Journal
BLOOD
Volume 131, Issue 9, Pages 974-981Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2017-10-810366
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Funding
- Spanish Ministry of Economy and Competitiveness [SAF2015-68472-C2-1-R]
- Rosetrees
- Swedish Orphan Biovitrum AB
- Rosetrees Trust [M8-F1-CD1, M465, M8-F2-CD1] Funding Source: researchfish
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To date, the pathogenic mechanisms underlying Schnitzler syndrome remain obscure, in particular, the interplay between the monoclonal protein and increased interleukin-1 beta (IL-1 beta) production, although interest in the contribution of genetic factors has been fueled by detection of somatic NLRP3 mosaicism in 2 patients with the variant-type Schnitzler syndrome. At 2 specialist UK centers, we have identified 21 patients who fulfilled diagnostic criteria for Schnitzler syndrome with urticarial rash, fever, arthralgia, and bone pain; 47% reported weight loss, 40% fatigue, and 21% lymphadenopathy. An immunoglobulin M (IgM) kappa paraprotein was detected in 86%; the remainder had IgM lambda or IgG kappa. Patients underwent searches for germ line and somatic mutations using next-generation sequencing technology. Moreover, we designed a panel consisting of 32 autoinflammatory genes to explore genetic susceptibility factor(s) to Schnitzler syndrome. Genetic analysis revealed neither germ line nor somatic NLRP3, TNFRSF1A, NLRC4, or NOD2 mutations, apart from 1 patient with a germ line NLRP3 p. V198M substitution. The proinflammatory cytokines and extracellular apoptosis-associated speck-like protein with caspase recruitment domain (ASC) measured in the serum of Schnitzler syndrome patients during active disease were significantly higher than healthy controls. Ninety-five percent 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 disease pathogenesis; although elevated levels of ASC, IL-6, and IL-18 in patients' serum, and the response to anakinra, suggest that Schnitzler syndrome is associated with upregulated inflammasome activation. Despite its rarity, Schnitzler syndrome is an important diagnosis as treatment with IL-1 antagonists dramatically improves quality of life for patients.
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