Background/Purpose:

Schnitzler’s syndrome is characterized by chronic urticaria, intermittent fever, arthralgia, bone pain, gammopathy and marked systemic inflammation. The striking response to IL-1 blockade suggests that Schnitzler’s syndrome is an IL-1 mediated condition of the expanding spectrum of systemic autoinflammatory disorders. However, the mechanism leading to the increased IL-1 activity has remained elusive. We aim to identify genetic predisposition in patients with Schnitzler’s syndrome.

Methods:

Genomic DNA was extracted from peripheral blood mononuclear cells from 4 patients with a clinical diagnosis of Schnitzler’s syndrome. DNA sequencing was performed in both directions of NLRP3 gene regions, including exon 3 which contains the majority of mutations associated with the cryopyrinopathies. Genetic data of patients was compared with the reference sequence for mutations.

Results:

Of the 4 patients with Schnitzler’s syndrome, 2 had classical findings of monoclonal IgM, kappa; one with polyclonal IgA; and one with polyclonal IgG and IgA. All of the 4 patients were refractory to non-biologic immunosuppressive treatment but achieved sustained clinical remission with daily use of anakinra. DNA sequence analysis of NLRP3 revealed a disease-associated mutation encoding the V198M substitution in the patient with polyclonal IgG and IgA. However, this mutation was not found in the other 3 patients. No other disease-associated mutations were identified in NLRP3 for this patient or in the other 3 patients.

Conclusion:

Genetic studies of Schnitzler’s syndrome have been scanty primarily due to the rarity of the condition and the results have been mixed. Our 4 patients consist of classical (2 cases) and atypical (2 cases) Schnitzler’s syndrome. The V198M mutation was found in one with atypical Schnitzler’s syndrome (polyclonal IgG and IgA). Interestingly, this mutation was previously reported in one patient with classical Schnitzler’s syndrome with monoclonal IgM, kappa (1). However, another genetic study on a patient with classical Schnitzler’s syndrome found no mutations in NLRP3 (2). The distinct feature of Schnitzler’s syndrome is its gammopathy which is poorly responsive to IL-1 blockade suggesting that IL-1 may not mediate the gammopathy. Complete analysis of NLRP3 exons and their flanking regions in this cohort is underway as disease-associated mutations outside of exon 3 have been reported and there may be as yet unknown mutations involved in this phenotype. The presence of an NLRP3 mutation in another patient with Schnitzler’s syndrome confirms the finding that this disorder is inflammasome-mediated.

References:

1. Loock J, Lamprecht P, Timmann C, Mrowietz U, Csernok E, Gross WL. Genetic predisposition (NLRP3 V198M mutation) for IL-1-mediated inflammation in a patient with Schnitzler syndrome. J Allergy Clin Immunol. 2010;125:500-2.

2. Ryan JG, de Koning HD, Beck LA, Booty MG, Kastner DL, Simon A. IL-1 blockade in Schnitzler syndrome: ex vivo findings correlate with clinical remission. J Allergy Clin Immunol. 2008;121:260-2.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/nlrp3-gene-analysis-for-patients-with-schnitzlers-syndrome/