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LIVE BLOG: Drug Reactions

In this live blog from the 11th Annual SDPA conference in Atlanta, Dr. Cindy Owen discusses drug reactions. Below are some of the highlights of her lecture.

General Principles:

  • Drug reactions mimic naturally occurring disease, thus a knowledge of drug reactions encompasses a general knowledge of all inflammatory and some neoplastic dermatologic disorders.
  • Drug reactions range widely from mild asymptomatic rashes to life-threatening syndromes and encompass a wide array of morphologies.
  • The prevalence of cutaneous adverse drug reactions in hospitalized patients has been reported to be around 2%. 
  • Drug-related rash is reported for nearly all prescription medications.

 

Majority of ADRs are “Type A”– dose-dependent and predictable based on the pharmacology of the drug. 

 

Idiosyncratic, or “Type B”, reactions are unpredictable and are related to patient-specific factors that enhance susceptibility: 

  • inadequate metabolic detoxification of the drug resulting in toxic metabolites, or
  • immunologically mediated allergic reactions

 

Types of hypersensitivity reactions based on cytokines and cytotoxic factors: 

? Type I: immediate, anaphylactic

? Type II: cytotoxic 

? Type III: immune complex 

? Type IV: delayed type (T cell mediated)

? ? ? ?

IVa– Th1 (IFN?, TNF?) IVb– Th2 (IL-4/13, IL 5, eosinophils) IVc– cytotoxic T cells (perforin, granzyme, granulysin) IVd– T cells (CXCL8, GM-CSF, neutrophils)

 

The morphology of drug eruptions can include exanthematous, pustular, bullous, urticarial, lichenoid, psoriasiform, lupus-like, phototoxic, vasculitic, among others. 

 

Identifying the Guilty Drugs

  • recent administration, although there are exceptions e.g. drug induced LE syndromes
  • certain patterns of reaction are strongly linked to a specific agent
  • exclude other causes of the cutaneous reaction

 

The Usual Suspects

  • antibiotics
  • anti convulsants
  • nonsteroidal anti inflammatory drugs
  • thiazide derivatives
  • allopurinol
  • telaprevir
  • note: the PDR lists rash as potential toxicity for almost all drugs

Steps in the Approach to a Suspected Cutaneous Drug Reaction

  • clinical diagnosis
  • analysis of drug exposure
  • differential diagnosis of the rash
  • literature search 
  • confirmation
    • future use of patch tests or lymphocyte transformation testing?
  • advise the patient 
  • report to regulatory agency or manufacturer 

 

Especially in cases that resemble more common skin diseases, diagnosis of drug-induced disease requires a high index of suspicion. 

Medication lists should be reviewed and the timing of medication initiation and rash onset analyzed.

Fixed Drug Eruption:

  • Lesions develop 1-2 weeks after initial exposure. 
  • With subsequent exposures the lesion recur within 24 hours at the same site and possibly with the addition of new sites. 
  • Lesions favor the lips, face, hands, feet, or genitalia.
  • Biopsy can be useful if diagnosis in doubt
  • Causes: 
    • tetracycline
    • sulfonomides
    • nsids
    • barbiturates

Urticarial Drug Reaction:

  • Presents within minutes to hours after exposure. 
  • Accounts for about 10% of adverse cutaneous drug reactions. 
  • Can be immunologic (penicillins, cephalosporins, sulfonamides, tetracyclines) or non-immunologic (opioids, radiocontrast media, angiotensin-converting enzyme inhibitors).
  • IgE-mediated immediate hypersensitivity reaction can be accompanied by flushing, angioedema, nausea/vomiting/diarrhea, laryngeal edema, bronchospasm, or hypotension. 

Serum Sickness-like Reaction:

  • Fever, rash (urticaria or morbilliform), and arthralgia develop 1-3 weeks after medication initiation. 
  • Unlike true serum sickness, hypocomplementemia, immune complex deposition, vasculitis, and renal disease are not seen. 
  • Cefaclor is the classically associated medication, other reports implicate infliximab, bupropion, and minocycline, among others.

Acute Generalized Exanthematous Pustulosis (AGEP):

  • AGEP consists of small, uniform pustules on an erythematous base, begins in and favors intertriginous zones. 
  • Associated findings are fever and leukocytosis, otherwise systemic symptoms are not seen.
  • Develops 1-3 weeks after medication exposure. 
  • Resolves with superficial desquamation 2 weeks after removal of inciting drug. 
  • Antibiotics and calcium channel blockers are frequently implicated.

Drug Induced Hypersensitivity Vasculitis:

– Usually a small vessel vasculitis manifesting with palpable purpura of the lower extremities (or other dependent area). 

  • Onset is 1 to 3 weeks after the start of the culprit medication. 
  • Systemic vasculitis may occur and be life-threatening, especially with involvement of the kidneys, CNS, or lungs. 
  • Eosinophils in tissue can be helpful in distinguishing hypersensitivity vasculitis from other vasculitic syndromes.
  • Drugs commonly responsible include:
    • antibiotics
    • thiazide
    • diuretics
    • NSAIDs
    • propythiouracil
    • phenytoin
  • If drug induced, will resolve in 2 weeks
  • Must differentiate from other vasculitic syndromes (infection, autoimmune disease)

Exanthematous (Morbilliform) Drug Eruption:

  • The most common drug-induced eruption, accounting for up to 80% of rashes attributed to drugs. 
  • pruritic papules on trunk, extremities which coalesce into plaques
  • Patients with HIV, bone marrow transplant, or certain underlying infections (eg, mononucleosis) are at highest risk. 
  • This rash appears between 4 and 21 days after drug initiation. 
  • Discontinuation of the drug results in resolution of the rash within one week. 
  • Treat symptomatically with antihistamines and topical steroids. 
  • Be sure to look for systemic findings that would signify a more serious adverse reaction, such as DRESS (see below).
  • What looks like morbilliform drug eruption can be a severe cutaneous adverse reaction either unrecognized or in evolution
  • Thorough history, review of systems, physical examination, and laboratory evaluation will distinguish

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS):

  • Sometimes called hypersensitivity syndrome or drug-induced hypersensitivity syndrome.
  • Associated mortality is up to 10%. 
  • Ranges in incidence from 1 in 1000 to 1 in 10,000 drug exposures
  • DRESS presents 2-8 weeks after drug initiation and can persist or recur even after drug discontinuation.
  • Most common presentation is a morbilliform rash, but can be variable and include pustules, vesicles, purpura, or erythroderma. 
  • Other physical examination findings to note are facial edema, lymphadenopathy, and fever. 
  • Hematologic abnormalities include eosinophilia (not present in all cases), atypical lymphocytes, lymphopenia, lymphocytosis, thrombocytopenia, or thrombocytosis. 
  • The most commonly involved internal organs are liver (liver function test elevation), kidney (creatinine elevation, hematuria, or proteinuria), and lung (interstitial lung disease). 
  • Myocarditis, pancreatitis, and thyroiditis are also reported. 
  • Associated medications are 
    • antibiotics, 
    • anti-epileptics, 
    • allopurinol, 
    • oxicam NSAIDs, 
    • nevirapine, 
    • dapsone, 
    • sulfasalazine, 
    • telaprevir
    • among others.

 – Treatment is removal of offending medication, and long taper of high dose steroids with or without IVIG.

  • Steroid-sparing agents may be required in persistent or recurrent DRESS. 
  • Type I diabetes and autoimmune thyroid disease can occur in the months to years following DRESS.

Stevens Johnson Syndrome (SJS)/ Toxic Epidermal Necrolysis (TEN):

  • SJS—dusky lesions and flat atypical targets with isolated lesions predominating over confluent areas and mucosal involvement, affecting less than 10% body surface area (BSA). 
  • TEN—poorly delineated erythematous plaques, flat atypical targets, epidermal detachment with confluent patches dominating over isolated lesions and mucosal involvement affecting >30% BSA.
  • SJS-TEN overlap—between 10 and 30% BSA affected. 
  • The mortality for SJS is 5% while that for TEN can be over 30%. 
  • Onset is 7-30 days after drug administration; anticonvulsants can be up to 2 months after initiation.

High risk medications for SJS/TEN are:

  • allopurinol, 
  • sulfamethoxazole, 
  • sulfasalazine, 
  • antiepileptics, 
  • nevirapine, and 
  • oxicam NSAIDs. 

Evaluate mortality risk in TEN using the SCORTEN prognostic tool. 

Calculate the score daily for the first 5 days of admission and take the highest score

SCORTEN:

Prognostic Factor (one point each)
Age >40 years
Heart rate >120 bpm
Cancer or hematologic malignancy
BSA involved on day 1 above 10%
Serum urea level >28 mg/dL
Serum bicarbonate <20 meq/L
Serum glucose >252 mg/dL

SCORTEN* MORTALITY RATE (%)

0-1 3.2
2 12.1
3 35.8
4 58.3
>/=5 90

  • Early withdrawal of causative medications and supportive care are essential. 
  • Ophthalmologic management is also key.
  • Special care may be required to prevent long-term complications at mucosal sites, especially in patients with ocular or vaginal disease.
  • Pharmacologic therapy for SJS/TEN is debated, as no targeted therapies have been clearly proven effective. 
  • Corticosteroids remain controversial, but cyclosporine, IVIG, plamapheresis, and anti-TNF alpha agents have been reported in uncontrolled studies. 
  • Thalidomide was shown in a randomized controlled trial to increase mortality and should be avoided.

Conclusions:

  • Maintain a high index of suspicion for drug-induced skin disease. 
  • Look for cutaneous clues to potentially severe reactions—facial edema, mucous membrane involvement, skin pain or detachment, purpura, erythroderma. 
  • Search for systemic symptoms or signs of severe adverse reactions—fever, malaise, sore throat, arthralgia, lymphadenopathy. 
  • Check basic labs if suspicion exists for systemic involvement. 
  • Create a timeline of drug exposures in patients with many medications to help determine a possible culprit. 
  • There is no confirmatory test for a drug cause, though the Naranjo criteria can be used to determine probability. 
  • No currently available in vitro or in vivo tests have proven to have sufficient specificity or sensitivity to confirm drug causation. 
  • Prevention may be possible in some cases, however, with HLA associations identified within the burgeoning field of pharmacogenetics.

 

 

Image: Stromholm

 




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