A 74-year-old patient received benralizumab for severe asthma. One month after, he developed erythroderma associated with palmoplantar keratoderma. Skin biopsy revealed perivascular and atypical lymphocytic infiltrate with irregular nuclear contours and mild epidermotropism. Peripheral blood immunophenotyping revealed an expanded CD4+ T-cell population containing 20% of CD7+CD26-CD158k+ atypical T cells, i.e. 0.6 G/L of Sezary cells. The CD4:CD8 ratio was 6:1 and T-cell clonality was the same in skin and blood. Therefore, we concluded that the patient had stage IVB1b SS.

We measured the patient’s cytokine signature using a 27-multiplex bead-based Luminex assay. The patient sample was compared to the plasma of 2 untreated IVB1b stage SS patients, and to that of 2 healthy donors. Plasma levels of of eotaxin, IL-4, IL-17 and CCL3 were higher in our patient, whereas levels of CXCL10 were lower (Fig 1). IL-5 level was too low to be detected in all specimens.

The patient was treated with extracorporeal photopheresis and methotrexate, while maintaining benralizumab, which allowed a good control of both asthma and SS.

In SS, both malignant and tumor microenvironment cells are characterized by a Th2 bias that results in skewed anti-tumor response. Indeed, since Th1 environment enhances antitumor immune responses, the inhibition of Th2 pathway could be beneficial in patients with SS. However, our observation, as well as reported cases of worsening or development of SS under dupilumab (anti-IL-4/13) suggests the existence of paradoxical phenomena.
We observed in our patient a clear elevation of eotaxin and a mild increase of IL-4, which are both actors of Th2 inflammation in asthma, as well as in SS. Similarly, recent studies suggest a role for IL-17 in the tumor escape mechanism in SS. Furthermore, CCL3 is a chemokine for which the receptor is CCR4, a tumor cell and regulatory T cell receptor, which is particularly involved in the development of SS. Finally, the decrease of CXCL10 could be responsible for the loss of Sezary cell epidermotropism and their presence in the blood.

However, dedicated studies are needed to establish a causal link between IL-5 inhibition and these immunological alterations that may have contributed to the development of SS in our patient.

Our observation reminds us that the immunological consequences of cytokine pathway therapeutic inhibition remain poorly understood, and encourages caution regarding this type of adverse effect as more and more cytokine inhibitors are emerging on the market.