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

• Published in: Arthritis & rheumatology (Hoboken, N.J.) Vol. 63; no. 7; pp. 2142 - 2148
• Main Authors: Jéru, Isabelle, Hentgen, Véronique, Normand, Sylvain, Duquesnoy, Philippe, Cochet, Emmanuelle, Delwail, Adriana, Grateau, Gilles, Marlin, Sandrine, Amselem, Serge, Lecron, Jean‐Claude
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.07.2011; Wiley
• Subjects: Biological and medical sciences; Diseases of the osteoarticular system; Enzyme-Linked Immunosorbent Assay; Genetics; Hereditary Autoinflammatory Diseases - drug therapy; Hereditary Autoinflammatory Diseases - genetics; Hereditary Autoinflammatory Diseases - immunology; Humans; Immunology; Interleukin 1 Receptor Antagonist Protein - therapeutic use; Interleukin-1beta - metabolism; Intracellular Signaling Peptides and Proteins - genetics; Life Sciences; Male; Medical sciences; Prospective Studies; Signal Transduction; Resistance; Interleukin 1β; Treatment; Interleukin 1; Rheumatology
• ISSN: 0004-3591; 2326-5205; 1529-0131; 2326-5191
• 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.