ALden Algorithm: Determines the probability that Allopurinol is the culprit drug in SJS/TEN.
Culprit Factors
Time from Drug Intake to Reaction
Daily Dosage of Allopurinol
Other Suspect Drugs Present?
Awaiting Analysis
Enter the medication timeline and dosage details to evaluate the probability of Allopurinol causality.
Guidelines & Evidence
Verified
Last Review: 2026-07-17
When to Use
When to Use
ALDEN (Algorithm of Drug Causality for Epidermal Necrolysis) is applied per-drug in a patient with confirmed Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN) to determine which medication(s) among all those the patient is taking are most likely responsible. It is specifically designed for the SJS/TEN context — with timing windows, dechallenge and rechallenge weights calibrated to the distinctive immunopathology of epidermal necrolysis.
Appropriate Application
Confirmed SJS (< 10% TBSA epidermal detachment) or TEN (> 30%) or SJS/TEN overlap (10–30%)
Applied independently to every drug the patient was taking at or before the index day (day of first skin symptom)
Used to prioritize drug discontinuation when polypharmacy is present
Used to guide definitive allergy documentation and family genetic counseling post-episode
Academic/epidemiological case investigation for pharmacovigilance
When NOT to Use
AGEP, DRESS, or other SCARs (ALDEN timing/weighting is calibrated specifically to SJS/TEN)
As a substitute for immediate drug discontinuation — stop all non-essential drugs first, then calculate
When the "index day" cannot be reliably established — score validity depends on this anchor
How it Works
Scoring Parameters
Delay to onset (from initial drug intake to index day): +3 (5–28 days — peak causality window); +2 (1–4 days first exposure or 5–28 days rechallenge); 0 (< 1 day or 29–56 days); −3 (> 56 days or < 1 day on rechallenge).
Probability of drug presence in the body on the index day: +3 (yes — drug still detectable based on half-life); 0 (unknown/uncertain); −3 (no — drug eliminated before index day).
Prechallenge: −1 if prior exposure to same drug without reaction (reduces causality likelihood).
Rechallenge: +4 if drug re-administered and same reaction recurred; −2 if re-administered without reaction.
Dechallenge: +1 if disease progression stopped after drug was stopped (note: heavily discounted because SJS/TEN has a natural plateau regardless of drug status).
Drug notoriety: +3 if drug is high-risk for SJS/TEN (e.g., allopurinol, carbamazepine, lamotrigine, nevirapine, cotrimoxazole, oxicam NSAIDs); +2 if probable risk; +1 if possible; 0 if no known association; −1 if drug has never caused SJS/TEN.
Exclude other causes: −1 if another highly notorious drug was also taken in the causality window (competing cause); −1 if mycoplasma infection or other confirmed infectious trigger is present.
Score Interpretation
| < 0 | Very unlikely — drug is not the cause |
| 0–1 | Unlikely |
| 2–3 | Possible |
| 4–5 | Probable |
| ≥ 6 | Very probable — strongest causal signal |
Index Day Definition
The "index day" is defined as the first day of skin symptoms (mucosal erosions, skin pain, or early blistering). It is NOT the day of maximum epidermal detachment. Accurate index day ascertainment is critical — scoring breaks down if anchored incorrectly.
Pathophysiological Basis
SJS/TEN results from drug-specific cytotoxic CD8+ T cells and NK cells targeting keratinocytes expressing drug-HLA complexes. The 5–28 day sensitization window reflects the time required for T-cell expansion after first exposure. Drugs like carbamazepine (HLA-B*15:02) and allopurinol (HLA-B*58:01) have pharmacogenomic associations that explain their extreme TEN risk in predisposed populations. ALDEN captures this by weighting drug notoriety based on population-level pharmacovigilance data (primarily EuroSCAR case-control studies).
Clinical Pearls
Clinical Pearls
A drug started > 8 weeks before the index day or < 1 day before (on first exposure) scores negatively and is very unlikely to be the culprit.
Rechallenge data (+4 if positive) dominates the score — it should never be performed deliberately in SJS/TEN; value is only from inadvertent rechallenge data.
ALDEN is more sensitive than the French pharmacovigilance method: it attributed probable/very probable causality in 69/100 cases vs. 23/100 (P < 0.001) and showed strong correlation with EuroSCAR case-control results (r = 0.90).
In polypharmacy, ALDEN often identifies one clear frontrunner — if two or more drugs score "probable" or above, document all; HLA testing (e.g., HLA-B*15:02 screen before carbamazepine) can add clarity.
Herpes simplex virus (HSV) infection is a major non-drug trigger for SJS — when serology confirms HSV, drug scores should be reduced by the "exclude other causes" penalty.
Comparison to General ADR Scales
The Naranjo ADR scale was not designed for SJS/TEN and uses non-specific criteria. ALDEN is the validated reference tool for epidermal necrolysis drug causality. Regulatory pharmacovigilance bodies in France have adopted ALDEN as their reference method for SJS/TEN case assessment.
Limitations
ALDEN requires accurate clinical history — unreliable in unconscious patients or when onset date is uncertain.
Drug notoriety scores are based on epidemiological literature; for newly marketed drugs with insufficient data, assign 0 (no known association) and flag for pharmacovigilance reporting.
Dechallenge is minimally informative in SJS/TEN because the disease plateaus irrespective of drug status — this is explicitly acknowledged in the ALDEN weighting.
Next Steps
Immediate Management (Parallel with ALDEN)
01
Stop ALL non-essential medications immediately — do not wait for ALDEN calculation. ALDEN is used for attributing causality retrospectively and for allergy documentation, not to delay discontinuation.
02
Transfer to specialist center (burn unit or dermatology ICU) if SCORTEN ≥ 2.
03
Initiate supportive care: wound management, ophthalmology consult (ocular involvement in >80% of cases), nutrition, analgesia.
For Any Drug Scoring ≥ 4 (Probable or Very Probable)
01
Permanently list as severe allergy in the medical record with specific ICD-10 adverse drug reaction code.
02
Provide the patient and family with written documentation — carry card or MedicAlert bracelet.
03
Screen at-risk family members where relevant pharmacogenomic associations exist (e.g., HLA-B*15:02 before carbamazepine in Southeast Asian patients; HLA-B*58:01 before allopurinol).
04
Report to national pharmacovigilance authority (Yellow Card, FDA MedWatch, EMA EVDAS).
05
Identify pharmacologically related compounds to avoid — e.g., aromatic anticonvulsants have cross-reactivity patterns in SJS/TEN.
Specific High-Risk Drug Classes
Aromatic anticonvulsants (carbamazepine, phenytoin, phenobarbital, lamotrigine): highest population attributable risk for SJS/TEN globally.
Allopurinol: leading cause in Asia; HLA-B*58:01 screening mandated in Taiwan, Thailand, and recommended by AAD for at-risk populations.
Sulfonamides (cotrimoxazole): particular risk in HIV-positive patients.
Nevirapine: major risk in sub-Saharan Africa where HIV prevalence is high.
Oxicam NSAIDs (piroxicam, tenoxicam): risk identified in EuroSCAR data.
The Evidence
Derivation & Validation Study
ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson Syndrome and toxic epidermal necrolysis: comparison with case-control analysis.
Sassolas B et al. • Clin Pharmacol Ther.. 2010;88(1):60-8. n=100 EN cases; ALDEN attributed probable/very probable causality in 69% vs. 23% with French pharmacovigilance method (P < 0.001). Correlation with EuroSCAR case-control r = 0.90 (P < 0.0001).
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Origins & History
ALDEN was developed by Dr. Bruno Sassolas (CHU Morvan, Brest, France) and Professor Jean-Claude Roujeau (Hôpital Henri Mondor, Créteil, France) in collaboration with the EuroSCAR international consortium, including Professor Maja Mockenhaupt (Dokumentationszentrum schwerer Hautreaktionen, Freiburg, Germany). Published in 2010 in Clinical Pharmacology & Therapeutics, it arose from the recognized inadequacy of general adverse drug reaction algorithms (such as Naranjo) for a condition where timing is highly specific and drug notoriety is a dominant prognostic signal. ALDEN has been adopted as a reference causality tool by French pharmacovigilance authorities and is widely used in academic reporting of SJS/TEN cases internationally.
Prof. Jean-Claude Roujeau (1945–2022), Hôpital Henri Mondor / Université Paris-Est Créteil, was the leading co-architect of ALDEN and the internationally recognized authority on SJS/TEN for over three decades, founding the EuroSCAR and RegiSCAR networks.
Last Comprehensive Review: 2026-07-17