Cutaneous Drug Reactions With Systemic Features

Pseudolymphoma

Although some clinicians use the term drug-induced pseudolymphoma interchangeably with DRESS, pseudolymphoma applies only to patients who have both clinical and histologic features, suggestive of lymphoma. The drug eruption is subacute, usually composed of single or multiple nodules, with no accompanying systemic signs. It is not considered a premalignant state. The most common drugs that have been associated with pseudolymphoma are the aromatic anticonvulsants (e.g., phenytoin, phenobarbital, and carbamazepine), along with valproic acid and lamotrigine. Other drugs associated with the development of pseudolymphoma include amlodipine, tamoxifen, and vaccines containing aluminum hydroxide. The syndrome occurs after 1 week to 2 years of exposure to the drug ( Box 67.3 ). The symptoms and physical findings generally resolve within 7 to 14 days of drug discontinuation. Histopathologically, two types of pseudolymphoma are distinguished: T-cell pseudolymphoma (upper dermal band-like pattern that simulates mycosis fungoides) and B-cell pseudolymphoma (nodular pattern). Management of drug-induced pseudolymphoma often involves no treatment other than withdrawal of the offending agent. Complete blood cell count (CBC) and serum chemistries are usually within normal limits. Long-term follow-up is necessary to rule out the possibility of pseudo-pseudolymphoma (i.e., a true lymphoma).

Anticonvulsants

Q67.2 DRESS has been commonly associated with the aromatic anticonvulsants, namely phenytoin, phenobarbital, oxcarbazepine, and carbamazepine. The nonaromatic anticonvulsant, lamotrigine, may induce DRESS as well. Several mechanisms have been implicated in DRESS syndrome, including the formation of toxic metabolites by phenytoin, carbamazepine, and phenobarbital. Human herpesvirus (HHV)-6 reactivation, well described in organ transplant recipients, has also been associated with DRESS. HHV-6 reactivation is considered to be a diagnostic criteria for the Japanese consensus group for DRESS. Cytomegalovirus (CMV), Epstein-Barr virus (EBV) and HHV-7 reactivation have also been implicated in a minority of cases. Viral infections may act as, or generate the production of, “danger signals” leading to damaging immune responses to drugs, rather than immune tolerance. Danger signals can be exogenous, endogenous, intracellular or secreted from distressed and injured cells; as well danger signals include proinflammatory cytokines (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1). Alternatively, herpesvirus reactivation in DRESS may result from an allergic immune response to a drug, with an innate ability to stimulate T cells, which may have harbored the latent herpesvirus.

In one study, 75% of a series of patients, with anticonvulsant DRESS to one aromatic anticonvulsant, showed in vitro cross-reactivity to the other two. Nonaromatic anticonvulsants and benzodiazepines have been well tolerated, as alternative treatments in patients with reactions to aromatic anticonvulsants. In addition, in vitro testing showed that there is a familial occurrence of hypersensitivity to aromatic anticonvulsants. Q67.2 Although lamotrigine is not an aromatic anticonvulsant, there have been several reports documenting a DRESS associated with its use as well.

Sulfonamide Antibiotics

Sulfonamide antibiotics have also been reported to cause DRESS in susceptible individuals. The primary metabolic pathway for sulfonamides involves acetylation to a nontoxic metabolite, followed by renal excretion. An alternative metabolic pathway, quantitatively more important in slow acetylators, involves the cytochrome P-450 (CYP) enzymes. Q67.3 These enzymes can transform the parent compound to reactive metabolites, namely hydroxylamines and nitroso compounds, that produce cytotoxicity, independent of preformed drug-specific antibody. In most individuals, detoxification of the metabolites occurs. Patients who are unable to detoxify this metabolite via reduction (e.g., glutathione-deficient patients) may be at higher risk for DRESS. The detoxification defect is present in 2% of the population, but only one in 10,000 people manifests symptoms of sulfonamide-induced DRESS. Notably, patients’ siblings and other first-degree relatives are at an increased risk (perhaps one in four) of having a similar defect. Q67.4 Other aromatic amines, such as procainamide, dapsone, and acebutolol, are metabolized to similar compounds. It may be prudent to recommend avoidance of aromatic amine drugs in patients who develop symptoms compatible with a sulfonamide DRESS because of the potential for cross-reactivity. All sulfonamide antibiotics (sodium sulfacetamide, silver sulfadiazine, sulfamethoxazole) should be avoided in patients with a history of DRESS to a sulfonamide antibiotic. Also as sulfasalazine has been shown to be cross-reactive with sulfamethoxazole, this drug should also be avoided. However, cross-reactivity with sulfonamides should not occur with related drugs that are not aromatic amines (e.g., sulfonylureas, thiazide diuretics, furosemide, acetazolamide). This principle, regarding lack of cross-reactivity between aromatic and nonaromatic sulfonamides, pertains to the full spectrum of cutaneous reactions to sulfonamide antibiotics, including DRESS.