INTRODUCTION

Methotrexate (MTX) is a folate antagonist that inhibits dihydrofolate reductase (DHFR). It is widely prescribed in dermatology because of its efficacy and low cost. MTX cutaneous toxicity is usually described when it is used in high doses (e.g., chemotherapy), yet it may be observed even during treatment with low-dose methotrexate. Herein, we report a case of cutaneous toxicity and severe leukoneutropenia after a single low dose of methotrexate in a hemodialysis patient.

CASE REPORT

A 59-year-old patient on hemodialysis (3 sessions/week) for four years for end-stage CKD secondary to polycystic kidney disease. The patient received an initial injection of 10 mg of methotrexate for an extension of his psoriasis. After three days, he developed pharyngitis with dysphagia and odynophagia, and was initiated on amoxicillin-clavulanic acid. The evolution was marked by the appearance of erythematous-pustular lesions on the trunk and hands. On examination, there was cheilitis, stomatitis with inflammation of the pharyngeal mucosa, erosions in the mouth and nasal cavities, purple erythematous lesions dotted with pustules, painful on palpation, on the back and palms of the hands with desquamation, and a tender erythematous patch on the external genitalia (Figs. 1 – 3). The patient’s general condition deteriorated, with a fever of 38.8°C. Histological examination showed a detached epidermis with necrosis in the basal layers associated with spongiosis, exocytosis, and vesicles containing polymorphic inflammatory elements; edematous dermis with perivascular and perifollicular inflammatory infiltrate and sometimes at the dermal-epidermal junction, this infiltrate consisting of lymphocytes and polymorphonuclear cells – some of which were eosinophilic-; extravasation of red blood cells without fibrinoid necrosis of the vascular wall. Paraclinical findings included leukoneutropenia (leukocytes 300/mm3), Hb 12.5 g/dL, platelets 163,000/mm3, and a decrease in serum folate (2.8 ng/L). Liver and hemostasis tests and LDH and fibrinogen levels were normal. On the basis of the clinical data and paraclinical investigations, the diagnosis of methotrexate toxicity was established.

	Figure 1: (a and b) Acral erythema on the back and palms of the hands progressing to desquamation.
	Figure 2: (a and b) Cheilitis and nasal cavity erosions.
	Figure 3: Erythema of the external genitalia.

Methotrexate treatment was discontinued and the patient received four injections of calcium folinate (100 mg/injection), two injections of filgrastim (30 MUI), omeprazole 40 mg/d, and skin care based on neutral emollients and bicarbonate serum for mouthwash. On the third day, the patient developed septic shock related to febrile neutropenia and died.

DISCUSSION

Low-dose methotrexate (7.5 mg to 25 mg/week) utilized in dermatology is [1] more often than not well-endured. Methotrexate toxicity is rare if the dose is low and adherence to the suggested rules. Several idiosyncratic or dose-dependent toxicities have been noted including hepatotoxicity, pneumonitis, acute kidney failure, stomatitis [2], central nervous system involvement [1], gastrointestinal ulceration/erosion, and pancytopenia [1,2].

Toxic epidermal necrolysis (TEN), papular rash, vasculitis, psoriatic plaque erosions or ulcerations, keratinocytic dystrophy, erythema multiforme, drug hypersensitivity syndrome (DRESS), Stevens–Johnson syndrome, and photosensitive dermatitis accounted for the majority of methotrexate-induced skin reactions [1,3].

Skin erosions have been depicted as possible early signs of systemic methotrexate toxicity in patients with psoriasis [4–6]. Stomatitis has been reported to precede or accompany pancytopenia during methotrexate therapy [4]. Hematological toxicity has been reported even after a single low dose of methotrexate [7]. The skin and hematological toxicity, induced even with low doses of methotrexate, may be explained by the rapid cell turnover in these tissues [6], and therefore a particular cellular sensitivity to the cytocidal effects of methotrexate. The toxic effects of low-dose methotrexate appear to be characterized by dysplasia in rapidly renewing tissues, with cytomorphological abnormalities in bone marrow and keratinocyte dystrophy in the epidermis [8].

Acral erythema or palmoplantar erythrodysesthesia is a side impact of high-dose chemotherapy, which is clinically manifested by dysaesthesia and tingling of the palms and soles, followed by the development of symmetrical, well-defined, painful erythema, which may advance to bullae formation and desquamation [1,9]. Although the pathophysiology remains poorly understood, the foremost widely accepted theory is direct cytotoxicity by chemotherapeutic agents on epidermal cells [1].

With regard to the histological characteristics of methotrexate-induced skin lesions, little data is available [8]. The histopathological aspects reported in the literature include focal keratinocyte necrosis [10], incipient epidermal necrosis [11], and severe keratinocyte dystrophy with hypertrophied keratinocytes due to a direct toxic effect in the epidermis [8], similar to the epidermal dysmaturation reported in patients receiving cytotoxic drugs [12]. In our case, the histological study showed keratinocyte necrosis in the basal layers associated with spongiosis and exocytosis, in addition to a perivascular, perifollicular dermal inflammatory infiltrate and sometimes at the dermal-epidermal junction without fibrinoid necrosis of the vascular wall.

Several risk factors have been implicated in the development of methotrexate toxicity [1,5,13]:

Occasionally, methotrexate-induced skin toxicity may occur in the absence of any known risk factors [8,15], suggesting a role for folate-dependent enzyme polymorphisms. Methotrexate is a highly selective competitive inhibitor of the enzyme dihydrofolate reductase and, as a result, decreases the production of thymidylate and DNA. Four enzymes involved in purine synthesis have been implicated in the systemic toxicity of methotrexate in patients with rheumatic diseases, yet these findings have not yet been demonstrated in dermatological diseases [8].

In our patient, renal failure was the main risk factor for triggering methotrexate toxicity due to impaired urinary elimination, as well as a probable role for concomitant antibiotic administration and advanced age.

Management of methotrexate toxicity is based on [2,3]:

Methotrexate toxicity may be life-threatening, even at low doses, especially if associated with pancytopenia. For instance, Kivity et al. reported a 25% mortality rate in a series of 28 patients with low-dose methotrexate toxicity [13].

CONCLUSION

Methotrexate may cause significant cutaneous and visceral toxicity, even at low doses. Therapeutic management is based on early discontinuation of methotrexate and effective skin care.

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