Phenotypic switching from atopic dermatitis to psoriasis is a significant adverse effect of dupilumab.1 Cases of dupilumab-induced Generalized Pustular Psoriasis (GPP) have been reported but remain rare.2–7

An 82-year-old male presented with an acute onset of generalized pustular eruption two weeks after starting treatment with dupilumab. He had a two-year history of generalized adult-onset eczema with a baseline EASI of 26.4. His eczema had been confirmed on histopathology, which showed spongiosis with focal eosinophilia, and had only partially responded to topical corticosteroids. He did not report joint pains, fevers, rigors, or preceding coryzal symptoms. He did not have a history of psoriasis or previous smoking, and there were no other recent changes to his medications.

Examination revealed well-demarcated erythematous plaques with overlying pustules affecting the abdomen, back and all four limbs (Fig. 1A). Psoriasiform plaques were also seen on the scalp, extending beyond the frontal hairline. There were coalescing pustules over palmar surfaces (Fig. 1B) but no oral mucosal involvement or palpable lymphadenopathy. The patient remained with stable vital signs and no fever.

Figure 1.

(A) Well-demarcated erythematous plaques with overlying pustules affecting the back and upper limbs (abdomen and lower limbs not shown). (B) Coalescing pustules over the bilateral palmar surfaces.

Histopathology demonstrated psoriasiform hyperplasia with Kogoj’s spongiform pustules, consistent with pustular psoriasis (Fig. 2). Swabs of pustules were negative for bacterial, fungal and viral studies. Full blood examination was unremarkable aside from mild neutrophilia and eosinophilia. His blood tests showed no evidence of immunosuppression, autoimmune diseases, or malignancies, with calcium levels and serum protein electrophoresis also within the normal range.

Figure 2.

Histopathology findings demonstrating features in keeping with pustular psoriasis, with evidence of psoriasiform hyperplasia and Kogoj spongiform pustule (Hematoxylin & eosin ; ×10).

A diagnosis of dupilumab-induced GPP was made. Dupilumab was discontinued and the patient was treated with intensive topical therapy and oral cyclosporine 175 mg twice daily (5 mg/kg/day). Cyclosporine was gradually reduced over six months, and methotrexate 15 mg weekly was initiated. His rash improved significantly within two weeks after starting treatment, and the response remained at follow-up three years later.

Dupilumab is a human monoclonal IgG4 antibody targeting the Interleukin (IL)-4 Receptor subunit α (IL-4Rα).1 This inhibits IL-4/13 signaling pathways that mediate T-helper-2 cell (Th-2) immune response involved in Atopic Dermatitis (AD).1 Psoriasis is driven by Th1/Th17 cell response with increased Tumor Necrosis Factor-α (TNF-α), IL-17, and IL-23 levels. A widespread psoriasiform eruption caused by dupilumab, such as GPP or erythrodermic psoriasis, remains rare.8

A literature review on Medline, Embase and PubMed identified six cases of histologically confirmed dupilumab-induced pustular psoriasis (Table 1).2–7 The median age of patients, including our case, is 22-years, and the symptoms began one day to three months after starting dupilumab. All but one patient developed erythematous plaques with pustulosis affecting multiple body areas. All cases resolved promptly within a median time of two weeks following topical or systemic treatments and cessation of dupilumab. Three cases received systemic immunosuppression with corticosteroids or oral cyclosporine, and two received oral antibiotics, but without confirmation of bacterial infections.

The immune mechanisms of AD and psoriasis exist on polar ends of the T-cell spectrum. IL-4 acts directly on T-cells, dendritic cells and keratinocytes to inhibit IL-23 production and the downstream Th17 polarisation.8 Therefore, IL-4 inhibition by dupilumab can induce a shift from Th2-polarised atopic response to a psoriasis-like, Th17/Th1-dominant pattern.1 Increased IL-36 expression is also important in dupilumab-induced GPP.8,9 The secretion of IL-36 by keratinocytes induces neutrophil infiltration and pustule formation.9 IL-36 interacts reciprocally with Th17 cytokines by regulating Th17 differentiation and maintenance, but also is upregulated by the Th17 cytokines such as TNF-α and IL-17.9 This immunological interplay can be exacerbated by IL-4/IL-13 signaling blockade, predisposing patients to GPP.8,9

A differential diagnosis for generalized pustular eruption following drug use is Acute Generalized Exanthematous Pustulosis (AGEP).10 GPP patients typically present with concurrent psoriasiform plaques and frequently extracutaneous symptoms such as arthritis.10 AGEP occurs acutely after administration of a causative drug and has a predilection for flexural areas.10 AGEP resolves with cessation of offending agent and supportive management, whereas GPP often requires systemic treatment such as oral acitretin or immunosuppressants.10 Of note, three cases in our review showed rapid resolution with cessation of dupilumab and topical therapy only, a clinical course more typical for AGEP.

In conclusion, dupilumab can trigger phenotypical transformation to GPP, and clinicians must remain vigilant to the development of generalized erythematous plaques with pustules post-dupilumab use.