Abstract
Objective. Lowering serum uric acid (SUA) levels can essentially cure gout; however, this is not widely practiced. To summarize epidemiologic evidence related to this causal link, we conducted a systematic review of the published literature reporting the association between SUA level and incident and recurrent gout (i.e., gout flares).
Methods. We systematically searched Medline, EMBASE, and the Cochrane Database of Systematic Reviews using separate search strategies for incident gout and recurrent gout. We screened 646 abstracts to identify 8 eligible articles reporting gout incidence and 913 abstracts to identify 18 articles reporting recurrent gout.
Results. For both gout incidence and recurrence, a graded trend was observed where the risk was increased with higher SUA levels. Gout incidence rates per 1000 person-years from population-based studies ranged from 0.8 (SUA ≤ 6 mg/dl) to 70.2 cases (SUA ≥ 10 mg/dl). Recurrent gout risk in clinical cohorts ranged from 12% (SUA ≤ 6 mg/dl) to 61% (SUA ≥ 9 mg/dl) among those receiving urate-lowering therapy (ULT), and 3.7% (SUA 6–7 mg/dl) to 61% (SUA > 9.3 mg/dl) after successful ULT. Retrospective database studies also showed a graded relationship, although the strength of the association was weaker. Studies reporting mean flares or time-to-flare according to SUA showed similar findings.
Conclusion. This systematic review confirms that higher SUA levels are associated with increased risk of incident and recurrent gout in a graded manner. Although few prospective cohorts have evaluated incident and recurrent gout according to SUA, the existing evidence underscores the need to treat to SUA targets, as recommended by the American College of Rheumatology and the European League Against Rheumatism.
Gout is one of the most common inflammatory arthritic diseases1, with an estimated prevalence of about 4% among adults in the United States2. It is characterized by the formation of monosodium urate (MSU) crystals in the synovial fluid of the joints, as well as in other tissues3. The most common symptom is sudden and severe pain in the joint along with swelling and redness, with the first metatarsophalangeal joint of the big toe being the most frequently affected. The clinical burden among individuals with gout is not limited to rheumatologic disease; however, those with gout have a greater likelihood of developing diabetes mellitus4 and cardiovascular disease, and are at increased risk of all-cause death compared with those without gout5. Appropriate management of the symptoms of gout is important, not only because of the high patient burden and negative effect of gout on health-related quality of life, but also to reduce the risk of irreversible joint damage, chronic pain and disability, other serious chronic conditions, and premature death6.
Hyperuricemia is a key causal factor for gout7, and all patients with gout are expected to experience at least some periods of hyperuricemia7,8,9,10,11. Treatment targets for gout in clinical practice as well as clinical trials have focused on lowering serum uric acid (SUA) to the subsaturation range, (e.g., < 6.0 mg/dl or < 5.0 mg/dl)12,13,14. Because supersaturation and crystallization of MSU occur when the urate level is about 6.8 mg/dl or higher, reducing SUA levels to below this threshold ensures that MSU crystals can dissolve, which serves to prevent acute gout flares, remove tophi, and improve longterm prognoses14,15.
Despite this causal relation between hyperuricemia and gout13,16,17, and the expected curing of gout by effective urate reduction1,11,14, this is not widely accepted and practiced. To summarize epidemiologic evidence related to this causal link, we conducted a systematic review of the published literature reporting (1) the association between prior SUA levels and the risk of incident gout among gout-free individuals, and (2) the frequency or risk of recurrent gout (or gout flares) according to SUA level among individuals with preexisting gout.
MATERIALS AND METHODS
The systematic literature review was undertaken in July 2015 using 2 search strategies conducted in Medline, EMBASE, and the Cochrane Database of Systematic Reviews to identify relevant citations published and indexed prior to this date. Conference abstracts were considered for inclusion if they were dated within 2 years of the search (i.e., July 2013 to July 2015). The first search strategy aimed to identify any observational studies that estimated the risk of incident gout according to SUA level among gout-free individuals, while the second search strategy aimed to identify any observational studies or randomized trials that reported the risk of recurrent gout according to SUA level among those with preexisting gout. Our inclusion criteria (according to the Population, Intervention, Comparisons, Outcomes, and Study Design) are described in Table 1. No limitations on language were specified for the search.
Inclusion criteria according to PICOS for the risk of incident gout and recurrent gout.
The search strategy included terms related to gout, incidence, SUA, and observational studies (for the incident gout search strategy), and recurrent gout, flares, and SUA (for the recurrent gout search strategy). Two investigators independently reviewed all abstracts identified by the search strategy against the inclusion criteria. Article eligibility was decided by consensus, and if discrepancies occurred between the studies selected by the 2 reviewers, a third reviewer provided arbitration.
Similarly, data extraction was performed by 2 investigators to obtain data on study and patient characteristics, and reported outcomes. Any discrepancies observed between the data identified by the 2 reviewers were resolved by consensus. Study characteristics extracted consisted of features of design, inclusion and exclusion criteria, sample size, study location(s), and periods over which the risk of incident or recurrent gout were ascertained. Patient characteristics included the mean age and sex distribution, comorbidities, risk factors for gout, and family history. The quality of the studies included was assessed by the Strengthening of Reporting of Observational Studies in Epidemiology checklist18.
Data on incident gout were extracted, including the proportion developing gout, the rate of gout per person-year, and the relative risk (RR), hazard ratio (HR), or incidence rate ratio (IRR) of developing gout. Data on SUA level were extracted as either the proportion of the sample within a given SUA level category or as the mean SUA for the sample or subgroup. Data on the risk of recurrent gout included the number and proportion of those developing recurrent gout flares and the mean number of flares.
These data were summarized in tabular form or synthesized graphically. Estimates were stratified by study design (prospective vs retrospective) and timing of SUA assessment [prior to flare assessment (prospective assessment of flares) or after flare assessment (retrospective assessment of flares)] for the risk of recurrent gout.
For the risk of incident gout, IRR were calculated if that measure was not presented in the original article. To do so, the incidence rate observed among those with gout at higher SUA levels was divided by the incidence rate of the referent category (i.e., the lowest SUA category). For recurrent gout, risk ratios were calculated to compare the proportion of those with gout experiencing flares according to SUA category.
RESULTS
We screened 646 abstracts to identify 8 eligible articles describing incident gout, and 913 abstracts to identify 17 studies (described in 18 articles) describing recurrent gout (Figure 1A and Figure 1B). The list of included studies for both searches are provided in Supplementary Table 1A and Supplementary Table 1B (available with the online version of this article). The quality of reporting was generally high, although 7 studies provided few details on potential sources of bias19,20,21,22,23,24,25 and 4 studies were unclear on the funding source or role of the funders of the study21,23,26,27.
Flow diagram for study inclusion for (A) incident gout and (B) recurrent gout.
SUA and incident gout
Of the 8 studies identified focusing on incident gout, 5 (62.5%) presented estimates according to SUA category7,16,28,29,30. Of the 5 studies, 3 prospectively evaluated the incidence of gout from population-based samples while 2 were non-population–based studies. For the risk of incident gout, a graded trend was observed where the risk of gout increased with higher SUA levels.
From the 3 prospective population-based studies16,29,30, incidence rates of gout per 1000 person-years ranged from 0.8 new cases at the lowest SUA level (< 6 mg/dl) to 70.2 new cases at SUA level ≥ 10 mg/dl (Table 2). IRR, reflecting the increased risk of developing gout for patients in each SUA category compared with the lowest SUA category, were also higher with higher SUA levels (Figure 2). Because the Normative Aging Study included only men, IRR (95% CI) among men in the study ranged from 1.1 (0.3–2.0 for SUA of 6.0–6.9 mg/dl) to 87.8 (86.8–88.7 for SUA ≥ 10.0 mg/dl)29. Sex-specific IRR were also available from the Framingham Heart Study, and ranged from 2.4 (1.5–4.0) for women with SUA of 5.0–5.9 mg/dl, up to 47.9 (24.0–95.5) for men with SUA ≥ 8.0 mg/dl16.
The increased risk of incident gout by IRR with 95% CI according to SUA category. Bhole, et al16 presented HR rather than IRR. CI for Trifirò, el al7 are presented in the plot, but are smaller than the box size (i.e., they are entirely contained within the box). Sample size data by which to calculate CI for Chen, et al30 were unavailable. IRR: incidence rate ratio; SUA: serum uric acid.
The risk of incident gout according to SUA category, overall and by sex, from prospective population-based studies.
IRR for the 2 remaining studies, 1 prospective28 and 1 retrospective7, that also measured incident gout according to SUA categories are also presented in Figure 2. Ascertainment of SUA status was incomplete in the retrospective database study, where SUA levels were recorded on 2021 individuals (65.9%) with gout and 3103 non-gout individuals (33.7%)7. Although exact categories of SUA varied between studies, findings consistently showed a higher risk of incident gout among those with higher SUA levels.
Seven of the 9 studies (77.8%) reported the mean SUA levels according to the development of incident gout during the followup (Supplementary Table 2, available with the online version of this article)16,28,29,30,31,32,33. Mean SUA levels among gout-free individuals ranged from 5.0 ± 1.1 mg/dl among women ≤ 50 years of age31 to 6.8 mg/dl among men28. Mean estimates among those who developed incident gout ranged from 6.1 ± 1.7 mg/dl among women ≤ 50 years of age31 to 8.8 ± 1.8 mg/dl among individuals with rheumatologist-managed gout30. When mean SUA levels were compared between those who developed gout and those who remained gout-free, mean SUA was up to 1.6-fold higher among those who developed gout.
SUA and recurrent gout
Of the 18 studies identified reporting on recurrent gout, 7 presented data on the proportion of the sample experiencing flares according to SUA categories19,21,22,23,34,35,36 and 10 studies (in 11 articles) presented data on mean flares according to mean SUA level19,20,24,25,26,27,37,38,39,40,41. Similar to studies for incident gout, a graded trend was observed where the risk of recurrent gout increased with higher SUA levels.
Flares according to SUA category
Of the 7 studies presenting data on flares according to SUA category, 5 measured SUA prior to assessing flares (Table 3)22,23,34,35,36. Two of those were prospective clinical cohort studies that required clinical confirmation of flare status22,23 and 3 were retrospective cohorts where gout flares were based on administrative data without clinical confirmation34,35,36. A graded relationship was observed where the proportion of patients experiencing flares was higher among those with higher SUA levels. The risk of recurrent gout in clinical cohorts ranged from 12% at SUA level ≤ 6 mg/dl to 61% at SUA level ≥ 9 mg/dl among those receiving urate-lowering therapy (ULT), whereas it ranged from 3.7% at SUA level > 6 mg/dl to < 7 mg/dl to 61% at SUA level > 9.3 mg/dl after successful ULT therapy22,23.
The proportion of patients with recurrent gout, increased risk of flares, and flares per gout flare patient, according to SUA level.
Estimates from the retrospective cohorts without clinical confirmation of gout flares also showed a graded relationship (Table 3), although the magnitude of the association was smaller and the periods over which flares were assessed varied (from 1 to 5 yrs of followup). The proportions of patients experiencing flares in the lowest SUA category (< 6 mg/dl) varied from 23% over 5 years of followup to 46% over 2 years of followup34,35,36. Two of the retrospective studies also presented estimates of the mean number of flares per patient, which were also higher among those with higher SUA levels.
Risk ratios comparing the percentage of patients with recurrent gout according to SUA category were calculated; all comparisons showed a significantly increased risk with higher SUA levels (Table 3). Estimates from the 2 prospective studies suggest about a 4- to 9-fold increased risk of recurrent gout for patients with SUA in the 6 mg/dl or 7 mg/dl to 9 mg/dl range, and a 7.5- to 16.5-fold increased risk for patients with SUA > 9 mg/dl22,23. Findings from the retrospective studies also demonstrated increasing risk with higher SUA levels, although the magnitude of the risk increases was less, because of the higher proportions of patients with recurrent gout in the lower SUA categories (Table 3).
Two of the 7 studies presenting data on the risk of recurrent gout according to SUA category reported on flare frequency according to whether target SUA levels were achieved over the same period. The risk of recurrent gout was also higher among those with higher SUA levels. In 1 of these studies, a mean of 1.2 flares was observed over a 3-month period among those with SUA < 6.0 mg/dl, compared with 3.2 flares among those with SUA ≥ 6 mg/dl19. In the other, a mean of 1.0 flare was observed over a 12-month period among those with SUA ≤ 6.0 mg/dl, compared with 6.0 flares among those with SUA > 6 mg/dl21.
Flares according to mean SUA
Among the 10 studies presenting mean flares per patient according to mean SUA level, time periods and study designs varied. Nonetheless, a graded relationship was also observed, where the mean number of flares was higher among those with higher SUA levels (Figure 3). Average estimates ranged from 2 flares per year per patient at a mean SUA level of 6.4 mg/dl to 4.6 flares per year per patient at a mean SUA level of 9.0 mg/dl26,39.
Mean (SD) flares according to mean (SD) SUA level stratified by timing of flare assessment. One randomized trial that described outcomes over 6 months among patients undergoing active treatment to lower SUA reported 3.4 mean flares among the sample with a mean SUA of 9.8 mg/dl at baseline24,25. SUA: serum uric acid.
DISCUSSION
We aimed to systematically review the literature to date reporting on the association between SUA and both incident gout and recurrent gout flares. Our findings confirm that higher SUA levels are associated with an increased risk of incident and recurrent gout in a graded manner, corroborating the key role of urate lowering in gout care. Nevertheless, there is a notable lack of understanding among many healthcare providers as to the true value of lowering SUA, and thus gout remains both underdiagnosed and undertreated despite the availability of effective SUA-lowering therapy14,42. However, data from our systematic review underscore the need to treat to SUA target levels, as recommended by the gout care guidelines from the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR).
Gout incidence rates from prospective cohort studies ranged from fewer than 3 new cases per 1000 person-years at < 6 mg/dl (i.e., the usual therapeutic level) to 70 new cases per 1000 person-years at SUA > 10 mg/dl. Gout recurrence risk from prospective studies ranged from about 10% at SUA < 6 mg/dl to about 50% with SUA between 6 mg/dl and 9 mg/dl; this risk was as high as 60% to 90% among those with SUA > 9 mg/dl over the study period22,23. Findings from retrospective studies showed a consistent trend regarding the graded relationship, but estimates tended to be of lower magnitude. Nonetheless, data from both retrospective and prospective studies strongly corroborate efforts to lower SUA to prevent both incident and recurrent gout, and to treat to a target of < 6 mg/dl43. These findings were supported by a large chart review from the United States published after completion of our current review that highlighted the inadequacy of gout management in real-world settings and the negative clinical implications of high SUA44.
We found that relatively few prospective studies examined the relationship between SUA, incident gout, or recurrent gout flares. This paucity of relevant data may reflect the lack of research interest in the rheumatology field, given the well-established pathophysiology of gout and routine anecdotal observations in experienced rheumatology care. Regardless, our findings appear to call for further studies on the topic, to achieve a sufficient level of corresponding evidence. To that effect, because of the lack of high-quality clinical research evidence that tight control of SUA levels improves clinical outcomes in patients with gout, rheumatology guidelines have not resonated well in the gout care guidelines for primary care providers and consequently in their actual practices.
One weakness of the retrospective studies assessing gout incidence identified in our review was the incomplete ascertainment of SUA levels in a large proportion of otherwise eligible patients. Because measuring SUA is not a routine component of general clinical practice45, it is likely that individuals without gout who had SUA measures available (even if SUA was < 6 mg/dl) would have some clinical reason for the suspicion of gout, and would therefore not be entirely representative of the unaffected (i.e., gout-free) general population. Thus, estimating outcomes based on such a non-representative, non-gout sample could bias the results. For example, Trifirò, et al had SUA measurements for only about 40% of the sample under study, and a rationale for why some individuals would have these measures (particularly those without gout) was not available7. The incidence of gout among those with SUA < 6 mg/dl observed by Trifirò, et al was considerably higher than estimates from other studies included in our review16,28,29,30.
Moreover, although we identified more studies using administrative data to assess the risk of gout flares, the accuracy of their findings may be lower because clinical ascertainment of gout cases and validation of gout flares are challenging26,34,35,36. Most of these studies used a common approach to identify flares that involved a physician- or hospital-based claim for joint pain or gout followed by another gout-related investigation, prescription, or procedure within 7 days; however, no validation component was reported among the identified studies. This is important because estimates of the proportion of patients experiencing flares in the lowest SUA category were higher from retrospective studies compared with prospective clinical studies, although estimates of patients experiencing flares at higher SUA levels were similar between these 2 study types. This discrepancy suggests that the approach used in the retrospective studies may be overestimating the true risk of flares, particularly among those with lower SUA levels. Consequently, the incremental risk of flares at higher SUA levels from retrospective studies would be underestimated because the risk of their baseline reference group is artificially high. These differences between prospective and retrospective studies further highlight the importance of prospective studies with an appropriate case validation component.
Strengths of our systematic review include a comprehensive approach to evidence synthesis, namely through the systematic searching of multiple biomedical databases as well as the inclusion of articles from different geographic areas, study designs, and choice of measures for SUA and definitions of gout and its flares. However, because of these broad inclusion criteria, several notable differences exist among included studies. First, SUA measures differed between studies, and some studies presented mean SUA rather than estimates according to SUA category. Even within studies that presented estimates according to SUA categories, the classifications themselves varied. Further, studies used thresholds of < 8 mg/dl or < 9 mg/dl to define an intermediate risk category, which meant that the definition for the highest SUA category would also differ between studies. Second, the timing of the SUA measure varied considerably across studies, and SUA measures occurred both prior to and following the assessment of gout incidence or recurrence. Third, because some studies did not present the number of patients for SUA subgroups and/or patients with flares, it was challenging to calculate estimates of association measures (for example, RR or IRR). Importantly, future investigations for the study question ought to involve full sets of effect estimates (both relative and absolute) according to SUA categories of narrow widths to present flexible data with which to understand and compare gout incidence and recurrence estimates. Fourth, in some studies, sample sizes within an individual SUA category were small, which would affect the precision of associated estimates of the risk of incident or recurrent gout. Finally, results from retrospective database studies included for recurrent gout may have been affected by lack of relevant information, such as increased gout flares following the initiation of ULT, the timing of SUA measurements in relation to acute attacks, and the potential influence of risk factors other than hyperuricemia. This could have contributed to the generally lower magnitude of association as compared with prospective clinical studies.
Our systematic review synthesized findings from published articles on the risk of incident and recurrent gout, and found that existing data are consistently pointing to a graded relationship in which higher SUA levels are associated with an increased risk of incident gout and recurrent flares. However, the study design, SUA categorization, and timing of the outcome measures varied substantially among included studies, calling for further evidence from prospective studies specifically designed to comprehensively evaluate these variables. Nevertheless, these findings together with the totality of the existing pathophysiologic evidence underscore the critical need to treat to SUA target levels, as recommended by the gout care guidelines from the ACR and EULAR14,43,46.
ONLINE SUPPLEMENT
Supplementary material accompanies the online version of this article.
Footnotes
Funded by Takeda Pharmaceuticals International Inc.
- Accepted for publication November 23, 2016.
