The Majority of Generalized Pustular Psoriasis without Psoriasis Vulgaris Is Caused by Deficiency of Interleukin-36 Receptor Antagonist

Abstract

Generalized pustular psoriasis (GPP) is a rare inflammatory skin disease that can be life-threatening. Recently, it has been reported that familial GPP is caused by homozygous or compound heterozygous mutations of IL36RN. However, the majority of GPP cases are sporadic and it is controversial whether IL36RN mutations are a causative/predisposing factor for sporadic GPP. We searched for IL36RN mutations in two groups of GPP patients in the Japanese population in this study: GPP without psoriasis vulgaris (PV), and GPP with PV. Eleven cases of GPP without PV (GPP alone) and 20 cases of GPP accompanied by PV (GPP with PV) were analyzed. Surprisingly, 9 out of 11 cases of GPP alone had homozygous or compound heterozygous mutations in IL36RN. In contrast, only 2 of 20 cases of GPP with PV had compound heterozygous mutations in IL36RN. The two cases of GPP with PV who had compound heterozygous mutations in IL36RN are siblings, and both cases had PV-susceptible HLA-A*0206. We determined that GPP alone is a distinct subtype of GPP and is etiologically distinguished from GPP with PV, and that the majority of GPP alone is caused by deficiency of the interleukin-36 receptor antagonist due to IL36RN mutations.

442 European consensus statement on phenotypes of pustular psoriasis

“…Also, 82% of GPP patients who did not suffer from concomitant PV had mutations in IL36RN compared to 10% of those affected by GPP with PV [14]. The same pattern was confirmed by a European study finding IL36RN mutations in 46% of GPP patients without PV and 17% in GPP with PV [15].…”

Acrodermatitis Continua of Hallopeau Treated Successfully with Ustekinumab and Acitretin after Failure of Tumour Necrosis Factor Blockade and Anakinra

“…It has been hypothesized that such mutations could be associated with the response of generalized pustular psoriasis [12] or ACH [9] to anakinra [13,14], but this has not been demonstrated [14,16]. Indeed, IL-36RN gene mutations do not account for all cases of pustular psoriasis [13,14,17,18]; moreover, the consequences of IL-36RA deficiency on the expression of pro-inflammatory cytokines are not fully known, and, although IL-36RA deficiency may induce increased production of IL-1, it has not been demonstrated that IL-1 blockade was the most relevant strategy in that context [16]. Tauber et al [16] suggested that anakinra would account for partial benefit in pustular psoriasis, since it counteracts only one of the various inflammatory signalling pathways induced by IL-36, and they did not rule out a potential clinical interest of ‘targeted inhibition of one of several effector inflammatory cytokines such as (…) TNF or eventually IL-6, IL-8 or IL-23/Th17 axes' [16].…”

Secukinumab in the Treatment of Generalized Pustular Psoriasis: A Case report

“…However, evidence suggests that genetic factors distinct from those associated with chronic plaque psoriasis contribute to GPP. In particular, mutations in the IL36RN gene, which encodes the interleukin-36 receptor antagonist (IL-36Ra), an anti-inflammatory cytokine in the IL-1 family that inhibits proinflammatory signal pathways by preventing the binding of IL-36 to its receptor, have been detected in some patients with GPP (1,2). Traditionally this form of pustular psoriasis has been treated with acitretin or methotrexate, which still comprise the first-line treatments.…”