Dimorphic exanthema manifested as reticular maculopapular exanthema and erythema multiforme major associated with pyrazolon derivatives

ARTICLE

The non-steroidal anti-inflammatory drugs, especially various pyrazole or pyrazolon derivatives, were one of the classes of drugs commonly implicated in erythema multiforme or Stevens-Johnson syndrome/toxic epidermal necrolysis. Reticular exanthem was a rare morphological pattern of maculopapular drug eruptions. Here we report a case of dimorphic exanthema presenting with partly reticular maculopapular exanthema and erythema multiforme-like lesions, associated with pyrazolon derivatives. Patch testing showed negative reaction to the suspected drugs. The possible mechanism underlying the association of dimorphic exanthema with NSAIDs is discussed.

Key words: antipyrine, dimorphic exanthema, erythema multifome, NSAIDs, reticular exanthem.

Cutaneous manifestations are the most frequently observed adverse reactions to drugs and antipyretic/anti-inflammatory analgesics are among the most common culprit substances [1]. Common morphologic patterns are exanthematous, urticaria and/or angioedema and fixed drug eruption, while erythema multiforme (EM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe adverse reactions [1]. The exanthematous or maculopapular eruptions could be further classified as scarlatiniform, rubelliform, morbilliform, large-spot eruptions, polycyclic and polygyratic erythema, reticular eruptions, sheet-like erythema and papular eruptions [2]. While certain drugs are commonly associated with a specific reaction, most drugs are capable of causing several different types of eruptions [1]. However, the concurrence of two different morphologic patterns (dimorphic) of drug eruption in the same individual has rarely been described. Here we report a case of EM major presenting simultaneously with reticular exanthema as well as erythema multiforme-like eruptions, most likely caused by two pyrazolon derivatives, mepirizole and antipyrine.

Case report

A 70-year-old male with a history of hypertension under enalapril treatment for 4 years presented with high fever (39.0° C), malaise, myalgia, arthralgia and generalized skin rash, which had started 3 days after he had received intravenous injections of Sulkern (containing antipyrine) and oral mepirizole due to fever and headache. Previous exposure to the same medications did not cause any skin rash. There was no known history of herpes labialis or herpes genitalis. Skin examinations showed widespread erythematous to violaceous, partially coalescent maculopapules as well as centrally dark discoloration of some large macules over the abdomen, genitalia, back of the trunk and extremities including palms and soles (Fig. 1), while clear-cut florid erythematous reticular exanthem predominated separately around the neck and chest (Fig. 2). Bilateral conjunctivitis and extensive oral ulcers with painful ingestion were also noted. Laboratory examinations revealed abnormal results of leukocytosis (white cell count 18.3 x 10³/mL with 90% neutrophils), elevated C-reactive protein value (177 mg/dL), and elevated liver function values (GOT/GPT = 186/184 U/L). Under the clinical diagnosis of EM major, he was given oral cyproheptadine, intraveous methylprednisolone (beginning with 40 mg/d for 4 days then tapering to 20 mg/d for 3 days) and prophylactic antibiotics (cephalothin 4 g/d for 7 days). The general condition and the skin lesions improved rapidly. The reticular exanthema completely resolved in 7 days without any residue, while the EM-like lesions disappeared in 14 days with post-inflammatory hyperpigmentation. A skin biopsy taken from the lower abdomen demonstrated histopathologically vacuolar interface dermatitis with many necrotic keratinocytes and a sparse lymphocytic infiltrate in the upper dermis obscuring the dermo-epidermal junction. Three weeks later after cessation of treatment, patch testing carried out with mepirizole and antipyrine, 50% in petrolatum, respectively, did not show any reaction by reading at 72 hrs [3].

Discussion

Our case was unusual in that two kinds of skin lesions coexisted (dimorphic exanthema); one was the partly reticular maculopapular exanthema, the other the EM-like lesions with mucosal involvement and showing typical histopathological findings. EM is a very well recognized pattern of adverse cutaneous drug reaction [1], however, no generally accepted classification of the EM spectrum exists [4], although it was recently suggested that EM major and SJS could be separated as two distinct clinical disorders with similar mucosal erosions but different patterns of cutaneous lesions [5]. Our case posed difficulties in classification; the mucosal involvement and the absence of typical blisters/erosions corresponded morphologically more to erythema multiforme major while the history of drug exposure, lack of herpes infection, and widespread skin lesions seemed to favor the diagnosis of SJS.

The non-steroidal anti-inflammatory drugs (NSAIDs) were one of the classes of drugs most commonly implicated to cause EM and SJS/TEN [6] and might include salicylates, fenbrufen, ibuprofen, sulindac, paracetamol, and various pyrazole or pyrazolon derivatives, among which sulindac and phenylbutazone appeared to be most often associated [6]. In one recent report, however, only oxicam NSAIDs (piroxicam and tenoxicam) seemed to be associated with significantly large increases in the risk of SJS/TEN (multivariate relative risk, 22) [7]. Clinical use of aminopyrine as well as antipyrine was sharply curtailed in western Europe and North America after their potentially fatal bone-marrow toxicity, agranulocytosis [8]. Antipyrine, however, is still available in some countries, usually in analgesic mixtures, as happened in our case.

Reticular forms of drug eruptions have rarely been described. Diclofenac and D-penicillamine have been mentioned by Bork to cause reticular exanthema [2]. Wright et al. described an unusual case of bleomycin-induced extensive reticular pigmentation, which microscopically showed marked increase of melanin pigment in the basal keratinocytes and a number of melanophages in the upper dermis [9]. Aihara et al. reported a reticular pattern of coalescent violaceous lichenoid papules and pigmentation due to nandrolone furylpropionate [10].

Many in vitro tests may help to assess the culpability of a drug under stringent conditions. Although patch testing is useful for confirming clinical diagnoses of fixed drug eruptions and the predictive value on involved areas has been reported to be as high as 75-86% [3, 11], it had only a weak sensitivity in SJS/TEN, reaching less than 10% (2/22) in one study, and among them all of the 7 patch tests to NSAIDs were negative [12]. Lymphocyte transformation test, which is more often positive than other test procedures [13], is not available in our department.

Most drug eruptions are due to non-immunological mechanisms resulting from direct activation of effector pathways [14]. Immune-mediated reactions to NSAIDs are unusual but severe cutaneous drug eruptions are considered to occur through an immune-mediated mechanism. Re-exposure to the specific drug could lead to activation of the circulating or mucocutaneously infiltrating drug-specific memory T cells [15]. In our case, it could be assumed that both non-immune mediated and immune-mediated drug eruptions were present at the same time; while the former led to reticular maculopapular exanthema, the latter to the EM-like lesions. This could be evidenced by the typical histopathological findings of the EM-like lesions and their more lasting duration (14 days) as compared to the reticular eruptions (7 days) after commencement of treatment. It will be interesting to see if the newly specific COX-2 inhibitors will be associated with a lower incidence of severe cutaneous drug reactions.

References

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Article accepted on 10/6/02