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!