Introduction
Gout is a common disease with increasing prevalence. Its manifestation, progression, adequate therapeutic interventions, and related comorbidities are therefore frequently discussed in the literature. Less attention is paid to the question of whether gout has an impact on mortality. However, this long-term outcome is relevant not only for the patient. New light should also be shed on the significance of this disease and consequently on the treatment and care of gouty patients, as these often remain suboptimal [
1].
Gout is a crystal deposition disease in which renal elimination of uric acid is insufficient. The increased uric acid level can lead to the formation of monosodium urate crystals in synovial fluid or soft tissues. This results in painful inflammation of the joints, which is why the disorder is also known as
inflammatory arthritis [
1,
2]. The typical initial presentation of gout is podagra [
3]. Gout is characterized by recurrent acute episodes and can become a chronic condition [
3‐
5].
The prevalence of gout has increased in recent decades. This might be the result of a changing diet and an ageing population [
2,
3]. Despite methodologic challenges, the international prevalence is estimated at up to 1% to 2% [
1,
6,
7]. Men are more likely to be affected than women, and the prevalence increases with age [
1,
8].
In 2006, the European League Against Rheumatism (EULAR) developed evidence-based recommendations for the diagnosis and management of gout [
1,
9], according to which the disease may be diagnosed by monosodium urate crystals in synovial fluid, podagra, or tophus, while a raised serum urate level alone is not specific to gout [
1]. Risk factors for the development of gout are diet [
2,
5]; genetic predisposition [
2,
4]; hyperuricemia [
4,
10]; and comorbidities such as diabetes, hypertension, obesity, heart failure, and renal insufficiency [
2,
6,
11].
The management of gout aims at lowering and maintaining serum urate levels below the saturation point (6.8 mg/dL, or 408 μmol/L). This helps to dissolve existing monosodium urate crystals and to prevent further crystals from forming [
1,
9]. In addition, special diets, weight reduction, and reduced alcohol consumption are among the nonpharmacologic interventions [
4].
The objective of this review is to scrutinize in a systematic manner whether there is an association between gout and all-cause or cardiovascular mortality. Despite neither the management of gout nor economic aspects being considered, this systematic review is intended to impact on recurrent discussion about the management of gout. Furthermore, knowledge about the association of gout and mortality may underline the need for adequate care.
Discussion
Despite the differences among populations in the studies included, all multivariate regressions yielded the same result: There was an independent association between gout and all-cause mortality as well as cardiovascular mortality. Conclusions regarding the causes of this association cannot be drawn, as further research would be needed. This also applies to the question of whether there is an association between cardiovascular mortality and all-cause mortality. However, gout elevates the risk of mortality and thus makes gouty patients an at-risk population.
Patients in whom gout was newly diagnosed after a renal transplantation had an increased all-cause mortality risk, whereas this association was not significant in renal transplant patients with a history of gout [
20]. Another study confirmed the impact of gout on all-cause as well as cardiovascular mortality in renal transplant patients treated with dialysis [
21]. Furthermore, an independent association between gout and all-cause mortality as well as cardiovascular mortality was also found in patients with any gout or a history of this disorder, irrespective of CHD comorbidities [
24]. Another study confirmed the association between gout and all-cause mortality in patients with previous heart failure and acute gout within 60 days before their death [
20]. Gouty patients with hyperuricemia also had an increased all-cause and cardiovascular mortality risk [
23]. Finally, a study of an Asian population without specific comorbidities obtained the same result (ie, it indicated that gout is associated with all-cause as well as cardiovascular mortality) [
25••].
The number of studies evaluating the association between gout and all-cause or cardiovascular mortality is limited. More research has been conducted on the questions regarding whether gout is associated with death from CHD alone or CVD in general, and the impact of gout on cardiovascular events [
26‐
29]. Even these studies indicate corresponding results: Gout is a risk factor for CVD and for death caused by it.
The large number of study participants in each of the studies included strengthens the validity of the results, although the prevalence of gout in the study population was somewhat higher than the general estimated prevalence [
2,
6,
7]. Despite the heterogeneous study populations and differences in gout definition, all studies indicated an independent association between gout and all-cause as well as cardiovascular mortality (except for the study that calculated differences in the mortality rates instead of ARR/AHR) [
19]). That all multivariate regressions yielded consistent outcomes may be considered another validation of gout being a risk factor for mortality. Moreover, the specific characteristics of the study population reflected the typical characteristics of gouty patients: mainly male, older age, and comorbidities such as CVD or renal failure.
In spite of the consistent outcomes, the comparability of the studies is complicated by use of different definitions of gout. Wijands et al. [
30] described the challenge of defining gout in epidemiologic studies. It is difficult to apply diagnostic guidelines (eg, monosodium urate crystals), which are developed for use on an individual level, to large populations. Drawing on
ICD codes might offer a solution but implies several methodologic uncertainties [
30]. As a consequence, different definitions of a gout population might entail variant outcomes. This is in line with the studies analyzed in this review: The mortality risk varied depending on the gout definition [
22••,
23,
25••]. To resolve this challenge, several sensitivity analyses were conducted.
The impact of patient characteristics and comorbidities on the association between gout and mortality was determined in different subgroup analyses. Regarding race, subgroup analysis established a higher mortality risk in blacks [
21], which goes hand-in-hand with an increased risk of gout among this ethnic group. Contrary to the elevated risk of gout in men described in the literature, one study indicated a reverse effect, as the risk of all-cause mortality was higher in women than men [
21]. It could be concluded that gout is less common, but more serious, in women. Furthermore, results of a subgroup analysis with diabetes, one of the most common comorbidities in gout, were unexpected. Gouty patients with diabetes had a slightly lower mortality risk than those without this comorbidity [
21]. One explanation might be that monitoring is better in patients with diabetes, although further research is needed to verify this claim. These results should be interpreted with caution, as they originate from a study of patients with severe comorbidities (renal transplant patients treated with dialysis).
The effect of gout duration on the mortality risk was analyzed in only two studies, both of which reported an increased mortality risk in patients with new-onset gout and a slightly lower risk over time [
20,
24]. This indicates the need for early intervention and treatment of gout.
Finally, it should be noted that four of the seven studies included were explicitly not sponsored by pharmaceutical companies [
19,
21,
22••,
25••], two were partially supported by the industry [
23,
24], and information on sponsorship or conflict of interest was lacking in one study [
20].
Conclusions
Gout is independently associated with all-cause mortality and cardiovascular mortality. This was the message of six studies evaluating the association by multivariate regression. As described, study populations were heterogeneous, but the study outcomes were nevertheless consistent. The elevated mortality risk in patients with gout applies to gouty patients with typical characteristics (black, male, older age) and classical comorbidities (eg, diabetes, hypertension, hyperuricemia). Subgroup analyses suggest that patients with new-onset gout and female sex have a slightly elevated mortality risk. In addition to these two subgroups, gouty patients without comorbidities that require regular monitoring, such as diabetes, might be considered a vulnerable group. Not only these subgroups, but the generally increased mortality risk associated with gout should be borne in mind when treating this disorder. A need exists for adequate treatment of gout to fulfill the needs of these at-risk patients.