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Molecular genetic investigation, clinical features and response to treatment in 21 patients with Schnitzler's syndrome

Dorota M. Rowczenio, Shelly Pathak, Juan I. Arostegui, Anna Mensa-Vilaro, Ebun Omoyinmi, Paul Brogan, Dan Lipsker, Thomas Scambler, Roger Owen, Hadija Trojer, Anna Baginska, Julian D. Gillmore, Ashutosh D. Wechalekar, Thirusha Lane, Rene Williams, Taryn Youngstein, Philip N. Hawkins, Sinisa Savic and Helen J. Lachmann

Key points

  • We found no evidence of somatic NLRP3 mosaicism in the pathogenesis of Schnitzler's syndrome.

  • Pathogenic inflammasome activation is supported by: increased apoptosis-associated speck-like protein with CARD domain, IL-18, IL-6 and anakinra response.

Abstract

To date, the pathogenic mechanisms underlying Schnitzler's syndrome remain obscure, in particular the interplay between the monoclonal protein and increased IL-1beta production, although interest in the contribution of genetic factors has been fuelled by detection of somatic NLRP3 mosaicism in two patients with the variant-type Schnitzler's syndrome. At two specialist UK centres we have identified 21 patients, who fulfilled diagnostic criteria for Schnitzler's syndrome with urticarial rash, fever, arthralgia and bone pain; 47% reported weight loss, 40% fatigue and 21% lymphadenopathy. An IgM kappa paraprotein was detected in 86%, the remainder had IgM lambda or IgG kappa. Patients underwent search for germline and somatic mutations using the next generation sequencing (NGS) technology. Moreover, we designed a panel consisting of 32 autoinflammatory genes to explore genetic susceptibility factor(s) to Schnitzler's syndrome. Genetic analysis revealed neither germline nor somatic NLRP3, TNFRSF1A, NLRC4 or NOD2 mutations, apart from one patient with germline NLRP3 p.V198M substitution. The pro-inflammatory cytokines and extracellular apoptosis-associated speck-like protein with CARD domain (ASC) measured in the Schnitzler's syndrome patients' serum during active disease were significantly higher than healthy controls. 95% of our cohort achieved a complete response to recombinant IL-1 receptor antagonist (anakinra). Our findings do not support a role for somatic NLRP3 mosaicism in the disease pathogenesis; although elevated levels of ASC, IL-6 and IL-18 in patients' serum, and the response to anakinra, suggest that Schnitzler's syndrome is associated with upregulated inflammasome activation. Despite its rarity Schnitzler's syndrome is an important diagnosis as treatment with IL-1 antagonists dramatically improves patients' quality of life.

  • Submitted October 11, 2017.
  • Accepted December 8, 2017.