Rescue therapy in methotrexate toxicity: case report

INTRODUCTION

Methotrexate (MTX) is widely used in psoriatic patients. However, reports of MTX intoxication are uncommon.¹ The majority of cases involve individuals with accidental overdosage as a result of complicated weekly oral regimen being misunderstood.² The objectives of present study are to identify early features of MTX toxicity [MTX induced epidermal necrolysis (MEN)], to establish early diagnosis and prompt treatment to prevent further worsening and to discuss diagnostic modalities in MEN.

CASE REPORT

A 51-year-old male patient, known case of psoriasis presented with chief complaints of peeling of skin since 15 days and raw areas in the mouth since 5 days. Lesions were associated with itching and were insidious in onset. Patient had history of application of native medication, history of drug intake prior to worsening of lesions and history of peeling of skin in the past. Patient reported self-medication with tablet MTX 5 mg for 10 consecutive days following which lesions got aggravated.

On cutaneous examination, multiple erythematous tender plaques were observed over the scalp, trunk, bilateral upper and lower limbs; multiple erosions were present on the buccal mucosae (Figure 1), lower lip, hard palate; PASI was 20.8 and BSA was 28%. Patient was a known case of psoriasis since 15 years and was started on topical steroid clobetasol ointment. He had history of admission for exacerbation of psoriasis 12 years back and was started on MTX 5 mg 1-0-1 once a week (2 tablets once a week) since then. But he reported non-compliance with medication. On general examination, bilateral pedal edema was detected. Skin biopsy revealed hyperkeratosis, focal mild acanthosis and plasma crusting with trapped neutrophilic debris (Figure 2). Epithelial cells exhibit dysmaturation with mild pleomorphism and occasional civette bodies. Also seen is mild spongiosis and basal cell vacuolar degeneration (Figure 3). Upper dermis shows vascular proliferation and mixed inflammatory infiltrate with eosinophils (Figure 3). Diagnosis of psoriasis with MTX induced epidermal necrolysis was established.

Investigations revealed leucopenia (3940 cells/mm³). In view of absolute neutrophil count <1500/mm³, two doses of injection Filgrastim 300μg was given subcutaneously 1 day apart. On follow up, lesions subsided (Figure 4) and repeat counts were within normal limits (Table 1).

On discharge, patient was started on T. apremilast starter pack (for 1 week) along with topical agents for psoriasis. After the starter pack, patient was started on T. apremilast 30 mg 1-0-1. Patient was advised against self-medication and counselled regarding the consequences.

DISCUSSION

Unintentional overdose of pills is the most frequent cause of acute methotrexate toxicity.³ The most frequent reason for overdosing was listed as the long-term psoriasis treatment through self-medication.⁴ Long-term usage of MTX has produced positive results with a high level of safety if used properly as well as under strict supervision.⁵

In our case, mucocutaneous lesions served as the warning sign for early detection of drug toxicity. Laboratory investigations revealed leucopenia and on skin biopsy, diagnosis of psoriasis with MTX induced epidermal necrolysis was established. Skin biopsy in our case served as a vital diagnostic modality for the diagnosis of MTX toxicity.

Our case was treated with injection filgrastim 300 μg S/C on day 4 and 5 in view of leucopenia. Hematologic profile showed improvement from day 1 to day 6 (Table 1). Other treatment modalities in acute MTX toxicity include folinic acid (leucovorin) and glucarpidase. Folinic acid rescue regimen replenishes intracellular stores of reduced folate and attenuates the MTX toxicity.⁶ Glucarpidase enzyme works by rapidly metabolizing circulating (not intracellular) MTX to two inactive metabolites: Glutamate and 2,4-diamino-N-10-methylpteroic acid (DAMPA).⁷ Patient was started on T. apremilast on discharge. Due to its immunomodulatory properties, apremilast partially inhibits the expression of proinflammatory cytokines thereby promoting the production of anti-inflammatory cytokines that play a pathogenic role in psoriasis.⁸

In our case, self-medication was the cause for overdosage of the drug. This highlights the importance of advising on illness chronicity, particular dose and the effects of overdosing.

CONCLUSION

MTX toxicity, though rare, if addressed on time, can prevent further complications like multi organ failure and mortality. In our case, muco-cutaneous lesions served as a warning sign for early detection of drug toxicity which was further confirmed by skin biopsy and the presence of leucopenia and hence can be considered as vital diagnostic modalities for the diagnosis of MTX toxicity. Our case was treated with T. apremilast after discharge. On follow up, lesions subsided and repeat counts were within normal limits. Hence, we conclude that early diagnosis and prompt treatment prevented further complications in our case and helped in reverting the condition of the patient. Also, patients should be explained about the selected treatment regime and discouraged from self-medicating. Side effects should also be explained.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

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