药物不良反应的皮肤表现

藥物不良反應之皮膚表現,臺北市立聯合醫院皮膚科(和平)林瑞宜,2018年1月20日星期六,04:05:14,演講大綱,藥物不良反應之作用機轉過敏與非過敏如何診斷藥物過敏？藥物反應之作用之重要皮膚表現危險徵候,04:05:14,Mechanism of Adverse Drug Reactions,Type A: 藥理作用相關者(Pharmacological)依照藥理作用可預測者 為已知之作用效果之擴大表現者 常與劑量有關 必須降低劑量者. Type B: 特質性或過敏性(idiosyncratic or allergic)依照藥物之藥理作用無法來預測者奇異的或特直性的不良反應常非單純之劑量相關反應(dose-response relationship)發生不良反應時，誘因藥物常必須中止續用非用不可時，常須經過減敏步驟 (Desensitization),04:05:14,藥物過敏皮膚反應之診斷,是否為藥物過敏之皮膚反應？Allergic or pseudoallergic ?過敏或不良反應之類型為何？何種免疫反應？何種皮膚反應？誘發藥物為何？有無交互作用或交叉反應之藥物或情況？可能之預後嚴重性如何？,04:05:14,藥物反應之免疫作用機轉,Type I: IgE dependent (Anaphylaxis)蕁麻疹、血管性水腫、休克Type II: Cytotoxic (Biological)天疱瘡Pemphigus, Thromobocytopenic petechia,Type III: Immune-complex (Chemical, Connective )血管炎Vasculitis, 血清病serum sickness, Type IV: Cell mediated , Delayed typeGranulomatous, Eczematous史帝芬強生徵候群、毒性表皮壞死症 (SIS-TEN)Th1-INF-Mono, Th2-IL-5-Eosin, IL-8 PMN, CD4/8,04:05:14,Mechanism of Frug Hypersensitivity,Annals of Internal Medicine 2003, 139(8): 684,04:05:14,判斷ADR之原因藥物及嚴重度一、臨床特徵,原發皮疹之類型斑疹、丘疹、結節、膨疹、紫斑、水疱、膿疱皮疹之分布、數目及癢、痛等局部症狀有無波及粘膜併發症狀：全身性症狀發燒、關節痛內臟變化、多重器官淋巴腺腫 痛,04:05:14,判斷ADR之原因藥物二、病程、時序,應紀錄所有用藥史：種類及起訖過去，類似藥物、劑量變化其他可能交互作用之藥物，隱藏藥物藥物代謝相關之肝、腎功能變化開始發疹日期計算出服藥及發疹之間隔停藥後之反應再度使用之反應,04:05:14,皮膚藥物反應的簡單分類,立即性或延遲性，自限性或持續性蕁麻疹及血管性水腫、休克發疹(exanthema):麻疹樣藥疹侷限性或汎發型(+粘膜?)發疹型多型性紅斑，水疱、黏膜 (SJS/TEN)局部反應固定藥疹、光敏感性、水疱症、壞死等,04:05:14,Severe Cutaneous ADR,04:05:14,藥物反應的重要皮膚病變,發疹 樣藥疹：可能為下列之早期病變急性發疹樣膿疱症(AGEP)血管炎(血清病、免疫複合體病)紅皮症(剝脫性皮膚炎)伴隨系統症狀、嗜伊紅球症之藥疹(DRESS)SJS-TEN(毒性表皮壞死症)多型性紅斑 SJS TEN,04:05:14,立即性反應：Anaphylaxis,蕁麻疹Urticaria 血管性水腫Angioedema Anaphylaxis休克ADR之比例: Anaphylaxis 30%Urticaria 10% 為藥物引起服藥至發疹間隔：分鐘至小時Mortality：5%常見原因藥物：-lactam: Penicillins, Cephalosporins, NSAID, contrast media, monoclonal Aby,04:05:14,發疹樣藥疹Exanthematous Drug Eruption,常見之藥物不良反應皮疹From trunk to extremities Maculopapules or urticariamay confluent Purpura at ankle, feet, waistMucosa is spared可能有少數毛囊性膿疱ADR之比例: Child 10-20%, Adult 50-70%服藥至發疹間隔：4(7)-14days,04:05:14,發疹樣藥疹Exanthematous Drug Eruption,Type IV, or 非免疫性direct binding to MHC-2 in KC(sulfa)AminoPC in Infectious mononucleosis可能為嚴重之藥疹的前驅危險徵候毛囊一致性膿疱，紫斑，Nikolskys sign, 粘膜潰瘍系統性功能異常D Dx: Viral exanthema, Toxic shock syndrome, GVHD, Kawasakis, Stills,04:05:16,發疹樣藥疹Exanthematous Drug Eruption,Perifollicular papules with central pustules,Exanthematous Rash with Purpura: Vasculitis,04:05:16,發疹樣藥疹Exanthematous Drug Eruption,Mortality：單純發疹樣藥疹為:0%其他進展？可能為嚴重之藥疹的前驅可能為嚴重之藥疹的前驅Hypereosinophilia: DRESSPalpable purpura, arthritis: VasculitisFacial edema: DRESS, ErythrodermaMucosa involvement: TEN, SJS Painful skin: TEN,04:05:16,血管炎 Vasculitis,Palpable purpura可能伴隨蕁麻疹，發疹變化血清病、免疫複合體病 (Type III reaction)Dermato-arthritis syndrome r/o bacteremia/sepsis first可能波及多重器官ADR之比例: 10%服藥至發疹間隔：7-21days, challenge 3days,04:05:16,Leukocytoclastic Vasculitis,有硬結的紫斑Palpable purpura表面有無壞死現象？有無血尿？CheckCBC, WBC/DCLFTRFTC3, C4,04:05:16,血管炎 Vasculitis,Mortality：？常見原因藥物：Penicillins, NSAID(oral, topical) Sulfonamide, Cephalosporins, Anticonvulsant, Allopurinol, Thiazide, Bio products (G,M-CSF, biologics, etc.),04:05:16,DRESS : Drug Rashes with Eosinophilia and Systemic Symptoms,04:05:16,DRESS Hypersensitivity Syndrome伴隨系統症狀、嗜伊紅球症之藥疹,伴隨系統症狀、嗜伊紅球症之藥疹 Drug Rash (Reaction) with Eosinophilia and Systemic Symptoms 常與藥物之代謝有關，或病毒HHV-6,7Immune +, IL-5Th2eosinophilsADR之比例: 70-90%服藥至發疹間隔：15-40days停藥後持續數週至數月Mortality：5-10%,04:05:16,DRESS Hypersensitivity Syndrome,Febrile (85%) mobilliform rash(75%)麻疹樣、 浮腫、follicular accentuation，水疱、膿疱、紫斑、紅皮症好發於臉、上軀幹及四肢；臉浮腫特徵Systemic involvementHepatitis, myocarditis, interstitial pneumonitis, nephritis, thyroiditis etc.LymphadenopathyRx of Corticosteroids : first choiceMay relapse during tapering,04:05:16,DRESS Hypersensitivity Syndrome伴隨系統症狀、嗜伊紅球症之藥疹,常與藥物之代謝有關：phenytoin (arene oxide) 1:1000sulfonamide (hydoxylamine?) 1:10,000常見原因藥物： Aromatic Anticonvulsant( phenytoin, carbamazepine, phenobarbital)Allopurinol (in renal dysfunction)Lamotrigine (esp. with Valproate)Sulfonamide, dapsoneMinocycline, gold salt,急性發疹樣膿疱症Acute Generalized Exanthematous Pustulosis (AGEP),臉部或腋下鼠蹊開始水腫性紅斑有非毛囊性小膿疱,04:05:18,急性發疹樣膿疱症(AGEP) Acute Generalized Exanthematous Pustulosis,急性發燒，與皮疹同時或更早臉部或腋下鼠蹊等部位浮腫開始數小時內快速擴散軀幹及上肢會波及粘膜皮疹為多樣性，癢或熱感水腫性紅斑上有非毛囊性小膿疱水腫、紫斑，水疱，靶型疹皮疹持續1-2週Mortality：1-2%,04:05:18,AGEP / EMto Pseudoephedrine,04:05:18,急性發疹樣膿疱症(AGEP),可能是敏感之recall reactionPatch test: 陽性率達80%Neutrophilia, IL-3, 8, G-CSF from T cellsADR之比例: 70-90%服藥至發疹間隔：90%)臉部水腫Scaling：lamellar, crustybrannyHyper-/hypo-thermia, Tachycardia, CHFlymphadenopathyy, hepatomegalyEosinophilia and lymphopeniaADR之比例: 19% (5.5-42%)為藥物引起服藥至發疹間隔：wks to mons (epoprostenol)停藥後2-6wks緩解 Mortality：?,04:05:18,紅皮症(剝脫性皮膚炎),常見原因藥物：Allopurinol, Ampicillin/Amoxicillin/Penicillins, (14% floxacillin) carbamazepine (ox-), phenobabital, phenytoin dapsone, sulfasalazine, sulfonamide, clofazimine, omeprazole, phenothiazines, vancomycine, captopril, nefedipine, isoniazide, ethambutol (HIV+),04:05:18,Erythema Multiforme, SJS/TEN,Continuous spectrum or Different entity?多型性紅斑Erythema Multiforme史帝芬強生徵候群(SJS) Stevens-Johnson Syndrome 毒性表皮壞死症TEN Toxic Epidermal NecrolysisTarget erythema, Blisters, Tender skin, Epidermal detachment, Exfoliation, Multiple Mucosal involvement,04:05:18,EMSJS(10%)SJS/TENTEN(30%),04:05:18,Stevens-Johnson Syndrome & Toxic Epidermal Necrolysis,CategoryIncidence per mil-yrDrug related ratioMortalityPrimary eruptions (major feature)Isolate vs ConfluenceDetachment (% BSA)Interface vs NecrosisSystemic symptoms,TEN0.4-1.280-95%25-50% Red edema & denudedConfluence 30I NecrosisAlways,SJS1.2-6 50%5%Target & dusky redIsolated 多 Nusually,04:05:18,Toxic Epidermal Necrolysis,04:05:18,Stevens-Johnson Syndrome & Toxic Epidermal Necrolysis,Prodromal :