Chapter 056. Cutaneous Drug Reactions (Part 3)

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Delayed hypersensitivity mechanisms directed by drug-specific T cells are probably the most important mechanisms in the etiology of the most common drug eruptions—morbilliform exanthems—and also of rare and severe forms such as hypersensitivity syndrome, acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Drugspecific T cells have been detected in these types of drug eruptions. Contrary to what has been believed for years, the antigen is more often the native drug itself than its metabolites. It remains to better understand why the stimulation of T cells by medications leads to reactions that are clinically so diverse....

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Chapter 056. Cutaneous Drug Reactions (Part 3) DELAYED HYPERSENSITIVITY Delayed hypersensitivity mechanisms directed by drug-specific T cells are probably the most important mechanisms in the etiology of the most common drug eruptions—morbilliform exanthems—and also of rare and severe forms such as hypersensitivity syndrome, acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Drug- specific T cells have been detected in these types of drug eruptions. Contrary to what has been believed for years, the antigen is more often the native drug itself than its metabolites. It remains to better understand why the
stimulation of T cells by medications leads to reactions that are clinically so diverse. Some answers were provided by the study of effector cells obtained at the site of skin lesions. Drug-specific cytotoxic T cells have been detected in the skin lesions of fixed drug eruptions and of TEN. In TEN, blisters that result from accumulation of interstitial fluid under the necrotic epidermis contain T lymphocytes that are able to kill autologous lymphocytes and keratinocytes in a drug-specific, HLA-restricted, and perforin/granzyme-mediated pathway. Drug-specific clones producing CXCL8, a neutrophil-attracting chemokine, were obtained from skin tests of patients with AGEP, a neutrophil-mediated drug reaction. One may therefore assume that the final pattern of drug eruptions results both from the nature of effectors—cytotoxic T cells in blistering reactions, chemokines in reactions mediated by neutrophils or eosinophils—and from the intensity of stimulation and response. GENETIC FACTORS AND CUTANEOUS DRUG REACTIONS Specific genetically determined defects in the ability of an individual to detoxify toxic reactive drug metabolites predispose such individuals to the development of drug toxicity. It has also been suspected that a slow acetylator phenotype increases the risk of rash from sulfonamides. However, in two large
prospective cohorts of HIV-infected patients treated with sulfonamides, no association of drug eruption with acetylation genotype was found. Recent literature shows that genetic factors may be important predictors of severe drug reactions. Hypersensitivity to the anti-HIV medication abacavir was strongly associated with HLA B*5701. In Taiwan, within a homogeneous Han Chinese population, a 100% association was observed between SJS or TEN related to carbamazepine and HLA B*1502. In the same population, another 100% association was found between SJS, TEN, or hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DRESS) related to allopurinol and HLA B*5801. These observations have important theoretical implications. By pointing to HLA genes, they strongly support a key role for immune mechanisms. However, the strong associations found in Taiwan have not been observed in other countries with more heterogenous populations. Therefore, widespread practical applications of these findings are not yet possible. CLINICAL PRESENTATION OF CUTANEOUS DRUG REACTIONS Nonimmune Cutaneous Reactions EXACERBATION OR INDUCTION OF DERMATOLOGIC DISEASES
A variety of agents can exacerbate preexisting diseases or sometimes induce a disease that may or may not disappear after withdrawal of the inducing medication. For example, NSAIDs, lithium, beta blockers, and angiotensin- converting enzyme (ACE) inhibitors can exacerbate plaque psoriasis, while antimalarials can worsen pustular psoriasis. Acne may be induced by glucocorticoids, androgens, and lithium. Minocycline and thiazide diuretics may exacerbate subacute systemic lupus erythematosus, and pemphigus can be induced by D-penicillamine, captopril, and other ACE inhibitors. The hypothesis that a drug may be responsible should always be considered, especially in cases with atypical clinical presentation, unusual age of onset, or unexpected evolution. PHOTOSENSITIVITY ERUPTIONS Photosensitivity eruptions are usually most marked in sun-exposed areas but may extend to sun-protected areas. The mechanism is almost always phototoxicity. Phototoxic reactions resemble sunburn and can occur with first exposure to a drug. Their severity depends on the tissue level of the drug, its efficiency as a photosensitizer, and the extent of exposure to the activating wavelengths of ultraviolet light (Chap. 57). Common orally administered photosensitizing drugs include many fluoroquinolones and cycline antibiotics. Other drugs less frequently encountered are chlorpromazine, thiazides, and several NSAIDs (ibuprofen, naproxen,
piroxicam). Because UV-A and visible light, which trigger these reactions, are not easily absorbed by nonopaque sunscreens and are transmitted through window glass, photosensitivity reactions may be difficult to block. Photosensitivity reactions abate with removal of either the drug or ultraviolet radiation, use of high-potency sunscreens that block UV-A light, and treating the reaction as one would a sunburn. Rarely, individuals develop persistent reactivity to light, necessitating long-term avoidance of sun exposure.