Mycosis Fungoides Presenting After Dupilumab Therapy: Case Report and Systematic Review

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Introduction
Mycosis Fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma (CTCL) [1,2]. The disease is characterized by patches, plaques, and tumors that can be intensely pruritic and present in various sizes, shapes, and colors [2]. The cutaneous findings of MF can mimic other common cutaneous diseases such as atopic dermatitis, psoriasis, and parapsoriasis, making diagnosis challenging, and often requiring serial biopsies [3].

Patient demographics, clinical and histology before dupilumab therapy
19 studies were included, totaling 28 patients included in our series. 9 patients excluded after review of the publications due to insufficient length of dupilumab exposure (n=3) or its use reported in preexisting MF/CTCL subjects in the study (n=6) The demographics of the patients included in this study are summarized in table 1. There were 15 males and 13 females. There were 22 Caucasian, 2 African American and 4 Asians with an age range of 27-77 years and a mean of 55 years. Duration of disease ranged from 1 to 58 years, mean= 17.4. Patients starting dupilumab therapy had a history of AD or presumed AD although several did not report skin biopsy findings pretreatment (table 1), with associated diseases including IgE mediated disorders (asthma, allergic rhinitis, idiopathic eosinophilia, and conjunctivitis) (n=5), and single cases each, allergic contact dermatitis, maxillary sinus carcinoma, oropharyngeal cancer, and ichthyosis vulgaris.
Clinical presentation and distribution of the skin eruption was widespread with reports of extensive disease (>70% body surface area-BSA) or exfoliative erythroderma prior to starting dupilumab in 18/23 cases that described disease extent prior to dupilumab therapy. Pruritus was dominant in most cases with morphologies described including prototypical AD (lichenified and excoriated flexural patches and plaques), urticarial, palmoplantar dermatitis, ichthyosiform xerosis, blepharitis and conjunctivitis.

Post-dupilumab clinical and histologic findings
Clinical and histologic features that changed after dupilumab treatment are also summarized in table 1. The mean duration of therapy was 18.5 weeks prior to MF/CTCL diagnosis. There were 2 reports of complete clearing and 8 of partial improvement of symptoms while on dupilumab. But eventual worsening and associated with the progression of lesions occurred in all reports. Some describe the development of secondary lesions including thicker plaques, nodules, erosions, exfoliative erythroderma, and ulcerating tumors.

Discussion
In 2017, Dupilumab became FDA approved to treat adults with moderate/severe AD [25]. Dupilumab is a monoclonal IgG4 antibody that blocks the IL4 receptor alpha chain in the shared IL-4/ IL-13 receptor, leading to a decrease in TH2 cell cytokine-mediated signal transduction [26][27][28]. Common side effects include injection site reactions, headache, myalgia and blepharoconjunctivitis [28,29]. In this review, we have summarized a total of 28 cases (including 1 new case from the senior author's practice) that have a temporal association with the development of MF/CTCL, a mean time of 18.5 weeks on dupilumab therapy. Park et al and Schaefer et al have recently reviewed MF/CTCL in association with dupilumab or other biologic therapies [30,31], but these series did not apply stringent criteria of at least 6 weeks of dupilumab exposure as we have to underscore meaningful exposure to this agent in association with the evolution of MF/CTCL.
Heymann's commentary highlighted new reports of dupilumab in prurigo nodularis and bullous pemphigoid that appeared in the same journal issue as that of Espinosa et al [32], who reported 3 cases of AD developing MF while on dupilumab as well as 3 cases of MF who received it as adjuvant therapy for itching [12]. No adverse events were reported in the studies involving PN or BP, although the patients with AD who eventually were diagnosed with CTCL had worsening symptoms after various initial periods of improvement. In the same issue, the editor summarized several cases of MF after dupilumab treatment and commented on the role of IL-13 excess in lymphomas and the complex interplay of TH1/TH2 cell responses in the microenvironments of these diseases by paraphrasing the adage 'if it's dry, wet it and if it's wet, dry it' as not being the same as 'if it is upregulated, downregulate it' [33].
MF is a malignancy of TH2 T cells, and it is unclear how inhibition of the IL4/IL13 receptor might facilitate the proliferation of these cells. It is possible that blocking IL-4/IL-13 signaling on normal/reactive lymphocytes allows pre-existing small numbers of transformed T cells to proliferate. This is analogous to prior reports of progressive MF/ CTCL in response to other immunosuppressive regimens, including classical chemotherapy and calcineurin inhibitors [34].     It is not possible to tell if any/all these patients had preexisting MF/CTCL or whether this was de novo transformation into a malignancy. Due to the relatively short time frame for MF diagnosis, we review here (median time after dupilumab therapy was 8 months) and the overall rarity of this presentation compared to the extensive use of dupilumab in AD, we suspect that atypical T cells were already existing in many of these patients' skin prior to dupilumab therapy. Proliferative T cell neoplasia may have been thus allowed to progress, much the same as how the gradual diminution of host immunity with the advancing stage of CTCL has been classically described to promote progressive disease over time [35]. Additional hypotheses include the upregulation of IL-13Rα2, a decoy receptor involved in atopic dermatitis but not blocked by dupilumab [36]. IL-13Rα2 binding by the excess IL-13 could have autocrine effects in the microenvironment that may further stimulate the growth of the malignant cells as proposed by Wadele et al [37] and Geskin et al [38] and previously proposed in the figure published by Hollis et al [13]. Another possible mechanism is that malignant T cells may no longer bind dupilumab with the same efficacy of normal T cells [37][38][39].

Conclusion
All these mechanisms remain unproven but have a permissive effect of dupilumab in mycosis fungoides evolution. Dupilumab has been a very effective new agent in our armamentarium and these cases are best seen as a cautionary tale that clinicians pay attention to the patient's history and presenting symptoms when initiating this therapy and have a low threshold for biopsy of any lesions that are not classic. Atypical/poor responders should be closely followed up and repeat biopsies considered detecting any unmasked cases of CTCL as early in therapy as possible.