Impaired Skin Barrier Function and Downregulated Expression of Caspase-14 in Moderate to Severe Chronic Hand Eczema.

AIM: To investigate whether the skin barrier function is impaired with regard to the pH value, water content, transepidermal water loss (TEWL), and the integrity of the stratum corneum, and whether the expression of caspase-14 is altered in moderate to severe chronic hand eczema (CHE). METHODS: Thirty patients with moderate to severe CHE treated at our institute and 30 healthy volunteers were included in this study. The pH value, water content, TEWL, and the integrity of the stratum corneum were measured in all subjects. RESULTS: Significantly increased pH value, decreased water content, elevated TEWL, and impaired integrity of the stratum corneum were observed in the lesional skin of CHE patients compared with the nonlesional skin of CHE patients and the normal skin of healthy volunteers. The expression of caspase-14 decreased in the lesional and nonlesional skin of CHE patients compared with the normal skin of healthy volunteers, especially prominent in the nonlesional skin. The mean optical density (OD) value of immunohistochemical staining for caspase-14 was significantly lower in the nonlesional skin than in the lesional skin and normal skin (p < 0.01 for both). Although the mean OD value was lower in the lesional skin than in the normal skin, the difference was not statistically significant (p > 0.05). CONCLUSION: Skin barrier dysfunction indeed occurs in CHE patients, which may be related to mechanisms associated with a downregulated expression of caspase-14.

Can inhibiting dihydropyrimidine dehydrogenase limit hand-foot syndrome caused by fluoropyrimidines?

Hand-foot syndrome (HFS) is a cutaneous adverse event that occurs in some patients treated with fluoropyrimidines. Although it is not life threatening, HFS can severely disrupt the daily lives of patients. HFS appears more frequently with 5-fluorouracil (5-FU) delivered by continuous infusion or with the 5-FU oral derivative capecitabine than with bolus 5-FU therapy. HFS is a leading cause of treatment interruption, dosage reduction, or, even, therapy discontinuation for patients on a capecitabine regimen. Interestingly, addition of a dihydropyrimidine dehydrogenase (DPD) inhibitor, such as uracil, 5-chloro-2,4-dihydroxypyridine, or eniluracil, to the fluoropyrimidine treatment regimen significantly diminishes the incidence of HFS. DPD inhibitors were initially combined with fluoropyrimidines to increase the efficacy of the drugs by impairing the DPD-mediated catabolism of 5-FU. However, with the accumulating findings from clinical trials that show the benefits of DPD inhibition on decreasing the risk of HFS, consideration should be given to changing the recommendations for the treatment of cancer patients with fluoropyrimidines to include DPD inhibitor components as standard therapy.

Hand-foot syndrome variant in a dihydropyrimidine dehydrogenase-deficient patient treated with capecitabine.

We present a case with dihydropyrimidine dehydrogenase (DPD) deficiency that manifested a variant of hand-foot syndrome (HFS). A 52-year-old man received capecitabine for adjuvant treatment of rectal cancer. On the ninth day of the first cycle, he presented to the clinic with a rash on the dorsum of both hands accompanied by symptoms of pain, erythema, swelling, and desquamation consistent with grade 3 HFS. The palms of his hands and soles of his feet were only tender with no apparent rash or discoloration. Dihydropyrimidine dehydrogenase activity was evaluated by radio assay using peripheral blood mononuclear cells. Dihydropyrimidine dehydrogenase activity was below normal: 0.12 nmol/minute/mg protein. Capecitabine was not resumed, and the rash resolved in 3 weeks with the use of pyridoxine and Udderly Smooth balm. Interestingly, HFS is rarely seen with 5-fluorouracil regimens containing selective DPD-inhibitors. This patient with DPD deficiency manifested a variant of HFS. The pharmacologic basis for the development of HFS in DPD-deficient patients warrants further investigation. Dihydropyrimidine dehydrogenase deficiency, if undiagnosed, can lead to death. In addition to severe to life-threatening toxicities akin to 5-fluorouracil, capecitabine can lead to unusual variants of common toxicities, including HFS, in DPD-deficient patients.

Decreased lymphocyte aryl hydrocarbon hydroxylase and glutathione S-transferase activities in patients with hand dermatitis.

Aryl hydrocarbon hydroxylase (AHH) and glutathione S-transferase (GST) (EC 2.5.1.18) activity were measured in human lymphocytes of peripheral blood from 8 patients with irritant or allergic contact dermatitis of the hands, and compared with data from a control group. Both AHH and GST activity was found to be significantly depressed in the allergic and irritant contact dermatitis subjects, as compared with controls. It is suggested that AHH may be a quantitative marker of the inflammatory status.