Identifying the Culprit

Assessing Drug Causality in Severe Cutaneous Drug

Reactions using ALDEN

Jay-V James G. Barit

 Severe Cutaneous Drug
Reactions (SCARs)
• Stevens-Johnson syndrome and toxic epidermal necrolysis
(SJS-TEN)

• Drug rash with eosinophilia and systemic symptoms (DRESS)

/ drug-induced hypersensitivity syndrome (DIHS)

• Acute generalized exanthematous pustulosis (AGEP)

• Generalized bullous fixed drug eruption

• Anaphylaxis

• Anticoagulant-induced skin necrosis

 SJS-TEN
Severe, potentially fatal mucocutaneous reaction, most commonly
secondary to a drug
SJS-TEN and Culprit Drugs

• Risk of SJS-TEN seem to be limited to first 8 weeks of

treatment

• Drug used for a longer time unlikely to be cause of SJS-

TEN

• Typical exposure period before reaction: 4 days to 4

weeks of first continuous use of the drug

Drugs with SJS-TEN Risk

 The Need to Identify the
Culprit Drug
• Average mortality rate

• SJS: 1-5%

• TEN: 25-35%

• Early withdrawal of the offending drug: improved prognosis

10 -year observational study of 203 patients with SJS-TEN
Garcia-Doval et al, 2000

• Better prognosis for each day the drug was withdrawn earlier
(OR 0.69/day - [0.53-0.89])

• Increased risk of dying for those exposed to drugs with long

half-lives (OR 4.9 - [1.3-18.9])
 Drug Chart
2
Drugs 03/04 03/05 03/06 03/07 03/08 03/09 03/10 03/11
mos

Amlodipine

(t1/2=30-50hrs)

Carbamazepine

(t1/2=25-65hrs)

Paracetamol

(t1/2=2-3hrs)

Loratadine

(t1/2=3-20hrs) *
Onset of rapidly evolving
Onset of fever
pruritic rash
Algorithm for Drug Causality in
Epidermal Necrolysis (ALDEN)

• Developed as a rapid assessment tool

• Especially for those exposed to multiple medications

• Based on 6 parameters
Algorithm for Drug Causality in
Epidermal Necrolysis (ALDEN)
• Time delay from initial drug intake to onset of reaction

• Probability of drug presence in the body on index day

• Previous history of exposure to the same drug, with or without

reaction (prechallenge/rechallenge)

• Presence of drug beyond progression phase of the disease

(dechallenge)

• Drug notoriety as a cause of SJS/TEN based on previous studies

• Presence or absence of other etiologic causes

 Case
• 40/F on amlodipine for > 2 months for recently diagnosed
hypertension; no liver/kidney disease, no known drug allergies

• Developed trigeminal neuralgia and was given carbamazepine

by her neurologist

• 3 days after, develops undocumented fever, self-medicated with

paracetamol

• 6 days after, develops a pruritic erythematous rash; took

loratadine. Noted rapid development of more dusky patches
becoming blisters and erosions, oral ulcers, conjunctival
suffusion

• Has been taking paracetamol and loratadine with no previous

reactions
 Drug Chart
2
Drugs 03/04 03/05 03/06 03/07 03/08 03/09 03/10 03/11
mos

Amlodipine

(t1/2=30-50hrs)

Carbamazepine

(t1/2=25-65hrs)

Paracetamol

(t1/2=2-3hrs)

Loratadine

(t1/2=3-20hrs) *
Onset of rapidly evolving
Onset of fever
pruritic rash
 Delay from intake to onset
of reaction (index day)
Values Score Rules

Suggestive 3 5-28 days

Compatible 2 29-56 days

Likely 1 1-4 days

Unlikely -1 >56 days

Drug started on or
Excluded -3
after index day
In case of previous reaction to same drug:
suggestive (+3): from 1-4 days, likely (+1): from 5-56 days
 Drug Chart
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Drugs 03/04 03/05 03/06 03/07 03/08 03/09 03/10 03/11
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67 days - UNLIKELY (-1)

Amlodipine

(t1/2=30-50hrs)

6 days - SUGGESTIVE (+3)

Carbamazepine

(t1/2=25-65hrs)

3 days - LIKELY (+1)

Paracetamol

(t1/2=2-3hrs)

Started on index day - EXCLUDED (-3)

Loratadine

(t1/2=3-20hrs) *
Onset of rapidly evolving
Onset of fever
pruritic rash
 Current Scores
Drug Delay Presence Prechallenge Dechallenge Notoriety TOTAL

AMLO -1

CBZ 3

PARA 1

LORAT -3
 Drug present on the body
on index day
Values Score Rules

Continued up to index day or stopped <5x t1/2

Definite 0
before index day

Stopped at a point prior to index day >5x t1/2

Doubtful -1 but liver/kidney function alterations or
suspected drug interactions are present
Drug stopped at a point prior to index day by
Excluded -3 more than 5x t1/2, without liver/kidney function
alterations or suspected interactions
Suspected interaction was considered when more than five drugs were present in a
patient's body at the same time.
 Drug Chart
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Continued up to index day - DEFINITE (0)

Amlodipine

(t1/2=30-50hrs)

Continued up to index day - DEFINITE (0)

Carbamazepine

(t1/2=25-65hrs)

Stopped prior to index day >5x t1/2 - EXCLUDED (-3)

Paracetamol

(t1/2=2-3hrs)

Continued up to index day - DEFINITE (0)

Loratadine

(t1/2=3-20hrs) *
Onset of rapidly evolving
Onset of fever
pruritic rash
 Current Scores
Drug Delay Presence Prechallenge Dechallenge Notoriety TOTAL

AMLO -1 0

CBZ 3 0

PARA 1 -3

LORAT -3 0
Prechallenge/rechallenge
Values Score Rules

Positive specific for

4 SJS/TEN after use of same drug
disease and drug
Positive specific for SJS/TEN after use of similar drug or
2
drug other reaction with same drug
Other reaction after use of similar
Positive unspecific 1
drug
No known previous exposure to this
Not done/unknown 0
drug
Exposure to this drug without any
Negative -2
reaction (before or after reaction)
 Drug Chart
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No known previous exposure - NOT DONE/UNKNOWN (0)

Amlodipine

(t1/2=30-50hrs)

No known previous exposure - NOT DONE/UNKNOWN (0)

Carbamazepine

(t1/2=25-65hrs)

Exposure to drug without any reaction prior - NEGATIVE (-2)

Paracetamol

(t1/2=2-3hrs)

Exposure to drug without any reaction prior - NEGATIVE (-2)

Loratadine

(t1/2=3-20hrs) *
Onset of rapidly evolving
Onset of fever
pruritic rash
 Current Scores
Drug Delay Presence Prechallenge Dechallenge Notoriety TOTAL

AMLO -1 0 0

CBZ 3 0 0

PARA 1 -3 -2

LORAT -3 0 -2
 Dechallenge

Values Score Rules

Neutral 0 Drug stopped (or unknown)

Negative -2 Drug continued without harm

 Drug Chart
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Drug stopped or unknown - NEUTRAL (0)

Amlodipine

(t1/2=30-50hrs)

Drug stopped or unknown - NEUTRAL (0)

Carbamazepine

(t1/2=25-65hrs)

Drug stopped or unknown - NEUTRAL (0)

Paracetamol

(t1/2=2-3hrs)

Drug stopped or unknown - NEUTRAL (0)

Loratadine

(t1/2=3-20hrs) *
Onset of rapidly evolving
Onset of fever
pruritic rash
 Current Scores
Drug Delay Presence Prechallenge Dechallenge Notoriety TOTAL

AMLO -1 0 0 0

CBZ 3 0 0 0

PARA 1 -3 -2 0

LORAT -3 0 -2 0
 Type of Drug/Notoriety
Values Score Rules

Strongly associated 3 High-risk drug

Associated 2 Definite but lower risk

Several previous reports, ambiguous

Suspected 1
epidemiologgy results
All other drugs including newly released
Unknown 0
ones
No evidence of association (from previous
Not suspected -1
study with sufficient number of controls)
 REGISCAR Data

• Available at: http://www.regiscar.org/Office_1.html

• Drug Notoriety available in Excel file:

• http://www.regiscar.org/pdf/
Drug%20Notoriety%202015.%20revised%20may%20
2017.xls
 Drug Chart
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REGISCAR -1 (not suspected)

Amlodipine

(t1/2=30-50hrs)

REGISCAR 3 (strongly associated)

Carbamazepine

(t1/2=25-65hrs)

REGISCAR 0 (unknown)
Paracetamol

(t1/2=2-3hrs)

REGISCAR 1 (suspected)
Loratadine

(t1/2=3-20hrs) *
Onset of rapidly evolving
Onset of fever
pruritic rash
 Current Scores
Drug Delay Presence Prechallenge Dechallenge Notoriety TOTAL

AMLO -1 0 0 0 -1

CBZ 3 0 0 0 3

PARA 1 -3 -2 0 0

LORAT -3 0 -2 0 1
 Intermediate Score
• Sum of all previous criteria

• Delay from intake to onset

• Drug present on index day

• Prechallenge/rechallenge

• Dechallenge

• Notoriety
 Intermediate Score
Drug Delay Presence Prechallenge Dechallenge Notoriety TOTAL

AMLO -1 0 0 0 -1 -2

CBZ 3 0 0 0 3 6

PARA 1 -3 -2 0 0 -4

LORAT -3 0 -2 0 1 -4
 Other Cause

• Rank all drugs from highest to lowest intermediate score

• If at least one has an intermediate score >3, subtract 1

point from the score of each of the other drugs taken by
the patient (another cause is more likely)
 Final Scoring
• Final score from -12 to +10

• Greater than or equal to 6: Very probable

• 4-5: Probable

• 2-3: Possible

• 0-1: Unlikely

• Less than 0: Very unlikely

 Final Score
Intermediate
Drug Deduction Final Score Interpretation
Score

CBZ 6 6 VERY PROBABLE

AMLO -2 -1 -3 VERY UNLIKELY

PARA -4 -1 -5 VERY UNLIKELY

LORAT -4 -1 -5 VERY UNLIKELY

 Summary
• ALDEN is a quick assessment tool to determine causality
in SJS-TEN

• Particularly useful if with a lot of medications to consider

• Identification of the culprit drug is needed - prompt

withdrawal portends a better prognosis

• Consider other risk factors: genetics (e.g HLA types), HIV

infection/hematologic malignancy - increased risk for
ADRs
 References
• [cited 2019Mar10]. Available from: http://www.regiscar.org/Office_1.html

• Bolognia J, Schaffer JV, Cerroni L. Dermatology. Philadelphia?: Elsevier; 2018.

• Fitzpatrick TB, Goldsmith LA, Wolff K. Fitzpatricks dermatology in general medicine. New York: McGraw-Hill; 2012.

• Garcia-Doval I, Lecleach L, Bocquet H, Otero X-L, Roujeau J-C. Toxic Epidermal Necrolysis and Stevens-Johnson

Syndrome. Archives of Dermatology. 2000;136(3).

• Sassolas B, Haddad C, Mockenhaupt M, Dunant A, Liss Y, Bork K, et al. ALDEN, an Algorithm for Assessment of

Drug Causality in Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis: Comparison With Case–Control

Analysis. Clinical Pharmacology & Therapeutics. 2010;88(1):60–8.

• Whitney A High. Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations,

and diagnosis [Internet]. UpToDate. [cited 2019Mar10]. Available from: https://www.uptodate.com/contents/

stevens-johnson-syndrome-and-toxic-epidermal-necrolysis-pathogenesis-clinical-manifestations-and-

diagnosis#H61178315