LAUSR

Dear Editor, Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma (CTCL). With progression of the disease, Th2 profile predominates, with production of interleukin (IL)-4, IL-5, IL-10, IL-13. Dupilumab is an antagonist of IL-4 receptor-alpha. It was approved by the United States Food and Drug Administration (US FDA) and Brazil’s National Health Surveillance Agency (ANVISA) for moderate-tosevere atopic dermatitis (AD). Two studies described progression of CTCL after treatment with dupilumab for misdiagnosis of AD or MFassociated pruritus. These patients presented with thickening of the plaques or development of erythroderma and typical CTCL findings on skin biopsies after dupilumab. A previously healthy 51-year-old woman with no past medical history of AD presented with one-year history of pruritic cutaneous lesions that started on the hands and progressed to the trunk, upper, and lower limbs. Biopsy showed spongiotic dermatitis, eosinophilia, and mild exocytosis of lymphocytes. Topical and systemic steroids completely healed the lesions, but they rapidly recurred after suspension of the drugs. An immunologist prescribed azathioprine 50 mg/day, for a presumed diagnosis of AD. Due to lack of response after 2 months, azathioprine was stopped, and dupilumab was started. After eight cycles, mild relief in pruritus was observed, but lesions worsened with spreading of plaques and appearance of tumors, and she was referred to our institution. She had multiple patches, plaques, and ulcerated tumors (Figure 1). Hypothesis of tumoral-stage MF was raised. Multiple skin biopsies on different lesions (including a tumor on the left arm) showed spongiotic and psoriasiform dermatitis, exocytosis of few lymphocytes, and dermal eosinophils. However, one sample demonstrated a dense lymphohistiocytic lichenoid dermal infiltrate with atypical CD4 + CD7-lymphocytes, and monoclonal T-cell proliferation was detected by polymerase chain reaction (PCR) (Figure 2). Flow cytometry of a cutaneous tumor showed 94% of T-cells, 82% of CD4, 12% of CD8 (CD4/CD8 = 6.9). HTLV-1/2 and HIV-1/2 antibodies and HIV-1 antigen tests were negative. Positron emission tomography showed no lymph node or visceral involvement. No lymphocytosis was observed before or after dupilumab treatment, flow cytometry and search for T-cell clonality by PCR in the blood showed no malignant cells. Diagnosis of tumoral-stage MF was made. Treatment was started with acitretin and PUVA, with partial response. Dupilumab is a human monoclonal antibody approved by US FDA and Brazil’s ANVISA for severe and refractory AD. It binds to the IL-4 receptor-alpha. IL-4 and IL-13 share the same receptor, and the signaling cascades are blocked by dupilumab. There are controversies in the role of these cytokines in malignant diseases. Therapies used in advanced-stage MF include biologic response modifiers, which increase antitumor cytotoxicity. Studies with immune checkpoint inhibitors for CTCL are promising, but few data exist on efficacy and safety. New biologic therapies may alter the immunologic milieu in different settings. CTCL are challenging disorders, and pathogeneses of these diseases are not fully understood. There are complex interactions between Th1, Th2, and Th17 cytokines, regulatory T-cells, and malignant T-cells, and the effect on these interactions is unknown. Different from other cases reported in the literature, this patient developed tumoral lesions after dupilumab, and definition of the diagnosis was difficult due to the intense inflammatory findings observed in multiple skin biopsies. These reports emphasize the need for careful specialized clinical examination. If clinical picture is suggestive of CTCL, but skin biopsies do not show characteristic features, repeated biopsies in different topographies and types of lesions are