Recommendations for the Diagnosis and Management of Gout
The 10 final multinational recommendations are listed in Table 2 with the levels of evidence and grades of recommendation; a summary of the supporting evidence and the expert opinion on each recommendation are presented below. The level of agreement by the rheumatologists with the recommendations ranged from 8.1 to 9.2 (mean 8.7) on a 1–10 point scale where 10 represents full agreement. For every recommendation, the proportion of rheumatologists voting 7 or more was over 80%. Many rheumatologists felt that the recommendations were in full accordance with their current practice (Table 3). However, for two recommendations for which there was a lower accordance with current practice (comorbidity screen of renal function and cardiovascular risk factors, and achieve tight control of SUA in patients with tophi), there was a higher willingness to change current practice.
Four studies used MSU crystal identification as the reference standard to evaluate the diagnostic performance of over 60 individual clinical, laboratory and imaging findings. Most clinical, laboratory and x-ray features—including podagra and hyperuricaemia—show a low diagnostic utility as stand-alone findings with the exception of response to colchicine therapy and the presence of tophi. Advanced imaging techniques, such as ultrasound (US) and dual-energy CT, performed better.
Experts showed a strong consensus that identification of MSU crystals—in a joint fluid sample or in a tophi aspirate—is required for a definite diagnosis of gout. Since life-long urate-lowering therapy (ULT) is commonly prescribed after diagnosis, this procedure should be routinely undertaken. However, as this might prove difficult in some settings, it was felt that clinical or imaging findings could support a diagnosis. The presence of hyperuricaemia on its own is insufficient to establish a diagnosis of gout. Response of acute arthritis to colchicine could support a clinical diagnosis of gout, but was felt unhelpful in differentiating types of crystal arthritis (eg, gout and acute calcium pyrophosphate arthritis). Availability, cost and the need for trained personnel and specific equipment may limit the use of advanced imaging techniques in routine clinical practice.
The focus was on those comorbidities that could be both screened for and treated. An increased incidence of end-stage renal disease was found in patients with hyperuricaemia, but gout was not an independent predictor for this disease. However, a fourfold increase in mortality due to kidney disease has been reported in patients with gout compared with non-gouty patients. We identified evidence that hyperuricaemia may increase the risk of developing diabetes or hypertension; however, no prospective studies were identified that investigated the risk of these conditions in people with gout. The available data showed that hyperuricaemia does not increase the risk of developing coronary heart disease (CHD) or stroke. On the other hand, there was evidence to suggest that people with gout have an increased risk of developing CHD and slightly increased risk of CHD-related mortality.
Experts agreed to highlight the need to screen for renal disease on the basis of the strong evidence of association and the implications for gout therapy. Experts also agreed that hyperuricaemia and gout should be considered red flags for metabolic syndrome and cardiovascular diseases.
Twenty-six trials were included on treatment of acute gout flares (21 evaluated non-steroidal anti-inflammatory drugs (NSAIDs), five glucocorticoids, two colchicine, and one canakinumab). The available evidence showed that low-dose colchicine (total dose 1.8 mg in 24 h) was more effective than placebo and as effective as high-dose colchicine (total dose 4.8 mg), but lower doses of colchicine had a significantly better safety profile. There was no high-quality evidence comparing NSAIDs with placebo and no NSAID (conventional or selective COX-2 inhibitor) has proven superior to another. Three trials concluded that systemic glucocorticoids were as effective as NSAIDs, with a similar safety profile. Despite a comprehensive search strategy, no trials assessing intra-articular glucocorticoids or paracetamol in the treatment of acute gout flares were identified.
There was consensus that NSAIDs, colchicine and glucocorticoids (given as intra-articular, oral or intramuscular therapy) are all effective in the treatment of acute gout flares and that there was insufficient evidence to prioritise them. Individual treatment decisions should be based on consideration of an individual's characteristics and each drug's safety profile. Paracetamol, although not recommended as the primary therapy, can be useful as an adjunct analgesic.
There is no evidence to support the idea that intervening in lifestyle factors translates into improved outcomes in patients with gout. Despite a comprehensive search strategy, only one study assessing the efficacy of lifestyle interventions in the treatment of chronic gout was identified. The use of skimmed milk powder enriched with two dairy fractions (glycomacropeptide and G600 fat extract) did not result in a reduction in frequency of acute gout flares when compared with standard skimmed milk or lactose powder.
Current understanding of the lifestyle factors associated with gout is largely derived from large, cross-sectional, epidemiological studies. Given the lack of evidence supporting lifestyle interventions in the treatment of gout per se, experts recommend general healthy lifestyle habits such as would be advisable for all individuals. Regarding alcohol consumption, experts agreed that there should be more emphasis on discouraging beer and spirits over wine intake. Together with general lifestyle advice, education about the need for compliance with lifelong ULT was deemed essential.
Over 40 studies were included in the evaluation of the efficacy, cost-efficacy and safety of ULT. There is high-quality evidence that allopurinol, febuxostat (40–240 mg daily) and pegloticase (8 mg intravenously every 2 or 4 weeks) are more effective than placebo in lowering SUA levels in patients with gout. One study showed that benzbromarone was effective in patients who failed to reach target uric acid on allopurinol. Febuxostat (80–240 mg daily) was more effective than potentially suboptimal doses of allopurinol (300 mg in patients with normal renal function, 100–200 mg if renal insufficiency) in lowering SUA, with a similar overall safety profile. Step-up therapy with allopurinol (300–600 mg) or benzbromarone (100–200 mg) are both effective in lowering SUA levels. Pegloticase, although highly efficacious, is associated with an increase in acute gout flares, infusion reactions and increased withdrawals due to adverse events compared with placebo. Available evidence for cost-efficacy was at a high risk of bias or outdated. No studies addressed the sequence of ULT.
There was a strong consensus that allopurinol constitutes first-line ULT after consideration of its safety, efficacy and cost. Low starting doses can optimise safety and minimise the risk of acute flares; doses should be gradually increased until target SUA levels are achieved (see recommendation 8). Uricosurics—where available—and low to medium doses of febuxostat (40–120 mg) are alternatives in the presence of intolerance or non-responsiveness to allopurinol. Uricase should only be considered in selected patients without other therapeutic options. Pegloticase should not be combined with other ULT, as this may mask the increase in SUA levels warning of an increased risk of infusion reactions and anaphylaxis.
Four studies addressing flare prophylaxis when ULT is initiated were identified. In two randomised controlled trials, the use of colchicine (0.6–1.5 mg daily) for the initial 3–6 months after the start of ULT resulted in a reduction in the number of patients who developed acute gout attacks and a reduction in the severity of these flares compared with placebo. Despite an increase in diarrhoea in one study, overall adverse effects and withdrawals were similar between the colchicine and placebo groups. No evidence on the use of NSAIDs or glucocorticoids as prophylaxis was retrieved.
Experts considered that the need for acute gout flare prophylaxis when initiating ULT should be considered on an individual basis. Optimal duration is currently unclear and should be decided after assessing factors such as flare frequency, gout duration and the presence and size of tophi. There was no consensus on when ULT should be started after an acute attack. However, the majority felt that low initial doses of ULT, with slow dose increases, is an integral part of flare prevention, supporting the motto 'start low, go slow'.
Two studies, of low to moderate quality, showed that gradual dose escalation of allopurinol in patients with renal impairment resulted in a higher proportion of patients obtaining target SUA levels without a parallel increase in serious toxicity, when compared with the commonly used and more conservative dosing guidelines. Allopurinol has been compared with other ULTs in populations with renal impairment of mostly mild or moderate levels (creatinine clearance >30 mL/min). Both febuxostat (80 mg/day) and unadjusted benzbromarone (100–200 mg/day) resulted in a higher proportion of patients achieving target SUA compared with renal function-adjusted allopurinol (100–300 mg/day), with a similar safety profile. The combination of allopurinol and benzbromarone allowed a reduction in SUA levels except in cases of severe renal dysfunction.
The target for the treatment of any disease is either cure or control. Both of these goals may be abstract concepts and can be difficult to measure. Often a surrogate marker associated with the cure or control is used; in gout, this surrogate marker is SUA. The association of SUA with other potential outcomes was systematically reviewed. Six studies linked the reduction of SUA levels with a decreased rate of acute attacks, two studies with tophus regression, and three studies with crystal disappearance—either through US or synovial fluid microscopy. The quality of these studies was low to moderate. The most commonly used SUA cut-off point in studies was 0.36 mmol/L (6.0 mg/dL), but there is some evidence that lower SUA levels could lead to a higher speed of tophi reduction and a longer time to recurrence of acute attacks after treatment withdrawal. Numerous tools have been used for monitoring the different outcome domains in patients with gout, including biological markers, clinical features, patient-reported outcomes or imaging. The physical component of the SF-36 questionnaire, the Health Assessment Questionnaire, and tophus measurement by caliper or US have shown adequate clinimetric properties.
Experts considered that monitoring should include at least SUA levels, the frequency of gouty attacks, and tophi size, but recommended no specific tool. They agreed that the target should be an SUA level below 0.36 mmol/L, but recommended even lower cut-off points if tophi are present (see recommendation 9).
After a comprehensive search strategy, only four prospective studies assessing pharmacological agents for patients with tophaceous gout were identified: two randomised controlled trials with pegloticase, an open extension study with febuxostat, and a case series of patients with tophaceous gout on different ULTs. A sustained reduction in SUA led to tophi reduction and in some cases resolution, independently of which ULT was used. The only evidence for the use of surgery to treat tophi came from case reports and case series.
Experts agreed that a lower SUA level (0.3 mmol/L) should be a treatment target for patients with tophaceous gout, as the evidence suggested that lower SUA levels increase the speed of tophi reduction. Surgery should only be considered in selected cases (eg, nerve compression, mechanical impingement or infection).
Defining asymptomatic hyperuricaemia was controversial; the agreed definition excluded patients with a background of arthritis or tophi, but allowed the inclusion of patients with pre-existing renal or cardiovascular disease. After an extensive search, only three studies were retrieved. Patients with asymptomatic hyperuricaemia and normal renal function or chronic kidney disease at baseline were allocated to receive allopurinol or no treatment over a 3–12 month period; no significant differences were noted in glomerular filtration rate, serum creatinine or proteinuria between the two groups. No studies dealing with prevention of gout or cardiovascular disease met the inclusion criteria.
Although there was an absence of evidence supporting the use of ULT for asymptomatic hyperuricaemia, experts agreed that lifestyle advice on diet, weight loss or exercise would apply to patients with asymptomatic hyperuricaemia, especially after considering the increased risks stated in recommendation 2.
Results
The 10 final multinational recommendations are listed in Table 2 with the levels of evidence and grades of recommendation; a summary of the supporting evidence and the expert opinion on each recommendation are presented below. The level of agreement by the rheumatologists with the recommendations ranged from 8.1 to 9.2 (mean 8.7) on a 1–10 point scale where 10 represents full agreement. For every recommendation, the proportion of rheumatologists voting 7 or more was over 80%. Many rheumatologists felt that the recommendations were in full accordance with their current practice (Table 3). However, for two recommendations for which there was a lower accordance with current practice (comorbidity screen of renal function and cardiovascular risk factors, and achieve tight control of SUA in patients with tophi), there was a higher willingness to change current practice.
Recommendation 1: Diagnosis
Four studies used MSU crystal identification as the reference standard to evaluate the diagnostic performance of over 60 individual clinical, laboratory and imaging findings. Most clinical, laboratory and x-ray features—including podagra and hyperuricaemia—show a low diagnostic utility as stand-alone findings with the exception of response to colchicine therapy and the presence of tophi. Advanced imaging techniques, such as ultrasound (US) and dual-energy CT, performed better.
Experts showed a strong consensus that identification of MSU crystals—in a joint fluid sample or in a tophi aspirate—is required for a definite diagnosis of gout. Since life-long urate-lowering therapy (ULT) is commonly prescribed after diagnosis, this procedure should be routinely undertaken. However, as this might prove difficult in some settings, it was felt that clinical or imaging findings could support a diagnosis. The presence of hyperuricaemia on its own is insufficient to establish a diagnosis of gout. Response of acute arthritis to colchicine could support a clinical diagnosis of gout, but was felt unhelpful in differentiating types of crystal arthritis (eg, gout and acute calcium pyrophosphate arthritis). Availability, cost and the need for trained personnel and specific equipment may limit the use of advanced imaging techniques in routine clinical practice.
Recommendation 2: Comorbidity Screening
The focus was on those comorbidities that could be both screened for and treated. An increased incidence of end-stage renal disease was found in patients with hyperuricaemia, but gout was not an independent predictor for this disease. However, a fourfold increase in mortality due to kidney disease has been reported in patients with gout compared with non-gouty patients. We identified evidence that hyperuricaemia may increase the risk of developing diabetes or hypertension; however, no prospective studies were identified that investigated the risk of these conditions in people with gout. The available data showed that hyperuricaemia does not increase the risk of developing coronary heart disease (CHD) or stroke. On the other hand, there was evidence to suggest that people with gout have an increased risk of developing CHD and slightly increased risk of CHD-related mortality.
Experts agreed to highlight the need to screen for renal disease on the basis of the strong evidence of association and the implications for gout therapy. Experts also agreed that hyperuricaemia and gout should be considered red flags for metabolic syndrome and cardiovascular diseases.
Recommendation 3: Acute Gout
Twenty-six trials were included on treatment of acute gout flares (21 evaluated non-steroidal anti-inflammatory drugs (NSAIDs), five glucocorticoids, two colchicine, and one canakinumab). The available evidence showed that low-dose colchicine (total dose 1.8 mg in 24 h) was more effective than placebo and as effective as high-dose colchicine (total dose 4.8 mg), but lower doses of colchicine had a significantly better safety profile. There was no high-quality evidence comparing NSAIDs with placebo and no NSAID (conventional or selective COX-2 inhibitor) has proven superior to another. Three trials concluded that systemic glucocorticoids were as effective as NSAIDs, with a similar safety profile. Despite a comprehensive search strategy, no trials assessing intra-articular glucocorticoids or paracetamol in the treatment of acute gout flares were identified.
There was consensus that NSAIDs, colchicine and glucocorticoids (given as intra-articular, oral or intramuscular therapy) are all effective in the treatment of acute gout flares and that there was insufficient evidence to prioritise them. Individual treatment decisions should be based on consideration of an individual's characteristics and each drug's safety profile. Paracetamol, although not recommended as the primary therapy, can be useful as an adjunct analgesic.
Recommendation 4: Lifestyle
There is no evidence to support the idea that intervening in lifestyle factors translates into improved outcomes in patients with gout. Despite a comprehensive search strategy, only one study assessing the efficacy of lifestyle interventions in the treatment of chronic gout was identified. The use of skimmed milk powder enriched with two dairy fractions (glycomacropeptide and G600 fat extract) did not result in a reduction in frequency of acute gout flares when compared with standard skimmed milk or lactose powder.
Current understanding of the lifestyle factors associated with gout is largely derived from large, cross-sectional, epidemiological studies. Given the lack of evidence supporting lifestyle interventions in the treatment of gout per se, experts recommend general healthy lifestyle habits such as would be advisable for all individuals. Regarding alcohol consumption, experts agreed that there should be more emphasis on discouraging beer and spirits over wine intake. Together with general lifestyle advice, education about the need for compliance with lifelong ULT was deemed essential.
Recommendation 5: ULT
Over 40 studies were included in the evaluation of the efficacy, cost-efficacy and safety of ULT. There is high-quality evidence that allopurinol, febuxostat (40–240 mg daily) and pegloticase (8 mg intravenously every 2 or 4 weeks) are more effective than placebo in lowering SUA levels in patients with gout. One study showed that benzbromarone was effective in patients who failed to reach target uric acid on allopurinol. Febuxostat (80–240 mg daily) was more effective than potentially suboptimal doses of allopurinol (300 mg in patients with normal renal function, 100–200 mg if renal insufficiency) in lowering SUA, with a similar overall safety profile. Step-up therapy with allopurinol (300–600 mg) or benzbromarone (100–200 mg) are both effective in lowering SUA levels. Pegloticase, although highly efficacious, is associated with an increase in acute gout flares, infusion reactions and increased withdrawals due to adverse events compared with placebo. Available evidence for cost-efficacy was at a high risk of bias or outdated. No studies addressed the sequence of ULT.
There was a strong consensus that allopurinol constitutes first-line ULT after consideration of its safety, efficacy and cost. Low starting doses can optimise safety and minimise the risk of acute flares; doses should be gradually increased until target SUA levels are achieved (see recommendation 8). Uricosurics—where available—and low to medium doses of febuxostat (40–120 mg) are alternatives in the presence of intolerance or non-responsiveness to allopurinol. Uricase should only be considered in selected patients without other therapeutic options. Pegloticase should not be combined with other ULT, as this may mask the increase in SUA levels warning of an increased risk of infusion reactions and anaphylaxis.
Recommendation 6: Flare Prophylaxis
Four studies addressing flare prophylaxis when ULT is initiated were identified. In two randomised controlled trials, the use of colchicine (0.6–1.5 mg daily) for the initial 3–6 months after the start of ULT resulted in a reduction in the number of patients who developed acute gout attacks and a reduction in the severity of these flares compared with placebo. Despite an increase in diarrhoea in one study, overall adverse effects and withdrawals were similar between the colchicine and placebo groups. No evidence on the use of NSAIDs or glucocorticoids as prophylaxis was retrieved.
Experts considered that the need for acute gout flare prophylaxis when initiating ULT should be considered on an individual basis. Optimal duration is currently unclear and should be decided after assessing factors such as flare frequency, gout duration and the presence and size of tophi. There was no consensus on when ULT should be started after an acute attack. However, the majority felt that low initial doses of ULT, with slow dose increases, is an integral part of flare prevention, supporting the motto 'start low, go slow'.
Recommendation 7: Effect of Comorbidities on Drug Choice
Two studies, of low to moderate quality, showed that gradual dose escalation of allopurinol in patients with renal impairment resulted in a higher proportion of patients obtaining target SUA levels without a parallel increase in serious toxicity, when compared with the commonly used and more conservative dosing guidelines. Allopurinol has been compared with other ULTs in populations with renal impairment of mostly mild or moderate levels (creatinine clearance >30 mL/min). Both febuxostat (80 mg/day) and unadjusted benzbromarone (100–200 mg/day) resulted in a higher proportion of patients achieving target SUA compared with renal function-adjusted allopurinol (100–300 mg/day), with a similar safety profile. The combination of allopurinol and benzbromarone allowed a reduction in SUA levels except in cases of severe renal dysfunction.
Recommendation 8: Monitoring
The target for the treatment of any disease is either cure or control. Both of these goals may be abstract concepts and can be difficult to measure. Often a surrogate marker associated with the cure or control is used; in gout, this surrogate marker is SUA. The association of SUA with other potential outcomes was systematically reviewed. Six studies linked the reduction of SUA levels with a decreased rate of acute attacks, two studies with tophus regression, and three studies with crystal disappearance—either through US or synovial fluid microscopy. The quality of these studies was low to moderate. The most commonly used SUA cut-off point in studies was 0.36 mmol/L (6.0 mg/dL), but there is some evidence that lower SUA levels could lead to a higher speed of tophi reduction and a longer time to recurrence of acute attacks after treatment withdrawal. Numerous tools have been used for monitoring the different outcome domains in patients with gout, including biological markers, clinical features, patient-reported outcomes or imaging. The physical component of the SF-36 questionnaire, the Health Assessment Questionnaire, and tophus measurement by caliper or US have shown adequate clinimetric properties.
Experts considered that monitoring should include at least SUA levels, the frequency of gouty attacks, and tophi size, but recommended no specific tool. They agreed that the target should be an SUA level below 0.36 mmol/L, but recommended even lower cut-off points if tophi are present (see recommendation 9).
Recommendation 9: Tophi
After a comprehensive search strategy, only four prospective studies assessing pharmacological agents for patients with tophaceous gout were identified: two randomised controlled trials with pegloticase, an open extension study with febuxostat, and a case series of patients with tophaceous gout on different ULTs. A sustained reduction in SUA led to tophi reduction and in some cases resolution, independently of which ULT was used. The only evidence for the use of surgery to treat tophi came from case reports and case series.
Experts agreed that a lower SUA level (0.3 mmol/L) should be a treatment target for patients with tophaceous gout, as the evidence suggested that lower SUA levels increase the speed of tophi reduction. Surgery should only be considered in selected cases (eg, nerve compression, mechanical impingement or infection).
Recommendation 10: Asymptomatic Hyperuricaemia
Defining asymptomatic hyperuricaemia was controversial; the agreed definition excluded patients with a background of arthritis or tophi, but allowed the inclusion of patients with pre-existing renal or cardiovascular disease. After an extensive search, only three studies were retrieved. Patients with asymptomatic hyperuricaemia and normal renal function or chronic kidney disease at baseline were allocated to receive allopurinol or no treatment over a 3–12 month period; no significant differences were noted in glomerular filtration rate, serum creatinine or proteinuria between the two groups. No studies dealing with prevention of gout or cardiovascular disease met the inclusion criteria.
Although there was an absence of evidence supporting the use of ULT for asymptomatic hyperuricaemia, experts agreed that lifestyle advice on diet, weight loss or exercise would apply to patients with asymptomatic hyperuricaemia, especially after considering the increased risks stated in recommendation 2.