JAK inhibition in inflammatory bowel disease

Expert Review of Clinical Immunology

Volumn 13, Issue 7, 2017, Pages 693-703

  Olivera, Pablo ^a,b   Danese, Silvio ^c   Peyrin Biroulet, Laurent ^b  

^a CEMIC   (Argentina)

^b UNIVERSITY HOSPITAL OF NANCY   (France)

^c HUMANITAS CLINICAL AND RESEARCH CENTER   (Italy)

Author keywords

Crohn s disease; Inflammatory bowel disease; JAK inhibitors; small molecules; tofacitinib; ulcerative colitis

Indexed keywords

BARICITINIB; CREATINE KINASE; FILGOTINIB; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; JANUS KINASE; JANUS KINASE INHIBITOR; LOW DENSITY LIPOPROTEIN; PEFICITINIB; STAT PROTEIN; TOFACITINIB; UPADACITINIB; PIPERIDINE DERIVATIVE; PROTEIN KINASE INHIBITOR; PYRIMIDINE DERIVATIVE; PYRROLE DERIVATIVE;

ABSCESS; BREAST CANCER; BRONCHITIS; CARDIOVASCULAR DISEASE; CELLULITIS; CHOLESTEROL BLOOD LEVEL; CLOSTRIDIUM DIFFICILE INFECTION; CONTROLLED CLINICAL TRIAL (TOPIC); CREATINE KINASE BLOOD LEVEL; CROHN DISEASE; CYTOMEGALOVIRUS INFECTION; DRUG EFFICACY; DRUG SAFETY; DYSLIPIDEMIA; ENZYME INHIBITION; ESOPHAGUS CANDIDIASIS; EXTERNAL OTITIS; FEVER; FURUNCULOSIS; GASTROENTERITIS; HEADACHE; HERPES ZOSTER; HUMAN; INFLAMMATORY BOWEL DISEASE; INFLAMMATORY DISEASE; INFLUENZA; INTESTINE PERFORATION; LIPOPROTEIN BLOOD LEVEL; MULTICENTER STUDY (TOPIC); MYCOSIS; NEUTROPENIA; NON MELANOMA SKIN CANCER; NONHUMAN; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PNEUMOCYSTIS PNEUMONIA; PNEUMONIA; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RHEUMATOID ARTHRITIS; RHINOPHARYNGITIS; SIDE EFFECT; SIGNAL TRANSDUCTION; TUBERCULOSIS; ULCERATIVE COLITIS; UPPER RESPIRATORY TRACT INFECTION; URINARY TRACT INFECTION; ANIMAL; ANTAGONISTS AND INHIBITORS; CLINICAL TRIAL (TOPIC); METABOLISM; MOLECULARLY TARGETED THERAPY; RISK ASSESSMENT;

ANIMALS; ARTHRITIS, RHEUMATOID; CLINICAL TRIALS AS TOPIC; HUMANS; INFLAMMATORY BOWEL DISEASES; JANUS KINASES; MOLECULAR TARGETED THERAPY; PIPERIDINES; PROTEIN KINASE INHIBITORS; PYRIMIDINES; PYRROLES; RISK ASSESSMENT; SIGNAL TRANSDUCTION; STAT TRANSCRIPTION FACTORS;

EID: 85020781033     PISSN: 1744666X     EISSN: 17448409     Source Type: Journal    
DOI: 10.1080/1744666X.2017.1291342     Document Type: Review

References (91)

1. Abraham C, Cho JH., Inflammatory bowel disease. N Engl J Med. 2009;361:2066–2078.
2. Peyrin-Biroulet L, Loftus EV, Colombel J-F, et al. Long-term complications, extraintestinal manifestations, and mortality in adult Crohn’s disease in population-based cohorts. Inflamm Bowel Dis. 2011;17:471–478.
3. Umanskiy K, Fichera A., Health related quality of life in inflammatory bowel disease:the impact of surgical therapy. World J Gastroenterol. 2010;16:5024–5034.
4. Van Assche G, Dignass A, Panes J, et al. The second European evidence-based consensus on the diagnosis and management of Crohn’s disease:definitions and diagnosis. J Crohns Colitis. 2010;4:7–27.
5. Dignass A, Lindsay JO, Sturm A, et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2:current management. J Crohns Colitis. 2012;6:991–1030.
6. Dignass A, Van Assche G, Lindsay JO, et al. The second European evidence-based consensus on the diagnosis and management of Crohn’s disease:current management. J Crohns Colitis. 2010;4:28–62.
7. Burger D, Travis S. Conventional medical management of inflammatory bowel disease. Gastroenterology. 2011;140:1827–1837.e2.
8. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease:the ACCENT I randomised trial. Lancet. 2002;359:1541–1549.
9. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353:2462–2476.
10. Hyams J, Crandall W, Kugathasan S, et al. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children. Gastroenterology. 2007;132:863–873.
11. Vogelaar L, Spijker AV, van der Woude CJ. The impact of biologics on health-related quality of life in patients with inflammatory bowel disease. Clin Exp Gastroenterol. 2009;2:101–109.
12. Olivera P, Danese S, Peyrin-Biroulet L. Next generation of small molecules in inflammatory bowel disease. Gut. 2017;66:199–209.• This review discusses how small molecule drugs may address current treatments’ limitations and describes promising molecules.
13. Allez M, Karmiris K, Louis E, et al. Report of the ECCO pathogenesis workshop on anti-TNF therapy failures in inflammatory bowel diseases:definitions, frequency and pharmacological aspects. J Crohn’s Colitis. 2010;4:355–366.
14. Ben-Horin S, Chowers Y. Review article:loss of response to anti-TNF treatments in Crohn’s disease. Aliment Pharmacol Ther. 2011;33:987–995.
15. Roda G, Jharap B, Neeraj N, et al. Loss of response to anti-TNFs:definition, epidemiology, and management. Clin Transl Gastroenterol. 2016;7:e135.
16. Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med. 2003;348:601–608.
17. van der Valk ME, Mangen M-J-J, Leenders M, et al. Healthcare costs of inflammatory bowel disease have shifted from hospitalisation and surgery towards anti-TNFα therapy:results from the COIN study. Gut. 2014;63:72–79.
18. Mócsai A, Kovács L, Gergely P. What is the future of targeted therapy in rheumatology:biologics or small molecules? BMC Med. 2014;12:43.
19. Hanke T, Merk D, Steinhilber D, et al. Small molecules with anti-inflammatory properties in clinical development. Pharmacol Ther. 2015;157:163–187.
20. Ghoreschi K, Laurence A, O’Shea JJ. Janus kinases in immune cell signaling. Immunol Rev. 2009;228:273–287.
21. O’Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med. 2013;368:161–170.
22. Mavers M, Ruderman EM, Perlman H. Intracellular signal pathways:potential for therapies. Curr Rheumatol Rep. 2009;11:378–385.
23. Leonard WJ, O’Shea JJ. Jaks and STATs:biological implications. Annu Rev Immunol. 1998;16:293–322.
24. Coskun M, Salem M, Pedersen J, et al. Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease. Pharmacol Res. 2013;76:1–8.
25. Danese S, Grisham M, Hodge J, et al. JAK inhibition using tofacitinib for inflammatory bowel disease treatment:a hub for multiple inflammatory cytokines. Am J Physiol Gastrointest Liver Physiol. 2016;310:G155–62.• A review of the key cytokine pathways involved in IBD and how tofacitinib may interfere with them.
26. Boland BS, Sandborn WJ, Chang JT. Update on janus kinase antagonists in inflammatory bowel disease. Gastroenterol Clin North Am. 2014;43:603–617.
27. Witthuhn BA, Quelle FW, Silvennoinen O, et al. JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell. 1993;74:227–236.
28. Cho JH, Gregersen PK. Genomics and the multifactorial nature of human autoimmune disease. N Engl J Med. 2011;365:1612–1623.
29. Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491:119–124.
30. Shuai K, Liu B. Regulation of JAK–STAT signalling in the immune system. Nat Rev Immunol. 2003;3:900–911.
31. Heneghan AF, Pierre JF, Kudsk KA. JAK-STAT and intestinal mucosal immunology. Jak-Stat. 2013;2:e25530.
32. Mudter J, Neurath MF. Il-6 signaling in inflammatory bowel disease:pathophysiological role and clinical relevance. Inflamm Bowel Dis. 2007;13:1016–1023.
33. Sohn SJ, Barrett K, Van Abbema A, et al. A restricted role for TYK2 catalytic activity in human cytokine responses revealed by novel TYK2-selective inhibitors. J Immunol. 2013;191:2205–2216.
34. Suzuki A, Hanada T, Mitsuyama K, et al. CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation. J Exp Med. 2001;193:471–481.
35. Mudter J, Weigmann B, Bartsch B, et al. Activation pattern of signal transducers and activators of transcription (STAT) factors in inflammatory bowel diseases. Am J Gastroenterol. 2005;100:64–72.
36. Atreya R, Mudter J, Finotto S, et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation:evidence in crohn disease and experimental colitis in vivo. Nat Med. 2000;6:583–588.
37. Yen D, Cheung J, Scheerens H, et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest. 2006;116:1310–1316.
38. Atreya R, Neurath MF. Involvement of IL-6 in the pathogenesis of inflammatory bowel disease and colon cancer. Clin Rev Allergy Immunol. 2005;28:187–196.
39. Durant L, Watford WT, Ramos HL, et al. Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity. 2010;32:605–615.
40. Galien R. Janus kinases in inflammatory bowel disease:four kinases for multiple purposes. Pharmacol. Reports. 2016;68:789–796.
41. Uhlig HH, McKenzie BS, Hue S, et al. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity. 2006;25:309–318.
42. Ishizaki M, Akimoto T, Muromoto R, et al. Involvement of tyrosine kinase-2 in Both the IL-12/Th1 and IL-23/Th17 Axes In Vivo. J Immunol. 2011;187:181–189.
43. Bauer JH, Liu KD, You Y, et al. Heteromerization of the gammac chain with the interleukin-9 receptor alpha subunit leads to STAT activation and prevention of apoptosis. J Biol Chem. 1998;273:9255–9260.
44. Yuan A, Yang H, Qi H, et al. IL-9 antibody injection suppresses the inflammation in colitis mice. Biochem Biophys Res Commun. 2015;468:921–926.
45. Samanen J. Similarities and differences in the discovery and use of biopharmaceuticals and small-molecule chemotherapeutics. In:Ganellin CR, Jefferis R, Roberts S, editors. Introduction to biological and small molecule drug research and development:theory and case studies. Oxford:Elsevier Ltd.; 2013. p. 161–203.
46. Clark JD, Flanagan ME, Telliez J. Discovery and development of janus kinase (JAK) inhibitors for inflammatory diseases. J Med Chem. 2014;57:5023–5038.•• A comprehensive review of the development of JAK inhibitors for inflammatory conditions with focus in IBD.
47. Flanagan ME, Blumenkopf TA, Brissette WH, et al. Discovery of CP-690,550:a potent and selective Janus kinase (JAK) inhibitor for the treatment of autoimmune diseases and organ transplant rejection. J Med Chem. 2010;53:8468–8484.
48. Meyer DM, Jesson MI, Li X, et al. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm (Lond). 2010;7:41.
49. U.S. Food and Drug Administration. FDA approves Xeljanz for rheumatoid arthritis [Internet]. 2012. Available from:http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm327152.htm.
50. Wollenhaupt J, Silverfield J, Lee EB, et al. Tofacitinib, an oral Janus kinase inhibitor, in the treatment of rheumatoid arthritis:safety and efficacy in open-label, long-term extension studies over 8 years [abstract]. Arthritis Rheumatol. 2016;68(suppl 10):1-4550. [cited 2016 Oct 10]. Available from:http://acrabstracts.org/abstract/tofacitinib-an-oral-janus-kinase-inhibitor-in-the-treatment-of-rheumatoid-arthritis-safety-and-efficacy-in-open-label-long-term-extension-studies-over-8-years/.
51. Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367:495–507.
52. van Vollenhoven RF, Fleischmann R, Cohen S, et al. tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367:508–519.
53. Lee EB, Fleischmann R, Hall S, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. 2014;370:2377–2386.
54. Kremer J, Li Z-G, Hall S, et al. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis:a randomized trial. Ann Intern Med. 2013;159:253–261.
55. Burmester GR, Blanco R, Charles-Schoeman C, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors:A randomised phase 3 trial. Lancet. 2013;381:451–460.
56. van der Heijde D, Tanaka Y, Fleischmann R, et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate:twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum. 2013;65:559–570.
57. Wollenhaupt J, Silverfield J, Lee EB, et al. Safety and efficacy of tofacitinib, an oral janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies. J Rheumatol. 2014;41:837–852.
58. Harnett J, Curtis JR, Gerber R, et al. Initial experience with tofacitinib in clinical practice:treatment patterns and costs of tofacitinib administered as monotherapy or in combination with conventional synthetic DMARDs in 2 US health care claims databases. Clin Ther. 2016;38:1451–1463.
59. Papp KA, Menter MA, Abe M, et al. Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis:results from two randomized, placebo-controlled, phase III trials. Br J Dermatol. 2015;173:949–961.
60. Bachelez H, van de Kerkhof PCM, Strohal R, et al. Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis:a phase 3 randomised non-inferiority trial. Lancet. 2015;386:552–561.
61. Fridman JS, Scherle PA, Collins R, et al. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis:preclinical characterization of INCB028050. J Immunol. 2010;184:5298–5307.
62. Delachaume C, De Vriendt V, Laukens D, et al. P1586 the first JAK1-selective inhibitor, Filgotinib, displays similar molecular activity in the gut of mice with DSS-induced colitis and in cultures of colon biopsies from inflammatory bowel disease patients [Abstract]. United Eur Gastroenterol J. 2015;3:A602.
63. Ongenaert M, Dupont S, Vayssière B, et al. Sa1844 The JAK1-selective inhibitor, filgotinib, reverses the disease signature of colon mucosa in experimental colitis [Abstract]. Gastroenterology. 2016;150:S379.
64. Iwata S, Tanaka Y. Progress in understanding the safety and efficacy of Janus kinase inhibitors for treatment of rheumatoid arthritis. Expert Rev Clin Immunol. 2016;12:1047–1057.
65. Dougados M, van der Heijde D, Chen Y-C, et al. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs:results from the RA-BUILD study. Ann Rheum Dis. 2017;76:88–95.
66. Genovese MC, Kremer J, Zamani O, et al. Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med. 2016;374:1243–1252.
67. Papp KA, Menter MA, Raman M, et al. A randomized phase 2b trial of baricitinib, an oral Janus kinase (JAK) 1/JAK2 inhibitor, in patients with moderate-to-severe psoriasis. Br J Dermatol. 2016;174:1266–1276.
68. Genovese MC, Smolen JS, Weinblatt ME, et al. Efficacy and safety of ABT-494, a selective JAK-1 inhibitor, in a phase IIb study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Rheumatol. 2016;68:2857–2866.
69. Kremer JM, Emery P, Camp HS, et al. A phase 2b study of ABT-494, a selective JAK1 Inhibitor, in patients with rheumatoid arthritis and an inadequate response to anti-TNF therapy. Arthritis Rheumatol (Hoboken, N.J.). 2016;68:2867–2877.
70. Takeuchi T, Tanaka Y, Iwasaki M, et al. Efficacy and safety of the oral Janus kinase inhibitor peficitinib (ASP015K) monotherapy in patients with moderate to severe rheumatoid arthritis in Japan:a 12-week, randomised, double-blind, placebo-controlled phase IIb study. Ann Rheum Dis. 2016;75:1057–1064.
71. Papp K, Pariser D, Catlin M, et al. A phase 2a randomized, double-blind, placebo-controlled, sequential dose-escalation study to evaluate the efficacy and safety of ASP015K, a novel Janus kinase inhibitor, in patients with moderate-to-severe psoriasis. Br J Dermatol. 2015;173:767–776.
72. Sandborn WJ, Ghosh S, Panes J, et al. Tofacitinib, an Oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med. 2012;367:616–624.• Phase II trial showing good results of tofacitinib in ulcerative colitis.
73. Sandborn W, Sands BE, D’Haens GR, et al. 767 efficacy and safety of oral tofacitinib as induction therapy in patients with moderate to severe ulcerative colitis:results from two phase 3 randomized controlled trials [Abstract]. Gastroenterology. 2016;150:S157.•• Results of two Phase III trials of tofacitinib in UC patients.
74. Sandborn WJ, Ghosh S, Panes J, et al. A phase 2 study of tofacitinib, an oral janus kinase inhibitor, in patients with Crohn’s disease. Clin Gastroenterol Hepatol. 2014;12:1485–1493.e2.• A phase II trial showing moderate results of tofacitinib in CD patients.
75. Panés J, Sandborn W, Schreiber S, et al. 855 efficacy and safety of tofacitinib for oral induction therapy in patients with moderate to severe Crohn’s disease:results of a phase 2B randomized placebo-controlled trial [Abstract]. Gastroenterology. 2016;150:S182–S183.
76. D’Haens GR, Panaccione R, Higgins P, et al. 856 efficacy and safety of oral tofacitinib for maintenance therapy in patients with moderate to severe Crohn’s disease:results of a phase 2B randomized placebo-controlled trial [Abstract]. Gastroenterology. 2016;150:S183.
77. Vermeire S, Schreiber S, Petryka R, et al. Clinical remission in patients with moderate-to-severe Crohn’s disease treated with filgotinib (the FITZROY study):results from a phase 2, double-blind, randomised, placebo-controlled trial. Lancet. 2016;6736:1–10.
78. Pfizer Announces Positive Top-Line Results from Pivotal Phase 3 Maintenance Trial of Oral XELJANZ® (Tofacitinib Citrate) in Ulcerative Colitis [Internet]. 2016 [cited 2016 Oct16]. Available from:http://www.pfizer.com/news/press-release/press-release-detail/pfizer_announces_positive_top_line_results_from_pivotal_phase_3_maintenance_trial_of_oral_xeljanz_tofacitinib_citrate_in_ulcerative_colitis.
79. Yamaoka K. Benefit and risk of tofacitinib in the treatment of rheumatoid arthritis:a focus on herpes zoster. Drug Saf. 2016;39:823–840.
80. Winthrop KL, Yamanaka H, Valdez H, et al. Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis. Arthritis Rheumatol (Hoboken, NJ). 2014;66:2675–2684.
81. Strand V, Ahadieh S, French J, et al. Systematic review and meta-analysis of serious infections with tofacitinib and biologic disease-modifying antirheumatic drug treatment in rheumatoid arthritis clinical trials. Arthritis Res Ther. 2015;17:362.
82. Wollenhaupt J, Silverfield J, Lee EB, et al. Tofacitinib, an oral Janus kinase inhibitor, in the treatment of rheumatoid arthritis:safety and clinical and radiographic efficacy in open-label, long-term extension studies over 7 years [abstract]. Arthritis Rheumatol. 2015;67(suppl 10):1-4046. [cited 2016 Oct 10]. Available from:http://acrabstracts.org/abstract/tofacitinib-an-oral-janus-kinase-inhibitor-in-the-treatment-of-rheumatoid-arthritis-safety-and-clinical-and-radiographic-efficacy-in-open-label-long-term-extension-studies-over-7-years/.
83. Curtis JR, Lee EB, Kaplan IV, et al. Tofacitinib, an oral Janus kinase inhibitor:analysis of malignancies across the rheumatoid arthritis clinical development programme. Ann Rheum Dis. 2016;75:831–841.
84. Chakravarty EF, Michaud K, Wolfe F. Skin cancer, rheumatoid arthritis, and tumor necrosis factor inhibitors. J Rheumatol. 2005;32:2130–2135.
85. Souto A, Salgado E, Maneiro JR, et al. Lipid profile changes in patients with chronic inflammatory arthritis treated with biologic agents and tofacitinib in randomized clinical trials:a systematic review and meta-analysis. Arthritis Rheumatol (Hoboken, NJ). 2015;67:117–127.
86. Avina-Zubieta JA, Thomas J, Sadatsafavi M, et al. Risk of incident cardiovascular events in patients with rheumatoid arthritis:a meta-analysis of observational studies. Ann Rheum Dis. 2012;71:1524–1529.
87. Charles-Schoeman C, Fleischmann R, Davignon J, et al. Potential mechanisms leading to the abnormal lipid profile in patients with rheumatoid arthritis versus healthy volunteers and reversal by tofacitinib. Arthritis Rheumatol. 2015;67:616–625.
88. Kavanaugh AF, Geier J, Bingham C, et al. Real world results from a post-approval safety surveillance of Tofacitinib (Xeljanz):over 3 year results from an ongoing US-based rheumatoid arthritis registry [abstract]. Arthritis Rheumatol. 2016;68(suppl 10):1-4550. [cited 2016 Oct 5]. Available from:http://acrabstracts.org/abstract/real-world-results-from-a-post-approval-safety-surveillance-of-tofacitinib-xeljanz-over-3-year-results-from-an-ongoing-us-based-rheumatoid-arthritis-registry/.
89. Nielsen OH, Seidelin JB, Ainsworth M, et al. Will novel oral formulations change the management of inflammatory bowel disease? Expert Opin Investig Drugs. 2016;25:709–718.• This review describes promising new orally administrated therapies for IBD.
90. Löwenberg M, D’Haens G. Next-generation therapeutics for IBD. Curr Gastroenterol Rep. 2015;17:21.
91. Sandborn WJ. New targets for small molecules in inflammatory bowel disease. Gastroenterol Hepatol (N Y). 2015;11:338–340.