* Correspondence to:
Ryosei Nishimura, MD, PhD. Department of Pediatrics, School of Medicine,
Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa
University
13-1 Takara-machi, Kanazawa, Ishikawa 920-8641, Japan
Tel: +81-76-265-2314; Fax: +81-76-262-1866; E-mail: ryosein@me.com
Text word count: 500 words
A short running title: Methotrexate-induced acral erythema in
pediatric cases
Keywords: Acral erythema, hand-foot syndrome, palmar-plantar
erythrodysesthesia, methotrexate, chemotherapy side effects (3-6 words)
Table: 1
Supplemental figure: 1
TEXT:
Chemotherapy-induced acral skin reaction with sensory disorder has
become widely known as acral erythema or hand-foot skin reaction. The
incidence of acral skin reactions has increased with usage of kinase
inhibitors in addition to conventional chemotherapeutic agents,
especially in adult patients. In contrast, only a few dozen pediatric
cases of acral skin reaction have been reported, although pediatric
patients have increased the chance to receive kinase inhibitor
treatment. Here, we report high-dose methotrexate-induced acral erythema
in two pediatric patients with acute lymphoblastic leukemia (ALL).
Case 1 was a 6-year-old boy treated with oral 6-mercaptopurine once a
day for 8 weeks and 24-h infusion of high-dose methotrexate (2
g/m2) once every 2 weeks for four infusions. Three
days after the first methotrexate infusion, painful erythema and bullae
appeared in his left heel (Supplemental Figure 1) and he had disabled
walking with spontaneous recovery. Although we prevented acral erythema
with topical corticosteroid during and after the second methotrexate
infusion, more serious lesions emerged after the third and fourth
infusions. Therefore, systemic corticosteroid was needed to completely
recover these lesions.
Case 2 was a 12-year-old boy treated with the same chemotherapy regimen
as case 1 except for the methotrexate dose being 5
g/m2. Erythema only with slight pain appeared in his
bilateral heels (Supplemental Figure 1) after every methotrexate
infusion. However, the lesions did not disturb his activity and systemic
corticosteroid therapy was not required. Methotrexate clearance was not
delayed in both cases.
The etiology of acral erythema remains unclear. Histopathologic features
are nonspecific with findings of vacuolar degeneration of the basal
layer, necrosis of keratinocytes, loss of epithelial polarity, and
perivascular infiltration. Though acral erythema in much less common in
children than in adults, methotrexate has been reported as the prominent
causative agent of acral erythema in children. We summarized all 17
reported cases of methotrexate-induced acral erythema thus
far,2-13 including our two cases (Table).
Overall, pediatric methotrexate-induced acral erythema developed 1–3
days after administration and resolved within 1–3 weeks. Almost all
cases received high-dose methotrexate. Some physicians speculate that
methotrexate clearance delay and renal impairment caused by high-dose
methotrexate might be risk factors for acral erythema; however, in
reports with data description,2-6,9,10,13 9 of 12
pediatric patients did not show delayed methotrexate clearance and 8 of
9 pediatric patients did not show renal impairment. Interestingly, ALL
cases with methotrexate-induced acral erythema were older than the
susceptible age for ALL, most often in children aged 2–3 years. We
speculate that older children may have a higher risk of
methotrexate-induced acral erythema.
Although some cases spontaneously recovered, several therapies including
moisturizer,1,7,9 topical corticosteroid
therapy,10 systemic corticosteroid
therapy,4,13 and intravenous
immunoglobulin7 have been reported. Among them,
systemic corticosteroid therapy seems to be the most useful treatment,
similar to adult cases when the erythema developed.14Almost all cases were able to continue to receive high-dose methotrexate
therapy repeatedly, even though the dose of methotrexate was reduced in
some cases due to acral erythema-related severe pain, probably
contributing to maintain excellent cancer prognosis.