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Recalcitrant chronic urticaria treated with dupilumab: Report of two instances refractory to H1‐antihistamines, omalizumab and cyclosporine and brief literature review

Dear Editor, Chronic urticaria (CU) is a condition characterized by wheals and/or angioedema lasting for more than 6 weeks which is divided into two forms, that is, chronic spontaneous urticaria (CSU, without defined eliciting factors) and chronic inducible urticaria (CIndU, associated with a specific triggering factor). Current management guidelines recommend a stepwise approach, with second-generation H1-antihistamines at standard and high doses being the firstand second-line treatments, respectively. Omalizumab add-on second-generation H1-antihistamines occupies the third step, while cyclosporine is considered when previous therapies fail to achieve clinical response. Importantly, albeit most patients are controlled by such therapies, there still are nonresponding cases. In this regard, several alternative treatments have been proposed for recalcitrant CU, with variable degrees of success, mainly including methotrexate, tacrolimus, mycophenolate, dapsone, sulfasalazine and hydroxychloroquine. In addition, there is growing evidence supporting the usefulness of dupilumab, a monoclonal antibody against the interleukin (IL)-4 receptor alpha subunit (common to both IL-4 and IL-13 receptors), in the management of refractory CU. Indeed, although it is approved to treat moderate-to-severe atopic dermatitis, several studies/reports have shown that several dermatological conditions may benefit from IL4-IL-13 signaling blockade. Here, we describe two patients with CSU refractory to H1-antihistamines, omalizumab and cyclosporine who were successfully treated with dupilumab, also providing an up-to-date concise literature overview on the use of this agent in the management of recalcitrant CU (ie, resistant to high dose of second-generation H1-antihistamines or subsequent recommended lines of therapies). Two women, aged 63 (patient 1) and 52 (patient 2) years, were suffering from CSU (with wheals and lip angioedema) for 3 and 11 years, respectively. Medical history revealed a long-lasting Basedow-Graves's disease in patient 1 and a 10-year history of limited atopic dermatitis in patient 2 (periodically treated with topical steroids). Both patients had a history of primary/secondary failure to several agents used for their CSU, including standard and high dose of second-generation H1-antihistamines, montelukast (only patient 1), omalizumab, methotrexate (only patient 2) and cyclosporine. After failing all recommended therapeutic lines, dupilumab (600 mg, followed by 300 mg every other week) was started (off-label in patient 1 and to treat a concomitant atopic dermatitis reactivation in patient 2) with complete remission after 8 weeks of therapy. At months 5 (patient 1) and 23 (patient 2) of follow-up, patients were still free of manifestations. Table 1 shows all details of the patients. An electronic search was performed in November 2020 within the PubMed database by using “dupilumab” AND “urticaria” as search terms. English language papers on the use of dupilumab in recalcitrant CU (both spontaneous and inducible) were selected for the analysis; review articles were excluded. Quality of individual studies was evaluated according to guidelines by the Oxford Centre for Evidence-based Medicine. A total of four articles were finally included, two case series and two case reports for a total of 10 patients (eight with CSU and two with CIndU [one with adrenergic urticaria and one with cold urticaria]). A positive outcome was reached in all cases and no side effect was reported. Table 1 displays all the details of patients included from the literature search. Dupilumab may be considered as a possible effective and safe option for CU cases resistant/contraindicated to second or subsequent recommended lines of therapies (ie, high doses of secondgeneration H1-antihistamines, omalizumab and cyclosporine). It is possible that it may improve CU manifestations by both impeding Th2/IgE-driven mast cell degranulation/histamine release through IL-4 inhibition and limiting the IL-13 inflammatory cascade that leads to pruritus. Larger controlled studies are needed to validate the role of dupilumab in CU; results of ongoing trials might help in this regard.