Drug-Induced Skin Reactions

Predictable ADR

• Normal effects of drug is exaggerated to undesirable

• Often related to pharmacology/drug action

Unpredictable ADR

• Idiosyncratic, immunologic, allergic, carcinogenic, teratogenic, etc.

• Usually affects only a small percentage of patients

Assessment (Skin Reactions)

• Comprehensive patient history

- Concurrent medical conditions etc.

• Signs and symptoms

- Onset? Progression? Timeframe?

• Urgency

- Any signs of a systemic/generalized reaction?

• Medication history

- Could this be a drug-induced skin reaction?

• Differential diagnosis?

- I.e. What else can it be?

- Disease-relate problem OR

- Drug-related problem OR

- Food allergy

Patient Advice

• Information about the drug-induced ADR

- name Rx (if known) - potential for recurrence / severity etc.

- potential cross-reaction to other drugs

- genetic predisposition

• risk is higher in first-degree relatives of patients with a serious reaction such as hypersensitivity syndrome reaction, SJS, TEN

• NO genetic predisposition for most ADRs

• Medic Alert program if appropriate

Considerations

Before recommending Rx discontinuation, consider:

- Risks of continuing Rx vs. risks of d/c Rx

- To d/c Rx, is tapering needed / appropriate?

- If the Rx is discontinued, is a replacement Rx needed to continue treating the underlying medical condition that Rx was prescribed for?

Irritant Reactions

are localized (e.g. chemical vaginitis, vessication)

Allergic Reactions

depend on inducing an immune response; often systemic (I.e. may not be limited to skin manifestations)

type I (hives) and Type IV (local edema, inflammation)

What are the most common allergic skin reactions?

Type I (Allergic Reaction)

IgE-mediated. Activation of mast cells and basophils result in release of chemical mediators (histamine, leukotrienes...

Ex. Urticaria, angio-edema, anaphylaxis

Type II (Allergic Reaction)

Cytotoxic reactions. IgG or IgM-mediated. Antibody binding to cells with subsequent binding of complement and cell rupture.

Ex. Blood cell dyscrasias (e.g. hemolytic anemia, autoimmune thrombocytopenia)

Type III (Allergic Reaction)

Immune complex formation. Antigen-antibody immune complexes usually with IgG or IgM. Deposition of immune complexes in skin, kidneys, joints, GI tract etc.

Ex. Serum sickness, vasculitis

Type IV (Allergic Reaction)

Delayed cell-mediated hypersensitivity reactions. T-cell mediated. Can be further divided into subtypes based on T- lymphocyte subset and cytokine expression profiles.

Ex. Allergic contact dermatitis, SJS/TEN

Simple (Exanthematous) Eruptions

• The most common cutaneous ADRs

• Begin as erythematous macules and papules; become confluent and spread symmetrically.

• No blistering or pustules; no fever. May be pruritic

• Resolution begins with change in color from bright red to brownish red; may be followed by scaling or desquamation

• May resemble measles or scarlet fever

• Delayed hypersensitivity reaction

• Penicillins, cephalosporins, sulfonamides, anticonvulsants

- Allergic Reactions to Antibiotics

• Higher incidence in HIV+ve, ampicillin + allopurinol or with infectious mono, women

• Treatment: D/C Rx, symptomatic therapy

Simple Eruptions (Exanthematous Eruptions Timeframe)

Timeframe:

- Usually begins within 7-10 days after starting drug

• Onset may be earlier (2-3 days) in previously sensitized patient

• or onset may be late (10-14 days)

- Usually resolves within 7-14 days after discontinuing drug

7-10 days

Exanthematous Eruptions (Simple Eruptions) usually begin within ____________ after starting drug

7-14 days

Exanthematous Eruptions (Simple Eruptions) usually resolve within ___________ after discontinuing drug

DRESS (Exanthematous Eruptions)

• Systemic, multi-organ involvement (renal, liver, lung, bone marrow, heart, brain)

• Fever, lymphadenopathy, facial edema, eosinophilia, abnormal LFTs, renal dysfunction, beginning 2-8 weeks after starting drug (may be <15 days especially in children)

• May be fatal (Mortality rate ~ 10%)

• Allopurinol, sulfonamides, anticonvulsants (barbiturates, phenytoin, carbamazepine, lamotrigine), dapsone, vancomycin...

• May be associated with viral reactivation

• Treatment: D/C Rx, corticosteroids, symptomatic (based on disease severity assessment)

2-8 weeks

DRESS (Exanthematous Eruptions) causes fever, lymphadenopathy, facial edema, eosinophilia, abnormal LFTs, renal dysfunction, beginning __________ after starting drug (may be <15 days especially in children)

Mild DRESS

treat with topical very high potency steroids

- should be tapered over 6 weeks to 3 months

Moderate DRESS

consider topical very high potency steroid or systemic glucocorticoids (patients with moderate disease)

- should be tapered over 6 weeks to 3 months

Severe DRESS

treat with systemic glucocorticoids for ALL patients

- should be tapered over 3-6 months

corticosteroids

should be initiated in ALL patients with confirmed DRESS

Allopurinol

Genetic Marker for ______________ - HLA-B*5801 allele

- The HLA-B*5801 allele has been shown to be associated with the risk of developing _______________-related hypersensitivity syndrome and SJS/TEN (SCAR = Serious Cutaneous Adverse Reactions).

- The frequency of the HLA-B*5801 allele varies widely between ethnic populations

simple urticaria eruptions

- urticaria (serious!) or angioedema (serious!)

- may be caused by factors other than drugs!

• FOODS, physical factors (e.g. cold, pressure), infections, or may be idiopathic

• Drugs account for only 5-10% of urticaria cases

complex urticaria eruptions

serum sickness-like reactions (serious!)

• Fever, rash (usually urticarial), arthralgias occurring 1-3 weeks after starting Rx

• Not associated with immune complex formation, vasculitis or renal lesions (not true serum sickness)

Urticaria (Hives)

• Hives, wheals, angioedema, mucous membrane swelling etc. "The cutaneous manifestation of anaphylaxis"

• Extremely pruritic red raised wheals

• Type I usually

• Onset: Minutes to hours (anaphylactoid)

• Individual lesions last < 24 hrs, but new lesions continually develop

• May be the first indication of anaphylaxis

• DO NOT rechallenge!!

• Rxs: penicillins and related antibiotics, A.S.A., sulphonamides, X-ray contrast media, enzymes ,opiates, (latex)

urticaria (hives)

what is considered the cutaneous manifestation of anaphylaxis?

mins - hours (anaphylactoid)

onset of urticaria (hives) is...

< 24 hours

individual urticaria (hives) lesions last ___________ but new lesions continually develop

Latex Protein

• Immediate urticaria can develop from latex allergy

• Latex proteins in gloves, tubings.....Latex comes from the sap of the Hevea brasiliensis tree

• Poinsettia plant contains latex which may cross-react

Latex Allergy

• Linked to natural rubber latex (NRL) proteins

- Type I (IgE-mediated) reactions

- contact urticaria, asthma, anaphylaxis

- fatalities linked to high-risk patients with repeated exposure to NRL proteins due to surgical/medical procedures

• Other medical products implicated in NRL reactions include elastic bandages, tourniquets, Foley urinary catheter, Penrose drainage, and tape

• Nonoccupational sources of NRL protein include rubber innersoles of shoes, balloons, latex mattresses, household or work rubber gloves, and inflatable mattresses; and poinsettia plants have related latex

Latex Allergy Management

• AVOIDANCE

- Avoid latex and latex protein related items (gloves, condoms, balloons, poinsettia etc.)

• Use of powder-free, low-protein NRL gloves may reduce Sxs and sensitization

• Latex challenge - to confirm/exclude Dx

- is acceptable only in a controlled setting with emergency medical treatments on hand (not routinely done)

Latex challenge

to confirm /exclude Dx

- is acceptable only in a controlled setting with emergency medical treatments on hand (not routinely done)

Urticarial Eruptions Treatment

• D/C Rx; Do not rechallenge!

• Symptomatic management (e.g.antihistamines)

• Angioedema

- immediate therapy with epinephrine

- other supportive measures as needed

• Serum sickness-like reaction

- short course of oral corticosteroids if severe

• Avoid ASA / NSAIDS

- may exacerbate skin lesions

ASA and NSAIDs

should be avoided in Tx of urticarial eruptions as they may exacerbate skin lesions

epinephrine

urticarial eruptions with angioedema requires immediate therapy with...

oral corticosteroids

Urticarial eruptions with serum sickness-like reaction should be treated with short course of _________________________ if severe

Anaphylaxis Treatment

• Epinephrine

• Diphenhydramine

• Corticosteroids

• Maintain airway patency

- treatment of acute bronchospasm

• Maintain blood pressure control

- treatment of hypotension

- may be rapid and severe

• Other supportive measures as needed

Simple Blistering Eruptions

Fixed drug eruptions

Complex Blistering Eruptions

- Acute bullous disorders

• Stevens-Johnson Syndrome (SJS)

• Toxic epidermal necrolysis (TEN)

- Serious, life-threatening

- May be fatal (Mortality rates: SJS 5-15%; TEN 30-35%)

Fixed Drug Eruptions (Blistering Eruptions)

• Red or red/violet, raised lesions which may blister

• Pruritic; may also be burning or stinging

• Consistent location(s) each time drug is given "FIXED"

• Occurs within minutes to hours or days

• Lesion disappears within days, leaving hyperpigmented skin for months

• Phenolphthalein, tetracyclines, barbiturates, codeine, sulfonamides, acetaminophen, NSAIDS

• Treatment: D/C Rx, symptomatic therapy (e.g. moisturizer, topical corticosteroid)

Acute Bullous Disorders (Blistering Eruptions)

• Erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)

• Immune complex or cell-mediated response

• Acute onset (within 7-14 days):

- bullous formation

- Systemic, potentially life-threatening

- other Sxs (respiratory, fever, H/A)

• Sulfonamides, penicillins, anticonvulsants (hydantoins, carbamazepine, barbiturates, lamotrigine), NSAIDS (esp piroxicam), allopurinol, others

TEN symptoms

generalized tender / painful erythema followed by extensive epidermal necrosis and sloughing, resulting in marked loss of fluids & electrolytes & secondary infections

carbamazepine or phenytoin

HLA-B*15:02 is strongly associated with ______________________-induced SJS/TEN in populations where this allele is most common, such as in Southeast Asia

• testing for HLA-B15:02 should be done for all patients with ancestry in populations with increased frequency of HLA-B15:02, prior to initiating these drugs

15:02

The allele associated with carbamazepine or phenytoin-induced SJS/TEN is HLA-B*_____

5801

The allele associated with allopurinol-related hypersensitivity syndrome and SJS/TEN is HLA-B*____

carbamazepine

For ___________________, the HLA-A31:01 and HLA-B15:11 alleles may also be a risk factor for SJS/TEN but is more strongly associated with other reactions, such as DRESS

SJS/TEN Treatment

VERY IMPORTANT!!!!!!!!

• D/C Rx - avoid potential cross-sensitizers

• Support measures

- replace fluids, electrolytes, support BP, preventative eyecare, pulmonary, urology, GI

• Antibiotics (broad-spectrum)

- if secondary infections

• Biologic agent (e.g. etanercept)

• Reverse isolation

- gown, glove, mask

• Minimize long term sequalae (e.g. ocular damage)

• Provide patient education

Simple Pustular Eruptions

acneiform drug reactions

Complex Pustular Eruptions

acute generalized exanthematous pustulosis (AGEP)

Acneiform drug eruptions (Pustular eruptions)

• Drugs causing inflammation or comedone (whitehead/blackhead) "ACNE"

• Onset: 1-3 weeks

• Corticosteroids, androgenic hormones, anticonvulsants, isoniazid, lithium, others

• Treatment: D/C Rx. Can use topical tretinoin to manage the "acne" if Rx cannot be discontinued

topical tretinoin

Acneiform drug eruptions (Pustular) treatment = D/C Rx. Can use ________________ to manage the "acne" if Rx cannot be discontinued

1-3 weeks

Acneiform drug eruptions (Pustular) onset is...

AGEP (Clinical Presentation)

• acute onset (within days after starting Rx)

• fever

• cutaneous eruption with nonfollicular pustules

• generalized desquamation occurs two weeks after the initial reaction

- over 90% are Rx-provoked

AGEP (Pustular Eruptions)

• Diffuse erythema with many pustules

- 50% have other cutaneous lesions

- 25% have mucosal erosions

• Generalized desquamation 2 weeks later

• Rx causes:

- B-lactam antibiotics (penicillins, cephalosporins)

- Macrolides, tetracyclines

- Oral antifungals: e.g. itraconazole, terbinafine

- Calcium channel blockers

- Carbamazepine, acetaminophen, others.....

• Treatment: DC Rx, symptomatic therapy, corticosteroids if severe

- Generally there is complete resolution of skin lesions within a few weeks

Hyperpigmentation

• Related to increased melanin: hydantoins (phenytoin, nitrofurantoin, some metals)

• Direct deposition (e.g. silver, mercury, tetracyclines, antimalarials)

• Other mechanisms: some cytotoxic drugs cause banding on nails, pigmentation along veins (e.g.5-fluorouracil). Blue-grey hyperpigmentation from amiodarone.

Photosensitivity

an adverse cutaneous response to normally harmless doses of UV radiation

phototoxic

Drug absorbs UVA and damage sun-exposed skin. Dose related.

- amiodarone, tetracyclines, sulfonamides, psoralens, coal tar etc

photoallergic

Drug changed by UVA into an allergen. May occasionally spread beyond sun-exposed skin.

- Requires sensitization to Rx.

- sulfonamides, sulfonylureas, thiazides, NSAIDS, chloroquine, carbamazepine etc