3/17/2017

Drug reactions: Drug Eruptions‐ When to Worry 3 things you need to know 1. Type of drug reaction 2. Statistics: – Which drugs are most likely to cause that type of Lindy P. Fox, MD reaction?

Associate Professor 3. Timing: Director, Hospital Consultation Service – How long after the drug started did the reaction Department of Dermatology University of California, San Francisco begin? [email protected]

I have no conflicts of interest to disclose 1

Drug Eruptions: Common Causes of Cutaneous Drug Degrees of Severity Eruptions • Antibiotics Simple Complex • NSAIDs Morbilliform drug eruption Drug hypersensitivity reaction Stevens-Johnson syndrome •Sulfa (SJS) Toxic epidermal necrolysis (TEN) • Allopurinol Minimal systemic symptoms Systemic involvement • Anticonvulsants Potentially life threatening

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Morbilliform (Simple) Drug Eruption Morbilliform (Simple) Drug Eruption Per the drug chart, the most likely culprit is: Per the drug chart, the most likely culprit is:

Day Day Day ‐> ‐8 ‐7 ‐6 ‐5 ‐4 ‐3 ‐2 ‐1 0 1 Day ‐> ‐8 ‐7 ‐6 ‐5 ‐4 ‐3 ‐2 ‐1 0 1 A vancomycin x x x x A vancomycin x x x x B metronidazole x x B metronidazole x x C ceftriaxone x x x C ceftriaxone x x x

D norepinephrine x x x D norepinephrine x x x

E omeprazole x x x x E omeprazole x x x x

F SQ heparin x x x x F SQ heparin x x x x trimethoprim/ trimethoprim/ G xxxxxxx G xxxxxxx sulfamethoxazole sulfamethoxazole

Admit day Rash onset Admit day Rash onset

Morbilliform (Simple) Drug Eruption Drug Induced Hypersensitivity Syndrome

• Begins 5‐10 days after drug started • Skin eruption associated with systemic symptoms and • Erythematous macules, papules alteration of internal organ function • Pruritus • “DRESS”‐ Drug reaction w/ eosinophilia and systemic • No systemic symptoms symptoms • Risk factors: EBV, HIV infection • “DIHS”= Drug induced hypersensitivity syndrome • Treatment: • Begins 2‐ 6 weeks after medication started – D/C medication – time to abnormally metabolize the medication – diphenhydramine, topical steroids • Resolves 7‐10 days after drug stopped • Role for viral reactivation, esp HHV6 – Gets worse before gets better • Mortality 10%

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Hypersensitivity Reactions Drug Induced Hypersensitivity Syndrome Drugs • Aromatic anticonvulsants • Each class of drug causes a slightly different clinical picture – phenobarbital, carbamazepine, phenytoin • Facial edema characteristic of all – THESE CROSS‐REACT • Anticonvulsants: • Sulfonamides – 3 weeks • Lamotrigine – Atypical lymphocytosis, hepatic failure • Dapsone • Dapsone: • Allopurinol (HLA‐B*5801) – 6 weeks • NSAIDs – No eosinophilia • Other • Allopurinol: – Abacavir (HLA‐ B*5701) – 7 weeks – Nevirapine (HLA‐DRB1*0101) – Elderly patient on thiazide diuretic – Minocycline, metronidazole, azathioprine, gold salts – Renal failure – Requires steroid sparing agent to treat (avoid azathioprine) • Each class of drug causes a slightly different clinical picture

DIHS‐ Clinical Features Hypersensitivity Reactions Treatment • Rash • Stop the medication – FACIAL EDEMA • Follow CBC with diff, LFT’s, BUN/Cr • Fever (precedes eruption by day or more) • Avoid cross reacting medications!!!! • Pharyngitis – Aromatic anticonvulsants cross react (70%) • Hepatitis • Phenobarbital, Phenytoin, Carbamazepine • Arthralgias • Valproic acid and Keppra generally safe • Lymphadenopathy • Systemic steroids (Prednisone 1.5‐2mg/kg) • Hematologic abnormalities – Taper slowly‐ 1‐3 months – eosinophilia – atypical lymphocytosis • Allopurinol hypersensitivity may require steroid • Other organs involved sparing agent • NOT azathioprine (also metabolized by xanthine oxidase) – Interstitial pneumonitis, interstitial nephritis, thyroiditis – Myocarditis‐ acute eosinophilic mycocarditis or acute necrotizing • Completely recover, IF the hepatitis resolves eosinophilic myocarditis • Check TSH monthly for 6 months • EKG, echocardiogram, cardiac enzymes • Watch for later cardiac involvement (low EF)

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Consult: 2 days of redness, pustules, Acute generalized exanthematous pustulosis neutrophilia on azithromycin for bronchitis Clinical Features • Acute onset • Fever, neutrophilia • Edema (face, hands) • Additional morphologies – purpura, vesicles, bullae, erythema multiforme‐like lesions • Mucous membrane lesions! • May mimic pustular psoriasis • Typically resolves within 2 weeks of stopping medication, but may require systemic steroids

Acute Generalized Exanthematous Consult: 5 days of painful red lesion Pustulosis = Pustular Drug Eruption after taking tylenol for headache • EuroSCAR (97 cases of AGEP, 1009 controls): – Macrolides – Ampicillin/amoxicillin BJD 2007 Nov;157(5):989-96. – Quinolones – (hydroxy)chloroquine – Sulphonamides – Terbinafine – Diltiazem – No infections found – Not associated with personal or family history of psoriasis

•Mercury • Enterovirus infection Amantadine

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Consult: Blisters after starting Fixed Drug Eruption vancomycin • Morphology – Annular red plaque – Can have central bulla – Heals with marked hyperpigmentation • Pain is the major symptom • Limited number of lesions • “Fixed” is a curious phenomenon – if patient takes the same medication again, the same spots light up • Spontaneously resolves

Drug-Induced Linear IgA Disease Drug-Induced Linear IgA Disease

• Immune-mediated subepidermal blistering disease Common causes • Others – Antigen: 97 kDa of BPAG2 (BP180) – Vancomycin – Amiodarone – DIF: band-like (linear) IgA deposition at DEJ – Penicillins – Sulfamethoxazole – Cephalosporins – Diclofenac • Clinical features – Captopril – Furosemide – Subepidermal blisters accentuated in flexural areas – Glyburide – Morphology: herpetiform or rosette-like –GCSF • Can be caused by medications –IFN – Vancomycin most common – Lithium • Spontaneously resolves after stopping medication in – Phenytoin – Piroxicam most cases – Rifampin

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Consult: My skin hurts and is blistering Severe Bullous Reactions

• Stevens‐Johnson Syndrome • Toxic Epidermal Necrolysis (TEN)

Stevens-Johnson Syndrome (SJS) and Toxic Stevens-Johnson (SJS) versus Epidermal Necrolysis (TEN) Toxic Epidermal Necrolysis (TEN) • Medications Disease BSA – Sulfonamides – Aromatic anticonvulsants (carbamazapine [HLA‐ SJS < 10% B*1502], phenobarbital, phenytoin) – Allopurinol (HLA‐B*5801) SJS/TEN overlap 10-30% – NSAIDs (esp Oxicams) – Nevirapine (HLA‐DRB1*0101) TEN with spots > 30% – Lamotrigine – Weaker link: Sertraline, Pantoprazole, Tramadol TEN without spots Sheets of epidermal loss > 10% J Invest Dermatol. 2008 Jan;128(1):35‐44

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Stevens-Johnson (SJS) versus Toxic Epidermal Necrolysis (TEN) Question 2 SJS TEN What is the most important consult besides Atypical targets Erythema, bullae dermatology to get in a patient with Mucosal Skin pain SJS/TEN? membranes ≥ 2 Mucosal A. Renal membranes ≥ 2 B. Ophthalmology Causes: Causes: C. Allergy/immunology Drugs Drugs D. Wound care Mycoplasma E. GI/liver

HSV

Question 2 SJS/TEN: Emergency Management

What is the most important consult besides • Stop all unnecessary medications dermatology to get in a patient with – The major predictor of survival and severity of disease SJS/TEN? • Ophthalmology consult • Check for Mycoplasma‐ 25% of SJS in pediatric patients A. Renal • Treat like a burn patient B. Ophthalmology – Monitor fluid and electrolyte status (but don’t overhydrate) C. Allergy/immunology – Nutritional support D. Wound care – Warm environment – Respiratory care E. GI/liver • Death (up to 25% of patients with more than 30% skin loss, age dependent)

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SJS/TEN: Treatment

• Topical – Protect exposed skin, prevent secondary infection – Aquaphor and Vaseline gauze • Systemic‐ controversial – No role for empiric antibiotics • Surveillance cultures • Treat secondary infection (septicemia) – Consider antivirals, treat Mycoplasma if present – SJS: high dose corticosteroids ‐1.5‐2 mg/kg prednisone (no RCT) – TEN: IVIG 1g/kg/d x 4d – TNF blockade, cyclosporine

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