Dupilumab-associated mycosis fungoides: a cross-sectional study

Treating atopic dermatitis (AD) with dupilumab, a monoclonal antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13), may be associated with the progression of mycosis fungoides (MF). This study aims to examine the associations between the length of dupilumab treatment, age and sex, and the onset of MF. An institutional data registry and literature search were used for a retrospective cross-sectional study. Only patients with a diagnosis of MF on dupilumab for the treatment of AD and eczematous dermatitis were included. The primary outcome was the length of dupilumab exposure, age, sex, and the onset of MF. Linear correlations (Pearson) and Cox regression analysis were used to assess the correlation and the risk. A total of 25 patients were included in this study. Five eligible patients were identified at our institution. In addition, a PubMed review identified an additional 20 patients. At the time of MF diagnosis, the median age was 58, with 42% female. Disease history was significant for adult-onset AD in most patients (n = 17, 65.4%) or recent flare of AD previously in remission (n = 3, 11.5%). All patients were diagnosed with MF, and one patient progressed to Sézary syndrome while on dupilumab, with an average duration of 13.5 months of therapy prior to diagnosis. Tumor stage at diagnosis of MF was described in 19 of the cases and ranged from an early-stage disease (IA) to advanced disease (IV). Treatment strategies included narrow-band UVB therapy, topical corticosteroids, brentuximab, pralatrexate, and acitretin. Male gender, advanced-stage disease, and older age correlated significantly with the hazard of MF onset and a shorter time to onset during dupilumab treatment. Our results suggest a correlation between the duration of dupilumab treatment and the diagnosis of MF, the higher MF stage at diagnosis, and the shorter the duration of using dupilumab to MF onset. Furthermore, elderly male patients appeared to be more at risk as both male gender and older age correlated with a hazard of MF diagnosis. The results raise the question as to whether the patients had MF misdiagnosed as AD that was unmasked by dupilumab or if MF truly is an adverse effect of treatment with dupilumab. Close monitoring of these patients and further investigation of the relationship between dupilumab and MF can shed more light on this question .


Introduction
Dupilumab is a monoclonal antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) that is approved for the treatment of adults with moderate-to-severe atopic dermatitis (AD) [1].Mycosis fungoides (MF) and Sézary syndrome (SS) are the two most common cutaneous T cell lymphomas (CTCL) [2].AD, MF, and SS are believed to be driven by T cell helper-2 responses [3].Thus, it has been hypothesized that dupilumab may also be efficacious in treating MF and SS [4].However, several recent reports have described cases of new-onset MF following treatment with dupilumab with progression to SS in rare cases [3].AD and early stages MF may be similar both clinically and histologically.Early-stage MF is likely misdiagnosed as AD with the pivotal possibility of dupilumab promoting the transformation of AD into MF in these patients [5,6].Dupilumab may well serve as a catalyst for the progression of MF [5].Our aim was to investigate the relationship between dupilumab use for AD and the development of MF through a retrospective analysis of five patients from our institution and 20 patients who were reported in the literature that were diagnosed with MF/SS following dupilumab therapy for AD.

A-Retrospective cohort of our institution
An institutional data registry was used to conduct a retrospective chart review of patients who developed MF/SS while on treatment with dupilumab for AD between 2015 and 2022.Charts of identified patients were reviewed to extract clinical details, age, sex, past medical history, indication for dupilumab treatment, duration of dupilumab treatment, diagnosis, stage, flow cytometry, TCR gene rearrangement, and other treatments.Institutional review board approval was given.

B-Database from a literature review
A database search of PubMed was performed on June 23, 2022, using the search terms "Mycosis fungoides", and "dupilumab".Full article texts were reviewed.Reference lists were screened for additional articles.Patient details were extracted from published articles and submitted into a standardized data collection form.

Immunohistochemical studies
Five cases from our institution had undergone immunohistochemical staining with CD3, CD4, CD8, CD1a, and CD30.Two blind independent board-certified dermatopathologists reviewed multiple hematoxylin and eosin sections, as well as the corresponding immunohistochemical markers.

Data analysis
We included only cases that met the criteria for diagnosis of MF as recommended by the International Society for Cutaneous Lymphomas (ISCL) classification [7].Dupilumab was initiated for treatment of AD and eczematous dermatitis in all the included cases.Exclusion criteria included a previous history of CTCL, lack of histological features consistent with MF, and dupilumab used for the treatment of CTCL.Six patients were excluded based on the exclusion criteria.A total of 25 patients were included in the analysis to increase the sample size and obtain meaningful clinical conclusions.SPSS software (IBM Corp. Released 2020.IBM SPSS Statistics for Windows, Version 27.0.Armonk, NY: IBM Corp) was used to perform linear correlations (Pearson) and Cox regression to assess the correlation and the risk.[8]

Results
Five eligible patients were identified at our institution, and an additional 20 patients were rendered from PubMed review.All patients were treated with dupilumab for clinically presumed AD.The demographic and clinical characteristics of those 25 cases are described in Table 1.

Retrospective cohort of our institution
Disease history was significant for adult-onset AD in all patients (n = 5, 100%) and refractory AD in one case (20%).The median age of patients diagnosed with MF was 68 years old, with 20% women (n = 1).All patients were diagnosed with MF, with one patient progressing to SS while on dupilumab, with an average duration of 8.4 months of therapy prior to diagnosis.Tumor stage at diagnosis of MF was described as follows [IB (n = 2), IIB (n = 1), and IV (n = 2)] [7].Additional tests, including flow cytometry, were performed to confirm the diagnosis, showing an increase of abnormal CD4 + T Cell in the majority of cases and identifying Sezary cells in one case.T cell rearrangement showed delta chain + T cells in one case.Treatment strategies included narrow-band UVB therapy, topical corticosteroids, methotrexate, and radiation therapy.Patients from our institution demonstrated clinical findings of red erythematous patches and plaques with ichthyosiform scaling, xerosis, and lichenification (Fig. 1).

Systematic review
Our search delineated 8 studies on dupilumab-induced MF, in which 20 reported cases were identified [4,5,[9][10][11][12][13][14].Disease history was significant for adult-onset AD in most patients (n = 12, 60%) or recent flare of AD previously in remission (n = 3, 15%).The median age of patients diagnosed with MF was 58.5 years, with 45% women (n = 9).All patients were diagnosed with MF, with an average duration of 11.2 months of therapy prior to diagnosis.Tumor stage at diagnosis of MF was described in 14 patients and Diagnosis as recommended by ISCL classification for primary cutaneous lymphomas [7] b Tumor as defined by the 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas [7] c The ISCL/EORTC has suggested a threshold of 30% CD4 + /CD26-T cells for staging purposes in MF/SS, but currently no consensus [30] d Clonal T cell receptor gene rearrangements are frequently identified in MF skin lesions and may help to differentiate between early MF patches and benign mimics [31] * Patient also received guselkumab for 1 month and cyclosporine for 2 months during treatment timeline for suspected psoriasis on repeat biopsy ranged from an early-stage disease (IA) to advanced disease (IV) [7].Treatment strategies included narrow-band UVB therapy, topical corticosteroids, brentuximab, pralatrexate, and acitretin.

Immunohistochemical studies
Compared to pre-dupilumab, post-dupilumab skin biopsies of our five patients revealed an increase in atypical lymphocyte infiltrates tagging the dermal-epidermal junction and intraepidermal epidermotropism with dermal fibrosis (Fig. 2).The atypical lymphocytes were predominantly CD3-positive T cells with abnormal CD4: CD8 ratios, and rare CD30-positive cells (Fig. 2).

Correlation and risk analysis
The results of linear correlations (Pearson) showed an inverse relationship between the stage of MF at diagnosis and the length of dupilumab treatment (i.e., the higher the MF stage at diagnosis, the shorter the duration of dupilumab to MF onset (R 2 = 0.914; Fig. 3).Older age of patients correlated significantly with decreased time to MF onset (R 2 = 0.98) (Fig. 4), and Cox regression showed that male gender had a significantly higher risk of MF onset during dupilumab treatment (Log-Rank p-value < 0.001) (Fig. 5).

Discussion
Primary cutaneous T cell lymphomas (CTCL) are a heterogeneous group of non-Hodgkin lymphomas characterized by infiltration of the skin by mature malignant T-cells [15].MF and SS are the most common forms of CTCL accounting for around 50% of the primary CTCLs [16].MF is generally an indolent, progressive monoclonal proliferation of skin-homing memory T cells with the potential to progress to involve the lymph nodes, blood, and viscera [17].MF usually appears in the sixth decade of life with a 1.5-2:1 male: female ratio [18].There is usually a prolonged clinical course with evolution of skin findings that include scaly erythemic patches or plaques that can progress to tumors and may be localized or disseminated.It often begins as a nonspecific dermatitis or is presumed to be AD, with some postulating dermatitis changing into this T cell lymphoma by virtue of chronic antigen stimulation [19].SS is characterized by the triad of erythroderma, generalized lymphadenopathy, and the presence of malignant T cells with cerebriform nuclei (Sezary cells) in the blood, lymph nodes, and skin.[15,20] MF skin biopsies show features of epidermotropic lymphoid infiltrates composed of small to medium-sized lymphocytes with cerebriform nuclei [7].The histologic features of SS may show similar features as MF.However, in SS skin biopsies, epidermotropism may be minimal or absent, superficial perivascular infiltrates may be sparse, and up to one-third of SS skin biopsies may be specific.The neoplastic T cells have a mature T cell phenotype and most often have  1; Image 4B corresponds to case-4 in Table 1; Image 4C and 4F corresponds to case-1 in Table 1; image 4D and 4G corresponds to case-5 in Table 1) a characteristic CD3 + CD4 + CD7 − and/or CD26 − immunophenotype [7].Most cases are CD4 + , and there are cases of MF with CD8 dominance or CD4-, CD8-.Aberrant T cell phenotypes are common.[7] In 2019, the first reports of MF following the administration of dupilumab for treatment of AD were published [9].This raised questions and concerns over dupilumab's safety.The Food and Drug Administration approved dupilumab in 2017 for the treatment of moderate-to-severe AD in adults, which has been shown to have a strong efficacy in improving cutaneous disease and reducing pruritus [21].AD affects approximately 15-20% of children and 1-3% of adults worldwide and is commonly treated with emollients and topical corticosteroids [22,23].However, new therapies such as dupilumab have arisen in recent years.Dupilumab is a monoclonal antibody directed against the IL-4-receptor-alpha subunit, inhibiting the IL-4 and IL-13 pathways.These pathways play prominent roles in inflammation, epidermal barrier dysfunction, and itch in AD. [1] Lesions of CTCL have demonstrated a high expression of IL-13 receptors, which led to hypothesize that dupilumab may also be an effective treatment for MF and SS [4,26].We have reviewed the literature for cases of clearly diagnosed MF or SS, treated with dupilumab for the lymphoma, and the outcome.To our knowledge, there are five cases have been published wherein patients were treated with dupilumab for MF [5,24,25].Two patients reported improvement in pruritus and achieved partial remission of MF [24,25].One of these two patients reported enough improvement to decrease MF treatments [24].However, this patient was diagnosed with MF and concomitant AD and only showed a slight reduction in CTCL blood involvement on flow cytometry.Additionally, in both two cases, follow-up was limited to six months, and long-term results were not assessed.Thus, whether dupilumab was beneficial in these two patients may be difficult to discern.Three patients diagnosed with MF prior to the initiation of dupilumab developed worsening pruritus and increased body surface area of their associated rash [5].Additionally, all three patients developed increased blood involvement on flow cytometry and were diagnosed with SS while on treatment [5].Two of the three died of disease progression [5].These five cases highlight the need for caution when using dupilumab in patients with pre-existing MF.Furthermore, with the more widespread use of dupilumab therapy in patients with presumed AD, increased cases of MF and SS have been reported.This raises questions of whether there is a role of IL-13 in the pathophysiology of dupilumab-associated MF, or whether using dupilumab is a risk-free in patients with AD or other dermatologic conditions as an off-label medication.[14] Multiple theories have been postulated to explain this phenomenon, recognizing dupilumab as a catalyst for the progression of MF.The prevailing theory is that these patients had early-stage MF that was misdiagnosed as AD and that dupilumab exacerbated the MF [5].This theory is plausible due to the difficulty of distinguishing AD from early-stage MF both clinically and histologically.MF patients often present with complaints of pruritic scaly patches or generalized erythema, similarly to AD.
Additionally, patch-stage early MF mimics AD with higher proportions of reactive lymphocytes and a smaller proportion of neoplastic T lymphocytes.Thus, without a high degree of clinical suspension or classic clinical signs, MF may be misdiagnosed as AD.
However, the role that dupilumab plays in the evolution of AD into MF remains unknown.One theory behind this worsening is that this specific cohort of patients, who later developed MF while on dupilumab, had a CTCL resistant to the IL-4 and IL-13 blockade.[5] Another theory suggests that dupilumab hastens the progression of MF by altering the Th1/Th2 cytokine balance toward a primarily Th1-driven response which is characteristic of early-stage MF [14].Others have suggested that dupilumab promotes the malignant transformation of benign lymphoid infiltrates found in AD, leading to MF.This has been supported by the findings of MF evolving from chronic inflammatory states, such as AD.[27] Given the many theories, it is apparent that additional studies are warranted to further elucidate the causes and mechanisms behind the phenomenon, which may include additional malignancies, including Hodgkin lymphoma and nodal anaplastic large cell lymphoma.[28,29] Our results showed an inverse relationship between the stage of MF at diagnosis and the length of dupilumab treatment (i.e., the higher the MF stage at diagnosis, the shorter the duration of dupilumab to MF onset).Older age patients correlated significantly with a decreased time to MF onset and male gender had a significantly higher risk of MF onset during dupilumab treatment.This suggests that specific populations may be more at risk for quicker disease progression and aggressive forms of MF.Thus, close monitoring both clinically and histologically may be warranted in elderly male patients.

Limitations
Our study reviewed all published MF cases on dupilumab to our knowledge and provided an exploratory correlation analysis.This analysis was based on limited available observational data.Further studies are necessary to fully understand the relationship between age, gender, and duration of dupilumab treatment in patients who develop MF.

Conclusion
Our analysis showed a correlation between the duration of dupilumab treatment and the diagnosis of MF.In those diagnosed with MF while being on dupilumab, the more advanced the MF stage, the shorter the treatment duration to MF onset.Additionally, older age and male gender appear to have a higher risk of advanced MF stage.This raises the question as to whether these patients had MF underdiagnosed as AD exacerbated by dupilumab or if MF is induced by dupilumab.Despite dupilumab remaining an effective therapy for AD, close monitoring of elderly men with serial biopsies and close observation of clinical changes may be warranted.

Fig. 1
Fig. 1 Clinical images from our patients showing MF onset in Dupilumab patients.(Image 4A and 4E corresponds to case-2 in Table1; Image 4B corresponds to case-4 in Table1; Image 4C and 4F corresponds to case-1 in Table1; image 4D and 4G corresponds to case-5 in Table1)

Fig. 2 Fig. 3
Fig. 2 Examples of skin biopsies from our Dupilumab patients showing MF histology and immunoprofile

Fig. 4 Fig. 5
Fig. 4 Diagram showing the correlation between increased age and decrease time to MF onset in Dupilumab patients

Table 1
Characteristics of patients diagnosed with Mycosis fungoides or Sezary syndrome following treatment with dupilumab for atopic dermatitis a