RHEUMATOLOGY
Rheumatology 2014;53:19201926 doi:10.1093/rheumatology/keu157 Advance Access publication 23 April 2014
Review Prophylaxis for acute gout flares after initiation of urate-lowering therapy Augustin Latourte1,2, Thomas Bardin1 and Pascal Richette1,2 Abstract
RE VI EW
Key words: gout, flares, colchicine, non-steroidal anti-inflammatory drug, urate-lowering therapy, canakinumab, rilonacept, anakinra, corticosteroids.
Introduction Gout is an inflammatory arthritis caused by deposition in the joints of monosodium urate (MSU) crystals that result from chronic hyperuricaemia. It is the most prevalent form of arthritis in adult males, and the worldwide incidence and prevalence are steadily increasing [1]. MSU crystal deposition in joints may be responsible for painful acute gout flares (GFs). Recurrent flares are associated with high socio-economic burden due to the frequent use of health care and impaired work productivity. In addition, gout not properly treated can cause joint destruction and permanent disability. Long-term treatment of gout aims to reduce the urate level below the limit of MSU solubility, thus dissolving MSU crystal deposits and leading to the disappearance of gout features. International 1
Universite´ Paris 7, UFR Me´dicale, Assistance Publique-Hoˆpitaux de Paris, Hoˆpital Lariboisie`re, Fe´de´ration de Rhumatologie and 2INSERM 1132, Hoˆpital Lariboisie`re, Paris, France. Submitted 23 September 2013; revised version accepted 27 February 2014. Correspondence to: Pascal Richette, Hoˆpital Lariboisie`re, Fe´de´ration de Rhumatologie, Paris, France. E-mail: [email protected]
guidelines recommend urate-lowering treatment (ULT) targets of 60% of patients experienced acute attacks during the analysed period of 1 year. This proportion was significantly higher with 120 mg febuxostat than 80 mg febuxostat or allopurinol. Furthermore, GFs was one of the most frequent reasons given for study discontinuation. Thus prevention of GFs in the initial phase of ULT is a core aspect of the management of gout and should always be considered, in particular for those ULTs that drop urate rapidly, because such prevention might promote adherence to ULT.
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We then searched for all trials that examined the efficacy of prophylactic drugs during initiation of ULT by using the following search terms: gout, prophylaxis, prevention and randomized controlled trials (RCTs). Studies were eligible for inclusion if they were original articles of a randomized controlled design that included adults with gout and evaluated the prophylaxis of GFs following initiation of ULT. Studies were excluded if they were published in a non-English language, examined diseases other than gout, evaluated the treatment of acute GFs or their prophylaxis without initiating ULT or were a post hoc analysis of previously published data from RCTs. Other articles cited in this review were retrieved separately, either by checking references of relevant studies or by hand searching.
Other options are NSAIDs or corticosteroids. More recently, IL-1 inhibitors, known to be effective in managing autoinflammatory diseases [19], have demonstrated efficacy in the treatment of acute GFs [2022]. Colchicine, NSAIDs or corticosteroids, which are indicated for the treatment of acute GFs, may also be used for prophylaxis for GFs during the initiation of ULT, with low dosages (e.g. colchicine 0.5 mg once or twice a day), and given long term (i.e. up to 6 months), according to the individual risk of flares assessment.
Augustin Latourte et al.
TABLE 1 Design and main results of published reports of randomized controlled trials assessing prophylaxis for acute gout flares Mean number of flares per patient
Treatment References Schlesinger et al. [6]
Schumacher et al. [23]
Mitha et al. [8]
Borstad et al. [9]
2
ULT at Loading Total population baseline dose
Canakinumab
432
Allopurinol 100300 mg/day
Period analysed
Period analysed
16 weeks
16 weeks
108
0.75
44.4
55 54 54 54 53 54
0.51 0.45 0.23 0.41 0.23 0.7
27.3 16.7 14.8 18.5 15.1 16.7
2
Colchicine 0.5 mg/day 25 mg/day 50 mg/day 100 mg/day 200 mg/day 300 mg/day 50 mg/day day 1 to 425 mg/day weeks 812 Rilonacept
12 weeks
12 weeks
3
Placebo 160 mg/week 320 mg Rilonacept
42 41 241
0.79 0.15 16 weeks
45.2 14.6 16 weeks
3
Placebo 80 mg/week 160 mg 160 mg/week 320 mg Rilonacept
80 80 81 248
1.06 0.29 0.21 16 weeks
46.8 18.8 16.3 16 weeks
3
Placebo 80 mg/week 160 mg 160 mg/week 320 mg Colchicine
82 82 84 43
1.23 0.35 0.34 6 months
56.1 25.6 20.5 6 months
Placebo 0.6 mg twice a day
22 21
2.95 0.57
77 33
83
Allopurinol 300 mg/day
Allopurinol 300 mg/day
Allopurinol 300 mg/day
Allopurinol 100 mg/day
ULT: urate-lowering therapy.
Prophylactic treatments: current recommendations (EULAR, ACR) Adherence to treatment is a key issue in the management of chronic gout, because once prescribed, ULT should remain for life. Unfortunately, non-adherence among patients with gout who start ULT is common [27]. This adherence may be compromised both by GFs triggered after ULT initiation and by the practice of delaying the introduction of ULT a few weeks after resolution of a flare. Indeed, the latter tends to promote the idea that no additional treatment is needed once an acute attack has resolved. In contrast to EULAR recommendations [2, 28], ACR guidelines recommend that ULT be started during an attack, if antiinflammatory treatment has been introduced beforehand [3]. This strategy was supported by a recent RCT showing no difference in pain, recurrent flares or inflammatory markers with allopurinol initiated during an acute GF as compared with a 10-day delay in initiation [29].
1922
To prevent GFs, international recommendations [2, 18] suggest that pharmacological anti-inflammatory prophylaxis be systematically considered with ULT at its initiation. Of note, a recent study found that following patient education and with slow upward titration of ULT, mostly allopurinol, many patients chose not to take prophylaxis and did not experience a significantly greater flare rate [30]. These data suggest that slow titration could be a core aspect of the management of ULT in order to decrease the risk of flares. However, due to the lack of a control group, further specific studies to assess the impact of titration on the incidence of flares are required. The best duration for the prophylactic treatment is unknown and in the individual patient might depend on the severity of the crystal load, the velocity by which urate levels are lowered and the presence or not of factors known to trigger acute attacks. Data from pivotal trials conducted with febuxostat [26, 31, 32] have shown substantial rates of acute GFs in the first 6 months. Therefore
www.rheumatology.oxfordjournals.org
Downloaded from http://rheumatology.oxfordjournals.org/ at Northeastern University Libraries on October 20, 2014
Schumacher et al. [7]
Study phase Posology
Patients experiencing 51 flare, %
Prophylaxis for gout flares after initiation of urate-lowering therapy
prophylaxis for 6 months or until resolution of tophi is recommended by the ACR guidelines [18]. A shorter duration, 3 months, may be proposed after achieving the target urate level for patients without tophi detected on physical examination [18]. According to the most recent recommendation [18], the two first-line options are low-dose colchicine (0.5 mg once or twice a day) and low-dose NSAIDs (such as naproxen 250 mg orally twice a day). If these drugs are contraindicated, not tolerated or ineffective, low-dose corticosteroids (prednisone or prednisolone) may be used.
Colchicine
www.rheumatology.oxfordjournals.org
NSAIDs Although low-dose NSAIDs are sometimes used as an alternative to colchicine in daily practice, evidence from randomized trials on their efficacy as prophylactic treatment is scarce. Two trials of 156 patients compared azapropazone, an NSAID with uricosuric effects (600 mg twice daily) and allopurinol [38, 39]. Both drugs equally decreased urate levels. However, azapropazone had additional prophylactic benefit against acute attacks but a poorer safety profile, with increased incidence of gastrointestinal adverse events. As noted previously, the efficacy of low-dose NSAIDs as prophylaxis for GFs was also suggested in the phase 3 trials of febuxostat [34]. Considering all these data, the ACR recommended as a first-line prophylactic low-dose colchicine or naproxen 250 mg twice daily combined with a proton pump inhibitor, if indicated [18]. Of note, prescription of long-term NSAIDs, even at low dosages, in patients with gout requires carefully weighing the benefitrisk balance because of the cardiovascular, renal and gastrointestinal side effects of this class of drug [40, 41].
Corticosteroids Oral corticosteroids are a recommended alternative for GFs for patients with contraindication to colchicine and NSAIDs [18]. This recommendation is supported by data from two RCTs [42, 43]. The most recent compared prednisolone 35 mg/day and naproxen 500 mg twice daily to treat acute gout, and showed equivalence for both efficacy and safety [43]. In contrast, no trial has specifically evaluated low-dose steroids (50 mg vs colchicine. No evidence for a dose response for canakinumab was seen. The tolerance was similar in each group, but more infections were observed in the canakinumab groups. Infectious adverse events were reported in 18% of patients receiving canakinumab and 12% of patients receiving colchicine. Canakinumab should not be administered during an active infection and physicians should exercise caution when administering it to patients with underlying conditions that may predispose them to infections. Other side effects reported with canakinumab are neutropenia and injection site reactions. Three trials compared rilonacept with placebo for preventing GFs during the initiation of allopurinol 300 mg/day. In each trial a loading dose of rilonacept was initially administered, which was twice the dose administered weekly thereafter. In the phase 2 trial [7], 83 patients were randomized to receive rilonacept 160 mg/week or a placebo. The mean number of flares per patient at week 12 was significantly lower in the rilonacept than the placebo group (0.15 vs 0.79, P = 0.001). This beneficial effect occurred early and was maintained throughout the trial. Interestingly, no relapse was observed after the cessation of prophylaxis, and more patients in the rilonacept than the placebo group completed the evaluation period (98% vs 79%, P = 0.015). The rate of adverse events was similar between groups. Two phase 3 trials compared two doses of rilonacept, 80 and 160 mg/week, with placebo in patients who received allopurinol. In both studies the treatment was administered for 16 weeks and the primary outcome
was the number of flares per patient through week 16. In the first trial [23], of 241 patients, the mean number of flares per patient was significantly reduced in both rilonacept groups [1.06 in the placebo group vs 0.29 with rilonacept 80 mg and 0.21 with 160 mg (both P < 0.001)]. In the second trial [8], the mean number of flares per patient was reduced by 71.3% and 72.6% with rilonacept 80 and 160 mg, respectively (both P < 0.001). In these studies, the rate of adverse events was similar between groups, except for a higher risk of reaction at the injection site with rilonacept [8, 23]. In the second trial, 24% and 29% of patients developed anti-rilonacept antibodies in the 80 and 160 mg groups, respectively. The positivity of these antibodies was associated with higher injection site reaction rates [8]. The other most frequently reported adverse events were upper respiratory tract infection (including influenza viral infections) and headache. Rilonacept is not approved as prophylactic treatment for acute gout. Overall, IL-1 blockers seem to have a relatively good safety profile for short-term use and showed satisfactory efficacy in the prophylaxis of acute GFs. They could be good candidates as alternative therapy to colchicine, NSAIDs or corticosteroids in situations of contraindication or intolerance to these drugs. Their cost and their putative infectious adverse events [44] preclude their use as a firstline prophylactic option.
Prophylaxis for gout flares after initiation of urate-lowering therapy
Disclosure statement: P.R. received honoraria from AstraZeneca, Ipsen, Me´narini, Novartis, Savient and Sobi. T.B. has received honoraria for consultancies from Novartis, Ipsen, Menarini, Savient, AstraZeneca and Sobi and has received honoraria for talks from Savient, Menarini and Ipsen. The other author has declared no conflicts of interest.
References
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13 Pope RM, Tschopp J. The role of interleukin-1 and the inflammasome in gout: implications for therapy. Arthritis Rheum 2007;56:31838. 14 Martinon F, Pe´trilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006;440:23741. 15 Busso N, So A. Mechanisms of inflammation in gout. Arthritis Res Ther 2010;12:206. 16 Nuki G. Colchicine: its mechanism of action and efficacy in crystal-induced inflammation. Curr Rheumatol Rep 2008; 10:21827. 17 Terkeltaub RA. Colchicine update: 2008. Semin Arthritis Rheum 2009;38:4119. 18 Khanna D, Khanna PP, Fitzgerald JD et al. 2012 American College of Rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res 2012;64:144761.
3 Khanna D, Fitzgerald JD, Khanna PP et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res 2012;64:143146.
19 Dinarello CA. Blocking IL-1 in systemic inflammation. J Exp Med 2005;201:13559.
4 Jordan KM, Cameron JS, Snaith M et al. British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout. Rheumatology 2007;46:13724.
21 Schlesinger N, Alten RE, Bardin T et al. Canakinumab for acute gouty arthritis in patients with limited treatment options: results from two randomised, multicentre, activecontrolled, double-blind trials and their initial extensions. Ann Rheum Dis 2012;71:183948.
5 Becker MA, MacDonald PA, Hunt BJ, Lademacher C, Joseph-Ridge N. Determinants of the clinical outcomes of gout during the first year of urate-lowering therapy. Nucleosides Nucleotides Nucleic Acids 2008;27:58591. 6 Schlesinger N, Mysler E, Lin H-Y et al. Canakinumab reduces the risk of acute gouty arthritis flares during initiation of allopurinol treatment: results of a double-blind, randomised study. Ann Rheum Dis 2011;70:126471. 7 Schumacher HR Jr, Sundy JS, Terkeltaub R et al. Rilonacept (interleukin-1 trap) in the prevention of acute gout flares during initiation of urate-lowering therapy: results of a phase II randomized, double-blind, placebocontrolled trial. Arthritis Rheum 2012;64:87684. 8 Mitha E, Schumacher HR, Fouche L et al. Rilonacept for gout flare prevention during initiation of uric acid-lowering therapy: results from the PRESURGE-2 international, phase 3, randomized, placebo-controlled trial. Rheumatology 2013;52:128592. 9 Borstad GC, Bryant LR, Abel MP et al. Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol 2004;31:242932. 10 Joosten LAB, Netea MG, Mylona E et al. Engagement of fatty acids with Toll-like receptor 2 drives interleukin-1b production via the ASC/caspase 1 pathway in monosodium urate monohydrate crystal-induced gouty arthritis. Arthritis Rheum 2010;62:323748. 11 Richette P, Bardin T. Purine-rich foods: an innocent bystander of gout attacks? Ann Rheum Dis 2012;71: 14356. 12 Giamarellos-Bourboulis EJ, Mouktaroudi M, Bodar E et al. Crystals of monosodium urate monohydrate enhance lipopolysaccharide-induced release of interleukin 1 beta
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20 So A, De Smedt T, Revaz S, Tschopp J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther 2007;9:R28.
22 Terkeltaub RA, Schumacher HR, Carter JD et al. Rilonacept in the treatment of acute gouty arthritis: a randomized, controlled clinical trial using indomethacin as the active comparator. Arthritis Res Ther 2013;15:R25. 23 Schumacher HR Jr, Evans RR, Saag KG et al. Rilonacept (interleukin-1 trap) for prevention of gout flares during initiation of uric acid-lowering therapy: results from a phase III randomized, double-blind, placebo-controlled, confirmatory efficacy study. Arthritis Care Res 2012;64: 146270. 24 Dalbeth N, So A. Hyperuricaemia and gout: state of the art and future perspectives. Ann Rheum Dis 2010;69: 173843. 25 Sundy JS, Baraf HSB, Yood RA et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA 2011;306:71120. 26 Becker MA, Schumacher HR Jr, Wortmann RL et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005;353:245061. 27 Harrold LR, Andrade SE, Briesacher BA et al. Adherence with urate-lowering therapies for the treatment of gout. Arthritis Res Ther 2009;11:R46. 28 Bardin T, Richette P. New ACR guidelines for gout management hold some surprises. Nat Rev Rheumatol 2013;9: 911. 29 Taylor TH, Mecchella JN, Larson RJ, Kerin KD, Mackenzie TA. Initiation of allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial. Am J Med 2012;125:112634.
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1 Trifiro` G, Morabito P, Cavagna L et al. Epidemiology of gout and hyperuricaemia in Italy during the years 20052009: a nationwide population-based study. Ann Rheum Dis 2013;72:694700.
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30 Rees F, Jenkins W, Doherty M. Patients with gout adhere to curative treatment if informed appropriately: proof-ofconcept observational study. Ann Rheum Dis 2013;72: 82630.
37 Curiel RV, Guzman NJ. Challenges associated with the management of gouty arthritis in patients with chronic kidney disease: a systematic review. Semin Arthritis Rheum 2012;42:16678.
31 Schumacher HR Jr, Becker MA, Wortmann RL et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum 2008;59:15408.
38 Templeton JS. Azapropazone or allopurinol in the treatment of chronic gout and/or hyperuricaemia. A preliminary report. Br J Clin Pract 1982;36:3538.
32 Becker MA, Schumacher HR, Espinoza LR et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther 2010;12:R63.
34 Wortmann RL, Macdonald PA, Hunt B, Jackson RL. Effect of prophylaxis on gout flares after the initiation of uratelowering therapy: analysis of data from three phase III trials. Clin Ther 2010;32:238697. 35 Terkeltaub RA, Furst DE, Digiacinto JL, Kook KA, Davis MW. Novel evidence-based colchicine dose-reduction algorithm to predict and prevent colchicine toxicity in the presence of cytochrome P450 3A4/P-glycoprotein inhibitors. Arthritis Rheum 2011;63:222637. 36 Keenan RT, O’Brien WR, Lee KH et al. Prevalence of contraindications and prescription of pharmacologic therapies for gout. Am J Med 2011;124:15563.
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40 McGettigan P, Henry D. Cardiovascular risk with nonsteroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med 2011;8:e1001098. 41 Stamp LK, Chapman PT. Gout and its comorbidities: implications for therapy. Rheumatology 2013;52:3444. 42 Man CY, Cheung ITF, Cameron PA, Rainer TH. Comparison of oral prednisolone/paracetamol and oral indomethacin/paracetamol combination therapy in the treatment of acute goutlike arthritis: a double-blind, randomized, controlled trial. Ann Emerg Med 2007;49:6707. 43 Janssens HJEM, Janssen M, van de Lisdonk EH, van Riel PLCM, van Weel C. Use of oral prednisolone or naproxen for the treatment of gout arthritis: a double-blind, randomised equivalence trial. Lancet 2008;371:185460. 44 Tran TH, Pham JT, Shafeeq H, Manigault KR, Arya V. Role of interleukin-1 inhibitors in the management of gout. Pharmacotherapy 2013;33:74453.
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Rheumatology 2014;53:19201926 doi:10.1093/rheumatology/keu157 Advance Access publication 23 April 2014
Review Prophylaxis for acute gout flares after initiation of urate-lowering therapy Augustin Latourte1,2, Thomas Bardin1 and Pascal Richette1,2 Abstract
RE VI EW
Key words: gout, flares, colchicine, non-steroidal anti-inflammatory drug, urate-lowering therapy, canakinumab, rilonacept, anakinra, corticosteroids.
Introduction Gout is an inflammatory arthritis caused by deposition in the joints of monosodium urate (MSU) crystals that result from chronic hyperuricaemia. It is the most prevalent form of arthritis in adult males, and the worldwide incidence and prevalence are steadily increasing [1]. MSU crystal deposition in joints may be responsible for painful acute gout flares (GFs). Recurrent flares are associated with high socio-economic burden due to the frequent use of health care and impaired work productivity. In addition, gout not properly treated can cause joint destruction and permanent disability. Long-term treatment of gout aims to reduce the urate level below the limit of MSU solubility, thus dissolving MSU crystal deposits and leading to the disappearance of gout features. International 1
Universite´ Paris 7, UFR Me´dicale, Assistance Publique-Hoˆpitaux de Paris, Hoˆpital Lariboisie`re, Fe´de´ration de Rhumatologie and 2INSERM 1132, Hoˆpital Lariboisie`re, Paris, France. Submitted 23 September 2013; revised version accepted 27 February 2014. Correspondence to: Pascal Richette, Hoˆpital Lariboisie`re, Fe´de´ration de Rhumatologie, Paris, France. E-mail: [email protected]
guidelines recommend urate-lowering treatment (ULT) targets of 60% of patients experienced acute attacks during the analysed period of 1 year. This proportion was significantly higher with 120 mg febuxostat than 80 mg febuxostat or allopurinol. Furthermore, GFs was one of the most frequent reasons given for study discontinuation. Thus prevention of GFs in the initial phase of ULT is a core aspect of the management of gout and should always be considered, in particular for those ULTs that drop urate rapidly, because such prevention might promote adherence to ULT.
1921
Downloaded from http://rheumatology.oxfordjournals.org/ at Northeastern University Libraries on October 20, 2014
We then searched for all trials that examined the efficacy of prophylactic drugs during initiation of ULT by using the following search terms: gout, prophylaxis, prevention and randomized controlled trials (RCTs). Studies were eligible for inclusion if they were original articles of a randomized controlled design that included adults with gout and evaluated the prophylaxis of GFs following initiation of ULT. Studies were excluded if they were published in a non-English language, examined diseases other than gout, evaluated the treatment of acute GFs or their prophylaxis without initiating ULT or were a post hoc analysis of previously published data from RCTs. Other articles cited in this review were retrieved separately, either by checking references of relevant studies or by hand searching.
Other options are NSAIDs or corticosteroids. More recently, IL-1 inhibitors, known to be effective in managing autoinflammatory diseases [19], have demonstrated efficacy in the treatment of acute GFs [2022]. Colchicine, NSAIDs or corticosteroids, which are indicated for the treatment of acute GFs, may also be used for prophylaxis for GFs during the initiation of ULT, with low dosages (e.g. colchicine 0.5 mg once or twice a day), and given long term (i.e. up to 6 months), according to the individual risk of flares assessment.
Augustin Latourte et al.
TABLE 1 Design and main results of published reports of randomized controlled trials assessing prophylaxis for acute gout flares Mean number of flares per patient
Treatment References Schlesinger et al. [6]
Schumacher et al. [23]
Mitha et al. [8]
Borstad et al. [9]
2
ULT at Loading Total population baseline dose
Canakinumab
432
Allopurinol 100300 mg/day
Period analysed
Period analysed
16 weeks
16 weeks
108
0.75
44.4
55 54 54 54 53 54
0.51 0.45 0.23 0.41 0.23 0.7
27.3 16.7 14.8 18.5 15.1 16.7
2
Colchicine 0.5 mg/day 25 mg/day 50 mg/day 100 mg/day 200 mg/day 300 mg/day 50 mg/day day 1 to 425 mg/day weeks 812 Rilonacept
12 weeks
12 weeks
3
Placebo 160 mg/week 320 mg Rilonacept
42 41 241
0.79 0.15 16 weeks
45.2 14.6 16 weeks
3
Placebo 80 mg/week 160 mg 160 mg/week 320 mg Rilonacept
80 80 81 248
1.06 0.29 0.21 16 weeks
46.8 18.8 16.3 16 weeks
3
Placebo 80 mg/week 160 mg 160 mg/week 320 mg Colchicine
82 82 84 43
1.23 0.35 0.34 6 months
56.1 25.6 20.5 6 months
Placebo 0.6 mg twice a day
22 21
2.95 0.57
77 33
83
Allopurinol 300 mg/day
Allopurinol 300 mg/day
Allopurinol 300 mg/day
Allopurinol 100 mg/day
ULT: urate-lowering therapy.
Prophylactic treatments: current recommendations (EULAR, ACR) Adherence to treatment is a key issue in the management of chronic gout, because once prescribed, ULT should remain for life. Unfortunately, non-adherence among patients with gout who start ULT is common [27]. This adherence may be compromised both by GFs triggered after ULT initiation and by the practice of delaying the introduction of ULT a few weeks after resolution of a flare. Indeed, the latter tends to promote the idea that no additional treatment is needed once an acute attack has resolved. In contrast to EULAR recommendations [2, 28], ACR guidelines recommend that ULT be started during an attack, if antiinflammatory treatment has been introduced beforehand [3]. This strategy was supported by a recent RCT showing no difference in pain, recurrent flares or inflammatory markers with allopurinol initiated during an acute GF as compared with a 10-day delay in initiation [29].
1922
To prevent GFs, international recommendations [2, 18] suggest that pharmacological anti-inflammatory prophylaxis be systematically considered with ULT at its initiation. Of note, a recent study found that following patient education and with slow upward titration of ULT, mostly allopurinol, many patients chose not to take prophylaxis and did not experience a significantly greater flare rate [30]. These data suggest that slow titration could be a core aspect of the management of ULT in order to decrease the risk of flares. However, due to the lack of a control group, further specific studies to assess the impact of titration on the incidence of flares are required. The best duration for the prophylactic treatment is unknown and in the individual patient might depend on the severity of the crystal load, the velocity by which urate levels are lowered and the presence or not of factors known to trigger acute attacks. Data from pivotal trials conducted with febuxostat [26, 31, 32] have shown substantial rates of acute GFs in the first 6 months. Therefore
www.rheumatology.oxfordjournals.org
Downloaded from http://rheumatology.oxfordjournals.org/ at Northeastern University Libraries on October 20, 2014
Schumacher et al. [7]
Study phase Posology
Patients experiencing 51 flare, %
Prophylaxis for gout flares after initiation of urate-lowering therapy
prophylaxis for 6 months or until resolution of tophi is recommended by the ACR guidelines [18]. A shorter duration, 3 months, may be proposed after achieving the target urate level for patients without tophi detected on physical examination [18]. According to the most recent recommendation [18], the two first-line options are low-dose colchicine (0.5 mg once or twice a day) and low-dose NSAIDs (such as naproxen 250 mg orally twice a day). If these drugs are contraindicated, not tolerated or ineffective, low-dose corticosteroids (prednisone or prednisolone) may be used.
Colchicine
www.rheumatology.oxfordjournals.org
NSAIDs Although low-dose NSAIDs are sometimes used as an alternative to colchicine in daily practice, evidence from randomized trials on their efficacy as prophylactic treatment is scarce. Two trials of 156 patients compared azapropazone, an NSAID with uricosuric effects (600 mg twice daily) and allopurinol [38, 39]. Both drugs equally decreased urate levels. However, azapropazone had additional prophylactic benefit against acute attacks but a poorer safety profile, with increased incidence of gastrointestinal adverse events. As noted previously, the efficacy of low-dose NSAIDs as prophylaxis for GFs was also suggested in the phase 3 trials of febuxostat [34]. Considering all these data, the ACR recommended as a first-line prophylactic low-dose colchicine or naproxen 250 mg twice daily combined with a proton pump inhibitor, if indicated [18]. Of note, prescription of long-term NSAIDs, even at low dosages, in patients with gout requires carefully weighing the benefitrisk balance because of the cardiovascular, renal and gastrointestinal side effects of this class of drug [40, 41].
Corticosteroids Oral corticosteroids are a recommended alternative for GFs for patients with contraindication to colchicine and NSAIDs [18]. This recommendation is supported by data from two RCTs [42, 43]. The most recent compared prednisolone 35 mg/day and naproxen 500 mg twice daily to treat acute gout, and showed equivalence for both efficacy and safety [43]. In contrast, no trial has specifically evaluated low-dose steroids (50 mg vs colchicine. No evidence for a dose response for canakinumab was seen. The tolerance was similar in each group, but more infections were observed in the canakinumab groups. Infectious adverse events were reported in 18% of patients receiving canakinumab and 12% of patients receiving colchicine. Canakinumab should not be administered during an active infection and physicians should exercise caution when administering it to patients with underlying conditions that may predispose them to infections. Other side effects reported with canakinumab are neutropenia and injection site reactions. Three trials compared rilonacept with placebo for preventing GFs during the initiation of allopurinol 300 mg/day. In each trial a loading dose of rilonacept was initially administered, which was twice the dose administered weekly thereafter. In the phase 2 trial [7], 83 patients were randomized to receive rilonacept 160 mg/week or a placebo. The mean number of flares per patient at week 12 was significantly lower in the rilonacept than the placebo group (0.15 vs 0.79, P = 0.001). This beneficial effect occurred early and was maintained throughout the trial. Interestingly, no relapse was observed after the cessation of prophylaxis, and more patients in the rilonacept than the placebo group completed the evaluation period (98% vs 79%, P = 0.015). The rate of adverse events was similar between groups. Two phase 3 trials compared two doses of rilonacept, 80 and 160 mg/week, with placebo in patients who received allopurinol. In both studies the treatment was administered for 16 weeks and the primary outcome
was the number of flares per patient through week 16. In the first trial [23], of 241 patients, the mean number of flares per patient was significantly reduced in both rilonacept groups [1.06 in the placebo group vs 0.29 with rilonacept 80 mg and 0.21 with 160 mg (both P < 0.001)]. In the second trial [8], the mean number of flares per patient was reduced by 71.3% and 72.6% with rilonacept 80 and 160 mg, respectively (both P < 0.001). In these studies, the rate of adverse events was similar between groups, except for a higher risk of reaction at the injection site with rilonacept [8, 23]. In the second trial, 24% and 29% of patients developed anti-rilonacept antibodies in the 80 and 160 mg groups, respectively. The positivity of these antibodies was associated with higher injection site reaction rates [8]. The other most frequently reported adverse events were upper respiratory tract infection (including influenza viral infections) and headache. Rilonacept is not approved as prophylactic treatment for acute gout. Overall, IL-1 blockers seem to have a relatively good safety profile for short-term use and showed satisfactory efficacy in the prophylaxis of acute GFs. They could be good candidates as alternative therapy to colchicine, NSAIDs or corticosteroids in situations of contraindication or intolerance to these drugs. Their cost and their putative infectious adverse events [44] preclude their use as a firstline prophylactic option.
Prophylaxis for gout flares after initiation of urate-lowering therapy
Disclosure statement: P.R. received honoraria from AstraZeneca, Ipsen, Me´narini, Novartis, Savient and Sobi. T.B. has received honoraria for consultancies from Novartis, Ipsen, Menarini, Savient, AstraZeneca and Sobi and has received honoraria for talks from Savient, Menarini and Ipsen. The other author has declared no conflicts of interest.
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