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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