ul., Moscow, 129110.

Tel.: +7 (925) 100 51 22.

Мациевич Мария Владиславовна – кандидат медицинских наук, заведующая гастроэнтерологическим отделением.

129110, Москва, ул. Гиляровского, 57.

Тел.: +7 (925) 100 51 22.

macievich@gmail.comBueverovA. O.БуеверовА. О.
Russian Federation

Aleksey O. Bueverov - MD, PhD, Professor, Leading Research Fellow, Department of Hepatology MONIKI; Chair of Medical and Social Expert Assessment and Out-Patient Therapy, Postgraduate Medical Training Faculty; Leading Research Fellow, Department of Research on Innovative Therapy, Research Center, I.M. Sechenov First Moscow State Medical University.

61/2 Shchepkina ul., Moscow, 129110; 8/2 Trubetskaya ul., Moscow, 119991.

Буеверов Алексей Олегович – доктор медицинских наук, ведущий научный сотрудник отделения гепатологии ГБУЗ МО МОНИКИ; профессор  кафедры медико-социальной экспертизы и поликлинической терапии факультета послевузовского профессионального образования врачей; ведущий научный сотрудник научно-исследовательского отдела инновационной терапии научно-исследовательского центра Сеченовского Университета.

129110, Москва, ул. Щепкина, 61/2; 119991, Москва, ул. Трубецкая, 8/2.

PetrachenkovaM. Yu.ПетраченковаМ. Ю.
Russian Federation

Mariya Yu. Petrachenkova - MD, Gastroenterologist.

29 Marshala Timoshenko ul., 121359, Moscow.

Петраченкова Мария Юрьевна – врач-гастроэнтеролог.

121359, Москва, ул. Маршала Тимошенко, 29.

Tsentrosoyuz Clinical HospitalООО «Клиническая больница Центросоюза»Moscow Regional Research and Clinical Institute (MONIKI)ГБУЗ МО «Московский областной научно-исследовательский клинический институт им. М.Ф. Владимирского»I.M. Sechenov First Moscow State Medical UniversityФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава РоссииMedical Center "SM-Clinic"Медицинский центр «СМ-Клиника»191120184655045131711201817112018Copyright ©; 2018, Matsievich M.V., Bueverov A.O., Petrachenkova M.Y.Copyright ©; 2018, Мациевич М.В., Буеверов А.О., Петраченкова М.Ю.2018Matsievich M.V., Bueverov A.O., Petrachenkova M.Y.Мациевич М.В., Буеверов А.О., Петраченкова М.Ю.https://creativecommons.org/licenses/by/4.0https://almclinmed.ru/jour/article/view/887

Autoimmune hepatitis is a progressive immune-mediated liver disease of unknown etiology. Its key characteristics include hyper-gammaglobulinemia, circulating autoantibodies, and periportal inflammation seen in a liver biopsy sample. It is not infrequent that the lack of unified diagnostic tests makes the verification of the disease very challenging. Most patients respond well to standard immunosuppressive therapy; however, a significant proportion of them demonstrate side effects and disease relapses after treatment withdrawal. A wide range of side effects of systemic steroids and eventual disruptions with azathioprine (the agent of choice in the treatment algorithms for autoimmune hepatitis) supplies to the Russian market make it relevant to use alternative treatment regimens. In the real world practice, alternative treatment regimens are rarely used in such patients due to the absence of hard evidence of their efficacy. Low prevalence of autoimmune hepatitis, multiplicity of its clinical types, as well as a lack of understanding of its pathogeneticmechanisms hinder the synthesis of new agents and performing trials with already known immunosuppressants with a statistical power necessary to obtain persuasive data. One of solutions of the problem could be the accumulation of clinical data into registries for further systematization of the knowledge and formulation of new clinical guidelines.

Аутоиммунный гепатит – прогрессирующее иммуноопосредованное заболевание печени неизвестной  этиологии, к ключевым диагностическим характеристикам  которого  относят гипергаммаглобулинемию, циркуляцию в крови аутоантител и перипортальное воспаление, выявленное при исследовании гепатобиоптата. Отсутствие унифицированных диагностических тестов нередко  создает существенные трудности верификации заболевания.  Большинство пациентов хорошо отвечают на стандартную иммуносупрессивную  терапию, однако  значительная их часть сталкивается с побочными эффектами, а также рецидивом заболевания после отмены лечения. Широкий спектр побочных эффектов системных стероидов и периодические перебои  с поступлением на российский рынок азатиоприна  – препарата  первой  линии в схемах лечения аутоиммунного гепатита – ставят вопрос  об использовании альтернативных вариантов  лечения. В реальной  практике альтернативные  схемы редко  назначаются  таким пациентам в связи с отсутствием весомых доказательств  их эффективности. Невысокая распространенность аутоиммунного  гепатита, многообразие клинических вариантов заболевания, а также отсутствие понимания  механизмов  его формирования затрудняют синтез новых препаратов и проведение клинических исследований уже известных иммуносупрессоров с необходимой  для получения  убедительных данных мощностью. Решением  проблемы видится аккумулирование клинических данных в  регистры  для  дальнейшей   систематизации знаний и формулирования новых клинических рекомендаций.

autoimmune hepatitisprednisoloneazathioprineside effectalternative treatment regimenmycophenolate mofetilmercaptopurineliver toxicitycyclosporineаутоиммунный гепатитпреднизолоназатиопринпобочные эффектыальтернативные схемы лечениямикофенолата мофетилмеркаптопурингепатотоксичностьциклоспорин1. Zachou K, Muratori P, Koukoulis GK, Granito A, Gatselis N, Fabbri A, Dalekos GN, Muratori L. Review article: autoimmune hepatitis - current management and challenges. Aliment Pharmacol Ther. 2013;38(8):887-913. doi: 10.1111/apt.12470.2. Ивашкин ВТ, Буеверов АО. Аутоиммунные заболевания печени в практике клинициста. 2-е изд. М.: М-Вести; 2011.112 с.3. Широкова ЕН, Ивашкин КВ, Ивашкин ВТ. Аутоиммунный гепатит: новое в диагностике, патогенезе и лечении. Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2012;22(5):37-45.4. Baven-Pronk MAMC, Biewenga M, van Silfhout JJ, van den Berg AP, van Buuren HR, Verwer BJ, van Nieuwkerk CMJ, Bouma G, van Hoek B. Role of age in presentation, response to therapy and outcome of autoimmune hepatitis. Clin Transl Gastroenterol. 2018;9(6):165. doi: 10.1038/s41424-018-0028-1.5. Chen J, Eslick GD, Weltman M. Systematic review with meta-analysis: clinical manifestations and management of autoimmune hepatitis in the elderly. Aliment Pharmacol Ther. 2014;39(2):117-24. doi: 10.1111/apt.12563.6. Шапиро ИЯ, Сек Ок Сун. Молекулярные механизмы повреждения при аутоиммунном гепатите. Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2001 ;11(1 Прилож 12):20.7. Manns MP, Vogel A. Autoimmune hepatitis, from mechanisms to therapy. Hepatology. 2006;43(2 Suppl 1):S132-44. doi: 10.1002/hep.21059.8. Perumalswami P, Peng L, Odin JA. Vaccination as a triggering event for autoimmune hepatitis. Semin Liver Dis. 2009;29(3):331-4. doi: 10.1055/s-0029-1233537.9. Buechter M, Manka P, Heinemann FM, Lindemann M, Baba HA, Schlattjan M, Canbay A, Gerken G, Kahraman A. Potential triggering factors of acute liver failure as a first manifestation of autoimmune hepatitis - a single center experience of 52 adult patients. World J Gastroenterol. 2018;24(13):1410-8. doi: 10.3748/wjg.v24.i13.1410.10. Vispo E, Maida I, Moreno A, Barreiro P, Soriano V. Autoimmune hepatitis induced by pegylated interferon in an HIV-infected patient with chronic hepatitis C. J Antimicrob Chemother. 2008;62(6):1470-2. doi: 10.1093/jac/dkn416.11. Adar T, Mizrahi M, Pappo O, Scheiman-Elazary A, Shibolet O. Adalimumab-induced autoimmune hepatitis. J Clin Gastroenterol. 2010;44(1):e20-2. doi: 10.1097/MCG.0b013e3181a745e7.12. Czaja AJ, Manns MP. The validity and importance of subtypes in autoimmune hepatitis: a point of view. Am J Gastroenterol. 1995;90(8): 1206-11.13. Obermayer-Straub P, Strassburg CP, Manns MP. Autoimmune hepatitis. J Hepatol. 2000;32(1 Suppl):181-97.14. Mieli-Vergani G, Vergani D. Autoimmune hepatitis in children: what is different from adult AIH? Semin Liver Dis. 2009;29(3):297-306. doi: 10.1055/s-0029-1233529.15. Ichai P, Duclos-Vallee JC, Guettier C, Hamida SB, Antonini T, Delvart V, Saliba F, Azoulay D, Castaing D, Samuel D. Usefulness of corticosteroids for the treatment of severe and fulminant forms of autoimmune hepatitis. Liver Transpl. 2007;13(7):996-1003. doi: 10.1002/lt.21036.16. Czaja AJ, Bayraktar Y. Non-classical phenotypes of autoimmune hepatitis and advances in diagnosis and treatment. World J Gastroenterol. 2009;15(19):2314-28. doi: 10.3748/wjg.15.2314.17. Johnson PJ, McFarlane IG. Meeting report: International Autoimmune Hepatitis Group. Hepatology. 1993;18(4):998-1005. doi: 10.1002/hep.1840180435.18. Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, Chapman RW, Cooksley WG, Czaja AJ, Desmet VJ, Donaldson PT, Eddleston AL, Fainboim L, Heathcote J, Homberg JC, Hoofnagle JH, Kakumu S, Krawitt EL, Mackay IR, MacSween RN, Maddrey WC, Manns MP, McFarlane IG, Meyer zum Buschenfelde KH, Mieli-Vergani G, Nakanuma Y, Nishioka M, Penner E, Porta G, Portmann BC, Reed WD, Rodes J, Schalm SW, Scheuer PJ, Schrumpf E, Seki T, Toda G, Tsuji T, Tygstrup N, Vergani D, Zeniya M. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999;31 (5):929-38. doi: 10.1016/S0168-8278(99)80297-9.19. Hennes EM, Zeniya M, Czaja AJ, Pares A, Dalekos GN, Krawitt EL, Bittencourt PL, Porta G, Boberg KM, Hofer H, Bianchi FB, Shibata M, Schramm C, Eisenmann de Torres B, Galle PR, McFarlane I, Dienes HP, Lohse AW; International Autoimmune Hepatitis Group. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology. 2008;48(1):169-76. doi: 10.1002/hep.22322.20. Berchtold P, Seitz M. Immunosuppression - a tightrope walk between iatrogenic harm and therapy. Schweiz Med Wochenschr. 1996;126(38):1603-9.21. Liberal R, Krawitt EL, Vierling JM, Manns MP, Mieli-Vergani G, Vergani D. Cutting edge is-sues in autoimmune hepatitis. J Autoimmun. 2016;75:6-19. doi: 10.1016/j.jaut.2016.07.005.22. Cook GC, Mulligan R, Sherlock S. Controlled prospective trial of corticosteroid therapy in active chronic hepatitis. Q J Med. 1971;40(158):159-85.23. Soloway RD, Summerskill WH, Baggenstoss AH, Geall MG, Gitnick GL, Elveback IR, Schoenfield LJ. Clinical, biochemical, and histological remission of severe chronic active liver disease: a controlled study of treatments and early prognosis. Gastroenterology. 1972;63(5):820-33.24. Murray-Lyon IM, Stern RB, Williams R. Controlled trial of prednisone and azathioprine in active chronic hepatitis. Lancet. 1973;1 (7806):735-7. doi: 10.1016/S0140-6736(73)92125-9.25. Lamers MM, van Oijen MG, Pronk M, Drenth JP. Treatment options for autoimmune hepatitis: a systematic review of randomized controlled trials. J Hepatol. 2010;53(1):191-8. doi: 10.1016/j.jhep.2010.01.037.26. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Autoimmune hepatitis. J Hepatol. 2015;63(4):971- 1004. doi: 10.1016/j.jhep.2015.06.030.27. Manns MP, Woynarowski M, Kreisel W, Lurie Y, Rust C, Zuckerman E, Bahr MJ, Gunther R, Hultcrantz RW, Spengler U, Lohse AW, Szalay F, Farkkila M, Prols M, Strassburg CP; European AIH-BUC-Study Group. Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis. Gastroenterology. 2010;139(4): 1198-206. doi: 10.1053/j.gastro.2010.06.046.28. Peiseler M, Liebscher T, Sebode M, Zenouzi R, Hartl J, Ehlken H, Pannicke N, Weiler-Normann C, Lohse AW, Schramm C. Efficacy and limitations of budesonide as a second-line treatment for patients with autoimmune hepatitis. Clin Gastroenterol Hepatol. 2018;16(2): 260-7.e1. doi: 10.1016/j.cgh.2016.12.040.29. van Gerven NM, Verwer BJ, Witte BI, van Hoek B, Coenraad MJ, van Erpecum KJ, Beuers U, van Buuren HR, de Man RA, Drenth JP, den Ouden JW, Verdonk RC, Koek GH, Brouwer JT, Guichelaar MM, Mulder CJ, van Nieuwkerk KM, Bouma G; Dutch Autoimmune Hepatitis Working Group. Relapse is almost universal after withdrawal of immunosuppressive medication in patients with autoimmune hepatitis in remission. J Hepatol. 2013;58(1):141-7. doi: 10.1016/j.jhep.2012.09.009.30. Czaja AJ. Treatment of autoimmune hepatitis. Semin Liver Dis. 2002;22(4):365-78. doi: 10.1055/s-2002-35706.31. Liwinski T, Schramm C. Autoimmune hepatitis - update on clinical management in 2017. Clin Res Hepatol Gastroenterol. 2017;41(6): 617-25. doi: 10.1016/j.clinre.2017.07.002.32. Efe C, Taii HA, Ytting H, Aehling N, Bhanji RA, Hagstrom H, Purnak T, Muratori L, Werner M, Muratori P, Klintman D, Schiano TD, Montano-Loza AJ, Berg T, Larsen FS, Alkhouri N, Ozaslan E, Heneghan MA, Yoshida EM, Wahlin S. Tacrolimus and mycophenolate mofetil as second-line therapies for pediatric patients with autoimmune hepatitis. Dig Dis Sci. 2018;63(5): 1348-54. doi: 10.1007/s10620-018-5011-x.33. Zachou K, Gatselis N, Gabeta S, Saitis A, Koukoulis G, Dalekos GN. P1138: Long-term outcome of patients with autoimmune hepatitis receiv-ing mycophenolate mofetil (MMF) as first line treatment. J Hepatol. 2015;62(Suppl 2):S778-9. doi: 10.1016/S0168-8278(15)31335-0.34. Park SW, Um SH, Lee HA, Kim SH, Sim Y, Yim SY, Seo YS, Ryu HS. Mycophenolate mofetil as an alternative treatment for autoimmune hepatitis. Clin Mol Hepatol. 2016;22(2):281-5. doi: 10.3350/cmh.2015.0040.35. Zachou K, Gatselis NK, Arvaniti P, Gabeta S, Rigopoulou EI, Koukoulis GK, Dalekos GN. A real-world study focused on the long-term efficacy of mycophenolate mofetil as first-line treatment of autoimmune hepatitis. Aliment Pharmacol Ther. 2016;43(10):1035-47. doi: 10.1111/apt.13584.36. Hubener S, Oo YH, Than NN, Hubener P, Weiler-Normann C, Lohse AW, Schramm C. Efficacy of 6-mercaptopurine as second-line treatment for patients with autoimmune hepatitis and azathioprine intolerance. Clin Gastroenterol Hepatol. 2016;14(3):445-53. doi: 10.1016/j.cgh.2015.09.037.37. Than NN, Wiegard C, Mann J, Fussel K, Hirschfield G, Lohse AW, Adams D, Schramm C, Oo YH. P1199: Tacrolimus is safe and effective in patients with resistant type 1 autoimmune hepatitis. J Hepatol. 2015;62(Suppl 2):S805-6. doi: 10.1016/S0168-8278(15)31395-7.38. Al Taii H, Hanouneh MA, Hanouneh I, Lopez R, Zein N, Alkhouri N. The use of tacrolimus in refractory autoimmune hepatitis in children and adults: a single center experience. Scand J Gastroenterol. 2017;52(2):157-8. doi: 10.1080/00365521.2016.1236398.39. Aqel BA, Machicao V, Rosser B, Satyanarayana R, Harnois DM, Dickson RC. Efficacy of tacrolimus in the treatment of steroid refractory autoimmune hepatitis. J Clin Gastroenterol. 2004;38(9):805-9. doi: 10.1097/01.mcg.0000139050.67178.be.40. Thervet E, Zuber J, Sberro R, Canaud G, Anglicheau D, Snanoudj R, Mamzer-Bruneel MF, Martinez F, Legendre C. Immunosuppressive treatments: mechanisms of action and clinical use. Nephrol Ther. 2011;7(7):566-81. doi: 10.1016/j.nephro.2010.12.008.41. Zachou K, Gatselis N, Papadamou G, Rigopoulou EI, Dalekos GN. Mycophenolate for the treatment of autoimmune hepatitis: prospective assessment of its efficacy and safety for induction and maintenance of remission in a large cohort of treatment-naive patients. J Hepatol. 2011;55(3):636-46. doi: 10.1016/j.jhep.2010.12.032.42. Hlivko JT, Shiffman ML, Stravitz RT, Luketic VA, Sanyal AJ, Fuchs M, Sterling RK. A single center review of the use of mycophenolate mofetil in the treatment of autoimmune hepatitis. Clin Gastroenterol Hepatol. 2008;6(9):1036-40. doi: 10.1016/j.cgh.2008.04.006.43. Hennes EM, Oo YH, Schramm C, Denzer U, Buggisch P, Wiegard C, Kanzler S, Schuchmann M, Boecher W, Galle PR, Adams DH, Lohse AW. Mycophenolate mofetil as second line therapy in autoimmune hepatitis? Am J Gastroenterol. 2008;103( 12):3063-70. doi: 10.1111/j.1572-0241.2008.02180.x.44. Sharzehi K, Huang MA, Schreibman IR, Brown KA. Mycophenolate mofetil for the treatment of autoimmune hepatitis in patients refractory or intolerant to conventional therapy. Can J Gastroenterol. 2010;24(10):588-92.45. Yarur AJ, Abreu MT, Deshpande AR, Kerman DH, Sussman DA. Therapeutic drug monitoring in patients with inflammatory bowel disease. World J Gastroenterol. 2014;20(13): 3475-84. doi: 10.3748/wjg.v20.i13.3475.46. Deswal S, Srivastava A. Role of allopurinol in optimizing thiopurine therapy in patients with autoimmune hepatitis: A review. J Clin Exp Hepatol. 2017;7(1):55-62. doi: 10.1016/j.jceh.2017.01.115.47. Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G, Vergani D, Vierling JM; American Association for the Study of Liver Diseases. Diagnosis and management of autoimmune hepatitis. Hepatology. 2010;51 (6):2193-213. doi: 10.1002/hep.23584.48. Alvarez F, Ciocca M, Canero-Velasco C, Ramon- et M, de Davila MT, Cuarterolo M, Gonzalez T, Jara-Vega P, Camarena C, Brochu P, Drut R, Alvarez E. Short-term cyclosporine induces a remission of autoimmune hepatitis in children. J Hepatol. 1999;30(2):222-7. doi: 10.1016/S0168-8278(99)80065-8.49. Lohse AW, Herkel J, Weiler-Normann C. Can understanding the pathogenesis of autoimmune hepatitis lead to rational therapy? Dig Dis. 2017;35(4):367-70. doi: 10.1159/000456588.50. Weiler-Normann C, Schramm C, Quaas A, Wiegard C, Glaubke C, Pannicke N, Moller S, Lohse AW. Infliximab as a rescue treatment in difficult-to-treat autoimmune hepatitis. J Hepatol. 2013;58(3):529-34. doi: 10.1016/j.jhep.2012.11.010.51. Ytting H, Larsen FS. Everolimus treatment for patients with autoimmune hepatitis and poor response to standard therapy and drug alternatives in use. Scand J Gastroenterol. 2015;50(8): 1025-31. doi: 10.3109/00365521.2014.998271.52. Chen YY, Jeffery HC, Hunter S, Bhogal R, Birtwistle J, Braitch MK, Roberts S, Ming M, Hannah J, Thomas C, Adali G, Hubscher SG, Syn WK, Afford S, Lalor PF, Adams DH, Oo YH. Human intrahepatic regulatory T cells are functional, require IL-2 from effector cells for survival, and are susceptible to Fas ligand-mediated apoptosis. Hepatology. 2016;64(1):138- 50. doi: 10.1002/hep.28517.53. Than NN, Jeffery HC, Oo YH. Autoimmune hepatitis: progress from global immunosuppression to personalised regulatory T cell therapy. Can J Gastroenterol Hepatol. 2016;2016:7181685. doi: 10.1155/2016/7181685.