Drugs and nails

Ghetti E, Piraccini BM, Tosti A. Onycholysis and subungual haemorrhages secondary to systemic chemotherapy (paclitaxel). JEADV 2003; 17: 459–460. In this issue, Ghetti et al. report on the occurrence of onycholysis and subungual haemorrhages after paclitaxel therapy. This report adds to the ever-increasing list of cancer chemotherapeutic agents that are associated with certain nail abnormalities. Obviously, it is important for clinicians to recognize specific drug-induced side-effects. However, these reports may also provide us with molecular agents that can be used to analyse and dissect the homeostatic mechanisms that control the nail unit. Drug-induced nail abnormalities are characterized by the frequent involvement of all 20 nails, a temporal correlation with drug intake, and the usual disappearance upon cessation of the offending drug.1 Toenails may seem to be less affected, but this is probably due to the slower growth rates of these nails. Most commonly, the drug has a direct toxic effect on one of the components of the nail apparatus. Depending on which nail component(s) (nail matrix, bed, folds, plate (secondary to matrix involvement) or hyponychium) is affected, a variety of nail changes may be observed.2 For instance, drug toxicity to nail matrix keratinocytes may result in Beau's lines, onychomadesis, leuconychia, nail plate abnormalities such as brittle and thin nails, and decreased or increased nail growth rates. By contrast, drug toxicity to nail bed keratinocytes may result in onycholysis and pseudo-leuconychia. Nail abnormalities can also depend on the cell type that is affected. Many of the drug-induced nail pigmentation changes are the result of increased melanin production by nail matrix melanocytes. On occasion, the nail abnormalities are secondary to drug-induced toxicities outside the nail unit. For instance, splinter haemorrhages and subungual haematoma can be caused by vascular damage or impaired perfusion of the nail bed. Cancer chemotherapeutic agents often induce nail changes, and nail pigmentation is probably the most frequently observed nail abnormality.3 The mechanism of drug-induced hyperpigmentation is not fully understood, but this is most probably due to increased melanogenesis in matrix melanocytes. Different patterns of hyperpigmentation such as longitudinal bands, transverse bands and diffuse darkening have been described after the administration of many different cancer chemotherapeutic drugs. Beau's lines, transverse leuconychia and onychomedesis are the result of nail matrix toxicity, and can be seen after intensive or combined chemotherapy. Nail bed toxicity, as manifested in apparent leuconychia or onycholysis, may be seen in association with nail bed haemorrhage, which may be exacerbated by concurrent thrombocytopaenia. Acute paronychia has also been described after treatment with methotrexate.4 Taxanes, including paclitaxel (Taxol®) and docetaxel (Taxotere®), are chemotherapeutic agents that are used in the treatment of breast, ovarian and lung carcinomas. Their mechanisms of action are by stabilizing microtubule assembly and preventing microtubule depolymerization, which then results in mitotic arrest. Nail changes frequently occur after the administration of taxanes and they include pigmentary changes,5 nail bed discolouration,6 onycholysis,7, 9 subungual abscess,10 Beau's lines, subungual hyperkeratosis and nail bed purpura. These paclitaxel-induced nail abnormalities suggest that this drug not only is toxic to the nail matrix and nail bed keratinocytes but also may affect the vascularization of the nail unit structures. Exposure to sunlight might also precipitate taxane-induced nail changes.11 How paclitaxel can have such pleotropic effects on the different parts of the nail remains unknown. However, based on several case reports, including the report by Ghetti et al., it appears that the toxic effects of paclitaxel on the different nail components are independent of one another. For instance, nail bed disease as manifested by onycholysis can be observed in the absence of obvious nail matrix disease. This suggests that the observed onycholysis is the direct result of paclitaxel-induced toxicity on either nail bed keratinocytes or vasculature. The mechanism of how paclitaxel induces the observed nail abnormalities remains unclear. Obviously, inhibition of mitosis may interfere with nail matrix keratinocyte proliferation and result in nail plate abnormalities such as Beau's lines. However, the mechanism of onycholysis produced by paclitaxel remains obscure. It is noteworthy that many antimitotic agents such as 5-fluorouracil, etoposide, doxorubicin, leucovorin and mitoxantrone can induce onycholysis. The inhibition of nail bed keratinocyte proliferation by these drugs may be the common mechanism and the most likely cause of the induced nail onycholysis. Hence, adherence of the nail plate to the underlying nail bed is dependent on active proliferation and subsequent differentiation of the nail bed keratinocytes. Immunohistochemical studies using antibodies against proliferation markers, such as proliferating cell nuclear antigen (PCNA) and Ki-67, demonstrated labelling indices of 20% for the nail matrix but only 1% for the nail bed of healthy individuals.12 It is therefore surprising that antimitotic agents such as paclitaxel can induce marked onycholysis without accompanying nail matrix disease. Alternatively, it may be possible that paclitaxel-induced onycholysis is mediated by a mechanism other than its antimitotic effect. In this regard, UV radiation has been postulated to precipitate onycholysis in conjunction with paclitaxel administration. Finally, taxanes are toxic not only to the nail unit. Reversible but often complete alopecia is frequently observed after administration of taxanes. Hypersensitivity reactions,13 recall dermatitis,14 diffuse scleroderma-like illness,15 generalized pustular reaction16 and cutaneous necrosis have also been reported. In summary, taxanes are frequently used cancer chemotherapeutic agents that can affect the nail unit. Onycholysis and subungual haemorrhage are common nail abnormalities induced by taxanes, and patients should be informed of these distressing side-effects.