Dermatology Online Journal

Acute methotrexate toxicity seen as plaque psoriasis ulceration and necrosis: A diagnostic clue
Julie L Fridlington MD¹, Julia W Tripple MD², Jason S Reichenberg MD³, Clifton S Hall MD³, Dayna G Diven MD³
Dermatology Online Journal 17 (11): 2

1. Westlake Dermatology, Austin, Texas
2. The University of Alabama at Birmingham, Birmingham, Alabama
3. The University of Texas Southwestern, Austin, Texas

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Abstract

In addition to the well-known signs of methotrexate toxicity, rare cutaneous side effects have been described. These cutaneous signs may provide a diagnostic clue into the diagnosis of toxicity as well as facilitate early and aggressive therapy. We describe the case of a 37-year-old male, with a diagnosis of psoriasis, who developed characteristic signs and symptoms of acute methotrexate toxicity after receiving an unknown amount of intravenous methotrexate. The patient experienced a distinct change in the morphology of his existing psoriatic plaques, which became ulcerated and necrotic in the week following the methotrexate injection. Shortly after the development of cutaneous erosions, the patient developed pancytopenia, which ultimately led to his death. Ulceration and necrosis of cutaneous psoriasis plaques may serve as a herald for the impending development of life-threatening pancytopenia in patients with acute methotrexate toxicity.

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Case report

A 37-year-old Peruvian male with an 8-year history of psoriasis, poorly controlled with topical therapy, was admitted to our hospital from the emergency department for suspected Stevens-Johnson Syndrome. A dermatology consult was requested to assist in the diagnosis and management. The patient complained of gradual worsening of his psoriasis in the months leading up to admission. The patient admitted that 2 months prior to admission he self-administered an unknown amount of methotrexate mailed to him by his brother, a physician in Peru. The dosage of methotrexate was tolerated without any side effects and with mild improvement in his psoriasis plaques. Seven days prior to admission, he self-administered a second dose of methotrexate, again sent by his brother in Peru.

Three days after the second dose of methotrexate, the patient noticed increased erythema and tenderness of the existing psoriasis plaques, back pain, facial swelling, and oral erosions. He experienced gradual worsening of his symptoms with odynophagia and dysphagia and noted a new pustular eruption to his chest and face. The patient denied a history of herpes simplex, diarrhea, dysuria, hematuria, or use of other concomitant therapy, specifically oral antibiotics or non-steroidal anti-inflammatory drugs.

Figure 1	Figure 2
Figure 1. Erosions of the tongue and lips with crusting and fissuring. Figure 2. Scattered pustules on the chest over a background of erythema.

Physical exam revealed an alert male in moderate distress and discomfort with diffuse edema of his face, most pronounced in the perioral and periorbital areas. Crusting and fissuring of the lips and erosions to the hard and soft palates, tongue, and buccal mucosa were noted. Palmar erythema was also present. A diffuse pustular eruption with crusting was evident on the nasolabial folds, cheeks, chest, back, and neck. A mixture of brightly erythematous, guttate and plaque-type psoriatic plaques were noted on 15 percent of the body surface area including his trunk, arms, and lower extremities (Figures 1 and 2). There was no evidence of conjunctival or genital involvement and no evidence of vesicles or bullae. Nikolsky sign was negative.

Baseline laboratory testing revealed a complete blood count with white blood cell 5.1 /CMM (4-10 /CMM), granuloctyes 76 percent (40.0-73.0%), eosinophils 2.8 percent (0.0-6.0%), hemoglobin 14.8 G/DL (13.5-17.0 G/DL), and platelets 157 /CMM (150-400 /CMM). Baseline chemistry revealed an elevated creatinine of 2.7 mg/dl (0.7-1.70 mg/dl) and slightly elevated liver function tests with an alkaline phosphatase level of 73 u/l (34-122 u/l), alanine aminotransferase of 262 u/l (9-51 u/l), and aspartate aminotransferase of 136 u/l (13-40 u/l). Urinalysis was within normal limits.

Given these findings, our differential diagnosis initially included evolving drug hypersensitivity reaction, methotrexate toxicity, acute generalized eczematous pustulosis, and pustular psoriasis. Punch biopsy was performed on a pustule on the patient's chest.

Figure 3	Figure 4
Figure 3. Skin biopsy specimen from the chest (H&E, x100). There is a folliculocentric neutrophilic abscess in a background of interface dermatitis with epidermal acanthosis and lymphocytic exocytosis. There are dyskeratotic keratinocytes within the superficial and basal layers of the epidermis. Within the dermis, there is a lymphohistiocytic perivascular and interstitial inflammatory infiltrate with abundant eosinophils. Figure 4. Skin biopsy specimen from the chest (H&E, x400). High power-view shows eosinophilic spongiosis with basal vacuolar degeneration and numerous dyskeratotic keratinocytes.

Biopsy results revealed an interface reaction pattern with scattered necrotic keratinocytes and an intraepidermal pustule with associated neutrophils and eosinophils (Figures 3 and 4).

Figure 5	Figure 6
Figures 5 and 6. Necrosis and ulceration of psoriasis plaques on bilateral legs.

Upon follow up the next day, the patient had a distinct change in the morphology of his existing psoriasis plaques, all of which developed violaceous necrotic eschars. The patient also experienced shortness of breath requiring oxygen support via a nasal canula and worsening of his oral lesions, which prevented oral intake (Figures 5 and 6).

Follow up laboratory testing revealed a continued upward trend of his liver function tests, persistently elevated creatinine, and an alarming trend toward pancytopenia in his complete blood count with white blood cells 1.0 /CMM (4-10 /CMM), hemoglobin 12.6 G/DL (13.5-17.0 G/DL), and platelets 126 /CMM (150-400 /CMM).

Further questioning of the patient and his relatives revealed that the patient had indeed completed courses of antibiotics from a free community clinic in the weeks prior to hospital admission. The packages and labels were from Peru, but local Poison Control authorities were able to obtain information on the drugs. The patient had taken azithromycin and trimethoprim/sulfamethoxasole immediately prior to admission. The patient also admitted he had administered the methotrexate dose intravenously and was unsure how much methotrexate he actually took. It became clear that he may have injected much more than the 20 mg that was originally postulated.

Given this new information and findings of mucositis, neutropenia, acute hepatitis, and acute renal insufficiency, the patient was diagnosed with acute methotrexate toxicity two days after initial presentation to the hospital. Although the patient had received the methotrexate 9 days previously and his serum methotrexate level was less than 0.05 MCMOL/L, it was decided to treat him aggressively. He was immediately started on leucovorin (folinic acid) at 150 mg intravenously for 2 doses and then 50 mg every 6 hours with intravenous fluids and alkalinization of his urine with sodium bicarbonate.

The patient proceeded to develop pancytopenia, neutropenic fever, worsening renal failure, and diarrhea with episodic hypotension for which he received neupogen, fresh frozen plasma, and broad spectrum antimicrobial therapy. He required eventual transfer to the intensive care unit for intubation and pressor support. The patient expired 9 days after hospital admission, 15 days after the self-administered dose of intravenous methotrexate.

Discussion

Methotrexate, a folic acid antagonist that inhibits DNA and RNA synthesis by binding to the enzyme dihydrofolate reductase (DHFR), is widely used in the treatment of proliferative disorders ranging from neoplasms to psoriasis [1].

Methotrexate toxicity manifests itself in several forms including hepatotoxicity, pulmonary toxicity, acute renal failure, stomatitis, ulceration/erosion of the gastrointestinal tract, and pancytopenia [1, 2]. In addition to these manifestations, methotrexate can also cause more rare cutaneous side effects including burning sensation of the skin, sloughing over pressure points, severe mucositis, and Stevens-Johnson syndrome [3, 4, 5].

Since 1967, at least 17 reported cases of cutaneous erosions related to methotrexate toxicity have been reported; in most cases, some form of cutaneous pathology, most commonly psoriasis, existed prior to ulceration [6]. Two distinct clinical patterns of ulceration have been described. Type I ulceration is characterized as painful erosion of existing psoriatic plaques shortly after initiating methotrexate therapy. Type II ulceration occurs in skin not affected by psoriasis but affected by other pathology (i.e., stasis dermatitis), with variable relationship to the duration of methotrexate therapy [5]. Rarely, methotrexate ulceration has been described in the absence of underlying dermatitis [4].

It has been hypothesized that painful erosion of psoriatic plaques represents an early cutaneous sign of toxicity [5, 7]. Evidence supporting this theory comes from the histology of skin biopsies taken from the edge of erosions, which show hyperkeratosis, hypergranulosis, and epidermal hyperplasia as well as changes consistent with a direct toxic effect on the epidermis, such as swollen epidermal cells with decreased nuclear and cytoplasmic staining, vacuolated or dyskeratotic cells, and even epidermal necrolysis [5, 8]. It is thought that these hyperproliferative epidermal cells of psoriatic plaques take up more of the methotrexate than normal cells and are thus more susceptible to its toxic effects [4, 7].

Our patient's clinical course largely parallels that of other patients described in the literature. Mucositis and tenderness of plaques appeared between 3 and 7 days after exposure and maximal depression in leukocytes and platelets occurred approximately 1 week after administration [7, 9].

Interestingly, the patient's existing psoriasis plaques underwent a distinct change in morphology, all developing violaceous necrotic eschars prior to the onset of myelosuppression. This finding has rarely been reported and suggests that methotrexate toxicity can present initially as necrosis in existing psoriasis plaques, and may serve as an additional diagnostic clue of impending methotrexate toxicity.

Previous reports in the literature have described episodes of skin ulceration in patients who have recently started methotrexate or patients on chronic therapy who experience a dose escalation [5, 6, 7, 10]. Our patient gave a history of having only 1 other treatment with methotrexate two months prior to admission. He received his second dose 7 days before admission. Although, cutaneous ulceration has been seen at standard doses of methotrexate, in contrast to previous reports, our patient received a supratherapeutic dose of methotrexate prior to necrotic ulceration. Risk factors for cutaneous erosion include older age, concomitant usage of NSAIDS, and renal dysfunction [5, 10, 11].

Although our patient specifically denied concomitant use of trimethoprim/sulfamethoxazole, we later learned of its usage in the week prior to admission. Sulfonamides can cause significant and often deadly interactions with methotrexate. Sulfonamides interfere with the renal excretion of methotrexate and cause displacement of methotrexate from plasma proteins leading to increased serum levels. In addition, trimethoprim/sulfamethoxazole has an additive or synergistic toxicity with methotrexate [2]. Thus, the combination of the two drugs likely contributed to methotrexate toxicity in our patient.

Treatment of cutaneous erosions is mostly supportive because cutaneous erosions tend to heal quickly within 1 to 2 weeks of stopping or decreasing the dose of methotrexate [5, 7]. Evidence of significant myelosuppression should prompt immediate treatment with leucovorin, a functional folate co-enzyme that bypasses the inhibition of DHFR [1, 2]. Supportive treatment with intravenous hydration, urine alkalinization with sodium bicarbonate, and high dose leucovorin are effective in the management of acute toxicity [11]. Unfortunately, as occurred in our patient, if leucovorin is not administered within 24 hours of the methotrexate dose toxicity can be irreversible [12].

In conclusion, this case illustrates the importance of recognizing clinical signs of methotrexate toxicity and initiating therapy as soon as possible. It is crucial to point out that patients using methotrexate must avoid trimethoprim-sulfamethosoxazole. In our patient, the evidence for methotrexate toxicity included the characteristic finding of mucositis, but also a rare cutaneous reaction of psoriasis plaque necrosis and ulceration.

ACKNOWLEDGEMENT: Special thanks to Dr. Carlo Gavino with his help with the dermatopathology section of this paper.

References

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