Drug eruptions l 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 lp-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 l lékové exantemy 002 l lékové exantemy 003 l 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) l Makul l Makulopap l Makulopap l Papulozni-amoxicilin3 l Papulozni-amoxicilin4 l Papulozni-amoxicilin7 l foto 1-3 2008 315 l foto 1-3 2008 333 l 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) l lékové exantemy 004 l lékové exantemy 005 l Urtica1 l lékové exantemy 001 l foto 1-3 2008 305 Maculo-urticarial (penicillin) l foto 1-3 2008 307 foto 1-3 2008 310 l foto 1-3 2008 308 l 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) l 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) l AGEP-cotrimoxazol1 l AGEP-cotrimoxazol2 l AGEP-cotrimoxazol3 l 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) l lékové exanthemy 004 l lékové exanthemy 005 l lékové exanthemy 007 l 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: linfections, drugs, sarcoidosis, others l lAllergic reactions - II. type l - IV. type tuberculin l lmost common: contraceptives, sulfonamides l lékové exanthemy 009 l 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) l lékové exanthemy 001 l lékové exanthemy 002 l 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 l EEM-amoxicilin1 l 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 l lékové exantemy 006 l ATT00065 l lékové exanthemy 013 l 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 % l lékové exantemy 007 l 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) l lékové exanthemy 011 l lékové exanthemy 012 l ATT00067 l 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.