Severe cutaneous adverse

drug reactions

Maja Mockenhaupt
Dokumentationszentrum schwerer Hautreaktionen (dZh)
Department of Dermatology
Medical Center – University of Freiburg, Germany
International Registry of Severe Cutaneous Adverse
Reactions (SCAR) to Drugs and Collection
of Biological Samples

SCAR:
- Toxic epidermal necrolysis (TEN) and recently
- Stevens-Johnson syndrome (SJS) GBFDE

- Hypersensitivity syndrome (HSS) / Drug reaction with

eosinophilia and systemic symptoms (DRESS)
- Acute generalized exanthematous pustulosis (AGEP)
International Registry of Severe Cutaneous Adverse
Reactions (SCAR) to Drugs and Collection
of Biological Samples
Aims:
- to build an International Registry of SCAR for continuous
surveillance of new drugs
- to organize a centralized collection of biological samples
for immunologic and genetic investigations
- to constitute a cohort of ca. 300 patients in order to study the
outcome, prognostic factors, sequelae and impact on quality
of life
International Registry of Severe Cutaneous Adverse
Reactions (SCAR) to Drugs and Collection
of Biological Samples
Aims:
- to build an International Registry of SCAR for continuous
surveillance of new drugs
- to organize a centralized collection of biological samples
for immunologic and genetic investigations
- to constitute a cohort of ca. 300 patients in order to study the
outcome, prognostic factors, sequelae and impact on quality
of life
 Requirements

•  Initiation and organization of a network

•  Definition of clinical entities (phenotypes)
•  Systematic case ascertainment
•  Standardized case validation
•  Professional data management and
statistical analysis
Stevens-Johnson syndrome (SJS) /
Toxic epidermal necrolysis (TEN)
•  in the early phase confluent
macules and flat atypical targets
•  dark colour with necrosis and
detachment of the epidermis
•  hemorrhagic erosions of mucous
membranes
 SJS/TEN
Consensus definition
Amount of skin detachment (Bastuji-Garin et al, 1993)

•  <10%: SJS

•  10-30%: SJS/TEN-
overlap

•  >30%: TEN
 Diagnostics - SJS/TEN

•  check for positive Nikolsky‘s sign

•  Tzanck-test or better cryostat diagnostic
•  conventional skin biopsy and - if needed -
immunofluorescence test

→ specific laboratory parameters

do not exist !
SJS/TEN – Nikolsky‘s sign
Progression - SJS/TEN
Histopathology – SJS/TEN
 Erythema multiforme majus (EMM)
versus SJS
EMM
- scattered, typical and sometimes
atypical „giant“ targets
- induced by infections, mainly
mycoplasma in children, more
often herpes in adults

SJS/TEN
- confluent macules and blisters
leading to epidermal detachment
- mainly induced by drugs

Auquier-Dunant A et al, Arch Dermatol, 2002

Generalized bullous fixed drug eruption
(GBFDE)
 GBFDE
•  Round or oval plaques of a dusky violaceous or
brownish colour
•  Blisters and erosions develop on these plaques,
usually below 10% of the BSA
•  Negative Nikolsky’s sign
•  No or only mild mucosal involvement
•  Rarely fever and malaise
•  High risk of recurrent events with increased
severity and mortality (Lipowicz S et al, Br J Dermatol, 2013)
Age distribution in SJS/TEN
 Epidemiology of SJS/TEN

Incidence
1-2 cases per one million inhabitants per year

Mortality
≈ 45% in TEN with maculae
≈ 20-25% in SJS, SJS/TEN,TEN together

→ ≈ 70% in TEN-patients >65 years

Mockenhaupt M et al, J Invest Dermatol, 2005
Mockenhaupt M et al, Dr Safety & Pharmacoepi, 2011
SJS/TEN: Mockenhaupt M et al, J Invest Dermatol, 2008

AGEP: Sidoroff A et al, Br J Dermatol, 2007

17
 Risk factors for SJS/TEN

Medications associated with a high risk

for SJS/TEN
-  Nevirapine - Phenobarbital
-  Lamotrigine - Carbamazepine
-  Phenytoin - Oxicam-NSAIDs

-  Allopurinol - Sulfasalazine
-  Cotrimoxazole and other anti-infective sulfonamides
 Lamotrigine (n = 14)

9
8
8
7
6
Cases

5
4
3
3
2
2
1
1
0 0 0 0
0
1-7 8-14 15-21 22-29 30-37 38-45 46-56 >56

Days
 Risk factors for SJS/TEN

Medications associated with a moderate risk

for SJS/TEN
-  Quinolones
-  Cephalosporines
-  Macrolides

-  Tetracyclines
-  NSAIDs of the acetic acid type, e.g. diclofenac
 Risk factors for SJS/TEN

Medications NOT associated with a risk

for SJS/TEN
-  Beta-blockers - Furosemid
-  ACE-inhibitors - Insulin
-  Ca-channel-blockers - Other antidiabetics

-  Thiazid diuretics
-  NSAIDs of the propionic acid type, e.g. ibuprofen
 Early events in SJS/TEN
Based on 379 cases (EuroSCAR)

14#Days# 2#D# 1#D# 5#D#

ADMISSION&&

DIAGNOSIS&&

Beginning& FIRST& MAXIMUM&

of&drug&use& SYMPTOMS& DETACHMENT&
 MEDICATION HISTORY RegiSCAR
Interview n o. 9160189 Study

- -- -- -- -- -- -- -- -- -- - -- -- -- -- -- -- -- -- --

Ferro Sanol D. p.o. iron substitution

Amaryl p.o. hyperglycemia

Benalapril p.o. hypertension

Meto p.o. hypertension

Arelix p.o. hypertension

Iso Mack p.o. povd*

ASS p.o. povd*

Allopurinol p.o. hyperuricemia

- -- -- -- -- -- -- -- -- - -- -- -- -- -- -- -- --
03 .09. 10 .09. 17 .09. 24 .09. 01 .10. 07.10.
conju nctivitis
bu rnin g and swelling lip s

cutan eo us ero sio ns, exan thema,

erosions of lip s, o ral and n asal mu co sa

* povd: perip heral

occlusive vascular disease ho sp . ad missio n

first occurence of blister s or erosions Index-day: 30/09/04

 MEDICATION HISTORY RegiSCAR
Interview n o. 9160215 Study

- -- -- -- -- -- -- -- -- -- - -- -- -- -- -- -- -- -- --
Moxonidin p.o. hyperte nsion
Amlodipin p.o. hyperte nsion
Torasemid p.o. hyperte nsion
Ranitic p.o. ulcer prevention
Phe nhydan p.o. proph. of seizures

Dipidolor i .v. pain

Sab Simplex p.o. meteorism

Adalat p.o. hyperte nsion

Meronem i.v.

AC C p.o.
susp. infection

mucolysis „ALDEN“ (algorithm for

causality assessment in SJS/
Beloc-Zok p.o. hyperte nsion

Benalapri l p.o. hyperte nsion

TEN) is applied
ASS p.o. proph. of thrombosis

Kali nor p.o. hypopotassemia

Norvasc p.o. hyperte nsion

Reka wan p.o.

Clex ane s.c.

subst. of minerals

proph. of thrombosis
Sassolas B et al,
Haldol i.v. agitation

agitation
Clin Pharmacol Ther, 2010
Tavor i.v.

Haldol p.o. agitation

Tavor p.o. agitation

NaC l p.o. subst. of minerals

Orfiril p.o. proph. of seizures

Gastrosil p. o. nausea

Remergil p.o. agitation

Fenistil p.o. pruritus

- -- -- -- -- -- -- -- -- - -- -- -- -- -- -- -- --

28.10.
red eyes, erosive lip s,
28.09.: skin pain, pruritus, erythema Nikolski-sign +
ho sp . ad missio n 29.10.
fever, targ et lesio ns, genital itchin g
erosive o ral muco sa
skin blisters

first occurence of blisters or erosions Index-day: 24/10/04

 Algorithm - ALDEN

•  Relevant exposure window (4-28 days)

•  Recent start of drug intake (w/o prior use)
•  Drug notoriety (based on study results)
•  Half-life of active substances

→ was specifically created for SJS/TEN and

requires a clear diagnosis before application
 Causality assessment

ALDEN was applied to cases

• ascertained in 7 European countries (France,
Germany, Israel, Italy, Netherlands, Spain and
UK) between 01/2003 and 12/2012
• validated as “probable” or “definite” SJS/TEN
• developed outside the hospital ( community
cases ) or during hospitalization ( inhospital
cases )
 Causality assessment

1232 VALIDATED CASES OF SJS/TEN

114 CASES from TAIWAN or SOUTH-AFRICA

1118 EUROPEAN CASES

22 CASES with incomplete drug history

1096 analyzed CASES

819 COMMUNITY CASES 277 INHOSPITAL CASES

- Germany: 477 - Germany: 202
- other countries: 342 - other countries: 75
 Most frequent responsible drugs
#Drug Community cases Drug Inhospital cases
n=819 (%) n=277 (%)
Allopurinol 159 (19.4%) Allopurinol 27 (9.4%)
Lamotrigine 66 (8.1%) Phenytoin 22 (7.9)
Sulfamethoxazole 64 (7.8%) Sulfamethoxazole 18 (6.5%)
Carbamazepine 38 (4.5%) Ciprofloxacine 18 (6.5%)
Phenytoin 20 (2.4%) Pantoprazole 17 (6.1%)
Nevirapine 18 (2.2%) Acetylcystein 16 (5.8%)
Pantoprazole 16 (2%) Metamizole 15 (5.8%)
Diclofenac 12 (1.5%) Carbamazepine 13 (4.7%)
Sulfasalazine 11 (1.3%) Lamotrigine 11 (4%)
Amoxicillin 10 (1.2%) Amoxicillin 10 (3.6%)
Doxycycline 10 (1.2%) Ceftriaxone 10 (3.6%)
Omeprazole 10 (1.2%) Esomeprazole 9 (3.2%)
Ciprofloxacine 9 (1.1%) Phenobarbital 9 (3.2%)
Prednisolone 8 (1%) Prednisolon 8 (2.2%)
Drug causality by application of ALDEN
Based on 1096 cases (RegiSCAR)

Further differences between community and

inhospital cases
•  Older age of inhospital cases (64 compared to
52 in community cases)
•  Higher average number of drugs used before
SJS/TEN (7 in community cases, 20 in inhospital
cases; significant difference)
 Evolution of causality

RegiSCAR 2003-2012 EuroSCAR 1997-2001

Drug (n=819 cases) (n=379 cases)
attributable fraction# attributable fraction#

Allopurinol# 19.4% (159)# 14.2% (54)#

Lamotrigine# 8.1% (66)# 2.4% (9)#
Sulfamethoxazole# 7.8% (64)# 5.0% (19)#
Carbamazepine# 4.6% (38)# 7.1% (27)#
Phenytoin# 2.4% (20)# 4.5% (17)#
Nevirapine# 2.2% (18)# 4.0% (15)#
Pantoprazole# 2.0% (16)# 0% (0) #
Diclofenac# 1.5% (12)# 2.6% (10)#
Sulfasalazine# 1.3% (11)# 1.3% (5)#
Amoxicillin# 1.2% (10)# 0.8% (3)#
Drug causality by application of ALDEN
Based on 1096 cases (RegiSCAR)

NO&DRUG&1.8%#
Com 2.1%
UNLIKELY&/&
Inhosp 0
VERY&UNLIKELY&
11.2% Com 14.8%

POSSIBLE&
PROBABLE/& 20%
VERY&PROBABLE& Com 19.7
67.2% Inhosp 21%
Com 63.3%
Inhosp 78%
 Causality assessment
Based on current data
•  ≈ 67% of SJS/TEN-cases are drug-induced
•  among the ≈ 33% of cases without a patent drug
cause
- up to ≈ 20 % MAY BE drug-induced
- at least 13 % and up to 33% ARE NOT drug-induced
(idiopathic cases)
•  The 13-33% idiopathic cases include 2% without
any drug intake
Protopathic bias in SJS/TEN

NEW&DRUG(S)&
e.g.&analgesics,&&
anKpyreKcs,&&
secretolyKcs&

ADMISSION&&

DIAGNOSIS&&

FIRST& MAXIMUM&
SYMPTOMS& DETACHMENT&
 Causality assessment
•  Typical examples for drugs with this problem
are paracetamol (acetaminophen), ibuprofen,
acetysalicylic acid (ASA) and ambroxol
•  They cannot be blamed to have caused the
reaction, when
-  taken and tolerated multiple times before
-  when taken shortly (1-4 days) before the
onset of the reaction (objective signs) for
treatment of prodromal symptoms
 Causality assessment
Conclusion
• The most frequent inducer of SJS/TEN in Europe
is still allopurinol; the risk has even increased compared
to previous years
• Lamotrigine is now the second frequent cause of SJS/
TEN that develop in the community
• Antibacterial sulfonamides are still frequent causes of
SJS/TEN
→ it should be our common aim to push for a safer
use of these high risk drugs und reduce
morbidity and mortality
 Causality assessment

Conclusion
•  For some drugs alerts were raised (ACC, PPI), but
they were in 60% of the cases taken concomitantly
with a known high-risk drug
•  Metamizole was only a risk factor for inhospital
cases and has to be further investigated, esp. since
it is also a frequent cause of GBFDE
•  There are substantial differences in number and
type of drugs between community and inhospital
cases
International Registry of Severe Cutaneous Adverse
Reactions (SCAR) to Drugs and Collection
of Biological Samples
Aims:
- to build an International Registry of SCAR for continuous
surveillance of new drugs
- to organize a centralized collection of biological samples
for immunologic and genetic investigations
- to constitute a cohort of ca. 300 patients in order to study the
outcome, prognostic factors, sequelae and impact on quality
of life
 Cohort study - outcome

•  Follow-up investigation after 8±2 weeks

- clinical examination
- questionnaire
•  1-year follow-up
- SF-36 Health survey™: international standardized
questionnaire for assessment of the overall health status
and quality of life
- specific questions for SJS/TEN
•  5-year follow-up
- specific questions for SJS/TEN, modified and improved
based on the experience with the 1-year follow-up
 Cohort study – 5-year FU

Results
•  112/233 completed and returned questionnaires
could be analyzed
- 62 patients with SJS
- 35 patients with SJS/TEN-overlap
- 15 patients with TEN

•  Demography
- average age 44 years (range 19-66)
- ca. 60% women, ca. 40% men
 Cohort study – 5-year FU

Results
•  Frequency of late sequelae in general
- >90% of the patients still suffer from
sequelae 5 years after SJS/TEN
- <50% of the patients were able to get back
to all their normal activities, incl. work,
studies, sports etc.
- 10% were not back to work after 5 years; in
the 1-year follow-up study the percentage
was 25%
 Cohort study – 5-year FU

Results
• 62 SJS: rate of sequelae 88.7%

• 35 SJS/TEN-overlap: rate of sequelae 97.1%

• 15 TEN: rate of sequelae100%

→ many physicians, health care providers and

insurances are not aware of the magnitude of
this problem
 Cohort study – 5-year FU

Results
• Specific sequelae affect
- most often the skin (73%)
- and mucous membranes (57%)
- nails (52%)
- eyes (67%)

→ eye sequelae are the major burden for

these patients
 Cohort study – late sequelae

acute stage 3 months 3 years

Cohort study – late sequelae

4 months

acute stage
Cohort study – late sequelae

2 years
Cohort study – late sequelae

1 year and 2 months

2.5 years
 Sequelae of the eyes

Are the major burden (67%)

•  Frequent symptoms include
- photophobia
- extreme dryness
- watery eyes
- pain
- reduced visus
- trichiasis / ingrowing eyelashes
- chronic inflammation and scarring
 Sequelae of the eyes

Increased light sensitivity and Neovascularization after

reduced growth of eyelashes severe ocular involvement
Sequelae of the eyes

scarring 4 months after the acute stage

eye 49 years after SJS/TEN

 Impact of sequelae on daily life

• 
 Drug induced delayed multiple organ hypersensitivity
syndrome (DIDMOHS)

Drug X
hypersensitivity
Drug reaction
with eosinophilia
and systemic
symptoms
(DRESS) Drug Y organitis

Drug-induced
hypersensitivity
syndrome (DIHS) Hypersensitivity
syndrome (HSS)

Drug hypersensitivity syndrome (DHS)

Drug hypersensitivity with eosinophilia, virus activation

and involvement of liver (DHEVIL)
 DRESS
•  Multisystem disease
•  Drug-induced
•  Fever
•  „Rash“
•  Eosinophilia & atypical
lymphocytes
•  Lymphadenopathy
•  Involvement of liver and
other organs
→ Other explanation for
symptoms excluded!
 DRESS

Organ involvement
- lymphadenopathy (lymphnode enlargement
in several body areas)
- hepatitis
- pneumonic infiltrates
- interstitial nephritis
- arthralgia
- myocarditis
Kardaun S et al, Br J Dermatol, 2013
DRESS
 DRESS

,
 11.10.: cough;
12.10.: fever;
13.10.: itch, exanthem, lip erosions
16.10.: hospital admission; chest X-ray: interstitial pneumonia
21.10.: edema, hepatomegaly; 08.11.: discharge

16. Oct 20. Oct 22. Oct 24. Oct 25. Oct 26. Oct 08. Nov

ASAT (*N) 1,00 1,13 1,27 16,20 13,00 3,80 1,50

ALAT(*N) 0,47 0,82 0,94 9,59 12,41 8,65 2,00
GGT(*N) 0,67 4,97 6,56 5,38 2,30
AP(*N) 1,09
LDH(*N) 2,49 2,87 2,04
P-PPT(SEC) 32 35 48 36

Quick % 71 51 56 70

Leuco/ml 3100 3300 8600 12100 16200 17000

Eos % 4 14 3 2 2
Eos/ml 124 462 258 242 324
Lymphos% 13 22 7 12 27 32
 Diagnostics – DRESS

•  differential blood count for proof of eosinophilia and

atypical lymphocytes
•  investigation of further laboratory parameters for
clarification of organ involvement (liver- and kidney
values, CK, CK-MB, troponine, LDH)
•  serologies such as hepatitis A,B,C, EBV, CMV,
chlamydia, mycoplasma, HHV6 and ANA titer
•  skin biopsy
•  X-ray of thorax, ultra-sound of abdomen, if needed
organ biopsies
 DRESS validation score
SCORE6 -1 0 1 2 Min Max

Fever No Yes -1 0

Lymphadenopathy No Yes 0 1

Eosinophilia No >700 >1500 0 2

Atypical Lymphocytes No Yes 0 1

Skin -2 2

- extent > 50%

- suggestive for DRESS No Yes

- biopsy suggestive for DRESS No Yes

Organ involvement No Yes 0 2

Healing ≥ 15 days No Yes -1 0

Virusses, bacteria, ANA: negative No Yes 0 1

Endscore -4 9

Endscore <2: no case

Endscore 2-3: possible DRESS

Eindscore 4-5: probable DRESS Kardaun S et al, Br J Dermatol 2007;
156: 609-611
Eindscore >5: definite DRESS
 Analysis of DRESS
•  201 potential DRESS cases were enrolled from 2003
to mid 2009
•  117 cases were validated as probable or definite
DRESS by an expert committee

- 66 females, median age 41.5 yrs,

51 males, median age 53 yrs

→ significant difference !

- death rate 2% (Kardaun S et al, Br J Dermatol, 2013)

 Analysis of DRESS
•  201 potential DRESS cases were enrolled from 2003
to mid 2009
•  117 cases were validated as probable or definite
DRESS by an expert committee
- multiple organ involvement was frequent, predominantly
affecting liver (75%), kidney (36%) and lung (32%), but also
spleen (15%), muscle/heart (13%)
- eosinophilia was seen in 95%, atypical lymphocytes in 67%
- in all but 3 cases the disease lasted more then 15 days

Kardaun S et al, Br J Dermatol, 2013

 Drug risks

Strongly associated (« highly suspected ») drugs

-  Carbamazepin e - Allopurinol
-  Phenytoin - Sulfonamides
-  Phenobarbital - Dapsone
-  Oxcarbazepine - Goldsaltz
-  Minocycline - Lamotrigine

→ Carbamazepine and Allopurinol were the

inducing agents in 38% of cases
Kardaun S et al, Br J Dermatol, 2013
Comparison of time latency in DRESS and SJS/TEN
- carbamazepine -
60

50

40
percentage

30
DRESS
SJS/TEN
20

10

0
0-8 9-16 17-24 25-32 33-40 40-48 > 48
days

DRESS n = 23, SJS/TEN n = 27

Comparison of time latency in DRESS and SJS/TEN
- allopurinol -
35

30

percentage 25

20
DRESS
15
SJS/TEN

10

0
0-8 9-16 17-24 25-32 33-40 40-48 > 48
days

DRESS n = 21, SJS/TEN n = 49

 Timing „exposure - reaction“

The mean time latency between beginning

of drug use and onset of DRESS was
26.2 ± 19 days for all drugs with a (very)
probable causality, compared to e.g.
15 days (12-20) for carbamazepine in
SJS/TEN

Kardaun et al, Br J Dermatol, 2013

Mockenhaupt et al, J Invest Dermatol, 2008
Acute generalized exanthematous
pustulosis (AGEP)
 AGEP
•  Acute onset with fever
•  Large erythematous areas of skin
•  Dozens of sterile, non-follicular pinhead-sized
pustules, predominantly in the folds
•  Typical post-pustular desquamation after no
more than 4 to 10 days
•  Neutrophiles >7000/µl
•  Usually no involvement of internal organs
•  Only mild mucosal involvement
AGEP
AGEP
 Diagnostics

•  Smear preparation of pustules (for

exclusion of infectious diseases)
•  Differential blood count for proof of
neutrophilia
•  Skin biopsy for exclusion of other pustular
skin diseases (e.g. Psoriasis pustulosa)
Histopathology
 Histopathology

Problem in DD of AGEP and acute

generalized pustular psoriasis (von
Zumbusch type)
- typical psoriasiform changes in the
histopathology are often missing in
early pustular psoriasis
Halevy S et al, Br J Dermatol, 2010
 Non-pustular DD

Eruptions that are not primarily pustular

•  Drug reaction with eosinophilia and systemic
symptoms (DRESS)
•  Stevens-Johnson syndrome (SJS)
•  Toxic epidermal necrolysis (TEN)
AGEP versus DRESS
AGEP versus SJS/TEN
AGEP versus SJS/TEN
 AGEP validation score
Clinical features Histology
Morphology Other disease –10
Pustules
typical +2 Not representative/ no histology 0
compatible (with disease) +1 Exocytosis of PMN +1
insufficient 0
Erythema Subcorneal and/or intraepidermal non-spongiform pustules or
typical +2 NOS pustules with papillary edema or subcorneal and/or
compatible (with disease) +1 +2
insufficient 0
intraepidermal spongiform pustules or NOS pustules without
Distribution pattern papillary edema
typical +2
compatible (with disease) +1 Spongiform subcorneal and/or intra-epidermal pustules with papillary
edema +3
insufficient 0
Post-pustular desquamation
yes +1
no/insufficient 0
Course
Mucous membrane involvement Final score for AGEP:
yes
no
–2
0
< 0: excluded
Acute onset (< 10 days) 1-4: possible
yes 0
no –2 5-7: probable
Resolution (< 15 days)
yes 0
8-12: definite
no –4
Fever > 38°C
yes +1
no 0
PMN > 7000/mm3 Sidoroff A et al, J Cutan Pathol, 2001,28:113-119
yes +1
no 0
 EuroSCAR-study

Demographic data
•  estimated incidence:
1-5 per million population per year
•  mortality: < 5%
→ rather rough estimate for incidence,
since population-based data are not
yet available
Sidoroff A et al, Br J Dermatol, 2007
 Relative risks (RR) for drugs associated with AGEP

Case Control Odds (95% CI) Percentage of cases (%)

patients patients ratio* with use of “highly
Drug n=97 (%) n=1009 (%) suspected” drugs
started within 8 weeks

Pristinamycine 10 (10) 0 ∞ / >26 (26 - ∞) 10

Aminopenicillines 18 (19) 17 (2) 23 (10 - 54) 17

Quinolones 9 (9) 5 (0.5) 33 (8.5 - 127) 33
(Hydro)chloroquinn 7 (7) 2 (0.2) 39 (8 - 191) 0
Antibacterial 4 (4) 0 ∞ / >7.1 (7.1 - ∞)
sulfonamides 0
Terbinafine 4 (4) 0 ∞ / >7.1 (7.1 - ∞) 25
Diltiazem 7 (7) 10 (1) 15 (5.0 - 48) 0

Sidoroff A et al, Br J Dermatol, 2007 * multivariate analysis, if>3 cases and controls exposed
 Relative risks (RR) for drugs with less strong association

Drug / drug group Case Control Odds ratio (95% CI) Percentage of cases
patients patients (multi- (%) with use of
n=97 (%) n=1009 (%) variate) “highly suspected”
drugs started within 8
weeks

Corticosteroids 18 (19) 24 (2) 12 (4.6- 31) 56

Macrolides* 4 (4) 8 (1) 11 (2.7 - 48) 25

Oxicam-NSAIDS** 3 (3) 7 (1) 8.4 (1.7 - 42) 33

Antiepileptic drugs° 5 (5) 9 (1) 7.6 (1.6 - 36) 40

* other than pristinamycine; ** exposure window extended to 2 weeks;

° excluding valproic acid

Sidoroff A et al, Br J Dermatol, 2007

 Timing „exposure - reaction“

•  A delay of 2 -11 days between beginning of

drug use and onset of the adverse reaction is
the most suggestive timing supporting drug
causality in AGEP.

•  In case of exposure to several medications with

high expected benefits, the timing of administra-
tion is important to determine which one(s) must
be stopped and if someone may be continued
or re-introduced.
Severe cutaneous adverse reactions

unstructured diagnostics standardized diagnostic procedure with a score

 Clear diagnosis

Important, because of
•  different reaction pattern and prognosis
•  different drugs known to be associated
•  different exposure windows of drug use
before onset of the reaction
•  comparability for epidemiological studies
•  performance of genetic studies…….
Thank you very much for your attention !!!
 Thank you for your attention !!

Contact Address / RegiSCAR Coordinator:

Prof. Dr. Maja Mockenhaupt

Dokumentationszentrum schwerer Hautreaktionen
Department of Dermatology
Medical Center – University of Freiburg
Hauptstrasse 7
79104 Freiburg / Germany
dzh@uniklinik-freiburg.de
 RegiSCAR
International Registry of Severe Cutaneous Adverse
Reactions (SCAR) to Drugs and Collection
of Biological Samples
Participating countries
(2003-2005) since 2006 cases from
Austria France, Germany,
France Italy, Netherlands,
Germany Taiwan (2007)
Israel UK (2009-2012)
Italy South Africa (2009)
Netherlands Spain (2010)
 RegiSCAR
International Registry of Severe Cutaneous Adverse
Reactions (SCAR) to Drugs and
Collection of Biological
Samples
conflict of interest: nothing to declare
funding sources: grants from
- the European Commission (QLRT-2002-01738)
- GIS-Institut des Maladies Rares and
- INSERM (4CH09G),SIDACTION, ANRS in France,
- Else Kröner-Fresenius-Stiftung and
- DFG (FOR 534) in Germany
- a consortium of pharmaceutical companies