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Targeted review of IL36RN mutations in patients with generalised pustular psoriasis
James G Krueger1, Anna Pagotto2, Samuel Haftel2
1Laboratory for Investigative Dermatology The Rockefeller University New York New York USA.
Background:
Generalised pustular psoriasis (GPP) is a rare and chronic skin disease historically treated with therapies that were originally intended to treat plaque psoriasis (PsO). However, GPP and plaque PsO have distinct pathogeneses and clinical courses.
Objectives:
This study aimed to further characterise the unique genetic background of GPP by summarising evidence on the frequency and type of IL36RN gene mutation, a gene that normally suppresses proinflammatory responses, in patients with GPP compared to patients with GPP and plaque PsO, and patients with plaque PsO only.
Methods And Results:
A targeted literature review was conducted to identify studies reporting IL36RN mutations and/or HLA-Cw6 allele frequency in patients with GPP. Meta-analyses showed a significantly higher rate of IL36RN mutations in the GPP-only population compared to the GPP + plaque PsO population (OR 3.51; 95% CI 2.29, 5.38). Monoallelic mutations of IL36RN were found in up to 33.3%, and biallelic mutations in up to 73.2% of patients with GPP (GPP-only and GPP + plaque PsO), in contrast with mono- and biallelic frequencies of only 0%-11.9% and 0%, respectively, in patients with plaque PsO only. Mean age-of-onset ranged from 5.9 to 48.9 years old, with most studies reporting a GPP age-of-onset between 20 and 40 years old. Twenty-one mutations were identified in the biallelic state and three in monoallelic. The most reported mutations were c.115 + 6T > C (p. Arg10ArgfsX1) (18 studies); c.227 C > T (p.Pro76Leu) (10 studies); and c.338 C > T (p.Ser113Leu) (8 studies). Mutations varied depending on geography and ethnicity, with the most frequently reported mutation predominantly reported in East Asian studies and international studies that included Asian patients. Rates of HLA-Cw6, the risk allele most strongly associated with plaque PsO, were 0%-28.6% for patients with GPP, similar to rates in the general population (10.5%-20%).
Conclusion:
Considering the differences between GPP and plaque PsO in aetiology and disease symptoms, effective, GPP-specific treatment options are needed, and recent research suggests that blockade of IL-36 signalling may be an effective target for treatment of GPP.
