Methotrexate-Induced Acral Erythema with Bullous Reaction
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https://doi.org/10.5070/D33sh231vvMain Content
Methotrexate-Induced Acral Erythema with Bullous Reaction
Vida Feizy, MD1, Mohammad Reza Namazi, MD2, Behrooz Barikbin, MD1, Amirhoushang Ehsani, MD1
Dermatology Online Journal 9 (1): 14
From the Dermatology Departments of 1) Tehran and 2) Shiraz University of Medical Sciences, Iran. namazi_mr@yahoo.com Abstract
Chemotherapy-induced acral erythema (CIAE), a toxic reaction to a number of different chomotherapeutic agents, causes a symmetrical, painful erythema of both the palms and soles which is self-limiting. The association of this syndrome with methotrexate is unusual; only nine cases have been reported in the literature. We describe the tenth case of this syndrome associated with methotrexate, which is also the third case of the bullous variant of methotrexate-induced acral erythema. Our case is unusual in that the acral erythema was present only on the soles of the feet and in that it was associated with the presence of diffuse maculopapular lesions over the legs and trunk.
Case Report:
A 16-year-old male, a patient with acute lymphoblastic lymphoma-leukemia, was treated with intravenous methotrexate in an adult ALL protocol, at a dose of 1500 mg/m2 over six hours. Within 72 hours, a symmetrical, edematous, painful, red, violaceous erythema developed on the plantar surface of the both feet and the fleshy parts of the toes, relatively sparing the instep areas.
Over a 24-hour period, the plantar erythema became covered with large bullae, especially on the pressure points (Figure 1).
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| Figure 1 | Figure 2 |
|---|---|
| Figure 1. Methotrexate-induced erythema with bullae formation on plantar surface. | |
| Figure 2. Eruption of red, violaceous, small macules and papules, some with necrotic center, affecting the trunk. | |
Simultaneously, diffuse, maculopapular lesions, which were purpuric and necrotic at some sites, developed on the trunk (Figure 2) and legs.
Buccal mucositis was also present.
Histologic examination of the skin showed subepidermal bullae with keratinocyte necrosis and lymphocytic perivasculitis. The patient improved spontaneously in 10 days.
Discussion
Chemotherapy-induced acral erythema (CIAE), or palmoplantar erythrodysesthesia syndrome, is a cutaneous drug reaction that is most often induced by cytarabine, fluorouracil, and doxorubicin.[1]
The reaction is dose dependent, and may appear with bolus short-term infusions or low-dose, long-term infusions.[2] It is reported almost exclusively in adults, appearing 1 to 21 days after the administration of chemotherapy as a painful, edematous, symmetrical erythema on the palms of the hands and the soles of the feet. After several days, the erythema becomes violaceous and is most often associated with sloughing at pressure points.[2] The desquamation is often the most prominent part of the syndrome.
This syndrome is toxic rather than allergic and is responsive to dose reduction although not to folinic acid.[3] The large number of sweat glands on the palms and soles that may concentrate the chemotherapeutic agents may explain the localization of the toxicity.[4]
The histopathology is nonspecific, with necrotic keratinocytes and vacuolar changes along the basal cell layer.[5]
CIAE and acute graft vs. host disease (GVHD) can often be difficult to distinguish in the early stages and can sometimes occur together; repeat skin biopsies can sometimes help but clinically CIAE is self-limiting whereas GVHD is usually a progressive reaction and is often associated with gastro-intestinal disturbance and liver dysfunction.[5,6]
The patient usually recovers without complications, although rarely full thickness ischemic necrosis occurs in the areas of blistering.[2] Most cases require only supportive care. Cold compresses and elevation are helpful, and cooling the hands during treatment may reduce the severity of the reaction.[2] The chemotherapeutic schedule need not necessarily be modified in selected patients who develop acral erythema following high-dose methotrexate infusion.[7]
The association of acral erythema with methotrexate is unusual; only nine cases have been reported in the literature.[1, 3, 7, 8, 9] Our observation is also uncommon because of the presence of acral erythema only on the soles of the feet, sparing the palms, and because of the concomitant presence of diffuse macular lesions over the legs and trunk.
To our knowledge, this is the third report of bullous acral erythema attributed to methotrexate alone. This clinical form of the disease has usually been described for regimens containing cytarabine.[10]
References
1. Hellier I, Bessis D, Sotto A, et al. High-dose methotrexate-induced bullous variant of acral erythema. Arch Dermatol 1996;132:590-5912. Odom RB, James WD, Berger TG. Andrew's Diseases of the Skin. 9th edn. Philadelphia: W.B. Saunders Company. 2000:140.
3. Doyle L, Berg C, Mottino G, et al. Erythoma and desquamation after high-dose methotrexate. Ann Intern Med 1983;98:612-613.
4. Baack BR, Burgdrof WHC. Chemotherapy-induced acral erythema. J Am Acad Dermatol 1991;24:457-461.
5. Crider MK, Jansen J, Norins AL, et al. Chemotherapy-induced acral erythema in patients receiving bone marrow transplantation. Arch Dermatol 1986;122:1023-1027.
6. Azurdia RM, Clark RE, Friedmann PS. Chemotherapy-induced acral erythema (CIAE) with bullous reaction. Clin Exp Dermatol 1999;24:64-66.
7. Millot F, Auriol F, Brecheteau P, et al. Acral erythema in children receiving high-dose methotrexate. Pediatr Dermatol 1999;16[5]:398-400.
8. Ikeda H, Kawano H, Kitaura T, et al. Acral erythema associated with high-dose methotrexate infusion. Ann Pharmacother 1999;33(5):646. 9. Morrell DS, Challgren E, Eapen M, Esterly NB. Bullous acral erythema secondary to high-dose methotrexate. J Pediatr Hematol Oncol 2002;24(3):240.
10. Wahzer JF, Flowers FP. Bullous variant of chemotherapy-induced acral erythema. Arch Dermatol 1993;129:43-45.
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