B Y: P E T ER K O K K I N I AS P H A R M D , A R A S H P RE ET

K A U R , S A M A NE H G H A S S EM I

Severe Cutaneous Adverse

Reactions (SCAR)
Outline

Steven-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Acute Generalized Exanthematous Pustulosis (AGEP)

Practice-Case Based Questions/Discussion

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FDA FAERS
DASHBOARD
SNAPSHOT

FDA FAERS Database Snapshot. Retrieved March 7, 2022, from https://fis.fda.gov/sense/app/95239e26-e0be-42d9-a960-9a5f7f1c25ee/sheet/45beeb74-30ab-

46be-8267-5756582633b4/state/analysis
3
Pathogenesis Summary

Bellón T. Mechanisms of Severe Cutaneous Adverse Reactions: Recent Advances. Drug Saf. 2019 Aug;42(8):973 -992. doi: 10.1007/s40264-
019-00825-2. PMID: 31020549.
4
 Stevens-Johnson
Syndrome & Toxic
Epidermal
Necrolysis
(SJS/TEN)

Bellón, T. (n.d.). Mechanisms of severe cutaneous adverse reactions: Recent advances. Drug safety. Retrieved March 21, 2022,
from https://pubmed.ncbi.nlm.nih.gov/31020549/
Chang WC, Abe R, Anderson P, et alSJS/TEN 2019: From science to translation. J Dermatol Sci. 2020 Apr;98(1):2-12. doi: 10.1016/j.jdermsci.2020.02.003. Epub 2020
Mar 7. Erratum in: J Dermatol Sci. 2021 Nov;104(2):146-147. PMID: 32192826; PMCID: PMC7261636.
 Pathophysiology
• CD40 ligand cells may induce the
release of TNF–alpha, nitrous oxide,
interleukin 8 (IL-8), and cell adhesion
antibodies. TNF–alpha also induces
apoptosis.

• Both Th1 and Th2 cytokines are

present.
• The pharmacologic interaction of
drugs with the immune system could
result in binding of the responsible
drug to MHC-1 and the T cell receptor.

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis. DermNet. Retrieved March 12,

2022, from https://dermnetnz.org/topics/stevens-johnson-syndrome-toxic-epidermal-
6
necrolysis
 Presentation on Skin
• Body-Surface Area Coverage:
• SJS: <10% BSA
• TEN: >30% BSA
• SJS/TEN: 10-30% BSA

• Unexplained widespread skin pain

• A red or purplish rash that spreads
• Blisters on your skin and the
mucous membranes of the mouth,
nose, eyes and genitals
• Shedding/peeling of skin within
days after blisters form

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis. DermNet. Retrieved

March 12, 2022, from https://dermnetnz.org/topics/stevens-johnson- 7
syndrome-toxic-epidermal-necrolysis
 Drug Causes

Stevens-Johnson Syndrome/Toxic Epidermal

Necrolysis. DermNet. Retrieved March 12, 2022, from
https://dermnetnz.org/topics/stevens-johnson- 8
syndrome-toxic-epidermal-necrolysis
 • Provide supportive care with fluids,
electrolytes and gentle emollients
Treatment (white petrolatum).
• Provide saline to involved mucosal
surfaces.
Remove the offending • Use oral ‘swish and spit’ or Maalox for
pain management.
agent!!! • Provide ICU management in the case
of infection/sepsis, comorbid
conditions, extensive wound care or
internal organ involvement.
• Use antibiotics ONLY in the case of an
infection.
Fernando SL. The management of toxic epidermal necrolysis. Aust J of • Limit oral or systemic corticosteroid
Dermatol 2012; 53: 165–71. PubMed.
therapy!
Michaels B. (2009). The role of systemic corticosteroid therapy in erythema
multiforme major and stevens-johnson syndrome: a review of past and
current opinions. The Journal of clinical and aesthetic dermatology, 2(3),
51–55.

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis. DermNet.

Retrieved March 12, 2022, from https://dermnetnz.org/topics/stevens- 9
johnson-syndrome-toxic-epiderma l-necrolysis
 Drug Reaction with
Eosinophilia and Systemic
Symptoms (DRESS)

Click to add text

Cho, Y.-T., Yang, C.-W., & Chu, C.-Y. (n.d.). Drug reaction with eosinophilia and systemic symptoms (dress): An interplay among drugs, viruses, and immune system . International journal
of molecular sciences. Retrieved March 21, 2022, from https://pubmed.ncbi.nlm.nih.gov/28598363/
Bellón, T. (n.d.). Mechanisms of severe cutaneous adverse reactions: Recent advances. Drug safety. Retrieved March 21, 2022, from https://pubmed.ncbi.nlm.nih.gov/31020549/
James J;Sammour YM;Virata AR;Nordin TA;Dumic I; (n.d.). Drug reaction with eosinophilia and systemic symptoms (dress) syndrome secondary to furosemide: Case report and review
of literature. The American journal of case reports. Retrieved March 21, 2022, from https://pubmed.ncbi.nlm.nih.gov/29440628/
Pathophysiology
• Type IVb Th2-driven reaction

• Drug-specific immune response

• Associated reactivation of herpes virus family

• Abnormality of epoxide hydroxylase enzyme

• Association between DRESS risk and HLA-B*

variants

Cho, Y.-T., Yang, C.-W., & Chu, C.-Y. (n.d.). Drug reaction with eosinophilia and systemic symptoms (dress): An interplay among drugs, viruses, and immune
system. International journal of molecular sciences. Retrieved March 21, 2022, from https://pubmed.ncbi.nlm.nih.gov/28598363/
De, A., Rajagopalan, M., Sarda, A., Das, S., & Biswas, P. (2018). Drug reaction with eosinophilia and systemic symptoms: An update and reviewof recent literature. Indian
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journal of dermatology. Retrieved March 21, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838752/
 Presentation on Skin

• Characterized by fever and skin lesions

• Begins as non-specific widespread drug
eruption
• Commonly presents as: erythroderma, facial
edema
• Occasionally presents as: pustules, target
lesions, cheilitis
• Desquamation observed as rash resolves

Cho, Y.-T., Yang, C.-W., & Chu, C.-Y. (n.d.). Drug reaction with eosinophilia and systemic symptoms (dress): An interplay among drugs, viruses, and immune
system. International journal of molecular sciences. Retrieved March 21, 2022, from https://pubmed.ncbi.nlm.nih.gov/28598363/
Chen, Y.-C., Cho, Y.-T., Chang, C.-Y., & Chu, C.-Y. (2013, October 14). Drug reaction with eosinophilia and systemic symptoms: A drug-induced hypersensitivity syndrome
with variable clinical features. Dermatologica Sinica. Retrieved March 21, 2022, from https://www.sciencedirect.com/science/article/pii/S1027811713000839#bib14 12
 Drug Causes
• 80% of DRESS cases are due to drugs
• Common drug causes:
o Anticonvulsants (phenytoin, carbamazepine,
lamotrigine)
o Antimicrobial (beta lactams)
o Antiviral (nevirapine, abacavir)
o Antipyretics/analgesics (acetaminophen, ibuprofen)
o Allopurinol

Cho, Y.-T., Yang, C.-W., & Chu, C.-Y. (n.d.). Drug reaction with eosinophilia and systemic symptoms (dress): An interplay among drugs, viruses, and immune
system. International journal of molecular sciences. Retrieved March 21, 2022, from https://pubmed.ncbi.nlm.nih.gov/28598363/
De, A., Rajagopalan, M., Sarda, A., Das, S., & Biswas, P. (2018). Drug reaction with eosinophilia and systemic symptoms: An update and review of recent literature. Indian
journal of dermatology. Retrieved March 21, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838752/
Where did that medication go? Training & Education for Nurse Expert Consultants. (n.d.). Retrieved March 21, 2022, 13
from https://www.nurseexpertsolutions.com/blog/where-did-that-medication-go
Treatment
Supportive treatment with
Discontinue the offending
fluids, electrolytes, gentle
agent!!
skin emollients

For severe disease with

Topical corticosteroids for
organ involvement, use
symptomatic relief of
first-line systemic
pruritis
glucocorticoids

Cho, Y.-T., Yang, C.-W., & Chu, C.-Y. (n.d.). Drug reaction with eosinophilia and systemic symptoms (dress): An interplay among drugs, viruses, and immune
system. International journal of molecular sciences. Retrieved March 21, 2022, from https://pubmed.ncbi.nlm.nih.gov/28598363/
De, A., Rajagopalan, M., Sarda, A., Das, S., & Biswas, P. (2018). Drug reaction with eosinophilia and systemic symptoms: An update and reviewof recent literature. Indian
journal of dermatology. Retrieved March 21, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838752/
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 Acute Generalized
Exanthematous Pustulosis
(AGEP)

Feldmeyer, L., Heidemeyer, K., & Yawalkar, N. (2016). Acute Generalized Exanthematous Pustulosis: Pathogenesis, Genetic Background, Clinical Variants and
Therapy. International journal of molecular sciences, 17(8), 1214. https://doi.org/10.3390/ijms17081214
Pathophysiology

• T cell-related sterile neutrophilic

inflammatory response (type IVd reaction)
• Type IVd: T cells promote the recruitment of
neutrophils to affected tissue through the
secretion of IL-8/CXCL8
• CXCL8/IL-8 is thought to play a central role
in the formation of pustules by recruitment of
neutrophils

Feldmeyer, L., Heidemeyer, K., & Yawalkar, N. (2016). Acute Generalized Exanthematous Pustulosis: Pathogenesis, Genetic Background, Clinical Variants and
Therapy. International journal of molecular sciences, 17(8), 1214. https://doi.org/10.3390/ijms17081214

16
 Presentation on Skin
• AGEP develops as an acute rash with
pinhead-sized pustules on an
erythematous oedematous base which is a
redness and swelling of the skin at the
base.
• Involvement of mucous membranes is
unusual and, when present, is limited to
erosions of the lips.
• Systemic symptoms: Fever, elevated C-
reactive protein (CRP)/ neutrophils and
hypocalcemia (75% incidence rate)

Feldmeyer, L., Heidemeyer, K., & Yawalkar, N. (2016). Acute Generalized Exanthematous Pustulosis: Pathogenesis, Genetic Background, Clinical Variants and Therapy. International
journal of molecular sciences, 17(8), 1214. https://doi.org/10.3390/ijms17081214

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Drug Causes
Over 90% of cases of AGEP are provoked by
medications, most often beta-lactam antibiotics
(penicillin's, cephalosporins and quinolones). Other
drugs that may cause AGEP are reported to include:
• Tetracyclines

• Sulfonamides

• Oral antifungals, particularly terbinafine

• Calcium channel blockers such as diltiazem

• Hydroxychloroquine

• Carbamazepine

• Acetaminophen

Acute generalised exanthematous pustulosis. DermNet. Retrieved March 4, 2022, from https://dermnetnz.org/topics/acute-generalised-exanthematous-pustulosis
Acute generalised exanthematous pustulosis: Indian Journal of Dermatology . Retrieved March 21, 2022, from https://www.e-ijd.org/article.asp?issn=0019-
5154;year=2018;volume=63;issue=1;spage=22;epage=29;aulast=De
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 Treatment
Remove the offending agent!!!
Acute Phase- Use of medium
potency topical corticosteroids
Desquamation Phase- Use of
topical emollients can be useful
Use topical steroids instead of
oral
Acute generalized exanthematous pustulosis: a retrospective audit of practice between 1994 and 2011 at a single centre. Ingen-Housz-Oro S, Hotz C, Valeyrie-Allanore L,
Sbidian E, Hemery F, Chosidow O, Wolkenstein P. Br J Dermatol. 2015;172(5):1455. Dermatology Department, AP-HP, Henri Mondor Hospital, Créteil, France. 25399843

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Practice Case
• A 52-year-old male with a PMH of Type II diabetes mellitus, presented to the emergency
department complaining of two days of fever, sore throat, painful urination and a macular
rash on the chest and trunk (<10% BSA). The patient reported no new medications but did
take 2 tablets of Naproxen two day earlier in the setting of joint pain. Vital signs were
normal except for a temperature of 100.1°F. He was also noted to have significant
sloughing on both forearms. His WBC level was normal at 4.4 K/uL with slightly elevated
eosinophils of 10% (normal range 0-6%). The lab culture showed no bacterial growth.

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 Practice Case (Continued)

Which SCAR event has the patient likely

experienced? Support your reasoning with
evidence.
What interventions would you implement for the
patient?

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 Practice Case (Continued)

What interventions would you implement if the

WBC levels were elevated and why?

Would you consider corticosteroid therapy in this

patient? Why or why not?

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