In this study, we found significantly increased total number of deaths in the gout cases. After adjusting for age, sex, birthplace outside Sweden and relevant comorbidities we found a 3% increased risk in all-cause mortality among the gout cases. Furthermore, the gout patients had a significantly increased risk for death caused by CVD, renal disease, and diseases of the digestive system and a significantly decreased risk for death caused by dementia, lung diseases and neoplasms. Similar results were found in men and women when stratifying for sex. We found no significant temporal trends of death rate between the first and the last part of the study period.
As expected CVD was the main cause of death for patients with gout in our study in line with previous studies [14, 15, 18, 22, 37]. Not only do the patients have an extensive CVD morbidity at time of first gout diagnosis, but in addition gout is treated with acute medication with potentially cardiotoxic medicines such as NSAIDs or corticosteroids over time. This emphasizes the need for CVD screening in gout patients but also an increased use of ULT to diminish the need for acute treatment. Furthermore, gout comes with episodes of severe inflammation which may have negative impact on CVD. This is supported by results from the CARES trial in 2017 where treatment with the anti-inflammatory, anti-gout, interleukin-1 inhibitor canakinumab decreased the risk of recurrent cardiovascular events .
Death caused by renal disease was significantly increased in the gout patients in line with previous studies [18, 39]. Decreased renal secretion of urate by genetic predisposition and / or kidney disease is a major cause of hyperuricemia, which in a proportion will lead to gout . At time of diagnosis, the gout patients in this study had an increased occurrence of multiple risk factors for kidney damage such as hypertension, diabetes and obesity. In addition, they also have an increased use of acute medication with potentially nephrotoxic NSAIDs for gout attacks. With appropriate and increased use of ULT, such need for acute treatment could be diminished. The possible negative effect of gout upon kidney disease is still an unresolved matter where further research effort is needed .
In the present study, death due to infections was not increased in gout patients. The risk was found increased in the recent population based registry study from the southern county Skåne, Sweden  and in a in a cohort study from Taiwan comparing 6000 (1400 female) gout patients with the general population . A population based cohort study using data from the UK Clinical Practice Research Datalink that included 130 000 gout patients and 250 000 controls from 1987 to 2014 showed that patients with gout did not have an increased risk of infection-related mortality  while a Dutch prospective cohort study with crystal proven gout showed an increased risk for death due to infectious disease as well as cancer and CVD . Frequency of gout increases with age and so do comorbidities. A recent study from the US by Singh et al have shown an increase in serious infections leading to hospitalization over the last two decades in gout patients. The most common infections seen were pneumonia and sepsis, with age and comorbidities as the major identified contributing factors . In the present study, pneumonia and sepsis were the major infectious causes of death in both cases and controls. These findings emphasize the EULAR guidelines regarding vaccination from 2019 where it is advised to consider pneumococcal vaccination for the majority of patients with inflammatory rheumatic diseases .
In our study, gout protected against death by dementia which was also showed in the aforementioned population based registry study from the southern county Skåne, Sweden . Register studies have shown a decreased risk for dementia in gout individuals , metaanalysis of cross-sectional studies have shown protective effect of (increasing) urate on risk for Alzheimers dementia  while longitudinal studies show conflicting results [10–12]. In the present study, we lack data on urate levels. Obesity is strongly associated to both gout and hyperuricemia and was more common in the gout subjects in our study. The obesity paradox refers to the dual, age-dependent, effects on dementia, where overweight and obesity in middle age are associated with an increased future dementia risk in old age but when examined later in life higher BMI is linked to better cognition and decreased mortality  which may influenced the results in our study. It should be noted that our capture of obesity at baseline likely lacked sensitivity and we did not have data on BMI. Our findings are however supported by the observation that diagnosed dementia was less common in gout cases vs controls already at start of follow-up. The possible protective effect of hyperuricemia on dementia development needs to be further examined and related to the treatment target for urate suggested by current ACR and EULAR treatment guidelines [47, 48].
Gout has not been found to be associated to smoking [49, 50] although exposure to air pollution or inorganic dust may have a role in gout pathogenesis [51, 52]. Nevertheless, lung diseases were a more common comorbidity in the gout population of our study and in spite of this we saw a significant protective effect of gout on death by lung diseases in males which haven’t been shown in earlier studies [17, 26]. In the current study we have no data on smoking, however in 2017 we performed a questionnaire study on 800 gout patients in the same region of western Sweden as this study was performed and there we found no differences in frequency of current smoking compared to non-gout controls but a significantly higher degree of former smokers among gout patients in both males and females . The two most common lung related causes of death in the current study in both cases and controls were chronic obstructive pulmonary disease and interstitial pulmonary disease but small numbers limit further analysis.
Prevalence of neoplasms were higher at time of first gout diagnosis compared to non-gout controls in our study. In spite of this, we saw a a protective effect of gout on death attributed to cancer which haven’t been shown in earlier population based studies [17, 26]. Gout is characterized by hyperuricemia which has potent antioxidant properties possibly protecting against cancer. However, gout is also closely associated to insulin resistance, obesity and increased alcohol intake which are all well known carcinogenic risk factors. An increased risk for some cancers have been shown in gout patients, particularly urological cancers, cancers of the digestive system and lung cancer . In the current study, the four major causes of death by cancer were cancer of the prostate, lung, pancreas and large intestine / colon in both cases and controls. This mirrors the incidence and mortality of cancer in Sweden .
The increased risk of death from diseases of the digestive system in our study is supported by previous studies[17, 26]. Diagnosed alcohol related disorders were significantly higher at time of first gout diagnosis compared to the controls in our study. This was reflected in alcoholic liver disease being the only significantly increased cause-specific death related to diseases of the digestive system in the gout cases in the study.
Diabetes was one of the more common comorbidities at baseline in the gout patients of our study but in spite of this we could not find an elevated risk of death by diabetes which has been shown in earlier studies [17, 56].
General risk factors
Higher income is associated with decreased mortality in the Nordic countries  and lower level of education is a risk factor for increased mortality in the general population as well as in gout patients [19, 20]. The gout patients in our study had lower income and educational level compared to controls and they were also more often born outside Sweden. Increased mortality risk due to CVD and cancer has been shown in Swedish immigrants [58, 59]. The mortality risk increment in women compared to men with gout must be interpreted in the context of factors such as a lower overall mortality in women, higher age of gout onset and consequently more comorbidities at start and during follow-up .
There are some limitations to this study. First, as in all register studies there is a risk for misclassification of diagnosis. However, we have in a previous study found the gout diagnosis valid to a high degree . Secondly, obesity and alcohol abuse was in the study only defined with ICD-10 codes at baseline and we lack data specifically on BMI and alcohol intake, at baseline and during follow-up, which will lead to an underestimation of these risk factors. Third, we lack data on smoking. Fourth, urate may have a role in many of the mortality causes in the study, not least dementia, but we lack data on urate levels.
There are also some strengths to this study. The study is population based and the sample size is quite large minimizing the risk for selection bias. Data on cause of death, comorbidities and cancer were collected from three different registers which all have almost complete coverage of the population. The study was performed on incident cases of gout minimizing the risk for survival bias. Furthermore, sensitivity analysis was performed and showed no impact of competing causes of death on our results.