Comment
Mycosis fungoides is a rare chronic T-cell lymphoma that can smolder for decades as nonspecific dermatitis before declaring itself fully on skin biopsy.2 In many cases, MF masquerades as eczema, psoriasis, contact dermatitis, or other dermatitides, and it often responds to the same medications, making diagnosis even more challenging. Treatment options include topical steroids, narrowband UVB, topical nitrogen mustard, topical carmustine, and bexarotene gel for early-stage disease.3 Although it cannot be determined which patients will progress, some do, and therapies must then be upgraded.
We reported 3 patients with adult-onset dermatitis and multiple biopsies demonstrating nondiagnostic findings, which, in retrospect, likely represented early smoldering CTCL. Each of these patients was treated with dupilumab because multiple biopsies demonstrated findings consistent with nondiagnostic dermatitis, along with a lack of response to standard therapies. In all 3 cases, however, the patients had no history of eczema or atopy. After starting dupilumab, each patient had an acute exacerbation of dermatitis; immediately thereafter, biopsies were consistent with CTCL.
These patients most likely had smoldering CTCL that expressed itself fully after dupilumab was started. Biologic medications and their effects on the immune system have been shown to have multiple unanticipated effects on the skin.4-6 We are not insinuating that dupilumab was the cause of our patients having developed CTCL, but we do propose that the underlying interplay of dupilumab with the immune system might have accelerated progression of underlying CTCL, resulting in the lymphoma presenting itself clinically and histopathologically. We also must mention that all 3 cases could represent a “true, true, and unrelated” phenomenon.
A proposed mechanism for how dupilumab might hasten progression of CTCL is based on a functional increase of IL-13 available for binding at the IL-13 receptor (IL-13R) α2 site following blockade of the IL-13Rα1 site by dupilumab (Figure 3). The pathway that is blocked by dupilumab provides improvement in AD by blocking the α subunit of the IL-4R, making it a receptor antagonist for both IL-4 and IL-13. The IL-4R forms a heterodimer with both γ c and separately with IL-13Rα1. As a result, IL-4 and IL-13 cannot bind to their respective targets; thus, downstream signaling that is required for AD is halted.7 IL-13, in addition to IL-4R, also binds to an IL-13Rα2. IL-13 and both of its receptors are upregulated in CTCL, particularly IL-13Rα2.8
Figure 3. Proposed mechanism for promotion of cutaneous T-cell lymphoma (CTCL) by dupilumab. A, IL-4 and IL-13 bind to the type II IL-4 receptor (IL-4R). IL-13 also may bind at a distinct IL-13 receptor α2 (IL-13Rα2) site. B, Following blockade of the type II IL-4R, reduced binding at IL-4R may result in increased free IL-13 available for binding at the IL-13Rα2 site, which may have a role in promoting CTCL proliferation.
One of the principal ways that CTCL survives is through autocrine signaling, inducing more IL-13 and more IL-13Rα2, which is not seen in normal skin.8 Autocrine signaling plays a critical role in cancer activation and in providing self-sustaining growth signals to tumors.9 In addition, it has been documented that IL-13Rα2 has a higher affinity for IL-13 than the affinity of IL-13Rα1.10 As such, when the dupilumab receptor is blocked, our proposed mechanism of acceleration of CTCL is based on a functional increase in IL-13 available for binding at the IL-13Rα2 site, following indirect blockade of the α1 receptor with dupilumab, which effectively increases available IL-13 to be shunted down the tumorigenic pathway.
We recognize that this proposed mechanism is a theory; additionally, it should be noted that dupilumab is approved only for the treatment of AD and asthma. In our 3 cases, we used dupilumab off label in patients who did not have a clear case of AD or a childhood history of the disease.
When screening patients for the use of dupilumab, it is important to treat only those who have a classic history of moderate to severe AD, including itch, family history, and rash in the classic atopic distribution. We propose that these cases represent potential exacerbation of extant CTCL following exposure to dupilumab.
The manufacturer of dupilumab has reported 1 case of stage IV MF in a 57-year-old man 48 days after the first dose of dupilumab, leading to permanent discontinuation. The patient had ongoing disease at the time of the report, and the manufacturer stated that use of dupilumab was unrelated to disease.11 Studies are needed to explore any potential immunologic link between dupilumab and progression of CTCL.