Chapter 056. Cutaneous Drug Reactions (Part 3)

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 thestimulation of T cells by medications leads to reactions that are clinically so diverse....
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Chapter 056. Cutaneous Drug Reactions (Part 3) Chapter 056. Cutaneous Drug Reactions (Part 3) DELAYED HYPERSENSITIVITY Delayed hypersensitivity mechanisms directed by drug-specific T cells areprobably the most important mechanisms in the etiology of the most common drugeruptions—morbilliform exanthems—and also of rare and severe forms such ashypersensitivity 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 thenative drug itself than its metabolites. It remains to better understand why thestimulation of T cells by medications leads to reactions that are clinically sodiverse. Some answers were provided by the study of effector cells obtained at thesite of skin lesions. Drug-specific cytotoxic T cells have been detected in the skinlesions of fixed drug eruptions and of TEN. In TEN, blisters that result fromaccumulation of interstitial fluid under the necrotic epidermis contain Tlymphocytes that are able to kill autologous lymphocytes and keratinocytes in adrug-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 drugreaction. One may therefore assume that the final pattern of drug eruptions resultsboth from the nature of effectors—cytotoxic T cells in blistering reactions,chemokines in reactions mediated by neutrophils or eosinophils—and from theintensity of stimulation and response. GENETIC FACTORS AND CUTANEOUS DRUG REACTIONS Specific genetically determined defects in the ability of an individual todetoxify toxic reactive drug metabolites predispose such individuals to thedevelopment of drug toxicity. It has also been suspected that a slow acetylatorphenotype increases the risk of rash from sulfonamides. However, in two largeprospective cohorts of HIV-infected patients treated with sulfonamides, noassociation of drug eruption with acetylation genotype was found. Recent literature shows that genetic factors may be important predictors ofsevere drug reactions. Hypersensitivity to the anti-HIV medication abacavir wasstrongly associated with HLA B*5701. In Taiwan, within a homogeneous HanChinese population, a 100% association was observed between SJS or TEN relatedto carbamazepine and HLA B*1502. In the same population, another 100%association was found between SJS, TEN, or hypersensitivity syndrome/drugreaction with eosinophilia and systemic symptoms (DRESS) related to allopurinoland HLA B*5801. These observations have important theoretical implications. Bypointing to HLA genes, they strongly support a key role for immune mechanisms.However, the strong associations found in Taiwan have not been observed in othercountries with more heterogenous populations. Therefore, widespread practicalapplications of these findings are not yet possible. CLINICAL PRESENTATION OF CUTANEOUS DRUGREACTIONS Nonimmune Cutaneous Reactions EXACERBATION OR INDUCTION OF DERMATOLOGICDISEASES A variety of agents can exacerbate preexisting diseases or sometimesinduce a disease that may or may not disappear after withdrawal of the inducingmedication. For example, NSAIDs, lithium, beta blockers, and angiotensin-converting enzyme (ACE) inhibitors can exacerbate plaque psoriasis, whileantimalarials can worsen pustular psoriasis. Acne may be induced byglucocorticoids, androgens, and lithium. Minocycline and thiazide diuretics mayexacerbate subacute systemic lupus erythematosus, and pemphigus can be inducedby D-penicillamine, captopril, and other ACE inhibitors. The hypothesis that adrug may be responsible should always be considered, especially in cases withatypical clinical presentation, unusual age of onset, or unexpected evolution. PHOTOSENSITIVITY ERUPTIONS Photosensitivity eruptions are usually most marked in sun-exposed areasbut may extend to sun-protected areas. The mechanism is almost alwaysphototoxicity. Phototoxic reactions resemble sunburn and can occur with firstexposure to a drug. Their severity depends on the tissue level of the drug, itsefficiency as a photosensitizer, and the extent of exposure to the activatingwavelengths of ultraviolet light (Chap. 57). Common orally administered photosensitizing drugs include manyfluoroquinolones and cycline antibiotics. Other drugs less frequently encounteredare chlorpromazine, thiazides, and several NSAIDs (ibuprof ...