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Introduction

  1. Top of page
  2. Introduction
  3. Materials and Methods
  4. Results
  5. Discussion
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. REFERENCES

Gout is a disease caused by the deposition of monosodium urate (MSU) crystals in articular and periarticular tissues. The clinical consequences can include episodes of acute joint pain and inflammation, recurrent arthritis, persistent low-grade joint inflammation, subcutaneous tophi, and osteoarticular destruction leading ultimately to joint deformity. Quality of life can also be affected (1).

The disease is common, and there is evidence that the prevalence is increasing. A large multicenter study in England in the early 1990s reported a prevalence of 1%, more than 3 times higher than estimates from the 1970s (2). An increase in the prevalence of obesity was listed as a possible explanation (2). The UK prevalence of gout was reported to be 1.4% in 1999 (3). In the US, national survey data from 1992 indicated that the overall prevalence of gout was 0.84%; the prevalence increased with age, and was higher in men than in women at all ages (4). Studies have also reported increases in the incidence of gout in the US, and in the prevalence of gout in New Zealand (5, 6).

Hyperuricemia is an established and important risk factor for gout, and it has been known for more than a century that hyperuricemia can lead to MSU crystal formation (7–10). One large, prospective cohort study reported that other observed significant risk factors for gout (body mass index, age, hypertension, and cholesterol level) appeared to act through their effect of raising serum uric acid (sUA) levels (8).

It is important to emphasize that gout can be cured in the long term through the complete dissolution of MSU crystals. The therapeutic goals of long-term management of gout are to reduce the frequency of, and ultimately stop, acute flares; to trigger the dissolution and disappearance of tophi; and to prevent chronic arthropathy. This literature review attempts to determine 1) how sUA levels are associated with clinical outcomes in patients with hyperuricemia and gout; 2) whether lowering sUA levels to within a certain range is necessary and sufficient to achieve the therapeutic goals of long-term management; and 3) whether it is appropriate to aim to reduce sUA levels below a specific target level, and whether this target level should be different for patients with different types of gout.

Materials and Methods

  1. Top of page
  2. Introduction
  3. Materials and Methods
  4. Results
  5. Discussion
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. REFERENCES

We conducted a systematic search of the EMBASE literature database for original, English-language articles published in peer-reviewed journals between January 1995 and October 2005. The EMTREE keyword used in the EMBASE search was uric acid blood level (covering 10 related search terms including serum urate and serum uric acid). This term was used in searches alone, and in combination with the following terms: gout, hyperuricaemia, hyperuricemia, treatment outcome, disease marker, tophus, tophi, renal function, crystals, flares, acute arthritis, urate lowering therapy, arthropathy, and attacks.

The search yielded 549 articles. After review of the abstracts, 22 articles were retrieved, of which 11 were included in the final review. Overall, articles were excluded if they were not directly relevant to the 3 main areas of the review as stated above (for example, articles researching the link between hyperuricemia and conditions other than gout, such as the metabolic syndrome or hypertension, were excluded), or if they were case reports or review articles rather than clinical trials. We also excluded case reports and review articles, but accepted any other type of clinical study related to the research areas.

The reference lists of the 11 articles were checked for additional relevant articles that were not identified by the EMBASE search, or that were published before 1995. Also included in the review were additional articles selected from the authors' personal collections, including some articles published in 2006. Of the total of 23 study articles discussed in the main body of this review, 4 were randomized controlled studies (evidence level Ib), 1 was a case–control study (evidence level III), 16 were cohort studies (evidence level III), and 2 were basic research studies.

Results

  1. Top of page
  2. Introduction
  3. Materials and Methods
  4. Results
  5. Discussion
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. REFERENCES

Effect of sUA levels on crystal deposition

Levels of sUA above the saturation level can lead to MSU crystal deposition. In an in vitro study, MSU crystals were incubated with serum obtained from gouty and nongouty patients (11). MSU went into solution at initial sUA levels of ∼7 mg/dl. In samples with an initial sUA level above this threshold, precipitation of crystals occurred (11). The saturation level of MSU in plasma at 37°C was reported to be 6.8 mg/dl in another study (12).

A significant association between sUA levels and the risk of developing gout was observed in a long-term prospective study of 2,046 initially healthy men ages 21–81 years at baseline who were followed up for more than 15 years (8). The annual incidence rates of gouty arthritis were 0.1% in men with baseline sUA levels <7 mg/dl, 0.5% in those with sUA levels 7–8.9 mg/dl, and 4.9% in those with sUA levels ≥9 mg/dl. The cumulative incidence of gouty arthritis at 5 years was 22% in men with baseline sUA levels ≥9 mg/dl. The observation that 78% of men in this group had not developed gouty arthritis demonstrates that although gout is strongly associated with high sUA levels, it is not an inevitable consequence.

Studies of synovial fluid also indicate an association between sUA levels and the presence of MSU crystals. In a study of synovial fluid from asymptomatic knee joints of patients with gout, crystals were observed in samples from 36 of 37 patients who had never received urate-lowering therapy (ULT), compared with 10 of 20 patients receiving ULT (13). Similar findings were observed in a later study of synovial fluid from joints that were asymptomatic but had previously been inflamed: MSU crystals were seen in samples from all 43 patients who were not receiving ULT, compared with 34 of the 48 patients who were taking ULT (14). In the treated group, the absence of MSU crystals was significantly associated with lower sUA levels (median 350 μmoles/liter, or 5.85 mg/dl), the duration of therapy, and the time since the last attack (14). In a study following up patients with crystal-proven gout after 2–10 years, MSU crystals were seen in the knee synovial fluid from 14 of 16 patients with current sUA levels >6 mg/dl, compared with 7 of 16 patients with sUA levels ≤6 mg/dl (15).

Gout is a disease of MSU crystal deposition. The evidence discussed here underlines the logical link between sUA levels and deposition: the higher the sUA level above the saturation point, the more likely deposition will occur.

How do sUA levels affect clinical end points?

Gout attacks. In the latter study described above, the patients in the group with sUA levels <6 mg/dl had a mean of 1 gout attack in the most recent year, compared with 6 attacks in patients with higher sUA levels (15). The observation that patients with high sUA levels tend to have worse outcomes than patients with lower sUA levels was also seen in a retrospective study of 267 patients (16). As Figure 1 shows, the higher the average sUA level during the 3-year study period, the higher the incidence of recurrent gouty attacks more than 1 year after each patient's first visit (16).

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Figure 1. Relationship between average serum uric acid level and the incidence of acute gouty arthritis more than 1 year after each patient's first visit. (Reproduced from Shoji A, Yamanaka H, Kamatani N. A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy. Arthritis Rheum 2004;51:321–5.)

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Actively reducing high sUA levels in patients with gout has been shown to be associated with a reduction in the frequency of attacks. In a study following up 46 patients with gout over a period of up to 28 months, use of the ULT allopurinol reduced sUA levels from an average of 9.3 mg/dl to the normal range (levels not specified) in all patients (17). Acute attacks continued to occur for several weeks after initiating treatment, then became less frequent over a period of weeks and months, as sUA levels fell to the normal range or even below (levels not specified) (17). A study of 6 patients with gout found that 1 year of treatment with benzbromarone significantly reduced both sUA levels and frequency of acute attacks (18).

Treatment with ULT was also associated with improved clinical outcomes in a study of 36 patients with both gout and renal insufficiency (19). With treatment, 28 of the 36 patients achieved sUA levels <6 mg/dl. The mean number of gout attacks fell significantly from 3.4 in the 12 months before starting ULT to 0.71 in the first 6 months of treatment, 0.21 at 6–12 months, 0.06 at 12–18 months, and 0 at 18–24 months (19). A reduction in the incidence of gout flares over the course of 1 year was seen in a study of 756 patients with gout with baseline sUA levels ≥8 mg/dl who were treated with the ULTs allopurinol or febuxostat (20). The link between actively reducing high sUA levels and reducing the incidence of gout attacks was also seen in a study of men with gout who were given ULT (allopurinol or allopurinol plus probenecid) to reduce sUA levels to <5 mg/dl: after 2 years, 206 of 228 patients were free of attacks (21).

Initiating ULT can lead to an increased frequency of gout flares in the short term. Studies of patients with gout treated with ULT (allopurinol or febuxostat) found that the incidence of acute flares increased in the first 12 weeks after initiating treatment, before decreasing and continuing to decrease in the long term. The incidence of gout flares after the initiation of treatment was also higher with higher doses (20, 22). The efficacy of colchicine prophylaxis to cover the period of increased flares following initiation of ULT was demonstrated by a randomized placebo-controlled trial in which 43 patients with crystal-proven gout were given either colchicine or placebo when starting allopurinol treatment. The patients given colchicine experienced significantly fewer flares, and less severe flares, compared with patients given placebo (23). Attacks may still occur despite colchicine prophylaxis in some patients, particularly in refractory cases (24).

A study of 132 patients with gout who had an acute attack within 6 months of initiating ULT demonstrated that 40% of the attacks occurred in the first month. The researchers concluded that the reduction of sUA levels during the initiation of ULT should be as slow as possible to minimize the risk of attacks (25).

Tophi

High sUA levels in patients with gout have also been associated with the presence of tophi. A study of 60 patients with gout found that those with tophi on physical examination had significantly higher sUA levels than those without clinical tophi (26). Researchers conducting a small case–control study to investigate factors associated with the development of intradermal tophi in patients with gout concluded that a high prevalence of tophi seemed related to several factors: a long duration of disease before the first visit, a lack of regular past use of ULT, and long-term use of self-prescribed corticosteroids (27).

Dynamic associations between sUA levels and tophi development have been observed in several studies. In a 1-year study of 156 patients with tophi at baseline and sUA levels ≥8 mg/dl, ULT was associated with median percentage reductions in tophus area of 50–83%, depending on the ULT used and its dose, by week 52 (20). In another study, the reduction of sUA levels by ULT led to the dissolution of tophi in 18 of 20 patients in a mean of 14.2 months from the start of ULT (19). Tophi shrinkage, and a simultaneous increase in joint mobility, was also reported after reduction of sUA levels with allopurinol plus sulfinpyrazone in 3 of 8 patients with extensive tophaceous gout (28). Similar effects were seen in a study of 46 patients with gout started on allopurinol (many of whom were also taking a uricosuric agent) to control sUA levels: reductions in tophi size were seen after several weeks or months, and small tophi on ears, hands, and feet disappeared in some patients within 3–6 months (17).

There is also evidence that the lower the sUA level, the faster the speed at which tophi are reduced in size. In a long-term study of 63 patients with crystal-confirmed tophaceous gout, the mean sUA level during followup after 5 years of ULT was inversely proportional to the speed at which the size of target tophi was reduced. The reduction in tophi size was 0.53 mm/month in patients with sUA levels of 6.1–7 mg/dl; this velocity increased at lower sUA levels, reaching 1.52 mm/month at levels ≤4 mg/dl (29).

Nonsteroidal antiinflammatory drug use

Another reported advantage of reducing sUA levels is an association with a reduced need for nonsteroidal antiinflammatory drugs (NSAIDs) for the symptomatic treatment of acute flares. An observational study of 87 patients with gout who regularly used NSAIDs to control symptoms found that the use of ULT to control sUA levels ≤6 mg/dl enabled the withdrawal of NSAIDs over a period of 1 year, leading to a significant increase in the mean creatinine clearance rate (30). Renal function, as indicated by the creatinine clearance rate, improved in 30 of the 87 patients (34.5%) and worsened in 4 patients (4.6%). The researchers concluded that optimal control of hyperuricemia allows NSAID withdrawal and avoidance of renal function impairment caused by NSAIDs or by the hyperuricemia itself (30).

Is there an optimal therapeutic target level for sUA?

There is a clear body of evidence supporting the treatment of hyperuricemia in patients with gout to improve long-term clinical outcomes. But to what level should sUA be reduced? As previously discussed, studies have reported improved outcomes in patients with gout who achieved reductions to levels ≤6 mg/dl (360 μmoles/liter), compared with patients with higher levels: these improved outcomes include reductions in the frequency of attacks (15, 16, 20), reductions in tophus area (19, 20), depletion of urate crystal stores in synovial fluid (15), and improvements in renal function after withdrawal of NSAIDs (30).

In addition, a retrospective analysis of data from 350 gouty patients concluded that the range of sUA levels that minimizes the risk of gouty attacks during the first 6 months of ULT is 4.6–6.6 mg/dl (25). A retrospective study of managed-care data from the US found that among patients taking the ULT allopurinol, flares were experienced by 23% of those with sUA levels <6 mg/dl, compared with 33% of those with levels 6–8 mg/dl and 45% of those with levels >8 mg/dl. Despite pharmacotherapy, patients with sUA levels >6 mg/dl were 59% more likely to experience a gout flare during followup than those who had reached the target level (31).

The 6 mg/dl threshold is reiterated in the latest gout management guidelines from the European League Against Rheumatism (EULAR) published in 2006: “The therapeutic goal of anti-hyperuricaemic treatment is to promote crystal dissolution and prevent crystal formation. This is achieved by maintaining the serum uric acid below the saturation point for monosodium urate (≤360 μmol/L [6 mg/dL])” (32).

It should be recognized, however, that 6 mg/dl is, in effect, an arbitrary target level. Although clinical outcomes are consistently better in patients with sUA levels ≤6 mg/dl than in patients with levels >6 mg/dl, there is a lack of data on whether or not 6 mg/dl is a better cutoff than any other level below the MSU saturation point. There is evidence that the lower the sUA level, the better the outcome (16, 29), but formal evaluations of the benefits and risks associated with cutoff levels <6 mg/dl are currently lacking.

Some data from small studies suggest that the subpopulation of patients with chronic tophaceous gout could benefit from a target sUA level ≤6 mg/dl. A 10-year study of ULT in 14 patients who initially had clinical tophi found that the tophi increased in size in 7 patients with an average sUA level of 8.2 mg/dl during treatment, decreased in size in 6 patients with an average sUA level of 6.2 mg/dl, and disappeared completely in 1 patient who had the lowest average sUA level of 3.4 mg/dl (33). As already discussed, a study of 63 patients found that the velocity of tophi size reduction was greatest at low sUA levels (≤4 mg/dl) (29).

Discussion

  1. Top of page
  2. Introduction
  3. Materials and Methods
  4. Results
  5. Discussion
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. REFERENCES

There is consistent evidence linking sustained control of sUA levels to <6 mg/dl (360 μmoles/liter) with good long-term clinical outcomes, and eventually complete remission from symptoms, in patients with gout, although the literature is not extensive and many of the studies are relatively small. The proposed target level of 6 mg/dl, endorsed in the latest management guidelines from EULAR (32), is arbitrary in that there is a lack of data to support this target level being a better cutoff point than, for instance, 5.5 mg/dl, but there is consistent evidence that reducing sUA levels to at least 6 mg/dl is associated with clinical benefits.

Several authors of review articles have suggested that 6 mg/dl is an appropriate upper target level (34, 35), with one explicitly acknowledging that selection of 6 mg/dl as the threshold level is based on its relationship to the saturation point of MSU: “Unless uric acid is reduced to <6 mg/dL, crystals will not be absorbed and tophus formation will not be adequately prevented” (35). The author went on to suggest that sUA levels should be reduced to ∼5 mg/dl to deplete urate stores and prevent acute gouty attacks, tophi, and renal damage (35).

Based on all the published evidence, we propose that researchers consider using sUA levels more widely in clinical trials as a useful surrogate marker of treatment efficacy (and patient compliance). For now, the 6 mg/dl target threshold seems to be an appropriate level with which to distinguish controlled and uncontrolled patients for the purposes of clinical trials. Physicians can also consider using the sUA level as a surrogate marker for the effectiveness of ULT in clinical practice.

Research is clearly needed to further investigate the value of 6 mg/dl as a cutoff level, and whether it is any more appropriate than other levels. In addition, we need to conduct studies to help determine whether the use of a static cutoff level (ensuring that sUA levels are reduced to below a certain cutoff level) is better than the use of a moving or continuous cutoff level (the lower the sUA level, the better the outcome: analogous to the relationship between low-density lipoprotein levels and the risk of cardiovascular disease, for example).

More research is also needed in other areas; in particular, we believe it is important to study in more detail quality of life as a clinical outcome. The overriding concern of most patients with gout seen in clinical practice is to stop having the painful acute attacks; the extent to which these attacks, and also tophi, affect quality of life still needs to be determined. More data are also needed on whether subpopulations of patients with gout, such as those with chronic tophaceous gout, should have different target therapeutic sUA levels.

In clinical practice, the therapeutic target sUA level should be appropriate to the individual patient. Based on the currently available evidence, and in accordance with current guidelines, it seems appropriate that the initial target for most patients should be ≤6 mg/dl. To benefit the individual patient, particularly those with severe gout, reducing sUA levels as far as possible with ULT, as long as it is still tolerated, can be considered. Appropriate doses of ULT should be administered that reduce sUA levels steadily toward the target level, with appropriate use of prophylaxis, and sUA levels should be monitored regularly (at least monthly when beginning treatment or increasing the ULT dose) to gauge progress. It may be appropriate to increase the ULT dose, within the approved range for each drug, if sUA levels are not decreasing toward the target level. In the case of allopurinol, the maximum dose will depend on the patient's renal function (and what is allowed by the national regulatory agency). Regular renal function monitoring is necessary in all patients with renal dysfunction who are taking allopurinol, and there is evidence that this monitoring is neglected (36).

To help ensure compliance with ULT, patients need to be given 3 main messages: that the goal of treatment is to cure the disease by lowering sUA levels and achieving crystal dissolution, that treatment will be long term but not necessarily life long, and that there may be a short-term increase in flares after initiating ULT but this should be prevented by adequate prophylaxis and is not a reason to stop treatment without first consulting. Patients also need appropriate dietary advice.

In summary, a relatively small but consistent evidence base exists to strongly support an association between sUA level and clinical outcomes in gout, such that the sUA level appears to be an effective surrogate marker for treatment efficacy and long-term outcomes. A target sUA level ≤6 mg/dl (360 μmoles/liter) is recommended and is well supported by published evidence, although more research is needed. The management of gout can be optimized by effective patient education, individualizing treatment goals, regularly monitoring sUA levels over the long term, and making appropriate use of the tools available, including dietary advice, flare prophylaxis, and ULT, to reduce sUA levels and improve clinical outcomes.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Introduction
  3. Materials and Methods
  4. Results
  5. Discussion
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. REFERENCES

Dr. Lioté had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Perez-Ruiz, Lioté.

Acquisition of data. Perez-Ruiz, Lioté.

Analysis and interpretation of data. Perez-Ruiz, Lioté.

Manuscript preparation. Perez-Ruiz, Lioté.

ROLE OF THE STUDY SPONSOR

  1. Top of page
  2. Introduction
  3. Materials and Methods
  4. Results
  5. Discussion
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. REFERENCES

The authors received editorial/writing support from Excerpta Medica in the preparation of this manuscript, which was funded by Ipsen. The authors were fully responsible for content and editorial decisions for this manuscript.

REFERENCES

  1. Top of page
  2. Introduction
  3. Materials and Methods
  4. Results
  5. Discussion
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. REFERENCES