Immune-Mediated Cutaneous Reactions

Cutaneous reactions such as rash or Stevens-Johnson syndrome are also consist with initiation through protein haptenation, although in this case dendritic cell activation/ migration and T-cell propagation are involved [31]. Other immune mediators such as cytokines, nitric oxide and reactive oxygen species which may be linked to the formation of reactive metabolites may also be implicated, as may specific processes occurring at the level of the keratinocyte. 

Hypersensitivity reactions, such as pruritus, cutaneous vasculitis, and thrombocytopenia, are seen in some patients, and an immune-mediated systemic flulike syndrome with thrombocytopenia also has been described. Rifampin imparts a harmless red-orange color to urine, feces, saliva, sweat, tears, and contact lenses. Patients should be advised of such discoloration of body fluids. 

A fully robust animal model of NVP-induced hepatotoxicity has yet to be developed (Walubo et al. 2006), but Uetrecht and colleagues have characterized extensively a dose-dependent, NVP-induced, skin rash in female Brown Norway rats that resembles the idiosyncratic cutaneous reaction seen in humans and appears to be immune-mediated (Popovic et al. 2006 Shenton et al. 2007). An association between 12-hydroxy NVP metabolism and skin toxicity has been shown in a recent study (Chen et al. 2008), when it was found that 12-OH-NVP caused a rash at a lower dose than required for NVP. The authors proposed that the rash produced in rats may be due to quinonemethide formed in the skin via sulfation of 12-hydroxy NVP metabolite followed by loss of inorganic sulfate. 

Cutaneous reactions are among the most prevalent adverse effects of therapeutic drugs. Ranging from relatively minor skin rashes to more serious toxic consequences such as SJS and TEN, these cutaneous effects can impose major limitations on clinical therapeutic use. Mechanisms of adverse cutaneous drug reactions may be immune mediated, photochemical, directly related to therapeutic activity, or idiosyncratic toxidties for which the mechanisms are poorly understood. 

Summarized descriptions of the most important immune-mediated delayed cutaneous adverse drug reactions follow. Readers should refer to Sect. 3.6.3 for details of the mechanisms involved in these reactions. 

Serious immune-mediated reactions to antithymocyte globulin include anaphylaxis, severe cytokine release syndrome, and severe acute infusion-associated reactions. Serum sickness with fever, rash, arthralgia, and myalgia may appear 5-15 days after the initiation of therapy. Cutaneous reactions seen include urticaria, morbilliform eruptions, and acral erythematous eruptions preceding rash. 

Table 13.1). Other more severe symptoms sometimes reported are bronchospasm, chest pain, seizures, and systemic anaphylaxis that may be life-threatening. Reactions to oxaliplatin are similar to those seen in response to cisplatin and carboplatin, but the responses to oxali-plafin tend to be more heterogeneous and unpredictable with fewer cutaneous reactions idiosyncratic reactions like cytokine release syndrome and pulmonary fibrosis fewer reports of severe anaphylaxis and a higher incidence of respiratory symptoms including laryngeal spasms and hypoxemia A few cases of type II thrombocytopenia and type HI immune complex-mediated urticaria, joint pain, and proteinuria associated with oxaliplatin have also been reported. 

Although human anaphylaxis is a systemic reaction, the mouse model of passive cutaneous anaphylaxis (PGA) has been used extensively to enhance our understanding of mechanisms which also may contribute to systemic anaphylaxis. Unlike systemic anaphylaxis in the mouse, PGA appears to be entirely dependent on mast cells [4,6]. While IgE appears to be the primary antibody isotype that mediates PCA reactions in actively immunized mice, activation of FcyRIII by a fraction of IgGl antibodies (called anaphylactic IgGl) can also mediate PCA reactions in mice [4]. 

Mechanisms of non-immediate reactions are unclear but may be immunological and non-immunological. Delayed reactions of the IgE type are known (131). Aminopenicillins seem to be an important cause of non-immediate reactions (132-134). The morbilliform rash that begins 1-10 days after amoxicillin can be caused by a delayed cell-mediated immune reaction (135) as can fixed drug eruptions (136,137), toxic epidermal necrolysis (138-140), bullous erythroderma (141), and contact eczema (142). Investigation of these disorders should include delayed readings of skin tests (135). In patients with chronic urticaria, penicillin allergy was demonstrated by cutaneous tests. 

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