Lecture 32 - Drug Induced Skin Reactions

what are the 2 most common cutaneous drug reactions

Morbilliform/exanthematous eruption

Urticaria

what symptoms accompanied by a cuteneous drug reaction indicate a more severe reaction

Presence of a fever or other accompanying symptoms other than itch signals a more serious reaction (complex), which requires immediate referral

what are examples of simple reactions

Exanthematous eruptions, also known as morbilliform or maculopapular eruptions

what are qualities of simple reactions

Usually none, or limited, systemic symptoms (i.e. fever)

Benign and self limiting

Start as macules (pink/red in lightly pigmented skin; purple/brown/black in darkly pigmented skin), become confluent and later spread symmetrically, scaling and desquamation may follow

Itch may be present

what are qualities of complex reactions

Fever, arthralgia, shortness of breath, skin tenderness, mucous membrane involvement, angioedema or swelling of tongue, enlarged lymph nodes, end-organ injury

what kind of reactions are caused by type 1 IgE antibodies

urticaria, angioedema, anaphylaxis

what type of reactions are caused by type 2 cytotoxic drug-induced reactions

pemphigus and thrombocytopenia/purpura

what type of reactions are caused by type 3 immune complex reactions

vasculitis, serum sickness

what type of reactions are caused by type 4 delayed hypersensitivity reactions

exanthem, fixed and lichenoid drug

what type of reactions are caused by non-immune reactions

overdose, drug interactions

what type of reactions are idiosyndratic (don’t know cause)

DRESS (Drug-Related Eosinophilia with Systemic Symptoms), drug-induced lupus

what is the most common mechanism of drug reactions

type 4 delayed hypersensitivity

what are risk factors for drug induced skin reactions

women

elderly

immunosuppression (EBV, HIV)

number of drugs

genetic predisposition

prior history of drug reaction

primary drugs in hospitalized patients (penicillins, sulfonamides, NSAIDs)

what genetic factor is commonly associated with drug induced skin reactions

HLA-B variations

can you test your way out of a drug reaction

No genetic basis has been found for most adverse drug reactions, including penicillin-allergic reactions

what are considerations for skin-prick testing

Done 4-6 weeks post-reaction

Oral drugs can be crushed and dissolved for testing

Look for a hive response (IgE only)

Can get false positives and negatives

how can drug induced skin reactions be classified

according to timing into immediate reactions and delayed reaction

The most important information in determining if a rash/reaction is medication-related in its timing

what is considered an immediate reaction

< 1 hour from the last administered dose

e.g. urticaria, angioedema, anaphylaxis

what is considered a delayed reaction

> 1 hour and usually > 6 hours from last administered dose

occasionally weeks-months after the start of administration

e.g. morbilliform eruptions, fixed drug eruption, SJS, TEN, vasculitis

what is the clinical presentation of Exanthematous drug eruptions

Usually first appears on the trunk and then spreads to the limbs and neck

Distribution is bilateral and symmetrical maculopapular rash

Discrete lesions may merge together to form large patches or plaques

May be associated with a mild fever and itch. As it improves, the redness dies away and the surface skin peels off.

what is the mechanism of Exanthematous drug eruptions

Type 4 hypersensitivity reaction

what does “Morbilliform” mean

refers to rashes that resembles measles

Begins on trunk and upper extremities becomes confluent

Mucous membranes spared

what is the timeline for developing Exanthematous drug eruptions

Usually develops 7-14 days after starting a new medication

what are common causative agents of Exanthematous drug eruptions

Penicillins, sulfonamides, cephalosporins, anticonvulsants

how are Exanthematous drug eruptions treated

Stop the offending agent

Topical steroids for symptom relief and vasoconstriction

Resolves within 2 weeks without any complications or sequelae (residual symptoms)

what is the clinical presentation of Urticarial eruptions

Can affect any body site

Itchy and burning sensation (burning if deeper in skin)

Erythematous, edematous papules, and plaques, often surrounded by a vasoconstricted halo (wheals)

Angioedema – subcutaneous swelling of the skin or mucosa (eyelids, lips)

Lesions often last less than 24 hours and are characterized by spontaneous appearance and resolution

what is the mechanism of Urticarial eruptions

Type 1 hypersensitivity reaction mediated by IgE antibodies

what is the timeline of presentation of Urticarial eruptions

Appear within minutes to days of drug administration

Duration of individual lesions is less than 24 hrs

Urticarial vasculitis lesions last longer than 24 hrs

Acute urticaria <6 weeks

Chronic urticaria > 6 weeks

what are common causative agents of Urticarial eruptions

Antibiotics (penicillins, cephalosporins)

how are Urticarial eruptions treated

Stop the culprit drug

Consider oral antihistamines (usually at higher than standard dose for allergic rhinitis)

what is the clinical presentation of Fixed drug eruptions

Characterized by the formation of an erythematous or pigmented patch (round or oval shape)

Early lesions are sharply demarcated erythematous macules

Lesion may progress to become edematous, forming a plaque, which may evolve to become a bulla (blister) and then an erosion

Lesions are commonly solitary, however, there may be multiple lesions with random distribution

May become scaly and cause post-inflammatory hyperpigmentation

Patients do not generally report systemic symptoms (unless bullous form - rare)

what is the mechanism of fixed drug eruptions

likely a localized type IV hypersensitivity

how might the presentation of fixed drug eruptions vary

Classically a dusky, violaceous hue (non-pigmented fixed drug eruption exists)

Can be widespread (generalized fixed drug eruption)

what is a Generalised bullous fixed drug eruption

rare reaction

Numerous large blisters and erosions with normal skin between typically affecting <10% of the skin surface

Fever, malaise and arthralgia may be associated

what are common areas of involvement for fixed drug eruptions

Acral surfaces

Face/lips

Genitals

what is a potential consequence of fixed drug eruptions

post-inflammatory hypopigmentation after resolution

what are common causative agents for fixed drug eruptions

Tetracyclines

Sulfonamides

NSAIDs

Pseudoephedrine – associated with non-pigmented fixed drug eruption

how is a fixed drug eruption treated

Discontinuation of suspected medication

• Avoiding implicated medication indefinitely

Topical steroids/systemic corticosteroids

Generalized blisters require intensive care or burn wound care

what is the clinical presentation of Drug reaction with eosinophilia and systemic symptoms (DRESS)

Systemic symptoms (high fever) present followed by the development of a rash

Morbilliform presentation but targetoid lesions, blisters and pustules may be present

Erythroderma or exfoliative dermatitis may follow in some patients

Facial swelling or mucosal involvement (lips, mouth, throat, genitalia) in some

Multiple organ involvement (e.g.lymph nodes, blood, liver, lung, GI, kidneys, neurological system, heart)

what are common causative agents for DRESS

Anticonvulsants (phenytoin, carbamazepine, phenobarbital)

Antibiotics (dapsone, sulfonamides, minocycline)

Antiretrovirals

Allopurinol

NSAIDs

what is the timeline for developing DRESS

Develops 2 to 6 weeks after the drug was started

how is DRESS treated

Stop the culprit drug

Most cases require prolonged treatment with systemic corticosteroids

Slow taper over several weeks or even months

what needs to be monitored long term in DRESS patients

Thyroiditis

Hepatitis is responsible for most deaths from DRESS (10% mortality)

Monitor TSH and T4 at 3mos, 1 yr, and 2 yrs post reaction

Pancreatitis

Development of Type I diabetes mellitus possibly

Chronic exfoliative dermatitis

what is the clinical presentation of Stevens-Johnson syndrome (SJS) OR Toxic epidermal necrolysis (TEN)

Prodromal illness (resembling an upper respiratory tract infection) for several days before rash

An abrupt onset of a tender/painful red skin rash starting on the trunk and extending rapidly over hours to days onto the face and limbs

The lesions may be flat, red, diffuse (macule)

Diffuse erythema

Blister development

Blisters then merge to form sheets of skin detachment, exposing red, oozing dermis

Painful (mucous membranes hurt)

what is SJS or TEN characterized by

Mucocutaneous tenderness

Positive Nikolsky sign

Skin fragility and erosion/necrosis

Skin lesions typically arise first on palms and soles

Involvement of oral, genital, ocular mucosa, esophageal, respiratory tract

how is SJS or TEN classified

SJS <10% body surface area (BSA) epidermal detachment

SJS-TEN overlap : 10-30% BSA involvement

TEN >30% BSA epidermal detachment

what is the timeline for SJS/TEN presentation

usually occur 7-21 days after initiation of the responsible drug

how is SJS/TEN treated

Discontinue the offending medication

• Reduces risk of death by 30% per day

Systemic corticosteroids (Solu Medrol or dexamethasone)

Involve other care units: ophtho, urology, wound care, ICU, burn unit, plastics surgery

The following agents are debated for their role in management:

• Cyclosporine (~7 days)

• Etanercept 50mc SC x 1 dose

• IVIg

how can Photosensitivity & Phototoxic Reactions vary

idiopathic

secondary to endogenous substances (porphyrins as in porphyrias)

secondary to exogenous substances (medications)

what are the 2 major types of photosensitivity reactions

phototoxic reactions (most common)

photoallergic reactions

what is the clinical presentation of phototoxic reactions

appears identical to sunburn

involves sun-exposed sites only

secondary to tetracyclines, NSAIDs, thiazide diuretics

what is the clinical presentation of photoallergic reactions

secondary to a cell-mediated hypersensitivity to an allergen activated or produced by the effect of light on a drug

typically appears more eczematous

can be result of chronic dermatitis

involves both sun-exposed and non-sun exposed sites

secondary to quinolones, solfonamides, antimalarials, TCAs

how are Photosensitivity & Phototoxic Reactions treated

Discontinue offending agent

Topical corticosteroids

Use of broad spectrum sunscreen with an SPF of at least 30

what are non-pharm treatments for drug induced skin reactions

Care for the skin barrier, use unscented moisturizer or white petrolatum

Physical measure is helpful in cooling the skin by tepid showering

Tap water compresses can be used on blistering lesions

Oral lesions can be treated with warm water or saline rinses

how can arthralgia or pain be managed in drug induced skin reactions

Use acetaminophen or NSAID (as appropriate)

how can pruritus be managed in drug induced skin reactions

H1-antagonist antihistamines and nonsedating antihistamines

what is the appropriate dose of prednisone when using systemic treatment

1-2mg/kg/day

what are supportive measures for severe cutaneous reactions such as SJS/TEN

require intensive supportive care

Management of airway, monitor renal function, monitor fluid and electrolyte balance, more intensive pain control and infection prevention

what are monitoring and follow up parameters for drug induced skin reactions

After discontinuation of medication, most drug-induced cutaneous eruptions will resolve in 5–7 days

More severe drug reactions may take several months

Monitor for recurrence, development of malaise and fever = refer to physician

In DRESS, long term monitoring of organ functions may be required

what are red flags for drug induced skin reactions

Malaise or fever

Edema of the face, swelling of tongue

Lymph node involvement

Pustules and vesicle formation

Dusky or painful lesions

Skin fragility or tenderness

Mucous membrane involvement

Marked peripheral blood eosinophilia

Large body surface area involvement

Shortness of breath

What additional information are you looking for to gain understanding of the presenting illness?

immunizations?

other medications?

previous medication reactions?

change in products used at home? (e.g. laundry detergent)

previous viral illness

recent travel

What is your assessment of the presenting medical issue? What evidence supports this assessment?

exanthematous eruptions - simple reaction

What is your management (treatment) plan?

topical hydrocortisone

antihistamines

potentially change the amoxicillin to something else

What steps will you take in regards to monitoring and follow-up?

if no major symptoms present, would be appropriate to re-challenge allergy in the future

monitor for red flags and worsening