Conversely, factors providing negative regu- lation of melanogenesis include melatonin, interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-a and trans- forming growth factor (TGF)-b, interferon gamma (INF-g), glucocorticoids, triiodothyronine, and dopa- minergic and cholinergic agonists.21 It is interesting to consider here the potential influence of immunomodu- latory imide drug (IMiDs) analogues such as lenalido- mide, pomalidomide and thalidomide that have been utilized in recent years as anti-inflammatory and antic- ancer agents. These agents inhibit the cytokines TNF-a, IL-1b, IL-6, IL-12 and granulocyte-macrophage colony stimulating factor (GM-CSF). Such influences may explain the effect of IMIDs on FM, at least by remov- ing the inhibitory influences of IL-1, IL-6 and TNF-a.22 In addition, endocrine effects of thalidomide and its analogues on the hypophyseal-adrenal axis have been noted and could explain their action on hair pigmentation.23,24
Furthermore, although melanocytes of the hair follicles reach their peak proliferative capacity during the early and intermediate anagen phase, the loss of pigmentation in the hair shafts in grey hairs is not due to a complete loss of all follicular melanocytes. In fact, melanocytes have been found in the outer root
sheath of senile white hairs. Therefore, it is possible that lenalidomide is capable of stimulating migration and/or differentiation of melanocytes to promote repig- mentation of gray hair follicles.25 While we report the first case of hair repigmentation with lenalidominde, a reverse process of hair depigmentation has been observed with the tyrosine kinase inhibitor sunitinib. Reversible hair depigmentation observed with suniti- nib, which occurred along with the persistence of mel- anocytes associated with hair follicles, indicate that sunitinib did not affect the migration and survival of melanocytes.26 Another tyrosine kinase inhibitor, ima- tinib mesylate, was shown to induce skin depigmen- tation, but paradoxically caused skin27 and hair repigmentation.28
Our observation suggests that hair graying is not an irreversible process. Although there have been reports of hair pigmentation changes with certain classes of pharmaceuticals,26–28 this is the first report of hair repigmentation with lenalidomide. Of note, we found no reports of hair repigmentation with commonly used medications such as aspirin, dexamethasone or zoledro- nic acid. Metoprolol, levothyroxine and insulin have not been associated with reversal of graying in the exist- ing literature. Furthermore, the patient was not taking any herbal remedies of other over-the-counter medica- tions. The temporal sequence lenalidomide use-hair repigmentation supports the causal relationship between the two events. The hair pigmentation changes in our patient were progressive over the course of treat- ment. The mechanism of repigmentation with lenalido- mide remains unclear, and further observation is needed to gain insights into the pathogenesis of these hair changes. The application of this newly described side effect may prove useful in the reversal of aging process through promotion of gray hair repigmentation.