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

Rowczenio, DM; Pathak, S; Arostegui, JI; Mensa-Vilaro, A; Omoyinmi, E; Brogan, P; Lipsker, D; ... Lachmann, HJ; + view all (2017) Molecular genetic investigation, clinical features, and response to treatment in 21 patients with Schnitzler syndrome. Blood , 131 (9) pp. 974-981. 10.1182/blood-2017-10-810366. Green open access

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Abstract

To date, the pathogenic mechanisms underlying Schnitzler syndrome remain obscure, in particular, the interplay between the monoclonal protein and increased interleukin-1β (IL-1β) 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) κ paraprotein was detected in 86%; the remainder had IgM λ or IgG κ. 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.

Type: Article
Title: Molecular genetic investigation, clinical features, and response to treatment in 21 patients with Schnitzler syndrome
Open access status: An open access version is available from UCL Discovery
DOI: 10.1182/blood-2017-10-810366
Publisher version: https://doi.org/10.1182/blood-2017-10-810366
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Hematology, RECEPTOR ANTAGONIST ANAKINRA, PERIODIC SYNDROMES, FOLLOW-UP, EFFICACY, SAFETY, INFLAMMASOME, CANAKINUMAB, RILONACEPT, MOSAICISM, DISEASE
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10048100
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