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

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

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1
Université Pierre et Marie Curie-Paris 6, UMR S933, Paris, France.

Abstract

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.

PMID:
21480187
DOI:
10.1002/art.30378
[Indexed for MEDLINE]
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