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CONTENTS Serious drug reactions SJS/TEN DRESS Anaphylaxis Erythroderma Introduction Pathogenesis Classification Serious v/s Non serious reactions High Risk subjects Common drugs causing ADRs Common morphological patterns Non-serious drug reactions Urticaria/ Angioedema Fixed drug eruption Lichenoid drug rash Maculo-papular rash Photosensitive drug rash Erythema multiforme (EM) Acneiform drug rash Pigmentation Serious drug reactions SJS/TEN DRESS Anaphylaxis Erythroderma Acute Gen. Exanth. Pustulosis Approach to diagnosis Causality assessment Laboratory investigations Management Prevention Pharmacovigilance MCQs Photoquiz
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Cutaneous Drug Eruptions
Digital Lecture Series : Chapter 21 Dr. Lalit Kumar Gupta Sr.
Professor, Dermatology RNT Medical College, Udaipur Dr. Ankita
Srivastava Sr. Resident, Dermatology CONTENTS Serious drug
reactions SJS/TEN DRESS Anaphylaxis Erythroderma
Introduction Pathogenesis Classification Serious v/s Non serious
reactions High Risk subjects Common drugs causing ADRs Common
morphological patterns Non-serious drug reactions Urticaria/
Angioedema Fixed drug eruption Lichenoid drug rash Maculo-papular
rash Photosensitive drug rash Erythema multiforme (EM) Acneiform
drug rash Pigmentation Serious drug reactions SJS/TEN DRESS
Anaphylaxis Erythroderma Acute Gen. Exanth. Pustulosis Approach to
diagnosis Causality assessment Laboratory investigations Management
Prevention Pharmacovigilance MCQs Photoquiz Introduction
Hippocrates- First do no harm to your patient (Primum non nocere)
Adverse cutaneous drug reactions (ACDRs) are common reason for
dermatology consultations & cause significant morbidity and
mortality. Are generally underreported. Common consequence of
modern medication and polypharmacy. Can cause distress to both
patient and physician, may seriously affect doctor- patient
relationship & be a cause for litigation. Cutaneous drug
reactions can resemble almost anyinflammatory skin disease A great
mimicker. Anything you can think of Anything you can see and Some
things you dont even think of Can be due to a drug Introduction
Suspect the rash to be drug induced if it is itchy, generalised,
and appears suddenlyin a patient on any drug. Severity varies from
minor self limiting rash ( FDE and maculo-paular) to fatal
reactions like TEN and DRESS. Seen in around 5% of population
taking drugs, Approx. 2% ADRs are serious cutaneous adverse
reactions (SCAR) and % to 0.3% can be fatal Definition Unwanted
reactions that are not characteristic ofthe desired pharmacodynamic
effects and predicts hazard for future administration &
warrants prevention, specific treatment, alteration of dose or its
withdrawal Classification Based on Mechanism
Non-Immunological
More common (80%), often predictable, are dose dependent affecting
many/all people taking drugfor sufficient time at a sufficient dose
Immunological Less predictable, less common(20%), not dose
dependant, usually appear after the latent period required for the
induction of immune system, chemically related drugs may cross-
react Non-immunological drug reactions
Over dosage Stretch marks from systemic steroids, purpura resulting
from increased dosage of anticoagulants. Intolerance due to altered
metabolism Slow acetylators (INH induced lupus erythematosus)
Jarisch-Herxheimer reaction Due to bacterial endotoxins and
microbial antigens that are liberated by the destruction of
microorganism example : Penicillin therapy for syphillis
Non-immunological drug reactions
Pharmacological adverse effects Hair loss with chemotherapeutic
drugs Cumulative side effects Argyria with silver intake Change in
ecological balance Acute vaginal candidiasis with use of
broadspectrum antibiotics Idiosyncratic reaction Ampicillin induced
rash in infectious mononucleosis Immunological drug reactions
Coombs and Gell classification Type I : Ig E dependent -
Urticaria/Angioedema Type II :Cytotoxic reaction - Purpura Type III
: Immune complex reaction - Vasculitis Type IV : Cell-mediated
hypersensitivity - Maculopapular rash,Lichenoid eruptions, DRESS,
FDE, SJS/TEN, dermatitis, Erythroderma Classification according to
severity/prognosis
A more practical approach in clinical practice Simple / Non serious
(involve only skin) Maculopapular rash (self-limiting) Localised
FDE Photosensitivity Acneiform eruption Lichenoid eruption
Pigmentation Hair loss Striae Classification according to
severity/prognosis
Serious (poor prognosis/life threatening) - SCAR A rash resulting
in serious skin damage/involve multiple organs/ requires
hospitalization or prolongs hospital stay/cause significant
morbidity, death Erythema Multiforme (EM) major Stevens Johnson
Syndrome (SJS) Toxic Epidermal Necrolysis (TEN) Drug Rash with
Eosinophilia and Systemic Symptoms (DRESS) Generalized FDE
Anaphylaxis Erythroderma Classification according to
severity/prognosis
However, this classification too has some drawbacks a drug reaction
appearing to be non serious initially may turn out to be a fatal
one, for e.g. MP rash may be the initial manifestation of DRESS or
TEN Urticaria can occur as a part of anaphylaxis. Localised FDE may
convert into generalised one on repeated exposure to the causative
agent Features suggesting severe drug rash (SCAR)
Facial edema,mucosal involvement Skin tenderness, bullous skin
lesions, purpura, skin necrosis and necrolysis Presence of signs
and symptoms like fever, malaise, pharyngitis, meningism, wheeze
and arthritis Systemic involvement e.g hepatitis, pneumonitis High
risk subjects for ADRs?
Polypharmacy/Patients on multiple drugs Past H/O drug
reaction/allergy. Family history of drug reaction (genetic
predisposition) as in anticonvulsants. Patients with autoimmune
connective tissue diseases like SLE, rheumatoid arthritis.
Immunocompromised patient e.g. AIDS Certain viral infections (HHV,
EBV, CMV & HIV) Renal/hepatic impairment Role of genetics in
ACDRs
There is a stronggenetic predisposition to develop serious drug
reactionslike DRESS, SJS/TENS, LE. This is mediated through some
HLA associations or genetic variation in drug metabolising enzymes.
This tendency may be familial seen in siblings or first degree
relatives who may also be at increased risk to develop serious drug
reactions. Thus family counselling may play an important role in
prevention of ADRs. Role of genetics in ACDRs
A strongassociation is noted for SJS/ TEN & DRESS related to
allopurinol and HLA B* 5801 and between SJS or TEN with
caramazepine & HLA B*1502 HLA DR4is significantly more
commonlyassociated with hydralazine induced LE c/t idiopathic LE
due to their slow acetylator status Drug-virus interaction &
ACDRs
Presence/ reactivation of viruses like EBV HHV6,7, CMV and HIV
greatly enhance the risk of drug reactions. HIV/AIDS patients have
up to 100 fold risk to develop reactionsto cotrimoxazole,
anticonvulsants and antiretrovirals , particularly nevirapine.
Patients with infectious mononucleosis on ampicillin have % risk of
maculopapular rash (c/t 3-7%). Pts may tolerate the drug when
viralinfection clears. Common drugs causing reactions
Sulphonamides Antibiotics NSAIDs Antiepileptics Allopurinol
Antihypertensives Antimalarials Antitubercular Antiretrovirals
(nevirapine) 75% . Clinical patterns of adverse drug reactions
(ADRs)
Exanthematous reactions Urticaria, Angioedema Anaphylaxis Fixed
drug eruption L ichenoid eruption Photosenstivity reactions
Acneiform eruption Erythema multiforme Psoriasiform rash
Pigmentation Hair loss Severe cut. Adverse Drug Reaction (SCAR)
Stevens Johnson Syn (SJS) Toxic Epidermal Necrolysis (TEN) Drug
hypersensitivity reaction(DHS/ DRESS) Acute generalised exanthem
pustulosis (AGEP) Exfoliative dermatitis Serum Sickness like rash
Maculopapular (MP) / Exanthematous rash
Most common pattern. Begins within 1 wk; lasts approx. 2 wks.
Itchy, discrete/confluent, symmetric, often begins on trunk and
spreads peripherally. Mostly self limiting rash; may sometimes
progress to more severe conditions like DRESS, erythroderma and
TEN. Maculopapular drug rash
Watch for warning signs like high fever, facial edema, purpura,
skin tenderness A close differential is infectious exanthema,
particularly in children Penicillins, sulfonamides, antiepileptics
and antiretrovirals are common offenders Urticaria /
Angioedema
Second most common rash Transient edematous, erythematous wheals
Angioedema- deeper, mucosal last longer, may be painful May be part
of anaphylaxis, vasculitis or serum sickness May involve IgE
mediation or direct mast cell degranulation Angiodemais common with
ACE - I and may develop even months to years later and can be fatal
Aspirin/NSAIDS, penicillins, ACE-I, radiocontrast media Urticaria /
Angioedema Fixed Drug Eruption (FDE)
Circular, erythematous macules/plaques with sharp borders. Healing
with hyperpigmentation is characteristic. Lesions usually recur on
same site(s) upon readministration of the offending drug within 30
min to a few hours. Common sites: Hands, feet, lips and genitalia.
Usually localised, can become generalised with repeated exposure of
the offending drug. Some unusual variants of FDE include bullous,
linear and nonpigmenting. Sulfonamides, NSAIDs, fluoroquinolones,
metronidazole, tetracyclines are some of the common offenders.
Fixed drug eruption (FDE)
FDE on forearm caused by cotrimoxazole multiple lesions due to
ofloxacin Fixed drug eruption (FDE) Lichenoid eruption These
closely resemble lichen planus, but differ from LP in being more
extensive, having less frequent mucosal involvement and appear more
psoriasiform. Histologically, focal parakeratosis, exocytosis of
lymphoid cells in upper epidermis and eosinophils in dermis may
differentiate it from idiopathic LP. Chloroquine, gold,
phenothiazines, antihypertensives, -blockers,ACE-I, NSAIDs. .
Photosensitive drug rash
Sunburn like or delayed reactions. The drug may be continued in
lower doses and patient is advised to avoid sun or take drug in
evening. Tetracycline, NSAIDs, quinolones, nalidixic acid,
naproxen, quinines, thiazides, sulphonamides, amiodarone are common
agents. Photosensitive drug rash
Photosensitivity to tetracycline Photosensitive rash due to
thiazides Erythema multiforme (EM)
Characterised by typical target lesions (central zone of dusky
erythema or purpura, a middle paler zone of oedema, outer ring of
erythema with a well-defined edge). Lesionsdistributed acrally and
symmetrically. Infections such as Herpes simplex virus, mycoplasma
are more common causes than drugs. Mucosal involvement affecting
oral cavity (characteristic hemorrhagic crusting) and eyes may
occur. Sulfonamides, penicillins, quinolones, tetracycline,
rifampicin, anticonvulsants, NSAIDs, nevirapine, phenothiazines,
thiazides. Erythema multiforme (EM)
Hemorrhagic crusting and oral erosions Target lesions over forearm
Acneiform Eruption Monomorphic lesions (papules or pustules)
localised primarily on trunk and upper extremities rather than face
as in acne vulgaris. Lesions can occur at any age, usually after
adolescence. Absence of comedones differentiate it from acne
vulgaris. Corticosteroids, phenytoin, isoniazid, oral
contraceptives, androgens, iodides, vit B12, lithium. . Acneiform
Eruption Pigmentation Drug induced pigmentation is common amongst
Indians and may result from various mechanisms like increased
melanin synthesis, drug deposition (clofazimine, argyria) or as a
post inflammatory event (FDE). Sun exposure may further aggravate
pigmentation Nail pigmentation may sometimes be associated
Minocycline, antimalarials, amiadarone, phenothiazines, alkylating
agents, zidovudine, gold and silver salts, clofazimine Drug induced
Pigmentation
Minocyline induced pigmentation Zidovudinepigmentation of skin and
nails Clofazimine induced Some other morphological patterns
Causative Drugs Pit. Rosea Like Eruption Gold,- Blockers,
Captopril, Isotretinoin, Omeprazole, Allopurinol, Barbiturates
Psoriasiform Antimalarials, Blockers, ACE Inhibitors, NSAIDS
Hypertrichosis Corticosteroids, Phenytoin, Cyclosporine, Minoxidil
Alopecia Chemotherapeutic Agents, Anticonvulsants, Warfarin,
Antithyroid Drugs, Retinoids Scleroderma Like Reactions
d-penicillamine, Bleomycin, Vitamin K, Pentazocine Some other
morphological patterns
Causative Drugs Erythema nodosum Oral contraceptives, halogens,
penicillin, sulfonamides and tetracycline Vasculitis Allopurinol,
NSAIDs, cimetidine, gold, minocycline, penicillin, phenytoin,
quinolones, sulfonamide, tetracycline Drug - induced Lupus
erythematosus Isoniazid, procainamide, hydralazine, OCP, Thiazides,
B-blockers, anticonvulsants, Captopril Drug - induced pemphigus
Captopril, d-penicillamine, penicillin, rifampicin, cephalosporin,
pyrazolone derivatives Stevens-Johnson Syndrome (SJS) and Toxic
Epidermal Necrolysis (TEN)
Spectrum of a serious drug reaction characterised by widespread
epidermal and mucosal necrosis/necrolysis, along with multisystem
involvement SJS has a mortality of about 5% and TEN of about 30%
Drugs - antiepileptics, antiretrovirals, sulphonamides,
fluoroquinolones, aminopenicillins BSA Involved Nomenclature 30%
TEN SJS / TEN Sudden onset with prodromal symptoms - Fever,
malaise, arthralgia followed by mucosal and cutaneous involvement
in the form of skin tenderness, purpura, bullae, atypical target
lesions and subsequent peeling of skin in large sheets Severe
mucosal involvement (oral, ocular, genital, tracheobrochial,
oesophageal) can occur and affect feeding, breathing and vision and
may lead to long-term complications particularly in the eyes.
Complications such as septicemia, fluid and electrolyte imbalance,
respiratory failure, renal failure and gastrointestinal bleeding
may cause death SJS / TEN Extensive mucosal (oral and ocular) as
well as cutaneous involvement Widespread necrosis of skin SJS / TEN
TEN (Pre and Post steroid treatment)
. Drug rash with eosinophilia and systemic symptoms (DRESS)
Synonyms: DIHS Drug induced hypersensitivity syndrome Potentially
life threatening, idiosyncratic drug reaction characterised by
triad of fever, skin rash and internal organ involvement Develop
2-6 wks after drug intake Begins as generalised maculopapular rash
and may progress to erythroderma or SJS/ TEN like picture Facial
edema is characteristic Eosinophilia, atypical lymphocytes,
hepatitits and lymphadenopathy are common DRESS / DIHS Reactivation
of HHV - 6 and other herpes viruses can occur and lead to prolonged
clinical course. Steroids are usually required for a longer period
of time and should be tapered slowly. Phenytoin, phenobarbitone,
carbamazepine, lamotrigine,dapsone, sulfonamides, minocycline,
allopurinol, nevirapine, abacavir, NSAIDs. Drug rash with
eosinophilia and systemic symptoms (DRESS)
Dapsone induced DRESS, pre & post treatment Anaphylaxis A
potentially life-threatening, acute systemic allergic reaction; IgE
mediated. Early warning signs include premonitory dizziness or
faintness, skin tingling & reddening of bulbar conjunctiva.
Later followed by flushing, urticaria, angioedema, bronchospasm,
abdominal pain& vasomotor collapse. Penicillins,
cephalosporins, radiocontrast media, animal sera, aspirin &
other NSAIDS, anaesthetics, dextrans,ACE-inhibitors Erythroderma
Syn. exfoliative dermatitis
Involvement of >90% BSA with erythema, oedema and scaling Lead
to systemic and life threatening complications like cardiac
failure, fluid and electrolyte imbalance, loss of thermal control
and sepsis Anticonvulsants, chloroquine, ATT, chlorpromazine,
lithium, sulfonamides, nevirapine . Erythroderma Acute generalised
exanthematous pustulosis - AGEP, (Pustular drug rash)
Characterised by sudden appearance of sterile non-follicular
confluent pustules, predominantly over face or flexures,
accompanied by leukocytosis and fever. Disseminates rapidly and
settle spontaneously with desquamation. May be confused with
generalised pustular psoriasis Develop within few hours to days of
drug intake, have shorter latency Ampicillin, macrolides,
tetracyclines are common culprits Acute generalised exanthematous
pustulosis - AGEP, (Pustular drug rash) Pityriasis rosea like
rash
Some ADR patterns Bullous drug rash to furosemide Pityriasis rosea
like rash to metronidazole Some ADR patterns Cushingoid facies and
Hypertrichosisto oral steroids Striae due to steroids abuse
Diagnosis / Clinical characteristics of ADRs
H/o drug intake Usually sudden onset Often pruritic B/L symmetric
(FDE#) Should subside on withdrawal (dechallenge) Reappear on
rechallenge Evaluation of patient with ADRs
Keep a high index of suspicion History of drug intake &
temporal correlation with development of rash Recognize the
morphological pattern of rash Could rash be related to drug-
Probability ? Dechallenge Rechallenge (if possible) If drug rash is
probable, clinical or lab factors that indicate it to be serious
(SCAR)? How to manage it? Prevent future episode Report to
competent authorities History In the absence of any specific
laboratory investigation, the diagnosis of drug rash is essentially
clinical. A thorough history is most essential andshould include:
Onset and progression pattern of rash Duration Complete drug
details including any herbal / ayurvedic / homeopathic medications,
newly introduced drugs, drugs which are being taken since long
duration should also be noted Interval between drug introduction
and onset of rash (ADRs have variable latency periods) Past H/O
drug reaction Family H/O drug reaction Evaluation ADRs Assess the
comorbid state(s):
For which the drug was prescribed eg. Epilepsy A safer drug needs
to be substituted for eg. sodium valproate may be safely
substituted for aromatic anticonvulsants like phenytoin,
carbamazepine, phenobarbitone. Which may predispose the patient for
ADRs e.g. autoimmune diseases, HIV and other immunosuppressive
states. Examination Morphology of lesions, distribution and extent
of lesions
Extent/BSA involved- rule of 9 is useful Look for the warning signs
of severe drug reaction : Mucous membraneinvolvement Blisters, skin
necrosis, purpura , Nikolskys sign in TEN Facial oedema High fever,
dyspnoea, signs of sepsis, hepatitis, renal failure - feature of
DRESS Angioedema; breathlessness, eye, tongue swelling Laboratory
investigations
These are not very sensitive/specific; only adjunctive role. Patch
test : may be useful in maculopapular drug eruption and FDE. For
urticarial drug eruption Radioallergosorbent (RAST) test Prick
testing Intradermal skin testing Serum tryptase levels in
anaphylaxis Skin biopsy : may be helpful in confirming the
diagnosis sometimes in lichenoid eruptions andvasculitis. Assessing
drug causality
In the absence of any specific and validated in vivo and in vitro
laboratory investigations, the diagnosis of ADRs is mainly clinical
Rechallenge/Oral provocation is the only method to certainly prove
the causality of reaction due to a drug This has to be performed
under supervision by experts with graded and incremental dose of
drug, preferably indoors. It should be strictly avoided in pts with
SCAR Several methods to assess drug causality are used but the most
practical is Naranjo scale which uses different set of questions
and scoring is done based on their answers Probability assessment:
Naranjo alogrithm
To assess the probability of the event being an ADR, Naranjo scale
is widely used. It is based on a set of certain questions and
scoring is done on the basis of their answers. Although Naranjo
scale is most widely used, some other scales are also in use. One
such scale is UMC (Uppsala monitoring centre) in which the causal
assessment is categorized into certain, probable, possible and
doubtful as described below: Certain: rash occurs in plausible time
relation to drug intake; cant be explained by concurrent
disease/drug(s); plausible response to withdrawal and rechallenge
(if done) Probable: reasonable time relation to drug intake;
unlikely attributable to other disease/drug(s); reasonable response
to withdrawal; rechallenge not required Possible: reasonable time
relation to drug intake; could be explained by other concurrent
disease/drug(s); drug withdrawal information lacking/unclear
Doubtful/unlikely: improbable temporal relationbetween drug intake
and rash, easily explained by other concurrent disease/drug(s)
Naranjo Score Score 9 : Definite Score 5-8 : Probable Score 1-4 :
Possible Score 0 : Doubtful Final score obtained is utilised to
assess the probability of an ADR. Management Withdrawal of the
suspected drug(s) is the first and most important approach mainly
in serious ADRs. In milder reaction a close observation and treat
through approach can be adopted as many reactions abate
spontaneously despite continuation of drug. In serious reactions
the suspected/causative drug need to be stopped immediately or
substituted withstructurally unrelated drugs. This may be
practically difficult if the patient is on many/ life saving
drug(s) and safer alternatives are not available. Management - ADRS
Non-specific therapy depends on the type & severity of rash.
Milder rash can be managed with antihistaminics, emollients with or
without topical corticosteroids and calamine lotion. For severe,
life-threatening ADRs like SJS-TEN and DRESS specific therapy may
have to be given and include: Systemic steroids Cyclosporine IvIg
Antivirals may be added if viral reactivation is suspected in DRESS
General supportive measures
Are very important in serious reactions like SJS / TEN, DRESS, AGEP
and erythroderma and include : Monitoring of pulse, BP, RR,
temperature, input / output charting Fluid & electrolyte
balance Thermoregulation Prevention of sepsis Maintaining nutrition
For mucosal involvement - care of eyes, oral and genital mucosa
Treatment of Anaphylaxis
Stop drug, check airway, intravenous cannulation,BP monitoring, O2
/ assisted respiration. Inj. Adrenaline ml, 1:1000, SC / IM. Inj.
Chlorpheniramine maleate (CPM) mg iv. Inj. Hydrocortisone, 250 mg
iv & 100mg 6 hrly. Prednisolone 40mg/day - 3days. Inj.
Aminophylline 250mg over 5min-250 mg in 0.9% NaCl in 6 hrs.
Prevention Avoiding further exposure to causative drug.
Avoid exposure to cross-reactive drugs. Make patient aware of all
such drugs so that these drugs are not taken inadvertently. Being
vigilant for ADRs when starting a drug, specially those with a high
potential for ADRs. Also be careful while using newer / newly
approved drugs as their adverse effect profile may not be
well-known. Proper recording / documentation and reporting of ADR.
Pharmacovigilance Many times, ADRs go unreported.
Thus there is a need for PHARMACOVIGILANCE. Defined as the science
and activities relating to the detection, assessment, understanding
and prevention of adverse effects or any other drug related problem
(WHO). Educating clinicians about ADRs, official regulation of drug
use and rational use of drugs is very important and essential for
prevention of ADRs and ensuring drug safety. Summary Any drug can
cause reaction in any person, any time.
ADR can mimic almost any skin disease. Antibiotics, analgesics
& antiepileptics are responsible for >75% ADR. Angioedema,
fever, mucosal lesions, extensive skin lesions herald severe
reaction. Withdrawal of culprit drug is most important part of
management in serious drug reactions. Avoiding suspected and
chemically related drugis important in order to prevent recurrence
which may be severer than the initial episode(s). Reporting ADRs to
competent agency (pharmacovigilance) is important to ensure drug
safety. MCQs Q.1) Which of the following is the most common pattern
of adverse cutaneous drug reaction? Urticaria Maculopapular rash
FDE SJS Q.2) Which of the following ADR is usually localised :
DRESS TEN Ans : Q. 1 B, Q. 2 C MCQs Q.3) Which of the following
antiepileptic drugs is generally considered safe from the point of
severe ADR? Phenobarbitone Sod. Valproate Phenytoin Carbamazepine
Q.4) Severe mucosal involvement is a feature of : SJS-TEN DRESS
Erythroderma Erythema nodosum Ans : Q. 3 B (Rest all drugs are
common cause of severe reactions including SJS-TEN and DRESS), Q. 4
A MCQs Q.5) Drugs causing hypertrichosis are: Corticosteroids
Phenytoin
Cyclosporine All of the above Ans : Q. 5 D Photo Quiz Ans : Fixed
Drug Eruption Q. What is the diagnosis? Photo Quiz Q. What is the
diagnosis?
Ans : Erythema multiforme target lesions Q. What is the diagnosis?
Photo Quiz Ans : Clofazimine induced hyperpigmentation Q. Which
anti leprosy drug may result in this cutaneous adverse effect?
Thank You!