A Case of Sézary Syndrome in a Patient Treated with Dupilumab for Atopic Dermatitis

Dear Editor, Dupilumab is an effective treatment for atopic dermatitis (AD) which is a human monoclonal immunoglobulin G (IgG) antibody that inhibits interleukin-4 and 13 signalling.[1] However, several unexpected phenomena have been reported with its use, especially cutaneous T-cell lymphomas (CTCL), including Sézary syndrome (SS) and mycosis fungoides (MF).[2] Here, we report a patient who developed SS during dupilumab treatment for AD. A 33-year-old man was diagnosed with AD in childhood. As his AD was not well controlled, he was started on dupilumab, which was effective for one year. Thereafter, he developed erythema and lymphadenopathy. The patient was diagnosed with exacerbation of AD and was switched to upadacitinib (15 mg/day). After two weeks, the patient developed fever (39°C), generalized erythema with severe itching, and lymphadenopathy [Figure 1a − f]. Then the patient was referred to our hospital. The results of the blood tests were as follows: white blood cell count 57,500/μL (lymphocytes 90.5%), soluble IL-2 receptor 8739 U/mL and human T-lymphocyte virus type I negative. Blood smear microscopy revealed abnormal lymphocytes with coarsely aggregated nuclear chromatin and an irregularly shaped nucleus [Figure 1g]. Computed tomography revealed enlarged lymph nodes throughout the body [Figure 1h, i]. Histopathological examination of the skin biopsy showed dense cellular infiltration primarily in the upper dermis [Figure 2a, b]. Pautrier's microabscesses were found in the epidermis. Immunohistochemical staining revealed predominantly CD3+, CD4+, CD5+ and CD20− lymphocytes [Figure 2c−f]. Therefore, the patient was diagnosed to have SS.Figure 1: Clinical appearance of the patient, Microscopic examination of blood smear, and CT findings. Generalized erythema and lymphadenopathy over the (a) face, (b) anterior aspect of upper body, (c) axilla, (d) periauricle, (e) back, and (f) lower extremities. (g) Most lymphocytes had an abnormal morphology with coarsely aggregated nuclear chromatin with irregularly shaped nucleus. Enlarged lymph nodes could be seen throughout the body, including in the (h) axillary and (i) inguinal regionsFigure 2: Histopathological examination and immunohistochemical staining. Pautrier's microabscesses were observed within the epidermis. Dense cell infiltration was seen in the upper dermis consists of medium-sized lymphocyte-like cells with an irregularly shaped nucleus (a, b). H-E × 40 (a), H-E × 100 (b) Immunohistochemical staining showed positively for CD3 (c), CD4 (d), and CD5 (e); however, CD20 (f) was negativeDupilumab is more effective than conventional treatments for moderate-to-severe AD. However, various unexpected phenomena resulting from dupilumab administration, especially CTCL (SS and MF), have been reported.[2] In total, 47 cases of cutaneous lymphoma (37 with MF and 7 with SS) have been reported after dupilumab administration [Table 1]. Guenova et al. reported that T-helper (Th1) cells were dominant in the initial stage of MF, whereas Th2 cells were predominant in the tumour stage.[3] Thus, the use of dupilumab at the 'patch stage' of MF may promote tumour progression. In contrast, it might lead to the recovery of Th1 responses at the tumour stage.[3] SS is also associated with Th2 response.[4] Both malignant Sézary cells and benign reactionary cells have a predominance of Th2-associated cytokines. Dupilumab reportedly reduces pruritus and improves lymph node and skin involvement in patients with SS.[5] Furthermore, dupilumab reduces Th2 bias in the blood and skin, which might lead to recovery in SS. However, it remains uncertain whether dupilumab unmasks CTCL or triggers conversion to CTCL via an immunomodulatory shift.Table 1: 47 cases of cutaneous lymphoma after dupilumab administrationUpadacitinib, an orally administered selective Janus kinase (JAK)-1 inhibitor, is a novel treatment for AD. JAK inhibitors have been determined to be effective for the treatment of peripheral T- and B-cell lymphoproliferative disorders in several clinical trials (ClinicalTrials.gov. https://www.clinicaltrials.gov/), which indicate that JAK inhibitors have therapeutic applications for CTCL. In conclusion, distinguishing between severe AD and early CTCL is difficult. We recommend that a skin biopsy and blood tests should be performed before initiating dupilumab or upadacitinib. Abbreviations IL = interleukin, Th2 = T-helper 2, AD = atopic dermatitis, CTCL = cutaneous T-cell lymphomas, MF = mycosis fungoides, SS = Sézary syndrome, JAK = Janus kinase, RA = rhewmatoid arthritis Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.