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8 Draft Report on
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10 Severe Cutaneous Adverse Reactions

11 (SCAR)
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13 Council for International Organizations

14 of Medical Sciences (CIOMS)
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41 Copyright © 2024 by the Council for International Organizations of Medical Sciences (CIOMS)
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55 Severe Cutaneous Adverse Reactions. A consensus by a CIOMS Working Group. Geneva, Switzerland: Council for International
56 Organizations of Medical Sciences (CIOMS), 2024. doi:
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70 responsible, in their capacity as experts, for the views expressed in this publication. These views do not necessarily
71 represent the decisions, policies or opinions of a specific organization or agency. It is anticipated that this document
72 will prove useful to all stakeholders involved with medicines safety from pre -clinical development through clinical trials
73 to the clinical use of drugs postmarketing.

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74 ACKNOWLEDGEMENTS
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76 This page is intentionally left blank. It will be completed in the final publication.

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77 TABLE OF CONTENTS
78
79 ACKNOWLEDGEMENTS ...................................................................................................... iii
80 TABLE OF CONTENTS ......................................................................................................... iv
81 TABLES AND FIGURES....................................................................................................... vii
82 ABBREVIATIONS AND ACRONYMS ................................................................................. viii
83 FOREWORD………………………………………………………………………………………..xi
84 EXECUTIVE SUMMARY .................................................................................................... ..xiii
85 INTRODUCTION………………………………………………………………………………......xv
86 References ………………………………………………………………………………………...xvi
87 CHAPTER 1. WHAT ARE SEVERE CUTANEOUS ADVERSE REACTIONS?...............1
88 1.1 Introduction ........................................................................................................... 1
89 1.2 SCAR and non-SCAR........................................................................................... 2
90 1.3 Benign cADRs (non-SCAR ADRs) ....................................................................... 3
91 1.4 Different types of SCAR........................................................................................ 6
92 1.4.1 SJS/TEN/EMM ...................................................................................................... 6
93 [Link] Epidemiology......................................................................................................... 6
94 [Link] Common etiology (medicinal products) ................................................................ 6
95 [Link] Clinical characteristics (that assist diagnosis by highlighting key clinical
96 manifestations)...................................................................................................... 7
97 [Link] Laboratory features ............................................................................................... 8
98 [Link] Prognosis and outcome (long-term sequelae) ..................................................... 9
99 1.4.2 DRESS/DIHS ........................................................................................................ 9
100 [Link] Epidemiology......................................................................................................... 9
101 [Link] Common etiology (medicinal products) ................................................................ 9
102 [Link] Clinical characteristics (that assist diagnosis by highlighting key clinical
103 manifestations)...................................................................................................... 9
104 [Link] Prognosis and outcome (long-term sequelae) ................................................... 13
105 1.4.3 AGEP .................................................................................................................. 13
106 [Link] Epidemiology....................................................................................................... 13
107 [Link] Common etiology (medicinal products) .............................................................. 13
108 [Link] Clinical characteristics (that assist diagnosis by highlighting key clinical
109 manifestations).................................................................................................... 14
110 [Link] Laboratory features ............................................................................................. 14
111 [Link] Prognosis and outcome ...................................................................................... 15
112 1.4.4 GBFDE ................................................................................................................ 15
113 [Link] Epidemiology....................................................................................................... 15
114 [Link] Common etiology (medicinal products) .............................................................. 15

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115 [Link] Clinical characteristics (that assist diagnosis by highlighting key clinical
116 manifestations).................................................................................................... 15
117 [Link] Laboratory features ............................................................................................. 16
118 [Link] Prognosis and outcome ...................................................................................... 16
119 1.5 SJS/TEN/DRESS/AGEP overlap........................................................................ 17
120 References……… .................................................................................................................. 17
121 CHAPTER 2. DIAGNOSIS AND IDENTIFICATION OF SCAR CASES ........................ 20
122 2.1 Introduction ......................................................................................................... 20
123 2.2 Patient history ..................................................................................................... 21
124 2.3 Assessing severity .............................................................................................. 22
125 2.4 SCAR case definition and diagnosis .................................................................. 22
126 2.5 Interactions between patient, family, healthcare professional and regulatory
127 agencies for reporting ......................................................................................... 27
128 References………………………………………………………………………………………….29
129 CHAPTER 3. CASE M ANAGEMENT IN CLINICAL CARE ........................................... 31
130 3.1 Introduction ......................................................................................................... 31
131 3.2 Special populations ............................................................................................. 36
132 3.3 cADRs induced by targeted therapy[] or immunotherapy .................................. 37
133 3.4 Guidance and investigation postreaction ........................................................... 37
134 References ………………………………………………………………………………………….37
135 CHAPTER 4. BIOMARKERS FOR SCAR ...................................................................... 39
136 4.1 Introduction ......................................................................................................... 39
137 4.2 HLA and immune-related genetic biomarkers .................................................... 40
138 4.2.1 SJS/TEN.............................................................................................................. 41
139 4.2.2 DRESS................................................................................................................ 43
140 4.2.3 AGEP .................................................................................................................. 43
141 4.3 Circulating and tissue specific biomarkers to aid in the clinical evaluation of
142 SCAR………………………………………………………………………………….45
143 4.4 Developing and implementing biomarker testing recommendations ................. 46
144 References ................................................................................................................... 47
145 CHAPTER 5. CAUSALITY ASSESSMENT OF SCAR IN PRE- AND
146 POSTAUTHORIZATION SURVEILLANCE ............................................. 50
147 5.1 Introduction ......................................................................................................... 50
148 5.2 Global introspection methods ............................................................................. 51
149 5.3 Tools to support investigation of causality between medicinal product
150 and SCAR……………………………………………………………….…………….69
151 References ………………………………………………………………………………………….55
152

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153 CHAPTER 6 PRE-AUTHORIZATION SAFETY DATA COLLECTION AND
154 ANALYSIS................................................................................................56
155 6.1 Introduction ......................................................................................................... 56
156 6.2 Investigator assessment ..................................................................................... 56
157 6.3 Risk factors and confounding factors ................................................................. 59
158 References ………………………………………………………………………………………….64
159 CHAPTER 7. POSTAUTHORIZATION SAFETY DATA COLLECTION AND
160 ASSESSMENT…………………………………………………………………66
161 7.1 Introduction ......................................................................................................... 66
162 7.2 Sources of data ................................................................................................... 66
163 7.3 Assessing causality with postauthorization information ..................................... 72
164 References ………………………………………………………………………………………….73
165 Additional references for sections 7.3.1 and . 7.3.2…………………………………………….75
166 CHAPTER 8. RISK MINIMIZATION………………………………………………………….76
167 8.1 Introduction ......................................................................................................... 76
168 8.2 Risk management ............................................................................................... 77
169 8.3 Routine risk minimization measures................................................................... 78
170 8.4 Additional risk minimization measures ............................................................... 80
171 8.5. Evaluating the effectiveness of risk minimization............................................... 82
172 References ……………………………………………………………………………………….…83
173 APPENDIX 1 PRODUCT LABEL EXAMPLES…………………………………………..…84
174 Medicinal Product A ............................................................................................................... 84
175 Medicinal Product B ............................................................................................................... 85
176 Medicinal Product C ............................................................................................................... 87
177 Medicinal Product D ............................................................................................................... 87
178 Patient Information Leaflet (PIL): ........................................................................................... 88
179 Medicinal Product E ............................................................................................................... 90
180 Medicinal Product F ............................................................................................................... 90
181 References………………………………………………………………………………………….91
182 APPENDIX 2 EXAMPLES OF TARGETED FOLLOW-UP FORMS TO BE USED FOR
183 ALL SCAR REPORTS .............................................................................. 92
184 APPENDIX 3 SCAR WORKING GROUP MEMBERS AND MEETINGS ...................... 95
185 APPENDIX 4 LIST OF COMMENTATORS…………………………………………………97
186
187

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188 TABLES AND FIGURES
189
190 TABLE 1. COMPA RIS ON BE TWEEN SCA R AND NON-S CAR ............................................... 5
191 TABLE 2. J-SCAR DIAGNOSTIC CRITERIA FOR DRUG-INDUCE D HYPERSENSITIVITY
192 SYNDROME ........................................................................................................10
193 TABLE 3. REGISCA R SCORING SYSTEM FOR DRESS DIAGNOS IS ...................................11
194 TABLE 4. EXAMPLE OF INFORMATION TO BE PROVIDED TO THE PATIENT AND THE
195 PATIENT’S FAMILY .............................................................................................28
196 TABLE 5. HLA ALLE LES ASSOCIA TED WITH SJS/ TE N .......................................................41
197 TABLE 6. HLA ALLE LES ASSOCIA TED WITH DRESS .........................................................43
198 TABLE 7. POTE NTIAL SCA R INITIAL ASSESSMENT IN THE CLINICAL TRIAL SE TTING .....59
199 TABLE 8. AGE DIS TRIBUTION FOR SCA R..........................................................................61
200 TABLE 9. COMORB ID ME DICAL CONDITIONS A T THE TIME OF SCA R DIAGNOSIS ...........61
201 TABLE 10. KEY HLA ASSOCIA TIONS WITH SCA R................................................................61
202
203
204
205 FIGURE 1. SCAR AND CA DRS ............................................................................................... 3
206 FIGURE 2. CHARACTERIS TIC MORBILIFORM ERUPTION IN A PATIENT WITH DAPSONE-
207 INDUCE D REA CTION ........................................................................................... 4
208 FIGURE 3. E XTENS IVE SKIN DE TA CHME NT CHA RACTE RIS TIC OF TEN.............................. 7
209 FIGURE 4. TYPICAL ROUND TARGET LESIONS WITH A DARKER CENTRE SURROUNDED
210 BY A LIGHTER, PALE PINK RING AND A BRIGHT RED OUTERMOST RING IN A
211 PATIENT WITH EMM ............................................................................................ 8
212 FIGURE 5. NUMEROUS PINPOINT, NONFOLLICULA R PUSTULES AND CONFLUENT PUS
213 LAKES ON OEDEMATOUS ERYTHEMATOUS PLAQUES ON THE INNER THIGH
214 OF A PATIE NT WITH AGEP .................................................................................14
215 FIGURE 6. MANY WELL-DEMARCATED, DUSKY RED, ROUND OR OVAL PATCHES WITH
216 BLISTERS AND EROSIONS ON THE TRUNK AND LIMBS OF A PATIENT WITH
217 GBFDE ................................................................................................................16
218 FIGURE 7. THE SCAR TIMELINE ..........................................................................................57
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228 ABBREVIATIONS AND ACRONYMS
229

230 ACLE Acute Cutaneous Lupus Erythematosus

231 ADR Adverse Drug Reaction
232 AE Adverse Event
233 AGEP Acute Generalized Exanthematous Pustulosis
234 AGPP Acute Generalized Pustular Psoriasis
235 aGVHR Acute Graft Versus Host Reaction
236 ARDS Acute Respiratory Distress Syndrome
237 ART Antiretroviral Therapy
238 BSA Body Surface Area
239 CBC Complete Blood Count
240 CHMP Committee for Medicinal Products for Human Use of the European
241 Medicines Agency
242 CI Confidence Interval
243 CKD Chronic Kidney Disease
244 CIOMS Council for International Organizations of Medical Science
245 CMV Cytomegalovirus
246 CRP C-reactive Protein
247 cADR Cutaneous Adverse Drug Reaction
248 CTCAE Common Terminology Criteria for Adverse Events
249 CYP Cytochrome P450
250 CYP2C9 Cytochrome P450 2C9
251 DHCP Dear Healthcare Provider
252 DHPC Direct Healthcare Professional Communication
253 DI SCLE Drug-Induced Subacute Cutaneous Lupus Erythematosus
254 DIHS Drug-Induced Hypersensitivity Syndrome
255 DPT Drug Patch Testing
256 DRESS Drug Reaction with Eosinophilia and Systemic Symptoms
257 EBV Epstein-Barr Virus
258 ECG Electrocardiogram
259 EHR Electronic Health Record
260 ELISpot Enzyme Linked Immunosorbent Spot
261 EMA European Medicines Agency
262 EMM Erythema multiforme Major
263 EN Epidermal or Epithelial Necrolysis
264 EU European Union
265 ExDerm Exfoliative Dermatitis
266 FDA U.S. Food and Drug Administration
267 FDE Fixed Drug Eruptions
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268 GBFDE Generalized Bullous Fixed Drug Eruptions
269 G-CSF Granulocyte Colony Stimulating Factor
270 GM-CSF Granulocyte/Macrophage Colony-Stimulating Factor
271 GPP Generalized Pustular Psoriasis
272 GWAS Genome-Wide Association Study
273 H&E Hematoxylin and Eosin
274 HCP Healthcare Professional
275 HHV Human Herpes Virus
276 HHV6 Human Herpes Virus 6
277 HIV Human Immunodeficiency Virus
278 HLA Human Leukocyte Antigen
279 ICD-CM International Classification of Diseases - Clinical Modification
280 ICH International Council for Harmonisation of Technical Requirements for
281 Pharmaceuticals for Human Use
282 ICSR Individual Case Safety Report
283 ICU Intensive Care Unit
284 IQR Interquartile Range
285 IRIS Immune Reconstitution Inflammatory Syndrome
286 IVIG Intravenous Immunoglobulin
287 JAK Janus Kinase
288 LE Lupus Erythematosus
289 MedDRA Medical Dictionary for Regulatory Activities
290 MHC Major Histocompatibility Complex
291 MPE Maculopapular Exanthem
292 NPV Negative Predictive Value
293 NSAID Non-Steroidal Anti-Inflammatory Drugs
294 OR Odds Ratio
295 PE Paraneoplastic Erythroderma
296 PGx Pharmacogenomic
297 PPV Positive Predictive Value
298 PT Preferred Term
299 PV Pharmacovigilance
300 PUVA Psoralen Combined with Ultraviolet A
301 REMS Risk Evaluation and Mitigation Strategies
302 RMP Risk Management Plan
303 SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2
304 SCAR Severe Cutaneous Adverse Reaction(s)
305 SCLE Subacute Cutaneous Lupus Erythematosus
306 SLE System Lupus Erythematosus
307 SmPC Summary of Product Characteristics

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308 SJS Stevens-Johnson Syndrome
309 SOC System Organ Class
310 SSSS Staphylococcal Scalded Skin Syndrome
311 SUSAR Suspected unexpected serious adverse reaction
312 TARC Thymus and Activation-Regulated Chemokine
313 TB Tuberculosis
314 TBSA Total Body Surface Area
315 TEN Toxic Epidermal Necrolysis
316 TEN Like LE TEN-Like Lupus Erythematosus or Lupus-Associated TEN
317 TNF Tumour Necrosis Factor
318 UK United Kingdom
319 US United States
320 WHO World Health Organization
321 WHO-UMC WHO Uppsala Monitoring Centre
322
323
324

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325 FOREWORD
326 Severe Cutaneous Adverse Reactions (SCAR) such as Stevens-Johnson syndrome/toxic
327 epidermal necrolysis (SJS/TEN) are associated with significant patient morbidity and mortality.
328 These reactions may result in death or life-threatening conditions, inpatient hospitalization or
329 prolongation of existing hospitalization, or significant disability/incapacity.
330 The SCAR Working Group of the Council for International Organizations of Medical Sciences
331 consists of a diverse and comprehensive group of major stakeholders, i.e. academia/research
332 organizations, clinicians, medicinal product1 developers/industry and regulatory authorities, to
333 assist in establishing a balanced, global perspective on the approach for SCAR detection,
334 susceptibility factors, severity, outcome and probability through causality assessment tools,
335 monitoring and risk management during the medicinal product development and
336 postauthorization phases.
337 The panel of experts encompassed wide participation, with members from several World Health
338 Organization regions, to ensure comprehensiveness, synergies and global impact.
339 To increase participation and input from individual experts and leading institutions globally, the
340 draft document was posted for public consultation prior to finalization. This report takes into
341 account the comments received as a result of the public consultation.
342 CIOMS SCAR Working Group Objectives

343 The intent is to provide a guidance for medicinal product developers, regulatory authorities,
344 healthcare professionals and scientists in academic and research organizations regarding:
345  Diagnosis of SCAR in patients.

346  Interpretation and management of SCAR safety signals for a medicinal product considering
347 that SCAR assessments differ between clinical practice, clinical trial and observational
348 studies, and that there is a need to enhance safety of medicinal product development and in
349 medicinal product life-cycle management.

350  SCAR data analysis of suspected unexpected serious adverse reactions during clinical trials,
351 individual case safety reports in the postauthorization phase, aggregate data from clinical
352 trials and observational studies using this consensus report on the terminology and level of
353 evidence needed to assess safety, data standards, and data acquisition.

354  Data capture and analysis of safety signals of a SCAR for a medicinal product during
355 preauthorization clinical trials through adopting standards for data and biospecimen
356 acquisition and management, to allow future biomarkers development and validation.

357  Proposed causality assessment process in clinical trials and the postauthorization phase,
358 including assessment of SCAR data for strength of evidence or degrees of uncertainty in
359 causal association.

360  Assessment of SCAR safety data for special populations with impaired immune status, such
361 as cancer patients, patients with autoimmune diseases, the elderly, and paediatric patients.

1 The CIOMS Cumulative Glossary w ith a Focus on Pharmacovigilance (version 2.0) defines “medicinal product” according to the
definition below . “Medicinal product” w ill be used interchangeably w ith the term “drug” in this report.
Any substance or combination of substances:
presented as having properties for treating or preventing disease in humans; or
w hich may be used in or administered to humans either w ith a view to restoring, correcting or modif ying physiological functions by
exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.
Note: In other jurisdictions, this may be called a medicine, medical product or a drug, and may include biologicals and vaccines.
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362  Validation of traditional and new biomarkers, also through combining large SCAR safety
363 datasets across many clinical trials and postauthorization data in different patient populations
364 to generate sufficient data for detecting rare SCAR induced by a medicinal product

365  Prevention and mitigation of SCAR induced by medicinal products. The aim of this report is
366 to create a global consensus reference for regulators, patient organizations, scientists,
367 industry and clinicians involved in product life cycle management or clinical practice.

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368 EXECUTIVE SUMMARY
369 Following is a brief description of each chapter:
370 Chapter 1: What are Severe Cutaneous Adverse Reactions?

371 This chapter describes the differences between cutaneous adverse drug reactions (cADRs) and
372 severe cutaneous adverse reactions (SCAR) in terms of epidemiology, etiology, clinical
373 characteristics, prognosis and outcome of the various SCAR conditions.
374 Chapter 2: Diagnosis and identification of SCAR cases

375 The first step in analysing a putative SCAR is to make a tentative diagnosis. DRESS, AGEP
376 and some other SCAR conditions have defined diagnostic criteria which may overlap and can
377 hence be challenging to diagnose in the earliest stages. A SCAR diagnosis should consider
378 patient history, visual assessment (appearance, morphology), severity and the presence of
379 systemic symptoms, followed by a clinical investigation of potential causes or causality
380 assessment in the individual patient.
381 Chapter 3: Case management in clinical care

382 Withdrawal of the culprit medicinal product is the cornerstone of care for SCAR. Additionally,
383 management and supportive care are elucidated in this chapter.
384 Chapter 4: Biomarkers

385 Numerous investigations have uncovered many promising biomarkers to identify individuals at
386 risk of developing SCAR, confirm and diagnosis of SCAR early, and inform prognosis. Human
387 leukocyte antigen (HLA) variants are consistently associated with the risk for SCAR and testing
388 results are clinically actionable for many culprit medicinal products, most significantly for anti-
389 epileptics and allopurinol. Several histopathologic, blister fluid and serum biomarkers have been
390 identified that appear to be specific to SCAR and could enable earlier diagnosis. Some may
391 even represent possible therapeutic targets. However, more research is needed to confirm their
392 utility in the diagnostic workup of SCAR.
393 Chapter 5: Causality assessment of SCAR in pre- and postauthorization surveillance

394 Causality assessments aim to determine the procedure to determine the relationship between the
395 medicinal product and the adverse event (AE). Methods such as Bradford Hill criteria, Global
396 Introspection, operational algorithms, probabilistic approaches are presented for SCAR. Also
397 presented are adjudication, targeted follow-up form, and assessment of the aggregate data.
398 Chapter 6: Pre-authorization safety data collection and analysis

399 Prompt recognition of SCAR enhances patient safety and enables the assessment of the impact
400 on the clinical trial programme. Risk factors such as patient population, pharmacology, and
401 pharmacogenomics should all be considered when setting up preauthorization surveillance.
402 Chapter 7: Postauthorization safety data collection and assessment

403 Data sources for postauthorization surveillance include spontaneous reports, electronic health
404 records (EHRs), registries, clinical trial data and preclinical data.

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405 Chapter 8: Risk minimization

406 Prompt evaluation and discontinuation of the potentially offending medicinal product(s) are the
407 most appropriate immediate interventions in the management of drug-induced SCAR once
408 detected, based on the benefit risk balance of the treatment for the given patient. Key
409 developments in SCAR research include new technologies allowing the identification of genetic
410 risk factors with improved sensitivity, specificity and efficiency. Routine risk minimization
411 measures and additional risk minimization measures for SCAR are presented with examples.
412

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413 INTRODUCTION
414 An adverse event (AE) is any untoward medical occurrence that may present during treatment
415 with a medicinal product (drug or biological product), but which does not necessarily have a
416 causal relationship with this treatment. An AE therefore can be any unfavourable and
417 unintended sign (for example, an abnormal laboratory finding) symptom or disease that is
418 temporally associated with the use of a medicinal product, whether or not it is related to this
419 medicinal product.
420 An adverse drug reaction (ADR), as established by regional regulations, guidance, and
421 practices, concern noxious and unintended responses to a medicinal product. The phrase
422 “responses to a medicinal product” means that a causal relationship between a medic inal
423 product and an AE is at least a reasonable possibility.[1]
424 Skin is the most commonly affected organ by ADRs by not only small molecules in medicinal
425 products, including vaccines and other etiologies. Cutaneous ADRs (cADRs) affect 2% to 3% of
426 all hospitalized patients.[2] cADRs have a wide spectrum of clinical manifestations, are caused
427 by various medicinal products, and result from different pathophysiologic mechanisms. Hence,
428 their diagnosis and management are challenging, but approximately 0.1-1% of patients with
429 medicinal product eruptions are serious ADRs. In regulatory guidelines, a serious AE or
430 adverse reaction to a medicinal product is defined as any untoward medical occurrence that at
431 any dose satisfies any of the following criteria:[1,3]
432 • results in death,
433 • is life-threatening,
434 • requires inpatient hospitalization or prolongation of existing hospitalization,
435 • results in persistent or significant disability/incapacity,
436 • is a congenital anomaly/birth defect, or
437 • other medically important event or reaction.[1,4]
438 Severe cutaneous adverse reactions (SCAR) are rare, idiosyncratic disorders that are most
439 often induced by medicinal products but may also be reactions to other kinds of exposure, and
440 associated with significant morbidity, usually leading to hospitalization. SCAR consist of
441 Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with
442 eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis
443 (AGEP), and generalized bullous fixed drug eruptions (GBFDE). The annual incidence of
444 SJS/TEN is estimated at 1-5 per million person-years. Utilizing spontaneous reports of
445 suspected adverse reactions from healthcare professionals (HCPs) and patients may generate
446 a signal for SCAR as a potential ADR even with a single, well-documented report on an
447 individual patient. This may indicate possible causality with the medicinal product, particularly
448 for serious SCAR that are rare in the general population or SCAR that are rare in the absence
449 of medicinal product exposure.[1,4]
450 Future needs

451 Medicine-induced SCAR are rare serious AEs that pose substantial hurdles to medicine
452 developers, regulators, healthcare professionals and patients as well as patient acceptance of
453 therapeutic options and adherence. Further work is necessary to continue the advancement of
454 science, medicine and regulation to better identify, characterize and mitigate SCAR risks.

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455 The following highlight some of the main topics that need further progress:
456 For healthcare professionals:

457  The lack of consensus in clinical guidance regarding SCAR in special populations,
458 especially cancer patients, patients with pre-existing autoimmune diseases, the elderly, and
459 children;
460  There is mounting concern in relation to the ongoing health burden of SCAR and the
461 emergence of SCAR related to novel biological medicinal products as well as the
462 increasing cost of diagnosis and management.
463 For regulatory authorities and the biopharmaceutical industry:
464  The need for comprehensive, proactive and systematic workflows for safety data capture and
465 analysis during medicinal product development;
466  The lack of harmonized case definitions of SCAR types, the need to ensure completeness
467 of safety assessment and management in medicines development, as well as consensus
468 guidance on the design of studies to develop and validate new technologies and
469 biomarkers;
470  The lack of evidence-based practice to promote consistent pharmacovigilance and risk
471 management of SCAR in clinical trials and postauthorization studies during medicinal
472 product development and postauthorization phases;
473  The lack of specific information provided in the Summary of Product Characteristics
474 (SmPC) about SCAR: the information is overall quite similar for all concerned medicinal
475 products even if they do not carry the same risk of SCAR.
476 Furthermore, the magnitude of attrition of new chemical entities during medicinal product
477 development that accounts for up to > 80% from phase I to application for marketing
478 authorization has put an unsurpassable barrier for the clinical translation of new medicinal
479 products. This has taken the pharmaceutical industry to a point where a revision of current
480 approaches is necessary.
481 References

1 ICH Topic E2A Clinical Safety Data Management: definitions and standards for expedited reporting, 1995. Guidance document
2 Wolf R, Orion E, Marcos B, Matz H. Lif e-threatening acute adverse cutaneous drug reactions. Clinics in Dermatology 23:171-181,
[Link] Abstract
3 CIOMS. CIOMS IV: Benefit-Risk Balance for Marketed Drugs: Evaluating Safety Signals. 1998
4 CIOMS ICH Glossary, v3. Serious Adverse Event: E19 A Selective Approach to Safety Data Collection in Specific Late-Stage Pre-
approval or Post-Approval Clinical Trials -- Step 4 (final); 27 September 2022 – Glossary
482

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483 CHAPTER 1.
484 WHAT ARE SEVERE CUTANEOUS ADVERSE REACTIONS?
485

486 Chapter summary

487  Severe cutaneous adverse reactions (SCAR) comprise Stevens-Johnson syndrome

488 (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic
489 symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) and
490 generalized bullous fixed drug eruptions (GBFDE).

491  Clinical phenotypes of cutaneous adverse drug reactions (cADRs) are very diverse and
492 most of them are benign non-life-threatening reactions such as maculopapular exanthema
493 (MEP), urticaria, fixed drug eruptions (FDE), lichenoid eruptions, vasculitis and others.
494 Maculopapular exanthem (MPE) is the most common benign cADR to medicinal products.

495  SJS, SJS/TEN-overlap and TEN represent different severity spectra of the same disease,
496 epidermal necrolysis (EN), which needs to be distinguished from erythema multiforme
497 major (EMM) which is exclusively due to infections.

498  DRESS is a multi-systemic ADR with a heterogeneous presentation and variable clinical
499 course. Initial symptoms may be prodromal in nature such as fever and malaise.
500 Cutaneous eruptions are extensive and may be polymorphic in presentation, including
501 maculopapular eruptions, infiltrated plaques, pustules, target-like lesions, purpura,
502 eczematous lesions and erythroderma. Facial erythema and swelling are prominent
503 features of DRESS. Various internal organs may be involved including the liver, kidneys,
504 lungs, heart, nervous system and others.

505  AGEP is characterized by a sudden onset of numerous pinpoint, non-follicular sterile

506 pustules on oedematous erythematous skin. The most characteristic feature of AGEP is
507 its clinical course. It has a very rapid onset and equally rapid resolution.

508  GBFDE is characterized by well-demarcated, round, or oval erythematous, violaceus or

509 dusky red patches with blisters and erosions. Most patients report a positive history of
510 similar eruptions. GBFDE may be confused as SJS/TEN due to the extensive bullous
511 eruption with erosions.
512 Conclusions or recommendations

513 It is important to distinguish SCAR from cADRs in terms of epidemiology, etiology, clinical
514 characteristics, prognosis and outcomes.

515 1.1 Introduction

516 An ADR, as defined by the World Health Organization (WHO), is “any noxious, unintended and
517 undesired effect of a medicinal product, given at normally used dose in man, for the prevention,
518 diagnosis or treatment of any condition or for the modification of physiological function”.[1]
519 Cutaneous adverse drug reactions (cADRs) are common, comprising 10 to 30% of all reported
520 ADRs.[2,3] Among hospitalized patients, the incidence of cADRs has been estimated to be 2 to
521 3%.[4] Cutaneous manifestations of ADRs range from benign maculopapular eruption to life-
522 threatening toxic epidermal necrolysis and from those localized only to skin to those associated
523 with systemic disease.
524

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525 Three prospective studies which investigated the epidemiology of dermatologist-diagnosed
526 cADRs in a hospital setting documented prevalence rates of 3.6 to 7 per 1000 hospitalized
527 patients. The first study from France detected 48 cADRs among 13 294 hospitalizations over six
528 months, yielding a prevalence of 3.6 per 1000 hospitalized patients.[5]
529 Reactions were considered serious in 34% of cases because they were responsible for
530 hospitalization (18%), increased the duration of hospitalization (14%) or were life threatening
531 (2%). The second study from Mexico documented a cADR prevalence of 7 per 1000 inpatients
532 (35/4765 hospital discharges over 10 months) and 17% were severe.[6] The third study from
533 Malaysia identified 43 cADRs among 11017 hospitalized patients over a six month period,
534 yielding a prevalence of 3.9/1000 admissions and 51.2% were SCAR.[7]
535 SCAR comprise Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug
536 reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous
537 pustulosis (AGEP) and generalized bullous fixed drug eruptions (GBFDE). Medicinal products
538 are responsible for > 85% of SCAR in adults.[8] T-cell-mediated delayed hypersensitivity
539 reactions, triggered by interactions between small-molecule drugs, HLA class I molecules and
540 T-cell receptors, underlie the pathogenesis of most SCAR.
541 1.2 SCAR and non-SCAR

542 The majority of cADRs are non-serious and not life-threatening. A serious AE or reaction to a
543 medicinal product is defined as any untoward medical occurrence that at any dose satisfies any
544 of the following criteria:[9,10]
545 • results in death,
546 • is life-threatening,
547 • requires inpatient hospitalization or prolongation of existing hospitalization,
548 • results in persistent or significant disability/incapacity,
549 • is a congenital anomaly/birth defect, or
550 • other medically important event or reaction.[9,11]
551 SCAR are a heterogeneous group of delayed T-cell-mediated hypersensitivity reactions, which
552 are most frequently triggered by medicinal products.[8] They are life-threatening and therefore,
553 serious reactions with reported case fatality between 5% for SJS and 30% for TEN. However,
554 SCAR are not exclusively caused by medications and can be induced by various non-medicinal
555 product causes including infections.[8-14]

2
556
557 Figure 1. SCAR and cADRs

558 For instance, SJS and TEN which represent different severity spectra of the same disease, now
559 termed epidermal or epithelial necrolysis (EN), are not caused by medications in about 1/3 of
560 cases.[13,14] For effective pharmacovigilance and benefit–risk management of medications,
561 accurate estimates of the incidence of SCAR are important to characterize and quantify SCAR
562 risk[9,10]. Based on the CIOMS definition, medicinal product-induced SCAR are attributable to
563 any medicine with a causality grading of at least “possible”, which may improve the accuracy of
564 SCAR evaluation in pharmacovigilance.
565 1.3 Benign cADRs (non-SCAR ADRs)

566 Clinical phenotypes of cADRs are very diverse and most of them are benign non-life-threatening
567 reactions such as maculopapular exanthem (MPE), urticaria, FDE, lichenoid eruptions, vasculitis
568 and others. A summary of differences between SCAR and non-SCAR is provided in Table 1 below.
569 MPE is the most common benign cADR to medicinal products.[7-13] MPE is characterized by a
570 maculopapular/morbilliform eruption which usually appears one to two weeks after medicinal
571 product exposure but may occur up to one week after stopping it. On re-exposure to the causative
572 or related medicinal product, onset of MPE is much shorter, within one to three days after re-
573 exposure. Medicinal products commonly implicated are penicillin, sulfonamides, cephalosporins
574 and anti-epileptics. MPE resolves within one to two weeks on medicinal product withdrawal. It is a
575 generally benign reaction but may be a first sign of DRESS. Factors favouring DRESS are fever,
576 extensive skin involvement affecting more than 50% body surface area (BSA), facial swelling and a
577 delayed onset of two to six weeks. (Figure 2)
578

3
579
580 Figure 2 Characteristic morbiliform eruption in a patient with dapsone -induced reaction
581 This figure was provided by the Working Group and included in the report with appropriate permission

582 Morbilliform rashes are a common manifestation of viral infections but unlike medicinal product
583 eruptions which usually first appear on the trunk and then spread to the limbs and neck, a viral
584 exanthem usually starts on the face and exhibits a cephalic-caudal spread. MPE is also a well-
585 known eruption seen in patients with infectious mononucleosis after exposure to aminopenicillins.
586 Another notable benign, non-life-threatening cADR is a FDE which characteristically recurs on the
587 same site or sites each time a culprit medicinal product is consumed.[15-17]
588 Skin lesions are well-demarcated, round, or oval erythematous or violaceus patches which may
589 be surmounted by bullae. FDE typically settled with hyperpigmentation on medicinal product
590 withdrawal. If patient is re-exposed to causative or related medicinal product, the same
591 pigmented patch become red and swollen again and patient may develop more lesions with
592 repeated exposures. The lesions usually develop within 30 minutes to eight hours of taking the
593 medicinal product.
594 Sites of predilection include hands and feet, lips, eyelids, and genitalia. Blisters and extensive
595 ulceration may occur on mucosal sites (lips, vulva, penis). Medicinal products frequently
596 implicated include non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics (namely
597 sulfamethoxazole, tetracyclines, dapsone), barbiturates and paracetamol/acetaminophen.
598 FDE may be solitary at first, but with repeated exposure to the culprit medicinal product, new
599 lesions appear, and existing ones may increase in size leading to GBFDE. Hence, patients with
600 FDE should be educated to avoid implicated and cross-reacting medicinal products to prevent
601 potentially life-threatening GBFDE, which has a similar prognosis to SJS/TEN.[16]

4
 SCAR Non-SCAR cADRs
Frequency  SJS/TEN: 1–13 cases per  10-30% of all reported
million persons per ADRs.[2,3]
year.[6-8,12,17-33]  2-3% of all hospitalized
 DRESS: 21.8 cases per patients.[4]
million persons.[18]  0.36-0.7% (dermatologists
 AGEP: 1-5 cases per million diagnosed) of hospitalized
persons per year.[19-26] patients in 3 prospective
studies.[5-7]
Common etiology  Allopurinol All medicinal products may
 Antibiotics cause non-SCAR cADRs
 Antiepileptic agents
 Nonsteroidal anti-
inflammatory drugs (NSAIDs)
 Sulfonamides
Latency period from medicinal Variable, but for SJS/TEN and  1-3 days for urticaria or
product exposure to onset of skin DRESS, it is usually longer than FDEs
rash for non-SCAR cADRs  1-2 weeks for MPE or
 SJS/TEN 7-21 days other non-SCAR cADRs
 DRESS: 17-31 days
 AGEP: 1-2 days
 GBFDE: a few hours
General symptoms Fever, general malaise, and sore May have mild fever
throat are common
Skin manifestations Widespread lesions, rapid Localized or widespread
progression lesions; mainly macular or
 Blisters popular lesions; no
 Targetoid lesions blisters/pustules/skin
 Pustules pain/Nikolsky sign
 Facial swelling
 Purpuric changes
 Skin pain (especially in
SJS/TEN and GBFDE)
 Nikolsky sign in SJS/TEN
Mucosal involvement Often Very rare
Hospitalization for intensive care Needed Usually not needed
Laboratory data Variable, but relatively more Uncommon, except mild
common than non-SCAR eosinophilia
 SJS/TEN and AGEP:
Leukocytosis
 DRESS: leukocytosis,
eosinophilia, atypical
lymphocytosis, abnormal
liver/renal function tests
Visceral organ involvement Variable, but relatively more Rare
common than non-SCAR
 Very common in DRESS
Outcome Life threatening Benign, non-life threatening
 SJS/TEN: case fatality 5-30%
 DRESS: 2-10%
 AGEP: < 5%
 GBFDE: ~10%
602 Table 1. Comparison between SCAR and non-SCAR

5
603 1.4 Different types of SCAR
604 1.4.1 SJS/TEN/EMM
605 [Link] Epidemiology

606 SJS, SJS/TEN-overlap and TEN represent different severity spectra of the same disease,
607 namely epidermal necrolysis (EN). The latter, however, is distinct from erythema multiforme
608 major (EMM), which is exclusively the result of infections. In the past, EMM was assumed to be
609 a less severe form of SJS because of similar clinical and histopathologic features, but it is not a
610 SCAR. A number of studies have explored the incidence of drug-induced epithelial necrolysis.
611 Hospital-based studies and studies using large electronic databases documented an annual
612 incidence of 1–13 cases per million persons.[5-33] A prospective population-based study that
613 used the German SCAR registry estimated the incidence of SJS/TEN in Germany to be one to
614 two cases/million population/year.[27] A nation-wide population-based study that used a national
615 health insurance database in South Korea from 2010 to 2013 reported 5.9 cases of
616 SJS/TEN/million/year.[32]
617 A study conducted in the United Kingdom (UK) using Clinical Practice Research Datalink from
618 1995 to 2013 validated 551 cases, yielded an incidence of 5.76 SJS/TEN cases/million/year.[33]
619 The twofold increased risk of SJS/TEN observed among Asians and Blacks in this study
620 confirmed the finding of an earlier study from the United States (US), which was based on the
621 Nationwide Inpatient Sample from 2009 to 2012 and documented an incidence of 12.7 cases of
622 SJS /TEN/million adults/year with an increased risk in nonwhite populations (Asians; OR 3.27,
623 95% CI 3.02, 3.54 and Blacks; OR 2.01, 95% CI 1.92, 2.10).[31] SJS and TEN can occur at any
624 age, but the median age among more than 2200 and 2635 EN incidents in Germany and
625 France, respectively, was about 50 years old with a slight female preponderance.[17,27]
626 [Link] Common etiology (medicinal products)

627 Although SJS and TEN are life-threatening SCAR, infections such as mycoplasma pneumonia
628 and herpes simplex virus were also implicated as causes.[33] No offending agent was identified
629 in about 15-30% of cases. The EuroSCAR group identified allopurinol, anti-infective
630 sulfonamides, antiepileptic agents (namely carbamazepine, phenobarbital, phenytoin and
631 lamotrigine), and NSAIDs of the oxicam type as high-risk drugs for induction of EN based on
632 two case-controlled studies; first, conducted from 1989 to 1995, included 372 cases and 1720
633 controls and another between 1997 and 2001 of 379 validated cases and 1505 controls.[12,34]
634 A study by the Asian SCAR consortium of 1028 validated cases of SJS/TEN treated from 1998
635 to 2017 showed that anti-epileptics were the most common culprits followed by anti-infectives
636 and allopurinol.[35] Oxcarbazepine, sulfasalazine, COX-II inhibitors, and strontium ranelate
637 were identified as potentially new causes in Asia.
638 In addition to sulfa drugs and beta-lactam antibiotics, quinolones were also a common cause
639 while several medications (e.g. oseltamivir, terbinafine, isotretinoin, and sorafenib) labelled as
640 carrying a risk of SJS/ TEN by FDA were not found to have caused any of the cases in the
641 Asian countries investigated in this study.
642
643
644
645
646

6
647 [Link] Clinical characteristics (that assist diagnosis by highlighting key clinical
648 manifestations)

649 SJS/TEN are characterized by EN with varying degree of blistering, skin detachment and
650 sloughing. By consensus, SJS, SJS/TEN overlap and TEN are defined as EN with skin
651 detachment affecting < 10%, 10-30% and >30% of the total body surface area (TBSA)
652 respectively. Drug-induced SJS/TEN usually developed 4-28 days after initiation of culprit
653 drugs. Cutaneous manifestation is often preceded by a prodromal period with symptoms such
654 as fever, malaise, sore throat and cough.
655 Typical cutaneous lesions start as purpuric macules or atypical target lesions on upper torso,
656 proximal limbs and face before spreading to the rest of body including palms and soles. Skin
657 pain is an important early symptom and lesional skin is tender with dusky or vesicular centres
658 that progress to become confluent areas of dusky erythema or flaccid bullae with a positive
659 Nikolsky sign. Extensive necrolysis leads to sheets of denuded epidermis that exude serum,
660 bleed easily and may become secondarily infected (Figure 3).

661
662 Figure 3. Extensive skin detachment characteristic of TEN
663 This figure was provided by the Working Group and included in the report with appropriate permission

664 Mucosal involvement is universal, with two or more mucosal surfaces being involved in up to
665 80% of cases.[36] Oral involvement is most common, with haemorrhagic mucositis and
666 ulceration occurring in 93-100% of cases.[37,38] Ocular involvement is seen in 60-100% of
667 cases with severity ranging from conjunctival hyperaemia to complete epidermal sloughing of
668 the ocular surface. Early ophthalmologist consultation is essential to prevent long term ocular
669 sequelae. Genital involvement is seen in up to 71% of female patients. SJS/TEN may also
670 involve other organs including pulmonary, hepatic, gastrointestinal, otorhinolaryngologic,
671 genitourinary and renal systems.[5,36]
672 SJS/TEN may be distinguished from EMM, which is characterized by a typical round target
673 lesion with a darker centre with or without a blister surrounded by a raised, lighter, pale pink ring
674 and a bright red outermost ring (Figure 4), whereas atypical target lesions in SJS are irregular in
675 shape and flat.

7
676
677 Figure 4. Typical round target lesions with a darker centre surrounded by a lighter, pale pink
678 ring and a bright red outermost ring in a patient with EMM
679 This figure was provided by the Working Group and included in the report with appropriate permission

680 Classic target lesions of EMM are predominantly on the limbs and acral regions whereas EN
681 lesions start on the torso before they become generalized. Additionally, EMM occurs in younger
682 patients and is exclusively associated with infections whereas SJS is predominantly a SCAR
683 which affects older adults. German registry data show that 65% of SJS patients were older than
684 40 years whereas more than 80% of patients with EMM were younger than 40 years and 45%
685 were under 18 years.[27,38]
686 GBFDE is an important differential diagnosis of SJS/TEN. The classic, discrete, large and well-
687 defined violaceous or brownish round or oval patches with or without a central blister are very
688 characteristic and can be readily distinguished from the confluent purpuric macules and patches
689 of SJS and the large, denuded epidermis of TEN.
690 Patients with GBFDE usually do not have fever and the typical haemorrhagic mucosal
691 involvement of SJS/TEN. Patients with GBFDE often have a history of previous eruptions in
692 which the healed hyper-pigmented patches become inflamed again on re-exposure to culprit
693 medicinal products. Staphylococcal scalded skin syndrome (SSSS) is another disease with
694 blisters and skin detachment, but target or haemorrhagic mucosal lesions are not present and
695 SSSS mainly affects children.
696 [Link] Laboratory features

697 Histopathologically, EN is characterized by variable keratinocytes necrosis and basal layer

698 liquefaction degeneration. With advanced disease, full-thickness epidermal necrosis occurs with
699 sub-epidermal bullae. This is accompanied by mild perivascular mixed infiltrates of
700 predominantly lymphocytes and histiocytes with some eosinophils. SJS/TEN may be
701 distinguished from SSSS by the level of epidermal detachment, which is sub-corneal in SSSS
702 and sub-epidermal in SJS/TEN. Widespread keratinocyte necrosis is characteristic of SJS/TEN.
703 It is difficult to distinguish early stage SJS/TEN from EMM by histology because both diseases
704 are characterized by a vacuolar or lichenoid interface with scattered necrotic keratinocyte and a
705 mixed perivascular infiltrate. As both diseases progress, a sub-epidermal split with increased
706 epidermal necrosis is observed. A heavier lymphocytic infiltrate favours EM while increased
707 eosinophils and confluent epidermal necrosis favours SJS/TEN. Histology is particularly useful
708 to rule out SSSS which is characterized by a superficial sub-corneal blister, lack of epidermal
709 necrosis and minimal inflammatory cells.
710
711
8
712 [Link] Prognosis and outcome (long-term sequelae)

713 EN is a potentially life-threatening SCAR with an overall case fatality between 10% and
714 20%.[17-31] Potential prognostic markers associated with death include delayed transfer to a
715 specialist unit, advancing age, increasing skin detachment, presence of septic aemia and
716 granulocytopenia. Survivors may have long-term physical sequelae such as cutaneous and
717 ophthalmologic scarring, dyspigmentation, dental complications, genitourinary symptoms and
718 pulmonary disease.[39,40] Long-term psychological outcomes include post-traumatic stress
719 disorder anxiety, depression and decreased health-related quality.[39-42]
720 A recent survey conducted at 11 academic health centres in the U.S. between 1 January 2009,
721 and 30 September 2019 which included 121 adult survivors of EN showed that the most
722 common physical sequelae were cutaneous problems (84.3%), followed by ocular problems
723 (59.5%) and oral mucosal problems (50.8%). Of screened participants, 53.3% of were positive
724 for depression and 43.3% were positive for anxiety.[40]
725 1.4.2 DRESS/DIHS
726 [Link] Epidemiology
727 DRESS/DIHS is a rare, multi-systemic SCAR. The epidemiology of DRESS is not well
728 characterized. However, it is estimated to occur in up to 2 per 100,000 patients based on
729 EHRs.[18] and accounts for 10-20% of cADRs seen in a hospitalized setting.[43,44]
730 [Link] Common etiology (medicinal products)

731 Aromatic antiepileptic (such as carbamazepine, phenytoin, lamotrigine, oxcarbazepine,

732 phenobarbital) are the most common causal drugs, accounting for 35% of cases. Other highly
733 associated medications include allopurinol, infective sulfonamides and other antibiotics such as
734 vancomycin, minocycline and amoxicillin.[45] A prolonged latency between drug initiation and
735 the onset of reaction is characteristic of DRESS with a median latency estimated at 22 days
736 (IQR 17-31 days).[44] However, shorter latency periods have been reported for cases due to
737 iodinated contrasts and antibiotics.[46,47]
738 In recent years, various pharmacogenetic associations between certain medicinal products and
739 ethnicity have been established. These include HLA-A*32:01 and vancomycin-induced DRESS
740 in Europeans; HLA-A*3101 and carbamazepine-induced DRESS in European, Japanese and
741 Han Chinese; B*1301 and dapsone-induced DRESS in Han Chinese; and B*13:01, B*15:01
742 and phenytoin-induced DRESS in Han Chinese and Thai.[48,49]
743 [Link] Clinical characteristics (that assist diagnosis by highlighting key clinical
744 manifestations)

745 DRESS is a multi-systemic ADR with a heterogeneous presentation and variable clinical
746 course. Diagnostic criteria based on the Japanese (J-SCAR) and RegiSCAR criteria are shown
747 in Tables 2 and 3 below. Initial symptoms may be prodromal in nature such as fever and
748 malaise.

9
 1. Maculopapular rash developing > 3 weeks after starting with a number of drugs a
2. Prolonged clinical symptoms 2 weeks after discontinuation of the causative drug
3. Fever > 38º C
4. Liver abnormalities (alanine aminotransferase > 100U/L) b
5. Leukocyte abnormalities (at least one present)
a. Leukocytosis (> 11x109/L)
b. Atypical lymphocytosis (> 5%)
c. Eosinophilia (> 1.5x109/L)
6. Lymphadenopathy
7. Human herpesvirus 6 reactivation
a Thereare eight drugs to treat the majority of cases in Japan: carbamazepine, phenytoin,
phenobarbital, zonisamide, mexiletine, dapsone, salazosulfapyridine and allopurinol.
b Thiscan be replaced by other organ involvement, such as renal involvement
749 Table 2. J-SCAR diagnostic criteria for drug-induced hypersensitivity syndrome [50]
Permission obtained from Oxford University Press

A diagnosis is confirmed by the presence of all seven of the above criteria (typical DIHS) or five
of the criteria (1 to 5, atypical DIHS).

10
 Assessment/ Score -1 0 1 Comment

Fever ≥ 38.5º C No/U Yes Acute episodes

Enlarged lymph nodes No/U Yes >1cm, ≥ 2 different areas (right side plus left side is
not adequate)

Eosinophilia No/U Yes Score 2 for extreme eosinophilia

˙Eosinophils≧700/μL or ˙Eosinophils ≥1500/μL or
˙≥10% if leukocyte <4000/μL ˙≥20% if leukocyte <4000/μL

Atypical lymphocytes No/U Yes

Onset < 21 days before hospitalization
Skin rash

Extent > 50% body surface area No/U Yes

Rash suggesting DRESS No U Yes ≥2 symptoms: purpuric change, facial edema,

infiltration, psoriasiform desquamation

Biopsy suggesting DRESS No Yes/U Score -1 if results fit any other specific
dermatopathologic diagnosis

Organ involvement Excluding other causes, score max. of 2

Liver: any criterion Yes ALT>2*UNL, twice on successive dates

D-bil.>2*UNL, twice on successive dates
AST, T-bil., ALP all>2*UNL, once

Kidney: any criterion Yes Creatinine>1.5* patient’s baseline

Proteinuria above 1g/day

Lung: any criterion Yes Evidence of interstitial lung (CT, x-ray)

No/U Abnormal bronchoalveolar lavage
Abnormal blood gases

Muscle/Heart: any criterion Yes Raised creatine kinase

Raised troponin T
Abnormalities in the echocardiogram

Pancreas Yes Amylase >2* UNL

Other organs Yes Central nervous system, splenomegaly

Rash resolution ≥ 15 days No/U Yes

Excluding other causes No/U Yes Score 1 if ≥ 3 tests are performed and negative

Hepatitis A, B, C At least 2 tests are negative and 1 unknown:

negative

Mycoplasma/Chlamydia At least 1 test is negative and 1 unknown: negative

Antinuclear antibody

Blood culture Sampling within 3 days of hospitalization

Final Score
Final scores: <2: excluded; 2-3: possible; 4-5: probable; >5: definite
Abbreviations: ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; CT, computed tomography; D-bil., direct
bilirublin; max., maximum; T-bil., total bilirulin; U, unknow n; UNL: upper normal limit
750 Table 3. RegiSCAR scoring system for DRESS diagnosis [51]
751 Permission obtained from Elsevier
752
11
753 Cutaneous eruptions are extensive and may be polymorphic in presentation. These include
754 maculopapular eruptions, infiltrated plaques, pustules, target-like lesions, purpura, eczematous
755 lesions and erythroderma. Facial erythema and swelling are prominent features of DRESS.
756 Mucosal involvement is not a prominent feature, unlike SJS/TEN.
757 Various internal organs may be involved including the liver, kidneys, lungs, heart, nervous
758 system and others. In a prospective multinational registry, RegiSCAR, the most frequently
759 involved organs are the liver (75%), kidneys (37%) and lungs (32%).[44] Although a cutaneous
760 eruption is the most striking feature, the onset and clinical course of the internal organ may not
761 parallel that of the skin.
762 Liver involvement: The patterns of liver injury in DRESS can be classified into cholestatic
763 (37%), hepatocellular (19%) and mixed (27%). Up to 50% of cases may have severe
764 involvement with liver enzymes being more than 10 times higher than the upper limit of
765 normal.[52] Acute liver failure is uncommon and transplant is rarely required.
766 Kidney involvement: Renal involvement in DRESS occurs in up to 40% of patients and up to
767 8% of patients may develop acute renal failure.[53] Renal involvement occurs more commonly
768 in cases associated with allopurinol and vancomycin.[44-54]
769 Cardiac involvement: Cardiac involvement occurs in up to 20% of cases and presenting
770 features include tachycardia, dyspnoea, hypotension, chest pain and electrocardiogram (ECG)
771 changes. Myocarditis can occur months after the offending medicinal product has been
772 discontinued and when the cutaneous and laboratory features have abated, leading to its
773 under-diagnosis.
774 There are two forms of DRESS-associated myocarditis: hypersensitivity myocarditis (acute
775 eosinophilic myocarditis) and a more severe form, acute necrotizing eosinophilic myocarditis. In
776 the more severe form, acute necrotizing eosinophilic myocarditis, case fatality approximates
777 50%.[55]
778 Pulmonary involvement: Pulmonary involvement may initially present with dyspnoea, cough or
779 pleurisy. The manifestation is diverse, ranging from impaired pulmonary function tests,
780 interstitial pulmonary infiltrates, pneumonia, pulmonary nodules, effusion and acute respiratory
781 distress syndrome (ARDS). In a systematic review of reported DRESS/DIHS cases with
782 pulmonary involvement, pneumonitis was the most common (50%), followed by ARDS (31%)
783 and pleural effusion (23%).[56]
784 Blood: Haematologic abnormalities are common in DRESS/DIHS with eosinophilia (95%) and
785 atypical lymphocytes (70%) being the most common. Other findings include, leukocytosis,
786 neutrophilia, lymphocytosis, monocytosis, thrombocytosis and thrombocytopenia.[44]
787 Other reported systemic involvements include neurological (e.g. encephalitis, Bell’s palsy,
788 peripheral neuropathy), gastrointestinal (e.g. cholecystitis, pancreatitis, colitis, intestinal
789 perforation), myositis as well as thyroid dysfunction. The acute phase of the disease is
790 prolonged. 90% of cases persist beyond 15 days and up to 20% of patients persist beyond 90
791 days.[57]
792 In addition, the clinical course may be punctuated by relapses and flare-ups. The latter occur in
793 up to 25% of DRESS and such reactions are typically cutaneous, although organ involvement
794 may occur as well.[58]
795 Flare-up reactions typically occur in patients treated with systemic corticosteroids that has
796 undergone rapid dose tapering and this may be related to a viral reaction of human herpes
797 virus. Relapses can occur with the re-introduction of structurally different drugs, antibiotics in
798 particular, which were administered during the acute phase of the disease.[59]

12
799 [Link] Prognosis and outcome (long-term sequelae)

800 The case fatality in DRESS vary between 2-10%. The presence of cytomegalovirus (CMV)
801 reactivation is a poor prognostic factor.[60] Long-term sequelae have been reported in up to 12 %
802 of survivors, such sequelae are typically autoimmune in nature and consist of Grave’s disease,
803 type 1 diabetes mellitus, vitiligo, alopecia areata, autoimmune hemolytic anemia, lupus
804 erythematosus.[61-63]
805 1.4.3 AGEP
806 [Link] Epidemiology

807 AGEP was originally classified as a variant of generalized pustular psoriasis (GPP), termed
808 exanthematic pustular psoriasis. In a comprehensive review of 104 GPP cases in 1968, Baker
809 & Ryan, identified five cases of exanthematic GPP which were characterized by acute onset of
810 numerous discrete pustules in patients with no known history of psoriasis. Exanthematic GPP
811 usually develops after upper respiratory tract infection (URTI) or after ingestion of drugs used to
812 treat URTI. It is self-limiting and resolved spontaneously in one to two weeks.[64] Without a
813 prior history of psoriasis and the lack of recurrence, the authors postulated that these skin
814 eruptions were likely triggered by drugs and/or infections[53,65] Baker and Ryan’s description
815 of exanthematic GPP is reminiscent of AGEP, a term coined by Beylot et al.[65] in 1980 to
816 describe this distinctive drug-induced eruption.
817 AGEP is a rare SCAR with reported incidence of one to five cases per million per year.[19] A
818 recent retrospective review of 340 probable or definite cases of AGEP based on EuroSCAR
819 criteria from 10 academic dermatology departments in the U.S. between January 1, 2000, and
820 July 30, 2020 showed a female preponderance (62.9%) with a mean age of 57.8 (±17.4)
821 years.[20] Female preponderance was also observed in the EuroSCAR study of nine cases[21]
822 as well as studies from France[22], Israel[23,24], Malaysia[25], Singapore[26] and Taiwan.[66]
823 Although no gender variation was observed in some studies, a recent literature review of 250
824 case reports or case series which included 297 AGEP confirmed a female preponderance.[67]
825 [Link] Common etiology (medicinal products)

826 The majority (>85%) of AGEP cases are drug-induced.[64,65] Infections with Parvovirus B19,
827 CMV, Coxsackie B4 and Mycoplasma pneumoniae have been implicated. However, the
828 EuroSCAR case control study of 97 cases of AGEP with 1009 normal controls found no
829 significant risk for infections.[21] Hypersensitivity to mercury, Rhus (lacquer) and spider bites
830 have also been reported as triggers for AGEP.[65] Aminopenicillins, pristinamycin,
831 sulfonamides, quinolones, hydroxychloroquine, terbinafine and diltiazem are frequent causative
832 drugs, but the list of reported culprit medicinal products is very long. A recent review identified
833 93 drugs, which caused 259 positive patch tests in 248 patients with AGEP. Beta-lactam
834 antibiotics caused the highest number of reactions (25.9%), followed by other antibiotics
835 (20.8%), iodinated contrast media (7.3%), and corticosteroids (5.4%), together accounting for
836 nearly 60% of all AGEP cases. The highest number of AGEP cases to individual drugs was to
837 amoxicillin (n = 36), followed by pristinamycin (n = 25), diltiazem (n = 14), amoxicillin-clavulanic
838 acid (n = 13), clindamycin (n = 11), and iomeprol (n = 8).[68] In the US study of 340 validated
839 cases, AGEP was attributed to medicinal products (85.6%), intravenous contrast agents (2.1%),
840 infection (0.9%), or unknown (11.5%) and β-lactam antimicrobials (41.7%) were the most
841 common drug classes that were implicated, followed by non–β-lactam antimicrobials (33.8%),
842 anticonvulsants (6%) and calcium channel blockers (3.3%).
843
844

13
845 [Link] Clinical characteristics (that assist diagnosis by highlighting key clinical
846 manifestations)

847 AGEP is characterized by a sudden onset of numerous pinpoint, non-follicular sterile pustules
848 on oedematous erythematous skin. The most characteristic feature of AGEP is its clinical
849 course. It has a very rapid onset and equally rapid resolution.(Figure 5)

850
851 Figure 5. Numerous pinpoint, nonfollicular pustules and confluent pus la kes on oedematous
852 erythematous plaques on the inner thigh of a patient with AGEP
853 This figure was provided by the Working Group and included in the report with appropriate permission

854 Skin lesions appear rapidly within 24-48 hours of medicinal product exposure and resolve as
855 rapidly within five to seven days upon medicinal product withdrawal followed by collarette pin-
856 point desquamation. Distribution is usually widespread but may be limited, in which case lesions
857 are usually confined to body folds. Flexural predominance and facial involvement are
858 characteristic. Mucosal involvement is uncommon. It is reported in about 20% and usually
859 manifest as nonerosive cheilitis. Skin eruption is usually pruritic. The pinpoint pustules may
860 coalesce to form bigger, but subcentimetre pustules. Atypical presentations such as huge
861 erosions resembling TEN, purpuric and erythema multiforme-like lesions have been reported.
862 Skin eruptions in AGEP are often accompanied by fever 38.0 °C. AGEP usually resolves fully
863 within 15 days. In a study of 58 patients with AGEP, 17% had internal organ involvement
864 (namely hepatic, renal and pulmonary dysfunction) that resolved on drug withdrawal and
865 supportive treatment with no mortality.[19] Neutrophilia, elevated CRP and re-challenge are
866 identified as risk factors for organ involvement. In a recent U.S. study, 8.4% of 298 patients with
867 AGEP had an acute elevation of aspartate aminotransferase and alanine aminotransferase
868 levels with a peak at 6 (IQR, 3-9) days and 7.8% of 319 patients experienced acute kidney
869 insufficiency, with at 4 (IQR, 2-5) days after onset of AGEP. Reported case fatality of AGEP is
870 5% mainly due to secondary infections in older patients with comorbidities. All-cause mortality in
871 the study population within 30 days was 3.5%, but none was deemed to be due to AGEP.[64]
872 [Link] Laboratory features

873 AGEP is almost always accompanied by absolute neutrophilia (>7000/mL) which was seen in
874 about 85% of 309 cases with available data in the U.S. study.[64] Thirty to 50% of patients had
875 eosinophilia and 65-75% of patients had hypocalcemia.[21,64] Key histopathologic features of
876 AGEP include intra-corneal, sub-corneal and intra-epidermal spongiform pustules containing a
877 mixed infiltrate of neutrophils and eosinophils.[69] Other epidermal features include keratinocyte
878 necrosis, neutrophilic exocytosis and mild psoriasiform hyperplasia. Characteristic dermal
879 findings are papillary oedema, a neutrophil-rich superficial to mid-dermal perivascular and
880 interstitial infiltrates that regularly contain eosinophils. Red blood cell extravasation and mild
881 leukocytoclasia are common, but frank vasculitis is not a feature.
882
14
883 [Link] Prognosis and outcome

884 AGEP is a rare distinctive SCAR. It may be associated with systemic complications in a minority
885 of patients and typically resolves upon withdrawal of culprit medicinal products. Reported case
886 fatality is <5%.
887 1.4.4 GBFDE
888 [Link] Epidemiology

889 GBFDE may be defined as widespread typical FDE with blisters and erosions affecting more
890 than 10% of BSA on at least three out of six sites:
891 1) head and neck,
892 2) anterior trunk,
893 3) back,
894 4) upper limbs,
895 5) lower limbs and
896 6) genitalia.[17]
897 FDE is most common in adults, but can affect children and the elderly whereas GBFDE mainly
898 affects elderly patients.[15-17] In a survey of 58 patients with GBFDE, the median age of
899 patients was 78 years (range 68–84 years).[16]
900 [Link] Common etiology (medicinal products)

901 Since GBFDE may evolve from FDE after repeated exposure to the culprit medicinal product,
902 implicated medicinal products are similar to those responsible for FDE, namely NSAIDs,
903 antibiotics (namely sulfamethoxazole, tetracyclines, dapsone), barbiturates and
904 paracetamol/acetaminophen. Other implicated substances include tartrazine in food and cold
905 medication, and quinine in alcoholic beverages made with tonic water. GBFDE has been
906 reported following influenza and COVID-19 vaccination.[70,71]
907 [Link] Clinical characteristics (that assist diagnosis by highlighting key clinical
908 manifestations)

909 GBFDE is characterized by well-demarcated erythematous, violaceous or dusky red round or

910 oval patches with blisters and erosions. Most patients report a positive history of similar
911 eruptions. GBFDE may be confused with SJS/TEN due to the extensive bullous eruption with
912 erosions. Clinical clues which favour a GBFDE diagnosis are (Figure 6):
913 1) characteristic well-demarcated erythematous, violaceous or dusky red round or oval
914 patches, which resolves with typical hyperpigmentation
915 2) absence of small spots and targetoid lesions,
916 3) lack of or minimal mucosal involvement,
917 4) lack of constitutional symptoms such as fever, and
918 5) rapid onset of rash within a few hours after drug exposure compared to 1-3 weeks
919 reported in EN.
920

15
921
922 Figure 6. Many well-demarcated, dusky red, round or oval patches with blisters and erosions
923 on the trunk and limbs of a patient with GBFDE

924 [Link] Laboratory features

925 GBFDE and SJS/TEN share overlapping histopathologic features. Histopathologically, GBFDE
926 is characterized by subepidermal blisters, vacuolar interface dermatitis with variable mild to
927 moderate density of perivascular and interstitial infiltrate, composed of eosinophils and
928 lymphocytes in both the superficial and deep dermis. Pigmentary incontinence is a typical
929 feature and discrete apoptotic/necrotic keratinocytes are scattered throughout the epidermis. In
930 contrast, SJS/TEN, especially TEN, is characterized by a near absence of or sparse
931 inflammatory infiltrate and extensive, confluent full-thickness epidermal necrosis.
932 [Link] Prognosis and outcome

933 GBFDE is generally associated with a much better prognosis than SJS/TEN based on case
934 reports and small case series. However, a case control study comparing 58 patients with GBFDE
935 to 170 patients with SJS/TEN showed that there was no significant difference in the case fatality
936 between the two groups. This study population was drawn from patients reported to the
937 EuroSCAR group as potential SJS/TEN and diagnosis of GBFDE was validated based on the
938 presence of at least two of the following criteria:
939 1) similar reaction in the past,
940 2) fewer than two mucous membranes involved,
941 3) absence of spots or target lesions,
942 4) large and well-demarcated blisters and erosions, and
943 5) lesions and erosions on at least two different sites of the body regardless of the extent of
944 the lesions.
945 However, 31% of the 58 patients[16] had at least two affected mucosal sites. A validated
946 international diagnostic criterion for GBFDE is needed to determine the burden of this rare SCAR
947 accurately.

16
948 1.5 SJS/TEN/DRESS/AGEP overlap

949 Because the initial presentation of SCAR may vary, diagnosis is difficult and suggests the
950 possibility of overlap among SCAR may occur. AGEP, with a confluence of pustules resulting in
951 superficial detachment, may manifest similar to TEN.[72] Cases of “overlap” between DRESS
952 and TEN have been reported, suggesting the difficulty in classifying SCAR under certain
953 circumstances.[73] Various T-cell - mediated delayed hypersensitivity reactions can be related
954 to the preferential activation of medicinal product-specific T cells with distinct functions. These
955 complex immune reactions are not exclusive and may be combined. Therefore, an overlap of
956 immune reactions is possible, even if one type is often dominant, and could explain clinical
957 ambiguities among SCAR.
958 A retrospective study of SCAR cases revealed the frequent occurrence (n = 45; 21%) of SCAR
959 cases that were based on different diagnoses (possible, probable or certain), which reflects the
960 clinical ambiguity among several SCAR.[74] In such situations, the clinician is confronted with
961 an uncertain diagnosis of several disease entities. However, only three “true” overlap SCAR
962 were documented, representing 2.1% of the 145 confirmed SCAR cases.[74] The above results
963 indicate that overlap of SCAR does exist but is rare, if the retrospective analysis was performed
964 using a diagnostic algorithm.
965 References

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966

19
967 CHAPTER 2.
968 DIAGNOSIS AND IDENTIFICATION OF SCAR CASES
969

970 Chapter summary

971  The first step in analysing a putative SCAR is to make a diagnosis even if tentative.
972 DRESS, SJS/TEN and some other SCAR conditions have defined diagnostic criteria
973 which may overlap and can hence be challenging to diagnose in the earliest stages.

974  The HCP must determine medicinal product exposure (name and dosage) and lag
975 period (the time between initiation of the medicinal product and the onset of the first
976 symptoms of the ADR).

977  All medications, especially those taken in the eight weeks prior to the cADR, must be
978 considered as possible causative agents.
979 Conclusions or recommendations
980 A SCAR diagnosis should consider patient history, visual assessment (appearance,
981 morphology), severity and the presence of systemic symptoms, skin histopathology, followed
982 by a causality assessment in the individual patient.

983 2.1 Introduction

984 ADRs have a wide spectrum of clinical manifestations. They are caused by various medicinal
985 products and result from varied pathophysiologic mechanisms. Hence, their diagnosis and
986 management are challenging. cADRs can range in clinical manifestations; from a mild
987 exanthem involving only the skin to a reaction including systemic symptoms in addition to the
988 skin manifestations, which can be fatal such as in the cases of life-threatening ADRs.[1]
989 Generally, cADRs are either common and mild or rare and severe reactions. However,
990 medicinal products associated with common and severe reactions are typically not approved
991 for clinical use. Rare and mild reactions usually go unnoticed or are not reported by patients.
992 In most cases, cADRs are classified as “simple” or “complex.” A “simple” reaction only involves
993 the skin, while a “complex” reaction includes systemic involvement of organs in addition to
994 involvement of the skin.[2]
995 2.1.1 Diagnosis

996 The diagnosis of a cADR is generally based on three key clinical elements:
997 1) Appearance: the morphology of the cADR including four main categories of the primary
998 lesion: maculopapular (exanthem, enanthem), urticarial, bullous and pustular.
999 2) Systemic signs that differentiate between a simple reaction involving only the skin and a
1000 complex reaction that comprises systemic involvement in addition to the skin.
1001 3) Histology: histopathology and, if relevant, direct immunofluorescence studies of skin
1002 biopsies to confirm the clinical impression and to distinguish between a cADR and other
1003 skin diseases.
1004 2.1.2 Criteria for diagnosis
1005 If available, validated diagnostic criteria of specific types of cADRs should be used. Currently,
1006 only AGEP and DRESS have published validated diagnostic criteria. This chapter provides a
1007 practical approach to diagnosing and identifying SCAR cases.[3,4]
20
1008 2.2 Patient history
1009 2.2.1 Patient history including time to onset

1010 First, the patient’s exposure to the medicinal product must be ascertained by the patient, the
1011 patient’s family, pharmacists or others who might know which medications the patient was
1012 taking prior to the AE. Second, it is crucial to carefully analyse the lag period of an ADR when
1013 determining the causative agent since different cADRs have different timelines. The lag period
1014 can be defined as the time between initiation of the medicinal product and onset of the first
1015 symptoms of the ADR.
1016 All medications, especially those taken in the eight weeks prior to the cADR, must be
1017 considered as possible causative agents and physicians should ask patients about any over-
1018 the counter medications as well as prescription medicinal products. The physician can
1019 produce a graphic illustration of the medicinal product exposure timeline so as to visualize the
1020 chronology. For each medicinal product, the timeline should include the start date of the
1021 medication, dosage and end date as well as any signs or symptoms present throughout this
1022 period.
1023 Evaluating systemic signs that differentiate between a simple and a complex reaction is
1024 essential. Systemic involvement is determined by assessing the patient’s symptoms such as
1025 fever, facial oedema, malaise, chills, dyspnoea, cough, palpitations, nausea, vomiting,
1026 diarrhoea, sore throat and arthralgia. Additional information to be gathered includes known
1027 medicinal product allergies of the patient and his/her family members, and baseline health
1028 status including cutaneous diseases.[5,6]
1029 2.2.2 Morphology description and physical exam findings
1030 It is advisable to assess primary lesion morphology of the cutaneous eruption, which includes
1031 the four following main types: exanthematous, urticarial, pustular, and blistering. Moreover,
1032 diagnosing cADRs involves two major steps, namely determining morphology and examining
1033 systemic involvement.
1034 Physical examination includes:

1035  Assessment of patient’s basic signs: heart rate, blood pressure, oxygen saturation and fever,
1036  Assessment of the morphology of primary and secondary skin lesions,
1037  Assessment of mucous membrane involvement: ocular, oral and genital,
1038  Additional assessments: facial oedema perianal area, nails and hair, palpation of lymph nodes.
1039
1040 2.2.3 Additional clinical information
1041 [Link] Skin biopsy (hematoxylin and eosin stain (H&E), immunofluorescence studies)

1042 Skin biopsy for histology must be conducted, and, if relevant, direct immunofluorescence studies as
1043 well.
1044 [Link] Specialty consultation

1045 In patients with a suspected complex cADR (systemic involvement), it is prudent to conduct a
1046 multidisciplinary assessment based on the clinical signs and symptoms in both the acute
1047 stage and follow-up period subsequent to recovery.[7-9]

21
1048 [Link] Assessing systemic involvement

1049 We recommend that patients with cADRs be assessed for systemic involvement because the
1050 severity of skin manifestations does not always mirror the severity of the systemic
1051 involvement. In addition to assessing systemic involvement based on the patient’s signs and
1052 symptoms, basic laboratory screening is advised, which includes a full blood count, liver and
1053 renal function tests, and urine analysis.
1054 2.3 Assessing severity
1055 The severity of SCAR depends mostly on the haemodynamic status and the extent of
1056 cutaneous and systemic involvement. The following clinical and histopathological findings
1057 were found to be validated values for determination of severity in various types of SCAR.
1058 SCORTEN
1059 This scoring system was developed to assess illness severity and predict mortality in patients
1060 with TEN. To optimize the predictive value of this tool, SCORTEN is to be performed on days
1061 1 and 3[10] postadmission.[11]
1062 Drug-Induced Hypersensitivity Syndrome and Drug Reaction with Eosinophilia and Systemic
1063 Symptoms Severity Score
1064 This scoring system is based on a variety of factors including age, allopurinol exposure, need
1065 for pulsed prednisone, duration of medicinal product exposure after symptom onset, fever
1066 duration, percent BSA, appetite loss, liver involvement, renal dysfunction and C-reactive
1067 protein (CRP). Higher scores (≥4) were associated with CMV reactivation and CMV-related
1068 complications, higher steroids doses, longer hospitalizations and higher risk of fatal
1069 outcomes.[12]
1070 2.4 SCAR case definition and diagnosis
1071 2.4.1 SJS and TEN
1072 [Link] Criteria for diagnosis

1073 SJS and TEN can be defined as different degrees of a severe, acute and life-threatening
1074 mucocutaneous reaction. Therefore, SJS/TEN can be referred to as a single entity on this
1075 disease spectrum. The SJS/ TEN classification as defined by Bastuji-Garin et al., is based on
1076 the extent of epidermal detachment and the presence of characteristic skin lesions.
1077 When evaluating the extent of epidermal detachment, only necrotic skin that is already
1078 detached (e.g. blisters, erosions), or detachable skin (positive Nikolsky sign whereby slight
1079 rubbing of the skin results in exfoliation of the outermost layer) should be considered.
1080 Diagnostic criteria based on clinical characteristics of skin and mucous membranes, histology
1081 assessment, lag period and systemic signs remain to be defined.[13]
1082 [Link] Histology

1083 Among the typical histopathologic characteristics are extensive keratinocyte destruction and
1084 apoptosis with separation of the epidermis from the dermis at the dermo-epidermal junction. In
1085 addition, a pauci-cellular, dermal mononuclear infiltrate has been commonly described as well
1086 as lymphocytes that cross the dermo-epidermal junction with moderate infiltration of the
1087 epidermis.[14]
1088

22
1089 [Link] Genetics

1090 In the last few decades, progress has been made in understanding the pathogenic
1091 mechanisms of SJS/TEN, in particular, the important role of HLA alleles. Recognition of the
1092 culprit medicinal products by specific HLA molecules contributes to the pathogenesis of
1093 inducing cytotoxic responses in SJS/TEN.
1094 Although association with a specific HLA risk allele might be necessary, it is not sufficient for
1095 SJS/TEN to develop. Individual differences in medicinal product metabolism or clearance may
1096 also be significant in SJS/TEN development, recovery or prognosis.[15]
1097 [Link] Biomarkers2
1098 A rapid immunochromatographic test for serum granulysin was found to be useful in predicting
1099 SJS/TEN.[16]
1100 [Link] Skin testing
1101 The value of medicinal product skin tests in SJS/TEN:

1102  patch tests can be done but are rarely positive;

1103  prick tests add no value and intradermal medicinal product tests are forbidden since it
1104 may induce a flare up reaction.[17]
1105 [Link] Pitfalls in diagnosis
1106 The major differential diagnoses of SJS/TEN include:

1107  Staphylococcal Scalded Skin Syndrome,

1108  GBFDE,
1109  Acute Graft-Versus-Host Reaction,
1110  TEN-Like Lupus Erythematosus or Lupus-Associated TEN
1111  Autoimmune blistering diseases,
1112  Bullous phototoxic reactions,
1113  AGEP,
1114  DRESS, and
1115  Erythema multiforme (minor and major).[18]

2 See also Chapter 4

23
1116 2.4.2 DRESS and DIHS
1117 [Link] Criteria for diagnosis

1118 DRESS is characterized by stepwise multi-organ involvement that may include skin,
1119 haematological and solid organs. Cutaneous manifestations of DRESS are diverse. There are
1120 two diagnostic criteria: the Japanese consensus group criteria (2006) and the RegiSCAR
1121 group criteria (2007).
1122 An important distinction between the two scoring systems is the requirement of human herpes
1123 virus-6 (HHV6) reactivation for typical DIHS in the Japanese scoring system.[19,4]
1124 [Link] Histology

1125 Histopathological characteristics of patients with DRESS are generally non-specific. No single
1126 finding can be used to distinguish DRESS from other cADRs or inflammatory skin disorders.
1127 Several commonly encountered histopathological patterns were identified in skin specimens of
1128 patients with DRESS such as spongiosis, interface dermatitis, vascular damage and
1129 superficial perivascular infiltration.
1130 A retrospective analysis of patients with DRESS found that spongiosis and keratinocyte
1131 damage were the most common epidermal changes. Spongiosis was associated with non-
1132 serious DRESS whereas confluent keratinocyte necrosis correlated with serious DRESS and
1133 frequent vascular changes.
1134 A moderate, dermal perivascular lymphocytic infiltrate was invariably present, containing
1135 eosinophils, neutrophils and/or atypical lymphocytes in most cases.[20] Another study found
1136 that the histopathology of DRESS features various associated inflammatory patterns in a
1137 single biopsy.[21] Although differentiated histopathological features of patients with DRESS
1138 cannot be identified, there are characteristics that might provide clues for diagnosis or indicate
1139 severity. The most important of these observations is the co-existence of the aforementioned
1140 patterns in a single skin specimen.
1141 Approximately 50–60% of patients with DRESS have at least two of the above-mentioned
1142 patterns in a single specimen.[21,22] In addition, patients with three histopathological patterns
1143 (spongiosis, interface dermatitis and vascular damage) that co-exist in a single specimen have
1144 a considerably higher likelihood of having a definite case of DRESS.[22]
1145 [Link] Genetics

1146 It is generally believed that DRESS is the result of a complex interaction between exposure to
1147 a medicinal product, genetic predisposition and viral reactivation. HLA alleles are among the
1148 most important risk factors for DRESS.
1149 Since certain high risk alleles are more present in some ethnicities than in others, ethnicity is a
1150 significant predisposing factor for DRESS. More specifically, the culprit medicinal product is
1151 believed to interact with a particular HLA to form a complex-hapten which is then presented to
1152 naive T cells via the T-cell receptor, thereby stimulating an immune response.[23]

24
1153 [Link] Biomarkers3

1154 Thymus and activation-regulated chemokine (TARC) recruits Th2-polarized T cells into local
1155 inflammation sites, leading to a Th2-type immune reaction. TARC levels were found to be
1156 markedly higher in patients with DRESS than in patients with other cADRs. Hence, the
1157 baseline serum TARC level can be used as a marker for the early diagnosis of the DRESS in
1158 patients presenting with a maculopapular rash.[24]
1159 [Link] Skin testing
1160 The value of medicinal product skin tests in DRESS:

1161  patch tests can be useful and must be performed at least six months after the
1162 disappearance of the rash and biological disturbances,
1163  prick tests may add value only in some cases with delayed reactions and intradermal
1164 medicinal product tests have to be cautiously applied.[17]
1165 [Link] Pitfalls in diagnosis

1166 There are many conditions that mimic DRESS. Differential diagnoses include viral infections
1167 such as Epstein-Barr virus (EBV), Severe Acute Respiratory Syndrome coronavirus-2 (SARS-
1168 CoV-2), CMV and Human Immunodeficiency Virus (HIV) as well as bacterial sepsis, toxic
1169 shock syndrome, Kawasaki disease, Still disease, lymphoma, mycosis fungoides,
1170 hypereosinophilic syndrome, connective tissue diseases, hemophagocytic syndrome, and
1171 angio-immunoblastic lymphadenopathy and other cADRs.[25]
1172 2.4.3 AGEP
1173 [Link] Criteria for diagnosis

1174 AGEP is defined as a severe acute pustular cutaneous reaction characterized by a rapid
1175 clinical course. Generally, the morphology of AGEP is an acute oedematous erythema with a
1176 burning sensation and/or itch, which leads to the development of dozens to hundreds of small
1177 (pinhead sized) non-follicular sterile pustules with a tendency toward large folds or widespread
1178 distribution. Fever and leukocytosis with neutrophilia are almost always present.
1179 The AGEP validation score developed by the Euro-SCAR study group is a standardized
1180 scoring system comprising data about clinical features (morphology and clinical course) and
1181 histopathology. Based on this score, AGEP cases can be placed into the following categories:
1182 no AGEP, possible AGEP, probable AGEP and definite AGEP.[3]
1183 [Link] Histology

1184 The histopathological features of AGEP consist of sub-/intra-corneal and/or intra-epidermal

1185 pustules or a combination thereof. The primary epidermal features are necrotic keratinocytes
1186 such as incidental segmental necrosis and spongiosis with neutrophil exocytosis. The primary
1187 dermal features are papillary oedema with mixed superficial interstitial and mid/deep-dermal
1188 infiltrates containing neutrophils and eosinophils.[26]
1189 [Link] Genetics

1190 Genetic predisposition plays an important part in the pathogenesis of AGEP. Specific HLAs
1191 were found to be more common in AGEP patients than in the general population.[27] Also,
1192 mutations in the IL36RN gene were found in some patients with AGEP.[28]

3 See also Chapter 4

25
1193 [Link] Biomarkers4

1194 A recent publication stated that IL17E, inducible nitric oxide synthase and arginase1 may
1195 serve as new biomarkers in the identification of neutrophilic dermatoses including AGEP.[29]
1196 [Link] Skin testing

1197 The value of medicinal product skin tests in AGEP:

1198  patch tests are useful,

1199  prick tests and intradermal medicinal product tests add no value.[17]
1200 [Link] Pitfalls in diagnosis

1201 Differential diagnoses of AGEP include a variety of rashes and skin diseases with pustules,
1202 mainly pustular psoriasis; subcorneal pustular dermatosis (Sneddon-Wilkinson); pustular
1203 vasculitis and DRESS.[30]
1204 2.4.4 GBFDE
1205 [Link] Criteria for diagnosis

1206 The diagnosis of GBFDE can often be made on clinical grounds based on distinctive
1207 appearance and history of a similar eruption with medicinal product exposure. Skin biopsy
1208 may be performed to confirm the diagnosis when the clinical presentation is ambiguous. No
1209 diagnostic criteria exist.
1210 [Link] Histology

1211 Characteristic histopathologic findings of GBFDE consist of a sub-epidermal blister or vacuolar

1212 alterations at the dermo-epidermal junction and a variable number of necrotic keratinocytes
1213 within lesional intact epidermis. Though the infiltrate of inflammatory cells is variable, there is
1214 usually a brisk, moderately dense perivascular infiltrate of lymphocytes and interstitial
1215 eosinophils. GBFDE shows increased inflammation with eosinophils, fewer necrotic
1216 keratinocytes and more melanin-containing dermal macrophages compared with SJS/TEN.
1217 Nevertheless, GBFDE may have full-thickness epidermal necrosis, which histologically
1218 strongly resembles and may be almost indistinguishable from SJS/TEN.[31]
1219 [Link] Genetics

1220 In GBFDE, CD8+ T cells play a critical inflammatory role by recognizing certain medicinal
1221 products in association with specific major histocompatibility complex (MHC) class I molecules
1222 found on keratinocytes. There are several examples of HLA-A or HLA-B associated with
1223 GBFDE.[32]
1224 [Link] Biomarkers5
1225 Serum granulysin levels have been found to be significantly lower in GBFDE compared to
1226 SJS/TEN, leading some authors to advocate the use of a serum granulysin test as a method
1227 to rapidly diagnose SJS/TEN.[33]

4 See also Chapter 4

5 See also Chapter 4
26
1228 [Link] Skin testing

1229 Patch testing is the best confirmation method. Patch testing is conducted on a hyper-
1230 pigmented site in an area of previous FDE, exploiting normal skin as a control. Patch testing
1231 should be performed a few weeks after the lesions resolve to avoid a false negative result due
1232 to a refractory period.[34] An additional method of FDE confirmation is performed using the
1233 lymphocyte transformation test, which aims to measure a sensitized T-cell reaction in
1234 response to the in vitro addition of the medicinal product.[35]
1235 [Link] Pitfalls in diagnosis

1236 The most important differential diagnosis is between GBFDE and SJS/TEN. Patients with
1237 GBFDE tend to be older and less likely to have constitutional symptoms than patients with
1238 SJS/TEN. Mucosal involvement is less frequent and less severe in GBFDE. GBFDE always
1239 presents within one to two weeks (but most frequently within 48 hours) of ingestion of the
1240 causative medicinal product, while latency between medicinal product exposure and clinical
1241 presentation of SJS/TEN is most commonly one to three weeks. SJS/TEN skin lesions tend to
1242 coalesce and may have atypical targets, while GBFDE patches and bullae tend to be well-
1243 demarcated and have larger areas of normal skin between lesions. GBFDE heals with
1244 hyperpigmentation but no scarring, whereas SJS/TEN is associated with scarring. A history of
1245 a similar less severe skin eruption induced by the culprit medicinal product can often be
1246 elicited in cases of GBFDE.[36]
1247 2.5 Interactions between patient, family, healthcare professional and
1248 regulatory agencies for reporting
1249 2.5.1 Patient and family
1250 Good communication strategies will aid in the interactions with a patient and their family
1251 following a suspected SCAR. Physicians are recommended to:
1252 1) Listen to the patient in a respectful and empathetic manner in order to characterize their
1253 experience. This is part of the diagnostic process.
1254 2) Acknowledge the reality of the experience for the patient.
1255 3) Offer the patient clear information on his/her suspected SCAR (see Table 4 below), the
1256 name of the suspected offending medicinal product if it is known, potential cross-
1257 reacting medicinal products, and medicinal product, which can be safely taken as a
1258 substitute. In addition, advise the patient to wear a medic-alert bracelet.
1259 4) Include family counselling in the management plan given that the predisposition to some
1260 SCAR may be genetic.

27
1261 2.5.2 Healthcare professionals

1262 Healthcare professional (HCPs) should obtain information about a SCAR such as type and
1263 culprit medicinal product(s) and incorporate the information into the patient’s medical records..
1264 At a minimum, the HCP should inform the patient and family of which SCAR was experienced
1265 using appropriate patient-focused language and the culprit medicinal product(s), if identified.
Severe Cutaneous Adverse Reactions A group of hypersensitivity reactions with a variety
of clinical signs and symptoms that are typically
triggered by taking medications.
Stevens-Johnson syndrome and toxic epidermal A hypersensitivity reaction which can involve the
necrolysis skin and mucous membranes (such as the eyes,
mouth/throat, genital areas) and cause widespread
redness of the skin and blistering with burn-like
lesions from large areas of detached skin.
Drug reaction with eosinophilia and systemic A hypersensitivity reaction which can include fever,
symptoms and drug-induced hypersensitivity widespread skin rash, multiple organ involvement
syndrome (such as liver, heart, and lung), and an increase of
eosinophils in the blood.
Acute generalized exanthematous pustulosis A hypersensitivity reaction that presents with fever,
increased white blood cells, and widespread
redness of the skin with small pustules. The small
pustules can merge and lead to large areas of
detached skin.
Generalized bullous fixed drug eruption A hypersensitivity reaction that typically starts with
round red/purple or hyperpigmented lesions that
can have blistering within the lesions. With
repeated occurrence, more lesions appear and can
be widespread and appear similar to Stevens-
Johnson syndrome/toxic epidermal necrolysis.
1266 Table 4. Example of information to be provided to the patient and the patient’s family

28
1267 2.5.3 Regulatory agencies

1268 If a SCAR has occurred subsequent to treatment with a medicinal product, patients and
1269 healthcare professionals should report it to the manufacturer and appropriate regulatory
1270 agencies, using the applicable regional pharmacovigilance reporting system. Manufacturers
1271 are required by law to report suspected ADRs to regulatory agencies and some regulatory
1272 agencies are required to report ADRs that have occurred outside their jurisdictions, which has
1273 led to the creation of global databases, e.g. MedWatch, the FDA Safety Information and
1274 Adverse Event Reporting Program[37] and EudraVigilance maintained by European Medicines
1275 Agency (EMA)[38] for the European Union (EU) regulatory network. Many countries are
1276 members of the WHO Programme for International Drug Monitoring and in this context provide
1277 their national suspected ADR reports to the WHO Collaborating Centre Uppsala Monitoring
1278 Centre (UMC) which maintains the global database VigiBase for collecting and analysing the
1279 reports.[39]
1280
1281
1282
1283
1284
1285
1286 References

1 Chung W-H, Wang C-W, Dao R-L. Severe cutaneous adverse drug reactions. J Dermatol 2016 Jul;43(7):758–66. PubMed
Abstract
2 Naldi L, Crotti S. Epidemiology of cutaneous drug-induced reactions. G Ital Dermatol Venereol. 2014;149(2):207–218. PubMed
Abstract
3 Sidoroff A, et al. Acute generalized exanthematous pustulosis (AGEP)—a clinical reaction pattern J Cutan Pathol. 2001;28(3):
113–19. PubMed Abstract
4 Kardaun SH, et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome
really exist? Br J Dermatol. 2007;156: 609–11. Journal Full Text
5 Nigen S, Know les SR, Shear NH. Drug eruptions: approaching the diagnosis of drug induced skin diseases. J Drugs Dermatol.
2003;Jun;2(3):278–299. PubMed Abstract
6 Dodiuk-Gad RP, Chung W-H, Shear NH. Adverse Medication Reactions. In: Clinical and basic immunodermatology. 2017;Springer. Journal
Full Text
7 Brüggen MC, et al. Supportive care in the acute phase of Stevens -Johnson syndrome and toxic epidermal necrolysis: an
international, multidisciplinary Delphi-based consensus. Br J Dermatol. 2021 Sep;185(3):616-626. PubMed Abstract
8 Dodiuk-Gad RP, et al. Major psychological complications and decreased health-related quality of life among survivors of
Stevens–Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol. 2016 Aug;175(2):422–4. PubMed Abstract
9 Olteanu C, et al. Severe Physical Complications among Survivors of Stevens -Johnson Syndrome and Toxic Epidermal
Necrolysis. Drug Saf. 2018 Mar;41(3):277-284. PubMed Abstract
10 Guégan S, et al. Performance of the SCORTEN during the first five days of hospitalization to predict the prognosis of
epidermal necrolysis. J Invest Dermatol. 2006 Feb;126(2):272-6. doi: 10.1038/[Link].5700068. PubMed Abstract
11 Bastuji-Garin S, et al . SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Investig Dermatol.
2000;115(2):149–53. PubMed Abstract
12 Mizukaw a Y, et al. T. Drug-Induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms severity
score: A useful tool for assessing disease severity and predicting fatal cytomegalovirus disease. Journal of the American
Academy of Dermatology. 2019 Mar;80(3), 670-678.e2. PubMed Abstract
13 Bastuji-Garin S, et al. Clinical classification of cases of toxic epidermal necrolysis, Stevens -Johnson syndrome, and erythema
multiforme. Arch Dermatol. 1993 Jan;129(1):92-6. PubMed Abstract
14 Quinn AM et al. Uncovering histologic criteria w ith prognostic significance in toxic epidermal necrolysis. Arch Dermatol. 2005
Jun;141(6):683-7. PubMed Abstract
15 Chung W-H, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004 Apr 1;428 (6982):486. PubMed
Abstract
16 Fujita Y, et al. Rapid immunochromatographic test for serum granulysin is useful for the prediction of Stevens –Johnson
syndrome and toxic epidermal necrolysis. J Am Acad Dermatol. 2011;65(1):65–8. PubMed Abstract
17 Barbaud A. In vitro and In vivo tests in cutaneous adverse drug reactions. In: Advances in Diagnosis and Management of
Cutaneous Adverse Drug Reactions: Current and Future Trends. 1st edition. Shear NH, Dodiuk-Gad RP (eds.) Springer Nature
Singapore. 2018;pp.247-263. PubMed Abstract

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 18 Dodiuk-Gad RP, et al. Stevens-Johnson Syndrome and toxic epidermal necrolysis: an update. Am J Clin Dermatol. 2015 Dec
16(6):475-493. PubMed Abstract
19 Shiohara T, Inaoka M, Kano Y. Drug-induced hypersensitivity syndrome (DIHS): a reaction induced by a complex interplay
among herpes viruses and antiviral and antidrug immune responses. Allergol Int, 2006;55(1): p. 1-8. Journal Full Text
20 Skow ron F, et al. Drug reaction w ith eosinophilia and systemic symptoms (DRESS): clinicopathological study of 45 cases. J
Eur Acad Dermatol Venereol. 2015 Nov;29(11):2199-205. PubMed Abstract
21 Ortonne N, et al. Histopathology of drug rash w ith eosinophilia and systemic symptoms syndrome: a morphological and
phenotypical study. Br J Dermatol. 2015 Jul;173(1):50-8. PubMed Abstract
22 Cho Y-T, et al. Co-existence of histopathological features is characteristic in drug reaction w ith eosinophilia and systemic
symptoms and correlates w ith high grades of cutaneous abnormalities. J Eur Acad Dermatol Venereol. 2016 Dec;30(12):
2077-2084. PubMed Abstract
23 Deshpande P, et al. Immunopharmacogenomics: Mechanisms of HLA -Associated Drug Reactions. Clin Pharmacol Ther. 2021
Sep;110(3): 607–615. PubMed Full Text
24 Choudhary R, et al. Clinical, biochemical, and serologic predictors of drug reaction w ith eosinophilia and systemic symptoms
syndrome: A prospective case–control study. J Am Acad Dermatol. 2021 Oct;85(4):901–909. PubMed Abstract
25 Kardaun SH. Drug reaction w ith eosinophilia and systemic symptoms. In: Advances in Diagnosis and Management of
Cutaneous Adverse Drug Reactions: Current and Future Trends. 1st edition. Shear NH, Dodiuk-Gad RP (eds.) Springer Nature
Singapore. 2018;pp. 87-104. PubMed Abstract
26 Halevy S, et al. The spectrum of histopathological features in acute generalized exanthematous pustulosis: a study of 102
cases. Br J Dermatol. 2010 Dec;163(6):1245–52. PubMed Abstract
27 Jantararoungtong T, et al. Genotyping HLA alleles to predict the development of severe cutaneous adverse drug reactions
(SCARs): state-of-the-art. Expert Opin Drug Metab Toxicol. 2021 Sep;17(9):1049-1064. Journal Full Text
28 Onoufriadis A, et al. Mutations in IL36RN/IL1F5 are associated w ith the severe episodic inflammatory skin disease know n as
generalized pustular psoriasis. Am J Hum Genet 2011 Sep 9;89:432–7. PubMed Abstract
29 Stalder R, et al. Interleukin-17E, inducible nitric oxide synthase and arginase1 as new biomarkers in the identification of
neutrophilic dermatoses. Clin Exp Dermatol. 2022 Apr;47(4):675-683. PubMed Abstract
30 Halevy S. Acute Generalized Exanthematous Pustulosis. In: Advances in Diagnosis and Management of Cutaneous Adverse
Drug Reactions: Current and Future Trends. 1st edition. Shear NH, Dodiuk-Gad RP. (eds.). Springer Nature Singapore. 2018; pp.
105-122. PubMed Abstract
31 Patel S, et al. Fixed Drug Eruptions: An Update, Emphasizing the Potentially Lethal Generalized Bullous Fixed Drug Eruption.
Am J Clin Dermatol. 2020 Jun;21(3):393-399. PubMed Abstract
32 Pirmohamed M. Genetic factors in the predisposition to drug-induced hypersensitivity reactions. AAPS J. 2006 Feb 3;8(1):E20–6.
PubMed Abstract
33 Cho Y-T, et al. Generalized bullous fixed drug eruption is distinct from Stevens -Johnson syndrome/toxic epidermal necrolysis
by immunohistopathological features. J Am Acad Dermatol. 2014 Mar;70(3):539–48. PubMed Abstract
34 Andrade P, Brinca A, Gonçalo M. Patch testing in fixed drug eruptions -- a 20-year review. Contact Dermatitis. 2011
Oct;65(4):195–201. PubMed Abstract
35 Demir S, et al. Generalized Fixed Drug Eruption Induced by Fluconazole Without Cross-Reactivity to Itraconazole: Lymphocyte
Transformation Test Confirms the Diagnosis. Drug Saf Case Rep. 2018 Jan 2;5(1):2. PubMed Abstract
36 Anderson HJ, Lee JB. A Review of Fixed Drug Eruption w ith a Special Focus on Generalized Bullous Fixed Drug Eruption.
Medicina (Kaunas) 2021 Sep 1;57(9):925. PubMed Abstract
37 FDA Safety Information and Adverse Event Reporting Program
38 EMA. EudraVigilance
39 WHO Uppsala Monitoring Centre
1287

30
1288 CHAPTER 3.
1289 CASE MANAGEMENT IN CLINICAL CARE
1290

1291 Chapter summary

1292  Treatment goals in the management of SCAR include withdrawal of the culprit
1293 medicinal product, symptom management, avoidance of acute morbidity and fatal
1294 outcomes as well as the long-term monitoring and treatment of chronic sequelae.

1295  The culprit medicinal product that is responsible for the SCAR should be identified and
1296 withdrawn immediately. SCAR cases should be managed in reference centres.

1297  Supportive care is the cornerstone of treatment and involves fluid and nutrition
1298 optimization, skin care and dressings, thermoregulation, pain management as well as
1299 the monitoring and treatment of organ complications and infections.

1300  Various systemic treatments have been proposed for SJS/TEN, DRESS and AGEP,
1301 but the level of evidence remains low.
1302  Long-term follow up of SCAR cases is required in order to prevent and mitigate long-
1303 term sequelae.
1304 Conclusions or recommendations
1305 Early diagnosis and transfer of SCAR to a reference centre is vital. Key management
1306 principles include the withdrawal of the culprit medicinal product and supportive care. The
1307 use of specific immunomodulatory treatments requires further validation.

1308 3.1 Introduction

1309 In all cADRs, identification and withdrawal of the culprit medicinal product is the cornerstone
1310 of care. Withdrawal of drugs, particularly those with a short half-life, has been shown to
1311 improve outcomes in SJS/TEN.[1]
1312 In some cases, the decision to “treat-through” the reaction can be made if the benefits outweigh
1313 the risks such as in the context of life-sustaining treatments for which there are no alternative
1314 medicinal products, the disease phenotype is benign and there are no features of progression to
1315 SCAR. Investigations, supportive care and specific therapy are tailored according to phenotype,
1316 severity and clinical course.
1317 3.1.1 Management of benign cADRs (non-SCAR)

1318 Exanthematous drug eruptions (also known as morbilliform drug eruptions, maculopapular
1319 rash) are the most common cADRs, accounting for up to 80% of cases.[2] However, an
1320 exanthematous reaction may be the initial presentation of SCAR as such, serial examination
1321 and follow-up is warranted.
1322 Exanthematous drug eruptions are self-limiting. Emollients and antihistamines may provide
1323 symptomatic relief of pruritus. Potent topical corticosteroids are often prescribed to reduce
1324 the inflammation and symptoms associated with the rash. However, clinical evidence for
1325 such an approach is lacking. Systemic corticosteroids are rarely required.[2]
1326
1327

31
1328 3.1.2 Management of SCAR

1329 The treatment goals in SCAR include symptom management, avoidance of short-term
1330 morbidity, prevention of death as well as prevention and treatment of long-term sequelae. It
1331 involves both supportive care and specific treatment for each disease entity. It is
1332 recommended that SJS/TEN cases should be managed in reference centres. These are
1333 usually specialized dermatological centres, burn or intensive care units (ICU) with significant
1334 experience and protocols in place for the management for such rare conditions. It has been
1335 shown that delayed transfer to such units is associated with poorer outcomes.[3] Similarly,
1336 prognosis is improved when care is delivered in centres with higher volumes.[4]
1337 3.1.3 Supportive care

1338 The extensive involvement of the skin in SCAR impairs its physiological function, resulting in
1339 increased fluid loss, hypovolemia, hypothermia, protein loss, risk of bacteraemia and multi-
1340 organ failure. The aim of supportive care is to restore homeostatic function and manage the
1341 complications associated with skin failure.
1342 Components of supportive care include the following:
1343 [Link] Fluids and nutrition

1344 SCAR are catabolic states and there is also increased transepidermal water loss, particularly
1345 in SJS/TEN. This is compounded by decreased oral intake in many patients with severe
1346 oropharyngeal involvement, particularly in SJS/TEN. Strict monitoring of fluid intake and
1347 output is essential. Fluid resuscitation and replacement is necessary.
1348 Fluid and electrolyte derangements are most marked in SJS/TEN, and an initial resuscitation
1349 of 2ml/kg/% TBSA detached has been proposed and subsequent fluid requirements should
1350 achieve urinary output of 0.5 to 1ml/kg/h.[5] Enteral feeding is preferred. However, oral
1351 intake of food may be limited by pain, and a nasogastric tube may be required in order to
1352 achieve nutritional demands. Estimated caloric requirements is at 20-25 cal/kg/d during the
1353 initial catabolic state of SJS/TEN and 25-30 cal/kg/d during the period of anabolic
1354 recovery.[5]
1355 [Link] Thermoregulation

1356 The ambient temperature should be maintained at 28°C to prevent hypothermia.

1357 [Link] Skin, mucosal and wound care

1358 In a SCAR without epidermal detachment (DRESS, AGEP), liberal application of emollients
1359 and potent/ultrapotent corticosteroids has been advocated. Patients with SJS/TEN should be
1360 nursed in single rooms with reverse barrier nursing, if available. The ideal wound care
1361 strategy in SJS/TEN has not been established and remains variable across centres.
1362 Generally, it may involve either a surgical approach whereby the detached epidermis is
1363 removed operatively and replaced with either biologic membranes or dressings or a
1364 conservative approach whereby the detached/detachable skin is left in situ as a biological
1365 dressing.
1366 In the conservative approach, minimal manipulation of the skin is advocated. Saline or
1367 antiseptic baths can be used, followed by petrolatum jelly and non-adhesive dressing.
1368 Secondary dressings may be applied to absorb the exudate. To date, there have been no
1369 controlled studies that evaluate these two approaches. However, a conservative approach
1370 may result in less severe postinflammatory skin changes and avoid the risks associated with
1371 sedation and anaesthesia in the surgical approach.[6,7]

32
1372 During the acute phase of a SCAR, mucosal surfaces can be involved, particular in
1373 SJS/TEN. The use of emollients and topical corticosteroids are recommended to reduce
1374 mucosal adhesions and long-term scarring. Oral mouthwash and topical oral analgesia may
1375 be helpful in reducing the mucosal discomfort. Similarly, urogenital involvement can affect up
1376 to 70% of patients. Early assessment by urologists/gynaecologists may be necessary to
1377 avoid long-term scarring.[8] In addition, the use of non-adhesive dressings, topical
1378 corticosteroids and vaginal moulds/dilators can be used to reduce strictures.
1379 [Link] Pain management

1380 In general, most SCAR are not painful with the exception of SJS/TEN. SJS/TEN is an
1381 intensely painful disease and the pain is aggravated by movement and wound manipulation.
1382 Pain severity should be monitored via a visual analogue scale of 0-10. Appropriate analgesia
1383 (paracetamol/acetaminophen, opioids) should be administered with the aim of reducing the
1384 pain score to two or below.
1385 [Link] Monitoring of internal organ complications
1386 SCAR are systemic conditions and the degree and characteristic of internal organ
1387 involvement vary according to the specific type of SCAR. Serial monitoring of routine
1388 investigations such as complete blood count (CBC), liver function tests, renal panel, cardiac
1389 and muscle enzymes may be required. In some setting, imaging studies such as
1390 radiographs, ultrasound, computed tomography and magnetic resonance imaging may be
1391 required. Due to the systemic nature of SCAR, a collaborative, multi-disciplinary approach is
1392 necessary.
1393 [Link].1 AGEP
1394 Systemic complications occur in about 15% of cases of AGEP, with the liver being the most
1395 commonly affected organ. Other affected organs include kidneys, lungs and bone marrow.
1396 These complications are generally mild and typically improve subsequent to medicinal
1397 product withdrawal.[9,10]
1398 [Link].2 DRESS/DIHS

1399 Systemic complications occur in at least 90% of patients and up to 20% of patients may
1400 have more than two organs involved.[11] The onset and clinical course of visceral
1401 involvement may not parallel skin involvement, hence, systematic follow-up and monitoring
1402 are needed. The liver is the most common visceral complication, occurring in up to 50-90%
1403 of cases.
1404 Other organs involved include the kidneys, lungs, cardiac, bone marrow, and central and
1405 peripheral nervous system involvement. Multiple organ involvement, such as pulmonary and
1406 cardiac involvement, and human herpes viral reactivation may confer a poorer
1407 prognosis.[12,13]
1408 [Link].3 SJS/TEN

1409 Systemic complications are common in SJS/TEN and may be renal, pulmonary,
1410 gastrointestinal, or haematologic in nature though can arise in other organs as well.
1411 Pulmonary complications occur in up to 40% of patients and include specific changes such
1412 as trachea/bronchial mucosal sloughing as well as non-specific presentation of infection,
1413 pulmonary oedema and atelectasis.[14] Pulmonary involvement is a poor prognostic factor
1414 for mechanical ventilation and death. Acute renal failure occurs in up to 20% of patients with
1415 SJS/TEN. Risk factors for acute renal failure include sepsis, allopurinol, NSAIDs and
1416 antibiotics as culprit drugs as well as hypoalbuminemia and chronic kidney disease.[15]
33
1417 Disseminated intravascular coagulation occurs in up to 20% of cases, and blood component
1418 transfusion may be necessary.[16] Leukopenia can occur during the acute phase of the
1419 disease and granulocyte-colony stimulating factor (G-CSF) may be required.[17] In view of
1420 multi-organ involvement, facilities and expertise for mechanical ventilation, organ support
1421 and ICU care should be made available.
1422 [Link] Management of bacteraemia

1423 Bacteraemia and sepsis can be SCAR complications, particularly in SJS/TEN. Sepsis
1424 increases the risk of fatal outcomes for SJS/TEN by three- to four-fold and accounts for up to
1425 50% of all fatal outcomes for SJS/TEN.[18,19] The routine use of prophylactic antibiotics is
1426 not recommended in SJS/TEN, however, empirical antibiotics should be started once
1427 infection is suspected. Frequent sampling of the blood and skin may aid in the early
1428 diagnosis and management of bacteraemia.
1429 Hypothermia and raised procalcitonin may be predictive of positive blood cultures.[17] Skin
1430 sampling has a good negative predictive value for bacteraemia. If skin cultures are negative
1431 for Staphylococcal aureus or Pseudomoinas aeruginosa, it is unlikely that the blood cultures
1432 would be positive for such organisms.[20] Antimicrobial therapy should be culture directed,
1433 and dependent on the institutional microbiogram. Initial empirical therapy should include
1434 coverage for Staphylococcal aureus, Pseudomonas aeruginosa and other gram-negative
1435 bacteria. In burn units and ICUs, coverage for nosocomial organisms should be considered.
1436 [Link] Management of ocular complications

1437 Acute eye involvement occurs in up to 80% of patients with SJS/TEN.[21] The presentation
1438 ranges from conjunctival hyperaemia to extensive corneal ulcerations. As such, ophthalmic
1439 review and management during the acute and chronic phase of SJS/TEN is mandatory.
1440 During the acute phase of disease, in addition to topical eye drops such as lubricants,
1441 corticosteroids and antibiotics, systemic corticosteroids and amniotic membrane
1442 transplantation may be p.[22]
1443 [Link] Laboratory tests

1444 In view of systemic complications and the involvement of internal organs in SCAR, various
1445 laboratory tests and investigations may be performed, as indicated.

1446  CBC, renal function, LFT, muscle/cardiac enzymes, thyroid function tests, arterial blood
1447 gases, coagulation profile,
1448  Blood/wound/urine cultures, procalcitonin as indicated,
1449  Hepatitis serology, mycoplasma, chlamydia serology, anti-nuclear antibodies as
1450 indicated (particularly in DRESS),
1451  Human herpes viral serology (HHV6, EBV, CMV) may be needed to confirm diagnosis
1452 as well as a prognostic factor in DIHS/DRESS,
1453  Imaging studies: Ultrasound/computed tomography/magnetic resonance imaging may
1454 be needed to assess for internal organ involvement,
1455  ECG/Echocardiography may be necessary to assess for cardiac involvement.
1456 3.1.4 Specific treatment

1457 Although specific therapy is dependent on the type of SCAR, treatment recommendations
1458 are generally limited by the quality of the evidence.

34
1459 [Link] SJS/TEN

1460 Supportive care remains the cornerstone of management. Current evidence is unable to
1461 support the routine use of any immunomodulatory agent over another. Various
1462 immunomodulatory agents have been proposed. These agents include systemic
1463 corticosteroids, cyclosporine, intravenous immunoglobulins (IVIG) with/without
1464 corticosteroids, anti-tumour necrosis factor (TNF)-alpha with/without corticosteroids and
1465 plasmapheresis. There have been two randomized controlled studies evaluating therapy in
1466 SJS/TEN. The first trial by Wolkenstein et al. evaluated the use of thalidomide, an inhibitor of
1467 TNF-alpha, was prematurely stopped due to increased mortality in the active arm.[23] The
1468 second, by Wang et al., evaluated the efficacy of etanercept, also a TNF-inhibitor, versus
1469 systemic corticosteroids.
1470 There was no significant difference in terms of fatal outcomes, although both interventions
1471 showed a decrease in case fatality compared to that predicted by SCORTEN.[24] Several
1472 recent meta-analysis suggested that cyclosporine, etanercept, systemic corticosteroids as
1473 well as IVIG in combination with corticosteroids may have survival benefits. However, there
1474 was significant heterogeneity in these studies and study quality was poor.[25-27] Until
1475 improved evidence emerges, specific immunomodulatory treatments cannot be
1476 recommended in a routine manner.
1477 [Link] DRESS
1478 There are no randomized trials that evaluate treatment for DRESS. In view of disease
1479 heterogeneity, a step ladder approach has been proposed.[28] In mild disease (no internal
1480 organ involvement, or mild liver involvement), systemic corticosteroids may be withheld and
1481 symptomatic treatment consisting of emollients and potent to ultrapotent topical corticosteroids
1482 may be sufficient.[29] If systemic corticosteroids are used, a slow taper is required to reduce
1483 the likelihood of flares. In severe disease (severe organ involvement, e.g. liver, renal,
1484 pulmonary, neurological, cardiac involvement), systemic corticosteroids are recommended. As
1485 systemic corticosteroid treatment increases the risk of infections, careful surveillance of
1486 infective complications are warranted. Various other immunomodulatory agents suc h as
1487 cyclosporine, IVIG, janus kinase (JAK) inhibitors have been utilized but evidence remains
1488 limited. In addition to immunomodulatory agents, organ support and emergent transplantation
1489 may be required in fulminant cases.
1490 [Link] AGEP
1491 AGEP is generally self-limiting, although in some cases, it may cause fatal oucomes.
1492 Symptomatic treatment with emollients and topical potent to ultrapotent corticosteroids may
1493 suffice.[10,11]
1494 [Link] GBFDE

1495 GBFDE is an extensive, bullous variant of FDE and may be challenging to differentiate from
1496 SJS/TEN. The prognosis of GBFDE is comparable to cases of SJS/TEN matched for age
1497 and extent of epidermal involvement. As such, similar supportive management principles to
1498 SJS/TEN should be carried out.[30] Likewise, supportive care is the most important
1499 component of care. Although the use of various immunomodulators such as corticosteroids
1500 and cyclosporine has been reported, evidence for such treatments remains anecdotal.
1501
1502
1503

35
1504 3.2 Special populations
1505 3.2.1 Paediatric SJS/TEN

1506 The prognosis of paediatric SJS/TEN is better compared to adult cases with an overall case
1507 fatality of 3% in TEN.[31] Unlike adult cases, which are attributed to medications in close to
1508 80-90%, medications account for only 50% of paediatric cases with infections and idiopathic
1509 cases accounting for the rest.[32] As such, investigations evaluating for infective triggers
1510 such as Mycoplasma pneumoniae and Chlamydia pneumoniae, as well as appropriate
1511 antimicrobial treatment is warranted. In addition, recurrences of up to 18% have been
1512 reported,[33] and this may be due to higher incidence of infections as a trigger and possible
1513 misclassification of paediatric cases as EMM, which is more frequently recurrent compared
1514 to TEN.
1515 Similar to the adult population, no immunomodulatory therapy has been shown to confer
1516 conclusive benefit. Whilst adult cases are recommended to be transferred to SJS/TEN
1517 reference centres, in paediatric populations, this may need to be balanced with the
1518 availability of paediatric expertise and facilities.[34]
1519 3.2.2 Pregnancy

1520 SJS/TEN is rare in pregnant patients due to the reduced medicinal product intake during
1521 gestation and younger age. The majority of reports are from HIV-positive patients who
1522 developed the reaction following the use of nevirapine.[35] Acute uro-gynaecological care in
1523 such patients is essential to prevent strictures as well as for normal vaginal delivery after the
1524 initial episode of SJS/TEN. Other specific pregnancy complications include premature labour
1525 and the need for emergent caesarean section, which accounts for up to 50% of all
1526 pregnancies in SJS/TEN.
1527 Specific treatment recommendations mirror that for the general adult population. Maternal-
1528 fetal transmission of SJS/TEN is rare and has been anecdotally reported.[36] In a systematic
1529 review, maternal and neonatal mortality in SJS/TEN has been reported as 2.1% and 4.9%,
1530 respectively.[37] Pregnant cases of SJS/TEN should be managed in facilities with access to
1531 obstetric and neonatal expertise and facilities.
1532 3.2.3 Renal failure

1533 In a multi-centre cohort in the U.S., dialysis prior to presentation of SJS/TEN was the
1534 strongest independent prognostic factor for fatal outcomes (Odds Ratio of 16).[38]
1535 3.2.4 Coloured skin

1536 In the U.S., SJS/TEN was associated with skin colour or genetic factors, particularly Asians
1537 and Blacks with respective odds ratio of 3.3 and 2, respectively.[39] Such differences might
1538 be due to the inherent pharmacogenetic risks in certain ethnicities and the causal medicinal
1539 product. The initial presentation of SCAR may be under-recognized in skin of colour and
1540 may lead to a delay in diagnosis and treat.

36
1541 3.3 cADRs induced by targeted therapy[6] or immunotherapy

1542 The spectrum of cADRs is varied, ranging from common and benign to severe. Such
1543 reactions are typically classified according to the Common Terminology Criteria for Adverse
1544 Events (CTCAE) grading and management is grade dependent. Maculopapular rash or MPE
1545 is the most common presentation, but SCAR such as SJS/TEN have been reported. In
1546 SCAR, immunotherapy should be permanently discontinued.
1547 Prednisolone/methylprednisolone is recommended based on consensus, however, evidence
1548 for this or other immunomodulatory agents is lacking. In severe cases, urgent dermatological
1549 consultation, inpatient care and transfer to reference centres may be necessary.[40]
1550 3.4 Guidance and investigation postreaction

1551 Following the acute phase of the reaction, treatment/management goals include:

1552  Permanent discontinuation of culprit medicinal product, medicinal product allergy notification,
1553 allergy alert/bracelet. Cross-reactive medications to the culprit medicinal product should be
1554 avoided as well. For example, all oxicam NSAIDs such as meloxicam and piroxicam should
1555 be avoided in any case of oxicam NSAID-induced SCAR. Similarly, aromatic anticonvulsants
1556 such as phenytoin, phenobarbital and carbamazepine should be avoided in any aromatic
1557 anticonvulsant-induced SCAR.
1558  Long-term multi-disciplinary follow up to detect and manage any chronic complications
1559 from SCAR. (See also Chapter [Link] and Chapter [Link])
1560 Additional allergological evaluation to confirm medicinal product causality including both skin tests
1561 and in vivo tests may be available in specialty/research centres. (See also Chapter 2.4 and Chapter
1562 5.3.1)
1563
1564 References

1 Garcia-Doval I, et al. Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early w ithdrawal of causative drugs
decrease the risk of death? Arch Dermatol. 2000 Mar;136(3):323-7. PubMed Abstract
2 Stern R. Exanthematous Drug Eruptions. N Engl J Med. 2012 Jun 28;366(26):2492-501. No abstract available
3 Clark AE, et al. Delayed admission to a specialist referral center for Stevens-Johnson syndrome and toxic epidermal necrolysis is
associated w ith increased mortality: A retrospective cohort study. JAAD Int. 2021 May 6;4:[Link] Full Text
4 Traikia C, et al. Individual‐ and hospital‐level factors associated with epidermal necrolysis mortality: a nationw ide multilevel
study, France, 2012–2016. Br J Dermatol. 2020 Apr;182(4):900-906. PubMed Abstract
5 Creamer D, et al. U.K. guidelines for the management of Stevens–Johnson syndrome/toxic epidermal necrolysis in adults
2016. Br J Dermatol. 2016 Jun;174(6):1194-1227. Journal Full Text
6 Dorafshar AH, et al. Antishear therapy for toxic epidermal necrolysis: an alternative treatment approach: Plast Reconstr Surg.
2008 Jul;122(1):[Link] Abstract
7 Haravu PN, Gottlieb LJ, Vrouwe SQ. Antishear Therapy for Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A
Follow -up Study. J Burn Care Res. 2021 Nov/Dec;42(6).p. 1152-1161. PubMed Abstract
8 Meneux E, et al. Vulvovaginal involvement in toxic epidermal necrolysis: a retrospective study of 40 cases. Obstet Gynecol
1998 Feb;91(2):283-7 PubMed Abstract
9 Hotz C, et al. Systemic involvement of acute generalized exanthematous pustulosis: a retrospective study of 58 patients. Br J
Dermatol 2013;169:1223-32. PubMed Abstract
10 Oh DAQ, et al. Acute generalized exanthematous pustulosis: epidemiology, clinical course and treatment outcomes of
patients treated in an Asian academic medical center. JAAD Int 2021 Feb14;3:1-6. PubMed Abstract
11 Kardaun SH, et al. Drug reaction w ith eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug
reaction. Results from the prospective RegiSCAR study. Br J Dermatol 2013 Nov;169(5):1071-80. PubMed Abstract
12 Eshki M, et al. Tw elve-year analysis of severe cases of drug reaction with eosinophilia and systemic symptoms: a cause of
unpredictable multiorgan failure. Arch Dermatol 2009 Jan;145(1):67-72. PubMed Abstract
13 Mizukaw a Y, et al. Drug induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms severity
score: A useful tool for assessing disease severity and predicting fatal cytomegalovirus diseases. J Am Acad Dermatol 2019
Mar;80(3):670-678.e2. PubMed Abtract
14 Lebargy F, et al. Pulmonary complications in toxic epidermal necrolysis: a prospective clinical study. Intensive Care Med.
1997 Dec;23(12):1237-44. PubMed Abstract
15 Hung C-C, et al. Acute renal failure and its risk factors in Stevens-Johnson syndrome and toxic epidermal necrolysis. Am J
Nephrol. 2009;29(6):633-8. PubMed Abstract

6 American Cancer Society Definition of Targeted Therapy

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 16 Chen CB, et al. Disseminated intravascular coagulopathy in Stevens-Johnson syndrome and toxic epidermal necrolysis. J
Am Acad Dermatol. 2021 Jun;84(6):1782-91. PubMed Abstract
17 De Sica-Chapman A, et al. Granulocyte colony-stimulating factor in toxic epidermal necrolysis and Chelsea and
Westminster TEN management protocol. Br J Dermatol. 2010 Apr;162(4):860-5. PubMed Abstract
18 Koh HK, et al. Risk factors and diagnostic markers of bacteremia in Stevens -Johnson syndrome and toxic epidermal
necrolysis: A cohort study of 176 patients. J Am Acad Dermatol. 2019 Sep;81(3):686-693. PubMed Abstract
19 de Prost N, et al. Bacteremia in Stevens-Johnson syndrome and toxic epidermal necrolysis: epidemiology, risk factors, and
predictive value of skin cultures. Medicine. 2010 Jan;89(1):28-36. PubMed Abstract
20 Lecadet A, et al. Incidence of bloodstream infections and predictive value of qualitative and quantitative skin cultures of
patients w ith overlap syndrome or toxic epidermal necrolysis: A retrospective observational cohort study of 98 cases. J Am
Acad Dermatol. 2019 Aug;81(2):342-347. PubMed Abstract
21 Gueudry J, et al. Risk factors for the development of ocular complications of Stevens-Johnson syndrome and toxic
epidermal necrolysis. Arch Dermatol. 2009 Feb;145(2):157-62. PubMed Abstract
22 Kohanim S, et al. Acute and Chronic Ophthalmic Involvement in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis –
A Comprehensive Review and Guide to Therapy. II. Ophthalmic Disease. Ocul Surf. 2016 Apr;14(2):168-88. PubMed Abstract
23 Wolkenstein P, et al. Randomised comparison of thalidomide versus placebo in toxic epidermal necrolysis. The Lancet.
1998;352(9140):1586-9. PubMed Abstract
24 Wang CW, et al. Randomized, controlled trial of TNF-α antagonist in CTL-mediated severe cutaneous adverse reactions. J
Clin Invest. 2018 Mar1;128(3):985-996. PubMed Abstract
25 Zimmermann S, et al. Systemic Immunomodulating Therapies for Stevens-Johnson Syndrome and Toxic Epidermal
Necrolysis: A Systematic Review and Meta-analysis. JAMA Dermatol. 2017 Jun 1;153(6):514-522.
doi:10.1001/jamadermatol.2016.5668. PubMed Abstract
26 Torres-Navarro I, de Unamuno-Bustos B, Botella-Estrada R. Systematic review of BRAF/MEK inhibitors-induced Severe
Cutaneous Adverse Reactions (SCARs). J Eur Acad Dermatol Venereol. 2021 Mar;35(3):[Link] Abstract
27 Tsai T-Y, et [Link] toxic epidermal necrolysis with systemic immunomodulating therapies: A systematic review and netw ork
meta-analysis. J Am Acad Dermatol. 2021 Feb;84(2):[Link] Abstract
28 Cabañas R, et al. Spanish Guidelines for Diagnosis, Management, Treatment, and Prevention of DRESS Syndrome. J
Investig Allergol Clin Immunol. 2020; 30(4):[Link] Abstract
29 Funck-Brentano E, et al. Therapeutic management of DRESS: a retrospective study of 38 cases. J Am Acad Dermatol. 2015
Feb; 72(2):246-52. PubMed Abstract
30 Lipow icz S, et al. Prognosis of generalized bullous fixed drug eruption: comparison w ith Stevens -Johnson syndrome and
toxic epidermal necrolysis. Br J Dermatol. 2013 Apr;168(4):726-32. PubMed Abstract
31 Hsu DY, et al. Pediatric Stevens-Johnson syndrome and toxic epidermal necrolysis in the United States. J Am Acad
Dermatol. 2017 May;76(5):811-817.e4. PubMed Abstract
32 Levi N, et al. Medications as risk factors of Stevens-Johnson syndrome and toxic epidermal necrolysis in children: a pooled
analysis. Pediatrics. 2009 Feb; 123(2): e297-304. PubMed Abstract
33 Finkelstein Y, et al. Recurrence and outcomes of Stevens-Johnson syndrome and toxic epidermal necrolysis in children.
Pediatrics. 2011 Oct;128(4):723-8. PubMed Abstract
34 McPherson T, et al. British Association of Dermatologists’ guidelines for the management of Stevens -Johnson syndrome/toxic
epidermal necrolysis in children and young people. Br J Dermatol. 2019 Jul;181(1):37-54. PubMed Abstract
35 Knight L, et al. Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Maternal and Foetal outcomes in tw enty-two
consecutive pregnant HIV infected w omen. PLoS oNE 2015;10:[Link] Full Text
36 Rodriguez G, et al. Toxic epidermal necrolysis in a mother and fetus. J Am Acad Dermatol. 2006 Nov;55:S96-S98 Journal Full Text
37 Sharma AN, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis in pregnant patients: A systematic review. Int
J Womens Dermatol. 2020 Apr;13;6(4):239-247. PubMed Abstract
38 Noe M, et al. Development and Validation of a Risk Prediction Model for In-Hospital Mortality Among Patients With Stevens-
Johnson Syndrome/Toxic Epidermal Necrolysis – ABCD-10. JAMA Dermatol. 2019 Apr 1;155(4):448-454. PubMed Abstract
39 Hsu D, et al. Morbidity and Mortality of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in United States Adults.
J Invest Dermatol. 2016 Jul;136(7):1387-1397. PubMed Abstract
40 Thompson JA, et al. Management of Immunotherapy-Related Toxicities, Version 1.2019, J Natl Compr Canc Netw . 2019 Mar
1;17(3):255-289. PubMed Abstract
1565

38
1566 CHAPTER 4.
1567 BIOMARKERS FOR SCAR
1568 Chapter summary
1569 Life-threatening ADRs should be routinely reported to identify possible biomarkers
1570 associated with the reaction, but underreporting is a major limitation in the real world.
1571 Additionally, the understanding of all the factors associated with disease progression and the
1572 long-term outcomes of ADRs is limited. Therefore, collaborative efforts are needed to
1573 improve global surveillance to decrease reporting bias and provide more accurate estimates
1574 of disease epidemiology, causes and effects of the disease.[1] In addition, it is critical to
1575 collect biospecimens from incident cases at various time points, and follow patients long-
1576 term to ascertain outcomes, so that biomarker discovery efforts can take advantage of more
1577 complete and comprehensive data to discover and validate biomarker-based approaches to
1578 guide care.
1579 Conclusions or recommendations
1580 Race and ethnicity have been recognized as a major factor contributing to interindividual
1581 variability in response. For example, abacavir hypersensitivity syndrome is more prevalent in
1582 white populations due to a higher frequency of the HLA-B*57:01 allele in this population,
1583 whereas the frequency of carriers of the HLA-B*58:01 allele is higher in Asian
1584 populations.[2-4] The predictive value of any biomarker depends on the frequencies of that
1585 marker and the associated ADR in the study population.[3] For this reason, further research
1586 is needed to identify genomic markers for particular demographic clusters in admixed
1587 populations that may have increased risk for developing certain ADRs.
1588 Except for HLA-B*1502/carbamazepine in some Asian populations, HLA testing is not yet
1589 being routinely performed pre-emptively in clinical practice.[4] Large randomized controlled
1590 pharmacogenomic (PGx) trials are often expected to show the clinical utility of HLA testing,
1591 but this may not be feasible for such rare ADRs. Additional implementation studies will
1592 further characterize barriers to testing and find the best solutions, such as overcoming
1593 obstacles in information technology and infrastructure, translating raw genotyping lab results
1594 to actionable information to guide prescribing and improving HCP awareness and education.

1595 4.1 Introduction

1596 SCAR such as SJS/TEN, and DRESS are associated with significant patient morbidity and
1597 mortality. These ADRs are the result of complex, heterogeneous, and distinct immunological
1598 responses following exposure to various medicinal products. Leveraging the knowledge of
1599 biomarkers to predict the risk of SCAR or its outcome can greatly improve the safe use of
1600 medications. A great deal of progress has been made in understanding the biological
1601 underpinnings of SJS/TEN and other forms of SCAR to enable the development of
1602 biomarkers that may be used across the continuum of patient care to mitigate risks and
1603 improve outcomes .
1604 A biomarker is “a characteristic that is objectively measured as an indicator of normal
1605 biological processes, pathogenic processes, or biological responses to an exposure or
1606 intervention, including therapeutic interventions.” To that extent, biomarkers may include
1607 molecular, histologic, radiographic or physiologic characteristics.[5] Safety biomarkers, a
1608 category of biomarkers, are “biomarkers measured before or after an exposure to a medical
1609 product or an environmental agent to indicate the likelihood, presence, or extent of toxicity
1610 as an adverse effect.”[5]

39
1611 Safety biomarkers can be used to identify patients in whom initiation of a particular medicinal
1612 product may lead to significant risk of ADR, such as different HLA alleles or polymorphisms
1613 in medicinal product-metabolizing encoding genes;[6-8] when used in this way, this type of
1614 biomarker may also be referred to as a predictive biomarker. Safety biomarkers also may be
1615 used to detect or monitor ADRs (e.g. when tissue damage occurs, certain proteins may be
1616 detectable in the blood like transaminase elevations in the setting of liver injury); when used
1617 in this way this type of biomarker may also be referred to as a monitoring biomarker. In
1618 addition, biomarkers may be used as part of the diagnostic evaluation to confirm the
1619 presence of a particular ADR, and once diagnosed, to evaluate prognosis or the likelihood of
1620 a particular outcome. The functions of a biomarker are not mutually exclusive; a biomarker
1621 that is used for diagnosis may also predict response to certain therapies.
1622 Overall, biomarkers can play a critical role in 1) identifying patient populations who are more
1623 likely to respond to medical treatments and those who are susceptible to ADRs, both of
1624 which are major goals of precision medicine, 2) enabling early diagnosis to distinguish SCAR
1625 from less critical conditions before significant damage occurs, and 3) characterizing the likely
1626 course of progression. Therefore, this chapter provides an overview of biomarkers that have
1627 been scientifically validated to predict the risk of SCAR, as well as some areas of continued
1628 biomarker development, to maximize the benefits and reduce the risk of harm associated
1629 with administering medicinal products.
1630 4.2 HLA and immune-related genetic biomarkers

1631 The most extensively studied biomarkers for SCAR risk are genetic variations in the HLA
1632 system. The HLA system is a member of the MHC, a region of the human genome located
1633 on the short arm of chromosome 6p21.3. HLA is a highly polymorphic gene system and an
1634 important modulator for immune responses and hypersensitivity reactions to specific
1635 medicinal products. HLA antigens are expressed on the surface of many cells and play a
1636 major role in self-recognition, evoking the immune response to an antigenic stimulus and the
1637 orchestration of cellular and humoral immunity.[9]
1638 Because HLA molecules need to present such a wide variety of “self” and “non-self”
1639 molecules, the HLA genes are both numerous and highly polymorphic. More than 9000 HLA-
1640 B alleles have been identified and could play a significant role in the pathogenesis of many
1641 immunologic ADRs.[10] For example, HLA-B variants have been associated with severe
1642 hypersensitivity reactions to abacavir, allopurinol, carbamazepine and phenytoin.[6,11,12]
1643 HLA-B molecules present endogenous or processed exogenous antigens to T cells, thereby
1644 eliciting an adaptive immune response. HLA restriction is required for the activation of
1645 medicinal product-specific T cells by the culprit medicinal product. The T-cell receptor of the
1646 effector T cell is thought to recognize the medicinal product–peptide complex bound by the
1647 specific HLA-B molecule on the antigen presenting cell, resulting in the release of immune
1648 mediators and leading to robust adaptive immune reactions such as SCAR.[13] The
1649 relationships between different HLA alleles and the risk of medicinal product-induced
1650 SJS/TEN, DRESS and other skin reactions are well established and guidelines for genetic
1651 testing have been developed in some regions of the world with high frequencies of certain
1652 HLA alleles.[6-15] The most widely reported HLA genotypes associated with SCARs include
1653 HLA-B*15:02 for carbamazepine and phenytoin (Han Chinese), HLA-A*31:01 for
1654 carbamazepine (Europeans and Koreans), HLA-B*58:01 for allopurinol (East Asians), HLA-
1655 B*59:01 for methazolamide (Koreans and Japanese), and HLA-B*13:01 for dapsone
1656 (Asians).[16,17] The following sections summarize available evidence related to
1657 predisposing genetic factors for selected medicinal products and SCAR-related events.
1658

40
1659 4.2.1 SJS/TEN

1660 The development of SJS/TEN in response to medicinal product exposure is the result of
1661 many genetic and non-genetic factors.[13] While the exact immunohistopathology of
1662 SJS/TEN is not fully understood, a variety of factors and characteristics are implicated.
1663 Medicinal product-specific CD8+ T cells and NK cells have been shown to be the major
1664 inducer of keratinocyte apoptosis. Specific T-cell receptors recognize a medicinal product (or
1665 its metabolites) presented by specific HLA alleles, which can lead to activation of medicinal
1666 product-induced cytotoxic T cells with release of multiple cytokines, chemokines, signals, and
1667 soluble cytotoxic mediators, such as Fas-Fas ligand, granulysin, perforin, granzyme B and
1668 tumour necrosis factor alpha (TNF-α).[13] The IL-15 cytokine, a major NK cell priming signal,
1669 passes through the JAK-STAT pathway with downstream effects on the PI3K/AKT/mTOR
1670 pathway and with effects on NK and CD8+ T cells, playing a vital role in most cellular
1671 processes, such as proliferation, adhesion, migration and invasion.[18,19]
1672 Numerous studies have demonstrated a strong association between select HLA alleles and
1673 drug-induced SCAR.[20] A sampling of different alleles that have been identified as risk
1674 factors for SJS/TEN in different populations are summarized in Table 5.
Drug Risk alleles Populations Studied

Allopurinol A*32:02, B*58:01, C*03:02 European, Korean, Vietnamese, Han

Chinese, Japanese, Thai
Carbamazepine A*24:02, A*31:01, B*15:02, B*15:11, European, Han Chinese, Japanese,
B*15:21, B*57:01 Korean, Indian, Malaysian, Thai,
Taiwanese, Filipino
Lamotrigine A*31:01, A*68:01, B*58:01, C*07:18, Han Chinese, European, Thai, Korean
DQB1*06, DRB1*13
Methazolamide B*55:02, B*59:01 Han Chinese, Japanese, Korean
Phenytoin B*13:01, B*15:02, B*56:02, B*15:13, East Asian, Han Chinese, Malaysian,
Cw*08:01, DRB1*1602 Thai
Sulfamethoxazole A*29, B*38, B*44, DR*07, A*11:01 European, Japanese
1675 Table 5. HLA alleles associated with SJS/TEN
1676 Adapted from Gibson, et al. 2023[20]
1677 Permission obtained from Elsevier

1678 Chung, et al. were the first to identify an association between carbamazepine-induced
1679 SJS/TEN and HLA genetic polymorphisms, particularly the HLA-B*15:02 allele, in Han
1680 Chinese patients in Taiwan, with 100% sensitivity and 97% specificity.[21] This finding has
1681 been replicated in a large number of populations in Southeast Asia. Even though SJS/TEN is
1682 an infrequent AE, the risk is significant among carriers of the HLA-B*15:02 allele (OR 26.01;
1683 95% CI 15.88–42.60; p < 0.00001) in meta-analyses of data from different populations.[22]
1684 While the incidence of SJS/TEN is lower in non-Asian populations, efforts have uncovered
1685 additional genetic variants that increase the risk for SJS/TEN in carbamazepine-treated
1686 patients. Specifically, HLA-A*31:01 was reported to be a significant risk factor in European
1687 populations, although the relative risk is much more modest than that observed for HLA-
1688 B*15:02.[22] Several similar studies have also demonstrated that HLA-B*15:02 is also with a
1689 higher risk of SJS/TEN in patients treated with phenytoin. In addition, drugs that are
1690 structurally related to carbamazepine such as oxcarbazepine and eslicarbazepine also likely
1691 carry the same risk, and experimental studies have identified structural elements that
1692 selectively interact with HLA-B*15:02.[23] As such, many anti-epileptics carry some shared
1693 HLA-related risk for developing SJS/TEN.
1694

41
1695 Collectively, these findings represent an opportunity for broader implementation of routine
1696 HLA genotyping in clinical practice to prevent medicinal product-induced SCAR and reinforce
1697 the need for racial and ethnic diversity in developing and validating novel biomarkers to
1698 optimally manage ADRs. Following extensive replication of HLA alleles as a risk factor for
1699 SJS/TEN, certain geographical regions have implemented prospective genetic testing prior to
1700 administration of carbamazepine. A study including 23 hospitals in Taiwan demonstrated
1701 reductions in the incidence of carbamazepine induced SJS/TEN by screening patients for
1702 HLA-B*15:02 and avoidance of carbamazepine in HLA-B*15:02 carriers.[24] Unfortunately,
1703 the overall incidence of SJS/TEN was not reduced in part because of a shift to other drugs
1704 that also cause SJS/TEN.[25]
1705 Allopurinol, a widely prescribed drug for the management of gout and hyperuricemia, is
1706 another major cause of SJS/TEN. Extensive studies have linked SJS/TEN induced by
1707 allopurinol to genetic polymorphisms in the HLA system, mainly HLA-B*58:01.[26] For
1708 example, a study investigated the relationship between SJS/TEN and HLA-B*58:01 in a Thai
1709 population that has a high allelic frequency of this allele. Twenty-seven allopurinol-induced
1710 SJS/TEN and 54 allopurinol-tolerant patients were enrolled in the study. The presence of HLA-
1711 B*58:01 and HLA-B genotypes in these patients were analysed. All 27 (100%) allopurinol-
1712 induced SJS/TEN patients who were examined carried HLA-B*58:01 whereas only seven
1713 (12.96%) of the control patients had this allele. The risk of allopurinol-induced SJS/TEN was
1714 significantly greater in patients with HLA-B*58:01 when compared with those who did not carry
1715 this allele, with an odds ratio of 348.3 (95% confidence interval=19.2-6336.9, P = 1.6×10−13).
1716 The sensitivity and specificity of the HLA-B*58:01 allele for prediction of allopurinol-induced
1717 SJS/TEN were 100% and 87%, respectively.[27]. This association however is less strong in
1718 Japanese where only 36–40% of allopurinol-induced SCAR patients are HLA-B*58:01 positive,
1719 or in European patients where only 55–64% of patients with SJS/TEN carry this allele.
1720 Although the frequency of HLA-B*58:01 in different populations varies significantly (up to 20%
1721 in Taiwan and less than 2% in Europeans), which consequently influence the frequency of
1722 SCAR in the different populations, race and ethnicity also seems to have some influence on
1723 the capacity to develop this reaction.[25,28] The percent of HLA-B*58:01 negative individuals
1724 with allopurinol-induced SCAR is higher in Europeans and Japanese, suggesting other
1725 possible risk factors.[29]
1726 To evaluate the use of prospective screening for the HLA-B*58:01 allele to identify
1727 Taiwanese individuals at risk of SCARs induced by allopurinol treatment, a national cohort
1728 study enrolled 2926 people who had an indication for allopurinol treatment but had not
1729 previously taken allopurinol.[30] Participants who tested positive for HLA-B*58:01 (19.6%,
1730 n=571) were advised to avoid allopurinol and were referred to an alternate drug treatment or
1731 advised to continue with their study treatment. SCAR did not develop in any of the
1732 participants receiving allopurinol who screened negative for HLA-B*58:01.[30] By contrast,
1733 seven cases of SCAR were expected, based on the estimated historical incidence of
1734 allopurinol-induced SCARs nationwide (0.30% per year, 95% confidence interval 0.28-
1735 0.31%; P=0.0026).[30]
1736 These results suggest that HLA-B*58:01 screening of about 110,000 new users of allopurinol
1737 in Taiwan each year could prevent about 330 cases of allopurinol-induced SCARs every
1738 year.[30] Prospective screening of the HLA-B*58:01 allele, coupled with an alternative
1739 medicinal product treatment for carriers, could significantly decrease the incidence of
1740 allopurinol-induced SCAR in high-risk patients.
1741
1742

42
1743 From a pathophysiological standpoint, trigger medicinal products are thought to constitute
1744 the main target of the immune response. However, the strength of association between
1745 medicinal products and SJS/TEN is modulated by interindividual and interethnic variations in
1746 the HLA repertoire. In fact, distinct HLA variants might segregate with selected ethnicities
1747 and different ancestral population groups. Additional inherited factors may promote altered
1748 medicinal product metabolism and variably combine with HLA-related factors to contribute to
1749 SJS/TEN susceptibility.[31]
1750 4.2.2 DRESS

1751 In drug hypersensitivity, several models were proposed for recognition of the small drug
1752 compounds by T cells with subsequent initiation of the immune response. Traditionally,
1753 DRESS is classified as a type IVb reaction that corresponds with CD8+ and CD4+ T-cell
1754 responses underlying the production of interferon-γ, IL-4, IL-5, and IL-13, resulting in
1755 eosinophilia.[32] DRESS is a complex syndrome with a broad spectrum of clinical features.
1756 As with SJS/TEN, several studies have been conducted to identify genetic susceptibilities to
1757 DRESS in various populations. HLA-A*31:01 has surfaced in a several studies of patients
1758 with Chinese, Japanese, European and North African ancestry as a risk factor for
1759 carbamazepine-induced DRESS. Other similar studies have been conducted to compare
1760 HLA allele frequencies in population or tolerant controls.[20] Selected drugs where multiple
1761 loci have been identified are shown in Table 6.
Drug Risk alleles Populations studied
Korean, European, Han Chinese, Thai,
Allopurinol A*32:02, B*58:01, C*03:02 Vietnamese
Japanese, European, Han Chinese,
Carbamazepine A*31:01, B*15:11, B*58:01 Korean
A*02:07, A*31:01, A*68:01, B*58:01,
Lamotrigine C*07:18, DQB1*06, DRB1*13 European, Thai, Korean
Nevirapine C*08:02, B*14:02, CW4, DRB1*01:01 Japanese, European, Han Chinese
Sulfamethoxazole A*11:01, B*13:01 Japanese, Asian, Han Chinese
1762 Table 6. HLA alleles associated with DRESS
1763 Adapted from Gibson, et al. 2023[20]
1764 Permission obtained from Elsevier

1765 For vancomycin, a study was conducted through an EHR-connected biobank that was
1766 coupled with prospective case ascertainment, in which 23 cases of DRESS were compared
1767 to 46 matched, vancomycin-tolerant controls. HLA-A*32:01 was present in 83% of the cases
1768 and none of the controls (p=1x10-8). In an enzyme linked immunosorbent spot (ELISpot)
1769 assay wherein case or control peripheral blood mononuclear cells were incubated with
1770 vancomycin showed that almost all ELISpot-positive cases carried HLA-A*32:01 (11/12,
1771 92%) but none of 24 controls. In silico molecular docking analysis was used to evaluate
1772 interactions between HLA-A*32:01 and vancomycin, showing that vancomycin can
1773 potentially bind the antigen binding clef of this variant.[33]
1774 4.2.3 AGEP

1775 AGEP is a SCAR characterized by the acute onset of many pinpoint (< 5 mm), non-follicular
1776 sterile pustules scattered on edematous and erythematous skin.[34,35] The pathophysiology
1777 of AGEP has been classified as an immune T cell-mediated disease.[35] This immune
1778 process is initiated upon exposure to an offending agent, leading to formation of a medicinal
1779 product epitope by antigen presenting cells. This causes activation and proliferation of
1780 medicinal product-specific CD4+ and CD8+ T cells and the subsequent release of cytotoxic
1781 proteins such as perforin, granzyme B and Fas ligand.

43
1782 These cytotoxic proteins induce apoptosis of keratinocytes in the epidermis, resulting in
1783 tissue destruction and vesical formation. The CD4+ T cells release an increasing amount of
1784 C-X-C motif chemokine ligand 8 (CXCL8), INF-γ, and granulocyte/macrophage colony-
1785 stimulating factor (GM-CSF). CXCL8 is a potent neutrophilic chemotactic cytokine that
1786 recruits neutrophils into the vesicles and transforms the vesicles into sterile pustules.
1787 Increased levels of INF-γ and GM-CSF synergistically enhances viability of neutrophils and
1788 amplifies formation of sterile pustules.
1789 Very little information is available regarding clinical biomarkers for AGEP. A recent case
1790 series identified variants in the IL36 receptor antagonist (IL36RN) gene that may have
1791 potential significance in the pathogenesis of AGEP.[36] IL-36 R blocks pro-inflammatory
1792 cytokines IL-36-α, -β and -γ. Variants in the IL36RN gene results in increased downstream
1793 production and release of these pro-inflammatory cytokines and chemokines such as IL-1,
1794 IL-6, IL-12, IL-23 and IL-17, leading to inflammation and potentially a predisposition to
1795 AGEP.[36] However, while psoriasis was not documented in any of the cases in this study,
1796 IL36RN variants are also present in generalized pustular psoriasis, which could potentially
1797 be a confounding factor.
1798 4.2 Medicinal product metabolism-related genetic biomarkers

1799 Polymorphisms in the genes encoding medicinal product-metabolizing enzymes or medicinal

1800 product-transporter proteins can significantly influence systemic concentrations of medicinal
1801 products, and for many medicinal products variability in systemic exposure can result in
1802 ADRs. To this end, the inter-individual variability in medicinal product metabolism and the
1803 formation of active metabolites could modulate this degree of engagement between the
1804 HLA-B molecule and T cells.
1805 Cytochrome P450 (CYP) 2C9 (CYP2C9) is a drug metabolizing enzyme that is involved in
1806 the metabolism of numerous drugs, notably phenytoin. A genome-wide association study
1807 (GWAS) that compared differences in the frequency of nearly one million variants in 48
1808 SJS/TEN cases and 130 tolerant controls (from Taiwan, Japan and Malaysia), found that the
1809 CYP2C9*3 variant, which results in an amino acid change (p.Ile359Leu) and decreases
1810 enzyme activity, was overrepresented in patients who received phenytoin and developed
1811 SJS/TEN compared to phenytoin-tolerant controls (from Taiwan, Japan and Malaysia).[37]
1812 Additional studies confirmed this finding, and a subsequent meta-analysis has shown a
1813 significant association between phenytoin induced SJS/TEN and CYP2C9*3, especially in
1814 the Thai population.[38] Phenytoin is primarily metabolized to an inactive metabolite by
1815 CYP2C9, and therefore, reduced CYP2C9 activity leads to higher systemic phenytoin
1816 concentrations, which may increase the risk of SCAR. Patients who are intermediate or poor
1817 metabolizers of CYP2C9 (e.g. have variant genotypes such as *1/*3, *2/*2 or *3/*3, which
1818 reduce CYP2C9 activity) exhibit higher plasma phenytoin concentrations compared to
1819 patients who are normal metabolizers (e.g. *1/*1).[12]
1820 The GWAS also found that patients with SJS/TEN had higher phenytoin concentrations than
1821 tolerant controls. Thus, patients who are known to be intermediate or poor metabolizers may
1822 ultimately require lower doses of phenytoin to maintain similar steady-state concentrations
1823 compared to normal metabolizers, and higher concentrations may increase the risk for
1824 SCAR.

44
1825 DRESS is a severe T-cell-mediated hypersensitivity reaction to a medication or its active
1826 metabolites, which may be associated with enzymatic defects in drug metabolism.[39]
1827 Polymorphisms in genes encoding drug-metabolizing enzymes, such as CYP enzymes,
1828 N-acetyltransferase or drug transporter proteins have been associated with several ADRs
1829 and may possibly contribute to the pathogenesis of DRESS.[7,13]
1830 The GWAS that identified CYP2C9*3 as a significant risk factor for SJS/TEN also showed
1831 that DRESS risk was increased among CYP2C9*3 carriers.[40]
1832 The precise mechanism by which CYP2C9 variants increase SCAR risk in phenytoin treated
1833 patients is not established though it appears to be related to drug or metabolite
1834 concentrations. A study involving the immediate reactions to metamizole identified an
1835 association between the higher frequency of slow arylamine N-acetyltransferase type 2
1836 (activity (commonly referred to as slow acetylators) and the increased risk of
1837 agranulocytosis.[13,41] Impairment of these enzymes causes a reduced degradation of toxic
1838 metabolites such as 4-methylaminoantipyrine or 4-aminoantipyrine.[41] As such, other
1839 metabolic disturbances that result in the accumulation of immunogenic metabolites could be
1840 at play. Other medications including aromatic anticonvulsants are metabolized by the hepatic
1841 CYP450 enzymes and oxidation by aromatic hydroxylase may produce the arene oxides,
1842 which are the toxic metabolites.[42] Overall, alteration in the activity of drug-metabolizing
1843 enzymes leads to the accumulation of toxic metabolites which dysregulate the immune
1844 response, stimulating cell necrosis and/or apoptosis.[13]
1845 4.3 Circulating and tissue specific biomarkers to aid in the clinical evaluation of SCAR

1846 Numerous studies have identified potential biomarkers in serum or skin (including blister
1847 fluid) that are diagnostic, prognostic or predictive. Granulysin has emerged as a biomarker
1848 that is present in various forms of SCAR. Granulysin is a cytotoxic molecule that is released
1849 from cytotoxic T lymphocytes and natural killer cells that plays a role in host defenses
1850 against pathogens. Granulysin is present in the blister fluid of patients with SJS/TEN and
1851 was shown to be toxic to keratinocytes.[43] Histopathology studies have also shown higher
1852 skin granulysin expression in various forms of SCAR, including SJS/TEN and DRESS,[44]
1853 and it is also found in the serum of patients with SJS/TEN.[45] While granulysin appears to
1854 not be specific to SJS/TEN it could be an earlier indicator of SCAR. Similarly, several studies
1855 have also shown that various other immune mediators such as soluble Fas ligand[46]
1856 granzyme B, and perforin[47] are also consistently elevated among patients with SCAR at
1857 various stages following clinical presentation. A body of literature is also available to suggest
1858 that various cytokines may be detected. However, the data for most biomarkers are less
1859 consistent with respect to correlations with disease severity and prognosis. It is possible that
1860 multicomponent biomarkers could be developed to differentiate SCAR from less severe skin
1861 reactions, the likelihood of progression to TEN and potentially long-term outcomes.[48,49]
1862 Similar studies have also been conducted in DRESS. Biomarkers that have demonstrated
1863 promise include granulysin, TARC/CCL/17, soluble ST2, sOX40, CCL-27, IL15, galectin-7,
1864 RIP-3, and a variety of cytokines, which have been measured in either serum or skin lesions,
1865 some of which appear to track with disease onset and severity.[32,48,49]
1866 Beyond the traditional drug specific immune response, DRESS can be also sustained by
1867 viral reactivation.[50] Clinical viral reactivation occurs up to two weeks after the onset of
1868 DRESS symptoms and is associated with worse prognosis in disease duration, relapse,
1869 constitutional symptoms and organ involvement compared with patients with no viral
1870 reactivation.[50]
1871
1872
45
1873 Viral reactivation may take part in DRESS pathogenesis in the following four ways:

1874  direct organ damage,

1875  induction of antiviral immune responses,
1876  enhancement of systemic inflammation reactivation due to immune cell
1877 proliferation.[50]
1878 A typical feature of DRESS is the reactivation of latent HHV), namely HHV6, HHV7, EBV,
1879 and CMV. High viral load and antibody titres are considered poor prognostic markers in
1880 DRESS treatment outcomes.[13,50] DRESS is the result of complex interplay of genetic
1881 factors, especially HLA alleles, immunological response (T cell), and abnormality of
1882 medicinal product metabolizing enzymes and herpesviruses family member reactivation
1883 (HHV6, HHV7, EBV, CMV).[13,50] Nevertheless, clinical viral reactivation is a probable
1884 cause of chronic recurrence of DRESS-related skin rash despite cessation of the culprit
1885 medicinal product.[13,50]
1886 4.4 Developing and implementing biomarker testing recommendations
1887 Prescribing guidelines generated by different national and international working groups for
1888 translation of HLA-pharmacogenetic testing into clinical practice are operational in many
1889 countries. The Clinical Pharmacogenomics Implementation Consortium (CPIC) and the
1890 Dutch Pharmacogenomics Working Group ([Link] have written
1891 prescribing guidelines based on HLA genotype for carbamazepine,[51,52]
1892 oxcarbazepine,[51,52] phenytoin,[12] allopurinol, [6,53] flucloxacillin[52] and lamotrigine.[52]
1893 Genetic testing coupled with a robust clinical decision support system may enable clinicians
1894 to optimize medicinal product selection. To this end, these genotype-based treatment
1895 guidelines may help to facilitate the use of pharmacogenetic tests for patient care. However,
1896 testing is not routine in many parts of the world primarily because of the rarity of SCAR.
1897 Alternatively, in regions where the incidence is lower, testing may be targeted to certain
1898 subsets of patients in which the allele frequency and risk for the ADR is higher. An example
1899 of this is seen for carbamazepine where regulatory authorities have incorporated testing
1900 recommendations in medicinal product labelling for patients of Asian ancestry:
1901
Carbamazepine Boxed Warning (U.S. Prescribing Information):
SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS,
INCLUDING TOXIC EPIDERMAL NECROLYSIS (TEN) AND STEVENS-
JOHNSON SYNDROME (SJS), HAVE BEEN REPORTED DURING TREATMENT
WITH [CARBAMAZEPINE]. THESE REACTIONS ARE ESTIMATED TO OCCUR
IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN
POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED
TO BE ABOUT 10 TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE
ANCESTRY HAVE FOUND A STRONG ASSOCIATION BETWEEN THE RISK OF
DEVELOPING SJS/TEN AND THE PRESENCE OF HLA-B*1502, AN INHERITED
ALLELIC VARIANT OF THE HLA-B GENE. HLA-B*1502 IS FOUND ALMOST
EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF
ASIA. PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS
SHOULD BE SCREENED FOR THE PRESENCE OF HLA-B*1502 PRIOR TO
INITIATING TREATMENT WITH [CARBAMAZEPINE]. PATIENTS TESTING
POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH
[CARBAMAZEPINE] UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK
(SEE WARNINGS AND PRECAUTIONS, LABORATORY TESTS).

1902 Novartis Pharmaceuticals. “Tegretol (Package Insert).” (2023).

46
1903 Race and ethnicity have been recognized as a major factor contributing to interindividual
1904 variability in SCAR. For example, abacavir-hypersensitivity syndrome is more prevalent in
1905 white populations due to a higher frequency of the HLA-B*57:01 allele in this population,
1906 whereas the frequency of carriers of the HLA-B*58:01 allele is higher in Asian
1907 populations.[54-,55,56] The predictive value of any biomarker depends on the frequencies of
1908 that marker and the associated ADR in the study population.[55] For this reason, further
1909 research is needed to identify genomic markers for particular demographic clusters in
1910 admixed populations that may have increased risk for developing certain ADRs.
1911 Regardless of the approach, biomarker testing recommendations from regulatory authorities
1912 or developers of clinical guidelines have to consider many factors including: 1) the extent of
1913 evidence to support the association and information on the relevant population, because the
1914 rarity of the events makes populations studies difficult to conduct so experimental evidence
1915 and replication of findings is critical; 2) allele distributions for genetic factors because the
1916 frequency of variants that increase risk may vary widely based on ancestry; 3) screening
1917 considerations because the rarity of events tends to make the yield of screening quite low so
1918 identification of multiple factors that increase risk can help make testing more efficient; 4)
1919 clinical recommendations to guide prescribing because the potential benefits and risks of
1920 alternative treatment strategies may influence outcomes; and 5) uncertainty and limitations
1921 because any predictor of SJS/TEN or other SCAR is likely to be imperfect and patients may
1922 remain at risk despite having negative test results.
1923 Application of HLA genotyping as a screening tool has significant limitations and should
1924 never be a substitute for appropriate clinical vigilance and individualized patient
1925 management. Clinicians should diligently monitor patients for development of
1926 hypersensitivity reactions, regardless of the absence or presence of a biomarker associated
1927 with the ADR.
1928 Additionally, other factors can contribute to the risk for development of an ADR, such as
1929 medicinal product dose and duration, concomitant medications and the risk for drug-drug
1930 interactions, comorbidities, age and environmental factors. Therefore, clinicians should
1931 consider the totality of information and manage each patient individually.
1932 The evidence base for other circulating and tissue biomarkers has not yet reached a level to
1933 support routine clinical testing yet remain an area of ongoing research.
1934
1935
1936
1937
1938
1939
1940 References

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Taiw an: national prospective cohort study. BMJ, 2015. 351: p. h4848. BMJ Abstract and Full Text
31 Lerch, M., et al., Current Perspectives on Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Clin Rev Allergy
Immunol, 2018. 54(1): p. 147-176. PubMed Abstract
32 Chen, C.B., et al., Advances in understanding of the pathogenesis and therapeutic implications of drug reaction w ith
eosinophilia and systemic symptoms: an updated review. Front Med (Lausanne), 2023. 10: p. 1187937. Frontiers Full Text
33 Konvinse, K.C., et al., HLA-A*32:01 is strongly associated with vancomycin-induced drug reaction with eosinophilia and
systemic symptoms. J Allergy Clin Immunol, 2019. 144(1): p. 183-192. PubMed Abstract
34 Szatkow ski, J. and R.A. Schw artz, Acute generalized exanthematous pustulosis (AGEP): A review and update. J Am Acad
Dermatol, 2015. 73(5): p. 843-8. PubMed Abstract
35 Sussman, M., et al., Pustular Psoriasis and Acute Generalized Exanthematous Pustulosis. Medicina (Kaunas), 2021. 57(10).
PubMed Abstract
36 Feldmeyer, L., K. Heidemeyer, and N. Yaw alkar, Acute Generalized Exanthematous Pustulosis: Pathogenesis, Genetic
Background, Clinical Variants and Therapy. Int J Mol Sci, 2016. 17(8). PubMed Abstract
37 Chung, W.H., et al., Genetic variants associated with phenytoin-related severe cutaneous adverse reactions. JAMA, 2014.
312(5): p. 525-34. PubMed Abstract
38 Wu, X., W. Liu, and W. Zhou, Association of CYP2C9*3 w ith phenytoin-induced Stevens-Johnson syndrome and toxic
epidermal necrolysis: A systematic review and meta-analysis. J Clin Pharm Ther, 2018. 43(3): p. 408-413. Wiley Summary
39 Choudhary, S., et al., Drug Reaction w ith Eosinophilia and Systemic Symptoms (DRESS) Syndrome. J Clin Aesthet
Dermatol, 2013. 6(6): p. 31-7. PubMed Abstract
40 Suvichapanich, S., et al., Association analysis of CYP2C9*3 and phenytoin-induced severe cutaneous adverse reactions
(SCARs) in Thai epilepsy children. J Hum Genet, 2015. 60(8): p. 413-7. PubMed Abstract
41 Radulovic, I., et al., NAT2 polymorphisms as a cause of metamizole-induced agranulocytosis. Pharmacogenet Genomics,
2021. 31(6): p. 140-143. PubMed Abstract
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 42 Vazquez, M., P. Fagiolino, and E.L. Marino, Concentration-dependent mechanisms of adverse drug reactions in epilepsy.
Curr Pharm Des, 2013. 19(38): p. 6802-8. PubMed Abstract
43 Chung, W.H., et al., Granulysin is a key mediator for disseminated keratinocyte death in Stevens -Johnson syndrome and
toxic epidermal necrolysis. Nat Med, 2008. 14(12): p. 1343-50. PubMed Abstract
44 Weinborn, M., et al., Histopathological study of six types of adverse cutaneous drug reactions using granulysin expression.
Int J Dermatol, 2016. 55(11): p. 1225-1233. PubMed Abstract
45 Abe, R., et al., Granulysin as a marker for early diagnosis of the Stevens -Johnson syndrome. Ann Intern Med, 2009. 151(7):
p. 514-5. No abstract available.
46 Murata, J., R. Abe, and H. Shimizu, Increased soluble Fas ligand levels in patients w ith Stevens -Johnson syndrome and
toxic epidermal necrolysis preceding skin detachment. J Allergy Clin Immunol, 2008. 122(5): p. 992-1000. PubMed Abstract
47 Posadas, S.J., et al., Delayed reactions to drugs show levels of perforin, granzyme B, and Fas -L to be related to disease
severity. J Allergy Clin Immunol, 2002. 109(1): p. 155-61. PubMed Abstract
48 Copaescu, A., et al., An Updated Review of the Diagnostic Methods in Delayed Drug Hypersensitivity. Front Pharmacol,
2020. 11: p. 573573. PubMed Abstract
49 Yoshioka, M., Y. Saw ada, and M. Nakamura, Diagnostic Tools and Biomarkers for Severe Drug Eruptions. Int J Mol Sci,
2021. 22(14). PubMed Abstract
50 Ramirez, G.A., et al., Drug Reaction w ith Eosinophilia and Systemic Symptoms (DRESS): Focus on the Pathophysiological
and Diagnostic Role of Viruses. Microorganisms, 2023. 11(2). PubMed Abstract
51 Phillips, E.J., et al., Clinical Pharmacogenetics Implementation Consortium Guideline for HLA Genotype and Use of
Carbamazepine and Oxcarbazepine: 2017 Update. Clin Pharmacol Ther, 2018. 103(4): p. 574-581. PubMed Abstract
52 Dutch Pharmacogenetics Working Group (DPWG). KNMP Pharmacy Organization
[Link]
53 van der Pol, K.H., et al., Dutch pharmacogenetics w orking group guideline for the gene-drug interaction of ABCG2, HLA-B
and Allopurinol, and MTHFR, folic acid and methotrexate. Eur J Hum Genet, 2022. PubMed Abstract
54 Mallal, S., et al., Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1
reverse-transcriptase inhibitor abacavir. Lancet, 2002. 359(9308): p. 727-32. PubMed Abstract
55 Hetherington, S., et al., Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet, 2002.
359(9312): p. 1121-2. PubMed Abstract
56 Manson, L.E.N., J.J. Sw en, and H.J. Guchelaar, Diagnostic Test Criteria for HLA Genotyping to Prevent Drug
Hypersensitivity Reactions: A Systematic Review of Actionable HLA Recommendations in CPIC and DPWG Guidelines. Front
Pharmacol, 2020. 11: p. 567048. PubMed Abstract
1941

49
1942 CHAPTER 5.
1943 CAUSALITY ASSESSMENT OF SCAR IN PRE- AND
1944 POSTAUTHORIZATION SURVEILLANCE
1945

1946 Chapter summary

1947 Causality assessment is the procedure by which the relationship between a product and AE
1948 is established. Standard methods such as Bradford Hill criteria, global introspection,
1949 operational algorithms, probabilistic approaches are described for SCAR. Adjudication,
1950 targeted follow-up forms and assessment of aggregate data are also presented.
1951 Conclusions or recommendations
1952 1) The standard causality methods may be used to evaluate a potential causal
1953 relationship between a product and adverse skin events.
1954 2) The Algorithm for Assessment of Drug Causality for Epidermal Necrolysis (ALDEN)
1955 was created to assess causality of individual reports of SJS/TEN takes into account
1956 the most relevant factors such as latency and medicinal product half-life, class effect
1957 and alternative etiologies.
1958 3) When possible, additional tools such as patch testing or delayed intradermal testing
1959 and expert adjudication of individual cases can further support a causal relationship.
1960 4) SCAR-specific targeted questionnaires offer valuable information for a timely and
1961 comprehensive assessment of causality.
1962
1963 5.1 Introduction

1964 Causality assessment is a procedure whose purpose is to determine the relationship

1965 between an intervention, namely a medicinal product, and an AE. If a causal relationship
1966 with the AE is considered at least a reasonable possibility, the event is considered an ADR.
1967 The assessment of causality is at the heart of pharmacovigilance, which relies on the
1968 information collected from healthcare professionals including clinical trial investigators.
1969 Once a SCAR diagnosis is confirmed, a detailed medical history including all medicinal
1970 products and/or supplements will inform the assessment of a causal relationship between
1971 the AE and the medicinal product. In general, it is recommended to conduct a review of
1972 medical events and exposures, including dates and timelines over an eight-week period prior
1973 to the reported onset of the SCAR[1] and the patient’s skin risk profile.[2]
1974 In certain circumstances, it may be useful to consider medicinal product exposures over a
1975 longer timeline, taking into account factors such as treatment indication, patient population
1976 characteristics, and medicinal product mechanism of action. Validated medicinal product
1977 causality assessment tools also help to avoid implicating the medicinal product(s) introduced
1978 for early symptoms of SCAR and are discussed in this chapter.
1979 In the pre-authorization phase, clinical trial participants benefit from close safety surveillance
1980 and any suspected ADR will be investigated, which will include a causality assessment of the
1981 individual case. In the postauthorization phase, patients and healthcare professionals are
1982 encouraged to report suspected ADRs to their regional reporting schemes. Also, it is
1983 important to note that causality assessment of individual cases is not required for reporting
1984 purposes.

50
1985 When a suspected ADR is reported by a healthcare professional or patient, the manufacturer
1986 may perform a causality assessment of that reaction, although this is not mandatory.
1987 However, even if the causality assessment considers a causal relationship of the AE and the
1988 medicinal product as an unlikely cause or is excluded altogether, the company is still
1989 required to report the case to the appropriate regulatory bodies. The causality assessment
1990 outcome can be part of this submission.
1991 Manufacturers and regulatory bodies are required to perform continuous safety surveillance
1992 in the postauthorization phase based on the totality of all available evidence. However, such
1993 surveillance does not only include causality assessment of individual cases if this is feasible
1994 based on the nature of these cases and available information about them, but more
1995 importantly, also includes causality assessment of safety concerns. Whereas causality
1996 assessment at case level investigates if an AE in a given patient is caused by a medicinal
1997 product, causality assessment conducted on the basis of all evidence examines whether the
1998 medicinal product can cause the AE in patients who will receive the medicinal product in the
1999 future. Approaches for causality assessment on the basis of all evidence are also discussed
2000 in this chapter.
2001 5.2 Global introspection methods
2002 Global introspection methods rely on detailed clinical information for individual cases of
2003 suspected ADRs. The WHO-UMC for International Drug Monitoring has developed a practical
2004 tool which combines the assessment of clinical and pharmacological case information and the
2005 quality of this information to assess causality. The WHO/UMC causality tool takes into account
2006 the temporal relationship, laboratory values, dechallenge and rechallenge outcomes, as well as
2007 the presence of possible alternative etiologies to classify the likelihood of a causal relationship
2008 of a given case into Certain, Probable/Likely, Possible, Unlikely, Conditional/Unclassified, and
2009 Unassessable/Unclassifiable.[3]The global introspection method implicitly relates to the
2010 diagnosis-making process which remains subjective and demonstrated poor intra- and interrater
2011 reproducibility.[4-7]
2012 5.2.1 Operational algorithms
2013 The second category of causality assessment methods consists of questionnaire-based
2014 operational algorithms for individual cases of suspected ADRs.[3] Algorithms are designed to
2015 reduce intra- and interrater variability, increase reliability and validity of causality
2016 assessment. The Naranjo scale is the commonly used algorithm to assign a probability
2017 scale to medicinal product-event relationship.[8] It was originally developed by
2018 pharmacologists/physicians and psychiatrists at the University of Toronto for use in
2019 controlled trials and registration studies of new drugs.[8,9] The Naranjo approach is simple
2020 to apply in the assessment of causality of individual case reports from spontaneous
2021 postauthorization reporting[10], or observational studies.[11,12] The Naranjo scale can be
2022 used for assessment of adverse skin events.[13] However, the high variability of weighting
2023 assigned to each causality criterion can lead to the imprecise expression of the final
2024 result.[14] Slight variations of the Naranjo scale, such as the Liverpool algorithm, have
2025 been shown to reduce interrater variability.[15]
2026 5.2.2 Probabilistic methods
2027 Probabilistic methods calculate the probability of causality based on available knowledge of
2028 the type of suspected medicinal product, its potential to cause a specific ADR (prior estimate)
2029 and specific findings in individual case reports of suspected ADRs, in combination with
2030 background information (posterior estimate).[8]

51
2031 The probabilistic approach derived from Bayes’ theorem, offers a formal causal assessment in
2032 determining the probability of medicinal product causation. While highly reliable, these
2033 methods remain too complex and time consuming for routine practice.[7,16]
2034 These tools are not specific to an ADR and can be further refined to the type of medicinal
2035 product-induced injury such as the Roussel Uclaf Causality Assessment Method for drug-
2036 induced liver injury[17] or the Algorithm for Assessment of Drug Causality for Epidermal
2037 Necrolysis (ALDEN) that is specific to cases of SJS/TEN.[18]
2038 [Link] ALDEN

2039 ALDEN is a probabilistic method aimed at assessing the causality of individual cases of
2040 SJS/TEN. ALDEN was developed for use in case–control studies (SCAR and
2041 EuroSCAR)[19,20] and a case registry (RegiSCAR).
2042 The ALDEN score also takes into account the latency between start of medicinal product
2043 intake and index day (day of SJS/TEN symptom onset), presence/availability of the
2044 medicinal product in the body before index day (taking into account the medicinal product’s
2045 half-life and the patient’s hepatic and renal function), information on previous and later intake
2046 as well as the discontinuation of the medicinal product (if available), type of medicinal
2047 product and its possible induction potential (based on medicinal product lists that have to be
2048 updated regularly), and alternative reasons.
2049 The ALDEN criteria includes a criterion on medicinal product “notoriety” for SJS/TEN
2050 assigning no points for medicinal products not previously identified as culprits, ‘including
2051 those newly released to the market”[18] and thus a new medicinal product culprit would not
2052 contribute to the total score and causality classification. Numeric score values allow the
2053 causality assessment of every single medicinal product a patient used four weeks before the
2054 SJS/TEN. The numeric score values are classified as “very improbable”, “improbable”,
2055 “possible”, “probable”, or “very probable”. Given that ALDEN is more sensitive than global
2056 introspection or operational algorithms, it can be considered a reference tool in
2057 SJS/TEN.[18]
2058 5.2.3 The Bradford Hill criteria

2059 The Bradford Hill criteria consist of nine principles that can be useful in establishing a causal
2060 relationship between an observation at population level and a suspected cause based on all
2061 available evidence. These criteria have been widely used in epidemiology and public health
2062 research and include the strength in terms of effect size, consistency across clinical findings,
2063 specificity, temporal sequence, biological gradient in terms of dose-response relationship,
2064 biologic plausibility, coherence with non-clinical findings, experimental evidence and
2065 analogous evidence.[21]
2066 In pharmacovigilance, the Bradford Hill criteria are considered relevant for causality
2067 assessment[21] and have become the basis for several methods, which have five criteria in
2068 common: challenge, dechallenge, rechallenge, previous bibliographic description and
2069 etiologic alternatives.[21]
2070
2071
2072
2073
2074
52
2075 5.3 Tools to support investigation of causality between medicinal product and SCAR
2076 5.3.1 Tests

2077 Patch or delayed intradermal testing provide evidence to support the assessment of
2078 causality. In general, diagnostic patch testing (DPT) is performed after but within one year of
2079 the acute phase of the hypersensitivity reaction.
2080 DPT is generally safe but has been associated with a high incidence of non-life-threatening
2081 systemic reactions among HIV-infected patients with antituberculosis drug-related cADRs,
2082 including SJS/TEN.[22,23] For SJS/TEN the optimum time for a diagnostic rechallenge is
2083 during the acute stage. In DRESS, which formed the majority of the cases, it should be
2084 performed 5-8 weeks after the initial cADR. Other authors have suggested that rechallenge
2085 following cADR should be deferred by a period equivalent to over five times the elimination
2086 half-life of the drug and not earlier than four weeks after the episode. This could be related to
2087 transient, nonspecific residual reactivity to drugs often induced by persisting viral or immune
2088 reactivation during the acute stage, causing high background proliferation and activity,
2089 regardless of stimulus.[22,23]
2090 These tests are of particular interest when several medicinal products are co-administered
2091 and/or to clarify the phenotype.[24] For abacavir, DPT has helped define the phenotype of
2092 immunologically-mediated abacavir hypersensitivity with a diagnostic sensitivity of
2093 87%.[25-27] The in vivo skin testing has shown a negative predictive value (NPV) of
2094 approximately 90% for skin reactions depending on the drug tested. The negative results
2095 may support a rechallenge in the absence of safe, alternative treatments.[28]
2096 DPT has also been used to investigate the cross-reactivity to anti-epileptic agents that are
2097 considered as therapeutic alternatives.[29] A large multi-centre study showed a high degree
2098 of variability of the DPT results in both drug and clinical phenotype in patients diagnosed
2099 with DRESS, AGEP or SJS/TEN within one year of event resolution.[30]
2100 In vitro testing, such as lymphocyte proliferation assays and those to identify and characterize
2101 drug-specific immune cell populations or key cytokines involved in skin reactions are still under
2102 development and are not used for routine diagnostic testing.[31,32] HLA pharmacogenomic
2103 testing can be used in a clinical setting to identify if patients are at risk for SCAR.[33]
2104 5.3.2 Adjudication
2105 [Link] Independent clinical trial review board

2106 Event adjudication is a process where an independent review board of medical specialists
2107 assesses relevant events for fulfilment of predefined clinical criteria. It is used in clinical trials
2108 to manage subjective evaluations and enhance a harmonized approach.
2109 The adjudicator refers to one or more assessors, independent from site investigators, who
2110 use information collected in the trial to assess the same outcome. In order for relevant
2111 information to be captured when there is a suspicion of SCAR in a clinical trial, AE-specific
2112 follow-up forms are developed by sponsors and submitted to investigators for completion.
2113 This allows the creation of a standardized process for the assessment of AE reports and
2114 enhanced case documentation to support appropriate diagnosis and causality assessment.
2115 Considering the low frequency of SCAR, a panel of independent experts is rare. More often,
2116 independent dermatology experts are involved to review and assess a adverse skin event
2117 that is considered a potential SCAR.

53
2118 Inclusion of a blinded independent dermatologist or allergist is considered a strength when
2119 planning for clinical trials where suspected SCAR are foreseen, as it allows for accurate
2120 monitoring and assessment of adverse skin events.[34]
2121 [Link] Other clinical tools

2122 In addition to an independent expert in cADRs, integration of skin biopsy results,

2123 photographs and investigator trainings and materials may allow for more accurate monitoring
2124 and evaluation of adverse skin events.[34]
2125 5.3.3 Targeted follow-up forms

2126 Targeted Follow-up Forms can be used to document relevant information that will allow
2127 appropriate SCAR assessment. Certain limitations and difficulties are acknowledged when
2128 collecting the information proposed on the follow-up forms, such as the paucity of biopsies
2129 typically performed on cutaneous lesions, incomplete information obtained from the reporter
2130 on the characteristics of cutaneous lesions or absence (or insufficient quality) of photographs
2131 of cutaneous lesions under standardized conditions. In addition, there is the potential for
2132 missing data entry (e.g. subjects who withdraw from studies, lack of follow-up in the
2133 postauthorization period).
2134 Important elements to be captured on the follow-up forms may include medical history/risk
2135 factors, AE information (e.g. nature of first symptoms, type of cutaneous event, extent of a
2136 rash/distribution of cutaneous lesions, associated symptoms, evidence of internal organ
2137 involvement), evidence of viral infection, whether photosensitivity is suspected, whether
2138 photographs were taken, if the medicinal product was stopped or dosage reduced and the
2139 outcome of the event. A systematic approach for assessment of the SCAR signal is key to
2140 complement the adjudication process. This topic is further discussed in Chapter 6
2141 (“Preauthorization Safety Data Collection and Analysis”). Scientific adjudication is required to
2142 assess the causal relationship between the suspect culprit medicinal product and SCAR.
2143 This approach includes the following steps:

2144  Case definition, described in more detail in Chapter 1 “What are Severe Cutaneous
2145 Adverse Reactions”,
2146  Pattern analysis: evaluating the number of cases with a compatible chronology, cases
2147 without a suggestive chronology, cases with no chronology available and cases where
2148 the diagnosis of SCAR was not confirmed. In addition, evaluating the number of cases
2149 with concomitant exposure to medicinal products known to induce SCAR and/or with
2150 possible underlying conditions that may provide alternative explanations (e.g.
2151 infections, systemic lupus erythematosus [SLE], T-cell lymphoma),
2152  Literature review: to evaluate whether there are cases of SCAR reported with the
2153 suspected culprit medicinal product or within the product class in key epidemiological
2154 studies on SJS/TEN (e.g. EuroSCAR).
2155
2156
2157
2158
2159
2160
2161
2162
54
2163 References

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Clinical Features and Pathogenesis. J Allergy Clin Immunol Pract. 2022 Feb 14;10(5):P1155–1167.e5. JACI Abstract
2 Litt’s Drug Eruption & Reaction Database [w ebsite]. Boca Raton (FL): CRC Press LLC; 2024
([Link] accessed 27 March 2024 [subscription required]).
3 World Health Organization (WHO)-Uppsala Monitoring Centre. The use of the WHO-UMC system for standardized case
causality assessment. Available from: [Link]
4 Blanc S, et al. Judgments of trained observers on adverse drug reactions. Clin Pharmacol Ther. 1979 May;25:493-498. Clin
Pharmacol Ther. Abstract
5 Karch FE, et al. Adverse drug reactions-a matter of opinion. Clin Pharmacol Ther 1976(5 Pt 1):489-492. Clin Pharmacol Ther.
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6 Koch-Weser J, Sellers EM, Zacest R. The ambiguity of adverse drug reactions. Eur J Clin Pharmacol. 1977 Jan 3;11(2):75-
78. PubMed Abstract
7 Kramer MS. Difficulties in assessing the adverse effects of drugs. Br J Clin Pharmacol. 1981;11 Suppl 1:105S-110S. PubMed
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8 Naranjo CA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981
Aug;30(2):239-245. Clin. Pharmacol Ther. Abstract
9 Mashford ML. The Australian method of drug-event assessment. Special w orkshop--regulatory. Drug Inf J. 1984;18(3-4):271-3.
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10 FDA. FDA Adverse Event Reporting System
11 Davies EC, et al. Adverse drug reactions in hospital in-patients: a prospective analysis of 3695 patient-episodes. PLoS One
2009 Feb 11;4:e4439. PLoS One Open Access Article
12 Reis AM, Cassiani SH. Adverse drug events in an intensive care unit of a university hospital. Eur J Clin Pharmacol. 2011
Jun;67(6):625-32. PubMed Abstract
13 Copaescu AM, Trubiano JA. The assessment of severe cutaneous adverse drug reactions. Aust Prescr. 2022 Apr;45(2):
43-8. PubMed Abstract
14 Pere JC, et al. Computerized comparison of six adverse drug reaction assessment procedures. Clin Pharmacol Ther. 1986
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PLoS One 2011;6:e28096. PLoS One Open Access Article
16 Lanctot KL, Naranjo CA. Computer-assisted evaluation of adverse events using a Bayesian approach. J Clin Pharmacol. 1994
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17 Danan G, Benichou C. Causality assessment of adverse reactions to drugs--I. A novel method based on the conclusions of
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18 Sassolas B, et al. ALDEN, an algorithm for assessment of drug causality in Stevens -Johnson Syndrome and toxic epidermal
necrolysis: comparison with case-control analysis. Clin Pharmacol Ther. 2010 Jul;88(1):60-8. PubMed Abstract
19 Mockenhaupt M, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks w ith
emphasis on recently marketed drugs. The EuroSCAR-study. J Invest Dermatol. 2008 Jan;128(1):35-44. PubMed Abstract
20 Roujeau JC, et al. Medication Use and the Risk of Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis. N Engl J
Med. 1995;333:1600-1608. NEJM Full Text
21 Hill AB. The environment and disease: association or causation? J R Soc Med. 1965;58:295-300. Journal Full Text
22 Lehloenya RJ, et al. Diagnostic patch testing follow ing tuberculosis-associated cutaneous adverse drug reactions induces
systemic reactions in HIV-infected persons. Br J Dermatol. 2016 Jul;175(1):150-6. PubMed Abstract
23 Lochmatter P, Zaw odniak A, Pichler WJ. In vitro tests in drug hypersensitivity diagnosis. Immunol Allergy Clin North Am.
2009 Aug;29(3):537-54. PubMed Abstract
24 Pavlos R, et al. Fever, rash, and systemic symptoms: understanding the role of virus and HLA in severe cutaneous drug
allergy. J Allergy Clin Immunol Pract 2014 Jan-Feb;2(1):21-33. PubMed Abstract
25 Saag M, et al. High Sensitivity of Human Leukocyte Antigen-B*5701 as a Marker for Immunologically Confirmed Abacavir
Hypersensitivity in White and Black Patients. Clin Infect Dis. 2008 Apr;46(7):1111-1118. Journal Full Text
26 Phillips EJ, et al. Clinical and immunogenetic correlates of abacavir hypersensitivity. AIDS 2005 Jun 10;19(9):979-81.
PubMed Abstract
27 Mallal S, et al. HLA-B*5701 Screening for Hypersensitivity to Abacavir. N Engl J Med. 2008 Feb 7;358(6):568-79.
NEJM Full Text
28 Waton J, et al. Negative predictive value of drug skin tests in investigating cutaneous adverse drug reactions. Br J Dermatol
2009 Apr;160(4):786-94. PubMed Abstract
29 Lin YT, et al. A patch testing and cross-sensitivity study of carbamazepine-induced severe cutaneous adverse drug
reactions. J Eur Acad Dermatol Venereol. 2012 Jan 3;27(3):356-364. Europe PMC Abstract
30 Barbaud A, et al. A multicentre study to determine the value and safety of drug patch tests for the three main classes of
severe cutaneous adverse drug reactions. Br J Dermatol. 2013 Mar;168(3):555-62. PubMed Abstract
31 Rive CM, Bourke J, Phillips EJ. Testing for Drug Hypersensitivity Syndromes. Clin Biochem Rev. 2013 Feb;34(1):15-38. PubMed
Abstract and Full Text
32 Keane NM, et al. HLA Class I restricted CD8+ and Class II restricted CD4+ T cells are implicated in the pathogenesis of nevirapine
hypersensitivity. AIDS 2014 Aug 24;28(13):1891-1901. AIDS Abstract
33 FDA BEST (Biomarkers, EndpointS, and other Tools) Resource 2016
34 Krueger et al. Cutaneous Adverse Events in the Randomized, Double-Blind, Active-Comparator DECIDE Study of
Daclizumab High-Yield Process Versus Intramuscular Interferon Beta-1a in Relapsing Remitting Multiple Sclerosis. Adv Ther.
2016; 33(7):1231–1245 PubMed Abstract and Full Text

2164

55
2165 CHAPTER 6.
2166 PRE-AUTHORIZATION SAFETY DATA COLLECTION AND ANALYSIS
2167
2168 Chapter summary

2169 This chapter provides guidance to investigators about the information to be collected during
2170 the initial assessment of a potential SCAR. The chapter also addresses the risk factors
2171 associated with the development of SCAR and contains an overview of differential
2172 diagnoses that may act as confounding factors when analysing a SCAR.
2173 Subsections contained in this chapter:
2174  Investigator assessment,
2175  Risk factors and confounding factors
2176 Conclusions or recommendations

2177 When appropriate assessment of a SCAR during clinical development has been conducted,
2178 communicating the SCAR to various stakeholders in the clinical trials is important. Timely
2179 awareness by stakeholders, including study participants, investigators and regulatory
2180 authorities, is necessary to allow prompt identification of these events and rapid intervention,
2181 thereby ensuring patient safety. Additionally, sponsors of a clinical trial where a SCAR has
2182 been reported may consider implementing protocol changes to allow for continued
2183 monitoring and additional characterization of a potential SCAR.

2184 6.1 Introduction

2185 Timely recognition of a potential SCAR case by investigators is of utmost importance for
2186 patients’ safety and assessing the impact of such a reaction on the clinical programme. Initial
2187 steps in this assessment require the acquisition of detailed information about the suspected
2188 AE that could suggest and confirm a SCAR diagnosis.
2189 6.2 Investigator assessment

2190 SCAR needs to be promptly recognized because of the associated high morbidity and
2191 mortality as well as the potential impact on a clinical programme. A clinical trial participant
2192 presenting with a widespread rash temporally associated with a potential culprit medicinal
2193 product should trigger an evaluation of a possible SCAR case (SJS, TEN, DRESS/DIHS,
2194 AGEP or GBFDE).
2195 Clinical trials whose patient population include high-risk patients for the occurrence of SCAR
2196 (e.g. HIV-infected patients, oncology patients, patients with SLE)[1] and/or exposure to
2197 medicinal products (either as an investigational medicinal product or concomitant
2198 medication) with a known risk of inducing SCAR (e.g. aromatic anticonvulsants, allopurinol,
2199 antiretrovirals, oxicams) should lead the sponsor and investigators to consider the
2200 occurrence of possible SCAR. Additionally, investigators overseeing clinical trials whose
2201 population is comprised of elderly patients should keep in mind that prompt diagnosis is of
2202 utmost importance, since higher mortality rates and clinical complications are more
2203 frequently observed in older patients.[2-4]

56
2204 When a SCAR is suspected, the first measure should be to interrupt the treatment with the
2205 alleged culprit medicinal product. An assessment of the likelihood that the investigational
2206 medicinal product is implicated is required, taking into consideration two main points, namely
2207 the information that is available on other medicinal products within the same class and that
2208 elicit similar reactions, and time to onset of the reaction.
2209 Additionally, all concomitant medications need to be evaluated and, once a particular SCAR
2210 diagnosis is suspected (e.g. DRESS, SJS/TEN), the typical latency period should be compared
2211 with the time elapsed since last exposure to the suspected medicinal product.(Figure 7.)

2212
2213 Figure 7. The SCAR timeline
2214 References:[5-24]

2215 The pattern of skin involvement and accompanying signs/symptoms can suggest SCAR and
2216 certain characteristics might suggest a particular diagnosis. SJS/TEN may present with
2217 blisters, skin detachment, exfoliation, positive Nikolsky’s sign, oral and genital mucosa
2218 involvement, as well as eye involvement (e.g. corneal ulcers, conjunctivitis). The occurrence
2219 of a prodromal period is common with SJS/TEN, usually preceding skin manifestations by
2220 three days and presenting with fever, myalgia, arthralgia, malaise, photophobia or
2221 conjunctival itching or burning.
2222 In DRESS/DIHS, fever, facial oedema and lymph node enlargement are typically present. In
2223 addition, a long latency period is typically observed (2-8 weeks) and the clinical resolution
2224 usually follows a protracted course (>15 days).[6,7] In a clinical trial setting, a patient with
2225 characteristic lesions and systemic symptoms should be evaluated for exposures to new
2226 medicinal products, recent dosage changes or use of known high-risk medicinal products,
2227 which occurred 2-8 weeks prior to the onset of lesions or systemic symptoms. The
2228 investigational medicinal product should also be assessed for a possible contributive role. It
2229 is noteworthy to mention that several recently developed medicinal products have been
2230 reported as DRESS/DIHS syndrome culprits, such as anti-hepatitis C virus agents
2231 (boceprevir and telaprevir), targeted therapies for oncological diseases (sorafenib,
2232 vismodegib and vemurafenib), rivaroxaban and febuxostat.[7] The diagnosis of
2233 DRESS/DIHS should be guided by a scoring system, such as RegiSCAR and J-SCAR,[6,8]
2234 to the extent that clinical and laboratory information is available.

57
2235 FDE is characterized by the occurrence of erythematous macules/plaques, residual
2236 hyperpigmentation, and a history of recurring lesions in the same affected area, after
2237 exposure to various medicinal products (NSAIDs, paracetamol/acetaminophen, antibiotics).
2238 GBFDE is a rare and more severe form of FDE, presenting with blisters and is clinically
2239 similar in appearance to SJS/TEN. The absence of constitutional symptom and internal
2240 organ involvement, presence of well-demarcated blisters and erythematous patches,
2241 absence or paucity of mucosal erosions, a history of similar eruptions and onset within hours
2242 of exposure to the associated medicinal product favour a GBFDE diagnosis.[4]
2243 In a 2013 study, Lipowicz et al. compared GBFDE cases with SJS/TEN cases and found that
2244 although the majority of patients with GBFDE had skin detachment of less than 10% of BSA
2245 (30/58 patients), the mortality rate was significant and comparable to SJS/TEN (22% versus
2246 28%).
2247 The most characteristic feature of AGEP is the presence of widespread sterile pustules, with
2248 an initial predilection for flexural areas and subsequent spread to trunk and limbs. Systemic
2249 manifestations and laboratory abnormalities can also occur, such as fever, leukocytosis,
2250 neutrophilia and eosinophilia,[9] as well as mucous membrane involvement in about 20% of
2251 the cases (typically limited to oral mucosa).[10] A rapid onset (hours to a few days) after
2252 medicinal product exposure is also observed and can help differentiate from other SCAR.
2253 In all potential SCAR, because appropriate diagnosis considers clinical, histopathologic and
2254 laboratory features, a specialist in the management of medicinal product-induced cutaneous
2255 lesions should be consulted, such as a dermatologist, allergist or other subject matter expert.
2256 A skin biopsy for histopathologic examination may provide useful information for the
2257 assessment of the event as well as key information to help distinguish between different
2258 SCAR entities (e.g. SJS/TEN versus GBFDE) and other conditions in the SCAR differential
2259 (e.g. autoimmune blistering diseases).[11]
2260 Table 7 provides recommended information to be collected by the investigator in case a
2261 SCAR diagnosis is suspected. This information may help to confirm the diagnosis and inform
2262 causality assessment.
Medicinal product - Published evidence including notoriety for the known medicinal product: e.g.
characteristics aromatic anticonvulsants, sulfonamides, oxicam NSAIDs
- For medicinal products under investigation, potential pharmacodynamic interactions
such as chemical structure, metabolites or mechanisms of action should be
considered
Patient characteristics - Demographics: age, gender, genetic background
- Patients with HIV infection, malignancies, SLE or other autoimmune diseases,
transplant patients.
- Genetic risk factors: presence of medicinal product-specific HLA risk alleles and
known exposure to certain agents (e.g. DIHS/DRESS/SJS/TEN induced by
dapsone and HLA-B*13:01[12], SJS/TEN induced by carbamazepine and HLA-
B*15:02[12], DIHS/DRESS/SJS/TEN induced by allopurinol and HLA-B*58:01[12]
Skin involvement - Time to onset of cutaneous lesion
characteristics - Time to resolution of the event, if reaction is resolved
- Description of rash, distribution, location and morphology of cutaneous lesions (e.g.
presence of papules, macular papules, exanthema, pustules, urticaria, blisters,
bullae, exfoliation, oedematous plaques, hyperpigmentation, target-like lesions,
positive Nikolsky’s sign)
- Approximate body surface area affected: <10%, 10-30%, >30%
- History of recurring skin lesions at the same site (GBFDE)
- Biopsy and immunofluorescence results, if available
- Patch testing, prick testing, lymphocyte stimulation testing, immunophenotyping or
HLA genotyping, if available

58
 Presence of accompanying - Presence of oral or genital mucosa involvement
and/or preceding signs and - Fever (body temperature >38 °C)
symptoms - Other constitutional signs/symptoms: fatigue, arthralgia
- Enlarged lymph nodes (DRESS/DHS)
- Facial oedema (DRESS/DIHS)
- Eye involvement (conjunctivitis, corneal ulcer), (SJS/TEN)
Presence of Accompanying - Leukocytosis
Laboratory Abnormalities - Lymphocytosis
- Lymphopenia
- Presence of atypical lymphocytes (DRESS/DIHS)
- Eosinophilia
- Thrombocytopenia (DRESS/DIHS)
- Evidence of internal organ involvement (DRESS/DIHS): AST and/or ALT increase,
creatinine increase, proteinuria, haematuria, decreased creatinine clearance,
cardiac enzymes elevation, amylase and/or lipase increase.
- Evidence of reactivation of herpes viruses (HHV6 - DRESS/DIHS)
2263 Table 7. Potential SCAR initial assessment in the clinical trial setting

2264 6.3 Risk factors and confounding factors

2265 6.3.1 Risk factors
2266 The process for monitoring and identifying potential SCAR cases during preauthorization
2267 clinical development and postauthorization depends on the predilection of the medicinal
2268 product association with SCAR. The following paragraphs will briefly cover several risk
2269 factors that should be considered: patient population (age, comorbidities, genetic
2270 background), pharmacology (class and target) of the medicinal product, and
2271 pharmacogenomics, when assessing the risk for SCAR in a clinical programme.
2272 Patient population
2273 Patient population characteristics including age, comorbidities and genetic background must
2274 be considered when determining SCAR risk for the patient and/or patient population. It is
2275 uncommon for SJS/TEN to occur in children less than two years of age[13]. Singh et al.
2276 published a retrospective study[14] evaluating EHRs of a tertiary hospital in Northern India,
2277 in which the majority of SCAR occurred in the older age group (41-65 years old).
2278 Replotting the data (Table 6) shows that approximately 50% (42-59%) of each SCAR
2279 (SJS/TEN, DRESS and AGEP) and exfoliative dermatitis (ExDerm) occurred in the 41–65
2280 year old age group and that the youngest age group (0-18 years old) consistently
2281 represented the lowest proportion for each SCAR.
2282 In addition to the age of the individual, comorbidities are important risk factors for SCAR.
2283 SCAR tend to be more common in immunocompromised patients such as individuals with HIV
2284 infection, as well as individuals with malignancy or hepatic disease.[15,16] To understand the
2285 comorbidity impact on SCAR risk, Table 7 replots the data from Singh et al. Acute infections
2286 were found to be the most common comorbidities for SJS/TEN and DRESS, while seizure
2287 disorder and diabetes were the most common comorbidities for AGEP and ExDerm.
2288 Specific genetic associations and HLA alleles may be over or under expressed in different
2289 patient populations (Table 8).[9] The linkage between abacavir hypersensitivity and HLA
2290 B*57:01 is an example that illustrates how over assignment of the clinical syndrome and low
2291 allele frequency in certain population groups can wrongly lead to the assumption that a HLA
2292 association to a particular drug hypersensitivity is restricted to race.[9,17] A case-control study
2293 was able to demonstrate the 100% sensitivity of HLA-B*57:01 as a marker for immunologically
2294 confirmed abacavir hypersensitivity, in both US white and black patients, demonstrating the
2295 clinical utility of allele screening that is generalizable across races.[18]

59
2296 Pharmacology
2297 The most common compound classes that induce SCAR include antibiotics, anticonvulsants,
2298 analgesics, antituberculosis agents, antiretroviral and herbal agents.[19,20] In addition to the
2299 compound classes listed above, immune-modulatory targets and/or modalities may induce
2300 SCAR.[21,22]
2301 Pharmacogenomics
2302 Associations between SCAR and specific class I and class II HLA alleles are medicinal product-
2303 specific and can vary across different populations.(Table 8)[9-25] A comprehensive review of
2304 pharmacogenomic markers in SCAR has recently been published.[24] Currently, there is no
2305 specific pharmacogenomic marker or panel that will indicate a higher risk of SCAR for an
2306 investigational new medicinal product or recently authorized product, but the literature
2307 highlights[25,26,27] the importance of pharmacogenomics in determining SCAR risk factors in the
2308 postauthorization phase.

60
2309
2310 Table 8. Age distribution for SCAR
2311 Adapted from Singh et al.[14]
2312 Permission obtained from John Wiley & Sons

2313
2314 Table 9. Comorbid medical conditions at the time of SCAR diagnosis
2315 Adapted from Singh et al.[14]
2316 Permission obtained from John Wiley & Sons

2317
Drug and Clinical Presentation HLA Allele Population
Abacavir Hypersensitivity Syndrome B*57:01 5-8% White
<1% African
<1% Asian
Allopurinol SJS/TEN and DRESS/DIHS B*58:01 9-11% Han Chinese
1-6% White
Carbamazepine SJS/TEN B*15:02 10-15% Han Chinese
<0.1% White
Carbamazepine DRESS A*31:01 Chinese
Europeans
Japanese
2318 Table 10. Key HLA associations with SCAR
2319 Adapted from Peter et al.[9]
2320 Permission obtained from Elsevier

61
2321 6.3.2 Confounding factors

2322 Clinical entities that mimic SCAR manifestations and are considered differential diagnoses
2323 include infections, autoimmune disorders and haematologic malignancies. Cutaneous
2324 eruptions that are due to an underlying disease (e.g. haematologic malignancies presenting
2325 with skin changes, autoimmune disease flares) may initially manifest with extensive skin
2326 involvement. Such eruptions need to be considered and ruled out as required.
2327 On an individual level, there may be additional confounding factors and one must be aware
2328 that in clinical trials these factors might impact the study outcome if not addressed properly.
2329 To illustrate the importance of excluding possible confounding factors, RegiSCAR, a scoring
2330 system for the diagnosis of DRESS, has a criterion for the evaluation of other potential
2331 causes (Chapter [Link] Clinical characteristics). If three of the following tests are performed
2332 and negative, one additional point is added to the patient’s total score, in favour of DRESS:
2333 hepatitis A virus, hepatitis B virus, hepatitis C virus, mycoplasma, chlamydia, antinuclear
2334 antibody, blood culture.
2335 [Link] Skin manifestations of the underlying disease

2336 Paraneoplastic erythroderma (PE) is described in association with haematologic

2337 malignancies, such as acute myeloid lymphoma and solid tumours (e.g. lung, prostate,
2338 thyroid, liver, ovaries, breast). Hence, an acute onset of erythroderma in oncology patients
2339 might be solely related to the underlying disease. PE can manifest as generalized erythema
2340 (>90% of BSA), scaling, with or without lymphadenopathy. According to Curth’s postulates,
2341 which are criteria used to identify a relationship between an internal malignancy and a
2342 cutaneous disorder, the malignancy and the skin disease run a parallel course. Successful
2343 treatment of the tumour leads to regression of the skin disease and, conversely, recurrence
2344 of the tumour leads to the return of cutaneous signs and symptoms.[28]
2345 Leukaemia cutis is characterized by the infiltration of leukaemic cells into the epidermis,
2346 dermis or subcutaneous tissue. It may precede, follow, or occur concomitantly with systemic
2347 leukaemia in 2.1- 30% of patients.[29] Typical manifestations include macules, papules,
2348 plaques, nodules, ulcers and blisters, but an erythrodermic form has been described in a
2349 patient with newly diagnosed acute myeloid leukaemia shortly after induction
2350 chemotherapy.[30]
2351 Patients with HIV infection are prone to syndromes manifesting with fever and rash due to
2352 the disease itself, infections or ADRs. Importantly, immune reconstitution inflammatory
2353 syndrome (IRIS) is an entity linked to the introduction of antiretroviral therapy (ART). IRIS
2354 occurs in 10- 25% of patients who start highly active ART and is dependent on factors such
2355 as low baseline CD4 cell count.[31] A study with 423 ART-naive patients with HIV infection
2356 found a median IRIS onset of 48 days.[32] IRIS-related cutaneous manifestations might
2357 have several presentations, depending on the eliciting agent and whether it is linked to an
2358 opportunistic infection. One example of a dermatological manifestation of IRIS is eosinophilic
2359 folliculitis, which can present with pruritic, erythematous papules or pustules, leukocytosis,
2360 eosinophilia and mimic AGEP.[33,34] Cutaneous leishmaniasis has also been described in
2361 the context of IRIS, with disseminated erythematous papules, oral and genital mucosa
2362 ulcers.[35]

62
2363 [Link] Infections

2364 Numerous infectious entities can present with clinical manifestations undistinguishable from
2365 SCAR and this can lead to a delayed interruption of the offending agent and possible
2366 introduction of ineffective treatments. For DRESS/DIHS, due to concomitant fever and
2367 lymphadenopathy, viral diseases such as infectious mononucleosis, parvovirus B19
2368 infection, Coxsackie infection, measles, dengue and viral hepatitis,[7,8] belong to the list of
2369 differential diagnoses to be considered. A retrospective analysis conducted in 2013 found
2370 that half of the patients with DRESS were initially diagnosed with infection (13/26 patients),
2371 which resulted in unnecessary treatment with antibiotics. It is worth mentioning that a rash
2372 occurring in the setting of infectious mononucleosis and concomitant treatment with a
2373 penicillin-derived agent (e.g. ampicillin, amoxicillin) is not uncommon and may represent a
2374 transient virus-mediated immune alteration.[36]
2375 AGEP presents with a combination of fever, leukocytosis and pustules, which can be easily
2376 confused with an acute infectious event. Pustulosis acuta generalisata is a differential
2377 diagnosis to be considered, usually occurring in children (although reported in adults as
2378 well) following a streptococcal infection.[10,37] Similarly, Staphylococcal scalded skin
2379 syndrome (SSSS) or Ritter disease is another possible differential diagnosis of infectious
2380 etiology for SJS/TEN and AGEP, more frequently seen in children and in adults with
2381 immunosuppression. It results from an infection with exotoxin-producing strains of
2382 Staphylococcal aureus (possible primary sources: impetigo, conjunctivitis, pharyngitis, otitis,
2383 wound infection) and presents with desquamation, blistering and constitutional symptoms,
2384 in the absence of mucosal involvement.[38]
2385 [Link] Autoimmunity

2386 Acute cutaneous lupus erythematosus (ACLE) may manifest as an acute onset of
2387 generalized rash in sun-exposed areas and since it is frequently associated with SLE,
2388 systemic manifestations and laboratory abnormalities can also be found. A severe subtype
2389 of ACLE, TEN-like ACLE, has been described, presenting with bullous lesions and epidermal
2390 detachment.[39,40] Characteristic histopathologic features and presence of elevated
2391 antinuclear antibody titres and positive anti-dsDNA antibodies can help distinguishing ACLE
2392 from SCAR.[41-43]
2393 A specific form of subacute cutaneous lupus erythematosus (SCLE), drug-induced (DI-
2394 SCLE), may also have a clinical presentation that can mimic SCAR. It can arise within weeks
2395 to years of medicinal product exposure, with a median latency of six weeks.[41] The most
2396 commonly implied drugs are thiazides, terbinafine, calcium channel blockers, angiotensin-
2397 converting enzyme inhibitors and TNF-inhibitors.[41] DI-SCLE has also been reported to
2398 occur in patients with prior diagnosis of SLE[44] and can be associated with Ro ⁄SSA
2399 autoantibodies in > 80% of patients. Histopathology shows lupus erythematosus-specific
2400 changes and the SCLE lesions may last for weeks to months.[41]
2401 Another autoimmune entity worth highlighting in this section is a subtype of pustular
2402 psoriasis: acute generalized pustular psoriasis (AGPP), also known as generalized pustular
2403 psoriasis of von Zumbusch. Medicinal product administration (e.g. lithium, progesterone,
2404 phenylbutazone, antimalarials, fluoxetine, ustekinumab, infliximab, adalimumab and
2405 apremilast), medicinal product withdrawal (e.g. systemic corticosteroids) and infections (e.g.
2406 upper respiratory tract infection) can be precipitating factors for AGPP.[45]

63
2407 Its clinical presentation resembles AGEP, with a sudden appearance of widespread sterile
2408 pustules on painful plaques/erythema and systemic symptoms (fever, malaise, arthralgia).
2409 Similar to AGEP, mucosal involvement can occur, but factors such as history of prior
2410 episodes, personal or family history of psoriasis and presence of arthritis contribute to an
2411 AGEP diagnosis.
2412 [Link] Peripheral T-cell lymphomas

2413 Angio-immunoblastic T-cell lymphoma, a mature peripheral T-cell lymphoma, can exhibit a
2414 similar clinical presentation to DRESS, with widespread rash, lymphadenopathy, peripheral
2415 eosinophilia, atypical lymphocytosis and other internal organ involvement.[46] The occurrence
2416 of B-symptoms (fever, malaise and weight loss)[47] prior to the onset of rash can be a clue for
2417 the diagnosis and is present in 55-77% of patients, as well as hepatosplenomegaly.[48]
2418 Histolopathogical examination of the skin might not be conclusive for the diagnosis and a
2419 lymph node biopsy might be required. Sézary syndrome, an aggressive type of cutaneous T-
2420 cell lymphoma, typically presents with erythroderma, pruritus and generalized
2421 lymphadenopathy, and can resemble DRESS. Peripheral blood findings such as circulating
2422 leukaemic “Sézary cells” (atypical mononuclear cells) and skin biopsy findings can help in the
2423 distinction. A patient diagnosed with DRESS with persistent cutaneous alterations and/or
2424 constitutional symptoms beyond the expected time for clinical resolution, should prompt the
2425 investigator to consider peripheral T-cell lymphomas as possible diagnoses.
2426
2427
2428
2429
2430
2431 References

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retrospective case series study. Am J Clin Dermatol. 2012 Feb 1;13(1):[Link] Abstract
2 Ezaldein et al. The effect of comorbidities on overall mortality in Stevens - Johnson Syndrome: an analysis of the Nationw ide
Inpatient Sample. Dermatol Online J. 2017 Apr 15;23(4). PubMed Abstract
3 Bastuji-Garin A, et al. SCORTEN. A Severity-of-Illness Score for Toxic Epidermal Necrolysis. J Invest Dermatol. 2000
Aug;115(2):149-53. J Invest Dermatol Full Text
4 Lipow icz S, et al. Prognosis of generalized bullous fixed drug eruption: comparison w ith Stevens -Johnson syndrome and toxic
epidermal necrolysis. Br J Dermatol. 2013 Apr; 168(4):726-732. PubMed Abstract
5 Alniemi DT, et al. Acute generalized exanthematous pustulosis: clinical characteristics, etiologic associations, treatments, and
outcomes in a series of 28 patients at Mayo Clinic, 1996-2013. Int J Dermatol. 2017 Apr;56(4):405-414. PubMed Abstract
6 Kardaun SH, et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a
DRESS syndrome really exist? Br J Dermatol. 2007 Mar;156(3):609-11. PubMed Abstract
7 Chu C-Y et al. Drug Reaction w ith Eosinophilia and Systemic Symptoms (DRESS): An Interplay among Drugs, Viruses, and
Immune System. Int J Mol Sci. 2017 Jun;18(6): 1243. Int J Mol Sci Full Text
8 Shiohara T et al. The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical
features and viral reactivations. Br J Dermatol. 2007 May 1;156(5):1083-4. Br J Dermatol Full Text
9 Peter J et al. Severe Delayed Cutaneous and Systemic Reactions to Drugs: A Global Perspective on the Science and Art of
Current Practice. J Allergy Clin Immunol Pract. May-Jun 2017;5(3):547-563. PubMed Abstract
10 Sidoroff et al. Acute generalized exanthematous pustulosis (AGEP) – a clnical reaction pattern. J Cutan Pathol. 2001
Mar;28(3):113-9. PubMed Abstract
11 Chu C Y et al. Generalized bullous fixed drug eruption is distinct from Stevens -Johnson syndrome/toxic epidermal necrolysis
by immunohistopathological features. J Am Acad Dermatol. 2014 Mar;70(3):539-48. Science Direct Abstract
12 Hama N, et al. Drug-Induced Hypersensitivity Syndrome (DIHS)/Drug Reaction w ith Eosinophilia and Systemic Symptoms
(DRESS): Clinical Features and Pathogenesis. J Allergy Clin Immunol. Prac. 2022 Feb 14;10(5):1155-1167. JACI in Practice
Full Text
13 Paulmann M, Mockenhaupt M. Fever in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Pediatric Cases:
Laboratory Work-up and Antibiotic Therapy. Pediatr Infect Dis J. 2017 May;36(5):513–515. PubMed Abstract
14 Singh GK, et al. A retrospective, 5-year, clinicoepidemiological study of severe cutaneous adverse reactions (SCARs). Int J
Dermatol. 2021 May;60(5):579-588. PubMed Abstract

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 15 Peter J, Choshi P, Lehloenya RJ. Drug hypersensitivity in HIV infection, Curr Opin Allergy Clin Immunol. 2019 Aug; 19(4): 272–
282. PubMed Abstract
16 Sekula P, et al. Comprehensive survival analysis of a cohort of patients w ith Stevens –Johnson syndrome and toxic
epidermal necrolysis. J. Invest. Dermatol. 2013 May;133 (5):1197–204. PubMed Abstract
17 Pavlos R, Mallal S, Philips E. HLA and pharmacogenetics of drug hypersensitivity. Pharmacogenomics. 2012
Aug;13(11):1285-306. PubMed Abstract
18 Saag M, et al. High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir
hypersensitivity in w hite and black patients. Clin Infect Dis. 2008 Apr 1; 46(7) 1111-8. PubMed Abstract
19 Roujeau JC, et al. Medication Use and the Risk of Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis. N Engl J
Med. 1995;333:1600-1608. NEJM Full Text
20 Mockenhaupt M. Epidemiology of cutaneous adverse drug reactions. Allergol Select. 2017 Aug 4;1(1):96-108. PubMed Abstract
21 Chen C-B, et al. Severe cutaneous adverse reactions induced by targeted anticancer therapies and immunotherapies.
Cancer Manag Res. 2018 May 17;10:1259–1273. PubMed Abstract
22 Gey A, et al. Severe cutaneous adverse reaction associated with vemurafenib: DRESS, AGEP or overlap reaction? J Eur
Acad Dermatol Venereol. 2016 Jan;30(1):178-9. Abstract not available
23 Su SC, et al. Severe Cutaneous Adverse Reactions: The Pharmacogenomics from Research to Clinical Implementation. Int
J Mol Sci. 2016 Nov 15;17(11):1890. PubMed Abstract
24 Ahmed AF, et al. Genetic Determinants in HLA and Cytochrome P450 Genes in the Risk of Aromatic Antiepileptic-Induced
Severe Cutaneous Adverse Reactions. J. Pers. Med. 2021 May 7,11(5):383. PubMed Abstract
25 Pavlos R, et al. Fever, rash and systemic symptoms: understanding the role of virus and HLA in severe cutaneous drug
allergy. J Allergy Clin Immunol Pract. 2014 Jan-Feb; 2(1): 21–33. PubMed Abstract
26 Dean L, et al., editors. Carbamazepine Therapy and HLA Genotype. In: Medical Genetics Summaries [Internet]. Bethesda
(MD): National Center for Biotechnology Information (US); 2012. 2015 Oct 14 [updated 2018 Aug 1]. PubMed Excerpt
27 Mallal S, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008 Feb 7;358(6):568-79. PubMed Abstract
28 Thiers B, et al. Cutaneous Manifestations of Internal Malignancy. CA Cancer J Clin. Mar 2009;59(2):73-98 ASC Journals Full Text
29 Wagner G, et al. Leukemia cutis - epidemiology, clinical presentation, and differential diagnoses. J Dtsch Dermatol Ges.
2012 Jan;10(1):27-3 PubMed Abstract
30 Donaldson M, et al. Rare case of leukemia cutis presenting as erythroderma in a patient w ith acute myeloid leukemia. JAAD
Case Rep. 2019 Feb;5(2):121–123. JAAD Case Reports
31 Müller M, et al. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic
review and meta-analysis. Lancet Infect Dis. 2010 Apr;10(4):251–61 PubMed Abstract
32 Murdoch D, et al. Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South
Africa: a prospective study. AIDS. 2008 Mar 12;22(5):601-10. PubMed Abstract
33 Huiras E, et al. Cutaneous manifestations of immune reconstitution inflammatory syndrome. Curr Opin HIV AIDS. 2008 Jul;3(4):453-60.
PubMed Abstract
34 Rajendran PM, et al. Eosinophilic folliculitis: before and after the introduction of antiretroviral therapy. Arch Dermatol. 2005
Oct;141(10):1227-31 PubMed Abstract
35 Vergara MP, et al. Tegumentary Leishmaniasis as a Manifestation of Immune Reconstitution Inflammatory Syndrome in 2
Patients w ith AIDS. J Infect Dis. 2005 Nov 15;192(10):1819-22 J Infect Dis Full Text
36 Thompson DF, et al. Antibiotic-Induced Rash in Patients With Infectious Mononucleosis. Ann Pharmacother.
2017 Feb;51(2):154–162 PubMed Abstract
37 Tabata N, et al. A Pediatric Case of Acute Generalized Pustular Eruption w ithout Streptococcal Infection. Case Rep
Dermatol. 2016 Jun 13;8(2):173–178 PubMed Abstract
38 Leung A, et al. Staphylococcal-scalded skin syndrome: evaluation, diagnosis, and management. World J Pediatr. 2018 Apr;14(2):116-120
PubMed Abstract
39 Cetin GY, et al. A case of toxic epidermal necrolysis-like skin lesions w ith systemic lupus erythematosus and review of the literature.
2013 Jul;22(8):839-46. PubMed Abstract
40 Napolitano M, et al. Toxic epidermal necrolysis-like acute cutaneous lupus erythematosus successfully treated with a single
dose of etanercept: report of three cases. J Am Acad Dermatol. 2013 Dec;69(6):e303-5. No abstract available
41 Grönhagen CM, et al. Subacute cutaneous lupus erythematosus and its association w ith drugs: a population-based matched
case–control study of 234 patients in Sw eden. 2012 Aug;167(2):296-305. PubMed Abstract
42 Low e G, et al. A systematic review of drug-induced subacute cutaneous lupus erythematosus. Br. J. Dermatol. 2011
Mar;164(3):465-72. PubMed Abstract
43 Marzano AV, et al. Drug-induced subacute cutaneous lupus erythematosus: evidence for differences from its idiopathic
counterpart. Br. J. Dermatol. 2011 Aug;165(2):[Link] Abstract
44 Keyes E, et al. Drug-induced subacute cutaneous lupus erythematosus in previously diagnosed systemic lupus
erythematosus patients: A case series. JAAD Case Rep. 2021 Jun;12:18–21 PubMed Full Text
45 Choon SE, et al. Clinical Course and Characteristics of Generalized Pustular Psoriasis. Am J Clin Dermatol. 2022
Jan;23(Suppl 1):21-29. PubMed Abstract
46 Mangana J, et al. Angioimmunoblastic T-Cell Lymphoma Mimicking Drug Reaction w ith Eosinophilia and Systemic Symptoms (DRESS
Syndrome). Case Rep Dermatol. 2017 Mar 21;9(1):74–79. PubMed Abstract
47 NIH National Cancer Institute. B-Symptoms Terms and Properties. NIH w ebsite
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Abstract
2432

65
2433 CHAPTER 7.
2434 POSTAUTHORIZATION SAFETY DATA COLLECTION AND
2435 ASSESSMENT
2436 Chapter summary

2437 Sources for postauthorization surveillance include spontaneous AE reporting systems, EHRs
2438 and registries. Analysis of individual case safety reports (ICSRs) and aggregate safety
2439 reports are central to the identification of patterns that are suggestive of SCAR.
2440 Conclusions or recommendations

2441  Postauthorization data sources provide valuable insight into the real-world occurrence
2442 of rare AEs such as SCAR.

2443  EHRs, designed for patient care and follow-up, may be used to confirm or reject true
2444 reports of SCAR and establish causality.

2445  SCAR - specific registries and networks bring together comprehensive elements and
2446 expertise needed to identify true SCAR and establish a causal relationship.
2447
2448 7.1 Introduction

2449 cADRs are amongst the most common AEs (2-3% of all AEs) reported throughout the
2450 lifecycle of medicinal products.[1,2] Since approximately 0.2-29.3% of patients with cADRs
2451 become severe and require hospitalization[3-7] it is essential to detect symptoms indicative
2452 of severity early during the process. While clinical trials offer precise data on the incidence
2453 (in the study population during the observation period of the trial) and severity of common
2454 AEs, the reports collected after authorization offer insights into the occurrence and nature of
2455 cADRs in the real-world setting. A close evaluation of preauthorization factors has shown
2456 that approximately 20% of safety issues leading to marketing withdrawals of a medicinal
2457 product or the addition of a boxed warning in its product labelling in the postauthorization
2458 phase were related to rare AEs such as serious skin and hypersensitivity reactions that are
2459 difficult to detect in preauthorization clinical trials.[8]
2460 7.2 Sources of data

2461 International guidelines, in particular those issued by CIOMS and ICH, outline the sources
2462 and analytical approaches for data on AEs arising from the use of medicinal products in the
2463 general population.[9,10] Data sources for postauthorization surveillance include
2464 spontaneous reports, electronic health records (EHRs), registries, along with clinical trial
2465 data and preclinical data.
2466 7.2.1 Spontaneous Adverse Event reporting systems
2467 Spontaneous reporting of AEs suspected to be an adverse reaction to a medicinal product is
2468 at the heart of postauthorization safety surveillance. Healthcare professionals and
2469 consumers spontaneously report AEs associated with an intervention, i.e. use of a medicinal
2470 product in an individual patient or consumer. The resulting ICSRs are designed to capture
2471 information that is relevant to the understanding of the AEs. ICSRs are submitted to the
2472 pharmaceutical company that is responsible for the medicinal product, and/or the applicable
2473 authority, in accordance with the spontaneous reporting system in that jurisdiction.
2474 Pharmaceutical companies are required to submit ICSRs to the regulatory authorities as per
2475 local regulation.
66
2476 In ICSRs, cADRs reported as serious, i.e. leading to or prolonging hospitalization or
2477 disability/incapacity, or are of a life-threatening nature and/or associated with a fatal
2478 outcome, or are otherwise medically serious[11], are specifically of interest in the detection
2479 and confirmation of serious SCAR. Medical history, concurrent medication along with start
2480 and stop dates, and the potential for skin/mucosal reactions (e.g. included in the label) are
2481 routinely used for assessment of a potential causal relationship to the medicinal products.
2482 Key information for appropriate causality assessment include the percentage of BSA,
2483 laboratory tests, timing and dose of suspected and/or concurrent medication as well as
2484 personal and family medical history. Furthermore, follow-up with the reporter of the ICSRs
2485 may be challenging and the source medical documents are rarely available. Often the AEs
2486 are not reported in real time[12] and underreporting is a well-recognized phenomenon of
2487 spontaneous reporting.[13] The aggregate data in large spontaneous reporting datasets are
2488 monitored and analysed for early identification of safety signals, especially for rare
2489 AEs.[14,15]
2490 The WHO’s Vigibase (over 20 million ICSRs[16], the EMA’s EudraVigilance data analysis
2491 system (EVDAS – 14.5 million ICSRs[17] and the US FDA MedWatch program (US FDA AE
2492 Reporting System – 2 million ICSRs/year[18] are monitored for events that are
2493 disproportionately reported for a medicinal product.[12-20] Medicinal product-event pairs of
2494 disproportionate reporting are reviewed to determine if there is a potential safety signal for
2495 further investigation of causality and potential need for regulatory action.[21] Patterns of
2496 spontaneous reporting in large datasets can be used to generate hypotheses on associations
2497 with specific or class of medicinal products[21-25] and build models to predict factors such as
2498 chemical structure[26] and/or molecular targets[27] linked to SCAR.
2499 7.2.2 EHRs
2500 EHRs contain detailed patient-level information collected by healthcare professionals for a
2501 variety of reasons, e.g. billing and reimbursement, laboratory parameters or medications
2502 prescribed for a specific event. In EHRs, the standard International Classification of
2503 Diseases Clinical Modification (ICD-CM) coding systems is used to structure the relevant
2504 information.[28] EHRs enable the study of common diseases, medicinal product response
2505 (efficacy or adverse) phenotypes and the genetic profile for several diseases.[29,30]
2506 The ICD-CM-based phenotyping algorithms applied to large insurance claims datasets such
2507 as US Kaiser Permanente and US FDA Sentinel Initiative and Medical Information Database
2508 Network can also inform the clinical course of the disease through longitudinal
2509 records[28,31], detection of rare AEs[32-37] and evaluation of safety signals with
2510 characterization of emerging safety topics following medicinal product authorization.[38,39]
2511 The correct diagnosis of SCAR is clinically challenging and routinely hindered by the
2512 circumstance of non-medicinal product related diseases such as EMM, being mistaken with
2513 SJS/TEN particularly in children.[40] Algorithms that combine clinical expertise, specific ICD
2514 codes, clinical course (including the duration of hospitalization) and number of medical
2515 encounters together with biomedical analytics have been used to explore patients with a
2516 high likelihood of rare AEs such as SJS/TEN.[41-45]

67
2517 In one study, the ICD-9 codes identified approximately 57 000 cases of potential SJS/TEN
2518 among approximately 60 million patients in 12 US research units and managed care
2519 organizations. The potential cases were further adjudicated by board-certified
2520 dermatologists. Multivariate models were used to detect factors independently associated
2521 with validated SJS/TEN case status.
2522 Length of hospitalization and application of new ICD codes specific to SJS/TEN increased
2523 the likelihood of SJS/TEN case status. The positive predictive value (PPV) of ICD-9 codes
2524 695.12-695.15 was 50% among hospitalized cases and of those hospitalized for three or
2525 more days, the PPV ranged from 57-92%. These results provide some support via a
2526 combination of search codes and search terms for identifying cases using EHR data.[41]
2527 A separate study demonstrated that the PPV for ICD codes specific to SJS/TEN was 29%.
2528 The addition of medicinal product-specific ICD codes with SJS/TEN-specific or erythema
2529 multiforme codes increased the PPV to 38% and maintained a 99.8% NPV for phenytoin-
2530 related SJS/TEN.[46]
2531 These exploratory and mining algorithms along with their performance metrics (e.g. PPV and
2532 NPV) rely on predetermined algorithm definition and selection criteria and need to adapt to
2533 the evolving clinical definitions of SCAR.[47] Because SJS/TEN is a rare and severe
2534 reaction, EHR-based algorithms should favour sensitivity over specificity (i.e. high NPV) with
2535 reasonable PPV. Innovative methodology and technology such as Boolean logic, natural
2536 language processing, and machine learning can be shown to produce reliable
2537 algorithms.[47]
2538 Furthermore, innovative technological solutions can be used to leverage the unstructured
2539 data (e.g. pictures, pathology records, clinical records including percentage of BSA and/or
2540 mucosal involvements) included in EHRs. Natural language processing and artificial
2541 intelligence offer the opportunity to automatically recognize and translate the unstructured
2542 data into specific data points accessible by automated search algorithms. The technology
2543 can also identify patterns to ascertain medicinal product causality particularly if multiple
2544 medicinal products were initiated within a short time period.[46]
2545 7.2.3 Registries and Networks

2546 In general, registries refer to both programmes that collect and store data and the records
2547 that are so created.[48] The National Committee on Vital and Health Statistics describes
2548 registries as “an organized system for the collection, storage, retrieval, analysis, and
2549 dissemination of information on individual persons who have either a particular disease, a
2550 condition (e.g. a risk factor) that predisposes [them] to the occurrence of a health-related
2551 event, or prior exposure to substances (or circumstances) known or suspected to cause
2552 adverse health effects.”[49] Additionally, EMA describes patient registries as “organised
2553 systems that use observational methods to collect uniform data on a population defined by a
2554 particular disease, condition or exposure, and that is followed over time” that can help
2555 monitor the safety of medicines.[50]
2556 The term patient registry is generally used to distinguish registries focused on health
2557 information from other record sets. Other terms also used to refer to patient registries include
2558 clinical registries, clinical data registries, disease registries and outcomes registries.[51,52]
2559 Coordination between registries to create a network may aid in data collection harmonization
2560 across different disease areas and interoperability between registries.[53] Registries include
2561 extensive records of healthcare knowledge beyond specific effects of a medicinal product of
2562 interest. The historical or contemporaneous control data included in the registries are
2563 increasingly used to gain insight into the “real world” data.[54]

68
2564 Registries or registry studies may be required as part of marketing authorization for several
2565 reasons:
2566 1) If the benefits, but more specifically the risks, are not completely understood at the
2567 time of authorization,
2568 2) Address a specific concern about safety or efficacy,
2569 3) Generate postauthorization data in more extensive patient populations while providing
2570 access in a restricted population.[55]
2571 Regulatory authorities may require “new registries” to be developed as well as the use of
2572 existing disease registries to perform “registry studies”.[54] FDA and EMA have developed
2573 detailed guidance for industry to address identified and potential safety concerns and how to
2574 deal with missing data.[56,57]
2575 A retrospective review identified a total of 73 registries for the 116 new drugs – 46 disease
2576 registries and 27 (exposure to a single) drug registries – approved by the Committee for
2577 Medicinal Products for Human Use (CHMP) in the EU between January 1, 2007 and December
2578 31, 2010. For nine drugs, the registry was a specific obligation imposed by the regulators. The
2579 level of innovation and the orphan status of the drugs were determinants positively predicting
2580 postauthorization registries (OR 10.3 [95% CI 1.0‐103.9] and OR 2.8 [95% CI 1.0‐7.5],
2581 respectively).[58]
2582 Effective coordination of medical, surgical, behavioural and basic scientific disciplines is
2583 required to efficiently reduce SCAR-related short- and long-term morbidity and mortality, and
2584 advance clinical care and research. Professional networks bring together SJS/TEN
2585 phenotype adjudication committees, centralized biological sample collection and repositories
2586 in platforms to study the pathogenesis and predictors of SCAR. These networks are
2587 leveraged to rigorously define criteria for clinical diagnosis, causality assessment, estimation
2588 of risk factors and centralized sample collection to aid the study of the mechanisms and
2589 search for treatment options.[46] Examples of registries and networks follow.
2590 RegiSCAR
2591 RegiSCAR is a multinational SCAR registry which includes medicinal product and biological
2592 samples aimed to reduce the medical and economic burden of SCAR on public health and to
2593 improve the safety of medication use. The objectives of RegiSCAR are:
2594 1) build a European Registry of SCAR for continuous surveillance of new medicinal
2595 products with adequate pharmaco-epidemiologic methodology and for providing
2596 reference information on SCAR
2597 2) organize a centralized collection of biological samples (plasma, lymphocytes, DNA and
2598 skin) to allow high quality studies on pharmacogenetics and investigations of the
2599 mechanisms of these reactions
2600 3) constitute a cohort of patients in order to study the outcome, prognosis factors,
2601 sequelae and impact on quality of life of these severe side effects of medicine.
2602 The RegiSCAR study includes all reports of SJS/TEN, AGEP and DRESS in patients
2603 hospitalized in one of the institutions participating in the network in six countries. In each
2604 country, a trained investigator interviews each case patient and collects information on
2605 medication use in the eight weeks prior to disease onset, recent infections, demographic
2606 information and relevant medical history in a standardized case record form. Each case
2607 record is ascertained by an international group of experts by means of a strict validation
2608 process.

69
2609 Skin biopsies (patients) and blood samples (patients and controls) are sent to a specialized
2610 tissue bank for separation and conservation of plasma, lymphocytes and DNA. The data
2611 registry provides estimates of the risks of medicinal products using case-control and case
2612 cross-over analyses as well as linkage to databases on medicinal product utilization.
2613 RegiSCAR also provides information on the outcome, allows the validation of prognosis
2614 indexes and gives insights on the effect of treatments.
2615 Biological samples are used to determine the phenotype, functions and antigenic specificity
2616 of lymphocytes isolated at the time of the reaction from the blood and skin of patients. In
2617 addition the samples are used to study the susceptibility genes by an association study
2618 directed first at candidate genes and second at the full genome by using 1000 single
2619 nucleotide polymorphisms and determine the serum level of a variety of cytokines that may
2620 have a prognostic value.[59]
2621 Australian Registry of Severe Cutaneous Adverse Reactions
2622 The Australian Registry of Severe Cutaneous Adverse Reactions (AUS-SCAR) is a
2623 multidisciplinary collaboration utilizing a range of clinical, health services and translational
2624 research methodologies to address the significant knowledge gaps in SCAR causality,
2625 prevention, diagnosis and treatment. AUS-SCAR collects prospective clinical data (medicinal
2626 product causality, treatments and outcomes) and bio-banked samples (DNA, blood and skin)
2627 from patients at 15 participating Australian sites. The data is subsequently used to examine
2628 SCAR epidemiology, causality, pharmacogenomic predictors and explore novel ex vivo/in
2629 vitro diagnostics.[60]
2630 International Registry for Toxic Epidermal Necrolysis
2631 The International Registry for Toxic Epidermal Necrolysis (IRTEN) is an international,
2632 observational web-based registry for prospective anonymized collection of clinical data and
2633 biological samples in individuals suffering of SJS/TEN. The IRTEN data is used to enhance
2634 the understanding of SJS/TEN including its epidemiology, clinical characteristics including
2635 outcome, short- and long-term complications, real-time data concerning causative medicinal
2636 products and therapy, with the ultimate aim of fostering improved patient care.[61]
2637 U.S. FDA Sentinel Initiative
2638 The Sentinel Initiative was launched in May 2008[62] in response to the FDA Amendments
2639 Act of 2007. The Initiative is the largest multisite distributed database in the world dedicated
2640 to marketed medical product safety. The Sentinel Operation Center leverages organizational
2641 partnerships in the areas of epidemiology, clinical medicine, pharmacy, statistics, health
2642 informatics, data sciences and network operations to support postauthorization safety
2643 analyses.[62] An important aspect of Sentinel’s active surveillance is to develop and
2644 understand the validity of algorithms for identifying health outcomes of interest.[62]
2645 Society of Dermatology Hospitalists SJS/TEN Study Group
2646 The Society of Dermatology Hospitalists (SDH) is a collaborative research effort of 18
2647 tertiary care centres. Retrospectively, SDH member institutions collected information on
2648 SJS/TEN patients related to disease course, management and outcomes. The SDH
2649 database includes 405 SJS/TEN cases in the United States between 2000 and 2015, with
2650 most treated after 2010. In this cohort, 66% of patients met the definition criteria for TEN
2651 (>30% BSA denuded) or SJS/TEN overlap (10–30% BSA denuded) at the time of admission.

70
2652 At the time of admission, the severity of illness score for TEN (SCORTEN)[63] predicted
2653 mortality for the cohort to be 20%. Actual mortality of patients in the cohort was 13.7%,
2654 yielding a standardized mortality ratio of 0.69 (95% confidence intervals 0.57, 0.78).
2655 Medications accounted for 91.3% of cases, predominantly implicating
2656 trimethoprim/sulfamethoxazole (26%).[46]
2657 Canadian Pharmacogenomics Network for Drug Safety
2658 The Canadian Pharmacogenomics Network for Drug Safety (CPNDS) is pan-Canadian active
2659 surveillance network that compiles the detailed information collected by trained active
2660 surveillance clinicians. The CPNDS database includes detailed clinical information with 93 974
2661 reports of medication use, including 10 475 reports of ADRs[64], which can be used to identify
2662 novel predictive genomic markers of severe ADRs in children and adults. The CPNDS was the
2663 first group to confirm the role of HLA markers for carbamazepine-related skin reactions in
2664 children.[65]
2665 The CPNDS actively investigates both previously identified pharmacogenomic biomarkers and
2666 novel genomic variations associated with severe reactions. Collaboration with the EpiPGX
2667 Consortium has led to the identification of over 80 SCAR cases related to anticonvulsants.
2668 Additionally, the CPNDS has published clinical practice guidelines for carbamazepine-related
2669 ADRs[66] and collaborates with several consortia to update guidelines and develop
2670 pharmacogenomic panels for commercial use that include ADR pharmacogenomic markers.
2671 International Consortium on Drug Hypersensitivity Network
2672 The International Consortium on Drug Hypersensitivity (ITCH) network was established to
2673 recruit patients with SCAR and includes approximately 1500 phenotyped cases from 12
2674 countries with associated genetic data.[67] The ITCH cohort has been used to identify
2675 medicinal product-specific genetic predisposing factors and genetic factors predisposing to
2676 SJS/TEN regardless of medicinal product etiology. GWASs conducted on 1260 SCAR cases
2677 in the cohort included quality control procedures (i.e. controlling for population stratification,
2678 imputation using the latest releases of genomic data and validation of imputed genetic
2679 variants).
2680 The ITCH database includes 177 SJS/TEN cases from Caucasian patients from three ethnic
2681 groups: Spanish, Italian and Northern European. Evaluation of the 177 SJS/TEN cases
2682 identified an HLA-B allele that is associated with SJS/TEN irrespective of drug. This HLA-B
2683 allele is present at 0.02% of the general Caucasian population (n = 9237 not exposed to drug)
2684 but is found at 100-fold higher frequency among SJS/TEN cases.[68] Medicinal product-
2685 specific analysis of cases in the ITCH cohort have replicated HLA allele associations
2686 previously identified in other populations. In 13 European patients with allopurinol-related
2687 SCAR of whom nine had SJS, HLA-B*58:01 was identified at a genome-wide significance level
2688 with an odds ratio of 36.[68] While the association of HLA-B*58:01 with SJS was just below
2689 genome-wide significance in this population, the odds ratio was higher at 45,[68] which is
2690 consistent with previous data suggesting that HLA-B*58:01 is present in approximately 60% of
2691 allopurinol-related SJS/TEN patients of European ancestry.
2692 Moreover, the ITCH network includes African recruitment sites. Evaluation of the African
2693 cohort has identified the association of HLA-C*04:01 with SJS/TEN secondary to nevirapine.
2694 Additional analysis of the interaction of HLA-C*04:01 with the endoplasmic reticulum
2695 aminopeptidase genes, which influence peptide processing, demonstrated that endoplasmic
2696 reticulum aminopeptidase 2 may have a protective effect.[69]
2697

71
2698 7.3 Assessing causality with postauthorization information

2699 The causality assessment of a suspected ADR is an essential approach in

2700 pharmacovigilance, as an attempt to investigate the association between the suspected ADR
2701 and the use of a certain medicinal product. Safety information collected during the
2702 postauthorization phase is one of the main sources for identifying SCAR because these
2703 reactions are usually rare and therefore may only be recognized after a medicinal product
2704 has been approved and used by a large number of patients.[70]
2705 7.3.1 Causality assessment for ICSRs

2706 Given the rare occurrence but high risk of adverse sequelae including fatal outcomes of
2707 SCAR, spontaneous reporting of suspected SCAR by healthcare professionals is key for the
2708 assessment and management of SCAR risk in the postauthorization phase. Additionally,
2709 applicable reporting systems including relevant case details permit a meaningful assessment
2710 of SCAR subsequent to treatment with a particular medicinal product. (See also Appendix 2
2711 Examples of Targeted Follow Up Forms). The determination of causality for ICSRs, in pre-
2712 and postauthorization phases alike, refers mainly to medical assessment as well as the use
2713 of defined algorithms (e.g. ALDEN score for SJS/TEN) (Chapter [Link] Algorithm of drug
2714 causality for epidermal necrolysis).
2715 There are different causality classifications available (e.g. WHO-UMC scale, Naranjo scale)
2716 [71,72], but preferably it is simplified to a binary yes/no causality[73], also in line with
2717 regulatory reporting requirements. However, to date there is no universally-accepted
2718 causality assessment scale. When assessing medicinal product causality in a patient with
2719 SCAR, several factors should be taken into consideration including SCAR type, day of
2720 symptom onset (“index day”), medicinal product notoriety, time since medicinal product
2721 intake and onset of reported event, dechallenge/rechallenge information, comorbidities,
2722 concomitant medications, and plausible or biologic or pharmacologic explanation. In general,
2723 for assessment of temporal relationship of medicinal product intake to event onset, i.e. five
2724 times the elimination half-life (“rule of five”) can be used. However, since elimination of a
2725 medicinal product varies from person to person due to factors like age, weight, other
2726 medications taken, as well as kidney function and/or liver function, the use of the elimination
2727 half-life can only be an estimate of how long it may take for the medicinal product to be
2728 removed from the body. Challenges for causality assessment especially in postauthorization
2729 reporting are incomplete case information, use of multiple medicinal products and inter-
2730 current or chronic underlying illness.

72
2731 7.3.2 Risk management planning and pharmacovigilance strategies

2732 With the potential for severe and life-threatening outcomes, additional risk management
2733 measures, in addition to routine risk minimization measures such as product labelling, may
2734 need to be implemented to prevent or reduce the severity of outcomes from SCAR. These
2735 risk minimization measures are discussed in Chapter 8.
2736
2737 References

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51 Dokholyan RS, et al. Regulatory and ethical considerations for linking clinical and administrative databases. Am Heart J. Jun
2009;157(6):971-982. PubMed Abstract
52 Hammill BG, et al. Linking inpatient clinical registry data to Medicare claims data using indirect identifiers. Am Heart J
2009;157:995-1000. PubMed Abstract
53 EMA. Patient Registry Initiative – Strategy and Mandate of the Cross-Committee Task Force. 5 May 2017.
54 Jonker CJ, et al. Drug Registries and Approval of Drugs: Promises, Placebo, or a Real Success? Clin Ther. 2018
May;40(5):768-773. PubMed Abstract
55 Eichler HG, et al. Adaptive licensing: taking the next step in the evolution of drug approval. Clin Pharmacol Ther. 2012
Mar;91(3):426-37. PubMed Abstract
56 FDA. Guidance for Industry. Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment. In: US
Department of Health and Human Services, editor; 2005.
57 EMA. Guideline on good pharmacovigilance practices (GVP), module V – risk management systems (Rev 2). In. 2017.
58 Jonker CJ, et al. Registries supporting new drug applications. Pharmacoepidemiol Drug Saf . 2017 Dec;26(12):1451-1457.
PubMed Abstract
59 RegiSCAR. The RegiSCAR Project. In.
60 (AUS-SCAR) ARoSCAR. In; 2019.
61 (IRTEN) IRfTEN. In.
62 Schneider G, et al. A systematic review of validated methods for identifying erythema multiforme major/minor/not otherw ise
specified, Stevens-Johnson Syndrome, or toxic epidermal necrolysis using administrative and claims data. Pharmacoepidemiol
Drug Saf. 2012 Jan;21 Suppl 1:236-9. doi: 10.1002/pds.2331. PubMed Abstract
63 Bastuji-Garin S, et al. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol. 2000
Aug;115(2):149-153. PubMed Abstract
64 Tanoshima R, et al. Analyses of Adverse Drug Reactions-Nationwide Active Surveillance Netw ork: Canadian
Pharmacogenomics Netw ork for Drug Safety Database. J Clin Pharmacol. 2019 Mar;59(3):356-363. PubMed Abstract
65 Amstutz U, et al. HLA-A 31:01 and HLA-B 15:02 as genetic markers for carbamazepine hypersensitivity in children. Clin
Pharmacol Ther 2013;94:142-149. PubMed Abstract
66 Amstutz U, et al. Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-
induced hypersensitivity reactions. Epilepsia. 2014 Apr;55(4):496-506. PubMed Abstract
67 Pirmohamed M, et al. Phenotype standardization for immune-mediated drug-induced skin injury. Clin Pharmacol Ther. 2011
Jun;89(6):896-901. PubMed Abstract
68 Yip VL, Pirmohamed M. The HLA-A*31:01 allele: influence on carbamazepine treatment. Pharmgenomics Pers Med. 2017
Jan 31;10:29-38. PubMed Abstract
69 Carr DF, et al. Genome-w ide association study of nevirapine hypersensitivity in a sub-Saharan African HIV-infected population.
J Antimicrob Chemother. 2017;72(4):1152-1162. (Abstract Journal Full Text)
70 Demoly P, et al. International Consensus on drug allergy. Allergy. 2014 Apr;69(4):420-37. PubMed Abstract
71 Naranjo CA, et al. A method for estimating the probability of adverse drug reactions. Clin. Pharmacol. Ther. 1981
Aug;30(2):239-245. Clin. Pharmacol. Ther. Abstract
72 World Health Organization (WHO)-Uppsala Monitoring Centre. The use of the WHO-UMC system for standardized case
74
causality assessment. Available from: [Link]
 73 CIOMS. Management of Safety Information from Clinical Trials, Report of CIOMS Working Group VI, 2005.
2738
2739 Additional references for sections 7.3.1 and 7.3.2
2740 1) EMA Good pharmacovigilance practice (GVP) Module IX, Signal management (Rev 1), 9
2741 October 2017 EMA/827661/2011
2742 2) Management of Safety Information from Clinical Trials, Report of CIOMS Working Group VI, 2005
2743 3) Wisniewski AFZ, et al. Good Signal Detection Prac tices: Evidence from IMI PROTECT. Drug Saf. 2016.
2744 4) EMA Good pharmacovigilance practice (GVP) Module VII, Periodic safety update report (Rev 1), 9
2745 December 2013 EMA/816292/2011
2746 5) ICH guideline E2C (R2) Periodic benefit-risk evaluation report
2747 6) FDA white paper, Data Mining at FDA, 2018 ([Link] data-
2748 mining-fda-white paper)
2749 7) U.S. Food & Drug Administration. ICH guideline E2C (R2) on periodic benefit–risk evaluation report
2750 (PBRER) Step 5, [Link]
2751 8) Ibrahim H, et al. Signal Detection in Pharmacovigilance: A Review of Informatics -driven Approaches for the
2752 Discovery of Drug-Drug Interaction Signals in Different Data Sources, Artificial Intelligence in the Life
2753 Sciences 1 (2021)
2754 9) Sriramakrishnan GV, et al. Pharmacovigilance, signal detection using statistical data mining
2755 methods, International Journal of Engineering & Technology, 7 (2.31) (2018) 122-126
2756
2757

75
2758 CHAPTER 8.
2759 RISK MINIMIZATION
2760
2761 Chapter summary

2762 Prompt evaluation and discontinuation of the potentially offending medicinal product(s) are
2763 the most appropriate immediate interventions in the management of SCAR once detected,
2764 based on the benefit-risk balance of the medicinal product for the given patient.
2765 Key developments in SCAR research include new technologies allowing the identification of
2766 genetic risk factors with improved sensitivity, specificity and efficiency.
2767 Routine risk minimization measures and additional risk minimization measures for SCAR are
2768 presented with examples.
2769 Conclusions or recommendations

2770 The recognition and diagnosis of SCAR can be challenging. Awareness of patients,
2771 caregivers, and HCPs of the risk of SCAR with medicinal products is paramount to ensure
2772 timely discontinuation of the medicinal product and administration of appropriate treatment,
2773 given their potential for severe and life-threatening outcomes. Hence, risk management,
2774 comprised of routine and additional risk minimization measures, is essential to ensure the
2775 safe use of these medications.
2776 The selection of risk minimization tools to inform patients and HCPs of a medication’s
2777 benefits and risks is vital for patients to make informed treatment decisions. Risk
2778 minimization for SCAR ensures awareness of recommendations for screening to identify
2779 patients at risk, characterization of the risk for timely recognition and recommended actions
2780 to monitor, manage and mitigate these risks to prevent or improve potential clinical adverse
2781 outcomes.

2782 8.1 Introduction

2783 Risk is defined as “[t]he probability of developing an undesirable outcome relating to the
2784 quality, safety or efficacy of the medicinal product”.[1] Risks are characterized by the
2785 following ADR attributes: severity (intensity), frequency, potential for prevention or early
2786 detection, extent of reversibility and range of outcomes. The regulatory categorization of AEs
2787 relevant to risks as “serious” or “non-serious” had been primarily used to provide guidelines
2788 for pharmaceutical companies for AE report submission to regulatory authorities.
2789 Seriousness should be distinguished from the severity of an event, which is the intensity of
2790 the event. Severity of an event, in addition to other attributes and patient risk factors, could
2791 lead to patient clinical outcomes that may need a particular type of intervention to mitigate.
2792 Grading of severity (i.e. mild, moderate, severe) may be dependent on medical judgement
2793 and patient perspective; however, grading systems for AEs and laboratory abnormalities are
2794 currently being utilized (e.g. CTCAE, Drug-Induced Liver Injury Network). The assessment of
2795 the severity of an adverse reaction or risk, its frequency, and other attributes and risk factors,
2796 are necessary to understand the impact of the adverse reaction on the benefit-risk profile of
2797 a product.
2798
2799
2800
76
2801 Categorical definitions of risks are utilized in regulatory risk management documents. The
2802 ICH Pharmacovigilance Guidance has provided the following categories of risks :[1]

2803  Identified Risk: an untoward occurrence for which there is adequate evidence of an
2804 association with the medicinal product of interest,
2805  Potential Risk: an untoward occurrence for which there is some basis for suspicion of
2806 an association with the medicinal product of interest but where this association has not
2807 been confirmed,
2808  Important identified risk and important potential risk: an identified or potential risk that
2809 can impact the benefit-risk profile of the product or have implications for public health.
2810 What constitutes an important risk will depend on several factors, including the
2811 seriousness of the risk, and the impact on the individual and public health. Typically,
2812 any risk that is likely to be included in the Contraindications or Warnings and
2813 Precautions section of the product information should be considered important.
2814 An additional concept that could constitute a form of risk for a medication and is therefore
2815 part of risk management activities and documents pertains to missing Information, which are
2816 gaps in knowledge about the safety of a medicinal product for a certain anticipated use or for
2817 use in particular patient populations.[2]
2818 8.2 Risk management

2819 Risk management entails the following reiterative cycle: identification,

2820 assessment/characterization, prevention/mitigation and measurement of the effectiveness of
2821 the risk minimization measures.[1,3] Once risks have been identified and assessed for
2822 clinical relevance, potential patient outcomes and overall impact, risk management strategies
2823 are then planned and developed. Risk management occurs throughout the medicinal product
2824 lifecycle.
2825 The primary objective of risk management strategies is to have better patient outcomes. To
2826 do this, pharmacovigilance activities for data collection and assessment are instituted to
2827 understand and characterize the risk. Additionally, risk minimization measures to reduce the
2828 frequency that the risk will occur (termed “risk prevention”) or/and reduce the severity when it
2829 does occur (termed “risk mitigation”) and reduce undesirable outcomes, may be
2830 implemented.[1] Although many risks cannot be eliminated, their frequency and/or severity
2831 may be substantially reduced by putting an appropriate risk minimization plan in place.
2832 Given that SCAR could occur, albeit infrequently, during clinical development, additional
2833 safety data may be needed either to provide additional evidence to further support the
2834 causal association between SCAR and an implicated medication or further characterize this
2835 risk in the postauthorization setting, where increased utilization by the indicated population is
2836 expected. Beyond routine standardized surveillance for SCAR, additional pharmacovigilance
2837 activities may also be required.
2838 These additional pharmacovigilance activities may include active and targeted surveillance
2839 in collaboration with key dermatology stakeholders or organizations that collect safety data
2840 relevant to SCAR, such as registries, networks and tertiary referral medical centres.
2841 Importantly, additional pharmacovigilance activities in the form of Postmarketing
2842 Requirements/Commitments and Post-Authorization Safety Studies may be required as a
2843 condition of authorization to further characterize the risk of SCAR from a medicinal product
2844 in the indicated population. The types of safety studies conducted to further characterize
2845 risks in the postauthorization setting include postauthorization observational studies, non-
2846 interventional safety studies, postauthorization surveillance safety studies[4] and pharmaco-
2847 epidemiologic studies utilizing real-world data.

77
2848 At authorization, risk management activities are described in detail in documents such as the
2849 Risk Management Plan (RMP) in the EU and the Pharmacovigilance Plan (PV Plan) and
2850 Approval Letters in the US. These risk management documents describe the activities and
2851 studies that will be conducted in the postauthorization setting to identify and/or further
2852 characterize the safety profile of the authorized medicinal product and the measures to
2853 prevent or minimize the risks associated with the medicinal product.[5]
2854 There are two types of risk minimization measures, routine and additional, which are further
2855 discussed below.
2856 8.3 Routine risk minimization measures

2857 Risk minimization measures that relate to standard activities and provide routine information
2858 on the benefits and risks of a medicinal product to the patient and HCP for all medicinal
2859 products are classified as routine risk minimization measures.
2860 These include product information, which is proposed by marketing authorization holders
2861 and agreed by regulatory authorities providing patients and HCPs on the appropriate and
2862 safe use of a medicinal product[1] (e.g. US Prescribing Information and for specific products,
2863 the Medication Guide, EU SmPC, the Canadian Product Monograph, the Japanese Product
2864 Information; patient information brochures; information on medicinal product packaging) as
2865 well as packaging size appropriate to the typical treatment duration and a risk-appropriate
2866 legal status of the product (i.e. prescription-only medication).[6]
2867 The information and recommendations outlined in the product information[1] should
2868 therefore support the optimal and safe use of a medicinal product in clinical practice with the
2869 goal of providing the appropriate medicine at the correct dose and timing, with an awareness
2870 of the benefits and risks of the product.
2871 Especially for medicinal products for which a causal association with a severe or potentially
2872 life-threating outcome of an ADR has been identified, adequate information and
2873 recommendations for monitoring and treatment are needed in the medicinal product’s patient
2874 brochure to ensure awareness and the actions that should be taken to manage the risk,
2875 including reporting specific signs and symptoms to HCPs[1] (e.g. US Patient Package Insert
2876 and Medication Guide or EU package leaflet).
2877 Information relevant to risks and severe and/or serious ADRs are usually included in specific
2878 sections of the label, such as “Warnings and Precautions” and “Undesirable Effects/Adverse
2879 Reactions,” and are reflected in the patient brochure.

78
2880 In addition to information regarding the character, severity, outcome(s) of the risk or ADR, an
2881 estimate of the frequency should be provided and expressed in a standard category of
2882 frequency.[7] If the frequency cannot be estimated from the clinical trials or postauthorization
2883 study data, the term ‘not known’ may be used. This may be applicable when the ADR has
2884 been identified from spontaneous reporting without knowledge of the exposure at population
2885 level.
2886 In general, the language used to describe the risks in the product information should be clear
2887 and concise. Detailed recommendations from regulatory authorities regarding the description
2888 and characterization of the risks, together with actions that may prevent and/or mitigate such
2889 risks can be found in regulatory guidance documents, including the EU Guideline on the
2890 Summary of Product Characteristics[8] and the U.S. FDA Guidance for Industry for product
2891 information.[9,10]
2892 Examples of language used to describe and/or characterize the risk of SCAR in product
2893 information of authorized medications can be found in Appendix 1.
2894 For some medicinal products, additional risk minimization measures may be required as part
2895 of the marketing authorization terms in addition to the product information, patient brochure,
2896 and product container/package information
2897 8.3.1. Routine risk minimization measures for SCAR

2898 SCAR, as described in Chapter 1 of this Report, are diverse cADRs that range from
2899 common, mild and self-limited cutaneous reactions with an estimated incidence of 0.3% to
2900 8%, to uncommon potentially life-threatening forms of delayed systemic hypersensitivity.
2901 Cutaneous clinical manifestations range from maculopapular exanthema, urticaria, FDE,
2902 phototoxic and photo-allergic eruptions to erythema-multiforme-like reactions.
2903 At baseline, routine risk minimization measures are necessary to provide prescribers and
2904 patients with information relevant to cADRs and SCAR. These include product information, the
2905 patient brochure and container/package information, as previously stated. (See examples:
2906 Medicinal Product A, Medicinal Product B, Medicinal Product C, Medicinal Product D)
2907 Of note, terminologies used in the product information should be considered carefully to
2908 ensure standardization and consistency. Terminologies should be standardized based on
2909 Medical Dictionary for Regulatory Activities (MedDRA)[11], as agreed in the ICH framework.
2910 For SCAR, the following MedDRA Preferred Terms (PTs) are available under the MedDRA
2911 version 26.1 Preferred Terms: ‘Stevens-Johnson syndrome’, ‘Toxic epidermal necrolysis’,
2912 ‘Acute generalized exanthematous pustulosis’, ‘Drug reaction with eosinophilia and systemic
2913 symptoms’, ‘Generalized bullous fixed drug eruption’, ‘SJS-TEN overlap’ and ‘AGEP-
2914 DRESS’.
2915 Because SCAR may potentially be severe and/or serious and possibly life-threatening, risk
2916 management of SCAR may necessitate strategies beyond these routine risk minimization
2917 measures. These will be addressed in the following sub-section (Additional risk minimization
2918 measures).

79
2919 8.4 Additional risk minimization measures

2920 In addition to routine measures adopted to address medicinal product risk, additional risk
2921 minimization measures are “interventions intended to prevent or reduce the probability of an
2922 undesirable outcome or reduce its severity should it occur”.[3] Additional risk minimization
2923 measures should be proposed when deemed essential for the safe and effective use of the
2924 medicinal product.
2925 These measures aim to ensure the following:
2926 • Guide appropriate patient selection with the exclusion of patients where use is
2927 contraindicated,
2928 • Support on-treatment monitoring of important risks and/or
2929 • Early identification and management of an adverse reaction to limit its
2930 severity/seriousness and mitigate adverse outcomes.[12]
2931 8.4.1 Additional risk minimization measures for SCAR

2932 In addition to routine risk minimization (e.g. product information), further risk minimization
2933 measures have been developed and implemented to expound on information found in the
2934 product information regarding risks, outcomes, screening, identification of patients at risk,
2935 monitoring and management. In the context of SCAR, these may include the following
2936 activities/programmes:

2937  Educational tools/training programmes, used to provide targeted information regarding

2938 risks to HCPs or patients (e.g. patient alert card), to supplement product information,

2939  Risk Evaluation and Mitigation Strategies (REMS), a medicinal product safety program
2940 implemented in the U.S. and required for certain medications to inform, educate and
2941 reinforce actions to reduce the frequency and/or severity of a safety outcome, such as
2942 a SCAR.[13] Elements to assure safe use (ETASU) may be a component of a REMS
2943 programme, in addition to materials distributed to HCPs, pharmacists, and nurses and
2944 handouts for patients, such as Medication Guides[14]

2945  Other risk minimization measures, such as Direct Healthcare Professional

2946 Communication (DHPC) or Dear Health Care Provider Letter (DHCP).
2947 An example of an additional risk minimization measure implemented for a SCAR associated
2948 with a medicinal product (Medicinal Product E) is provided below. Details can be found in
2949 Appendix 1.
2950 8.4.2. Educational tools for healthcare professionals

2951 Educational tools for HCPs provide specific recommendations on the use (what to do), the
2952 contra-indications (who the product should not be prescribed to), and/or warnings (e.g. how
2953 to prevent or manage the described risk or adverse reaction) associated with the medicinal
2954 product and the key risks that require additional minimization measures.[12] These
2955 educational tools may include guidance on prescribing (including selection of patients,
2956 testing, monitoring), special administration procedures and details of information to be given
2957 to patients and other information on managing risk.
2958 The type and format of a particular tool is dependent on the target audience, message and
2959 modalities of use of the medicinal product. Tools can include HCP training programmes
2960 featuring websites, brochures, posters and check lists (e.g. if certain actions need to be
2961 performed prior to prescribing a medication).
80
2962 For the example in Appendix 1 (Medicinal Product E), HCP educational programmes were
2963 developed to increase HCP awareness and understanding of the risk and expand on
2964 information that is included in the medicinal product information. These were published on a
2965 website aimed at HCPs. In addition, a slide presentation was included and provides
2966 guidance on HLA-B screening, information about diagnosis of hypersensitivity reaction,
2967 management and avoidance of rechallenge.
2968 8.4.3. Educational tools for patients and/or caregivers

2969 Educational tools targeting patients and caretakers aim to increase their awareness of risks
2970 associated with a medicinal product to inform their decision to initiate treatment, awareness
2971 of signs and symptoms of adverse reactions and/or risks for early recognition and
2972 awareness of the course of action to take should any of these sign or symptoms occur.[12] A
2973 patient alert card is a tool designed to inform patients of a particular risk.[1] It is used when
2974 patients are required to carry on them essential information about their current therapy and
2975 the main risks associated with this therapy The purpose is to alert HCPs of the risks and if
2976 needed, ensure medical intervention. In the US, some medicinal products are dispensed to
2977 patients with a Medication Guide, as part of authorized product information.
2978 The information contained in the patient alert card should be succinct and be kept to the
2979 minimum necessary to convey the key minimization messages and required action.[13] For
2980 the example of Medicinal Product E above, the patient alert card contains information about
2981 the clinical presentation of the hypersensitivity reaction and guides patients to call their
2982 HCPs immediately for guidance in case two or more of the following signs or symptoms
2983 occur: fever, skin rash (redness and/or itching), nausea, vomiting, diarrhoea, abdominal
2984 pain, severe tiredness, achiness or general ill feeling.

81
2985 8.4.4. Other examples of additional risk minimization measures

2986 Other examples of additional risk minimization measures are the DHPC in the EU, and the
2987 DHCP Letters and Medication Guide (as part of a REMS programme) in the U.S.
2988 DHPC are communications by which important information is delivered directly to individual
2989 HCPs by a marketing authorization holder or by a competent authority, to inform them of the
2990 need to take certain actions or adapt their practices in relation to a medicinal product.[15]
2991 DHCP Letters are correspondences to HCPs that are often in the form of a mass mailing
2992 from the manufacturer or distributor of a human medicinal product or from the US FDA.
2993 DHCP letters alert HCPs about new or updated information regarding a human medicinal
2994 product.[16] In the context of SCAR, DHPCs should be considered when there is a need to
2995 inform HCPs to take immediate action or change current practice in relation to a medicinal
2996 product. These situations include:

2997  a new warning or precaution of a SCAR risk in the product information,

2998  identification of a new risk of SCAR or change in the frequency or severity of a known
2999 SCAR risk,

3000  new recommendations for preventing or treating SCAR,

3001  an ongoing assessment of an important potential risk of SCAR, for which the data that
3002 is available at a particular point in time are insufficient to take regulatory action (in this
3003 case, the DHPC should encourage close monitoring of the safety concern in clinical
3004 practice as well as reporting and possibly provide information on how to minimize the
3005 potential risk).
3006 The content of the proposed DHPC should be agreed between the marketing authorization
3007 holder and the regulatory authority. An example of a DHPC issued in response to the risk of
3008 SCAR associated with a medicinal product (Medicinal Product F) is described in Appendix 1.
3009 8.5. Evaluating the effectiveness of risk minimization

3010 When an additional risk minimization measure is developed to prevent or mitigate a risk such
3011 as SCAR, planning is required on evaluating the effectiveness of the risk minimization tools,
3012 interventions or programmes. This is an integral and critical component of risk management
3013 to ensure that risk minimization measures change the behaviour of patients and HCPs and
3014 leads to improved patient outcomes.
3015 Studies have been conducted in which a number of approaches have been applied to
3016 evaluate the effectiveness of the risk minimization measures, interventions or programmes.
3017 The objectives of these studies are to identify factors that lead to a desired outcome and
3018 understand how the proposed tools, interventions or programmes impact these factors and
3019 outcomes when used in a ‘real-world’ setting.

82
3020 The initial step is to develop a study protocol prior to the implementation of the
3021 tool/intervention/programme that is being evaluated. The study should measure the
3022 effectiveness of a programme in several different aspects (i.e. domains or dimensions):
3023 programme coverage, efficacy/effectiveness, adoption, implementation and maintenance.
3024 Next, the study should evaluate the degree to which a proposed risk minimization
3025 programme is implemented in ‘real-world’ conditions as intended (implementation fidelity) in
3026 key areas (exposure, content, frequency, duration). Lastly, to appropriately evaluate the
3027 effectiveness of a risk minimization tool/intervention/programme, the study should provide a
3028 detailed analysis plan with prespecified outcome indicators that use clinically-relevant risk
3029 prevention or mitigation endpoints and thresholds which, in turn, must be met to determine
3030 success. Considerations include the use of appropriate comparators, performance measures
3031 and time points for analysis.[1]
3032 Details of the various approaches to consider when developing studies to evaluate the
3033 effectiveness of risk minimization measures are found in the Report of CIOMS Working
3034 Group IX: Practical Approaches to Risk Minimisation for Medicinal Products. Given the
3035 evolving landscape of risk management, the framework and methodologies that guide the
3036 development of effectiveness studies will continue to change to ensure that evaluations
3037 remain pragmatic and robust.[1]
3038 References

1 CIOMS. Practical Approaches to Risk Minimisation for Medicinal Products, Report of CIOMS Working Group IX; 2014
2 EMA. Guideline on good pharmacovigilance practices (GVP) Module V – Risk management systems (Rev 2). 2017
3 CIOMS. Cumulative glossary with a focus on pharmacovigilance. Geneva, Sw itzerland: Council for International
Organizations of Medical Sciences (CIOMS), 2022.
4 FDA. w [Link]/drugsatfda_docs/appletter/2013/[Link]
5 EMA. Guideline on GVP Annex 1 Definitions, 2014.
6 EMA. Guideline on good pharmacovigilance practices (GVP) 4 Module XVI – Risk minimisation measures: selection of tools
and effectiveness indicators (Rev 3), 1 February 2021 EMA/204715/2012
7 CIOMS. Guidelines for Preparing Core Clinical Safety Information on Drugs . Report of CIOMS Working Group III. 1995
8 European Commission. A Guideline on Summary of Product Characteristics (SmPC). Revision 2. 2009.
9 FDA. Guidance for Industry Warnings and Precautions, Contraindications, and Boxed Warnings Sections of Labeling for
Human Prescription Drug and Biological Products —Content and Format. [Link]
10 FDA. Guidance for Industry Adverse Reactions Section of Labeling for Human Prescription Drug and Biological Products —
Content and Format. [Link]
11 MEdDRA [Link]
12 EMA. Guideline on good pharmacovigilance practices (GVP) Module XVI – Risk minimisation measures: selection of tools
and effectiveness indicators (Rev 2)
13 FDA. [Link]
14 FDA. [Link]
15 FDA [Link]
16 FDA Guidance on Dear Health Care Provider Letter: Improving Communication of Important Safety Information
3039

83
3040 APPENDIX 1
3041 PRODUCT LABEL EXAMPLES
3042 Medicinal Product A

3043 Product Label

3044 4.4 Special warnings and precautions for use
3045 Hypersensitivity syndrome, SJS and TEN
3046 Medicinal Product A should be withdrawn immediately when a skin rash or other evidence of
3047 sensitivity occurs as this could result in more serious hypersensitivity reactions, which can
3048 manifest in many different ways, including maculopapular exanthema, hypersensitivity
3049 syndrome (also known as DRESS) and SJS/TEN.
3050 These reactions are clinical diagnoses, and their clinical presentations remain the basis for
3051 decision making. If such reactions occur at any time during treatment, Medicinal Product A
3052 should be withdrawn immediately. Rechallenge should not be undertaken in patients with
3053 DRESS and SJS/TEN. Corticosteroids may be beneficial in overcoming hypersensitivity skin
3054 reactions. Please see “Undesirable effects” table below.
3055 4.8 Undesirable effects
System Organ Class Frequency Adverse Reaction
Immune system disorders Uncommon Hypersensitivity reactions
Common Rash
Rare Stevens-Johnson Syndrome,
Skin and subcutaneous tissue Toxic Epidermal Necrolysis
disorders Very rare Fixed Drug Eruption
3056
3057 2. Serious hypersensitivity reactions, including skin reactions associated with exfoliation,
3058 fever, lymphadenopathy, arthralgia and/or eosinophilia including SJS and TEN occur rarely
3059 (see above table). Associated vasculitis and tissue response may be manifested in various
3060 ways including hepato-splenomegaly, hepatitis, vanishing bile duct syndrome (destruction
3061 and disappearance of the intrahepatic bile ducts), renal impairment and, very rarely,
3062 seizures. Other organs may also be affected (e.g. liver, lungs, kidneys, pancreas,
3063 myocardium, and colon).Very rarely acute anaphylactic shock has been reported. Such
3064 reactions may occur at any time during treatment. Medicinal Product A should be withdrawn
3065 immediately and permanently.
3066 Rechallenge should not be undertaken in patients with hypersensitivity syndrome and
3067 SJS/TEN. Corticosteroids may be beneficial in overcoming hypersensitivity skin reactions.
3068 When generalized hypersensitivity reactions have occurred, renal and/or hepatic disorder
3069 has usually been present particularly when the outcome has been fatal. Corticosteroids may
3070 be beneficial in overcoming hypersensitivity skin reactions.
3071 6. Skin reactions are the most common reactions and may occur at any time during
3072 treatment. They may be pruritic, maculopapular, sometimes scaly, sometimes purpuric and
3073 rarely exfoliative, such as SJS/TEN. The highest risk for SJS and TEN, or other serious
3074 hypersensitivity reactions, is within the first weeks of treatment.

84
3075 The best results in managing such reactions come from early diagnosis and immediate
3076 discontinuation of any suspect medicinal product. Medicinal Product A should be withdrawn
3077 immediately should such reactions occur. After recovery from mild reactions, allopurinol
3078 may, if desired, be re-introduced at a small dose (e.g. 50 mg/day) and gradually increased. If
3079 the rash recurs, Medicinal Product A should be permanently withdrawn as more severe
3080 hypersensitivity may occur.
3081 If SJS/TEN, or other serious hypersensitivity reactions cannot be ruled out, DO NOT re-
3082 introduce Medicinal Product A due to the potential for a severe or even fatal reaction. The
3083 clinical diagnosis of SJS/TEN remains the basis for decision making. If such reactions occur
3084 at any time during treatment, Medicinal Product A should be withdrawn immediately and
3085 permanently.
3086 Medicinal Product B
3087 Product Label
3088 4.4 Special warnings and precautions for use
3089 Warnings
3090 […]
3091 Patients and their relatives should be made aware of early toxic signs and symptoms
3092 indicative of a potential haematological problem, as well as symptoms of dermatological or
3093 hepatic reactions. If reactions such as fever, sore throat, rash, ulcers in the mouth, easy
3094 bruising, petechial or purpuric haemorrhage appear, the patient should be advised to consult
3095 the physician immediately.
3096 Serious dermatological reactions, including toxic epidermal necrolysis (TEN: also known as
3097 Lyell's syndrome) and SJS have been reported very rarely with Medicinal Product B.
3098 Patients with serious dermatological reactions may require hospitalization, as these
3099 conditions may be life-threatening and fatal. Most SJS/TEN cases appear in the first few
3100 months of treatment with Medicinal Product B. These reactions are estimated to occur in 1 to
3101 6 per 10,000 new users in countries with mainly Caucasian populations. If signs and
3102 symptoms suggestive of severe skin reactions (e.g. SJS, Lyell's syndrome/TEN) appear,
3103 Medicinal Product B should be withdrawn at once and alternative therapy should be
3104 considered.
3105 […]
3106 Cutaneous reactions
3107 Serious and sometimes fatal cutaneous reactions including TEN and SJS have been reported
3108 during treatment with Medicinal Product B. These reactions are estimated to occur in 1-6 per
3109 10 000 new users in countries with mainly Caucasian populations, but the risk in some Asian
3110 countries is estimated to be about 10 times higher.
3111 There is growing evidence of the role of different HLA alleles in predisposing patients to
3112 immune-mediated adverse reactions.
3113 The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous
3114 reactions from Medicinal Product B, such as anticonvulsant hypersensitivity syndrome or
3115 non-serious rash (maculopapular eruption).

85
3116 Hypersensitivity
3117 Medicinal Product B may trigger hypersensitivity reactions, including Drug Rash with
3118 Eosinophilia and Systemic Symptoms (DRESS), reactivation of HHV6 associated with
3119 DRESS, a delayed multi-organ hypersensitivity disorder with fever, rash, vasculitis,
3120 lymphadenopathy, pseudo lymphoma, arthralgia, leukopenia, eosinophilia, hepato-
3121 splenomegaly, abnormal liver function tests and vanishing bile duct syndrome (destruction and
3122 disappearance of the intrahepatic bile ducts), that may occur in various combinations. Other
3123 organs may also be affected (e.g. lungs, kidneys, pancreas, myocardium, colon).
3124 In general, if signs and symptoms suggestive of hypersensitivity reactions occur, Medicinal
3125 Product B should be withdrawn immediately. Patients who have exhibited hypersensitivity
3126 reactions to Medicinal Product B should be informed that 25-30 % of these patients may
3127 experience hypersensitivity reactions with oxacarbazepine.
3128 Cross-hypersensitivity can occur between Medicinal Product B and aromatic anti-epileptics
3129 (e.g. phenytoin, primidone and phenobarbital).
3130 4.8 Undesirable effects
3131 Summary of the safety profile
3132 Particularly at the start of treatment with Medicinal Product B, or if the initial dosage is too
3133 high, or when treating elderly patients, certain types of adverse reaction occur very
3134 commonly or commonly, e.g. CNS adverse reactions (dizziness, headache, ataxia,
3135 drowsiness, fatigue, diplopia), gastrointestinal disturbances (nausea, vomiting), as well as
3136 allergic skin reactions.
3137 Tabulated summary of ADRs compiled from clinical trials and spontaneous reports
System Organ Class Frequency Adverse Reaction

Not known** Drug Rash with Eosinophilia and Systemic

Symptoms (DRESS)

Very rare Stevens-Johnson syndrome*, toxic epidermal

necrolysis
Not known** Acute Generalized Exanthematous Pustulosis
(AGEP)**

3138
3139 * In some Asian countries also reported as rare. See also section 4.4 Special warnings and
3140 precautions for use.
3141 **Additional ADRs from spontaneous reports (frequency not known).
3142 […]
3143 There is increasing evidence regarding the association of genetic markers and the
3144 occurrence of cutaneous ADRs such as SJS, TEN, DRESS, AGEP and maculopapular rash.
3145 In Japanese and European patients, these reactions have been reported to be associated
3146 with the use of Medicinal Product B and the presence of the HLA-A*3101 allele. Another
3147 marker, HLA-B*1502 has been shown to be strongly associated with SJS and TEN among
3148 individuals of Han Chinese, Thai and some other Asian ancestry.

86
3149 Medicinal Product C

3150 Product Label

3151
3152 4.4 Special warnings and precautions for use
3153 […]
3154 Hypersensitivity
3155 Hypersensitivity and allergic reactions, including anaphylaxis and anaphylactoid reactions,
3156 may occur following a single dose (see section 4.8) and may be life-threatening. If such
3157 reactions occur, Medicinal Product C should be discontinued and an adequate medical
3158 treatment is required.
3159 […]
3160 4.8 Undesirable effects

System Organ Common Uncommon Rare Very Rare Frequency not

Class known

Skin and Stevens-Johnson Acute

Subcutaneous syndrome (potentially Generalized
Tissue life-threatening) Exanthematous
Disorders Toxic epidermal Pustulosis
necrolysis (potentially (AGEP)
life-threatening) Drug Reaction
with
Eosinophilia and
Systemic
Symptoms
(DRESS)
3161
3162 Medicinal Product D

3163 Product Label and Patient Information Leaflet

3164 Product Label
3165 4.4 Special warnings and precautions for use
3166 Life threatening adverse reactions
3167 Fatalities, although very rare, have occurred due to severe reactions including Stevens -
3168 Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis,
3169 aplastic anaemia, other blood dyscrasias and hypersensitivity of the respiratory tract.
3170 • Life-threatening cutaneous reactions SJS, TEN and DRESS have been reported with
3171 the use of Medicinal Product D.
3172 • Patients should be advised of the signs and symptoms and monitored closely for skin
3173 reactions. The highest risk for occurrence of SJS or TEN is within the first weeks of treatment.
3174 • If symptoms or signs of SJS, TEN (e.g. progressive skin rash often with blisters or
3175 mucosal lesions) or DRESS (e.g. fever, eosinophilia) are present, Medicinal Product D
3176 treatment should be discontinued.
3177 • The best results in managing SJS, TEN and DRESS come from early diagnosis and
3178 immediate discontinuation of any suspect medicinal product. Early withdrawal is
3179 associated with a better prognosis.

87
3180 • If the patient has developed SJS, TEN and DRESS with the use of Medicinal Product
3181 D, Medicinal Product D must not be re-started in this patient at any time.
3182 • At the start of treatment, the occurrence of a generalized febrile erythema associated with
3183 pustules, should raise the suspicion of acute generalized exanthematous pustulosis
3184 (AGEP); it requires cessation of treatment and contraindicates any new administration of
3185 Medicinal Product D alone or in combination with other medicinal products.
3186 […]
3187 4.8 Undesirable effects
System Organ Frequency Side effects
Class
Skin and Very rare Stevens-Johnson syndrome (SJS) *, toxic epidermal necrolysis (TEN) *.
subcutaneous tissue Acute generalised exanthematous pustulosis (AGEP).
disorders* Not known Acute febrile neutrophilic dermatosis (Sweet's syndrome), Drug reaction
with eosinophilia and systemic symptoms (DRESS)*

3188
3189 Description of selected adverse reactions
3190 Severe cutaneous adverse reactions (SCAR)
3191 Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with
3192 eosinophilia and systemic symptoms (DRESS) have been reported to be life-threatening.
3193 As with any other medicinal product, allergic reactions such as an itchy rash and hives may
3194 occur in patients with hypersensitivity to the components of the medicinal product. Very rare
3195 cases of AGEP have been observed.
3196 Patient Information Leaflet (PIL):
3197 2. What you need to know before you take Medicinal Product D
3198 Warnings and precautions
3199 Talk to your doctor or pharmacist before taking Medicinal Product D:
3200 • If you have severe allergies or asthma.
3201 • Potentially life-threatening skin rashes (SJS, TEN and DRESS) have been reported
3202 with the use of Medicinal Product D appearing initially as reddish target-like spots or
3203 circular patches often with central blisters on the trunk.
3204 • At the start of treatment, the occurrence of generalized skin redness with pustules,
3205 accompanied by fever, should raise the suspicion of a serious reaction called acute
3206 generalized exanthematous pustulosis (AGEP) (see section 4).
3207 • Additional signs to look for include ulcers in the mouth, throat, nose, genitals and
3208 conjunctivitis (red and swollen eyes).
3209 • These potentially life-threatening skin rashes are often accompanied by flu-like
3210 symptoms. The rash may progress to widespread blistering or peeling of the skin.
3211 • The highest risk for occurrence of serious skin reactions is within the first weeks of
3212 treatment.
3213 • If you have developed Stevens-Johnson syndrome, toxic epidermal necrolysis or drug
3214 reaction with eosinophilia and systemic symptoms with the use of Medicinal Product D,
3215 you must not be re-started on Medicinal Product D at any time.
88
3216 • If you develop a rash or these skin symptoms, stop taking Medicinal Product D, seek
3217 urgent advice from a doctor and tell him that you are taking this medicine.
3218 4. Possible side effects
3219 Like all medicines, Medicinal Product D can cause side effects, although not everybody gets
3220 them. You may experience the following side effects with this medicine.
3221 Stop taking Medicinal Product D and tell your doctor immediately if you have an allergic
3222 reaction. The chances of an allergic reaction are very rare (fewer than 1 in 10,000 people
3223 are affected), signs of an allergic reaction include:
3224 Allergic reactions
3225 • Difficulty breathing
3226 • Fainting
3227 • Swelling of face
3228 • Swelling of mouth, tongue or throat which may be red and painful and/or cause difficulty in
3229 swallowing
3230 • Chest pain
3231 • Red patches on the skin
3232 Common (less than 1 in 10 people)
3233 • Skin rashes
3234 Very Rare (less than 1 in 10,000 people)
3235 • Potentially life-threatening skin rashes (SJS, TEN) have been reported
3236 • Very rare cases of redness generalizing to the whole body (AGEP)
3237 • Mouth ulcers, cold sores and ulcers or soreness of your tongue
3238 • Skin lumps or hives (raised, red or white, itchy patches of skin)
3239 • Blisters on your skin or inside your mouth, nose, vagina or bottom
3240 • Inflammation of the eye, which causes pain and redness
3241 • The appearance of a rash or sunburn when you have been outside (even on a cloudy day)
3242 Not known (frequency cannot be estimated from the available data)
3243 • Drug reaction with eosinophilia and systemic symptoms (an allergic type reaction in
3244 which you may develop fever, skin rash, and abnormalities in blood and liver function
3245 tests (these may be signs of a multi-organ sensitivity disorder).
3246
3247 If any of the side effects get serious, or if you notice any side effects not listed in this leaflet,
3248 please tell your doctor or pharmacist.

89
3249 Medicinal Product E

3250 Additional Risk Minimization Measures: Healthcare Professional Guide and Patient Card
3251 Medicinal Product E hypersensitivity reaction is a delayed hypersensitivity reaction mediated
3252 via CD8+ T lymphocytes and strongly associated with the presence of the HLA-B*57:01
3253 allele.[1] This reaction is multi-systemic and typically presents with fever, rash, constitutional
3254 symptoms and gastrointestinal manifestations,[2] occurring usually within the first six weeks
3255 of treatment with Medicinal Product E. Upon diagnosis, treatment discontinuation is
3256 mandatory and subsequent treatment with Medicinal Product E is contraindicated, since it
3257 can result in a more severe, rapid, and potentially life-threatening reaction.[3]
3258 In 2002, the association between the MHC class I HLA-B*57:01 allele and a risk for
3259 Medicinal Product E hypersensitivity was described for the first time.[1,3] The prevalence of
3260 this allele varies according to the predominant populations of the geographic location, with
3261 an estimated prevalence of 5%-8% in predominantly Caucasian populations, 2-3 % in
3262 African Americans and <1% in Sub-Saharan Africa, Chinese and Japanese
3263 populations[4,5].Based on this demonstrated association and supported by the test’s
3264 comparatively high PPV for this outcome[3], HLA-B*57:01 testing prior to initiating treatment
3265 with Medicinal Product E, was recommended in the label. Subsequently, this test became
3266 part of the regulatory terms of marketing authorization and standard of care for HIV patients
3267 before initiating treatment with Medicinal Product E.
3268 Because of the potential severity, seriousness, outcomes and consequent impact on
3269 treatment, Medicinal Product E hypersensitivity reaction is classified as an important
3270 identified risk for the medicinal product.
3271 Both routine risk minimization measures and additional risk minimization measures are in
3272 place to prevent the risk of Medicinal Product E hypersensitivity in patients who test positive
3273 for this allele, and subsequently reduce undue exposure. The main guidance around HLA
3274 screening is provided in the product’s label (i.e., “HLA-B*5701 status must always be
3275 documented prior to initiating therapy”), but additional risk minimization measures have also
3276 been put in place to ensure awareness of the potentially life-threatening risk, and the
3277 recommended HLA screening to identify patients who may be at risk. These measures
3278 include a Healthcare Professional Guide for healthcare providers (HCPs) and a patient card
3279 for patients in the EU. In the US, the manufacturer of Medicinal Product E was required to
3280 distribute a Medication Guide to patients, as part of a REMS program.
3281 Medicinal Product F

3282 Additional Risk Minimization Measure: Direct Healthcare Professional Communication

3283 Cases of SJS and TEN were reported in patients treated with Medicinal Product F. The
3284 regulatory authority and the manufacturer agreed that a DHPC was necessary to be
3285 disseminated to for healthcare providers to ensure awareness of the newly identified risk of
3286 SCAR. The content of the DHPC included a background on the safety concern, summary of
3287 the findings, recommendations on treatment interruption (“Medicinal Product F should be
3288 withheld in patients with suspected SJS or TEN”) and discontinuation (“in case SJS or TEN
3289 is confirmed, and for any grade 4 rash/SCAR, treatment with Medicinal Product F should be
3290 permanently discontinued”). Lastly, the DHPC included instructions on reporting suspected
3291 adverse reactions to the regulatory authority or the manufacturer.
3292
3293
3294
90
3295 References

1 Mallal S, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1
reverse-transcriptase inhibitor abacavir. The Lancet. 2002 Mar 2;359(9308):727-32. PubMed Abstract
2 Peter JG, et al. Severe Delayed Cutaneous and Systemic Reactions to Drugs: A Global Perspective on the Science and Art
of Current Practice. J Allergy Clin Immunol Pract. May-Jun 2017;5(3):547-563 PubMed Abstract
3 Mallal S, et al. HLA-B*5701 Screening for hypersensitivity to abacavir. N Engl J Med. 2008 Feb 7;358(6):568-79. PubMed
Abstract
4 Phillips, et al. Genetic Screening to Prevent Abacavir Hypersensitivity Reaction: Are We There Yet?. Clin Infect Dis.
2006 Jul 1;43(1):103-5. Journal Article
5 Zhang, et al. Low prevalence of human leukocyte antigen-B*5701 in HIV-1-infected Chinese subjects: a prospective
epidemiological investigation. AIDS Res Ther. 2015; 12: 28. PubMed Abstract
3296

91
3297 APPENDIX 2
3298 EXAMPLES OF TARGETED FOLLOW-UP FORMS TO BE USED FOR
3299 ALL SCAR REPORTS
3300 Follow-up questionnaires
3301
3302 1. Extent of the rash:
3303 o ≥50% of the body surface area
3304 o <50% of the body surface area
3305
3306 2. Did the subject undergo skin biopsy?
3307 o Yes. If positive, select one option:
3308 o Result suggestive of a severe cutaneous adverse reaction (SCAR), such as Stevens
3309 Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized
3310 exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic
3311 symptoms (DRESS)
3312 o Result not suggestive of a severe cutaneous adverse reaction (SCAR)
3313 o Inconclusive result
3314 o No
3315
3316 3. Has the subject had facial swelling? (i.e., facial swelling during the event of rash)
3317 o Yes
3318 o No
3319 o Unknown
3320
3321 4. Has the subject had enlarged lymph nodes? (Presence of either localized [e.g. cervical, axillary,
3322 or inguinal lymph nodes) or generalised lymphadenopathy])
3323 o Yes
3324 o No
3325 o Unknown
3326
3327 5. Were atypical lymphocytes detected at some point during the evolution of the hypersensitivity event?
3328 o Yes
3329 o No
3330
3331 6. Did the subject have eosinophilia (>0.5×109/l or 500/μL) detected at some point during the
3332 evolution of the hypersensitivity event?
3333 o Yes
3334 o No
3335
3336 7. Have infectious causes been excluded? Has an infection screening been conducted due to t he
3337 events of fever + rash (e.g. blood count, CRP, blood culture, chest X-ray, urinalysis + urine
3338 culture)?
3339 o Yes
3340  Description of which tests:
3341 o No
3342 o Unknown
3343
3344 8. Did the subject have evidence of internal organ involvement?
3345 Select in case there is evidence of other organs being affected concomitantly to the event of ras h,
3346 resulting in liver, renal, cardiac, or pulmonary function alteration:
3347 o Yes. If positive, select all that apply:
3348 o AST/ALT increase
3349 o Renal involvement (creatinine and/or BUN increase, urinalysis alteration)
3350 o Cardiac involvement (clinical, laboratory or echocardiographic evidence of myocarditis)
3351 o Lung involvement (clinical or radiological evidence of pneumonitis)
3352 o Other
3353 o No
3354 o Unknown
3355 9. Concomitant medications

92
3356

3357

93
3358
3359

94
3360 APPENDIX 3
3361 SCAR WORKING GROUP MEMBERS AND MEETINGS
3362 The CIOMS Working Group on Severe Cutaneous Adverse Reactions included the following stakeholder
3363 groups: clinicians, international organizations, pharmaceutical industry, regulatory authorities.

3364 CLINICIANS

3365 Chia-Yu Chu National Taiwan University Hospital, Chinese Taipei

3366 Working Group Co-Chair

3367 Siew Eng Choon Monash University, Malaysia

3368 Roni P. Dodiuk-Gad Emek Medical Center, Israel
3369 Koji Hashimoto Ehime Prefectural University of Health Science, Japan
3370 Haur Yueh Lee Singapore General Hospital, Singapore
3371 Filippa Nyberg Karolinska University Hospital, Sweden
3372 Neil Shear Sunnybrook Health Sciences Centre, University of Toronto, Canada

3373 INTERNATIONAL ORGANIZATIONS

3374 Matt Doogue IUPHAR/University of Otago/Christchurch, New Zealand

3375 PHARMACEUTICAL INDUSTRY

3376 David Brott Takeda, USA

3377 Leslie Dondey-Nouvel Sanofi, France

3378 Alexandre Kiazand AstraZeneca, USA
3379 Gerd Kullak-Ublick* Novartis, Switzerland
3380 Ariel R. Porcalla AbbVie, USA
3381 Violeta Regnier Galvao Eli Lilly, USA
3382 Sarah Schlief Bayer, Germany

3383 REGULATORY AUTHORITIES

3384 Melissa Reyes FDA, USA

3385 Working Group Co-Chair

3386 Priya Bahri EMA, Netherlands

3387 Michael A. Pacanowski FDA, USA
3388 Youssef Roman FDA, USA
3389 Sabine Straus Medicines Evaluation Board, Netherlands
3390 Tien M. Truong FDA, USA
3391 Takahiro Ueda Pharmaceutical and Medical Devices Agency (PMDA), Japan
3392 *Alternate: Sylvia Lesperance, Novartis

3393 CIOMS

3394 Hervé Le Louet President

3395 Lembit Rägo Secretary General
95
3396 The Working Group met in a series of virtual meetings from 2021 to 2023 as follows:
3397 1. 2-3 February 2021
3398 2. 13 April 2021
3399 3. 29 June 2021
3400 4. 7 October 2021
3401 5. 13 December 2021
3402 6. 9 May 2022
3403 7. 12 September 2022
3404 8. 12 December 2022
3405 9. 14 March 2023
3406 10. 20 June 2023
3407
3408 The SCAR Working Group Editorial Team met three times in 2023, and included the
3409 following members:
3410 Siew Eng Choon Monash University, Malaysia
3411 Chia-Yu Chu National Taiwan University Hospital, Chinese Taipei
3412 Alexandre Kiazand Astra Zeneca, USA
3413 Haur Yueh Lee Singapore General Hospital, Singapore
3414 Sylvia Lesperance Novartis, Switzerland
3415 Lembit Rägo CIOMS
3416 Melissa Reyes FDA, USA
3417
3418
3419

96
3420 APPENDIX 4
3421 LIST OF COMMENTATORS
3422
3423
3424

97