Drug Eruptions

ABDELRAHMAN OBIEDAT
DINA DAHABREH
Cutaneous adverse reactions account for a third of all adverse
reactions to drugs.

Drug rashes are usually self-limiting and resolve completely upon

withdrawal of the culprit medication, but a small number (<2%) can
cause serious morbidity and mortality.
Diagnosis of drug-induced skin disease
may be difficult for a number of reasons:

1. Almost any drug can cause any rash.

2. Unrelated drugs can cause similar reactions.
3. The same medication can cause a different rash
in different individuals.
4. Patients may not volunteer information about
medicines that they have taken, which they
deem not to be relevant.
History:
The temporal association of the ingestion of the drug and
the onset of the eruption is key.
Note any medications taken for the first time in the 3
months prior to the appearance of the rash.
Patients should be specifically asked about any recent
changes to brand, dosing or preparation of long-term
medications.
Direct questioning about OTC preparations.
The patient should be asked about any history of
sensitivity to medications.
Examination:
The patient should be exposed fully.
oThe morphology of the rash should be described:

1- lichenoid  

2- urticated 

3- vasculitic 

4- maculopapular 

5- bullous 
oThe distribution of the rash should be noted:
(widespread? Limited? Acral (hands and feet)? Photo-
distributed?).

oThe mucosal sites – eyes, mouth, genitalia –  Severe

Cutaneous Adverse Reaction (SCAR) syndromes.

oCareful examination of the appendageal structures such

as hair, nails and teeth should also be carried out as
these can be affected by certain medications.
Investigations:
oSkin biopsy  But the result of this is likely to be delayed following an acute
presentation, and so action based on clinical assessment will usually precede
this.

oBlood tests (white cell counts and CRP levels)  To exclude infection.

oCertain investigations such as measurement of specific IgE, patch testing,

intradermal testing may be helpful.
 Pathogenesis
a) Immune-mediated rashes
The most common, and include hypersensitivity reactions types I to IV.
Type I reactions (immediate)  IgE / drug-specific receptors
bound to mast cells  manifest as urticaria or angio-oedema.
Type II reactions (cytotoxic reactions)  result in cutaneous
purpura.
Type III (immune complex-mediated) reactions  lead to
cutaneous vasculitis.
Type IV delayed hypersensitivity reactions (most common)
 result in generalized exanthems, phototoxic rashes and severe drug
reactions such as toxic epidermal necrolysis (TEN).
b) Non-immune-mediated rashes
Accumulation of medications in the skin
(causing pigment changes)

Slow acetylators (metabolism of drugs

affected)

Photosensitivity reactions (increased

susceptibility to UV light).
Clinical classification
1) Drugs which alter normal skin function.
2) Drugs which exacerbate an existing dermatosis.
3) Common drug-induced rashes
4) Severe drug-induced rashes – Stevens–Johnson syndrome (SJS)
and TEN, acute generalized exanthematous pustulosis (AGEP) and
drug reaction with eosinophilia and systemic symptoms (DRESS).
1) Drugs which alter normal skin
function

A) Photosensitivity
B) Pigmentation
C) Hair and Nails
 Photosensitivity
2 mechanisms of photosensitivity:
1- Phototoxic reactions
2- Photoallergic reactions
•Pigmentation
Include; Hyperpigmentation/ hypopigmentation/ discolouration
The pigmentary change may require light exposure to manifest.

Common examples:
Melasma  oral contraceptive pill.
The facial blue-black pigmentation  amiodarone.
Slate-grey pigmentation  Tetracycline antibiotics.
•Hair and nails
Excessive hair
Hypertrichosis is the growth of hair at sites which are not normally hair-
bearing.
Hirsutism is excessive growth of hair in the male pattern of hair growth,
especially in women.
Both hormonal and non-hormonal treatments may bring about this effect; the
most commonly implicated would include oral contraceptives, systemic steroids,
cyclosporine and phenytoin.
Hair loss:
(dramatic vs. insidious)
The temporal relationship between the onset of the hair loss and the
introduction of the medication depends on the part of the hair cycle which
the drug is interfering with.

oRapid and complete  anagen (‘growth’) phase.

Cytotoxic agents
Androgenic drugs promote (1)shrinkage of the hair follicles and
(2) shortening of anagen, and so can cause hair loss.

oDelayed, insidious hair loss  telogen (‘shedding’) phase

Drugs such as acitretin, statins and anti-thyroid drugs may have this effect.
Nails
Discoloration  (mepacrine / hydroxyurea).
Onycholysis (which is separation of the nail plate from the nail bed) 
cytotoxic agents.
 2) Drugs which exacerbate
pre-existing dermatosis
1. Psoriasis  beta blockers, lithium, antimalarial
medications, ACE inhibitors , Alcohol.
2. Eczema  statins and diuretics.
3. Acne  some forms of the oral contraceptive pills,
particularly progesterone-only pills.
Corticosteroids, cyclosporin and anti-epileptics
such as phenytoin.
4. Urticaria  (NSAIDs) and opiate analgesics by
lowering the threshold for mast cell degranulation.
5. Angio-odema  ACE inhibitors and ARBs.
3)Common drug-induced rashes
Drug-induced Exanthems
o Most common cutaneous reactions to drugs, 90% of all drug rashes.
o Rashes may be morbilliform (resembling measles) or maculopapular
(consisting of a mixture of raised and flat areas)
o Onset is typically within 7–10 days of starting the drug, representing a
delayed-type hypersensitivity.
oThe proportion of the body surface area (BSA) involved may vary, and
in cases where it exceeds 90%, the patient may be described as
erythrodermic.
o Systemic symptoms include pruritus, low-grade fever, elevation of
acute-phase proteins, and mild eosinophilia.
Maculopapular rash Morbilliform rash
Pathogenesis
oDrugs/metabolites may act as haptens, form covalent bonds with a
protein or peptide, and become antigenic
oHaptenated proteins are then processed by APCs to produce
haptenated peptides presented on MHC molecules.
oCD8+ effector T cells emigrate to tissues and kill cells in a
perforin/granzyme B-, and Fas/FasL-directed manner.
Eliciting drugs
oAntibiotics of any class
oAnti-hypertensive agents
oCholesterol-lowering drugs
Treatment
oPrompt withdrawal of the offending drug
oTopical corticosteroids one to two times per day for one week
oAntihistamines for symptomatic relief of exanthem and pruritus.
Drug-induced lupus
o Systemic signs and symptoms. The most common include fever, myalgias, rash,
arthritis, and serositis
o The frequency of these manifestations may vary with the drug
o Hematologic abnormalities and more severe manifestations, such as kidney
disease and central nervous system involvement, are uncommon
Drug-Induced Lupus
Eliciting drugs
o Isoniazid
o Hydralazine
o Procainamide
o Tumor-necrosis factor (TNF) alpha inhibitors (such as etanercept, infliximab and
adalimumab)
o Minocycline
o Quinidine
Diagnosis
o History of taking one or more of the drugs known to be associated
with this condition for at least one month, and often much longer and
the development of at least one clinical feature characteristic of SLE
o positive test for antinuclear antibodies (ANA)
o Anti-histone antibodies are strongly associated with some forms of
drug-induced lupus (present in >95 of cases)
o Anti-dsDNA antibodies are not found in most forms of drug-induced
lupus
o Spontaneous resolution of the clinical manifestations of the disease,
typically within several weeks after the offending drug has been
discontinued
 Drug-induced vasculitis
o Cutaneous small vessel vasculitis is a single organ vasculitis caused in
most cases by drugs
o 7 to 10 days after exposure
o typically presents with palpable purpura and/or petechiae, the
distribution is usually predominantly in the lower limbs.
o Associated with fever, urticaria, arthralgias, lymphadenopathy
o Drug vs Infection? it’s hard to know is it the antibiotic or the
viral/bacterial infection that caused the vasculitis
 if withdrawing the drug brings about resolution of the vasculitis, then this adds
weight to the diagnosis of a drug-induced phenomenon.
Eliciting drugs
o Antibiotics
o Anticonvulsants
o NSAIDs
 Lichenoid drug eruptions
o consist of purplish papules which may have a lace-like white change
on their surface
o The time interval between the initiation of the offending drug and the
appearance of the cutaneous lesions varies from months to a year or
more and depends upon the class of drug, dose, host reaction, and
concurrent medications
o The sites of predilection are the forearms, the neck and inner thighs,
but the eruptions can appear anywhere.
o Resolution following drug withdrawal can be slow and take up to
2months, and the post-inflammatory hyperpigmentation left behind
may be dramatic.
Eliciting drugs
oACE inhibitors
oThiazide diuretics
oAntimalarials
otetracyclines
oGold salts
oPenicillamine
oMepacrine
oBeta blockers
 Erythema nodosum
o A delayed-type hypersensitivity reaction that most often
presents as erythematous tender nodules on the shins
oThe characteristic histologic finding in EN is a septal panniculitis
(inflammation in the subcutaneous fat).
o Infective and inflammatory triggers are recognized (such as
tuberculosis, Yersinia infections, rheumatoid arthritis, lupus and
inflammatory bowel disease), EN may also be a drug-induced
phenomenon
Eliciting drugs
o OCP’s
o Penicillin
o Sulphonamide antibiotics
o Salicylates
 Fixed drug eruption
o A distinctive type of cutaneous drug reaction that characteristically
recurs in the same locations upon re-exposure to the offending drug
o The time frame varies from 2-24 hours
o Common sites include the torso, hands, feet, face and genitalia
o Resolves sometimes leaving post-inflammatory hyperpigmentation in
the skin
Eliciting drugs
oAntibiotics
oNSAIDs
oOCP
oBarbiturates
4) Severe drug reactions
in the skin
Stevens-Johnson syndrome (SJS) and
toxic epidermal necrolysis (TEN)
SJS/TEN
o Characterized by extensive necrosis and detachment of the epidermis, most
commonly triggered by medications.
o Variants of a disease continuum and are distinguished chiefly by severity, based
upon the percentage of body surface involved with blisters and erosions
- SJS classically denoting <10% BSA detachment
- TEN indicating >30% BSA involvement
- SJS–TEN overlap cases with between 10% and 30% loss.
o Preceeded by a prodrome of fever, malaise and common cold symptoms
o Skin pain is often the first cutaneous manifestation, prior to the appearance of the
rash
o Drug exposure before 1-4 weeks
Mucosal lesions

o Oral mucosa and the vermilion border are almost invariably involved, with
painful hemorrhagic erosions covered with a grayish-white membrane
o Ocular mucosa - severe conjunctivitis with a purulent discharge
o Urogenital mucosa- urethritis develops in up to two-thirds of patients, and
may lead to urinary retention
o Pharyngeal mucosa is affected in nearly all patients
o Intestinal mucosa involvement is rare
- Mortality from TEN may be as high as 90% and is estimated using the
SCORTEN tool
Eliciting drugs
o Allopurinol
o Aromatic anticonvulsants
o Antibacterial sulfonamides
o Lamotrigine
o Oxicam nonsteroidal anti-inflammatory drugs (NSAIDs)
Treatment
o Prompt withdrawal of culprit drug
o Supportive care
- The same principles as for major burns (wound care, fluid and
electrolyte management, nutritional support……)
 Drug reaction with eosinophilia and
systemic symptoms (DRESS)
o Rare, potentially life-threatening
o Skin eruption, hematologic abnormalities (eosinophilia,
atypical lymphocytosis), lymphadenopathy, and internal
organ involvement (liver, kidney, lung)
o Mortality is estimated at 5%, (fulminant liver failure)
o Latency period following drug exposure is 15-60 days
o Diagnosis often overlooked, symptoms of rash, fever and
lymphadenopathy attributed incorrectly to infection
Eliciting drugs
o Allopurinol
o Anti-convulsants
o Antibiotics
Treatment
o Withdrawal of the offending drug
o Corticosteroids
 Acute generalized exanthematous
pustulosis (AGEP)
o Rare pustular drug reaction recognizable by the
appearance of sheets of non-follicular pustules which
have a predilection for the major flexures (axillae, groin
and neck).
o Appears 3–7 days after ingestion of a culprit
medication
o Rash may be accompanied by fever and edema, and in
a small number of cases by systemic upset with
involvement of the lungs or the liver
o Antibiotics are the most common culprit drugs.
Source: ABC Dermatology the 6th edition
Thank you