Drug eruptions Drug eruptions l5% of all dermatoses l15% of drug side effects l lskin changes lmucosal involvement lpruritus lparaesthesia, pain Classification of drug reactions According to the time of onset of symptoms learly (up to 1 hour) llate (over 1 hour from the application of the drug) l l Hypersensitivity drug exanthema According to the involvement of immune mechanisms lallergic: l- antibody mediated l- cell mediated l non-allergic l - drug interaction with immune receptor of p-i concept cells l- pseudo allergic - anaphylactoid - no sensitization required Allergic reactions according to Coombs and Gell lType I. Anaphylactic - IgE antibodies l urticaria (nonsteroidal antirheumatic drugs) lType II. Cytotoxic - antibody dependent l thrombocytopenic purpura lType III. Immunocomplex l drug vasculitis lType IV. T cell mediated l IVa allergic contact dermatitis l IVb DRESS, maculopapular rash l IVc TEN, fixed drug rashes l IVd AGEP l Hypersensitivity drug rashes According to the mechanism of cell activation lreaction triggered by a hapten-carrier complex lreaction based on the pharmacological interaction of the drug with cell immune receptors lpseudoallergic reaction resulting from stimulation or inhibition of inflammatory cell receptors and enzymes l Hypersensitivity drug rashes According to severity lmild reactions lsevere, life-threatening reactions with possible organ involvement (anaphylactic shock, SCARs) l Drug rashes from other causes ● Overdose ● Cumulation ● Pharmacological side effects ● Drug interactions ● Microbial imbalance – dysmicrobia ● –Clinical signs ●Exfoliative erythroderma ●Haemorrhagic coumarin necrosis ●Alopecia diffusa toxica ●Acneiform eruptions ●Provocation of skin diseases ●Pigmentation (amiodarone) – ● History and diagnosis of drug rashes lHistory: lDrugs – targeted questions on: medications, vitamins, contraception, sedatives, laxatives, hypnotics, analgesics, inhalation, anaesthesia, external medications lComplementary and alternative medicine, self-medication lFood influences – ask about: dyes, fragrances, flavours, preservatives, tonics, artificial sweeteners lPrevious drug reactions lExposure - whether the substance (or a similar substance) has been administered in the past lTiming – onset of rash and administration of the drug (5-10 days from commencing the drug) lExclusion of other causes - other dermatoses, skin manifestations infectious and systemic diseases l l l History and diagnosis of drug rashes lElimination test – regression confirms the diagnosis lReexposure test – recurrence confirms the diagnosis lLaboratory tests: lIn vivo: l - Intradermal (scarification) in anaphylactic type I reactions l - Epicutaneous in a type IV hypersensitivity reaction (fixed drug rash) lIn vitro: l - RAST (penicillin) l - Other: lymphocyte transformation test, etc. lWhen more than one drug is given at the same time, the drug likely responsible is: lThe drug with a higher risk of rash lThe drug administered last l lékové exantemy 002 lékové exantemy 003 Pigm-amiodaron2 Drug rashes according to clinical findings lmaculopapular lurticaria llichenoid (β-blockers, gold) lacute generalised exanthematous pustulosis (terbinafine) lpapulopustular - acneiform (iodine, bromine, steroids) lpurpura lfixed erythema - rash (barbiturates, sulfonamides) lerythema nodosum (hormonal contraceptives, sulfonamides) lphotosensitivity reactions (thiazide diuretics, doxycycline, methotrexate) Makul Makulopap Makulopap Papulozni-amoxicilin3 Papulozni-amoxicilin4 Papulozni-amoxicilin7 foto 1-3 2008 315 foto 1-3 2008 333 foto 1-3 2008 336 Drug rashes lmaculopapular lurticaria llichenoid (β-blockers, gold) lacute generalised exanthematous pustulosis (terbinafine) lpapulopustular - acneiform (iodine, bromine, steroids) lpurpura lfixed erythema - rash (barbiturates, sulfonamides) lerythema nodosum (hormonal contraceptives, sulfonamides) lphotosensitivity reactions (thiazide diuretics, doxycycline, methotrexate) lékové exantemy 004 lékové exantemy 005 Urtica1 lékové exantemy 001 foto 1-3 2008 305 Maculo-urticarial (penicillin) foto 1-3 2008 307 foto 1-3 2008 310 foto 1-3 2008 308 lékové exanthemy 015 Drug rashes lmaculopapular lurticaria llichenoid (β-blockers, gold) lacute generalised exanthematous pustulosis (terbinafine) lpapulopustular - acneiform (iodine, bromine, steroids) lpurpura lfixed erythema - rash (barbiturates, sulfonamides) lerythema nodosum (hormonal contraceptives, sulfonamides) lphotosensitivity reactions (thiazide diuretics, doxycycline, methotrexate) ATT00073 Drug rashes lmaculopapular lurticaria llichenoid (β-blockers, gold) lacute generalised exanthematous pustulosis (terbinafine) lpapulopustular - acneiform (iodine, bromine, steroids) lpurpura lfixed erythema - rash (barbiturates, sulfonamides) lerythema nodosum (hormonal contraceptives, sulfonamides) lphotosensitivity reactions (thiazide diuretics, doxycycline, methotrexate) AGEP-cotrimoxazol1 AGEP-cotrimoxazol2 AGEP-cotrimoxazol3 AGEP-cotrimoxazol4 Drug rashes lmaculopapular lurticaria llichenoid (β-blockers, gold) lacute generalised exanthematous pustulosis (terbinafine) lpapulopustular - acneiform (iodine, bromine, steroids) lpurpura lfixed erythema - rash (barbiturates, sulfonamides) lerythema nodosum (hormonal contraceptives, sulfonamides) lphotosensitivity reactions (thiazide diuretics, doxycycline, methotrexate) lékové exanthemy 004 lékové exanthemy 005 lékové exanthemy 007 lékové exanthemy 008 Drug rashes lmaculopapular lurticaria llichenoid (β-blockers, gold) lacute generalised exanthematous pustulosis (terbinafine) lpapulopustular - acneiform (iodine, bromine, steroids) lpurpura lfixed erythema - rash (barbiturates, sulfonamides) lerythema nodosum (hormonal contraceptives, sulfonamides) lphotosensitivity reactions (thiazide diuretics, doxycycline, methotrexate) Erythema nodosum lMultifactorial etiology: l - infections, drugs, sarcoidosis, others l lAllergic reactions - II. type l - IV. type tuberculin l lMost common: contraceptives, sulfonamides lékové exanthemy 009 lékové exanthemy 010 Drug rashes lmaculopapular lurticaria llichenoid (β-blockers, gold) lacute generalised exanthematous pustulosis (terbinafine) lpapulopustular - acneiform (iodine, bromine, steroids) lpurpura lfixed erythema - rash (barbiturates, sulfonamides) lerythema nodosum (hormonal contraceptives, sulfonamides) lphotosensitivity reactions (thiazide diuretics, doxycycline, methotrexate) lékové exanthemy 001 lékové exanthemy 002 lékové exanthemy 003 Erythema multiforme lmultifactorial etiology: infections, drugs, neoplasia, autoimmune disease, idiopathic lforms: minor - target lesions l - up to 2 cm in size l - symmetrical in acral distribution l - most commonly HSV l - mortality 0 l l l l EEM-amoxicilin1 EEM-amoxicilin3 l major - target lesions with blisters l - acral distribution and torso l - blisters < 10 % surface l - most commonly HSV, mycoplasma l - mortality 1 % l lékové exantemy 006 ATT00065 lékové exanthemy 013 lékové exanthemy 014 Stevens-Johnson Syndrome (SJS) l atypical target lesions lprimarily the torso lblisters < 10 % suface l mucosal involvement l possible systemic symptoms lmost commonly drugs lmortality 6 % lékové exantemy 007 ATT00071 Toxic epidermal necrolysis (TEN, Lyell's syndrome) lcell-mediated cytotoxic immune response directed against epidermal antigens with high TNF α production → keratinocyte necrosis l ldrug (metabolite) binding to keratinocytes l lnecrosis of the entire epidermis Transitional form SJS / TEN latypical target lesions l mucosal involvement l blisters 10 - 30% lsystemic symptoms lmortality 25 % l TEN lrapidly merging erythema llinear separation of the epidermis lpositive Nikolsky phenomenon lmucosal involvement lsevere general condition (fever, impaired consciousness, glomerulonephritis, pneumonia and hepatitis) lmortality 40% (septicemia, gastrointestinal bleeding, renal failure, electrolyte imbalance) lékové exanthemy 011 lékové exanthemy 012 ATT00067 ATT00069 TEN most commonly triggering drugs lsulfonamides ltrimethoprim - sulfamethoxazole lcarbamazepine lphenytoin lphenobarbital lnon-steroidal anti-inflammatory drugs lallopurinol laminopenicillins l l l l Differential diagnosis of severe drug eruptions Disease Location Target lesions Mucous membranes blisters % surface mortality% EM minor acral typical ± 0 0 EM major acral, torso typical + < 10 1 SJS torso atypical ++ < 10 6 SJS/TEN torso atypical ++ 10-30 25 TEN torso atypical ++ > 30 40 EM = Erythema multiforme SJS = Stevens-Johnson syndrome TEN = Toxic epidermal necrolysis Conclusion lDrug rashes are usually mild, but in rare instances can be life-threatening (with mucosal involvement and organ failure) lDrug rashes occur most often within a few days of starting a new drug, but sometimes even after weeks or months of use lIn addition to drugs, other potential triggers - food, vitamins, food supplements, herbal preparations, self-medication and infectious diseases should be considered.