Abstract
IntroductionSchnitzler’s syndrome (SchS) is a disabling autoinflammatory disorder, characterized by a chronic urticarial rash, an M-protein, arthralgia, and other signs of systemic inflammation. Anti-interleukin-1 (IL-1) beta antibodies are highly effective, but the pathophysiology is still largely unknown. Here we studied the effect of in-vivo IL-1 inhibition on serum markers of inflammation and cellular immune responses.MethodsEight patients with SchS received monthly subcutaneous (s.c.) injections with 150 mg canakinumab for six months. Blood was drawn for measurement of serum markers of inflammation (12 times per patient) and for functional and phenotypic analysis of both freshly isolated and toll-like receptor (TLR)-ligand-stimulated peripheral blood mononuclear cells (PBMCs) (five times per patient). All data were compared to results of healthy controls.ResultsIL-6 levels in serum and in lysates of freshly isolated PBMCs and serum myeloid-related protein (MRP8)/14 and S100A12 levels correlated with disease activity. In vitro, LPS stimulation resulted in higher IL-6 and IL-1 beta production in PBMCs from symptomatic SchS patients compared to healthy controls, whereas patient cells were relatively hyporesponsive to poly:IC and Pam3Cys. The mRNA microarray of PBMCs showed distinct transcriptomes for controls, symptomatic patients and anti-IL-1-treated patients. Numbers of T- and B-cell subsets as well as M-protein concentrations were not affected by IL-1 inhibition. Free light chain levels were elevated in 4 out of 8 patients.ConclusionsIn conclusion, patient PBMCs are hyperresponsive to LPS, and clinical efficacy of IL-1 beta inhibition in patients with SchS is associated with in-vivo and ex-vivo suppression of inflammation. Interestingly, patient PBMCs showed divergent responses to TLR2/6, TLR3 and TLR4 ligands. Our data underscore that IL-1 beta plays a pivotal role in SchS.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0696-0) contains supplementary material, which is available to authorized users.
Highlights
Schnitzler’s syndrome (SchS) is a disabling autoinflammatory disorder, characterized by a chronic urticarial rash, an M-protein, arthralgia, and other signs of systemic inflammation
We showed that the clinical efficacy of IL-1β inhibition in patients with SchS is associated with suppression of inflammation, and that TLR4 is involved in the enhanced IL-1β production
Because binding to the administered antibodies probably interferes with detection, IL-1β could not be reliably measured during canakinumab treatment
Summary
Schnitzler’s syndrome (SchS) is a disabling autoinflammatory disorder, characterized by a chronic urticarial rash, an M-protein, arthralgia, and other signs of systemic inflammation. We studied the effect of several toll-like receptor (TLR) ligands on IL-1β, IL-6 de Koning et al Arthritis Research & Therapy (2015) 17:187 and tumor necrosis factor alpha (TNFα) production by PBMCs of eight classical and variant SchS patients, including two variant patients with NLRP3 mosaicism that were recently described [17] We performed these experiments, as well as serum cytokine measurements, leukocyte subset analyses and serum free lightchain analyses, on blood samples collected during a symptomatic episode, anakinra treatment, and at several time points during a trial with canakinumab [13] in order to investigate disease-specific characteristics and the effect of IL-1 on these markers. We identified MRP8/14 and S100A12 as markers of disease activity in SchS
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