The role of IL-1 in gout: from bench to bedside

The role of IL-1 in gout: from bench to bedside Abstract The translation of our knowledge of the biology of MSU crystal-induced IL-1 secretion gives rise to new targets and therapeutic strategies in the treatment of acute gout. The NACHT, LRR and PYD domains-containing protein 3 inflammasome is key to this, and is the subject of intense research. Novel pathways that modulate inflammasome activation, reactive oxygen species generation and extracellular processing of IL-1 have been described and show promise in in vitro and animal studies. Meanwhile, blocking IL-1 by various IL-1 inhibitors has shown the validity of this concept. Patients with acute gout treated with these inhibitors showed positive clinical and biological responses. More work needs to be performed to assess the risk/benefit profile of anti-IL-1 therapies as well as to identify those who will benefit the most from this novel approach to the treatment of gout. IL-1, inflammasome, gout, inflammation, anti-cytokine therapy Rheumatology key messages IL-1 secreted by MSU crystal-stimulated monocytes and macrophages is the starting point of gouty inflammation. Multiple pathways regulate and modify the activity of the NLRP3 inflammasome and some of them may be targets of novel therapies. Currently available IL-1 inhibitors have been shown to be effective in relieving the signs and symptoms of an acute gout attack. Introduction Following the discovery that microcrystals such as MSU are potent activators of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, IL-1 has emerged as the pivotal cytokine in acute gout in the past 10 years. In parallel, there has been an explosion of interest in innate immunity and the regulation of the innate immune response in human disease, and the discovery that dysfunction of some of these pathways gives rise to auto-inflammatory diseases. We now know a great deal more about NLRP3 inflammasome activation, in particular the role of the mitochondria and of oxidative stress in these processes. Alternative pathways of IL-1 activation by neutrophil proteases also contribute to the sum of IL-1 that is released during an acute attack. In this review, we will present recent data on the pathways that modulate NLRP3 activation by MSU and also summarize the clinical relevance of IL-1 inhibition in acute gout. History of the role of IL-1 in gout Prior to the discovery of the inflammasome-mediated mechanism of IL-1 processing, Duff and colleagues [1, 2] described the ability of MSU crystals to induce the release of IL-1 from monocytes and speculated that this cytokine may be the cause of fever in acute gout. However, research on IL-1 and gout was not pursued further for over 20 years, until there was a resurgence in interest that began with the discovery of the inflammasome. Inflammasome-dependent mechanisms for IL-1β production and pain Martinon described how the assembly of the NLRP3 inflammasome, composed of the adaptor protein apoptosis-associated speck-like protein containing a CARD, NLRP3 and caspase-1, was needed in order for MSU crystals to elicit active IL-1β secretion from monocyte-derived macrophages [3]. Since this initial study, many other agents and mechanisms that modulate NLRP3 inflammasome activity have been reported (see review by Guo et al. [4]), but in the context of MSU crystal activation, two observations deserve mention. The first is the need for monocyte-derived macrophages to be primed so that IL-1β transcription is active before the cell encounters microcrystals, and the second is the generation of reactive oxygen species (ROS) within the cell. The need for priming, an exogenous signal (also known as the second signal that acts in addition to MSU crystals) that induces toll like receptor-mediated transcriptional activation of a set of pro-inflammatory genes, may explain why the presence of crystals does not always elicit the symptoms of gout (as seen during the intercritical phase) and also why an acute attack may be triggered by certain foods. Damaged cells releasing S100 calcium-binding protein A8/9 [5], or long chain fatty acids can act as second signals for IL1-β transcription. The mechanism by which fatty acids stimulate macrophages was identified to be via the toll like receptor 2 pathway [6]. As for ROS, it is unclear what the main cellular source is in gout, or if ROS acts mainly on mitochondria to induce NLRP3 inflammasome assembly or whether other molecular intermediates are required. Recently, our group demonstrated that macrophage secretion of IL-1β upon MSU crystal stimulation was mediated by increased ROS generation by xanthine oxidase, the oxidized form of xanthine dehydrogenase. In particular, xanthine oxidase acted upstream to the phosphatidylinositol-3-kinase and protein kinase signalling pathway and led to NLRP3 inflammasome-dependent IL-1β secretion [7]. Table 1 summarizes the current data on the regulators and modulators of IL-1. Table 1 Summary of the experimental findings in the context of acute gout Inflammatory responses  Anti-inflammatory responses that switch off/control inflammation  Therapeutic approaches  NLRP3 inflammasome-dependent mechanism  Endogenous anti-inflammatory mediators  Dietary supplements      Complement activation (C5a) [8]   CIS, SOCS3, TGF-β1 [9]   Morin [10]          IL-1α and -1β secretion    Diminished IL-1β secretion    Diminished ROS generation          Inflammatory cell infiltration   MicroRNA miR-146a [11]    Diminished IL-1β secretion      Leukotriene B4 [12]    Diminished IL-1β expression   ω-3 fatty acids [13]          ROS generation   HDL [14]    Diminished NLRP3 inflammasome activation          IL-1α and -1β secretion    Diminished IL-1β expression    Diminished IL-1β secretion          Inflammatory cell infiltration    Diminished inflammatory cells infiltration            CXCL1/2 chemokines induction              Pain          Xanthine oxidase [7]              PI3K–AKT activation              ROS generation              IL-1α and -1β secretion              Pain      NLRP3 inflammasome-independent mechanism  Need for a second signal  Fusion protein      Neutrophils enzymes (cathepsin G, elastase, PR3) [15]   Products released by damaged cells [5]   Alpha-1-anti-trypsine-IgG1 Fc [18]          1β secretion   Ingested fatty acids [6]    Diminished PR3 activity      Syk activation [16]      Diminished IL-1β secretion          PI3K recruitment              NFκB activation              IL-1β secretion          Ca2+ influx [17]              Calpains activation              IL-1α secretion      Inflammatory responses  Anti-inflammatory responses that switch off/control inflammation  Therapeutic approaches  NLRP3 inflammasome-dependent mechanism  Endogenous anti-inflammatory mediators  Dietary supplements      Complement activation (C5a) [8]   CIS, SOCS3, TGF-β1 [9]   Morin [10]          IL-1α and -1β secretion    Diminished IL-1β secretion    Diminished ROS generation          Inflammatory cell infiltration   MicroRNA miR-146a [11]    Diminished IL-1β secretion      Leukotriene B4 [12]    Diminished IL-1β expression   ω-3 fatty acids [13]          ROS generation   HDL [14]    Diminished NLRP3 inflammasome activation          IL-1α and -1β secretion    Diminished IL-1β expression    Diminished IL-1β secretion          Inflammatory cell infiltration    Diminished inflammatory cells infiltration            CXCL1/2 chemokines induction              Pain          Xanthine oxidase [7]              PI3K–AKT activation              ROS generation              IL-1α and -1β secretion              Pain      NLRP3 inflammasome-independent mechanism  Need for a second signal  Fusion protein      Neutrophils enzymes (cathepsin G, elastase, PR3) [15]   Products released by damaged cells [5]   Alpha-1-anti-trypsine-IgG1 Fc [18]          1β secretion   Ingested fatty acids [6]    Diminished PR3 activity      Syk activation [16]      Diminished IL-1β secretion          PI3K recruitment              NFκB activation              IL-1β secretion          Ca2+ influx [17]              Calpains activation              IL-1α secretion      CIS: cytokine-inducible Src homology 2-containing protein; CXCL1/2: chemokine (C-X-C motif) ligand 1 and 2; HDL: high density lipoproteins; NFκB: nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K-AKT: phosphatidylinositol-3-kinase and protein kinase; ROS: reactive oxygen species; Syk: spleen tyrosine kinase; SOCS3: suppressor of cytokine signalling 3; TGF-β1: transforming growth factor beta 1. Two other molecular pathways have been reported to influence NLRP3 generation of IL-1 in gout: the complement component C5a and leukotriene B4 (LTB4). C5a potentiated IL-1α and IL-1β secretion in MSU-treated macrophages through the generation of ROS, leading to NLRP3 inflammasome activation and to IL-1β production and leucocyte infiltration [8]. LTB4 generated by the activity of 5-lipoxygenase modulated MSU-induced experimental arthritis and IL-1β secretion via ROS production [12]. Blockade of LTB4 led to reduced IL-1β production and neutrophil influx in the model. These results suggest that when MSU crystals interact with the lipid cell membrane, LTB4 production triggers ROS production, NLRP3 inflammasome activation and IL-1β secretion. Both pathways are potential novel targets for pharmacological intervention as treatment of acute gout. Inflammasome-independent mechanisms for IL-1β and IL-1α production In addition to NLRP3 inflammasome-dependent mechanisms, at least three inflammasome-independent mechanisms participate in MSU-induced IL-1 secretion. In an animal model of gout, pro-IL-1β was released extracellularly upon cell damage and cell death. Infiltrating neutrophils at the site of inflammation release proteases (cathepsin G, elastase and PR3) that are able to cleave pro-IL-1β to its active form [15]. Another inflammasome-independent pathway is through spleen tyrosine kinase activation in neutrophils exposed to MSU crystals, leading to phosphatidylinositol-3-kinase recruitment and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB)-mediated pro-IL-1β induction [16]. Finally, IL-1α may also take part in the inflammatory process of gout. IL-1α secretion induced by MSU crystals was inflammasome-independent, both in vivo and in vitro. MSU-induced IL-1α secretion was calcium (Ca2+)-dependent. In particular, Ca2+ influx causes activation of the Ca2+-dependent proteases calpains that are able to cleave IL-1α [17]. Potential modulators of IL-1 secretion in gout Omega-3 fatty acids, such as eicosapentaenoic acid and docosahexaenoic acid, are reported to have anti-inflammatory properties. Their therapeutic potential in gout has been explored. Bone marrow-derived macrophages treated with docosahexaenoic acid prior to MSU crystal stimulation secreted less IL-1, due to inhibition of NLRP3 inflammasome activation via a pathway dependent on G-protein-coupled receptor 40 and G-protein-coupled receptor 120, two G protein-coupled receptors [13]. Morin, a bioflavonoid known for its anti-inflammatory properties, decreased expression and secretion of the main MSU-induced proinflammatory cytokines and chemokines (IL-1β, IL-6, TNF-α and monocyte chemoattractant protein-1, decreased inflammatory enzymes (inducible nitric oxide synthases and cyclooxygenase 2) and decreased intracellular ROS levels in vitro. These effects could be accounted for by the inactivation of the NFκB signalling pathway [10]. Another promising target for therapy in gout is by inhibition of proteases that process IL-1β by the inflammasome-independent pathway. A recombinant human alpha-1-anti-trypsin–immunoglobulin G1 Fc fusion protein was able to attenuate inflammation in a mouse model of gouty arthritis [18]. In addition, it increased circulating levels of endogenously produced IL-1 receptor antagonist (IL-1Ra). These combined effects may reduce the activities of both IL-1α and IL-1β during an acute gouty attack. IL-1 blockade in gout in clinical practice There are currently four IL-1 inhibitors available for clinical use: anakinra, rilonacept, canakinumab and gevokizumab. Their characteristics are summarized in Table 2. Anakinra is an IL-1Ra that inhibits the binding of IL-1α and IL-1β to the IL-1R and has a short half-life [19]. Rilonacept, a fusion protein, also inhibits the binding of IL-1α and IL-1β, acting as a soluble decoy receptor [20]. Canakinumab is a human monoclonal antibody against IL-1β and has a long half-life [21]. Gevokizumab is a humanized mAb against IL-1β [22, 23]. As there are no published data supporting use of gevokizumab in microcrystalline rheumatic diseases, this drug will not be discussed further in this article. Table 2 Available drugs blocking the IL-1 pathway Drug name  Mode of action  Terminal half-life  Administration  Comments  Anakinra [19]  IL-1 receptor antagonist  4–6 h  Subcutaneous  No RCTs available in the treatment of gout  Rilonacept [20]  Fusion protein, acting as a soluble decoy receptor binding IL-1α and IL-1β  7–9 days  Subcutaneous  No longer commercialized  Canakinumab [21]  Human anti-IL-1β mAb  26 days  Subcutaneous  EMA approval for treatment of adult patients with frequent gouty arthritis and refractory to standard treatments  Gevokizumab [23]  Humanized anti-IL-1β mAb  23 days  Intravenous  No studies published in the treatment of gout  Drug name  Mode of action  Terminal half-life  Administration  Comments  Anakinra [19]  IL-1 receptor antagonist  4–6 h  Subcutaneous  No RCTs available in the treatment of gout  Rilonacept [20]  Fusion protein, acting as a soluble decoy receptor binding IL-1α and IL-1β  7–9 days  Subcutaneous  No longer commercialized  Canakinumab [21]  Human anti-IL-1β mAb  26 days  Subcutaneous  EMA approval for treatment of adult patients with frequent gouty arthritis and refractory to standard treatments  Gevokizumab [23]  Humanized anti-IL-1β mAb  23 days  Intravenous  No studies published in the treatment of gout  EMA: European Medicines Agency; RCTs: randomized controlled trials. Anakinra There have been no randomized controlled trials (RCTs) evaluating anakinra's efficacy in gout. So et al. [24] showed in 2007 in a proof-of-concept, open labelled, pilot study that anakinra given subcutaneously for 3 days in 10 patients with acute gouty arthritis was effective. No treatment-related adverse effects were reported. Chen et al. [25] published in 2010 a retrospective study of 10 patients treated with anakinra for gouty arthritis refractory to steroids, showing good, partial and no response in six, three and one patients, respectively. The authors pointed out a high rate of recurrent flares (90% of patients) during the month after treatment discontinuation. Ghosh et al. [26] studied retrospectively the use of anakinra in 26 hospitalized patients with acute gouty arthritis in whom standard therapy was either ineffective or contraindicated due to comorbidities. Patients were treated with various doses of anakinra but not >5 days. Seventy-three per cent of the patients had a complete resolution of symptoms after 5 days and there were no drug-related safety signals [26]. Ottaviani et al. [27] conducted in 2013 a multicentre retrospective study of 40 patients treated with anakinra for gouty arthritis. Ten patients were treated >10 days. There was good, partial and no response in 36, 2 and 2 patients, respectively. The authors reported seven infectious complications in six patients. They were mainly staphylococcal infections, which occurred in patients on long-term use of anakinra (⩾1 month) and were successfully treated with antibiotics. Anakinra was restarted in five of the six patients after the resolution of the infection [27]. Thus, there is evidence showing efficacy of anakinra in treating acute gouty arthritis, including hospitalized patients and patients with comorbidities, without short-term safety signals. However, there is still a need for evidence of higher quality with RCTs to confirm these data. The short half-life (4–6 h) of this drug limits its use in long duration treatments. Nevertheless, anakinra could be used in hospitalized patients with acute gouty arthritis when standard treatment (NSAIDs, colchicine, steroids) are ineffective or contraindicated. Rilonacept The published data will be summarized briefly, for although this drug has shown efficacy in some studies, its manufacturer has not pursued gout as a therapeutic indication and it is not currently a recognized treatment of gout. Acute gouty arthritis Rilonacept efficacy in acute gouty arthritis has been studied in a phase 3 RCT including 225 patients, with indomethacin as an active comparator. Table 3 summarizes the clinical features of this study. Patients treated with rilonacept or indomethacin as monotherapy were not formally compared in accordance with the pre-specified analysis plan, although indomethacin monotherapy seemed more efficacious, with a faster onset of action than rilonacept alone in this trial [mean change in numerical pain scale (0–10) from baseline at 72 h: −3.87 vs −1.81 for indomethacin and rilonacept, respectively]. The study failed to show a statistically significant difference in pain reduction between patients treated with rilonacept alone and rilonacept with indomethacin [28]. An earlier proof-of-concept single-blind trial included 10 patients with chronic (>6 months) active gouty arthritis who were treated weekly with rilonacept for 6 weeks. A 75% reduction of in pain was reported by 50% of the patients and a significant reduction of hsCRP was also observed [29]. Table 3 RCT investigating IL-1 blockers in acute gouty arthritis Reference  Phase  Patients treated (n)  Intervention  Comparator  Outcome description  Outcome results  Terkeltaub et al. [28]  Phase III  225  Rilonacept 320 mg single injection or placebo  Indomethacin 50 mg tid for 3 days and 25 mg tid up to 9 days or placebo  Mean change from baseline to averaged pain at 24–72 h on NRS (0–10)  Rilonacept + placebo: −1.81 (P < 0.0001) Rilonacept + indomethacin: −4.33 (P = 0.25) Placebo + indomethacin: −3.87  So et al. [30]  Phase II  200  Canakinumab 10/25/50/90/150 mg single subcutaneous injection or placebo  Triamcinolone 40 mg single intramuscular injection or placebo  Percentage change from baseline in VAS score at 72 h, mean  Canakinumab 10 mg: −67.0 (P = 0.33) Canakinumab 25 mg: −67.9 (P = 0.55) Canakinumab 50 mg: −65.1 (P = 0.34) Canakinumab 90 mg: −71.7 (P = 0.08) Canakinumab 150 mg: −84.6 (P < 0.001) Triamcinolone 40 mg: −57.8  Schlesinger et al. [31]  Phase III  228  Canakinumab 150 mg Single subcutaneous injection or placebo  Triamcinolone 40 mg single intramuscular injection or placebo  Difference (mm) in pain intensity on VAS (0–100 mm) at 72 h, mean (95% CI)  −11.4 (−18.2 to − 4.6)  Schlesinger et al. [31]  Phase III  226  −9.8 (−16.3 to − 3.2)  Reference  Phase  Patients treated (n)  Intervention  Comparator  Outcome description  Outcome results  Terkeltaub et al. [28]  Phase III  225  Rilonacept 320 mg single injection or placebo  Indomethacin 50 mg tid for 3 days and 25 mg tid up to 9 days or placebo  Mean change from baseline to averaged pain at 24–72 h on NRS (0–10)  Rilonacept + placebo: −1.81 (P < 0.0001) Rilonacept + indomethacin: −4.33 (P = 0.25) Placebo + indomethacin: −3.87  So et al. [30]  Phase II  200  Canakinumab 10/25/50/90/150 mg single subcutaneous injection or placebo  Triamcinolone 40 mg single intramuscular injection or placebo  Percentage change from baseline in VAS score at 72 h, mean  Canakinumab 10 mg: −67.0 (P = 0.33) Canakinumab 25 mg: −67.9 (P = 0.55) Canakinumab 50 mg: −65.1 (P = 0.34) Canakinumab 90 mg: −71.7 (P = 0.08) Canakinumab 150 mg: −84.6 (P < 0.001) Triamcinolone 40 mg: −57.8  Schlesinger et al. [31]  Phase III  228  Canakinumab 150 mg Single subcutaneous injection or placebo  Triamcinolone 40 mg single intramuscular injection or placebo  Difference (mm) in pain intensity on VAS (0–100 mm) at 72 h, mean (95% CI)  −11.4 (−18.2 to − 4.6)  Schlesinger et al. [31]  Phase III  226  −9.8 (−16.3 to − 3.2)  NRS: numerical rating scale; RCT: randomized controlled trial; VAS: visual analogue scale. Prevention of acute gout flares when starting uric acid lowering therapy Three RCTs investigated the efficacy of rilonacept to prevent acute gout flares during initiation of uric acid lowering therapy (ULT) [32–34] and a fourth study (1315 patients) was designed to assess safety of rilonacept treatment [35]. The studies' characteristics are summarized in Table 4. These studies consistently showed a decrease in the number of gout flares in patients treated with rilonacept compared with placebo. A RCT with 1315 patients assessed the safety of rilonacept compared with placebo when initiating a ULT therapy [35]. Sixty-seven per cent of patients presented an adverse event (AE) in the rilonacept compared with 59% in the placebo group. The most common reported AEs in both groups were headache, arthralgia and accidental overdose. Patients treated with rilonacept had slightly more frequently raised aminotransferase, creatinine kinase and triglycerides levels. There were more injection site reactions in the rilonacept group than in the placebo group (15% vs 3%). The incidence of serious infections was similar in both groups (0.5% with rilonacept and 0.9% with placebo), without any cases of opportunistic infection or tuberculosis to report. Upper respiratory tract infections consisted of around half of the reported infectious events in both groups. Six deaths were observed (rilonacept group: two myocardial infarctions, one cerebrovascular event; placebo group: one sudden cardiac death, one collapsed lung, one unknown aetiology). Only one death was considered to be related to the study treatment and was treated with placebo. Table 4 RCT investigating IL-1 blockers in prevention of acute gout flares during initiation of ULT Reference  Phase  Patients treated (n)  Intervention  Comparator  Treatment duration  ULT  Mean number of GF per patient Drug (max. dose) vs comparator (time point)  Patients with ≥1 GF (%) Drug (max. dose) vs comparator at week 16  Schumacher et al. [34]  Phase II  83  Rilonacept 160 mg subcutaneous once weekly  Placebo  16 weeks  Allopurinol  0.15 vs 0.79 (w12) P = 0.001  22.0 vs 47.6% (P < 0.02)  Schumacher et al. [33]  Phase III  240  Rilonacept 160 mg/80 mg subcutaneous once weekly  Placebo  16 weeks  Allopurinol  0.21 (95% CI: 0.09, 0.33) vs 1.06 (95% CI: 0.71, 1.42) (w16)  16.3 vs 46.8% (P < 0.001)  Mitha et al. [32]  Phase III  248  Rilonacept 160 mg/80 mg subcutaneous once weekly  Placebo  16 weeks  Allopurinol  0.34 (95% CI: 0.15, 0.52) vs 1.23 (95% CI: 0.89, 1.58) (w16)  20.5 vs 56.1% (P < 0.0001)  Sundy et al. [35]  Phase III  1315  Rilonacept 160 mg subcutaneous once weekly  Placebo  16 weeks  Allopurinol  0.51 (95% CI: 0.44, 0.59) vs 1.73 (95% CI: 1.44, 2.02) (w16)  25.7 vs 51.1% (P < 0.0001)  Schlesinger et al. [36]  Phase II  432  Canakinumab 25/50/100/200/300 mg subcutaneous single dose or 4-weekly intervals (50 mg day 1 and at week 4, 25 mg at weeks 8 and 12)  Colchicine 0.5 mg/day orally  16 weeks  Allopurinol  0.23 vs 0.75 (P ≤ 0.05) (w16)  15.1 vs 44.4% (P ≤ 0.05)  Reference  Phase  Patients treated (n)  Intervention  Comparator  Treatment duration  ULT  Mean number of GF per patient Drug (max. dose) vs comparator (time point)  Patients with ≥1 GF (%) Drug (max. dose) vs comparator at week 16  Schumacher et al. [34]  Phase II  83  Rilonacept 160 mg subcutaneous once weekly  Placebo  16 weeks  Allopurinol  0.15 vs 0.79 (w12) P = 0.001  22.0 vs 47.6% (P < 0.02)  Schumacher et al. [33]  Phase III  240  Rilonacept 160 mg/80 mg subcutaneous once weekly  Placebo  16 weeks  Allopurinol  0.21 (95% CI: 0.09, 0.33) vs 1.06 (95% CI: 0.71, 1.42) (w16)  16.3 vs 46.8% (P < 0.001)  Mitha et al. [32]  Phase III  248  Rilonacept 160 mg/80 mg subcutaneous once weekly  Placebo  16 weeks  Allopurinol  0.34 (95% CI: 0.15, 0.52) vs 1.23 (95% CI: 0.89, 1.58) (w16)  20.5 vs 56.1% (P < 0.0001)  Sundy et al. [35]  Phase III  1315  Rilonacept 160 mg subcutaneous once weekly  Placebo  16 weeks  Allopurinol  0.51 (95% CI: 0.44, 0.59) vs 1.73 (95% CI: 1.44, 2.02) (w16)  25.7 vs 51.1% (P < 0.0001)  Schlesinger et al. [36]  Phase II  432  Canakinumab 25/50/100/200/300 mg subcutaneous single dose or 4-weekly intervals (50 mg day 1 and at week 4, 25 mg at weeks 8 and 12)  Colchicine 0.5 mg/day orally  16 weeks  Allopurinol  0.23 vs 0.75 (P ≤ 0.05) (w16)  15.1 vs 44.4% (P ≤ 0.05)  GF: gout flare; RCT: randomized controlled trials; ULT: uric acid-lowering therapy. Canakinumab A phase 2 RCT investigated the dose and efficacy of canakinumab in acute gouty arthritis in patients unresponsive or with contraindications to NSAIDs or colchicine (Table 3). Patients included in all canakinumab groups showed a dose-dependent efficacy on pain, swelling, recurrence of flares and inflammatory markers compared with patients with triamcinolone. The dose of 150 mg of canakinumab was further studied in two phase 3 multicentre RCTs of 24 weeks’ duration including 456 patients [31]. Analysis of pooled data of both studies showed than the mean pain score 72 h after treatment, which was the primary end point, was significantly better in the canakinumab group than in the triamcinolone group. Secondary outcomes were also better in the canakinumab group. In these studies, canakinumab decreased the risk of new flares by 62% over a 12-week period compared with triamcinolone. However, patients treated with canakinumab experienced more AEs than patients receiving triamcinolone (66% vs 53%), which were usually mild or moderate. There were more infections (20% vs 12%), especially more serious infections (1.8% vs 0%) in the canakinumab group, but no opportunistic infections were reported. The four serious infectious events in the canakinumab group consisted of submandibular abscess, forearm abscess, pneumonia and gastroenteritis. Two deaths were observed and considered to be unrelated to treatment. One patient was treated with canakinumab (intracranial haemorrhage) and the other with triamcinolone (pulmonary embolism). A post hoc analysis of the same dataset using a composite end point also showed superiority of canakinumab over triamcinolone [37]. A multicentre RCT with 432 patients investigated the efficacy of canakinumab in preventing acute gout flares when starting allopurinol [36]. Patients were randomly attributed to a single dose of canakinumab (dose ranging from 25 to 300 mg), with 4-monthly canakinumab injections or with an oral dose of colchicine 0.5 mg daily for 16 weeks. Patients were followed up for 6 months. The mean number of flares per patient was lower, the mean duration of flares shorter and the time to the first new gout flare longer in all canakinumab groups compared with colchicine. With a canakinumab dose of 50 mg or more, a reduction in 62–72% in the mean number of flares per patient was observed compared with the colchicine group. Thus, there is evidence supporting the use of canakinumab to treat acute gouty arthritis. Although there is debate on the choice and the dose of the active comparator, the data showing sufficient efficacy to obtain approval by the European Medicines Agency in 2013 for its use in adult patients with frequent gouty arthritis (three or more attacks in the previous year) and in whom repeated courses of steroids are inappropriate and in whom colchicine and NSAIDs are either contraindicated, or not tolerated or do not show enough efficacy. Analysis of the same data set by the US Food and Drug Administration, however, did not result in approval, primarily because of safety concerns, especially the increased risk of infections that canakinumab poses. International recommandations In the ACR recommendations for the management of gout published in 2012, use of an IL-1 inhibitor (anakinra or canakinumab) to treat patients suffering from severe attacks of acute gouty arthritis refractory to other treatments was proposed. However, due to the absence of RCTs for anakinra and the safety concerns and the lack of US Food and Drug Administration approval for canakinumab, the role of IL-1 inhibition in acute gout was assessed as uncertain [38]. The 2016 EULAR recommendations for the management of gout consider IL-1 blockers as a valid approach to treat acute gout flares in patients with frequent flares and who present contraindications to colchicine, NSAIDs, oral and injectable corticosteroids. A current infection should be a contraindication to IL-1 blocker use. EULAR recommends adjustment of ULT to achieve the uricaemia target after a treatment with an IL-1 blocker. A head-to-head trial of anakinra vs a conventional anti-inflammatory agent for the treatment of flares was proposed for future research [39]. Cost implications Comparison between treatment costs is difficult to achieve as IL-1 inhibitors are not available in all countries and there is a high variability of drug prices between countries due to health systems specificities. Moreover, prices are defined for approved indications like rheumatoid for anakinra and cryopyrin-associated periodic syndromes for canakinumab and not for gout treatment. The cost of one dose of anakinra 100 mg in France in 2017 is €31, and thus the cost of a 3-day treatment for gout flare should be around €100. In the UK, the cost of one dose of canakinumab 150 mg was £9928 in 2013 and €11 000 in France in 2017 for cryopyrin-associated periodic syndromes indication [40, 41]. Rilonacept is no longer available on the market. Conclusions There is a wealth of basic and clinical data to show that IL-1 secretion plays a key role in acute gout, and therapies that block IL-1, either by binding to the cytokine or its receptor, are attractive strategies to curtail the inflammatory storm. Inhibition of IL-1 is feasible and a number of IL-1 inhibitors are already available, thus it could complement currently available approaches to alleviate the acute gout attack. Currently only one IL-1 inhibitor has gout as a therapeutic indication and many patients are treated on an off-label basis. The challenges that need to be addressed in the near future for this therapy to be more widely used are: to determine the precise clinical situations that justify using an IL-1 inhibitor; to prove its efficacy in controlled trials with an active comparator; and a rigorous cost–benefit analysis, in particular evaluating the potential infectious side effects to assure patients and physicians of the safety of such an approach. 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Ann Rheum Dis  2017; 76: 29– 42. Google Scholar CrossRef Search ADS PubMed  40 French Ministry of Social Affairs and Health. Drugs Prices Search Engine. http://medicprix.sante.gouv.fr/medicprix/recherchePresentationInitialisee.do (21 November 2017, date last accessed). 41 National Institute for Health and Care Excellence (NICE). Gouty arthritis: canakinumab. Evidence summary [ESNM23]. https://www.nice.org.uk/advice/esnm23/chapter/Key-points-from-the-evidence (21 November 2017, date last accessed). © The Author 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology Oxford University Press

The role of IL-1 in gout: from bench to bedside

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Abstract

Abstract The translation of our knowledge of the biology of MSU crystal-induced IL-1 secretion gives rise to new targets and therapeutic strategies in the treatment of acute gout. The NACHT, LRR and PYD domains-containing protein 3 inflammasome is key to this, and is the subject of intense research. Novel pathways that modulate inflammasome activation, reactive oxygen species generation and extracellular processing of IL-1 have been described and show promise in in vitro and animal studies. Meanwhile, blocking IL-1 by various IL-1 inhibitors has shown the validity of this concept. Patients with acute gout treated with these inhibitors showed positive clinical and biological responses. More work needs to be performed to assess the risk/benefit profile of anti-IL-1 therapies as well as to identify those who will benefit the most from this novel approach to the treatment of gout. IL-1, inflammasome, gout, inflammation, anti-cytokine therapy Rheumatology key messages IL-1 secreted by MSU crystal-stimulated monocytes and macrophages is the starting point of gouty inflammation. Multiple pathways regulate and modify the activity of the NLRP3 inflammasome and some of them may be targets of novel therapies. Currently available IL-1 inhibitors have been shown to be effective in relieving the signs and symptoms of an acute gout attack. Introduction Following the discovery that microcrystals such as MSU are potent activators of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, IL-1 has emerged as the pivotal cytokine in acute gout in the past 10 years. In parallel, there has been an explosion of interest in innate immunity and the regulation of the innate immune response in human disease, and the discovery that dysfunction of some of these pathways gives rise to auto-inflammatory diseases. We now know a great deal more about NLRP3 inflammasome activation, in particular the role of the mitochondria and of oxidative stress in these processes. Alternative pathways of IL-1 activation by neutrophil proteases also contribute to the sum of IL-1 that is released during an acute attack. In this review, we will present recent data on the pathways that modulate NLRP3 activation by MSU and also summarize the clinical relevance of IL-1 inhibition in acute gout. History of the role of IL-1 in gout Prior to the discovery of the inflammasome-mediated mechanism of IL-1 processing, Duff and colleagues [1, 2] described the ability of MSU crystals to induce the release of IL-1 from monocytes and speculated that this cytokine may be the cause of fever in acute gout. However, research on IL-1 and gout was not pursued further for over 20 years, until there was a resurgence in interest that began with the discovery of the inflammasome. Inflammasome-dependent mechanisms for IL-1β production and pain Martinon described how the assembly of the NLRP3 inflammasome, composed of the adaptor protein apoptosis-associated speck-like protein containing a CARD, NLRP3 and caspase-1, was needed in order for MSU crystals to elicit active IL-1β secretion from monocyte-derived macrophages [3]. Since this initial study, many other agents and mechanisms that modulate NLRP3 inflammasome activity have been reported (see review by Guo et al. [4]), but in the context of MSU crystal activation, two observations deserve mention. The first is the need for monocyte-derived macrophages to be primed so that IL-1β transcription is active before the cell encounters microcrystals, and the second is the generation of reactive oxygen species (ROS) within the cell. The need for priming, an exogenous signal (also known as the second signal that acts in addition to MSU crystals) that induces toll like receptor-mediated transcriptional activation of a set of pro-inflammatory genes, may explain why the presence of crystals does not always elicit the symptoms of gout (as seen during the intercritical phase) and also why an acute attack may be triggered by certain foods. Damaged cells releasing S100 calcium-binding protein A8/9 [5], or long chain fatty acids can act as second signals for IL1-β transcription. The mechanism by which fatty acids stimulate macrophages was identified to be via the toll like receptor 2 pathway [6]. As for ROS, it is unclear what the main cellular source is in gout, or if ROS acts mainly on mitochondria to induce NLRP3 inflammasome assembly or whether other molecular intermediates are required. Recently, our group demonstrated that macrophage secretion of IL-1β upon MSU crystal stimulation was mediated by increased ROS generation by xanthine oxidase, the oxidized form of xanthine dehydrogenase. In particular, xanthine oxidase acted upstream to the phosphatidylinositol-3-kinase and protein kinase signalling pathway and led to NLRP3 inflammasome-dependent IL-1β secretion [7]. Table 1 summarizes the current data on the regulators and modulators of IL-1. Table 1 Summary of the experimental findings in the context of acute gout Inflammatory responses  Anti-inflammatory responses that switch off/control inflammation  Therapeutic approaches  NLRP3 inflammasome-dependent mechanism  Endogenous anti-inflammatory mediators  Dietary supplements      Complement activation (C5a) [8]   CIS, SOCS3, TGF-β1 [9]   Morin [10]          IL-1α and -1β secretion    Diminished IL-1β secretion    Diminished ROS generation          Inflammatory cell infiltration   MicroRNA miR-146a [11]    Diminished IL-1β secretion      Leukotriene B4 [12]    Diminished IL-1β expression   ω-3 fatty acids [13]          ROS generation   HDL [14]    Diminished NLRP3 inflammasome activation          IL-1α and -1β secretion    Diminished IL-1β expression    Diminished IL-1β secretion          Inflammatory cell infiltration    Diminished inflammatory cells infiltration            CXCL1/2 chemokines induction              Pain          Xanthine oxidase [7]              PI3K–AKT activation              ROS generation              IL-1α and -1β secretion              Pain      NLRP3 inflammasome-independent mechanism  Need for a second signal  Fusion protein      Neutrophils enzymes (cathepsin G, elastase, PR3) [15]   Products released by damaged cells [5]   Alpha-1-anti-trypsine-IgG1 Fc [18]          1β secretion   Ingested fatty acids [6]    Diminished PR3 activity      Syk activation [16]      Diminished IL-1β secretion          PI3K recruitment              NFκB activation              IL-1β secretion          Ca2+ influx [17]              Calpains activation              IL-1α secretion      Inflammatory responses  Anti-inflammatory responses that switch off/control inflammation  Therapeutic approaches  NLRP3 inflammasome-dependent mechanism  Endogenous anti-inflammatory mediators  Dietary supplements      Complement activation (C5a) [8]   CIS, SOCS3, TGF-β1 [9]   Morin [10]          IL-1α and -1β secretion    Diminished IL-1β secretion    Diminished ROS generation          Inflammatory cell infiltration   MicroRNA miR-146a [11]    Diminished IL-1β secretion      Leukotriene B4 [12]    Diminished IL-1β expression   ω-3 fatty acids [13]          ROS generation   HDL [14]    Diminished NLRP3 inflammasome activation          IL-1α and -1β secretion    Diminished IL-1β expression    Diminished IL-1β secretion          Inflammatory cell infiltration    Diminished inflammatory cells infiltration            CXCL1/2 chemokines induction              Pain          Xanthine oxidase [7]              PI3K–AKT activation              ROS generation              IL-1α and -1β secretion              Pain      NLRP3 inflammasome-independent mechanism  Need for a second signal  Fusion protein      Neutrophils enzymes (cathepsin G, elastase, PR3) [15]   Products released by damaged cells [5]   Alpha-1-anti-trypsine-IgG1 Fc [18]          1β secretion   Ingested fatty acids [6]    Diminished PR3 activity      Syk activation [16]      Diminished IL-1β secretion          PI3K recruitment              NFκB activation              IL-1β secretion          Ca2+ influx [17]              Calpains activation              IL-1α secretion      CIS: cytokine-inducible Src homology 2-containing protein; CXCL1/2: chemokine (C-X-C motif) ligand 1 and 2; HDL: high density lipoproteins; NFκB: nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K-AKT: phosphatidylinositol-3-kinase and protein kinase; ROS: reactive oxygen species; Syk: spleen tyrosine kinase; SOCS3: suppressor of cytokine signalling 3; TGF-β1: transforming growth factor beta 1. Two other molecular pathways have been reported to influence NLRP3 generation of IL-1 in gout: the complement component C5a and leukotriene B4 (LTB4). C5a potentiated IL-1α and IL-1β secretion in MSU-treated macrophages through the generation of ROS, leading to NLRP3 inflammasome activation and to IL-1β production and leucocyte infiltration [8]. LTB4 generated by the activity of 5-lipoxygenase modulated MSU-induced experimental arthritis and IL-1β secretion via ROS production [12]. Blockade of LTB4 led to reduced IL-1β production and neutrophil influx in the model. These results suggest that when MSU crystals interact with the lipid cell membrane, LTB4 production triggers ROS production, NLRP3 inflammasome activation and IL-1β secretion. Both pathways are potential novel targets for pharmacological intervention as treatment of acute gout. Inflammasome-independent mechanisms for IL-1β and IL-1α production In addition to NLRP3 inflammasome-dependent mechanisms, at least three inflammasome-independent mechanisms participate in MSU-induced IL-1 secretion. In an animal model of gout, pro-IL-1β was released extracellularly upon cell damage and cell death. Infiltrating neutrophils at the site of inflammation release proteases (cathepsin G, elastase and PR3) that are able to cleave pro-IL-1β to its active form [15]. Another inflammasome-independent pathway is through spleen tyrosine kinase activation in neutrophils exposed to MSU crystals, leading to phosphatidylinositol-3-kinase recruitment and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB)-mediated pro-IL-1β induction [16]. Finally, IL-1α may also take part in the inflammatory process of gout. IL-1α secretion induced by MSU crystals was inflammasome-independent, both in vivo and in vitro. MSU-induced IL-1α secretion was calcium (Ca2+)-dependent. In particular, Ca2+ influx causes activation of the Ca2+-dependent proteases calpains that are able to cleave IL-1α [17]. Potential modulators of IL-1 secretion in gout Omega-3 fatty acids, such as eicosapentaenoic acid and docosahexaenoic acid, are reported to have anti-inflammatory properties. Their therapeutic potential in gout has been explored. Bone marrow-derived macrophages treated with docosahexaenoic acid prior to MSU crystal stimulation secreted less IL-1, due to inhibition of NLRP3 inflammasome activation via a pathway dependent on G-protein-coupled receptor 40 and G-protein-coupled receptor 120, two G protein-coupled receptors [13]. Morin, a bioflavonoid known for its anti-inflammatory properties, decreased expression and secretion of the main MSU-induced proinflammatory cytokines and chemokines (IL-1β, IL-6, TNF-α and monocyte chemoattractant protein-1, decreased inflammatory enzymes (inducible nitric oxide synthases and cyclooxygenase 2) and decreased intracellular ROS levels in vitro. These effects could be accounted for by the inactivation of the NFκB signalling pathway [10]. Another promising target for therapy in gout is by inhibition of proteases that process IL-1β by the inflammasome-independent pathway. A recombinant human alpha-1-anti-trypsin–immunoglobulin G1 Fc fusion protein was able to attenuate inflammation in a mouse model of gouty arthritis [18]. In addition, it increased circulating levels of endogenously produced IL-1 receptor antagonist (IL-1Ra). These combined effects may reduce the activities of both IL-1α and IL-1β during an acute gouty attack. IL-1 blockade in gout in clinical practice There are currently four IL-1 inhibitors available for clinical use: anakinra, rilonacept, canakinumab and gevokizumab. Their characteristics are summarized in Table 2. Anakinra is an IL-1Ra that inhibits the binding of IL-1α and IL-1β to the IL-1R and has a short half-life [19]. Rilonacept, a fusion protein, also inhibits the binding of IL-1α and IL-1β, acting as a soluble decoy receptor [20]. Canakinumab is a human monoclonal antibody against IL-1β and has a long half-life [21]. Gevokizumab is a humanized mAb against IL-1β [22, 23]. As there are no published data supporting use of gevokizumab in microcrystalline rheumatic diseases, this drug will not be discussed further in this article. Table 2 Available drugs blocking the IL-1 pathway Drug name  Mode of action  Terminal half-life  Administration  Comments  Anakinra [19]  IL-1 receptor antagonist  4–6 h  Subcutaneous  No RCTs available in the treatment of gout  Rilonacept [20]  Fusion protein, acting as a soluble decoy receptor binding IL-1α and IL-1β  7–9 days  Subcutaneous  No longer commercialized  Canakinumab [21]  Human anti-IL-1β mAb  26 days  Subcutaneous  EMA approval for treatment of adult patients with frequent gouty arthritis and refractory to standard treatments  Gevokizumab [23]  Humanized anti-IL-1β mAb  23 days  Intravenous  No studies published in the treatment of gout  Drug name  Mode of action  Terminal half-life  Administration  Comments  Anakinra [19]  IL-1 receptor antagonist  4–6 h  Subcutaneous  No RCTs available in the treatment of gout  Rilonacept [20]  Fusion protein, acting as a soluble decoy receptor binding IL-1α and IL-1β  7–9 days  Subcutaneous  No longer commercialized  Canakinumab [21]  Human anti-IL-1β mAb  26 days  Subcutaneous  EMA approval for treatment of adult patients with frequent gouty arthritis and refractory to standard treatments  Gevokizumab [23]  Humanized anti-IL-1β mAb  23 days  Intravenous  No studies published in the treatment of gout  EMA: European Medicines Agency; RCTs: randomized controlled trials. Anakinra There have been no randomized controlled trials (RCTs) evaluating anakinra's efficacy in gout. So et al. [24] showed in 2007 in a proof-of-concept, open labelled, pilot study that anakinra given subcutaneously for 3 days in 10 patients with acute gouty arthritis was effective. No treatment-related adverse effects were reported. Chen et al. [25] published in 2010 a retrospective study of 10 patients treated with anakinra for gouty arthritis refractory to steroids, showing good, partial and no response in six, three and one patients, respectively. The authors pointed out a high rate of recurrent flares (90% of patients) during the month after treatment discontinuation. Ghosh et al. [26] studied retrospectively the use of anakinra in 26 hospitalized patients with acute gouty arthritis in whom standard therapy was either ineffective or contraindicated due to comorbidities. Patients were treated with various doses of anakinra but not >5 days. Seventy-three per cent of the patients had a complete resolution of symptoms after 5 days and there were no drug-related safety signals [26]. Ottaviani et al. [27] conducted in 2013 a multicentre retrospective study of 40 patients treated with anakinra for gouty arthritis. Ten patients were treated >10 days. There was good, partial and no response in 36, 2 and 2 patients, respectively. The authors reported seven infectious complications in six patients. They were mainly staphylococcal infections, which occurred in patients on long-term use of anakinra (⩾1 month) and were successfully treated with antibiotics. Anakinra was restarted in five of the six patients after the resolution of the infection [27]. Thus, there is evidence showing efficacy of anakinra in treating acute gouty arthritis, including hospitalized patients and patients with comorbidities, without short-term safety signals. However, there is still a need for evidence of higher quality with RCTs to confirm these data. The short half-life (4–6 h) of this drug limits its use in long duration treatments. Nevertheless, anakinra could be used in hospitalized patients with acute gouty arthritis when standard treatment (NSAIDs, colchicine, steroids) are ineffective or contraindicated. Rilonacept The published data will be summarized briefly, for although this drug has shown efficacy in some studies, its manufacturer has not pursued gout as a therapeutic indication and it is not currently a recognized treatment of gout. Acute gouty arthritis Rilonacept efficacy in acute gouty arthritis has been studied in a phase 3 RCT including 225 patients, with indomethacin as an active comparator. Table 3 summarizes the clinical features of this study. Patients treated with rilonacept or indomethacin as monotherapy were not formally compared in accordance with the pre-specified analysis plan, although indomethacin monotherapy seemed more efficacious, with a faster onset of action than rilonacept alone in this trial [mean change in numerical pain scale (0–10) from baseline at 72 h: −3.87 vs −1.81 for indomethacin and rilonacept, respectively]. The study failed to show a statistically significant difference in pain reduction between patients treated with rilonacept alone and rilonacept with indomethacin [28]. An earlier proof-of-concept single-blind trial included 10 patients with chronic (>6 months) active gouty arthritis who were treated weekly with rilonacept for 6 weeks. A 75% reduction of in pain was reported by 50% of the patients and a significant reduction of hsCRP was also observed [29]. Table 3 RCT investigating IL-1 blockers in acute gouty arthritis Reference  Phase  Patients treated (n)  Intervention  Comparator  Outcome description  Outcome results  Terkeltaub et al. [28]  Phase III  225  Rilonacept 320 mg single injection or placebo  Indomethacin 50 mg tid for 3 days and 25 mg tid up to 9 days or placebo  Mean change from baseline to averaged pain at 24–72 h on NRS (0–10)  Rilonacept + placebo: −1.81 (P < 0.0001) Rilonacept + indomethacin: −4.33 (P = 0.25) Placebo + indomethacin: −3.87  So et al. [30]  Phase II  200  Canakinumab 10/25/50/90/150 mg single subcutaneous injection or placebo  Triamcinolone 40 mg single intramuscular injection or placebo  Percentage change from baseline in VAS score at 72 h, mean  Canakinumab 10 mg: −67.0 (P = 0.33) Canakinumab 25 mg: −67.9 (P = 0.55) Canakinumab 50 mg: −65.1 (P = 0.34) Canakinumab 90 mg: −71.7 (P = 0.08) Canakinumab 150 mg: −84.6 (P < 0.001) Triamcinolone 40 mg: −57.8  Schlesinger et al. [31]  Phase III  228  Canakinumab 150 mg Single subcutaneous injection or placebo  Triamcinolone 40 mg single intramuscular injection or placebo  Difference (mm) in pain intensity on VAS (0–100 mm) at 72 h, mean (95% CI)  −11.4 (−18.2 to − 4.6)  Schlesinger et al. [31]  Phase III  226  −9.8 (−16.3 to − 3.2)  Reference  Phase  Patients treated (n)  Intervention  Comparator  Outcome description  Outcome results  Terkeltaub et al. [28]  Phase III  225  Rilonacept 320 mg single injection or placebo  Indomethacin 50 mg tid for 3 days and 25 mg tid up to 9 days or placebo  Mean change from baseline to averaged pain at 24–72 h on NRS (0–10)  Rilonacept + placebo: −1.81 (P < 0.0001) Rilonacept + indomethacin: −4.33 (P = 0.25) Placebo + indomethacin: −3.87  So et al. [30]  Phase II  200  Canakinumab 10/25/50/90/150 mg single subcutaneous injection or placebo  Triamcinolone 40 mg single intramuscular injection or placebo  Percentage change from baseline in VAS score at 72 h, mean  Canakinumab 10 mg: −67.0 (P = 0.33) Canakinumab 25 mg: −67.9 (P = 0.55) Canakinumab 50 mg: −65.1 (P = 0.34) Canakinumab 90 mg: −71.7 (P = 0.08) Canakinumab 150 mg: −84.6 (P < 0.001) Triamcinolone 40 mg: −57.8  Schlesinger et al. [31]  Phase III  228  Canakinumab 150 mg Single subcutaneous injection or placebo  Triamcinolone 40 mg single intramuscular injection or placebo  Difference (mm) in pain intensity on VAS (0–100 mm) at 72 h, mean (95% CI)  −11.4 (−18.2 to − 4.6)  Schlesinger et al. [31]  Phase III  226  −9.8 (−16.3 to − 3.2)  NRS: numerical rating scale; RCT: randomized controlled trial; VAS: visual analogue scale. Prevention of acute gout flares when starting uric acid lowering therapy Three RCTs investigated the efficacy of rilonacept to prevent acute gout flares during initiation of uric acid lowering therapy (ULT) [32–34] and a fourth study (1315 patients) was designed to assess safety of rilonacept treatment [35]. The studies' characteristics are summarized in Table 4. These studies consistently showed a decrease in the number of gout flares in patients treated with rilonacept compared with placebo. A RCT with 1315 patients assessed the safety of rilonacept compared with placebo when initiating a ULT therapy [35]. Sixty-seven per cent of patients presented an adverse event (AE) in the rilonacept compared with 59% in the placebo group. The most common reported AEs in both groups were headache, arthralgia and accidental overdose. Patients treated with rilonacept had slightly more frequently raised aminotransferase, creatinine kinase and triglycerides levels. There were more injection site reactions in the rilonacept group than in the placebo group (15% vs 3%). The incidence of serious infections was similar in both groups (0.5% with rilonacept and 0.9% with placebo), without any cases of opportunistic infection or tuberculosis to report. Upper respiratory tract infections consisted of around half of the reported infectious events in both groups. Six deaths were observed (rilonacept group: two myocardial infarctions, one cerebrovascular event; placebo group: one sudden cardiac death, one collapsed lung, one unknown aetiology). Only one death was considered to be related to the study treatment and was treated with placebo. Table 4 RCT investigating IL-1 blockers in prevention of acute gout flares during initiation of ULT Reference  Phase  Patients treated (n)  Intervention  Comparator  Treatment duration  ULT  Mean number of GF per patient Drug (max. dose) vs comparator (time point)  Patients with ≥1 GF (%) Drug (max. dose) vs comparator at week 16  Schumacher et al. [34]  Phase II  83  Rilonacept 160 mg subcutaneous once weekly  Placebo  16 weeks  Allopurinol  0.15 vs 0.79 (w12) P = 0.001  22.0 vs 47.6% (P < 0.02)  Schumacher et al. [33]  Phase III  240  Rilonacept 160 mg/80 mg subcutaneous once weekly  Placebo  16 weeks  Allopurinol  0.21 (95% CI: 0.09, 0.33) vs 1.06 (95% CI: 0.71, 1.42) (w16)  16.3 vs 46.8% (P < 0.001)  Mitha et al. [32]  Phase III  248  Rilonacept 160 mg/80 mg subcutaneous once weekly  Placebo  16 weeks  Allopurinol  0.34 (95% CI: 0.15, 0.52) vs 1.23 (95% CI: 0.89, 1.58) (w16)  20.5 vs 56.1% (P < 0.0001)  Sundy et al. [35]  Phase III  1315  Rilonacept 160 mg subcutaneous once weekly  Placebo  16 weeks  Allopurinol  0.51 (95% CI: 0.44, 0.59) vs 1.73 (95% CI: 1.44, 2.02) (w16)  25.7 vs 51.1% (P < 0.0001)  Schlesinger et al. [36]  Phase II  432  Canakinumab 25/50/100/200/300 mg subcutaneous single dose or 4-weekly intervals (50 mg day 1 and at week 4, 25 mg at weeks 8 and 12)  Colchicine 0.5 mg/day orally  16 weeks  Allopurinol  0.23 vs 0.75 (P ≤ 0.05) (w16)  15.1 vs 44.4% (P ≤ 0.05)  Reference  Phase  Patients treated (n)  Intervention  Comparator  Treatment duration  ULT  Mean number of GF per patient Drug (max. dose) vs comparator (time point)  Patients with ≥1 GF (%) Drug (max. dose) vs comparator at week 16  Schumacher et al. [34]  Phase II  83  Rilonacept 160 mg subcutaneous once weekly  Placebo  16 weeks  Allopurinol  0.15 vs 0.79 (w12) P = 0.001  22.0 vs 47.6% (P < 0.02)  Schumacher et al. [33]  Phase III  240  Rilonacept 160 mg/80 mg subcutaneous once weekly  Placebo  16 weeks  Allopurinol  0.21 (95% CI: 0.09, 0.33) vs 1.06 (95% CI: 0.71, 1.42) (w16)  16.3 vs 46.8% (P < 0.001)  Mitha et al. [32]  Phase III  248  Rilonacept 160 mg/80 mg subcutaneous once weekly  Placebo  16 weeks  Allopurinol  0.34 (95% CI: 0.15, 0.52) vs 1.23 (95% CI: 0.89, 1.58) (w16)  20.5 vs 56.1% (P < 0.0001)  Sundy et al. [35]  Phase III  1315  Rilonacept 160 mg subcutaneous once weekly  Placebo  16 weeks  Allopurinol  0.51 (95% CI: 0.44, 0.59) vs 1.73 (95% CI: 1.44, 2.02) (w16)  25.7 vs 51.1% (P < 0.0001)  Schlesinger et al. [36]  Phase II  432  Canakinumab 25/50/100/200/300 mg subcutaneous single dose or 4-weekly intervals (50 mg day 1 and at week 4, 25 mg at weeks 8 and 12)  Colchicine 0.5 mg/day orally  16 weeks  Allopurinol  0.23 vs 0.75 (P ≤ 0.05) (w16)  15.1 vs 44.4% (P ≤ 0.05)  GF: gout flare; RCT: randomized controlled trials; ULT: uric acid-lowering therapy. Canakinumab A phase 2 RCT investigated the dose and efficacy of canakinumab in acute gouty arthritis in patients unresponsive or with contraindications to NSAIDs or colchicine (Table 3). Patients included in all canakinumab groups showed a dose-dependent efficacy on pain, swelling, recurrence of flares and inflammatory markers compared with patients with triamcinolone. The dose of 150 mg of canakinumab was further studied in two phase 3 multicentre RCTs of 24 weeks’ duration including 456 patients [31]. Analysis of pooled data of both studies showed than the mean pain score 72 h after treatment, which was the primary end point, was significantly better in the canakinumab group than in the triamcinolone group. Secondary outcomes were also better in the canakinumab group. In these studies, canakinumab decreased the risk of new flares by 62% over a 12-week period compared with triamcinolone. However, patients treated with canakinumab experienced more AEs than patients receiving triamcinolone (66% vs 53%), which were usually mild or moderate. There were more infections (20% vs 12%), especially more serious infections (1.8% vs 0%) in the canakinumab group, but no opportunistic infections were reported. The four serious infectious events in the canakinumab group consisted of submandibular abscess, forearm abscess, pneumonia and gastroenteritis. Two deaths were observed and considered to be unrelated to treatment. One patient was treated with canakinumab (intracranial haemorrhage) and the other with triamcinolone (pulmonary embolism). A post hoc analysis of the same dataset using a composite end point also showed superiority of canakinumab over triamcinolone [37]. A multicentre RCT with 432 patients investigated the efficacy of canakinumab in preventing acute gout flares when starting allopurinol [36]. Patients were randomly attributed to a single dose of canakinumab (dose ranging from 25 to 300 mg), with 4-monthly canakinumab injections or with an oral dose of colchicine 0.5 mg daily for 16 weeks. Patients were followed up for 6 months. The mean number of flares per patient was lower, the mean duration of flares shorter and the time to the first new gout flare longer in all canakinumab groups compared with colchicine. With a canakinumab dose of 50 mg or more, a reduction in 62–72% in the mean number of flares per patient was observed compared with the colchicine group. Thus, there is evidence supporting the use of canakinumab to treat acute gouty arthritis. Although there is debate on the choice and the dose of the active comparator, the data showing sufficient efficacy to obtain approval by the European Medicines Agency in 2013 for its use in adult patients with frequent gouty arthritis (three or more attacks in the previous year) and in whom repeated courses of steroids are inappropriate and in whom colchicine and NSAIDs are either contraindicated, or not tolerated or do not show enough efficacy. Analysis of the same data set by the US Food and Drug Administration, however, did not result in approval, primarily because of safety concerns, especially the increased risk of infections that canakinumab poses. International recommandations In the ACR recommendations for the management of gout published in 2012, use of an IL-1 inhibitor (anakinra or canakinumab) to treat patients suffering from severe attacks of acute gouty arthritis refractory to other treatments was proposed. However, due to the absence of RCTs for anakinra and the safety concerns and the lack of US Food and Drug Administration approval for canakinumab, the role of IL-1 inhibition in acute gout was assessed as uncertain [38]. The 2016 EULAR recommendations for the management of gout consider IL-1 blockers as a valid approach to treat acute gout flares in patients with frequent flares and who present contraindications to colchicine, NSAIDs, oral and injectable corticosteroids. A current infection should be a contraindication to IL-1 blocker use. EULAR recommends adjustment of ULT to achieve the uricaemia target after a treatment with an IL-1 blocker. A head-to-head trial of anakinra vs a conventional anti-inflammatory agent for the treatment of flares was proposed for future research [39]. Cost implications Comparison between treatment costs is difficult to achieve as IL-1 inhibitors are not available in all countries and there is a high variability of drug prices between countries due to health systems specificities. Moreover, prices are defined for approved indications like rheumatoid for anakinra and cryopyrin-associated periodic syndromes for canakinumab and not for gout treatment. The cost of one dose of anakinra 100 mg in France in 2017 is €31, and thus the cost of a 3-day treatment for gout flare should be around €100. In the UK, the cost of one dose of canakinumab 150 mg was £9928 in 2013 and €11 000 in France in 2017 for cryopyrin-associated periodic syndromes indication [40, 41]. Rilonacept is no longer available on the market. Conclusions There is a wealth of basic and clinical data to show that IL-1 secretion plays a key role in acute gout, and therapies that block IL-1, either by binding to the cytokine or its receptor, are attractive strategies to curtail the inflammatory storm. Inhibition of IL-1 is feasible and a number of IL-1 inhibitors are already available, thus it could complement currently available approaches to alleviate the acute gout attack. Currently only one IL-1 inhibitor has gout as a therapeutic indication and many patients are treated on an off-label basis. The challenges that need to be addressed in the near future for this therapy to be more widely used are: to determine the precise clinical situations that justify using an IL-1 inhibitor; to prove its efficacy in controlled trials with an active comparator; and a rigorous cost–benefit analysis, in particular evaluating the potential infectious side effects to assure patients and physicians of the safety of such an approach. 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RheumatologyOxford University Press

Published: Jan 1, 2018

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