Hepatitis tóxica autoinmune: ¿una o dos entidades

Registro Español de Hepatotoxicidad Raúl J. Andrade

Málaga 22 de Mayo , 2015

Patient

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

Can we distinguish DILI from AIH? Features AIH DILI

Severe changes (>2 portal inflamn., >4 necrosis, >1 fibrosis)

Prominent intra-acinar cells

eosinophils lymphocytes

Prominent portal cells

plasma cells neutrophils

Rosette formation

Cholestasis (HCC/ canalicular)

Suzuki. Hepatology 2011; 54, 931–939.

CP1020209-1

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

CP1020209-1

Idiopathic Autoimmune Hepatitis

• Inflammatory liver disease

• Unknown cause

• Autoantibodies

• Hyper γ-globulinemia

• Interface hepatitis Manns, MP, Czaja AJ, et al: Hepatology 51:2193, 2010

CP1020209-1

Idiopathic Autoimmune Hepatitis

• Inflammatory liver disease

• Unknown cause

• Autoantibodies

• Hyper γ-globulinemia

• Interface hepatitis Manns, MP, Czaja AJ, et al: Hepatology 51:2193, 2010

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

Types of Autoimmune Hepatitis Type 1 AIH

• ANA and/or SMA

• Adults and children

• Most common

• Genetic predisposition

(DRB1 alleles)

Type 2 AIH

• Anti-LKM1 • Mainly children

• Adults (USA), 4%

• Genetic predisposition (DQB1 alleles)

Czaja AJ, Manns MP: Am J Gastroenterol 90:1206, 1995 Homberg JC et al:

Hepatology 7:1333, 1987

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 41:146-150, 1994 Strettel MD et al: Gastroenterology 112:2028, 1997 DeBoer YS et al: Gastroenterology 147:443, 2014

10 10

Immune Injury Caused by Therapeutic Drugs Targets: drug-associated antigens or self

Immuno-allergic

Auto-immune

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

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

19 Mar 2015 Annual Meeting on DILI FDA/C-Path/PhRMA/AASLD

Reaction Pathways

Principal Autoantigens for Autoimmune Hepatitis are Drug Metabolizing Enzymes

Syndromes Characterized by Autoimmune Hepatitis

Implicated Autoantigen

Type 2 AIH CYP2D6

Autoimmune Polyglandular Syndrome Type 1

CYP1A2 CYP2A6

Tienilic acid-induced AIH CYP2C9

Christen U et al: Dig Dis 28:80-85, 2010 Lecoeur S et al: Mol Pharmacol 50:326-333, 1996 Obermayer-Straub P et al: Gastroenterology 121:668-677, 2001 Hardtke-Wolenski M et al: Hepatology doi: 10.1002/hep.27639

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: 820-827

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

Drugs and drug-induced autoimmune liver disease

Castiella et al., World J Hepatol 2014 Perdices et al Rev Esp Enf Dig 2014

Drug Patients treated,

n

Prescription, n

Cases, n

Proportion Per 100,000

95% CI 95% CI

Amoxicillin /clavulanate 35,252 83,379 15 2350 43 24 70 Diclofenac 54,889 112,801 6 9148 11 4 24 Azathioprine 532 3054 4 133 752 205 1914 Infliximab 593 a 4 148 675 184 1718 Nitrofurantoin 5476 12,034 4 1369 73 20 187 Isotretinoin 2169 7978 3 732 138 29 404 Atorvastatin 7385 34,171 2 3693 27 4 98 Doxycycline 32,677 54,232 2 16339 6 1 22

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

Epidemiology of Drug-induced Liver injury in Iceland n=251,860

Patient 2 • 48 lady • Obesity, F/H of CD

– Crohn’s large & small bowel- 2010

– Azathioprine DILI -2011 (ALT 196), withdrawn

• Infliximab Oct 2011 – ALT 470 u/l – ANA neg, SMA strongly

pos – US: hyperechoic liver

Follow up

• Adalimumab April 2012

Prevalence of Drug-induced AIH

• 10,270 in-patients (2000-11) • 136 (1.3%) DILI • 12 (8.8% of DILI): drug-induced autoimmune

hepatitis – 41.7% males, age range 17-73 – 8 (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; 46:1116-20.

*Partial list

Drugs & Hypersensitivity Reactions* FDA Postmarketing Safety Alerts: 1996-2014

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) 18 19 Mar 2015 Annual Meeting on DILI

FDA/C-Path/PhRMA/AASLD

*Partial list

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

19 19 Mar 2015 Annual Meeting on DILI FDA/C-Path/PhRMA/AASLD

22

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’ auto-reactive 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

23

Checkpoint Inhibitors Post-market: Life-threatening autoimmune AEs

19 Mar 2015 Annual Meeting on DILI FDA/C-Path/PhRMA/AASLD

• 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

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

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

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

Can we phenotype portal Inflammation?

• Eosinophilia = less inflammation, lower CD11b+ macrophage

• High IgG = higher CD11b+ macrophage

Foureau. Clin Exp Immunol 2014 180: 40–511

AIH with DILI 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

DI-AIH 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

IM-DILI 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.

Mixed autoimmune

type

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

DILI with positive autoantibodies

Patients with positive autoantibodies. The probability of developing DIAILD increases in second DILI episodes independently of the causal agent

Classification of drug-induced autoimmune liver disease

Castiella et al., World J Hepatol 2014

DIAH vs AIH DIAIH (n=21)

Idiopathic AIH (n= 51)

Valor p

Edad media, años 58 ± 16 55 ± 14 0,4 Sexo femenino, % 62 70 0,6 Hipertensión, n(%) 33 12 0,02 Diabetes mellitus, % 14 2 0,04 HLADR3+, n(%) 4 (36) 27 (61) 0,1 HLADR4+, n(%) 3 (27) 9 (20) 0,7 Enf autoinmunes, % 24 33 0,6

Necesidad tto, n(%) 17(81) 42(93) 0,193 Tiempo resolución (días), media 203±239 112±85 0,131 Valores analíticos, media BT (xLSN) 6 2 0,001 AST (xLSN) 23 11 0,001 ALT (xLSN) 27 14 0,001 GGT (xLSN) 9 5 0,02 FA (xLSN) 1,7 1,8 0,9

Ortega et al, EASL 2015

Autoimmune features in DILI

Positive AAbds (n=129)

Negative AAbds (n=371)

Valor p

Edad media, años 53 ± 17 49 ± 18 0,025 Sexo femenino, % 57 52 0,306 Hipertensión, n(%) 96 (23) 271 (22) 0,88 Diabetes mellitus, % 11 9 0,48

Necesidad tto, n (%) 116 (24) 296 (28) 0,460

Tiempo resolución (días), media

116±241 165±465 0,246

Valores analíticos, media BT (xLSN) 8 6 0,081 AST (xLSN) 26 24 0,748 ALT (xLSN) 30 27 0,326 GGT (xLSN) 6 6 0,858 FA (xLSN) 1.4 1.4 0,908

Ortega et al, EASL 2015

Autoimmune features in DILI

Positive AAbds (n=129)

HAI-DILI (n= 21)

Valor p

Edad media, años 53±17 58±15 0,292 Sexo femenino, % 57 62 0,813 Diabetes mellitus, % 11 14 0,709 Hipertensión arterial, n (%) 96 (23) 20 (35) 0,266

Necesidad tto, n (%) 116 (24) 21 (81) 0,000 Tiempo resolución (días), media

116±241 345±603 0,002

Valores analíticos, media BT (xLSN) 8 6 0,283 AST (xLSN) 26 23 0,618 ALT (xLSN) 30 27 0,658 GGT (xLSN) 6 8 0,020 FA (xLSN) 1.4 1.7 0,119

Ortega et al, EASL 2015

DIAH vs AIH

0%

10%

20%

30%

Estatinas AINEs Antibióticos Anti-TNF IECAs

HAI-DILI HAI

Ortega et al, EASL 2015

How to identify drug-induced 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 drug-withdrawal or complete withdrawal of immunosuppressive drugs whichever is later

Hennes. Hepatology 2008; 48:169-176. Aithal. Clin Pharmacol Ther 2011; 89:806-15.

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

Response to corticosteroids

Autoimmune titres evolution

IgG values evolution

Elements to be reported when a case of drug-induced autoimmune liver disease is suspected

Castiella et al., World J Hepatol 2014

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