Appearance of lentigines in an atopic dermatitis patient treated with dupilumab

Dupilumab, a human monoclonal antibody that inhibits the IL-4 and IL-13 pathway, is indicated for the treatment of moderate-to-severe atopic dermatitis. Despite its established clinical benefits and good safety profile, recent real-life studies have revealed cutaneous adverse events, such as facial erythema, psoriasiform reactions, rosacea and alopecia that were not previously documented in clinical trials.1 In this context, we present a case of lentigines that occurred at sites of resolved atopic dermatitis in a patient treated with dupilumab. The patient is an 8-year-old girl with a medical history of asthma, multiple food allergies and atopic dermatitis that manifested at 3 months of age. Despite treatment with topical corticosteroids and topical tacrolimus, her atopic dermatitis remained severe and refractory until she started treatment with dupilumab (300 mg every 4 weeks) in February 2021. The therapy led to a rapid and complete remission of her condition. However, after 6 months of treatment, multiple lentigines appeared at sites of resolved atopic dermatitis on her wrists, hands and knees (see Figures 1 and 2). The lesions are small hyperpigmented macules, they are fixed and persistent without improvement while continuing on dupilumab. In light of the characteristic clinic appearance, we did not perform a skin biopsy. The appearance of lentigines on sites previously affected by inflammatory dermatoses has been mostly described in psoriasis. These lentigines have been reported in resolved psoriatic lesions after various treatments, including topical treatment, phototherapy, apremilast and biologic.2 Although the development of lentigines at sites of resolved atopic dermatitis has been reported after treatment with topical corticosteroids and topical tacrolimus, it remains a rare phenomenon.3 The pathophysiology involved in the occurrence of lentigines is not yet well understood. However, some data have demonstrated the link between inflammatory pathway and melanogenesis. Thus, IL-4, a key cytokine involved in atopic dermatitis, exerts a direct inhibitory effect on melanogenesis via the JAK2-STAT6 pathway.4 The inhibition of this pathway with dupilumab could potentially lead to an unregulated upregulation of melanogenesis, consequently resulting in the formation of cutaneous lentigines. Furthermore, the emergence of lentigines, as opposed to diffuse skin hyperpigmentation, may be attributed to the presence of fibroblasts within the dermis. Indeed, some authors have demonstrated that the combination of reconstructed epidermis model with fibroblasts exposed to ultraviolet rays results in the formation of lentigines, rather than diffuse hyperpigmentation.5 Moreover, immunosuppressive therapies are known to augment melanocytic activity, and the relative immunosuppression caused by dupilumab could be associated with the emergence of lentigines.6 This hypothesis could also explain the occurrence of lentigines irrespective of the treatment used to manage skin inflammation (topical corticosteroids, mycophenolate mofetil, biologics etc.), as observed in psoriasis.3 Interestingly, while the pathway and its inhibition under treatment remains the same, only a minority of patients develop lentigines under treatment. Thus strongly suggests allelic variations that might predisposed to develop lentigines. These lentigines usually persist for many years and can sometimes induce an esthetical prejudice for the patients. However, it is important to explain to the patient that they are not associated with an increased risk of skin cancer. If needed, as other lentigines, they can be effectively treated with pigmentary lasers.7 It is crucial to acknowledge this rare and benign adverse event, in order to reassure the patients and to prevent the unnecessary discontinuation of an effective treatment. No conflict of interest. The patient's parents/guardians in this manuscript have given written informed consent to the publication of their case details. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.