A Pilot Study of IL-1 Inhibition by Anakinra in Acute Gout
Monosodium urate crystals stimulate monocytes and macrophages to release IL-1ß through the NALP3 component of the inflammasome. The effectiveness of IL-1 inhibition in hereditary autoinflammatory syndromes with mutations in the NALP3 protein suggested that IL-1 inhibition might also be effective in relieving the inflammatory manifestations of acute gout. The effectiveness of IL-1 inhibition was first evaluated in a mouse model of monosodium urate crystal-induced inflammation. IL-1 inhibition prevented peritoneal neutrophil accumulation but TNF blockade had no effect. Based on these findings, we performed a pilot, open-labeled study (trial registration number ISRCTN10862635) in 10 patients with gout who could not tolerate or had failed standard antiinflammatory therapies. All patients received 100 mg anakinra daily for 3 days. All 10 patients with acute gout responded rapidly to anakinra. No adverse effects were observed. IL-1 blockade appears to be an effective therapy for acute gouty arthritis. The clinical findings need to be confirmed in a controlled study.
Acute gout is a common cause of arthritis, affecting approximately 1% of the adult population, and epidemiological evidence suggests that its prevalence is increasing. Current treatments during an acute attack include nonsteroidal antiinflammatory drugs (NSAIDs), colchicine and corticosteroids. Although these agents are generally effective, they also present significant risks in patients who have pre-existing renal, cardiovascular and gastrointestinal diseases.
Gouty inflammation is due to monosodium urate (MSU) crystal-induced release of proinflammatory cytokines from leukocytes. Among the many cytokines implicated, IL-1 may have a special role in the inflammatory network, as MSU crystals stimulate IL-1 release by monocytes and synovial mononuclear cells. The MSU crystals trigger IL-1 release through innate immune pathways, which include TLR-2 and TLR-4, found on the surface of monocytes and macrophages, as well as the 'inflammasome' complex that leads to IL-1ß activation. The inflammasome acts as an intracellular sensor of inflammatory stimuli and regulates the activation of caspase-1. On assembly of the inflammasome, which consists of a member of the nucleotide-binding oligomerization domain-leucine rich repeat protein family (such as NALP1, NALP2, NALP3, or IPAF), the adaptor protein ASC and caspase-1, caspase-1 becomes active and cleaves pro-IL-1ß to release the mature p17 form of IL-1ß. Activators of the NALP3 inflammasome include ATP, the microbial cell-wall component muramyl dipeptide and bacterial RNAs. MSU and calcium pyrophosphate dihydrate crystals directly activate the inflammasome via NALP3 in monocytes or macrophages to release active IL-1ß and cause neutrophil influx into the peritoneal space when administered by intraperitoneal injection. These responses were abrogated in ASC or caspase-1 mice.
Spontaneous activation of the NALP3 inflammasome due to mutations in the NALP3 gene has been implicated in hereditary autoinflammatory syndromes such as Muckle-Wells syndrome and chronic infantile neurologic cutaneous articular. Affected patients respond dramatically to IL-1 inhibition, suggesting that IL-1ß plays a crucial role in the pathogenesis of inflammation in these conditions. Based on these findings, we questioned whether IL-1 inhibition may also have a beneficial effect in gouty inflammation.
As treatment with drugs currently used in acute gout is not always well tolerated or is contraindicated due to coexistent medical problems, we investigated the validity of IL-1 blockade as therapy in acute gout. We first analyzed the effects of IL-1 inhibition using the mouse peritoneal model of MSU-induced inflammation and then assessed the effects of anakinra in patients with acute gout who presented contraindications or were refractory to standard treatment in an open study.
Abstract and Introduction
Abstract
Monosodium urate crystals stimulate monocytes and macrophages to release IL-1ß through the NALP3 component of the inflammasome. The effectiveness of IL-1 inhibition in hereditary autoinflammatory syndromes with mutations in the NALP3 protein suggested that IL-1 inhibition might also be effective in relieving the inflammatory manifestations of acute gout. The effectiveness of IL-1 inhibition was first evaluated in a mouse model of monosodium urate crystal-induced inflammation. IL-1 inhibition prevented peritoneal neutrophil accumulation but TNF blockade had no effect. Based on these findings, we performed a pilot, open-labeled study (trial registration number ISRCTN10862635) in 10 patients with gout who could not tolerate or had failed standard antiinflammatory therapies. All patients received 100 mg anakinra daily for 3 days. All 10 patients with acute gout responded rapidly to anakinra. No adverse effects were observed. IL-1 blockade appears to be an effective therapy for acute gouty arthritis. The clinical findings need to be confirmed in a controlled study.
Introduction
Acute gout is a common cause of arthritis, affecting approximately 1% of the adult population, and epidemiological evidence suggests that its prevalence is increasing. Current treatments during an acute attack include nonsteroidal antiinflammatory drugs (NSAIDs), colchicine and corticosteroids. Although these agents are generally effective, they also present significant risks in patients who have pre-existing renal, cardiovascular and gastrointestinal diseases.
Gouty inflammation is due to monosodium urate (MSU) crystal-induced release of proinflammatory cytokines from leukocytes. Among the many cytokines implicated, IL-1 may have a special role in the inflammatory network, as MSU crystals stimulate IL-1 release by monocytes and synovial mononuclear cells. The MSU crystals trigger IL-1 release through innate immune pathways, which include TLR-2 and TLR-4, found on the surface of monocytes and macrophages, as well as the 'inflammasome' complex that leads to IL-1ß activation. The inflammasome acts as an intracellular sensor of inflammatory stimuli and regulates the activation of caspase-1. On assembly of the inflammasome, which consists of a member of the nucleotide-binding oligomerization domain-leucine rich repeat protein family (such as NALP1, NALP2, NALP3, or IPAF), the adaptor protein ASC and caspase-1, caspase-1 becomes active and cleaves pro-IL-1ß to release the mature p17 form of IL-1ß. Activators of the NALP3 inflammasome include ATP, the microbial cell-wall component muramyl dipeptide and bacterial RNAs. MSU and calcium pyrophosphate dihydrate crystals directly activate the inflammasome via NALP3 in monocytes or macrophages to release active IL-1ß and cause neutrophil influx into the peritoneal space when administered by intraperitoneal injection. These responses were abrogated in ASC or caspase-1 mice.
Spontaneous activation of the NALP3 inflammasome due to mutations in the NALP3 gene has been implicated in hereditary autoinflammatory syndromes such as Muckle-Wells syndrome and chronic infantile neurologic cutaneous articular. Affected patients respond dramatically to IL-1 inhibition, suggesting that IL-1ß plays a crucial role in the pathogenesis of inflammation in these conditions. Based on these findings, we questioned whether IL-1 inhibition may also have a beneficial effect in gouty inflammation.
As treatment with drugs currently used in acute gout is not always well tolerated or is contraindicated due to coexistent medical problems, we investigated the validity of IL-1 blockade as therapy in acute gout. We first analyzed the effects of IL-1 inhibition using the mouse peritoneal model of MSU-induced inflammation and then assessed the effects of anakinra in patients with acute gout who presented contraindications or were refractory to standard treatment in an open study.
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