A 55-year-old woman consulted in another hospital with a chief complaint of abdominal pain and skin lesions. After two days, she was transferred to our tertiary care center with a diagnosis of recurrent bouts of febrile pancytopenia, an acalculous cholecystitis, and a clinical suspicion of disseminated herpes zoster necessitating airborne precautions.

The patient had a personal history of Crohn’s disease treated with adalimumab and Methotrexate (MTX), the latter of which was a prescribed 15 mg weekly oral dose along with folic acid 15 mg. Six months earlier, she was hospitalized with a similar presentation (febrile pancytopenia with stomatitis). She was also known for a mixed anxiety-depressive disorder.

Upon her arrival to our center, the patient was transferred to the Intensive Care Unit (ICU) and rapidly intubated in the context of agitation and to facilitate central venous access for her transfusion needs. Upon examination, it was found that she had extensive stomatitis along with multiple skin ulcerations on her extremities (Figure 1).

Figure 1: Superficial ulcerated skin lesion (left lesion) on ankle.

Investigations revealed a pancytopenia. (hemoglobin 66 g/L, white blood cell count 1.6 × 10⁹/L and platelet 12 × 10⁹/L). She had an elevated C-reactive protein (180 mg/L). Her metabolic panel showed an alkaline phosphatase of 220 UI/L, ALT of 100 UI/L, AST of 80 UI/, albumin of 26 g/L, INR of 1.0 and creatinine of 50 umol/L. An extensive panel, including anti-nuclear antibody, rheumatoid factor, anti-neutrophil cytoplasmic antibodies, porphyrin urine screen, cryoglobulins, complements, viral hepatitis, HIV and syphilis serology, blood cultures and skin HSV/VZV PCR tests, were all negative. Her MTX and adalimumab had been stopped before her transfer to our hospital. The patient was put on piperacillin-tazobactam, intravenous acyclovir and had a percutaneous cholecystostomy tube inserted. She received blood and platelet transfusions. A skin biopsy was also performed. After a short ICU stay, the patient was transferred to the general ward for convalescence.

Upon questioning, the patient couldn’t tell us precisely her MTX intake and confirmed that she had been confused regarding the correct posology. With her consent, we got access to her MTX bottle. Her last refill dated from two weeks earlier, with a total of seventy-two pills prescribed (2.5 mg each). We concluded that there should have been sixty pills remaining with a respected posology of six pills weekly. However, there were only thirty pills remaining in the container, thus confirming a significant MTX overdose. We performed a serum MTX dosage two weeks after her last presumed intake which came negative. The patient didn’t receive leucovorin rescue therapy.

The pancytopenia corrected progressively with normalization of the blood count after two weeks. A skin biopsy demonstrated intraepidermal vesicles with keratinocytes that displayed ballooning degeneration and acantholysis. Some of the keratinocytes were multinucleated and contained pale ground-glass inclusions resembling a herpetic infection. We attributed her acute acalculous cholecystitis to MTX mucosal and digestive tract toxicity [1].

The patient was discharged after two weeks of hospitalization. She had a follow-up appointment with her gastroenterologist who discontinued her MTX. A psychiatric consultation revealed an unspecified cluster B personality disorder, and it was concluded that this condition had contributed to the incorrect pill intake. A bubble pack was prescribed for her other drugs and counseling was offered to the patient to reduce the risks of a subsequent intoxication.

MTX is an analog of folate and inhibits dihydrofolate reductase, and thus the synthesis of folic acid. Folic acid is essential for DNA synthesis. MTX is used in the treatment of oncological and nononcological diseases, such as rheumatoid arthritis, psoriasis and certain forms of leukemia, to name but a few. MTX can be associated with multiple potential adverse effects, most commonly involving the gastrointestinal tract. At higher doses, bone marrow suppression is seen [2]. Mucositis and skin erosions are caused by keratinocyte dystrophy and subsequent skin fragility [3]. Skin lesions due to acute MTX toxicity are still rare and can include ulcers, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and exfoliative dermatitis [4]. A retrospective case series study described common histologic skin features of five consecutive patients, which included focal necrosis of keratinocytes within the epidermis, severe keratinocyte dystrophy and multinucleate keratinocytes [5]. Our patient had mouth and skin ulcers that were finally attributed to MTX toxicity. Mouth lesions and two skin ulcers swabs were negative for HSV and VZV by PCR tests.

The recognition of a possible MTX intoxication took several days for multiple reasons. First, the relapsing character of her condition was not grasped immediately upon transfer. Secondly, the patient had been intubated on admission, which prevented us from obtaining a clear history. Finally, the patient had multiple confounding factors, including an acalculous cholecystitis and febrile neutropenia. It became clear that our patient had a misunderstanding of the correct posology of her medication. An Australian database identified twentytwo deaths linked to MTX intoxication, including seven cases in which erroneous daily dosing was documented.

Reasons for the errors included patient misunderstanding and incorrect packaging of dosette packs by pharmacists [6]. A 2004 publication of all MTX adverse-event reports submitted to the FDA between 1997-2001 reported 25 deaths related to medication errors. The most common types of errors involved confusion regarding the once-weekly dosage schedule (30%). Of those errors, 37% were attributable to the prescriber, 20% to the patient, 19% to dispensing, 17% to administration by a healthcare professional and 7% unspecified [7]. Too often, MTX intended for once-weekly administration is inadvertently taken daily [8]. The toxic effects of MTX are generally related to the duration of an exposure above a suprathreshold concentration rather than a single peak level [9].

For more than 30 years, folic acid has been a cornerstone approach to reduce MTX toxicity. On the other hand, folinic acid (leucovorin) is used as a MTX antidote in case of impaired excretion of the drug or overdoses.

In our case the serum MTX level was negative. That said, the drug’s half-life (three to ten hours) would have allowed its complete renal clearance in the two weeks’ interval since the last intake. At that time, there was no benefit of adding folinic acid, especially considering the clinical improvement of the patient.

This case illustrates the importance of recognizing potentially highly toxic medications in a patient’s drug chart. Surprisingly, despite the patient presenting a similar clinical spectrum six months prior, no one had initially suspected MTX intoxication as a potential culprit. This finding led to the interruption of the MTX treatment and to the prevention of further harm. Healthcare providers need to be informed about the potentially devastating consequences of a dosage error with MTX. Face-to-face counseling and supplemental written information should be provided, especially to vulnerable patients such as the elderly, patients with psychiatric conditions, and patients with chronic kidney diseases.

This research was supported in part by a grant from the Centre de formation médicale du Nouveau-Brunswick.