On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.78 no.6 Rio de Janeiro Nov./Dec. 2003
Ulceration of psoriatic plaques - cutaneous adverse effects of high dose methotrexate in psoriasis: a report of three cases*
Deborah Skusa de Torre AtaídeI; Luciana Dorigo Kucharski EsmanhotoII; Karin Adriane HelmerIII; Ivette Renata Caron GuerraIV; Christine de Campos Graf GuimarãesIV; Sandra MoritzIV, V
in Clinical Medicine.
IISpecializing in Dermatology at the Dermatology Service, Hospital de Clínicas, UFPR.
IIIResident in Dermatology at the Dermatology Service, Hospital de Clínicas, UFPR.
IVSpecialist in Dermatology, Brazilian Society of Dermatology / AMB.
VDermatologist, Dermatology Service, Hospital de Clínicas, UFPR.
The authors report three cases of psoriatic patients who inadvertently increased Methotrexate doses and presented with ulceration of cutaneous psoriatic lesions. Adverse cutaneous effects of Methotrexate are rare. At times they may be dose related, while at others they are idiosyncratic, or related to drug metabolism or drug interactions.
Key-words: methotrexate/adverse effects; psoriasis.
Psoriasis is a chronic skin disease frequently found in Brazil. Most patients can be treated with topical medications, though there are severe forms, such as psoriatic plaques - severe, pustulous, arthropathic and erythrodermic-which require systemic medication, such as cytotoxic and immunosuppressor agents.
Methotrexate was the first systemic drug to be found effective in treating psoriasis. It was approved by the FDA in 1972.1 It is one of the most frequently used drugs due to its effectiveness, low cost and easy-to-use posology. A regular weekly dose of 7.5 to 25 mg reduces the risk of acute toxicity, but there exist factors of individual (idiosyncratic) susceptibility and medication-related interactions or associated diseases that may favor it.2 Despite the fact that hepatotoxicity and myelotoxicity are the main problems associated with this treatment, cutaneous toxicity with epidermal necrosis may even occur.3
Patient, 56-year-old Caucasian male was a psoriasis patient 27 years ago. He made use of 100 mg of methotrexate over a two-week period. The psoriasis developed ulceration with increasing pain and secondary infections of the psoriatic plaques (Figure 1). The hemogram showed 1,000 leukocytes, and the histological evaluation of the skin lesion biopsy showed psoriasis-like dermatitis ulcerated in the reepithelization (Figure 2).
Patient, 79-year-old Caucasian male presented with psoriasis 17 years ago. He had been using methotrexate for over five years. The medication was discontinued in September 1999 due to a right renal clear cell carcinoma. The patient was submitted to nephrectomy and remained with discreet kidney function damage. In spite of this, he resumed medication without any medical assistance, with a 107.5 mg dose in 30 days. The disorder progressed with oral ulcers, pain, ulceration, bleeding and secondary infection in the skin lesions (Figure 3). The hemogram showed pancytopenia with hemoglobin 12, VCM 103, 1,800 leucocytes and 6,000 platelets. A bone marrow biopsy was performed, which showed megakaryocytosis. Histopathology of the skin demonstrated an acute and chronic process that was also ulcerated and non-specific.
Patient, 67-year-old Caucasian male, with hypertension and diabetes, presented with erythrodermic psoriasis a year ago. He had been using 12.5 mg methotrexate per week when, seeking faster improvement, he made use of 75 mg in four days' time. The condition evolved into diffuse myalgia, palmar blisters (already tattered by the time of consultation), oral ulcerations (Figure 4) and ulcerations of the psoriatic plaques, which presented with intense pain and secondary infection (Figure 5). The hemogram revealed 23% hematocrit, 600 leucocytes and 11,000 platelets.
All three patients were hospitalized and received folic acid in a 5 mg daily dose and 3 g cefazolin daily. There was full improvement of the ulcers and psoriasis, as well as medullary suppression, within roughly 20 days' time.
Methotrexate is an antimetabolic agent. It is an analogue to folic acid which inhibits dihydrofolate reductase, i.e. a necessary enzyme for synthesizing nucleotides and aminoacids. As such, methotrexate reduces DNA synthesis, inhibits mitosis and the proliferation of rapid cell division, as is characteristic in the epidermis and bone marrow.2
The most common side effects are gastrointestinal and hepatic complications (10-62%), as well as anorexia, nauseas, diarrhea, vomiting and increase of transaminases. Hematologic abnormalities are the second most frequent alteration, occurring in a proportion varying from three to 25% of cases. Leucopenia is more common than anemia or thrombocytopenia. Macrocytosis without anemia is very common in typically used doses in dermatology. Other less frequent effects are cephalea and pulmonary symptoms.4 There are also reports of a teratogenic and abortive potential.5 Cutaneous effects are rare and include erythematous rashes, blisters, skin ulcerations and necrosis consistent with toxic epidermal necrolysis, scaling, exacerbation of photosensitivity reactions, purplish lesions by vasculitis, urticaria (hives), in addition to acute ulcerations of the psoriasis lesions.1,5-7
In the three cases reported in this paper, the antimetabolic effect of the drug was marked to the point of hiding the histological alterations that are otherwise typical of psoriasis. The psoriasis-form dermatitis was transformed into a cutaneous ulceration.
The erosion pattern of psoriatic plaques is a characteristic phenomenon of the cases of acute toxicity by methotrexate and combines with myelosuppression.5 The precise reason for which the ulceration is restricted to psoriatic plaques remains unknown. One hypothesis suggests that such a phenomenon would be due to the greater drug captation capacity by the hyperproliferating cells of the plaques.2 There is also evidence that hypoxia, which is generated by the pressure of clothing and by attrition present in the natural cutaneous folds, favors ulcerations.8 In most of the cases reported in the literature, these cases of erosion appear as the drug's initial manifestation of toxicity, which may provide a diagnostic value.2 Ulcerations of the oral mucosa are also early signs of toxicity by methotrexate, which indicates that the dose must be tapered.6
The elimination of methotrexate occurs primarily by renal excretion (80 to 90%), mainly by glomerular filtration. The clearance of methotrexate may be altered by any condition or medication that modifies renal function.4 The authors believe that this was the cause of toxicity as experienced by the second patient, who was elderly and nephrectomized, given that the methotrexate dose ingested was not that high, i.e. roughly 25 mg weekly. Despite the fact that the third patient did not show true renal insufficiency, he had diabetes and systemic arterial hypertension, i.e. diseases that harm renal function by impeding the metabolization of an overdose of medication, which is what had occurred.
Administering sulfatrimethoprim, which inhibits the same enzyme as methotrexate (dihydrofolate reductase), may also have addictive effects and must be avoided.1,4 There is evidence that the use of non-hormonal anti-inflammatories interferes with renal elimination of methotrexate.2 However, none of the patients made use of these drugs.
Based on the action mechanism and toxicity of methotrexate by means of the pholate depletion, studies have been conducted on the daily supplementation of pholate as well as on the administering of pholate acid after methotrexate, with ensuing reduction of side effects and without loss of effectiveness.4 In other studies, pholic acid or pholate acid was administered daily, namely on days when the methotrexate was not used. Side-effects, such as nausea and megaloblastic anemia, were diminished without reducing the treatment's effectiveness.1
The toxic effects of methotrexate may have been minimized with the prophylactic administering of pholic acid. In the cases reported the pholic acid was utilized therapeutically, with good results.
The treatment of psoriasis with low doses of methotrexate is relatively safe as long as the instructions are followed.9
Methotrexate is an excellent therapeutic option for treating psoriasis. Yet owing to its significant effectiveness, the ease with which it can be acquired, its low cost and easy-to-use posology, it has been subject to indiscriminate use. In the cases reported, the drug was used wrongly, which reinforces the need for the proper guidelines a physician may offer. The dermatologist must inform patients and their relatives, when treating the elderly, of the risks of inadequate posology, as well as the clinical manifestations of the drug's toxicity. The prophylactic administering of pholate must also be done to achieve greater safety in the use of the medication. The authors believe that methotrexate must be used with caution in elderly patients, given that they have a natural loss of renal function which may result in their becoming intoxicated by the drug.
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8. Procter PR. Methotrexate-induced skin necrosis in psoriasis. S Afr Méd J. 1987; 72 (12):888. [ Links ]
9. Van Dooren-Greebe RJ, Kuijpers ALA, Mulder J et al. Methotrexate revisited: effects of long-term treatment in psoriasis. Brit J Dermatol 1994;130:204-210. [ Links ]
Deborah Skusa de Torre Ataíde
Portão Curitiba PR 80330-310
Tel/Fax: (41) 362-7763
Received in November,
29th of 2001
Approved by the Consultive Council and accepted for publication in March, 17th of 2003
* Work done at Dermatology Service, Hospital de Clínicas, Universidade Federal do Paraná (UFPR).