Did dupilumab unmask smoldering mycosis fungoides?

Abstract

We appreciate the article from Russomanno et al1Russomanno K. Carver DeKlotz C.M. Acceleration of cutaneous T-cell lymphoma following dupilumab administration.JAAD Case Rep. 2021; 8: 83-85https://doi.org/10.1016/j.jdcr.2020.12.010Abstract Full Text Full Text PDF PubMed Google Scholar on acceleration of cutaneous T-cell lymphoma (CTCL) after dupilumab administration that allows us to share our case and make an interesting observation regarding the evolution of CTCL after dupilumab therapy. Dupilumab, a monoclonal antibody targeting the interleukin 4 receptor α subunit, is now routinely prescribed for moderate-to-severe adult-onset eczema.2Silverberg J.I. Boguniewicz M. Hanifin J. et al.Dupilumab treatment in adults with moderate-to-severe atopic dermatitis is efficacious regardless of age of disease onset: a post hoc analysis of two Phase 3 clinical trials.Dermatol Ther (Heidelb). 2022; 12: 2731-2746https://doi.org/10.1007/s13555-022-00822-xCrossref PubMed Scopus (0) Google Scholar The presentation of CTCLs and mycosis fungoides (MF) after dupilumab initiation has been reported in recent literature.3Chiba T. Nagai T. Osada S.I. Manabe M. Diagnosis of mycosis fungoides following administration of dupilumab for misdiagnosed atopic dermatitis.Acta Derm Venereol. 2019; 99: 818-819https://doi.org/10.2340/00015555-3208Crossref PubMed Scopus (28) Google Scholar, 4Joshi T.P. Duvic M. Unmasking a masquerader: mycosis fungoides unveiled after dupilumab treatment.J Am Acad Dermatol. 2023; 88: e305-e306https://doi.org/10.1016/j.jaad.2023.01.047Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar This potentially fatal adverse outcome requires additional attention because the relationship between CTCLs and dupilumab use is not well understood.3Chiba T. Nagai T. Osada S.I. Manabe M. Diagnosis of mycosis fungoides following administration of dupilumab for misdiagnosed atopic dermatitis.Acta Derm Venereol. 2019; 99: 818-819https://doi.org/10.2340/00015555-3208Crossref PubMed Scopus (28) Google Scholar We present a case of rapidly progressive CD30+ MF in a patient after starting dupilumab for adult-onset eczema and offer a potential explanation for the observed findings. A 65-year-old Jamaican man originally presented with a 2-month history of pruritus and diffuse, scaly brown-violaceous plaques in a reticulated pattern (Fig 1, A-D). Skin punch biopsy revealed spongiotic dermatitis with eosinophils, consistent with eczematous dermatitis (Fig 1, E), and he was started on dupilumab 300 mg every 2 weeks. Initially, his eczema improved with dupilumab, reporting less pruritus and scaling. However, 6 months and 5 maintenance doses of dupilumab later, he presented with a new, morphologically distinct rash (Fig 2).Fig 2During dupilumab treatment. Clinical images depicting significant improvement of prior eczema but now presenting with new hypopigmented ovoid patches and plaques on the (A) back, (B) left arm, (C) chest and abdomen, and (D) posterior aspect of the left shoulder.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Shave biopsy samples from the posterior aspect of the scalp and trunk were obtained (Fig 3, A-C). Histology revealed dermal atypical CD4+ lymphocytes with epidermotropism (Fig 3, D). Immunohistochemistry studies showed that the infiltrate expressed CD2, CD3, and CD25; many lymphocytes (>25%) expressed CD30 (Fig 3, E) with negative ALK-1. Pertinent ancillary studies revealed an elevated level of lactate dehydrogenase, eosinophilia, and mild leukopenia, with negative peripheral flow cytometry, human immunodeficiency virus, and human T-lymphotropic virus type I/II. Taken altogether, this confirmed primary cutaneous CD30+ MF without large cell transformation. Cessation of dupilumab and treatment with topical steroids were initiated; however, the disease continued to progress rapidly. The patient completed a 2-week course of total skin electron radiotherapy to 12 Gy and is currently undergoing evaluation for brentuximab therapy. Although there are numerous reports of CTCLs mimicking and being difficult to differentiate from eczema, necessitating repeat biopsies, there is limited knowledge regarding the underlying mechanism.3Chiba T. Nagai T. Osada S.I. Manabe M. Diagnosis of mycosis fungoides following administration of dupilumab for misdiagnosed atopic dermatitis.Acta Derm Venereol. 2019; 99: 818-819https://doi.org/10.2340/00015555-3208Crossref PubMed Scopus (28) Google Scholar The improved appearance of the MF lesions after the patient’s eczema cleared prompted us to consider MF-induced autoeczema. Autoeczematization refers to the diffusion of cytokines and increased stimulation of T cells from one inflammatory cutaneous process inducing an inflammatory skin reaction at distant sites.5Kasteler J.S. Petersen M.J. Vance J.E. Zone J.J. Circulating activated T lymphocytes in autoeczematization.Arch Dermatol. 1992; 128: 795-798https://doi.org/10.1001/archderm.1992.01680160079008Crossref PubMed Scopus (24) Google Scholar We theorized that dupilumab “unmasked” the MF by clearing its neighboring autoeczema (Fig 4). Although there have been no reports of autoeczema associated with MF, these entities share 2 common immunologic profiles: increased circulating T cells with upregulated interleukin 2 and interleukin 13 expressions.4Joshi T.P. Duvic M. Unmasking a masquerader: mycosis fungoides unveiled after dupilumab treatment.J Am Acad Dermatol. 2023; 88: e305-e306https://doi.org/10.1016/j.jaad.2023.01.047Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 5Kasteler J.S. Petersen M.J. Vance J.E. Zone J.J. Circulating activated T lymphocytes in autoeczematization.Arch Dermatol. 1992; 128: 795-798https://doi.org/10.1001/archderm.1992.01680160079008Crossref PubMed Scopus (24) Google Scholar Although it is unclear whether the patient had preexisting MF before presenting with widespread eczema, we speculate that subclinical MF triggered an autoeczema reaction, making it difficult to appreciate where the MF was to be sampled at the initial visit. Only when the eczema improved several months into the dupilumab treatment could the MF patches and plaques be recognizable. This single observation warrants further consideration in past and future dupilumab-associated MF cases. None disclosed.

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