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Brief Report |

Therapeutic Efficacy of Interleukin 12/Interleukin 23 Blockade in Generalized Pustular Psoriasis Regardless of IL36RN Mutation Status

Akiko Arakawa, MD, PhD1; Thomas Ruzicka, MD1; Jörg C. Prinz, MD1
[+] Author Affiliations
1Department of Dermatology, University Hospital, Ludwig-Maximilian-University, Munich, Germany
JAMA Dermatol. 2016;152(7):825-828. doi:10.1001/jamadermatol.2016.0751.
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Importance  Generalized pustular psoriasis von Zumbusch type (GPP) is the most severe manifestation of psoriasis. The etiology of GPP is only partially understood, and GPP lacks approved treatments. Loss-of-function mutations in the interleukin 36 (IL-36) receptor antagonist (IL36RN), an inhibitor of innate immune activation in the skin, and therapeutic efficacy of IL-1 blockade in a subset of patients with GPP are viewed as evidence for an autoinflammatory pathogenesis. A pathogenic role of T cells has not been considered.

Objective  To test whether ustekinumab, a monoclonal antibody blocking IL-12 and IL-23, is an effective treatment modality for patients in whom GPP treatment with conventional psoriasis drugs or antagonists of tumor necrosis factor (TNF) has not been sufficiently effective, is contraindicated, or has lost efficacy.

Design, Setting, and Participants  We treated a series of 4 patients with GPP with ustekinumab, which was applied on an outpatient basis according to the dosing regimen approved for psoriasis vulgaris. In 3 patients it was combined with low doses of the retinoid acitretin. IL36RN mutations were determined in all 4 patients by means of targeted sequencing of genomic DNA.

Main outcome measures  The response to therapy was assessed by clinical examination.

Results  The 4 patients were female. Sequencing of IL36RN identified a homozygous mutation in case 1 (Pro76Leu). The other 3 patients carried no rare IL36RN variants. Overall GPP duration ranged from 50 to 146 months. Ustekinumab treatment is currently ongoing in all 4 patients without loss of efficacy, currently reaching treatment durations of 17 (case 1) to 44 months (case 3). Ustekinumab treatment induced sustained remissions in all 4 GPP patients. This response was independent of IL36RN mutations and consolidated by combination with low doses of the retinoid acitretin.

Conclusions and Relevance  Ustekinumab-induced remissions suggest that T cells play a crucial role in GPP pathogenesis based on the documented role that IL-12 and IL-23 play in autoimmune diseases through differentiating helper T cell 1 (TH1) and maintaining TH17 responses. Acitretin treatment may support ustekinumab efficacy, possibly by suppressing TH17 responses through the retinoid-related orphan receptors, RORγt and RORα. Combining IL-12/IL-23 blockade and acitretin may constitute an efficient treatment modality interfering with GPP pathomechanisms.

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Response of Generalized Pustular Psoriasis (GPP) to Ustekinumab Therapy in Patient With a Homozygous IL36RN Mutation (Case 1)

A, First onset of GPP with generalized erythematous skin inflammation covered by myriad sterile pustules. The pustulosis developed together with shivering, high fever, and laboratory signs of serious inflammation. Sequencing of IL36RN revealed a homozygous IL36RN mutation (Pro76Leu). B, Loss of response to tumor necrosis factor (TNF) blockade as reflected by progressive GPP flares despite application of etanercept and acitretin. C, Reinduced remission following exchange of etanercept for ustekinumab.

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