Mechanisms in cutaneous drug hypersensitivity reactions

Abstract

Cutaneous adverse drug reactions (CADRs) are considered a common problem in dermatology. They affect 2–6% of inpatients (1,2) and are a frequent cause of urgent dermatologic consultations (3). Most reactions resolve on drug suspension and symptomatic treatment but 2% can be severe with extracutaneous involvement and fatal outcome (4). Most CADRs are certainly not immune mediated, they are expected and represent an exaggerated pharmacologic effect. They are dose dependent and occur because of increased drug bioavailability either as a result of drug interactions or concomitant diseases. Papulopustular follicular eruptions, perionychia, and hair problems occur frequently on erlotinib or cetuximab that interfere with epidermal growth factor receptor (5), and skin and oral mucosa erosions can occur with metothrexate particularly in patients with low serum albumin, low renal clearance, or on concomitant nonsteroidal anti-infl ammatory drugs (NSAIDs). These predictable reactions, classifi ed as type A, may represent up to 70–80% of CADR (2,6) and are not the object of this chapter. Unpredictable, idiosyncratic CADR, classifi ed as type B, namely, drug “rashes” or “drug eruptions,” are those mostly dependent on immune hypersensitivity reactions. Their clinical presentation and time course is very heterogenous and their recognition is not always easy. Any drug can induce a CADR, each drug can induce several clinical reaction patterns, occurring immediately upon exposure or with a delay of hours, days, weeks, or even months, and there is no universal test to confi rm drug hypersensitivity. Some clinical patterns are very typical of a CADR, as toxic epidermal necrolysis (TEN), Stevens–Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), or fi xed drug eruption (FDE). But CADRs occur under a multitude of clinical presentations and at variable severity, often mimic skin diseases that are not usually drug induced (pemphigus, bullous pemphigoid, lupus erythematosus, psoriasis, and lichen planus) or present as maculopapular exanthemas (MPEs) or urticaria that may have other etiology (1,7). Also, it is often diffi cult to distinguish the relative contribution of the drug or other concurrent causes for the fi nal reaction, as in MPE of infectious mononucleosis induced by amoxicillin or in carbamazepine-induced drug reaction with eosinophilia and systemic symptoms (DRESS) with concomitant HHV-6 reactivation. Pathomechanisms in drug eruptions include a complex interplay of immune and infl ammatory effectors and different targets on the skin and, eventually, other organs. The full process from sensitization to the fi nal clinical reaction is not completely understood, but many progresses have been achieved in the last decades with important implications for our daily practice, both in the management of the reaction (diagnosis, treatment options, complementary tests to confi rm the culprit drug), preand postpreventive measures and, eventually, also to understand pathomechanisms involved in related dermatosis.