Cutaneous ulceration as a sign of methotrexate toxicity

ARTICLE

Methotrexate (MTX), a folate analogue drug, inhibits the DNA synthesis [1] (antimitotic effect), the lymphocyte proliferation and the polymorphonuclear chemotaxis [2] (anti-inflammatory and antiarthritic effects). MTX was initially employed as an antineoplastic agent in the treatment of carcinomas, leukemias and lymphomas (high-dose treatment). Ten years later (1958), MTX was introduced in the treatment of psoriatic disease and twenty years later it was rediscovered as an effective antirheumatoid agent (low-dose methotrexate therapy). On the skin, the most relevant antimitotic action of MTX is exerted on the epidermis. Nevertheless, recent in vitro studies showed that MTX was 10-100 times more effective at inhibiting the proliferation of lymphoid cell lines than cultured keratinocytes [3].

MTX was initially used in dermatological patients to treat psoriasis. Currently, psoriasis remains the first indication for MTX in dermatology, but this drug is also an alternative treatment in several cutaneous diseases, including dermatomyositis, systemic lupus erythematosus, sarcoidosis, Wegener's granulomatosis and other vasculitis, Behçet disease, systemic sclerosis, bullous pemphigoid, etc.

Adverse drug effects of MTX may be classified as type A - dose dependent (MTX toxicity); type B - idiosyncratic (e.g. MTX pneumonitis); type C - resulting from long-term therapy but anticipated, based on overall drug exposure (e.g. MTX hepatotoxicity); and type D - delayed effects occurring even after discontinuation of the drug (e.g. MTX in first trimester of pregnancy, inducing teratogenesis) [4].

Adverse cutaneous reactions to MTX are usually dose-related and have been mainly reported in patients receiving extremely large doses of chemotherapy [5] (Table I).

Painful erosion of psoriatic plaques has often been reported as an early manifestation of MTX toxicity, but cutaneous ulceration as a sign of MTX toxicity in patients without psoriasis has only been previously described in one case [6]. We report a patient with rheumatoid arthritis and without psoriasis who developed cutaneous ulceration on the knuckles as a sign of chronic MTX toxicity.

Case report

A 39-year-old woman without personal or familiar history of psoriasis was diagnosed in 1990 with a demyelinating disease (non multiple sclerosis) and treated with baclofen. In May 1998, after a bone marrow biopsy, the patient was diagnosed as having bone marrow infiltration by a low degree non-Hodgkin lymphoma without peripheral lymphadenopaties nor peripheral blood involvement. No treatment was established.

In October 1998 the patient was admitted in the Rheumatology Department with seronegative arthritis and she was treated with methotrexate (7.5 mg weekly) and indomethacin (150 mg daily). Two months later non painful ulcerations appeared on her knuckles with slow spreading. A cutaneous biopsy revealed a nonspecific ulceration. Indomethacin treatment was stopped, topical mupirocine and local care were recommended, and the lesions healed in 6 months.

In September 1999, the methotrexate dosage was increased to 15 mg weekly. In December 1999 ulceration reappeared with the same characteristics and localization (Fig. 1). A new skin biopsy was performed showing similar features. Mycological and bacteriological cultures of the lesions were negative.

Laboratory investigations showed an erythrocyte sedimentation rate of 61/100 mm/h, white blood cell count 12.22 x 10³ cells/mm³ (85% neutrophils), hemoglobin 12.2 g/dL, mean corpuscular volume 86.3 µm³, platelet count 225 x 10³/mm³, serum folic acid and cyanocobalamin levels were normal. Liver and renal function tests were normal. An oligoclonal serum IgG was detected. Rheumatoid factor, antinuclear antibodies, and complement levels were within normal limits. Cryoglobulins and antiphospholipid antibodies were negative. X-rays of the hands were normal, with no bone erosions.

Methotrexate toxicity was suspected and the drug was withdrawn. Two months later, cutaneous ulcerations were resolved with local care (Fig. 2).

Discussion

To design a safe and effective treatment with MTX, the provider must have knowledge of the pharmacology and the drug interactions of this effective but potentially dangerous drug. Absorption of oral MTX shows considerable variability. The drug uses the intestinal folate-specific transport system, localized on the proximal intestine, and the average of bioavailability is 80% of the oral dosage. The peak of plasmatic concentration is obtained two hours after the oral administration and the average life-time is 8 to 10 hours. At low doses, MTX is only moderately bound to proteins, with a reported range from 11 to 57%. MTX is metabolized by enzymatic addition of glutamyl residues and intracellular accumulation of MTX polyglutamates may affect the drug efficacy and cause long-term toxicity. The duration of the drug exposure determines the fraction of MTX that is metabolized to polyglutamates (8-55%). Low drug concentration tends to reduce somewhat the rate of polyglutamation. More than 80% of the drug is eliminated unchanged via glomerular filtration and tubular secretion. A smaller part is excreted through the biliary tract. Elimination is prolonged by renal tubular reabsorption and enterohepatic recirculation [7].

Several factors may increase the MTX toxicity. The more relevant ones are summarized in Table II. Bone marrow suppression and oral and gastrointestinal ulceration are well-known signs of MTX toxicity [5]. The most frequent mucocutaneous reactions to MTX treatment are ulcerations of the oral mucosa, burning sensation of the skin, photosensitivity, acral erythema, erythema multiforme, urticaria and vasculitis.

Skin ulceration has rarely been reported as an adverse effect of MTX in patients with psoriasis. Pearce et al. [8] in 1996 revised 47 patients, who developed ulceration or erosion of psoriatic plaques while being treated with MTX. The most common risk factors in these patients were alteration in the MTX dosage, and concomitant use of non-steroidal anti-inflammatory drugs (NSAIDS). Other associations and possible contributing factors included renal failure, infection, and pustular flare of psoriasis. Older age may also be a risk factor for toxicity. Cutaneous lesions were the presenting sign of MTX toxicity in most cases.

Ben-Amitai et al. [6] reported a patient without psoriasis who developed cutaneous ulcerations as a sign of MTX toxicity. The dosage of MTX treatment was 5 mg/daily for three years. During the last year deep recurrent ulcerations, 1-2 cm in diameter with irregular borders, located on the dorsal aspect of the right arm and palm, the left ankle and the anterior aspect of the right leg appeared. Histopathological examination showed unspecific ulceration and the lesions healed in five weeks after MTX was withdrawn.

Zackheim et al. [9] observed cutaneous ulceration in 5 of 29 patients with erythrodermic cutaneous T cell lymphoma treated with weekly MTX (25 to 125 mg). Cutaneous erosion and ulceration secondary to MTX therapy are probably more frequent than is found in the literature, because the causal relation might be not established in many cases.

Ulceration is considered as a toxic adverse effect, which may occur with or without other evidence of MTX toxicity. It is classified as a type A dose-related adverse effect and implies that withdrawal of the drug is not necessary, decreasing the dosage of the drug and elimination of risk factors that may induce MTX toxicity usually being effective.

In our case, the first episode of ulceration was probably caused by concomitant treatment with MTX and NSAIDs, and the second episode by the increase of MTX dosage. Nevertheless, the appearance of lesions only on the knuckles suggests that a local factor similar to that involved in pressure ulcers might be implicated. In the case of Ben-Amitai et al. [6] the ulcerations were also located over a bone plain, where local factors like pressure may play a relevant role.

Differential diagnosis in our case included vasculitis secondary to rheumatoid arthritis or MTX treatment (not present in two skin biopsies), infectious ulceration (cultures of lesions were negative), pyoderma gangrenosum (excluded by the skin biopsy), cryoglobulinemia (cryoglobulins were negative), antiphospholipid antibody syndrome (antiphospholipid antibodies were negative), nodulosis secondary to methotrexate treatment (none visible in the performed biopsies), and scleroderma.

In summary, ulceration secondary to MTX treatment is an exclusion diagnosis; a temporal relation with initiation, increase of the dose or concomitant therapies must be considered. Our patient is to our knowledge the second reported case of ulceration related to methotrexate treatment in patients without psoriasis and we think that the pathogenic mechanism of these ulcerations may be multifactorial, including direct toxicity of the drug in addition to local factors.

REFERENCES

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