Role of interleukin-1β in NLRP12-associated autoinflammatory disorders and resistance to anti-interleukin-1 therapy

Arthritis Rheum. 2011 Jul;63(7):2142-8. doi: 10.1002/art.30378.


Objective: A new class of autoinflammatory syndromes called NLRP12-associated disorders (NLRP12AD) has been associated with mutations in NLRP12. Conflicting data on the putative role of NLRP12 in interleukin-1β (IL-1β) signaling have been found in in vitro analyses. This prospective study was undertaken to assess the secretion of IL-1β and 3 IL-1β-induced cytokines (IL-1 receptor antagonist [IL-1Ra], IL-6, and tumor necrosis factor α [TNFα]) in patients' peripheral blood mononuclear cells (PBMCs) cultured ex vivo and to evaluate the patients' response to IL-1Ra (anakinra), a major drug used in the treatment of autoinflammatory disorders.

Methods: Patients' disease manifestations and cytokine measurements were recorded before anakinra treatment was started, during 14 months of therapy, and after discontinuation of anakinra treatment.

Results: Spontaneous secretion of IL-1β by patients' PBMCs was found to be dramatically increased (80-175 fold) compared to healthy controls. Consistent with these findings, anakinra initially led to a marked clinical improvement and to a rapid near-normalization of IL-1β secretion. However, a progressive clinical relapse occurred secondarily, associated with an increase in TNFα secretion, persistent elevated levels of IL-1Ra and IL-6, and a reactivation of IL-1β secretion. Anakinra was discontinued after 14 months of therapy.

Conclusion: Our findings provide in vivo evidence of the crucial role of IL-1β in the pathophysiology of NLRP12AD. This is the first time anakinra has been used to treat this disorder. This study provides new insights into the mechanisms underlying resistance to anti-IL-1 therapy observed in a few patients with autoinflammatory syndromes. Our data also point to the potential of ex vivo cytokine measurements as predictors of response to treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enzyme-Linked Immunosorbent Assay
  • Hereditary Autoinflammatory Diseases / drug therapy
  • Hereditary Autoinflammatory Diseases / genetics
  • Hereditary Autoinflammatory Diseases / immunology*
  • Humans
  • Interleukin 1 Receptor Antagonist Protein / therapeutic use*
  • Interleukin-1beta / metabolism*
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Male
  • Prospective Studies
  • Signal Transduction


  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1beta
  • Intracellular Signaling Peptides and Proteins
  • NLRP12 protein, human