Toxic Epidermal Necrolysis Like Reaction due to Low-dose Methotrexate in a Case of Cutaneous Lupus Erythematosus: A Rare Occurrence.

Sir,

Toxic epidermal necrolysis (TEN) is a serious variety of cutaneous adverse drug reaction (ADR), which is characterized by typical sheet-like erosions of the skin, involving more than 30% of the body surface area along with atypical targetoid lesions, often involving the mucosal surfaces.[1] Lupus erythematosus is one of the most common disorders treated by a dermatologist. In our setting, we often use methotrexate (MTX) (10–25 mg); which is deemed to be safe and effective. However, here, we report a case where a patient presented with TEN like skin eruption, even on low dose MTX therapy; one of the first such cases from this part of the world.

A 30-year-old male patient presented to our outpatient department with diffuse erythema and peeling of skin mainly involving the face, trunk, back, and extremities. He was prescribed MTX tablet 5 mg on 3 consecutive days in a week from a general physician for management of lupus erythematosus after appropriate investigations. The skin lesions developed approximately after 72 h of taking MTX tablet 5 mg on the 3rd day. The lesions started over face and gradually progressed to involve the trunk and extremities. There was no history of similar illness in the past. The patient was not taking any other systemic medication. Cutaneous examination revealed diffuse, confluent erythema, and erosions of the skin affecting mainly the face [Figure 1], trunk [Figures 2 and 3] and extremities [Figure 4] (>30% of body surface area was involved); with some ruptured blisters mainly over the back [Figure 3]. Skin tenderness was also elicited. Nikolsky's sign was found to be positive. Oral mucosa also showed the presence of erosions; rest of the mucosae was normal. Hair and nails were spared. Despite repeated prodding, the patient refused a skin biopsy and patch test with the suspected drug. Routine blood parameters were within normal limits except for leukocytosis. Re-challenge with MTX was not done considering the severity of the reaction. Rest of the systemic examination was unremarkable. A diagnosis of TEN was made; and the patient was treated successfully with conservative measures. We prescribed Mycophenolate mofetil for his skin condition; and advised him regular follow-up.

Figure 1

Erythematous, eroded areas involving the face, neck and upper chest, lip involvement can also be seen

Figure 2

Skin lesions involving the front of trunk

Figure 3

Skin lesions involving the back, few ruptured blisters can also be noted

Figure 4

Skin lesions involving the trunk and upper extremities

TEN is a life-threatening disease characterized by extensive destruction of the epidermis. The mortality rate averages 25-30% following septicemia and various metabolic disturbances. A large number of drugs have been implicated, but the most common triggers include antiepileptic drugs (phenytoin, barbiturates, carbamazepine and lamotrigine),[2] sulfonamides and trimethoprim, ampicillin and other beta-lactam antibiotics, allopurinol,[3] nonsteroidal anti-inflammatory drugs (especially pyrazolon derivatives, e.g., phenylbutazone and oxicam derivatives) and sulfonamide, cyclooxygenase-2 inhibitors (particularly valdecoxib, less commonly celecoxib),[4] terbinafine, antiretrovirals including nevirapine[5] and abacavir,[6] pentamidine, MTX,[7] etc.

MTX (4-amino-N10methyl pteroylglutamic acid) is a potent competitive antagonist (inhibitor) of the enzyme dihydrofolate reductase. MTX can be administered orally, intravenously, intramuscularly, or subcutaneously. This agent is approved for use by patients with malignancies, including cutaneous lymphomas, along with approval for psoriasis vulgaris,[89] psoriatic arthritis, and rheumatoid arthritis. However, it is widely used in dermatology practice (off label) for many other conditions, including bullous disorders, autoimmune connective tissue diseases (collagen vascular disorders), pityriasis rubra pilaris, pityriasis lichenoides et varioliformis acuta, sarcoidosis, and several unrelated diseases.

The main toxic effects of MTX are pancytopenia, gastrointestinal mucositis, hepatotoxicity, pulmonary toxicity, and acute renal failure. More adverse effect includes lymphoma, teratogenicity, and reversible oligospermia.[10] MTX may also cause cutaneous adverse effects such as acral erythema, papular eruption, epidermal necrosis or cutaneous ulceration,[11] vasculitis, etc.

Whether the epidermal necrolysis is an allergic or dose related toxicity reaction is still controversial. There are few reports of MTX induced TEN due to high dose of MTX,[1213] but TEN like presentation with low dose of MTX has rarely been reported;[7] that too in a case of psoriasis. However, in our case TEN like ADR occurred due to low dose MTX in a case of cutaneous lupus; the first such case being reported.

Effective communication with the patient with proper explanation of the weekly dosage schedule in both verbal and written form is mandatory to reduce the incidence of such adverse events.

Recently, a unifying concept of “acute syndrome of apoptotic pan-epidermolysis” has been proposed by Ting et al. in 2004. It encompasses all the life-threatening clinical situations of massive epidermal necrosis resulting from severe apoptotic injury, which may be drug induced or due to other causes such as LE, acute graft versus host disease, pseudoporphyria, etc.[14]

This rare case has been presented to make us aware about the occasional life-threatening adverse effects of MTX, even in low, recommended dosage. Hence, strict vigilance is needed before we prescribe this useful drug in all cases; to avoid any mishap.

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The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.