RUCAM, Strengths & Weaknesses

Maribel Lucena Servicio de Farmacologa Clnica, H.Universitario, Facultad de Medicina, Universidad de Mlaga, Spain
On behalf of the Spanish Group for the Study of Drug-Induced Liver Injury. CIBERehd

Drug-Induced Liver Injury Standardization of Nomenclature and Causality Assessment

NIH Workshop December 1-2, 2008 Lister Hill Auditorium - NIH Campus, Bethesda, MD

 Opportunity for a global dialogue Causality assessment is the Achilles heel of DILI Barrier for progress in mechanism research Need of agreement on instrument for validating DILI cases.

DILI Diagnosis
DILI may resemble any acute and chronic liver disease The signature (consistent clinical, pathologic and latency presentation) for a given drug may be variable. Hypersensitivity features occur in less than a quarter of patients DILI diagnosis relies on exclusion of other causes of liver injury Dechallenge requires follow-up

Qualities required for causality assessment

Validity the method is able to distinguish between cases where the drug is responsible and cases where it is not Reproducibility ensures an identical result regardless of who the user is and when the scale is used

Causality assessment methods

Expert judgement or global introspection
DILIN causality score

Probabilistic (Bayesian) approach

require precisely quantified information to model probability distributions for each parameter

Diagnostic scales and algorithms

Diagnostic scales
General scales for the assessment of ADR
Karch y Lasagna 1977 Kramer 1979 Naranjo 1981 Jones 1982 The French Method, Begaud 1984 Arimone 2006

Specific scales for DILI Striker decision tree 1992 Council International Organizations Medical Sciences / Roussel Uclaf Causality Assessment Method 1990 M & V/CDS 1997 DDW-J [modifies CIOMS scale] 2003

NARANJO SCALE Axis

Previous reports on the reaction Temporal illegibility in the onset of the reaction Improvement after drug withdrawal Positive re-challenge Exclusion of alternative causes for the ADR Placebo response Drug concentration and monitoring Dose relationship Previous exposure and cross reactivity Presence of any objective evidence
Scores 9 Definitive 5-8 Probable 1-4 Possible 0 Unlikely.

Numerical score 0 to 1 -1 to 2 0 to 1 -1 to 2 1 to 2 0 to 1 0 to 1 0 to 1 0 to 1 0 to 1

GARCIA-CORTES M, LUCENA MI, PACHKORIA K, ANDRADE RJ. Evaluation of the Naranjo Adverse Drug Reactions Probability Scale in the Causality Assessment of Drug-Induced Liver Injury Aliment Pharmacol Ther 2008; 27:780-789.

CORRELATION BETWEEN OBSERVERS WHEN APPLYING CIOMS AND NARANJO SCALES

CIOMS 250 200 150 100 50 0 1
Obs 1

NARANJO

Definite Probable Possible Unlikely

2
Obs 2

3
Obs 1

4
Obs 2

OBSERVERS Objective evidence: Hypersensitivite features Histological findings

Diagnostic scales
General scales for the assessment of ADR
Karch y Lasagna 1977 Kramer 1979 Naranjo 1981 Jones 1982 The French Method, Begaud 1984 Arimone 2006

Specific scales for DILI Striker decision tree 1992 Council International Organizations Medical Sciences / Roussel Uclaf Causality Assessment Method 1990 M & V/CDS 1997 DDW-J [modifies CIOMS scale] 2003

Scores for individual axes of the diagnostic scales CIOMS/RUCAM and Maria & Victorino
CIOMS/RUCAM (1990)
AXIS
CHRONOLOGICAL CRITERIA From drug intake until onset event From drug withdrawal until onset event Course of the reaction RISK FACTORS Age Alcohol +2 to +1 +1 to 0 -2 to +3

Maria & Victorino/CDS (1997)

AXIS
CHRONOLOGICAL CRITERIA From drug intake until onset event From drug withdrawal until onset event Course of the reaction +1 to +3 -3 to +3 0 to +3 -3 to +3 0 to +3

SCORE

SCORE

Highly probable>8; Probable 6-8; Possible 3-5; Unlikely 1-2; -3 to 0 -3 to +2 CONCOMITANT THERAPY BIBLIOGRAPHICAL DATA Excluded 0
EXCLUSION NON-DRUG RELATED -3 to +2

Probability of DILI ALTERNATIVE EXCLUSION +1 to 0 CIOMS: +1 to 0 EXTRAHEPATIC MANIFESTATION M&V: RECHALLENGE

0 to +3

Definite: > 17; Probable: 14-17; Possible: 10-13; Unlikely: 6-9; 0 to +2 BIBLIOGRAPHICAL DATA Excluded < 6
RECHALLENGE -2 to +3

CIOMS
(1990)

Mara & Victorino (1997)

Excluded Unlikely PossibleProbable Definite Total 21 4 1 26 2 3 8 30 5 48 23 7 9 90 99 228

Excluded Unlikely Possible Probable Definite Total

1 43 40 84

16 53 69

1 1

Weighted Kappa: 0.28

Total agreement in 42 cases (18%) Discrepancies of one level 110 (48.2%) Discrepancies of two level 70 casos (30.7%) Total disagreement in 6 cases (3%)
Lucena et al, Hepatology 2001.

M & V scale: poor performance

Reactions with long latency periods Evolution to chronicity: cholestatic pattern Fulminant hepatitis or Death

DDW-J (Digestive Disease Week-Japan Scale)

Scores Chronology Delay Onset >15 d HC pattern >30 d Chol/mix pattern Concomitant drugs Hypersensitivity Drug - Lymphocyte stimulation test (DLST) +2 to 0 Eosinophilia 6% +1 to 0
Takikawa et al., Hepatology Res 2003 Watanabe & Shibuya, Hepatology Res 2004

Omitted

287 Japanese DILI Cases classified the scores according to CIOMS scale or a modified diagnostic scale (DDW-J)
200 180 160 140 120 100 80 60 40 20 0 Unrelated Unlikely Possible CIOMS Probable Definite 5 0 4 1 39 11 102 69 170

173

DDW-Y

Bland-Altman plot of test-retest differences versus their mean

Rochon J et al. Hepatology 2008

Strenghts
Provide an uniform approach. Adds consistency to the diagnostic process Excellent teaching tool, emphasizes the features that merit attention Help improve the quality of the information recorded Improvement in inter-intra rater agreement Help standardize the reporting manner
Do not substitute common sense clinical judgement Designed for finding support for and less for excluding causality

RUCAM Limitations
Complexity. Ambiguous instructions Mixed cases included into the cholestatic group Disagreements in calculating time to onset Assignment difficult for cases with atypical time course Arbitrary risk factors: age 55y, alcohol, pregnant Unclear criteria for competing drug(s) Subjective interpretation of the drug hepatotoxic potential Relies largely on re-challenge, seldom done Incomplete work-up: uncertainty score Drug-induced adaptation or tolerance

RUCAM Limitations
Complexity. Ambiguous instructions Mixed cases included into the cholestatic group No evidence supporting the weighting and selection of domains

HC pattern (N=247)

Chol/Mix pattern (N=246)

TIME TO ONSET
From beginning of the +2 drug (5-90d) From cessation of the +1 drug(<15d, <30d) 77% 94% 81% 94%

COURSE
After cessation of the drug: decrease 50% within 30d for HC, 180d
for Chol/mix

60%

66%

RISK FACTOR
Age 55 y Alcohol ( or pregnancy in Chol/mix) 53% 20% 67% 21%

N=598
300 250 200 150 100 50 0 0-5

Time to onset (days)

5-30

30-90

90-180

180-365

>365

days

Time to onset according to Type Liver Injury

P75 P25

18 d

28 d

270

329

Time to onset: 90 days best cut-off

N=598
300 250 200 150 100 50 0 0-5

Duration treatment (days)

5-30

30-90

90-180 180-365

>365

days

Duration Treatment according to Type of Liver Injury

29 d

32 d

270

329

Duration treatment: 90 days best cut-off

Delay onset according to type of liver injury

8d

9d

61

64

Delay onset: 30 days best cut-off

HC pattern (N=247)

Chol/Mix pattern (N=246)

TIME TO ONSET
From beginning of the drug (5-90d) From cessation of the drug(<15d, <30d) 77% 94% 81% 94%

COURSE
After cessation of the +2 drug: decrease 50% within
30d for HC, 180d for Chol/mix

60%

66%

RISK FACTOR
Age 55 y Alcohol ( or pregnancy in Chol/mix) 53% 20% 67% 21%

Course of the reaction

Garcia-Muoz J Hepatol 2008; 48(suppl2): S336.

Natural History study 100 DILI cases HC damage recovery time

mean 90 days (IC 95% 73-106).

Chol/mix damage recovery time

mean 145 days (IC 95% 113-176),

HC pattern (N=247)

Chol/Mix pattern (N=246)

TIME TO ONSET
From beginning of the drug (5-90d) From cessation of the drug(<15d, <30d) 77% 94% 81% 94%

COURSE
After cessation of the drug: decrease 50% within 30d for HC, 180d
for Chol/mix

60%

66%

RISK FACTOR
Age 55 y +1 Alcohol +1 ( or pregnancy) in Chol/mix) 53% 20% 67% 21%

Incidence of drug-induced liver disease according to Age and Sex in 603 DILI patients
Incidence
90 80 70 60 50 40 30 20 10 0 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89

Man

Woman

Type of liver damage according to sex in patients younger or older than 60 years of age (n=603)
P<0.0001
100% 80% 60% 40% 20% 0% Cholestatic Hepatocellular Mixed
Point values might be assigned to both sexes over 60 men < 60y men >60y damage women >60y years of age with cholestaticwomen <60y and perhaps just to women less than 60 years of age with hepatocellular damage.

Risk Factors
Risk factors drug or drug class specific Incorporating immunological and genetic risk factors identified

HC pattern (N=247)
NO INFORMATION OR +0 INCOMPATIBLE ONSET WITH CONCOMITANTS DRUG(S) SEARCH FOR ALL NON DRUG +2 CAUSES PREVIOUS INFORMATION ON +2 HEPATOTOXICITY OF THE DRUG:
labelled in the products characteristic

Chol/Mix pattern (N=246)

87%

84%

84%

84%

67% 95%

72% 96%

RECHALLENGE
Not done or not interpretable

+0

Concomitant drugs
Inability to ascertain causality when two o more drugs are taken concomitantly and with the same temporal sequence. A given drug may cause different patterns of injury in different individuals When more than one drug could be the culprit, a blinded application of the scale can lead to a misleading causality assessment if only chronological criteria are taken into account potential for pharmacokinetic drug-drug interactions This domain should be removed

HC pattern (N=247)
NO INFORMATION OR +0 INCOMPATIBLE ONSET WITH CONCOMITANTS DRUG(S) SEARCH FOR ALL NON DRUG +2 CAUSES PREVIOUS INFORMATION ON +2 HEPATOTOXICITY OF THE DRUG:
labelled in the products characteristic

Chol/Mix pattern (N=246)

87%

84%

84%

84%

67% 95%

72% 96%

RECHALLENGE
Not done or not interpretable

+0

Test/Clinical features
1.Viral serology IgM anti HVA,IgM antiHBc Anti HCV, PCR-HCV IgM CMV,IgM EBV 8. Radiologic/endoscopy test 3. Autoimmunity( ANA, ANCA, AMA, ASMA, antiLKM1) 7. Hypotension, shock, cardiac insuficiency, vascular disease 2. Bacterial serology: if persistent fever,diarrhoea (Salmonella, Campylobacter,Listeria, Coxiella) 4. Ceruloplasmine ( patients<40y) 5. Alfa-1 Antitrypsin 6. Transferrin saturation( in anicteric hepatocellular damage)

Diseases
Viral hepatitis

Biliary obstruction Autoinmune Hepatitis.PBC Isquemic Hepatitis

Bacterial Hepatitis Wilsons Disease Deficit of -1antitrypsin Haemocromatosis

HC pattern (N=247)
NO INFORMATION OR +0 INCOMPATIBLE ONSET WITH CONCOMITANTS DRUG(S) SEARCH FOR ALL NON DRUG +2 CAUSES PREVIOUS INFORMATION ON +2 HEPATOTOXICITY OF THE DRUG:
labelled in the products characteristic

Chol/Mix pattern (N=246)

87%

84%

84%

84%

67%

72%

RECHALLENGE
Not done or not interpretable

+0

95%

96%

Drug Hepatotoxicity Potential

Summary Product Characteristics not periodically updated information imprecise can produce transient increases in transaminases It may cause hepatitis rarely Difficult to access by the physician New marketed drugs or in development absence of information Published reports: variable in quality Develop a data-base with up-todate list of hepatotoxins

HC pattern (N=247)
NO INFORMATION OR +0 INCOMPATIBLE ONSET WITH CONCOMITANTS DRUG(S) SEARCH FOR ALL NON DRUG +3 CAUSES PREVIOUS INFORMATION ON +2 HEPATOTOXICITY OF THE DRUG:
labelled in the products characteristic

Chol/Mix pattern (N=246)

87%

84%

84%

84%

67%

72%

RECHALLENGE
Not done or not interpretable

+0

95%

96%

RUCAM Challenges
Underlying liver disease Atypical presentation: Autoimmune hepatitis triggered by drugs Potential hepatotoxic drugs taken concomitantly and with the same temporal sequence No dechallenge information: FHF, Tx, Death Chronic outcome

New diagnostic scale in research setting

Authoritative Evidence-based criteria Refine weighting, simplified scoring Computer program Easily accessible, over the internet Abridge scale for the prompt recognition of DILI in clinical setting

Grupo de Estudio Hepatopatas Asociadas a Medicamentos

H.Torrecrdenas, Almera: MC Fernndez, G Pelez, M. Casado, JL Vega, H. Virgen Macarena, Sevilla: JA Durn, M. Villar . H. Universitario Virgen de Valme, Sevilla: M Romero, H. Central de Asturias, Oviedo: L Rodrigo-Saez, V. Cadaha, R. De Francisco. H. de Puerto Real, Cdiz: JM Prez-Moreno, M Puertas. H. Universitario San Cecilio, Granada: J Salmern, A Gila. H. Germans Trias i Puyol, Barcelona: R Planas,I Barriocanal, Eva Montan,J Costa. H. Universitario Virgen de las Nieves, Granada: R Martn-Vivaldi, F Nogueras. H. Costa del Sol, Mlaga: JM Navarro, JF Rodrguez. H. La Inmaculada. Hurcal-Overa, Almera: H Snchez-Martinez. H. Puerta del Mar, Cdiz: F Daz, MJ Soria, L Martn-Herrera H. Reina Sofa, Crdoba: JL Montero, M De la Mata. H. 12 de Octubre, Madrid: T. Muoz-Yage, J.A. Solis-Herruzo. H. Marqus de Valdecilla, Santander: F. Pons, R. Taheri.Amox/Clav H. Sant Pau, Barcelona: C Guarner, D Monfort. Fenitoina Furantoin H. Carlos Haya, Mlaga: M Jimnez. H. Xeral-Calde, Lugo: S. Avila-Nasi. Valproic Labetalol REG HEPATOX H. Nuestra Sra. de Aranzazu, San Sebastin: M. Garca-Bengoechea, A. Castiella. H. de Mendaro, Guipuzcuoa: S. Blanco. Paracetamol Troglitazone H. Clnico Provincial: M Bruguera H. Morales Messeguer: H Hallaf
Isoniazid Diclofenac

(GEHAM)