CHAPTER 23
DRUG ERUPTIONS
（薬 疹）
・ Drug reaction manifests variable clinical presentations consisting of commonly seen eruptions such as erythema, papules, vesicles or bulla, purpura, desquamation, pigmentation, and others.
・ The reaction occurs in the form of either localized or systemic fashion including mucosal area such as oral cavity, ocular region, and genitalia. In addition to skin lesions, drug reaction also associates various systemic complications such as lymphadenopathies, fever, arthralgia, myalgia, and even a multiple organ failure, often resulting in a threatning of patient's life.
A. Incidence of Drug Eruptions
1. approximately 0.2 - 0.6% (1950's).
2. approximately 2% of all new out-come patients (1970's).
B. Mechanisms Inducing Drug Eruptions
・ Drug eruptions are caused by either allergic or toxic (non-allergic) mechanisms.
1. Allergic reaction (types I, II, III, and IV)
The drug acts as an antigen and antigen-antibody reaction then occurs with activation of complement and subsequent tissue damage.
Two possible immunological pathways to provocate skin rashes;
a. Immunoglobulins (chiefly Ig E)-mediated reaction (immediate reaction).
b. Helper T lymphocyte-mediated (delayed hypersensitivity) or cytotoxic T lymphocyte-mediated reaction.
2. non-allergic reaction
A direct toxic effect of the drugs by over-dose administration and/or accumulation of drugs as a local or systemic event, interaction of drugs with bacterial or viral infection, and others, eventually resulting in a tissue damage.
C. Major Eruption Patterns and Clinical Manifestations
1. Urticarial eruption（蕁麻疹型薬疹）
a Allergic type reaction is mediated through specific-Ig E against drugs and the rash may commence within hours.
b Non-allergic type reaction is mediated by the histamin-releasing substances (opium...etc.) and drugs which act as a cycloxygenase inhibitior.
c Clinical discrimination between urticaria and urticarial drug eruption is hardly possible.
d. Penicillins and salycylates are the most probable causes.
2. Erythema multiforme including Stevens-Johnson syndrome（多型紅斑型薬疹）
スティーブンス・ジョンソン症候群を含む
a. Most of erythema multiforme eruption showing typical target lesins and localizing in extremities are occasionally caused by herpes infection, whereas severe form of this eruption involving mucosal membrane of oral cavity, ocular region and genitalia, is named Stevens-Johnson syndrome, which is almost always caused by drugs.
b. Barbiturates, gold, phenylbutazone, phenytoin, and sulphonamides, frequently induce this type of reaction.
3. Exanthematous eruption（湿疹型薬疹）
a. Synonyms: morbilliform drug eruption, maculopapular eruption.
b. The most common type of cutaneous drug eruption.
c. Eruptions are consisting of macules and/or papules, few mm to 1 cm in size and may progress to generalized exfoliative dermatitis, especially if drug is not discontinued.
d. Antibiotics, most commonly penicillin and its relative antibiotics, allopurinol, and carbamazepine often produce this type of drug eruption.
4. Bullous eruption（水疱型薬疹）
a. Non-specific bullous eruptions occur most commonly with barbiturates, iodides, and sulphonamides.
b. The blisters tend to be large and tense and may involve any part of the body, although the limbs are commoner than elsewhere.
5. Fixed drug eruption（固定薬疹）
a. The lesion may be solitary, but in some instances multiple, and involves any part of the body, although lips and perioral region, genitalia, and extremities are the common sites.
b. Clinical picture of typical fixed drug eruption consists of dusky red or violaceous macule, but occasionally bullous.
c. Tetracycline, barbiturates, and sulphonamides are the possible causes.
6. Purpura（紫斑型）
・This skin manifestation of drug reaction is usually caused by direct or indirect damage of blood vessels (mainly capillaries) and the lower limbs are the most common site due to increased venous pressure.
7. Lichenoidal eruption（扁平苔癬型薬疹）
a This skin rash is similar to that of lichen planus, which is mostly observed in the aged.
b. The lesion is violaceous and tend to leave residual pigmentation, although it occurs in confluent rather than discrete papules.
c. The most common site is a trunk, and it is not infrequent that rashes take more than 5 to 10 years to appear after administration of the drugs.
d. Thiazides diuretics, heavy metals, and phenothiazides, frequently provocate above lesions.
8. Photosensitivity（日光過敏症）
a. Eruptions due to photosensitivity is usually confined to exposed areas such as face, neck, and dorsal aspect of hands, and manifest acute eczematous lesions consisting of erythema, reddish papules and occasionally blisters.
b. This type of drug eruption is mediated by (a) photoallergic reaction or (b) phototoxic (non-allergic) mechanism.
c. Tetracycline, chlorothiazine, frocemide, benoxaprophen, and ketoprophen, are the frequent causative agents.
9. Acneform eruption（ざ瘡型皮疹）
a. The eruption consists of papular and pustular eruption and distributes on face, upper chest and back, where is so-called "seborrheic region".
b. Systemic steroids, androgens, oral contraceptives, iodides, bromides, and isoniazid are the frequent causes.
10. Toxic epidermal necrolysis (TEN; Lyell)（中毒性表皮壊死融解症）
a. Severe form of drug eruption, which is frequently threatning patient's life.
b. Epidermal necrosis results in denudation and erosion of skin, and ften progress to a falling of nails, teeth, and hair.
c. . Nikolsky phenomenon is frequently observed.
d. Barbiturates and antibiotics could induce this severe form of drug eruption.
11. Others
・ Following skin manifestations are frequently or infrequently associated with the drug eruptions.
a. Exfoliative dermatitis (erythroderma) 剥離性皮膚炎（紅皮症）
b. Lupus erythematosus 薬剤誘発ループス
c. Erythema nodosum 紅節性紅斑
d. Psoriasiform eruptions 乾癬型皮疹
e. Nail deformity and hair falling (alopecia) 爪変化及び脱毛
f. Pigmentation 色素沈着
g. Others
D. Histopathological Findings
1. Drug-induced vasculitis
a. Leukocytoclastic vasculitis; predominant infiltrates are leukocytes and their invasion into the walls of blood vessels as well as a fibrin deposition.
b. Lymphocytic vasculitis; infiltrating cells are lymphocytes and eosinophils in and/or in the walls of blood vessels without fibrin deposition.
2. Fixed drug eruption（固定薬疹）
・ Basically those seen in erythema multiforme.
a. Hydropic degeneration of basal layer leads to pigmentary incontinence.
b. The presence of large amount of dermal melanophages in upper dermis.
c. Scattered dyskeratotic cells with eosinophilic cytoplasm and pyknotic nuclei.
E. Laboratory Studies
・ There are no specific laboratory findings to reveal drug eruptions.
a. Occasional elevation of leukocytes and serum IgE level is frequently observed in bacterial infection as well as drug reaction.
b. Leukocytopenia and reduction of platelets are also seen in viral infection.
c. Autoantibodies such as anti-nuclear antibody, anti-SSA and -B, and others may suggest the presence of latent collagen disease.
F. Diagnostic Tools
1. Anamnesis
2. In vivo tests
a. Provocation (challenge) test（誘発試験）
b. Skin test
1) scratch test: immediate hypersensitivity
2) patch test: delayed hypersensitivity
3) others
3. in vitro tests
a. Lymphocyte-stimulation test (LST)
b. Radioallergosorbent test (RAST)
c. Others
4. Skin biopsy
G. Differential Diagnosis
a. Differential diagnosis of drug eruptions is often difficult to discriminate them from those of original skin diseases, which drug-induced lesions tend to mimic, such as bullous diseases, eczemas, urticaria, connective tissue diseases, and others.
b. Skin rashes due to viral infection is also problem some because of similarity to morbilliform eruption. However, precise anamnesis, careful inspection of skin eruptions, and skin biopsies as well as laboratory studies, could enable a correct diagnosis of drug eruptions.
c. Photo patch test should be required when photosensitivity due to drug is suspected.
H. Treatment and Clinical Course
1. Discontinuation of offending drugs as soon as possible is the most important.
2. Treatment of drug eruptions depends on the degree of severity and type of eruptions.
a. It is occasionally enough to administrate anti-histamine drugs per os with or without topical application of steroids.
b. In case of severe conditions such as Stevens-Johnson syndrome, TEN, and systemic bullous drug eruption, systemic steroid administration and drip infusion to improve general condition of patient are required.
＊Chapter 21: Drug Eruptions
・drug eruption:薬疹 ・lymphadenopaty:リンパ節腫脹
・urticaria:蕁麻疹 ・fever:発熱
・erythema multiforme:多形紅斑 ・arthralgia:関節痛
・exanthema:発疹、皮疹 ・morbilliform:麻疹様
・maculopapular:斑状丘疹状 ・fixed drug eruption:固定薬疹
・lichenoidal eruption:苔癬状皮疹 ・lichen planus:扁平苔癬
・photosensitivity:日光過敏 ・acne form:にきび様
・toxic epidermal necrolysis:中毒性表皮壊死
・exfoliative dermatitis:剥離性皮膚炎 ・erythroderma:紅皮症
・lupus erythematosus:紅斑性狼瘡 ・erythema nodosum:結節性紅斑
・psoriasifrom eruption:乾癬様皮疹 ・alopecia:脱毛症
・bullous disease:水疱性疾患 ・eczema:湿疹
・connective tissue disease:結合組織病（膠原病）