Università degli Studi di Milano Bicocca M. Di Mercurio

ASST Papa Giovanni XXIII di Bergamo

UOC Dermatologia

Cutaneous Adverse Drugs Reactions

Cutaneous Adverse Drugs Reactions

Adverse event that can probably / possibly / rarely happen

A known and unexpected response that occurs at normal dosages

Individual factors are often involved

Almost 3% of all nosocomial adverse drugs reactions

About 5% of hospitalizations in dermatology (cutaneous and/or systemic

manifestations)

Cutaneous Adverse Drugs Reactions

The skin is a major target of adverse drug reactions

Diagnosis

• clinical presentation (Rash 91.2% urticaria 5.9%, vasculitis 1.4% more

frequent)

•history of taking a drug

• If rash is associated with fever, lymphadenopathy and/or facial oedema

possible systemic involvement: i.e. Hypersensitivity Syndrome/DRESS

(Drug Reaction with Eosinophilia and Systemic Symptoms)

SKIN REACTIONS TO ‘DRUGS’ RECEIVED BY AT LEAST 1000 PATIENTS

Drugs Reaction rate (per 1000 recipients)

Ampicillin 52

Penicillin G 16

Cephalosporins 13

Packed red blood cells 8.1

Heparin 7.7

Nitrazepam 6.3

Barbiturates 4.7

Chlordiazepoxide 4.2

Diazepam 3.8

Propoxyphene 3.4

Guaifenesin 2.9

Furosemide 2.6

Phytonadione 0.9

Flurazepam 0.5

Chloral hydrate 0.2

Arndt KA, Jick H. Rates of cutaneous reactions to drugs. J Am Med Assoc 1976; 235:918-923.

Risk factors

Gender: F> M

Age

Multiple drugs intaking

Immunosuppression

Immunodeficiencies

Connective tissue diseases (SLE,

Dermatomyositis)

Viral infections (HIV, CMV, HHV-6 and -7, EBV)

Multi-organ involvement (DRESS)

Atopia

HLA-A*3101 (McCormack M et al. N Engl J

Med 2011;364:1126-33)

HLA-B*1502 (Chen P et al. N Engl J Med 2011;

364:1134-43)

HLA-B*5701 (Mallal S et al. N Engl J Med 2008;

358:568-79)

Kidney and liver failure

Pathogenesis

Immunological mechanism (unpredictable): hypersensitivity reactions

Non-immunological (sometimes predictable in relation to the

pharmacodynamics of the charged substance)

Idiosyncrasy with possible immunological mechanism (not predictable,

nor explicable based on the drug-dynamic properties of drugs, only

suspected)

Interaction between immunological factors and genetic predisposition ?

MECHANISMS OF CUTANEOUS DRUG-INDUCED REACTIONS

Immunologic mechanism (unpredictable)

• IgE-dependent drug reactions (type I): urticaria, angioedema and anaphylaxis

• Cytotoxic, drug-induced reactions (antibody against a fixed antigen; type II): petechiae secondary to drug-induced

thrombocytopenia

• Immune complex-dependent drug reactions (type III): vasculitis, serum sickness and certain types of urticaria

• Cell-mediated reactions (type IV) versus undefined: exanthematous, fixed and lichenoid drug eruptions, as well as Stevens–

Johnson syndrome (SJS) and TEN

Non-immunologic mechanisms (sometimes predictable)

• Overdose of drugs: differing rates of absorption, metabolism or excretion

• Pharmacologic side effects: chemotherapeutic agents target

• Cumulative toxicity: silver, minocycline and amiodarone

• Delayed toxicity: dose-dependent effect, which occurs months to years after the discontinuation of a medication

• Drug–drug interactions: (1) intestinal drug interactions; (2) displacement from binding proteins or receptor sites; (3) enzyme

stimulation or inhibition; and (4) altered drug excretion (tetracycline and calcium, methotrexate and sulfonamides,

cyclosporine and azoles, and methotrexate and probenecid)

• Alterations in metabolism: isoniazid may be associated with pellagra-like changes

• Exacerbation of disease: pre-existing dermatologic disease

Idiosyncratic with a possible immunologic mechanism (unpredictable)

• DRESS

• TEN/SJS

• Drug reactions in the setting of HIV infection

• Drug-induced lupus

Flow chart: Rational diagnostic

Clinical presentation

Time since hiring

Mechanism responsible for the events

Suspension Improvement

Change of medication

Test in vitro Lymphocyte transformation test and

Test in vivo: Patch test (sensitivity 30-60%) & delayed intradermal test

LOGICAL APPROACH TO DETERMINE THE CAUSE OF A DRUG ERUPTION

Drug responsibility assessment

Clinical characteristics

• Type of primary lesion

• Distribution and number of lesions

• Mucous membrane involvement

• Associated signs and symptoms: fever, pruritus, lymph node enlargement, visceral involvement

Chronological factors

• Document all drugs to which the patient has been exposed and the dates of administration

• Date of eruption

• Time interval between drug introduction (or reintroduction) and skin eruption

• Response to removal of the suspected agent

• Response to rechallenge

Literature search

• Bibliographic research (e.g. Medline)

• Drug Alert Registry or Medwatch

• Data collected by pharmaceutical companies

• In the case of recently released medications, extrapolation based on the class of drug

Cutaneous allergic responses to small

molecular weight substances (haptens)

T cell mediated (CD8+)

Haptens contacting the skin (i.e. metals)

Drugs

Allergic contact dermatitis

Exanthemas

Fixed drug eruption

Stevens-Jonhson syndrome

Lyell syndrome

AGEP

DRESS

Lichenoid eruptions

Others….

IgE mediated

Urticaria/angioedema syndrome

Main skin reactions induced by systemic drugs

Immunological

Urticaria / angioedema

Exanthematous dermatitis

Erythrodermas

Erythema multiforme

Stevens-Johnson / Lyell

Hypersensitivity Syndrome/DRESS: Drug

reaction with eosinophilia and systemic symptom

AGEP: acute generalized exanthematic pustulosis

Fixed drug erythema

Lichenoid eruptions

Vasculitis

Lupus erythematosus (SCLE)

Pemphigus and pemphigoid

Non immunological

Urticaria / angioedema

Phototoxic reactions

Purpuric dermatitis

Acneiform eruptions

Scleroatrophy

Lipoatrophy

Pigmentation disorders

Adnexal alterations

Aggravation of pre-existing

skin diseases

CHARACTERISTICS OF MAJOR DRUG-INDUCED ERUPTIONS

Clinical presentation Percentage drug-induced

(%)

Time interval Mortality

(%)

Selected responsible drugs

Exanthematous

eruption

Child: 10–20

Adult: 50–70 4–14 days 0

Aminopenicillins

Sulphonamides

Cephalosporins

Anticonvulsants

Allopurinol

Urticaria

Anaphylaxis

<10

30

Minutes to hours

Minutes to hours

0

5

Penicillin

Cephalosporins

NSAIDs

Monoclonal antibodies

Contrast media

Fixed drug eruption 100

First exposure: 1–2 wks

Re-exposure: <48 hs,

usually within 24 h

0

TMP-SMX

NSAIDs

Tetracyclines

Pseudoephedrine

Acute generalized

exanthematous

pustulosis (AGEP)

70–90 <4 days 1–2

β-Lactam antibiotics

Macrolides

Calcium channel blockers

Drug reaction with

eosinophilia and

systemic symptoms

(DRESS)

70–90 15–40 days 5–10

Anticonvulsants

Sulphonamides

Allopurinol

Minocycline

Lamotrigine (especially in

combination with valproate)

Stevens–Johnson

syndrome (SJS)

70–90

7–21 days

5

Anticonvulsants

NSAIDs

Allopurinol

Sulfonamides

Toxic epidermal

necrolysis (TEN)

30

Exanthematous/morbilliform/maculopapular rash

It is the most common drug-induced adverse reaction.

7-14 after taking the drug and frequent in multi-treated hospitalized patients.

Polymorphic: morbilliform or urticarioid lesions often confluent in annular macules, polycyclic

in the upper and lower limbs and in the trunk.

Mild/moderate itching with fever.

Impairment of the general state (liver function and plasma hyper eosinophilia) sometimes

prodrome of more severe forms.

Disappeared after stopping the drug.

Often involved T lymphocytes CD 4+ and CD8 + perforin+ granzyme+, MHC class II.

Non-defining histology: perivascular lymphocytic infiltrate and necrotic keratinocytes.

Dd: Viral rash

Mainly topical corticosteroid therapy

Exanthematous drug

eruptions: Numerous

pink papules on the

trunk due to a

cephalosporin (A).

Confluence of lesions on

the trunk (B) and annular

plaques on the forehead

(C) secondary to

phenobarbital.

Urticaria, Angioedema and Anaphylaxis

Type I mediated IgE immune reaction: mast cells and basophils from

whose degranulation histamine is released (frequent after exposure to

penicillin).

Appearance in a few minutes or hours.

Sometimes urticarial / vasculitic manifestations (type III I.R.) as

leukocytoclastic forms.

Anaphylactoid reactions: nonimmunological release of histamine from

radiographic contrast media.

Urticaria

Transient erythematous-edematous papules and plaques often associated with even very

intense itching, with central pallor of various sizes and numbers and annular, polycyclic

and/or figurative appearance. The whole body also involved soles of the feet and

capillaries.

Duration <24 h, if> 24 h and fixed lesions often vasculitis due to the persistence of

dermal hemorrhage.

Relapsing poussées manifestations resolving <6 wks (acute): Chronic urticaria> 6 wks

HISTOLOGY: Dermal edema with superficial and interstitial mononuclear infiltrate,

early stage neutrophils, rare eosinophils and mast cells. A more cellular infiltrate is

found in leukocytoclastic vasculitis.

Prick test, PRIST, RAST, but above all a history of recent drug intake.

Urticaria due to penicillin: many lesions flow into large plaques with a

figurative appearance

Transient dermal, subcutaneous and submucosal edema (associated

urticaria in 50% of cases) unilateral or pale-pink asymmetric to the face

(eyelids, lips, ears and nose), less frequent in extremities and genitals.

If tongue and oropharynx or epiglottis and larynx are involved is

possible upper airway obstruction (stridor).

Intestinal edema rarely causes pain, nausea, vomiting and diarrhea.

Risk factors: taking ACE inhibitors or C1q inhibitor deficiency due to

autoimmune or lymphoproliferative disorders

Angioedema

Acute reaction (minutes, 2-3 hours) with life-threatening

effects for the person with systemic symptoms such as

hypotension and tachycardia until cardiocirculatory collapse,

may or may not be associated with angioedema and skin

manifestations.

Therapy: Corticosteroids and subcutaneous epinephrine

Anaphylaxis

Idiopathic due to endogenous (porphyrins) or

exogenous (drugs) photosensitizers

Photosensibility

Phototoxicity

Common and expected reactions localized to the photo exposed region

Accumulation- and time-dependent

Direct interaction between UV and ROS-generating drugs, responsible

for cell damage

Appears as an exaggerated solar burn, but after a period time too short to

justify a simple photo-induced insult

Photo-onycholysis (separation of the lamina from the nail bed) and

pseudoporphyria (erosions and vesicles on the back of the hands and

face with normal blood and chemical values) are less frequent

Histology: keratinocytic necrosis, edema, dermal lymphocytic infiltrate

and vasodilation

MED (Minimal Erythematous Dose) decreased since taking the drugs

Reduction or discontinuation of the drug leads to resolution

Photoallergy

Non-dose-dependent idiosyncratic reaction

Cell-mediated hypersensitivity (IV) induced by UV with an activated

drug or its derivative as immunologically active protein (photoallergen)

Chronic course: lichenoid dermatitis-like manifestations, not confined to

the photo-exposed region and spreading beyond its limits

The associated itching leads to lichenification of the area

Chronic use of photoallergenic drugs leads to persistent hypersensitivity

over time

Photo-patch tests are useful as well as CST and sunscreen prevention

Most leukocytoclastic forms are idiopathic but post-infectious,

autoimmune and drug-induced forms must be excluded (10%)

Immunocomplexes (Ab against drug-derived haptens) in post-capillary

venules (small and medium vessels)

Mainly in the lower limbs: purpuric papules, urticarial lesions, ulcers,

nodules, pustules, point hemorrhages, pustules and necrosis

Often fever, myalgias, arthralgias, migraines

Infrequent arthritis, peripheral neuropathies, edema and tachypnea

Rarely systemic involvement: support CSS for faster healing

Onset 1-3 weeks after taking a drug whose suspension gives resolution

Vasculitis

Neutrophilic drug eruptions

AGEP: acute generalized exanthematic pustulosis

Sweet Syndrome

Halogenoderma

Neutrophilic eccrine hydrosadenitis (NEH)

AGEP

Acute febrile reaction (> 38 ° C) precedes a few days or accompanies the formation of

sterile, numerous, small (<5 mm), initially non-follicular pustules that arise on large

erythematous-edematous areas on the face and folds then spread to trunk and upper

limbs, burning and / or itchy; sometimes facial and hand edema, purpura, vesicles,

blisters, erythema multiform-like lesions

Appearance in less than 2 days; after 1-2 weeks a superficial flaking follows

Serum leukocytosis with marked blood neutrophilia, mild or moderate eosinophilia,

renal dysfunction and hypocalcemia.

Histology: spongiform pustules of the superficial epidermal layers, papillary edema,

mixed neutrophilic infiltrate and dermal and perivascular eosinophilic; less frequent

keratinocytic necrosis

Clinically indistinguishable by pustular psoriasis: useful clinical

presentation (rapid spread of AGEP accompanying lesions’) and the

histology (acanthosis characteristic of pustular psoriasis).

Confluence of pustules can lead to TEN.

DRESS can also be accompanied by pustules.

Incidence underestimated often confusing it with pustular psoriasis

90% drug-induced; sometimes mercury intoxication or intestinal virosis

Often encountered HLA-B5, -DR11 and -DQ3

Patch tests positivity> 80%: possible type IV I.R. (IL-3, IL-8, G-CSF)

Differential diagnosis AGEP

AGEP: (A) Diffuse

erythema of the buttock

(cephalosporin) and face

(B) studded with sterile

pustules (metronidazole).

Spongiform pustules are

seen within the epidermis

of lesional skin (C).

Courtesy of Kalman Watsky,M.D

Fever, neutrophilia and painful erythematous and edematous

plaques on the face and upper limbs with neutrophilic dermal

infiltrate

Only <5% is drug-induced and neutrophilia is often absent

due to the concomitant chemotherapy that causes neutropenia

Onset many days after intake (about 7-8 days)

Suspension leads to resolution in 1-3 days

Skin manifestations resolve in10-30 days

In severe forms CSS

Sweet Syndrome

Alogenoderma

Bromoderma, fluoroderma and iododerma, often due to kidney failure

Rare dermatoses arising from the use of drugs with bromides, fluorides,

iodides (antithyroid, cordarone, iodinated contrast agents, mucolytics)

Acne-like rash with pustules and less rarely granulomatous or vegetative

plaques, ulcers and blisters after chronic exposure, rarely after few days

Histology: dermal neutrophilic infiltrate and epidermal neutrophilic

exocytosis with consequent abscess formation up to papillomatosis

Dd: folliculitis, fungal infections, pyoderma gangrenosum, S. di Sweet,

vegetative pemphigus

CST therapy and diuretics to eliminate high serum halogen levels

Iododerma. Edematous erythematous

papules on the buttocks with central crusts

Neutrophilic eccrine hidradenitis.

Erythematous plaques on the leg which

may be confused with Sweet's syndrome.

Neutrophilic eccrine hydrosadenite (NEH)

Papules and erythematous plaques due to the presence of

a neutrophilic infiltrate around the eccrine glands

The cytarabine used in CML is often conveyed

Hypersensitivity Syndrome/DRESS: Drug Reaction

with Eosinophilia and Systemic Symptoms

Incidence: 0.1-0.01%. Gender: M / F = 1.34

Frequency> in the black race (African-Americans, Caribbean).

Age variable: correlated with drug.

Genetics: familiarity (greater in first degree relatives).

Mortality: 5-10%.

Drug metabolism alteration’s: 70-90% phenytoin, carbamazepine,

phenobarbital (detoxification defect and cross-reactivity), sulphonamides

(lymphocyte toxicity: from acetylation of the hydroxylamine metabolite),

allopurinol, minocycline, lamotrigine.

IL-5, released by activated T lymphocytes, determines eosinophilia

Ab anti HHV-6 and 7 have often elevated serum values

Onset 2-6 weeks after drug taking.

Hypersensitivity Syndrome/DRESS: Drug Reaction

with Eosinophilia and Systemic Symptoms

Fever in 85% of cases.

Morbilliform rash, gradually edematous: it starts on the face (periorbital)

Rostro-caudal progression: thorax, upper limbs.

Vesicles, blisters, follicular and non-follicular pustules, purpura,

erythroderma and progressive infiltration.

Frequent evolution in exfoliative dermatitis.

Mucosal involvement in 10% of cases.

Eosinophilia (> 1500 mm3), leukocytosis (> 50000 mm3), atypical

lymphocytosis (monucleotic-like Downey cells), LDH, ALT, AST, GGT,

hypogammaglobulinemia.

Sometimes lymphadenomegaly, arthralgias.

DRESS: Note the edema of

the face as well as

edematous pink papules in

this woman who had taken

carbamazepine.

Hypersensitivity Syndrome/DRESS: Drug Reaction

with Eosinophilia and Systemic Symptoms

Systemic involvement: mainly liver, kidneys, lungs, thyroid, pancreas,

bone marrow and rarely the brain.

Cutaneous and systemic clinical manifestations can last several months

after stopping the drug

Histology: dense superficial dermal lymphocytic infiltrate, eosinophils

and dermal edema, if the rash persists, the infiltrate becomes so dense as

to give a picture of pseudolymphoma

Dd: other drug reactions, acute viral infections, idiopathic hyper

eosinophilic syndrome, lymphoma and pseudolymphoma.

Hypersensitivity Syndrome/DRESS: Drug Reaction

with Eosinophilia and Systemic Symptoms

At least 3 criteria are required

Severe rash

Temperature

Hematologic abnormalities: Eosinophilia> 1.5 * 109 / L and / or atypical

lymphocytosis (Downey cells)

Systemic interest (of at least 1 organ): Adenopathy (> 2 cm), hepatitis

(transaminase 2v v.n.) nephritis, pneumonia (alveolar and interstitial

with lymphocytic and eosinophilic infiltrate), nephropathy, myocarditis

or pericarditis.

Bocquet H et al 1996 Semin cutan med Surg, 15: 250-257

RegiSCAR drug reaction with eosinophilia and systemic

symptom validation score

De A et al. Indian J Dermatol. 2018 Jan-Feb;63(1):30-40

Comparison among the proposed diagnostic criteria by Boquet et al and Japanese

study group of severe cutaneous adverse reactions to drugs and the inclusion

criteria for the RegiSCAR study before application of the validation score for

patients with DRESS

De A et al. Indian J Dermatol. 2018 Jan-Feb;63(1):30-40

Fixed drug eruption

Onset 1-2 weeks after the first exposure: a new exposure brings the

appearance of manifestations after 24h

One or more erythematous-edematous plaques, dark red-violet to grayish

color, sometimes with central blisters or epidermal detachment.

Locations: lips, face, hands, feet and genitals

Possible central erosion with resolution after several days from which a

post-inflammatory brown pigmentation remains

The resumption of the drug causes reappearance of the lesion (s) earlier

and at the same site

The non-pigmented form has plaques of even 10 cm in diameter and

resolves without outcomes

Histology: mixed lymphocyte and eosinophilic infiltrate with PMNs in

superficial and deep perivascular and interstitial site, some keratinocytic

necrosis and dermal melanophages in non-inflammatory forms

Differential diagnosis

if single lesions entomodermatosis, if multiple lesions with oral mucosa

involvement erythema multiforme minor and major or SJS, HSV in

genitalia, in the non-pigmented form bacterial infections

Fixed drug eruption

Well-demarcated

erythematous (A)

to violet-brown

plaques that can

develop a

detached

epidermis (B) or

erosion (C)

centrally. As

lesions heal,

circular areas of

hyperpigmentation

are commonly

seen (D).

phenophthalein

naproxen

ciprofloxin

trimethoprim-sulfamethoxazole

Courtesy of Kalman Watsky, M.D. D Courtesy of Jean Bolognia, M.D.

Linear IgA bullous dermatosis

Appearance after 1-15 days of vesicles and bubbles stretched in an

annular configuration, sometimes a TEN-like presentation

Histology: Subepidermal bubbles with dermal PMN

IFD: linear deposits of IgA at the dermoepidermic junction (lamina

lucida > lamina dense)

Resolution with suspension after 2-5 weeks

Pemphigus drug induced

Unknown pathogenesis, probably multifactorial: the thiol groups

(penicillamine) of the drugs bind like haptens to the desmosomes

determining the inflammatory response, therefore the acantholysis

and involvement of proteolytic enzymes

Intra-epidermal flaccid blisters, skin and mucous membrane erosions.

Histologically acantolysis and IFD in 90% Ab

10% cases of pemphigus are drug-induced occurring after weeks or

months from the start of treatment (ACE-I, b-lactamase)

recently are involved Ab anti PD-1 and PDL-1)

Lupus Erythematosus Drug-induced

Reactive metabolites interact with nuclear histones by acting as

haptens and activating the complement cascade.

It is important to distinguish drug-induced systemic LE from drug-

induced subacute cutaneous LE

No sex preference, fever, weight loss, pericarditis and pleuro-

pneumonia, rare renal and neurological involvement

Rare skin involvement (malar rash, photosensitive and discoid lesions or

multiform-like erythema and vasculitis)

Onset symptoms usually over a year after treatment.

Ab antihistone ≤ 95% of cases, but not specific (also in idiopathic SLE).

Ab anti dsDNA are negative. ANA (Ab antinuclear) may persist positive

6-12 m after drug discontinuation even though resolution is in 4-6 wks

Procainamide, hydralazine, chlorpromazine, isoniazid, methyldopa,

propylthiouracil, quinidine, D-penicillamine, and PUVA.

Minocycline gives positivity for anti-cytoplasmic antibodies (MPO/PR3)

Systemic Lupus Eritematosus Drug-induced

Subacute Cutaneous Lupus Erythematosus

(SCLE) Drug-induced

Psoriasiform and annular lesions, upper part of the trunk and extensor

surface of the arms, clinically and histologically indistinguishable from

the idiopathic shape. Anti-Ro/SSA+ and Anti-La/SSB+

Lansoprazole, hydrochlorothiazide, calcium channel blockers,

terbinafine, NSAIDs, griseofulvin, docetaxel, PUVA and interferon.

Resolution of the rash does not always occur after stopping the drug.

In patients treated with TNF-α blockers, ANA and anti-nDNA antibodies

tend to be positive and they can develop chronic skin lesions (discoid),

subacute cutaneous erythematosus and acute lupus.

Anticoagulant-induced skin necrosis

Rare, sometimes fatal reaction induced by warfarin or heparin.

Onset after 2-5 days for reduced protein C function (1/10000, risk> if

hereditary protein C deficiency)

Erythematous plaques develop into hemorrhagic and necrotic ulcers

because of ischemic infarction, due to occlusive thrombi in the skin

blood vessels and subcutaneous tissue in the thighs, sinuses and buttocks

Therapy: TAO suspension and administration of vit. K, heparin instead

of coumadin and intravenous protein C concentrates

If heparin necrosis the antibodies bind to heparin complexes and to the

platelet factor 4 inducing the platelet consumption aggregation. In

addition to the known thrombocytopenia, thrombosis and necrosis can

occur both at the injection site and far away in internal organs

Serum sickness-like rash

Most seen in children (1 in 2000 after taking cefaclor)

Fever, arthralgias/arthritis, urticarial/ measlesform rash, lymphadenopathy

Onset 1-3 weeks after drug intake

Unlike the 'real' serum disease induced by humanized and non-humanized

monoclonal Ab (antithymocyte globulin, tositumomab, infliximab) no

hypocomplementemia, circulating immune complexes, vasculitis and

kidney disease.

Less frequently bupropion, minocycline, penicillin and propranolol.

Mucosal ulcerations

Stomatitis with erosions and ulcerations are signs of drug-induced

mucocutaneous syndromes (fixed drug eruption, pemphigus or TEN) or

direct side effect of specific drugs such as immunosuppressants

(methotrexate) and chemotherapies (doxorubicin and 5-fluorouracil).

Severe ulcerative stomatitis due to metamizole, phenylbutazone,

oxifenbutazone, D-penicillamine and gold salts and dental material.

Sometimes neutropenia and agranulocytosis.

Penile ulceration sometimes from foscarnet.

Oral and gastrointestinal mucositis Cause of morbidity, often dose-limiting, 40% of patients undergoing

chemotherapy.

Two possible mechanisms involved:

a) direct cytotoxic effect on oral epithelial cells, mucosa appears

erythematous, edematous and ulcerated with pain, burning and

xerostomy, spontaneous healing is observed within 2 to 3 weeks.

b) indirect effects: overlapping infections (Candida, herpes simplex

virus) and/or hemorrhage, suppression of the bone marrow, observed in

the therapeutic nadir of the leucocytes count.

Preventive use of antiviral (acyclovir) and antifungal drugs (fluconazol)

and stimulant factors of granulomonocyte colonies (which reduce the

duration of neutropenia) have decreased the impact of overinfections.

Prevention: oral hygiene, antimicrobic, topical anesthetics, painkillers.

Alterations of hair grew

Several drugs act on the anagen or telogen phase.

Hair loss: 2-3 weeks after taking the drug, if telogen effluvium after 2-4

months

Non-scarring alopecia linked to self-solvent predisposing individual

factors with discontinuation of treatment.

Alopecia

It is often due to anagen effluvium in which there is a sudden

interruption of the mitotic activity of the cells of the rapidly replicating

hair matrix.

Mainly scalp hair, less frequently than eyebrows, axillary and pubic

regions. Hair loss is almost always reversible, and the severity of

alopecia depends mainly on drugs administered. Occasionally, patients

with straight hair develop curly hair when they grow back.

DRUG-INDUCED ALOPECIA

Telogen phase

Anticoagulants: heparin > warfarin

Anticonvulsants: carbamazepine, valproic acid, phenytoin

Antidepressants: imipramine, desipramine, maprotiline, fluoxetide

Antihypertensive agents: b-blockers: acebutolol, propanolol

ACE inhibitors: captopril, enalapril

Diuretics: spironolactone

Antimicrobials: gentamicin, thiamphenicol, fluconazole

Antithyroid drugs: carbimazole, thiouracils

Colchicine

Interferons

Lipid-lowering agents: clofibrate, cholestyramine

Lithium

NSAIDs: piroxicam, naproxen, indomethacin, ibuprofen

Oral contraceptives

Retinoids

Others: allopurinol, cimetidine, L-dopa, amphetamines, pyridostigmine,

bromocriptine

Anagen phase

Antineoplastic agents

Others: arsenic, bismuth, gold, thallium

DRUG-INDUCED ERUPTIONS DUE TO CHEMOTHERAPEUTIC AGENTS Mucocutaneous reactions Responsible drugs

Alopecia

Alkylating agents: cyclophosphamide, ifosfamide, mechlorethamine

Anthracyclines: daunorubicin, doxorubicin, idarubicin

Taxanes: paclitaxel, docetaxel

Etoposide, vincristine, vinblastine, topotecan, irinotecan, actinomycin D

Mucositis Daunorubicin, doxorubicin, high-dose methotrexate, high-dose melphalan, topotecan, cyclophosphamide, continuous infusions

of 5-fluorouracil and analogues of 5-fluorouracil

Extravasation reactions (e.g.

chemical cellulitis, ulceration)

Anthracyclines, carmustines, 5-fluorouracil, vinblastine, vincristine, mitomycin C

Tender sterile inflammatory

nodules at sites of chemotherapy

extravasation or administration)

5-fluorouracil, mitomycin C, paclitaxel, doxorubicin, epirubicin

Hyperpigmentation Alkylating agents: busulfan, cyclophosphamide, cisplatin, mechlorethamine

Antimetabolites: 5-fluorouracil, methotrexate, hydroxyurea

Antibiotics: bleomycin, doxorubicin

Mucosal hyperpigmentation Busulfan, 5-fluorouracil, hydroxyurea, cyclophosphamide

Nail hyperpigmentation 5-Fluorouracil, cyclophosphamide, daunorubicin, doxorubicin, hydroxyurea, methotrexate, bleomycin

Onycholysis Paclitaxel

Radiation recall Doxorubicin, daunorubicin, taxanes, actinomycin D, capecitabine, gemcitabine

Radiation enhancement Doxorubicin, hydroxyurea, taxanes, 5-fluorouracil, etoposide, gemcitabine, methotrexate

Photosensitivity 5-Fluorouracil and its analogues, methotrexate, hydroxyurea, dacarbazine, mitomycin C

Actinic keratoses: 5-fluorouracil and its analogues (e.g. capecitabine), pentostatin

Seborrheic keratoses: cytarabine, docetaxel

Squamous cell carcinoma: fludarabine

Acral erythema

(erythrodysesthesia)

Cytarabine, anthracyclines, 5-fluorouracil and its analogues, taxanes, tegafur, methotrexate, cisplatin

Neutrophilic eccrine hidradenitis Cytarabine, bleomycin, anthracyclines, cyclophosphamide, cisplatin, topotecan

Eccrine squamous

syringometaplasia

Cytarabine, cyclophosphamide, busulfan, carmustine, taxanes

Ulcerations Hydroxyurea (lower extremities)

Nodulosis MTX (but usually in patients with rheumatoid arthritis)

Lymphoma MTX (most commonly in patients with rheumatoid arthritis)

Squamous cell carcinoma Fludaribine, hydroxyurea, topical BCNU

Flushing Asparaginase, high-dose BCNU, mithramycin

Others Urticaria: asparaginase, bleomycin, chlorambucil, cyclophosphamide, daunorubicin

Exanthematous eruption: bleomycin, carboplatin, cytarabine, methotrexate, liposomal doxorubicin, paclitaxel

SJS/TEN: bleomycin, busulfan, cyclophosphamide, doxorubicin, etoposide, methotrexate

Cutaneous vasculitis: gemcitabine, busulfan, cyclophosphamide, hydroxyurea, levamisole

Dermatomyositis-like eruption: hydroxyurea

Cutaneous side-effects of

chemotherapeutic agents.

A) Ulceration due to

extravasation of doxorubicin.

B) Horizontal melanonychia

due to 5-fluorouracil.

C) Erythema of the ears due to

the cytarabine (cytosine

arabinoside), sometimes

referred to as ‘Ara-C ears’; the

petechiae are due to

thrombocytopenia.

D) Erythrodysesthesia due to

cytarabine with obvious

erythema of the plantar surface.

E) Necrosis of psoriatic plaques

due to an ‘overdose’ of

methotrexate.

F) Raynaud's phenomenon and

digital necrosis due to systemic

bleomycin. B–E Courtesy of Jean Bolognia M.D.

Drug-induced psoriasis

Drugs can: (1) re-exacerbate a pre-existing psoriasis, (2) increase it, (3)

make it appear de novo and (4) develop resistance to antipsychotic drug.

It can occur in sites of other skin reactions (e.g. exanthematic), reactive

isomorphism (Koebner phenomenon).

Forms: localized/diffused plaques, erythrodermic and pustular, palm-

plantar, scalp and nail.

Early onset (4 wks Terbinafine and NSAIDs), intermediate (4-12 wks

antimalarial and ACE-inhibitors), late (>12 wks, lithium & b-blockers).

Regression weeks or months after suspension of the triggering drug.

Histology: not always characteristic, more like a lichen dermatitis.

Acneiform eruption (and folliculitis)

About 1% of rashes from drugs.

Papules and/or pustules located on the face and upper trunk, same acne

sites, but with no comedons.

Drug-dependent pop-up interval

Corticosteroids, androgens, idantoin, lithium, halide and oral

contraceptives (more frequently those containing progestin with

androgen-like effects). Blocking antibodies and thyrosinkinase inhibitors

of the epidermal growth factor (EGFR). Less commonly azatioprine,

chinidine and hormone adrenocorticotrope.

CUTANEOUS SIDE EFFECTS OF KINASE INHIBITORS AND BLOCKING ANTIBODIES

Sorafenib Sunitinib Imatinib, bevacizumab Erlotinib, gefitinib, cetuximab,

panitumumab, lapatinib,

Targeted receptors VEGFR2, VEGFR2, PDGFR, EGFR

VEGFR3, VEGFR3, c-KIT

PDGFR,

RAF

PDGFR,

RAF

(A, B, C),

FLT3

Hair

depigmentation

− + − −

Hair

repigmentation

− − +/− −

Alopecia +/− − − +/− (frontal)

Curly, brittle hair − − − +/−

Facial hair growth

+/or trichomegaly

of eyelashes

− − − +

Paronychia − − − +

Periorbital edema − +/− + −

Facial erythema + − − +/−

Subungual

splinter

hemorrhages

+ + − −

Folliculitis − − − ++

Vaccine-induced eruptions

With the suspension of smallpox vaccinations in the general population,

the incidence of evident skin side effects due to today's vaccines is low.

Local inflammatory reactions:

erythema, edema and tumefaction (due to Arthus local reaction);

urticaria, angioedema, anaphylaxis mainly with live measles vaccines.

Sometimes lichen dermatitis, multiform erythema and autoimmune

reactions such as polyarteritis nodosa

BCG vaccination can give a local self-limiting benign reaction: pustula,

plaque or an ulcer with occasional formation of local abscess.

REACTIONS LOCALIZED TO SITES OF INJECTIONS OF MEDICATIONS (IN ADDITION TO

EXTRAVASATION OF THOSE ADMINISTERED INTRAVENOUSLY)

Insulin Erythema, pruritus, lipoatrophy, necrosis

Etanercept Erythematous plaques, leukocytoclastic vasculitis

GM-CSF, G-CSF Pustular reaction, urticarial plaque

Interferon Vasculopathy with necrosis, development of plaque of

psoriasis

Interleukin-2 Lobular panniculitis, granulomas

Vitamin K Erythematous plaque, often annular, morpheaform

plaque

Heparin Necrosis, ecchymosis

Low-molecular-weight, calcium-containing heparin Calcinosis cutis

Iron Hyperpigmentation

Hyaluronic acid, silicone Swelling, granulomatous reaction

Corticosteroids Dermal atrophy, lipoatrophy, telangiectasias, deposits,

hypopigmentation

Vitamin B Pruritus, morpheaform plaque

Enfuvirtide Erythematous or morpheaform plaque

Vaccines

Aluminium-containing vaccine Nodules, foreign body reaction

Multiform Erythema Self-resolving but potentially recurrent disease

After 24 hours of drug intake, fixed red papules appear mainly in the acral sites,

occasionally evolve into typical target or cockade lesions consisting of 3 different

zones or atypical papular lesions with only 2 zones of demarcation edge poorly defined

Previous infection mainly viral herpetic (history of cold sores in about 50% 3-14 days

before) or bacterial (M. pneumoniae) and infrequent mycotic (Histoplasma capsulatum)

Drugs are involved <10%

Rare mucous involvement and/or systemic symptoms in the lowest form unlike the

major where general state impairment is frequent

Clinical-histopathological correlation is straight for Dd with SJS and TEN

Does not give increased risk of TEN

It is mostly observed in young adult males. Incidence not known

Multiform Erythema Diagnosis

Due to the clinical similarity in EM minor/major, SJS and TEN were,

until recently, considered all part of the spectrum of a single disease

Clinical criteria for the distinction of the two forms of EM, SJS / TEN:

the type of elementary skin lesion,

distribution of skin lesions (topography),

presence or absence of obvious mucous lesions,

the presence or absence of systemic symptoms (see Table).

Phenotypic variety in EM

(A) Edematous/urticarial;

(B) urticarial lesions with

central crusting;

(C) erythematous plaques

with dusky centers;

(D) classic target lesions on

the palms.

Courtesy of Yale Residents Slide

Collection

Multiform Erythema Clinical features

Erythematous macules, round <3 cm, net edge with three distinct zones:

two concentric rings of red color (different evolutionary phase of the

same pathological process) surrounding a dark circular central area with

evident epidermal damage, then formation of bubbles or crusts.

Some patients develop only rare lesions with different evolution and

presentation, while others show all lesions in the same monomorphic

clinical appearance. Rarely lesions look like typically targets.

Many atypical papules: round, edematous, palpable (EM)

In the SJS or TEN lesions show only two zones poorly defined non-

palpable edge with potential central vesicle or bubble.

Topography EM Extremities (hands back and forearms), sometimes face, palms, neck,

trunk, less frequently legs or extended shapes as in the EM major.

They tend to cluster, especially on the elbows or knees.

Koebner Isomorphic phenomenon: scratches, erythema and/or edema of

folds at chronic trauma sites.

Serious involvement of the mucosa typical of the EM major

Vesicles-bubbles that turn into painful erosions to the lips, eyes and

genitals (large sizes of polycyclic appearance)

Systemic symptoms almost always present in EM major and

absent/limited in EM minor: fever, asthenia, arthritis with swelling,

occasionally atypical lung involvement-pneumonia precede and/or

accompany skin lesions.

Isomorphic phenomenon in EM.

Target lesions developing linearly

along a preceding animal scratch

Mucosal erosions and serous

crusting with an outer zone of

color change on the lips in

HSV-associated EM. Note the

two zones of color change on

adjacent skin.

Erythema Multiforme Histology

Useful to distinguish it from SLE and vasculitis, keratinocyte apoptosis

(no necrosis), then spongiosis and vacuolar degeneration of basal

keratinocytes, surface dermal edema and infiltrated perivascular

lymphonocyte with exocitosis in the epidermis

IgM and C3 around the surface blood vessels and at the dermo-epidermal

junction level. Specific HSV antigens were detected within keratinocytes

using immunofluorescence, and HSV genomic DNA was detected using

PCR of skin biopsy samples.

Not obvious necrosis as in SJS and TEN

Histology of a target lesion in erythema multiforme. An interface dermatitis

is present with exocytosis, apoptotic keratinocytes, and a perivascular

mononuclear cell infiltrate.

Erythema Multiforme Evolution

Abrupt onset within 24 hours and full development within 72 h of all

skin lesions, accompanied by itching or burning. The picture does not

change for at least 7 days and heals after 2 weeks without sequalae

except rarely corneal ulceration. Hyper- or post-inflammatory

hypopigmentation

Multiform Erythema Differential diagnosis

Often misdiagnosis of giant urticaria

Symmetric red papules or typical and atypical target lesions 'fixed' in the

same location for at least 7 days, while nettle lesions last at <24 hours at

a given site. The center of EM lesions show epithelial damage with crust

or bubble formation, while the center of giant urticaria is characterized

by normal skin or erythema without epidermal damage.

DIFFERENCES BETWEEN URTICARIA AND

ERYTHEMA MULTIFORME

Urticaria Erythema multiforme

Central zone is normal skin Central zone is damaged skin (dusky,

bullous or crusted)

Lesions are transient, lasting less

than 24 hours

Lesions ‘fixed’ for at least 7 days

New lesions appear daily All lesions appear within first 72

hours

Associated with swelling of face,

hands or feet (angioedema)

No edema

Topical treatment (topical antiseptics for skin lesions),

Systemic treatment in acute rash when trigger can be identified (HSV or

M. pneumoniae), preventive treatment of the recurrent disease.

In EM minor, symptomatic treatment is sufficient: antihistamines for os

for 3 or 4 days to reduce burning and itching.

In severe forms of EM with general state impairment: early therapy with

systemic corticosteroids (e.g. prednisone [0.5-1 mg/kg/die] or

methylprednisolone [1 mg/kg/die for 3 days]).

Multiform Erythema therapy

Prophylaxis before symptoms in EM HSV-associated often relapsed:

oral acyclovir (10 mg/kg/die in fractional doses),

valaciclovir (500-1000 mg/die depending on frequency of recurrences)

If not responsive, the dosage may be doubled, or the drug replaced

In patients with recurrent EM resistant to antiviral therapy of

prophylaxis: azathioprine (100 mg/day for several months), prednisone

(0.5 mg/kg/day for several months), thalidomide, dapsone, cyclosporin,

mycophenolic mofetil and PUVA.

Multiform Erythema therapy

ERYTHEMA MULTIFORME (EM) MINOR, EM MAJOR AND STEVENS–JOHNSON SYNDROME (SJS)

Type of skin

lesions

Distribution Mucosal involvement Systemic symptoms Progression to TEN Precipitating factors

EM minor Typical targets

± Papular

atypical targets

Extremities

(especially

elbows,

knees,

wrists,

hands), face

Absent or mild

Absent

No

Herpes simplex virus

Other infectious

agents

EM major Typical targets

± Papular

atypical targets

Occasionally

bullous lesions

Extremities,

face

Severe

Present

No

Herpes simplex virus

Mycoplasma

pneumoniae

Other infectious

agents

Rarely drugs

SJS Dusky macules

with or without

epidermal

detachment

Macular

atypical targets

Bullous lesions

(<10% BSA

detachment)

Trunk, face

Severe

Present

Possible

Drugs

PRECIPITATING FACTORS IN ERYTHEMA MULTIFORME

Infections (approx.

90% of cases)

Viral

Herpes simplex virus (HSV-1, HSV-2)

Parapoxvirus (orf)

Vaccinia (smallpox vaccine)

Varicella zoster virus (chickenpox)

Adenovirus

Epstein-Barr virus

Cytomegalovirus

Hepatitis virus

Coxsackievirus

Parvovirus B19

Bacterial

Mycoplasma pneumoniae

Chlamydophila (formerly Chlamydia) psittaci (ornithosis)

Salmonella

Mycobacterium tuberculosis

Fungal

Histoplasma capsulatum

Dermatophytes

Drugs (<10% of cases) Primarily:

Exposures Poison ivy

Systemic disease (rare) Inflammatory bowel disease

Lupus erythematosus (Rowell's syndrome)

Behçet's disease

STEVENS–JOHNSON SYNDROME (SJS) AND

TOXIC EPIDERMAL NECROLYSIS (TEN)

Rare, potentially fatal, severe adverse skin reactions characterized by

muco-cutaneous edema, erythema and extensive exfoliation.

Incidence: 1.2-6 (SJS) and 0.4-1.2 (TEN)/106 people. F:M=1.5:1 mostly

with age and immunodepression (HIV, lymphoma, radiotherapy for brain

tumors) up to 1000 times compared to the general population

Reduced ability to detox the intermediate metabolites of drugs

(sulfonamides as antibiotics, diuretics, anticonvulsants) whose antigenic

complexes with host tissues determine immune response, genetic

predisposition plays a relevant role (HLA-B12 for TEN, HLA-B-5,801

associated with allopurinol, HLA-B for carbamazepine-induced SJS)

STEVENS–JOHNSON SYNDROME AND

TOXIC EPIDERMAL NECROLYSIS

Even though a poor inflammation, presence of IL-6, TNF-, IFN-, IL-18

and FasL in the lesional epidermis and drug sensitization 1-3 weeks after

exposure could explain some mechanisms developing in SJS and TEN.

Prodromic symptoms (1-3 days before): fever, burning eyes, painful

dysphagia, anxiety and asthenia can precede skin manifestations of a

classic drug dermatosis quickly progressive with unclear course or term

Epidermal detachment of the body surface: SJS <10%, SJS/TEN 10-30%

Onset: 7-21 days after drug intake (NSAIDs, antibiotics, antiepileptics)

Mortality:1-5% for SJS until 25-35% for TEN (SCORETEN), in relation

to age (multi-treated) and the amplitude of epidermal detachment surface

STEVENS–JOHNSON SYNDROME AND

TOXIC EPIDERMAL NECROLYSIS

In physiological situations, apoptotic cells are quickly eliminated at an

early stage by phagocytes capable of detecting and internalizing them.

In situations where the incidence of apoptosis exceeds the ability of

phagocytes to eliminate apoptotic cells (cancer, autoimmune and

degenerative diseases, AIDS), these progressively become necrotic and

release their intracellular content, triggering an inflammatory response.

TNF family, binding to their specific cell death surface receptors, induce

apoptosis: among them is the Fas-FasL complex that can trigger it.

The skin is the 1st site of damage to the appearance of SJS and TEN.

MEDICATIONS MOST FREQUENTLY ASSOCIATED WITH

STEVENS-JOHNSON SYNDROME (SJS) AND TOXIC

EPIDERMAL NECROLYSIS (TEN)

Allopurinol

Aminopenicillins

Amithiozone (thioacetazone)

Antiretroviral drugs

Barbiturates

Carbamazepine

Chlormezanone

Phenytoin antiepileptics

Lamotrigine

Phenylbutazone

Piroxicam

Sulfadiazine

Sulfadoxine

Sulfasalazine

Trimethoprim–sulfamethoxazole

The Fas signaling pathway of apoptotic cell

death.

The death receptor Fas and its ligand FasL are

transmembrane proteins. Fas signaling is

triggered in the target cells by receptor

tri(multi)-merization, induced upon contact

with membrane-bound FasL from an adjacent

cell. Subsequently, recruitment of intracellular

signaling proteins FADD and pro-caspase-8

leads to autoactivation of the protease caspase-

8 and apoptosis due to subsequent activation of

downstream effector caspases (3, 6, 7), which

cause cellular disintegration and death.

The keratinocyte Fas–FasL

system in normal skin and its role

in toxic epidermal necrolysis

(TEN) and treatment with IVIG.

A) In normal skin, low levels of

FasL are expressed by keratinocytes

and localized intracellularly. B) In

lesional skin of TEN, high levels of

FasL are expressed by keratinocytes

and localized on the cell surface.

Upon contact with Fas, cell surface

FasL induces Fas multimerization

and rapid signaling leading to

keratinocyte cell death by apoptosis.

C) Inhibition by intravenous

immunoglobulins (IVIG) due to

their content of naturally occurring

antibodies that bind to and block the

function of the Fas receptor.

Severe conjunctival erosions and exudate in SJS

secondary to trimethoprim–sulfamethoxazole

therapy.

Hemorrhagic crusts and denudation of the lips

associated with bullous cutaneous lesions associated

with childhood SJS secondary to cotrimossazolo

Denuded lesions of the lips with minimal

cutaneous lesions in a child with SJS secondary

to antibiotic therapy. Courtesy of Yale Residents Slide Collection.

Histology of toxic epidermal necrolysis (TEN)

A) Histology of an early-stage lesion of TEN. Arrows: apoptotic

keratinocytes.

B) Histology of a late-stage lesion of TEN featuring separation of the

epidermis from the dermis, and full-thickness necrosis of the epidermis.

Clinical features of toxic

epidermal necrolysis (TEN).

A) Detachment of large sheets

of necrolytic epidermis (>30%

body surface area), leading to

extensive areas of denuded skin.

B) Hemorrhagic crusts with

mucosal involvement.

C) Epidermal detachment of

palmar skin.

CLINICAL FEATURES SJS & TEN

Skin lesions tend to appear first on the trunk, spreading to the neck, face

and root upper limbs. The distal part of the arms and legs are relatively

spared, but palms and plants can be an early site of involvement.

Erythema and erosions of buccal mucous, eyeballs and genitals are

present in more than 90% of patients and are very painful. The

epithelium of the airways is involved in 25%, less frequent

gastrointestinal lesions (esophagitis, diarrhea). Additional systemic

manifestations: lymphadenopathy, hepatitis and cytopenies.

SJS/TEN CLINICAL COURSE

First dark or purple erythematous macules, irregularly shaped with a

tendency to converge and in the presence of edema and mucosa

involvement, the risk of rapid progression SJS or TEN is very high.

In the absence of spontaneous epidermal detachment, Nikolsky sign + on

the erythematous areas should be sought.

In some patients, the macules may have a dark center, with a target

appearance, but lack the three concentric rings characteristic of typical

target lesions and the papular appearance.

SJS/TEN CLINICAL COURSE

Brown-red macular lesions take on a characteristic gray color with

progression towards full-thickness necrosis (hours-days).

The necrotic epidermis detaches from the underlying dermis with

consequential onset of flaccid blisters easily breaking (Nikolsky +).

Under the wet cigarette paper skin, there are large bleeding erosive areas

On the palm-plantar surfaces there are tight-roofed bubbles, because

here the epidermis is thicker and resistant to mild trauma.

CLINICAL FEATURES THAT DISTINGUISH STEVENS–JOHNSON SYNDROME (SJS),

TOXIC EPIDERMAL NECROLYSIS (TEN), AND SJS–TEN OVERLAP

Clinical entity SJS SJS–TEN TEN

Primary lesions

Dusky and/or dusky

red lesions

Flat atypical targets

Dusky and/or dusky

red lesions

Flat atypical targets

Poorly delineated

erythematous plaques

Epidermal detachment–

spontaneous or by friction

Dusky red lesions

Flat atypical targets

Distribution Isolated lesions

Confluence (+) on

face and trunk

Isolated lesions

Isolated lesions

Confluence (++) on

face and trunk

Isolated lesions (rare)

Confluence (+++) on face,

trunk and elsewhere

Mucosal involvement Yes Yes Yes

Systemic symptoms Usually Always Always

Detachment (% BSA) <10 10–30 >30

Stevens–Johnson

syndrome (SJS)

versus SJS–TEN

overlap.

In addition to mucosal

involvement and

widespread

erythematous papules,

there are small areas of

epidermal detachment

(arrows). Because the

latter involve <10%

body surface area, the

patient is classified as

having SJS.

Prognosis SJS/TEN

Three classes are obtained (SJS, SJS/TEN, TEN) by the surface calculation of

the spontaneous/inducible (Nikolsky + sign) detached epidermis involved (the

rule of 9 as in burns) and presence of mucosal erosions (up to 90%)

In EM: typical target lesions with more limited distribution of them

In SJS/TEN: target lesions atypical and widespread

In SJS/TEN risk factors towards death: entity of epidermal detachment,

advanced age, polytherapy, increase in serum urea, creatinine, glucose,

neutropenia, lymphopenia and thrombocytopenia, late suspension of the causal

drug (early withdrawal reduces death risk 30% per day).

Infections (S. aureus and P. aeruginosa).

Seven parameters (SCORTEN) evaluate severity of TEN and can predict death

SCORTEN

Prognostic factors

Points

Age >40 years

1

Heart rate >120 bpm 1

Cancer or hematologic malignancy 1

BSA involved on day 1 above 10%

1

Serum urea level (>10 mmol/l) 1

Serum bicarbonate level (<20 mmol/l) 1

Serum glucose level (>14 mmol/l) 1

SCORTEN Mortality rate (%)

0-1 3.2

2

12.1

3

35.8

4 58.3

5

90

SJS/TEN Sistemic Manifestations

Massive loss of transepidermal fluids, electrolyte imbalance, inhibition of

insulin secretion, insulin resistance and the onset of hypercatabolism can

unfortunately lead to ARDS and MOF despite proper support in intensive care.

Healing with reepithelization usually begins in few days and complete in 3

weeks, with proliferation and migration of keratinocytes from the surrounding

healthy epidermis sites and hair follicles;

It’s not always perfect, residual symblepharon, conjunctive synechiae,

entropion, internal eyelash growth, skin scars, irregular pigmentation, eruption

of melanocytic nevi, persistent mucous erosions, phimosis, vaginal synechiae

and hair loss.

Up to 35% of TEN survivors may have eye symptoms (Sicca syndrome to

blindness)

MANAGEMENT

There is no reliable in vitro test for rapid identification of guilty drugs.

The options would be:

Patch testing: low sensitivity SJS/TEN and re-expose the patient to the

suspected drug (avoidable and dangerous)

So medical history, clinical and probability (unlikely, possible, plausible,

probable, very likely) for each drug based on its own intrinsic ability to

cause SJS/TEN and extrinsic factors, such as the onset of SJS/TEN after

re-hiring a given drug that may, however, occur within 2 days previously

caused SJS or TEN.

DIFFERENTIAL DIAGNOSIS SJS-TEN

Staphylococcal Scalded Skin Syndrome SSSS (exotoxin vs. desmoglein 1 with

intraepidermal bubbles and detachment in the granular layer, epideryyide underlying

undead, in infants and young or immunodepressed children, saving the mugs sign

Nikolsky positive)

AGEP (rich infiltrated neutrophil, non-follicular pustiles <3 mm superficial epidermis

and spongiosis, but not full-thickness epidermal necrolysis, neutrophilia and

eosinophilia involvement of mucous 20%).

Multiform Eryhema, generalized fixed drug eruption, severe acute GVHD, burns

Paraneoplastic Pemphigus, drug-induced linear IgA bullous dermatosis

(Vancomicin) and severe acute GVHD may, in some circumstances, recall TEN.

In Kawasaki's disease the lips are red and dry ('cracked') but there are no hemorrhagic

crusts, mucous denudation, no boiled or target lesions, perineal exfoliation and

fingertips.

Vesicles and blisters observed in patients with acute/subacute Erythematosus Lupus

undergoing drug therapy ('acute pan-apoptotic epidermolysis syndrome' or ASAP).

SJS-TEN Treatment Early and immediate drug discontinuation

Supportive therapy as in severe thermal burns (for hypovolemia,

electrolyte imbalance, kidney failure and sepsis with hydration and

nutritional support) and specific therapy.

Special attention to face, eyes, nose, mouth, ears, anno-genital region,

axillary folds and interdigital spaces

CyA (3-4 mg/kg/die), plasmapheresis, CPM (100-300 mg/die), and N-

acetylcistein (2 g/6h), use CSS only for a short period of time.

IvIg with Ab blockers the Fas–FasL bond in high doses (0.75 g/kg/die

for 4 consecutive days) for the treatment of patients with TEN, quickly

block the progression of TEN (preliminary pilot study).

Benefit (with reduction in mortality), when IV Ig was used at a total

dose of 2 g/kg in 3-4 days.

Treatment of toxic epidermal necrolysis (TEN). Facial involvement of a patient with TEN

(50% body surface area involvement) before (A) and 3 weeks after (B) treatment with

intravenous immunoglobulin (0.75 g/kg/day for 4 days).