Erythema multiforme-like eruption from a slimming drug preparation cutaneous adverse drug reaction.

We report a case of a 34-year-old woman presenting with an erythema multiforme (EM)-like eruption. Lesions developed after a 12-day treatment with a slimming drug preparation (food integrator with thermogenic activity) and a herbal remedy (pilosella tincture). Serological investigations excluded viral or bacterial infections. Patch testing with galenic preparations of both drugs demonstrated sensitization to the slimming drug preparation. According to literature reports and immune-chemical properties, those components that are likely to have triggered the skin eruption are clorazepate dipotassium and theobromine. Their interaction with other two constituents such as pseudoephedrine hydrochloride and dehydrocholic acid may have caused the adverse reaction by means of a summation effect. There are no reports specifically about EM caused by a slimming drug preparation and no studies have identified thermogenic pills as cause of EM/EM-like eruption. Weight-loss compounds in slimming preparations should be kept in mind as a possible cause of drug-induced EM-like eruption.

INTRODUCTION

Erythema multiforme (EM) is an acute self-limited polymorphous eruption, probably mediated by deposition of immune complex in the superficial microvasculature of the skin. About 50% of EM cases are triggered by identifiable factors, that include drugs (20% of cases) and a viral or bacterial agent (i.e., Herpes simplex and Mycoplasma pneumoniae). Approximately half the cases are idiopathic.[1-3] Most commonly involved drugs include anticonvulsants, phenothiazines, nonsteroidal anti-inflammatory drugs, penicillins, and sulfonamides.[1-4] EM minor presents with mildly itchy, erythematous, expanding macules or papules that may coalesce and become generalized. “Target lesions” are typical, but arcuate lesion can also be present.[1-3]

CASE REPORT

A 34-year-old-woman was referred to our department because she had developed a macular–papular eruption involving the face, neck, arms, and trunk [Figure 1]. She complained moderate burning at the sites of eruption. Lesions appeared 2 days before and progressively spread without prodromic symptoms. The day before, the patient had been treated with oral prednisone and loratadine at the emergency room. Detailed clinical history did not reveal any significant medical disease, allergy, or skin manifestation. Twelve days before, she had started consuming a slimming drug preparation (2 or 3 pills twice a day before meals) and pilosella tincture (40 drops/day), which is a herbal remedy used in cellulitis and obesity due to its diuretic properties. The chemical composition of slimming preparation was pseudoephedrine hydrochloride 50 mg, theobromine 30 mg, caffeine 2 mg, vitamin C 100 mg, clorazepate dipotassium 1 mg, dehydrocholic acid 160 mg, magnesium stearate 2.4 mg, precipitated silica 0.8 mg, talc 0.8 mg, pregelatinized starch 156 mg.

Figure 1

The patient at presentation time: (a) face and neck involvement; and (b) trunk and arms involvement

We suggested her to discontinue these drugs and we performed allergological investigations on 4-weeks control. On this occasion, lesions had completely resolved, leaving moderate postinflammatory hyperpigmentation, especially on the neck area [Figure 2]. Prick tests with our standard allergen screening series were not consistent with respiratory allergy. Patch tests (PT) performed with the SIDAPA 2005 Standard series showed negative reactions. After 8 days we applied the second PT using the galenic preparations of the two drugs [Figure 3]: the pills were pulverized and then incorporated in vaseline 1%, and pilosella tincture was mixed in vaseline 1% too. Pills-PT tested positive on day 2 (+/–) and 4 (+) and negative on day 6. Tincture-PT showed negative results on all days’ readings. Intradermal test and oral challenge test were not performed: the patient's mother, who was her guardian, refused because of the potential risk of immunologic reactions. The laboratory tests showed normal blood cell count, protidogram, and liver enzymes, along with mildly elevated erythrocyte sedimentation rate. The serological results excluded infections from HSV-1, HSV-2, EBV, and Coxsackie virus A and B, Borrelia burgdorferi, Mycoplasma pneumonia, and Klebsiella pneumoniae. Given the absence of target lesions, a skin biopsy of a shoulder lesion was also carried out. Histopathological findings of an inflammatory pattern characterized by high-density lichenoid infiltrate rich in T cells, lymphocytes at the dermoepidermal junction, satellite cell necrosis, vacuolar degeneration of the basal layer, and dermal edema were suggestive of an EM-type drug eruption[1-3] [Figure 4].

Figure 2

(a) The patient at 1 month control, after having discontinued the slimming drug; and (b) the patient at 1 month control, after having discontinued the slimming drug

Figure 3

Galenic preparations of the slimming drugs: pilosella tincture and thermogenic pills

Figure 4

Lesional biopsy of shoulder skin showing lymphocytic infiltrate at the dermal-epidermal interface and superficial dermis and vacuolar degeneration of the basal layer, likely a type of erythema multiforme eruption

On 2, 6, 12 month follow-up, the patient had no more assumed slimming pills and similar eruptions never occurred.

DISCUSSION

The clinical history, the diagnostic investigations’ results and the 1-year follow-up findings indicate slimming pills as the triggering agent of the erythema multiforme -like eruption, excluding idiopatic EM. Those slimming pills are also known as “food integrators with thermogenic activity,” as they contain agents that are claimed to stimulate thermogenesis and increase metabolism and lipolysis (ie, pseudoephedrine hydrochloride [PSH], theobromine [TB], and caffeine [CF]. The role of vitamin C (VC) is to hypothetically reduce the effects of the free radicals generated by lipolysis, whereas clorazepate dipotassium (CLP) aims to mitigate possible side effects of PSH. Dehydrocholic acid (DHA) could stimulate solubilization of fatty acids. The remaining substances (ie, magnesium stearate, precipitated silica, talc and pregelatinized starch) act as thickeners or as excipients.

When considering these components, we focused our attention on those who were more likely to have immunogenic potential. Based on literature reports, we excluded CF, VC, and the four excipients/thickeners from analysis. Some reports indicate PSH as the cause of severe skin reactions, including recurrent pseudoscarlatina and nonpigmenting fixed drug eruption.[5] Its diastereomer ephedrine may cause dermatological side effects such as flushing and sweating. TB (3,7-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione), a methylxanthine, is a precursor molecule to Pentoxifylline (3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione). Pentoxifylline was reported to be associated with EM in 12 people over the last 13 years.[6] In addition, theophylline (3,7-diidro-1,3-dimetil-1H-purina-2,6-dione), which is an isomer of TB, figures in the list of EM-related drugs.[7] Given the chemical similarity between these three methylxanthines, we can hypothesize that the immunogenic potential of TB is similar to that of pentoxifylline and theophylline. CLP is a “classical” benzodiazepine. There are some reports of EM appearing after intake of benzodiazepines[4] and tetrazepam,[89] which is structurally similar to CLP. During the last 12 years, 97 cases of EM have been related to CLP use: these cases were observed among a total of 4290 people who experienced CLP side effects.[10] Regarding DHA, its documented side effects include exanthema macular, papular, rash.

There are no reports specifically about EM caused by a slimming drug preparation, and no studies have identified thermogenic stimulant pills as cause of either adverse skin reactions or EM/EM-like eruption. Our patient's eruption probably resulted from the interaction between these four potentially immunogenic components (ie, PSH, CLP, TB, and DHA). CLP is the only component that is reported to be a cause of EM. Although TB has not been related with EM or EM-like eruption yet it could be considered as a possible cause, given its similarity with the other EM-associated methylxanthines. Finally, PSH and DHA, which potentially cause rash and macular or papular rashes, may have contributed to the skin eruption too. Thus, our patient's adverse reaction is likely to result from a possible summation effect: each component may have stimulated an immune response with different intensity and this interaction can have triggered the eruption development. We then suggest that weight-loss compounds in slimming preparations should be kept in mind as a possible cause of drug-induced EM-like eruption. This would be particularly important in those countries where obesity is becoming a significant problem.