title: The role of interleukin-1 beta in the pathophysiology of Schnitzler's syndrome.
abstract: BACKGROUND
  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. 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.
  
  
  METHODS
  Eight 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.
  
  
  RESULTS
  IL-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.
  
  
  CONCLUSIONS
  In 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.
authors.affiliation: Departments of Dermatology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. heleen.dekoning@radboudumc.nl.|Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. heleen.dekoning@radboudumc.nl.|Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands. heleen.dekoning@radboudumc.nl.|Nijmegen Center for Immunodeficiency and Autoinflammation, Nijmegen, The Netherlands. heleen.dekoning@radboudumc.nl.
authors.forename: Heleen D
authors.initials: HD
authors.lastname: de Koning
authors.affiliation: Departments of Dermatology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. joost.schalkwijk@radboudumc.nl.|Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands. joost.schalkwijk@radboudumc.nl.|Nijmegen Center for Immunodeficiency and Autoinflammation, Nijmegen, The Netherlands. joost.schalkwijk@radboudumc.nl.
authors.forename: Joost
authors.initials: J
authors.lastname: Schalkwijk
authors.affiliation: Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. monique.stoffels@nih.gov.|Nijmegen Center for Immunodeficiency and Autoinflammation, Nijmegen, The Netherlands. monique.stoffels@nih.gov.
authors.forename: Monique
authors.initials: M
authors.lastname: Stoffels
authors.affiliation: Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. jjongekrijg@ziggo.nl.
authors.forename: Johanna
authors.initials: J
authors.lastname: Jongekrijg
authors.affiliation: Laboratory Medicine - Laboratory for Medical Immunology, Radboud University Medical Center, Nijmegen, The Netherlands. H.Jacobs@radboudumc.nl.
authors.forename: Joannes F M
authors.initials: JF
authors.lastname: Jacobs
authors.affiliation: Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. eugeneverwiel@hotmail.com.
authors.forename: Eugène
authors.initials: E
authors.lastname: Verwiel
authors.affiliation: Laboratory Medicine - Laboratory for Medical Immunology, Radboud University Medical Center, Nijmegen, The Netherlands. Hans.Koenen@radboudumc.nl.
authors.forename: Hans J P M
authors.initials: HJ
authors.lastname: Koenen
authors.affiliation: Laboratory Medicine - Laboratory for Hematology, Radboud University Medical Center, Nijmegen, The Netherlands. Frank.Preijers@radboudumc.nl.
authors.forename: Frank
authors.initials: F
authors.lastname: Preijers
authors.affiliation: Department of Paediatric Rheumatology and Immunology, University Hospital Muenster, Muenster, Germany. Dirk.holzinger@ukmuenster.de.|Institute of Immunology, University Hospital Muenster, Muenster, Germany. Dirk.holzinger@ukmuenster.de.
authors.forename: Dirk
authors.initials: D
authors.lastname: Holzinger
authors.affiliation: Laboratory Medicine - Laboratory for Medical Immunology, Radboud University Medical Center, Nijmegen, The Netherlands. Irma.Joosten@radboudumc.nl.
authors.forename: Irma
authors.initials: I
authors.lastname: Joosten
authors.affiliation: Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. Jos.vanderMeer@radboudumc.nl.|Nijmegen Center for Immunodeficiency and Autoinflammation, Nijmegen, The Netherlands. Jos.vanderMeer@radboudumc.nl.
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.affiliation: Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. Anna.Simon@radboudumc.nl.|Nijmegen Center for Immunodeficiency and Autoinflammation, Nijmegen, The Netherlands. Anna.Simon@radboudumc.nl.
authors.forename: Anna
authors.initials: A
authors.lastname: Simon
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers / Q000097:blood; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D019873:Schnitzler Syndrome / Q000097:blood* / Q000175:diagnosis* / Q000188:drug therapy
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D053583:Interleukin-1beta; C541220:canakinumab