Maculopapular Drug Eruption Research Articles

Lamotrigine-induced hypersensitivity syndrome in a Han Chinese patient with the HLA-B*5801 genotype

Antiepileptic drug (AED) therapy is the mainstay for treating epilepsy. Most of the adverse effects in AED therapy are mild, predictable, and dose-dependent. Cutaneous eruptions, which lead to drug withdrawal and hospitalization, are the most frequent idiosyncratic adverse reactions. Severe cutaneous adverse reactions (SCARs) with high morbidity and mortality, including Stevens– Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug-induced hypersensitivity syndrome, are not uncommon in AED therapy. A strong association between the allele of human leukocyte antigen HLA-B*1502 and carbamazepine-induced SJS has been found in Han Chinese [1]. The lower incidence of carbamazepine-induced SJS in Caucasians, in contrast to its higher incidence in Han Chinese, suggests that there is an ethnic difference in susceptibility. Lamotrigine, one of the newer AEDs, has been reported as a risk factor for skin rashes. We previously [2] identified the risk factors of skin rashes in the patients treated with an initially high dose and rapid escalation of the dose of lamotrigine, and co-medicated with valproic acid. The role of HLA B*1502 in lamotrigine-induced SJS has been investigated and no definite association was found in the studied Han Chinese population [3], which is the same as in Caucasians. In contrast, there seems to be a weak association between HLA B*5801 and lamotrigineinduced SCARs in Caucasians [4]. We report a female Han Chinese patient with epilepsy and lamotrigine-induced SCARs; a genetic study identified the HLA-B*5801 allele as a risk factor. A 32-year-old Han Chinese woman with epilepsy, treated in a special epilepsy clinic in National Cheng Kung University Hospital for years, had been given regular valproic acid therapy (400 mg/day) and had a seizure frequency of around once a month. As the frequency had increased to around once a week, lamotrigine (starting at 20 mg/day, with a 20 mg/week increase) was added. Four weeks later, with the lamotrigine dose at 100 mg/day, she was admitted because of a high fever, generalized erythema, and jaundice. The patient’s blood test revealed high levels of AST (413 U/L), GPT (496 U/L), total bilirubin (17.7 mg/dL), LDH (790 IU/L), alkaline phosphate (582 IU/L), and gamma-GT (821 U/L). Combined with the high fever and a generalized rash, the patient was diagnosed with drug hypersensitivity syndrome. A skin biopsy (Fig. 1) showed mild spongiosis and scattered necrotic keratinocytes in the spinous layer, and vacuolar interface alteration of the basal layers with an infiltration of small lymphocytes. She also showed a perivascular infiltrate of small lymphocytes with scattered neutrophils in the upper dermis. These findings are consistent with maculopapular drug eruption. Under the diagnosis of lamotrigine-induced SCARs, we performed genotyping for this patient and the results showed the J. C. Chow Y.-J. Wu J.-J. Tsai Department of Pediatrics, Chi-Mei Foundation Medical Center, Tainan, Taiwan

Histopathologic Features of Exanthematous Drug Eruptions of the Macular and Papular Type

Although exanthematous drug eruptions of the macular and papular type are common and often cause diagnostic problems, histopathologic features are not precisely defined in the literature. We present the first prospective histopathologic study of maculopapular drug eruption in 48 patients in whom the diagnosis had been made on the basis of clinical examination, history of a known offending drug, and follow-up. Because more than 1 biopsy was taken in 11 patients, 60 biopsy specimens could be examined. The most consistent epidermal features were mild spongiosis mainly of the lower layers (97% of biopsies), some hyperplasia (72%), a few lymphocytes (82%), and neutrophils (32%). The dermoepidermal junction revealed discrete vacuolization (97%), scattered lymphocytes (75%), and rare necrotic keratinocytes (32%). All cases showed a dermal perivascular inflammatory infiltrate that was superficial only in 72% of biopsies and superficial and deep in 28% of biopsies. An interstitial infiltrate in the papillary dermis could be found in 93%, more often patchy than lichenoid. In general, the perivascular infiltrate was mild and composed of lymphocytes (100%), eosinophils (60%), and neutrophils (50%). In the papillary dermis, neutrophils often outnumbered the eosinophils. Another feature were the clusters of neutrophils (38%) and eosinophils (20%) in the lumina of dilated, otherwise normal, blood vessels. Rashes induced by anticonvulsants and anxiolytics were characterized by predominance of neutrophils and largish lymphocytes. Edema of the papillary dermis was encountered frequently (85%), whereas wiry collagen bundles were an exceptional finding. In conclusion, our study defined a constellation of histopathologic findings highly suggestive of the diagnosis of exanthematous drug eruption of the macular and papular type.

Soluble FAS Ligand: A Discriminating Feature between Drug-Induced Skin Eruptions and Viral Exanthemas

The clinical spectrum of cutaneous eruptions comprises benign variants like maculopapular rashes (MPRs) and potentially life-threatening events such as toxic epidermal necrolysis (TEN). Apoptosis of keratinocytes is a common histopathological feature of all these drug eruptions. As in skin lesions of TEN and Stevens-Johnson syndrome patients, apoptosis of keratinocytes is often accompanied by an only sparse cellular infiltrate, a soluble fatty acid synthetase ligand (sFASL)-mediated mechanism of keratinocyte cell death is postulated. In MPR patients, evidence for the occurrence of a similar process could not be established so far. We therefore examined sera and lesional skin sections from patients with clinical variants of drug eruptions for FASL expression using a sandwich ELISA and immunohistochemistry, respectively. As controls, healthy persons and patients with other inflammatory skin diseases such as viral exanthema were analyzed. Elevated levels of FASL were detected not only in TEN patients but also in sera and lesional skin of patients with MPR. In contrast, sFASL was repeatedly negative in all viral exanthemas and healthy controls tested. Thus, determination of sFASL serum concentration may represent a discriminating tool between drug rashes and viral exanthemas.

T cells in drug allergy.

In recent years, increasing evidence has indicated an important role for T cells in various drug-induced diseases. A detailed analysis of patients with various drug allergies revealed the existence of drug-specific T cells in the circulation or in eluate from skin infiltration in bullous, pustular, and maculopapular drug eruptions. The drug-specific T cells use the ab-T cell receptor CD4+ or CD8+ and react with drugs acting as haptens (covalently bound to larger molecules, such as penicillins), but also recognize drugs if they are bound only in a labile way to major histocompatibility complex molecules (noncovalent drug presentation). Functional analysis revealed a predominant IL-5 production by drug-specific CD4+ T cells in maculopapular exanthema (MPE) and bullous skin diseases, while patients with acute generalized exanthematous pustulosis have a peculiar T cell subset secreting high amounts of IL-8. Moreover, in MPE CD4+, perforin+ T cells were found in vitro and in immunohistology that had cytotoxic potential and killed keratinocytes in vitro and in vivo.

Pathogenesis of Drug-Induced Exanthema

Background: In vitro data derived from drug-specific T cell clones have revealed that heterogeneous T cell subsets with distinct phenotypes (CD4+ > CD8+) and cell functions (strong IL-5 production, cytotoxic potential) are generated. The aim of this study was to elaborate the relevance of these findings in vivo. Methods: Skin biopsy specimens from drug-induced maculopapular exanthema and normal skin were analyzed for CD4, CD8, CD25, HLA-DR, CD54, perforin, granzyme B, IL-5 and IFN-γ using immunohistochemistry. Results: The majority of infiltrating lymphocytes in maculopapular drug eruptions were CD4+. Both CD4+ and CD8+ T cells expressed perforin and granzyme B and were partly located at the dermoepidermal junction and in the epidermis. In addition, strong immunoreactivity for IL-5 and moderate immunoreactivity for IFN-γ were observed in the mononuclear cell infiltrate. Conclusions: Our data indicate that skin infiltrating T cells with a cytotoxic potential and the ability to produce IL-5 and IFN-γ may contribute to the damage of keratinocytes and the activation of eosinophils, which are typical features of drug-induced maculopapular exanthema.

Langerhans' cell distribution in drug eruption.

The number in and distribution of Langerhans' cells were studied in 11 patients with a maculopapular drug eruption. The Langerhans' cells (LC) were identified with a monoclonal antibody to OKT6 antigen, by employing an immunofluorescence technique. Skin biopsies were taken from lesional and non-lesional skin during the acute stage of the disease. LC in the lesional biopsies increased in number by 66% (p less than 0.001) and displayed more intense staining and more prominent dendrites than did LC from non-lesional skin. Control biopsies, taken from identical sites at least 4 weeks after the eruption disappeared, exhibited a cell distribution similar to the non-lesional acute stage (p = N.S.). Delivery of drugs via the circulation and their distribution into the skin may cause a type IV immune reaction due to LC activation by a drug-carrier complex.

Langerhans' cell distribution in drug eruption.

The number in and distribution of Langerhans' cells were studied in 11 patients with a maculopapular drug eruption. The Langerhans' cells (LC) were identified with a monoclonal antibody to OKT6 antigen, by employing an immunofluorescence technique. Skin biopsies were taken from lesional and non-lesional skin during the acute stage of the disease. LC in the lesional biopsies increased in number by 66% (p less than 0.001) and displayed more intense staining and more prominent dendrites than did LC from non-lesional skin. Control biopsies, taken from identical sites at least 4 weeks after the eruption disappeared, exhibited a cell distribution similar to the non-lesional acute stage (p = N.S.). Delivery of drugs via the circulation and their distribution into the skin may cause a type IV immune reaction due to LC activation by a drug-carrier complex.

Cutaneous Drug Reactions in Human Immunodeficiency Virus Infection

In this issue of theArchives, Porteous and Berger 1 describe eight individuals with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) who experienced severe cutaneous adverse reactions to drugs, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Also in this issue, Garty 2 reports such a case. These adverse events, which were seen in individuals who received multiple medications, occurred from 1 to 21 days (median, 8 days) after therapy with the suspect drug was initiated. Five patients had had a history of prior maculopapular drug eruptions, and two of them had had a previously documented reaction to the suspect drug. In three of these eight cases sulfonamides were suspected. As suggested in this report, other drugs appear to be causes of these reactions as well, but the magnitude of this risk with other drugs is far less clear. The authors note that patients with AIDS and toxoplasmosis