Hepatitis tóxica autoinmune: una o dos entidades. Registro Español de Hepatotoxicidad Raúl J. Andrade Málaga 22 de Mayo, 2015

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1 Hepatitis tóxica autoinmune: una o dos entidades Registro Español de Hepatotoxicidad Raúl J. Andrade Málaga 22 de Mayo, 2015

2 18 yr male Jaundice H/O severe acne Unresponsive to isotretinoin (vit A) Minocycline Bil 85 µmol/l ALT 500 u/l ANA 1:400 IgG 18.3 (6-15) SMA positive Patient

3 Can we distinguish DILI from AIH? Features AIH DILI Severe changes (>2 portal inflamn., >4 necrosis, >1 fibrosis) Prominent intraacinar cells Prominent portal cells Rosette formation Cholestasis (HCC/ canalicular) eosinophils plasma cells lymphocytes neutrophils Suzuki. Hepatology 2011; 54,

4 Drug-induced liver injury Unexpected adverse event Varied latency Many clinical phenotypes Many histopathological patterns Diagnosis based in causality assessment process Lucena et al in Kaplowitz: Drug-induced liver disease 3ª Ed 2013 CP

5 Idiopathic Autoimmune Hepatitis Inflammatory liver disease Unknown cause Autoantibodies Hyper γ-globulinemia Interface hepatitis Manns, MP, Czaja AJ, et al: Hepatology 51:2193, 2010 CP

6 Idiopathic Autoimmune Hepatitis Inflammatory liver disease Unknown cause Autoantibodies Hyper γ-globulinemia Interface hepatitis Manns, MP, Czaja AJ, et al: Hepatology 51:2193, 2010 CP

7 Codified Criteria for Definite Diagnosis of Idiopathic AIH Absence of viral markers No or low likelihood of ETOH or drug-induced disease Autoantibodies 1:80 γ-globulin 1.5-fold ULN No cholestatic features International Autoimmune Hepatitis Group: J Hepatol 31:929, 1999 Manns MP, Czaja AJ et al: Hepatology 51:2193, 2010

8 Types of Autoimmune Hepatitis Type 1 AIH Type 2 AIH ANA and/or SMA Anti-LKM1 Adults and children Mainly children Most common Adults (USA), 4% Genetic predisposition (DRB1 alleles) Czaja AJ, Manns MP: Am J Gastroenterol 90:1206, 1995 Genetic predisposition (DQB1 alleles) Homberg JC et al: Hepatology 7:1333, 1987

9 Susceptility Alleles Implicated in Type 1 Autoimmune Hepatitis Northern Europeans North Americans Mexicans (Mestizo) Japanese & Chinese South Americans DRB1*0301 DRB1*0401 DRB1*0404 DRB1*0405 DRB1*1301 Fainboim L, et al: Hum Immunol 41: , 1994 Strettel MD et al: Gastroenterology 112:2028, 1997 DeBoer YS et al: Gastroenterology 147:443, 2014

10 Immune Injury Caused by Therapeutic Drugs Targets: drug-associated antigens or self Onset within 1-8 wks of treatment; can be as short as 1-2 days Multiple organs can be affected Multiple types of hypersensitivity Fever, rash, eosinophilia common in some forms Re-challenge has significant risk Immunoallergic Autoimmune Reaction Pathways Onset after prolonged treatment Sub-acute or chronic organ injury Characteristic range of affected organs can depend on the specific drug Characteristic autoantibody profiles for certain drugs, but many overlap 19 Mar 2015 Annual Meeting on DILI FDA/C-Path/PhRMA/AASLD 10 10

11 Principal Autoantigens for Autoimmune Hepatitis are Drug Metabolizing Enzymes Syndromes Characterized by Autoimmune Hepatitis Type 2 AIH Autoimmune Polyglandular Syndrome Type 1 Tienilic acid-induced AIH Implicated Autoantigen CYP2D6 CYP1A2 CYP2A6 CYP2C9 Christen U et al: Dig Dis 28:80-85, 2010 Lecoeur S et al: Mol Pharmacol 50: , 1996 Obermayer-Straub P et al: Gastroenterology 121: , 2001 Hardtke-Wolenski M et al: Hepatology doi: /hep.27639

12 Risk of Drug-Induced Autoimmune Hepatitis increases with a new DILI episode * 9 patients out of 742 in the Spanish DILI Registry (1.21%), with evidence of two distint DILI episodes produced by different drugs * Second episodes were associated with features of AIH up to more than 40% (4/9) Lucena et al J Hepatol 2011;55:

13 Drugs and drug-induced autoimmune liver disease Well stablished drugs: Minocycline Nitrofurantoin Oxyphenisatin, alpha-methyl-dopa, clometacin Emerging drugs: Statins Biologics agents: Infliximab Others: adalimumab, etanercept, efalizumab, ipilimumab Other drugs: Less compelling association (infrequent reports): atomoxetine, diclofenac, fenofibrate, pemoline, phenprocoumon, dihydralazine, tielinic acid, benzarone Castiella et al., World J Hepatol 2014 Perdices et al Rev Esp Enf Dig 2014

14 Drug Epidemiology of Drug-induced Liver injury in Iceland n=251,860 Patients treated, n Prescription, n Cases, n Proportion Per 100,000 95% CI 95% CI Amoxicillin /clavulanate 35,252 83, Diclofenac 54, , Azathioprine Infliximab 593 a Nitrofurantoin , Isotretinoin Atorvastatin , Doxycycline 32,677 54, Only drugs associated with at least 2 cases of DILI are shown. CI, confidence interval. a Most patients on infliximab received continuous prescriptions Björnsson et al Gastroenterology 2013

15 Patient 2 48 lady Obesity, F/H of CD Crohn s large & small bowel Azathioprine DILI (ALT 196), withdrawn Infliximab Oct 2011 ALT 470 u/l ANA neg, SMA strongly pos US: hyperechoic liver

16 Follow up Adalimumab April 2012

17 Prevalence of Drug-induced AIH 10,270 in-patients ( ) 136 (1.3%) DILI 12 (8.8% of DILI): drug-induced autoimmune hepatitis 41.7% males, age range (66.7%) jaundice at admission Severe portal inflammation; Prominent portal-plasma cells; Rosette formation; Severe focal necrosis more frequent in drug-induced autoimmune hepatitis 5 long-term immunosuppression free remission Licata. Dig Liver Dis 2014; 46:

18 *Partial list Drugs & Hypersensitivity Reactions* FDA Postmarketing Safety Alerts: Chlormezanone SJS/TEN Withdrawal Lamotrigine SCAR Boxed Warning Aseptic Meningitis Warning Valdecoxib SCAR Withdrawal Abarelix Immed Hypersens Withdrawal Abacavir Multiorg Hypersens Boxed Warning Carbamazepine SJS/TEN Boxed Warning Omalizumab Anaphylaxis Boxed Warning Phenytoin SJS/TEN/DRESS Modified Warning Ansenapine Anaphylaxis Warning Daptomycin Eosin Pneumonia Warning Telaprevir SJS/TEN/DRESS Boxed Warning Acetaminophen SJS/TEN/AGEP Warning Ziprasidone SCAR/DRESS Warning Benzoyl Peroxide, or Immediate Hypersensitivity OTC Communications Salicylate (Topicals) 19 Mar 2015 Annual Meeting on DILI FDA/C-Path/PhRMA/AASLD 18

19 Drug-induced Autoimmune Reactions FDA Approved Product Labels * Minocycline AI Syndromes, AIH Warnings Nitrofurantoin Hepatotoxicity, CAH Warning Procainamide Lupus-like syndrome Boxed Warning Hydralazine Lupus-like syndrome Warning Hypersensitive reactions Adverse Reactions Interferon β-1a AI Disorders, DILI Warnings Anaphylaxis Infliximab Hepatotoxicity, AIH Warnings Lupus like syndrome Hypersensitivity Metreleptin AI Disorders, AIH Warnings Hypersensitivity Ipilimumab Immune Mediated AR Warnings Hepatitis Pembrolizumab Immune Mediated AR Warnings Hepatitis *Partial list 19 Mar 2015 Annual Meeting on DILI FDA/C-Path/PhRMA/AASLD 19

20 Inducing Autoimmunity Use of checkpoint inhibitors for oncotherapy Inhibitors of CTLA-4, PD-1 and PD-1 ligands: Linked to high risk for autoimmune organ injuries mediated by souped-up autoreactive T & NK? cells Characteristic auto-abs not identified to date Autoimmune injuries: colitis > SCAR, hepatitis/alf, endocrine organs, nephritis & other organs with comparatively short latencies after treatment initiation Risk levels for life-threatening AEs sufficiently high for valuable assessment in clinical efficacy trials Predictors surrounding susceptibility factors in different organs for optimal patient treatment planning & risk management will require more study 19 Mar 2015 Annual Meeting on DILI FDA/C-Path/PhRMA/AASLD 22

21 Checkpoint Inhibitors Post-market: Life-threatening autoimmune AEs In first 3 yrs of ipilimumab marketing Serious AE reports submitted to FAERS (crude nos): Colitis ~ 380 reports Some reports of intestinal perforation Autoimmune hepatitis &/or Hepatic Failure ~ 50 reports Liver metastases (melanoma) often present Onset after a small no of q3wk infusions Some reports of fatal outcomes with rapidly deteriorating liver function 19 Mar 2015 Annual Meeting on DILI FDA/C-Path/PhRMA/AASLD 23

22 Drug-Induced Autoimmune Hepatitis: Clinical Characteristics and Prognosis * Overall 261 patients (204 females, median age 52) were identified, and 24 (9.2%) were DIAIH cases with a median age of 53 years (IQR 24-61). * Mostly Nitrofurantoin (n=11) and Minocycline (n=11) * A similar proportion of DIAIH patients had positive antinuclear antibodies (83% vs. 70%) and smooth muscle antibodies (50% vs. 45%) as compared to AIH patients. Björnsson et al Hepatology 2010;51:240

23 Drug-Induced Autoimmune Hepatitis: Clinical Characteristics and Prognosis * Histological grade and stage were similar in patients with DIAIH vs. AIH but none of the DIAIH patients had cirrhosis at baseline; this was present in 20% of matched AIH cases. * Liver imaging was normal in all minocycline cases. 8/11 (73%) of nitrofurantoin patients had abnormalities on hepatic imaging (mainly liver atrophy) a finding seen in only 8/33 (24%) of a random sample of the rest of the AIH group (p=0.0089). Björnsson et al Hepatology 2010;51:240

24 Drug-Induced Autoimmune Hepatitis: Clinical Characteristics and Prognosis * Corticosteroid responsiveness was similar in DIAIH and the AIH patients. * Discontinuation of immunosuppression was tried and successful in 14 DIAIH cases, with no relapses (0%) whereas 65% of the AIH patients had a relapse after discontinuation of immunosuppression (p<0.0001). Björnsson et al Hepatology 2010;51:240

25 Can we phenotype portal Inflammation? Eosinophilia = less inflammation, lower CD11b+ macrophage High IgG = higher CD11b+ macrophage Foureau. Clin Exp Immunol :

26 Classification of drug-induced autoimmune liver disease AIH with DILI DI-AIH IM-DILI Mixed autoimmune type DILI with positive autoantibodies Patients with known AIH. AIH quiescent: the drug may be the trigger of a new bout AIH under IS or corticosteroids treatment: Reactivation of known AIH upon introduction of a new drug. Often advanced fibrosis on histology Patients with a low grade disease not diagnosed before or predisposition to AIH. Drug produce an immune reaction that lead to a chronic process. Permanent need of IS. Habitually typical HLA-DR associated Fever, eosinophilia, lymphadenopathy, rash. Indistinguishable from true AIH: Mandatory IS treatment. Frequently spontaneous remission after drug cessation. Usually complete response to treatment and sustained remission without relapse. Patients with mixed clinical features of DI-AIH and IM-DILI. Complete response to IS treatment but with chronic course after withdrawal Patients under IS treatment for another autoimmune disease. Withdraw IS drugs is not possible. Remission cannot be evaluated Patients with positive autoantibodies. The probability of developing DIAILD increases in second DILI episodes independently of the causal agent Castiella et al., World J Hepatol 2014

27 DIAH vs AIH DIAIH Idiopathic AIH Valor p (n=21) (n= 51) Edad media, años 58 ± ± 14 0,4 Sexo femenino, % ,6 Hipertensión, n(%) ,02 Diabetes mellitus, % ,04 HLADR3+, n(%) 4 (36) 27 (61) 0,1 HLADR4+, n(%) 3 (27) 9 (20) 0,7 Enf autoinmunes, % ,6 Necesidad tto, n(%) 17(81) 42(93) 0,193 Tiempo resolución (días), media 203± ±85 0,131 Valores analíticos, media BT (xlsn) 6 2 0,001 AST (xlsn) ,001 ALT (xlsn) ,001 GGT (xlsn) 9 5 0,02 FA (xlsn) 1,7 1,8 0,9 Ortega et al, EASL 2015

28 Autoimmune features in DILI Positive AAbds Negative AAbds Valor p (n=129) (n=371) Edad media, años 53 ± ± 18 0,025 Sexo femenino, % ,306 Hipertensión, n(%) 96 (23) 271 (22) 0,88 Diabetes mellitus, % ,48 Necesidad tto, n (%) 116 (24) 296 (28) 0,460 Tiempo resolución 116± ±465 0,246 (días), media Valores analíticos, media BT (xlsn) 8 6 0,081 AST (xlsn) ,748 ALT (xlsn) ,326 GGT (xlsn) 6 6 0,858 FA (xlsn) ,908 Ortega et al, EASL 2015

29 Autoimmune features in DILI Positive AAbds HAI-DILI Valor p (n=129) (n= 21) Edad media, años 53±17 58±15 0,292 Sexo femenino, % ,813 Diabetes mellitus, % ,709 Hipertensión arterial, n (%) 96 (23) 20 (35) 0,266 Necesidad tto, n (%) 116 (24) 21 (81) 0,000 Tiempo resolución (días), 116± ±603 0,002 media Valores analíticos, media BT (xlsn) 8 6 0,283 AST (xlsn) ,618 ALT (xlsn) ,658 GGT (xlsn) 6 8 0,020 FA (xlsn) ,119 Ortega et al, EASL 2015

30 DIAH vs AIH 30% HAI-DILI HAI 20% 10% 0% Estatinas AINEs Antibióticos Anti-TNF IECAs Ortega et al, EASL 2015

31 How to identify drug-induced Hennes. Hepatology 2008; 48: Aithal. Clin Pharmacol Ther 2011; 89: AIH Score = 6 = borderline 88% sens. 97% spec. 7 or more definite AIH 81% sens. 99% spec. Lack of evidence of relapse within 18 moths of drugwithdrawal or complete withdrawal of immunosuppressive drugs whichever is later

32 Elements to be reported when a case of drug-induced autoimmune liver disease is suspected Previously obtained ANA Evolution: During the treatment with the suspicious drug After drug withdrawal Check for the presence of HLA-DR: HLA-DRB1*0301,0401,07,1301 Drug type Time to onset from the beginning of the treatment AIH diagnosed: During the course of treatment After withdrawal of the drug AIH scales for diagnosis: International autoimmune hepatitis group report (4) Simplified score (5) Previous DILI episodes Castiella et al., World J Hepatol 2014 Response to corticosteroids Autoimmune titres evolution IgG values evolution

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34 Grupo de Estudio Hepatopatías Asociadas a Medicamentos (GEHAM) H. Torrecárdenas, Almería: MC Fernández, G Peláez, M Casado H. Virgen Macarena, Sevilla: JA Durán, M. Villar. H. Universitario Virgen de Valme, Sevilla: M Romero, H. Central de Asturias, Oviedo: L Rodrigo-Saez, R Perez-Alvarez. H. de Puerto Real, Cádiz: JM Pérez-Moreno, M Puertas. H. Universitario San Cecilio, Granada: J Salmerón, A Gila. H. Germans Trias i Puyol, Barcelona: I Barriocanal, Eva Montané, J Costa. H. Costa del Sol, Málaga: JM Navarro, JF Rodríguez. H. 12 de Octubre, Madrid: T. Muñoz-Yagüe, J.A. Solis-Herruzo. H. Marqués de Valdecilla, Santander: F. Pons, J. Crespo H. Sant Pau, Barcelona: C Guarner, G Soriano H. Carlos Haya, Málaga: M Jiménez, R González-Grande H. Xeral-Calde, Lugo: S. Avila-Nasi. H. Puerta de Hierro, Madrid: J. L. Calleja, J. de la Revilla H. Nuestra Sra. de Aranzazu, San Sebastián: M. García-Bengoechea, J Arenas H. de Mendaro, Guipuzcuoa: A. Castiella, E. Zapata H. Alto Deba, Mondragón, Guipuzcuoa: P Otazua H. de Basurto, Bilbao: S. Blanco, P Martinez Odriozola H. Clínico Provincial: M Bruguera, P Ginés H. Morales Messeguer: H Hallal H. de Albacete, Albacete: J. M. Moreno H. Puerta del Mar, Cádiz: P. Rendón H. de Salamanca: F. González H. De Alcorcón: C. Fernández H. De Sagunto: J. Primo H. La Fe: M. Prieto H. Carlos III: J. Samaniego