Introduction

Methotrexate (MTX) is an effective but potentially toxic antimetabolite anticancer drug which has been in use since 1960s (1,2). Low-dose MTX therapy used in psoriasis rarely causes toxicity (3). A 67-year-old female patient, who had chronic plaque-type psoriasis for 15 years and has been used MTX 15 mg/sc/week for eight years, presented with ulcerations of psoriatic plaques on the chest and back, oral ulcers and pancytopenia. The diagnosis of low-dose MTX-induced toxicity was established.

Case

A 67-year-old female patient with a 15-year history of psoriasis was admitted to our hospital with a one week history of painful ulcers on psoriatic plaques and oral ulcers. It was learned from the patient’s history that she had been using 15 mg MTX injection weekly for eight years without any side effects. She reported non-adherence to medication occasionally. She had been taking drugs for hypertension and diabetes for the past 25 years. Other home medications included a proton pump inhibitor (PPI) (lansoprazole) and non-steroidal anti-inflammatory drugs (NSAIDs). Physical examination revealed confluent, shallow ulcerations covered by yellow fibrin or brown slough along the intermamarial area and buttocks on the declining psoriatic plaques (Figure 1). During the oral examination, ulcers and erosions, some of them covered with white membrane, on the buccal mucosa and tongue were noted (Figure 2).

A skin biopsy revealed changes consistent with MTX toxicity, including diffuse epidermal necrosis, acanthotic and spongiotic epidermis with overlying parakeratosis and scattered dyskeratotic keratinocytes. A mild superficial and perivascular lymphocytic infiltrate with rare eosinophils was detected within the dermis, underlying the ulcer. Fibroblast proliferation extended all the way into the subcutaneous septae (Figure 3). No evidence of infectious process or vasculitis was seen. Periodic acid-schiff was negative for fungi.

Laboratory studies revealed pancytopenia with a white blood cell count of 2.31 K/µL, platelet count of 33 K/µL, hemoglobin of 9.5 g/dL, hematocrit value of 28.3%, and absolute neutrophil count of 1.6 K/µL. Her creatinine and liver enzymes slightly elevated while serum albumine was low. MTX blood level was 0.04 μmol/L. Urinary tract infection was detected. Laboratory testing results are shown in Table 1. The patient was started on intravenous fluids and daily oral folic acid, and MTX was held. Her renal function returned to baseline after receiving fluids and her skin began to re-epithelialize. Blood counts began to normalize on day 7. Treatment was supportive.

Discussion

MTX is an antifolate agent used as a mainstay of treatment for psoriasis and rheumatoid arthritis because of its efficacy and long track record of safety (4). The most common minor adverse events associated with low-dose MTX use are stomatitis, headaches, nausea, fatigue, and anorexia (5,6). While hepatotoxicity has historically been the most feared side effect, pancytopenia is now emphasized as the most serious adverse event. It has been observed in approximately 1.5% of patients taking low-dose MTX (4,6,7). Psoriatic plaque erosion is a rare cutaneous manifestation of low-dose MTX toxicity with unknown prevalence and has been hypothesized that a painful erosion of psoriatic plaque is an early cutaneous sign of pancytopenia (8).

The most common risk factors for psoriatic plaque erosion are being the initiation or reinstatement of MTX after a drug hiatus, an increase in the MTX dose, renal impairment, and the use of NSAIDs or aspirin. Age >55, folate deficiency, low serum albumin level, and drug-drug interactions are also common risk factors (Table 2) (5,7,8).

Drug-drug interactions are key contributors to toxicity (Table 2). NSAIDs (drug retention), aspirin sulfonamides, penicillin, and colchicines (decreases MTX clearance), barbiturates, nitrofurantoin (impair folate absorption), trimethoprim-sulfamethoxazole, triamterene, pyrimethamine, ethanol (inhibit the enzyme dihydrofolate reductase) phenytoin, probenecid, salicylates, sulfonamides, tetracycline, chloramphenicol, sulfonylureas (displace MTX from albumin), PPIs (the renal excretion of MTX) are the main accused drugs (4,5,7,9).

In conclusion, we describe a patient with a rare presentation of low-dose MTX toxicity. Our patient’s risk factors for MTX toxicity were age, low serum albumine level, urinary tract infection, irregular use of MTX, renal impairment, and PPIs and NSAIDs usage. Particularly in elderly patients, risk factors for MTX intoxicity, especially drugs should be evaluated thoroughly. As it was in our case, PPIs and/or NSAIDs usage is a risk factor for MTX toxicity that we can easily overlook.

Ethics

Informed Consent: Consent form was filled out by all participants.

Peer-review: Externally and Internally peer-reviewed.

Authorship Contributions

Concept: Filiz Topaloğlu Demir. Design: Filiz Topaloğlu Demir. Data Collection or Processing: Yavuz Tezcan, Şerife Başaran. Analysis or Interpretation: Filiz Topaloğlu Demir. Literature Search: Zafer Türkoğlu. Writing: Filiz Topaloğlu Demir.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.