Discussion
Low-dose MTX is a rare cause of cutaneous lesions in patients with RA, but a few cases have been reported. At times, cutaneous lesions seen with MTX toxicity can be mistaken for infections and treated with a variety of antibiotics before they are properly identified.1
Methotrexate is a folic acid analog that inhibits the synthesis of DNA, RNA and proteins by binding to dihydrofolate reductase.2 The adverse effects of MTX related to folate antagonism include anemia, neutropenia, stomatitis, oral ulcers and diarrhea due to ulceration/erosion of the gastrointestinal tract. These toxicities can be prevented or alleviated with folate supplementation of 1–5 mg per day. Adverse effects unrelated to folate antagonism include hepatotoxicity, renal insufficiency, pneumonitis, pulmonary fibrosis, fatigue and nodulosis.2
The main cause for the development of adverse effects in our patient was incorrect administration. The patient took 2.5 mg of MTX daily for seven days instead of taking her prescribed dose of six tablets weekly. She did report compliance with taking folic acid 1 mg daily, so that was not a contributing factor.
Upon admission, the patient’s MTX level was checked and was below the level of detection. Because MTX is retained in cells in polyglutamed form, serum blood levels are not good indicators of toxicity. Rescue measures should be undertaken based on clinical symptoms of MTX toxicity and not on the basis of blood levels of the drug.3
Risk factors for development of MTX-induced lesions include new initiation of MTX or reinstatement after hiatus, recent escalation of MTX dose, inappropriate self-medication, renal impairment, age older than 55, folate deficiency, low serum albumin and drug-drug interactions (e.g., NSAIDs, aspirin, trimethoprim/sulfamethoxazole, etc.).3
Of note, our patient was also taking omeprazole and aspirin, and aspirin has been found to decrease MTX clearance by 35%.4 Recent studies have shown the concomitant use of high-dose MTX and proton pump inhibitors may increase MTX levels in the blood and lead to adverse reactions. The findings have mainly been studied with high-dose MTX.5
The histological findings on biopsy were similar to what has been described in literature. The biopsy revealed focal dermal-epidermal separation with keratinocyte dysmaturation and apoptotic keratinocytes, which are due to MTX’s direct toxic anti-metabolite effect on the epidermis.6 The biopsy also revealed irregular acanthosis and perivascular lymphohistiocytic infiltrate, with rarer neutrophils and a few scattered eosinophils. These features can also appear in MTX drug toxicity.3 Although not mentioned in our patient’s biopsy, histology can also reveal a papillary dermis that is edematous with ectatic vessels.3
Upon admission, our patient received 5 mg of oral folinic acid and was started on 1 mg of intravenous folinic acid daily, and on day 2 she was started on 10 mg of oral folinic acid every eight hours for two days. Within three days, the patient’s symptoms had started to improve, and laboratory testing revealed improving pancytopenia. Her rashes continued to heal and resolved within three weeks. Early aggressive therapy with folinic acid likely played a large role in our patient’s quick response to treatment.