Background: The aim of this study is to examine the occurrence of comorbidities at the time of first diagnosis of gout compared with matched population controls, overall and by sex, as well as to examine the crude and age- standardized prevalence of these comorbidities in men and women with gout at first diagnosis. Methods: A population-based study used data from Swedish national and regional registers, including 14,113 gout patients aged ≥ 20 years, with a first recorded diagnosis of gout between 1 January 2006 and 31 December 2012, and 65,782 population controls, matched by age, sex and county. Prevalence ratios (95% confidence intervals) comparing gout cases and controls were calculated, overall and by sex. Crude and age-standardized prevalence (95% confidence interval) of all comorbidities in gout patients were calculated, to show differences between sexes, taking also the higher age at diagnosis in women into account. Results: All examined comorbidities were 1.2–2.5-fold more common in gout patients at diagnosis than in population controls in both sexes. Women with gout were on average 6 years older than men at first gout diagnosis and most comorbidities, including obesity and diuretic use, were or tended to be more frequent in women than in men. When standardizing for age, women had a higher prevalence of thromboembolism (6.6% vs 5.2%) and chronic obstructive pulmonary disease (3.1% vs 2.4%). Men, on the other hand, had a higher prevalence of coronary heart disease (9.4% vs 6.4%), atrial fibrillation (9.0% vs 6.0%), congestive heart failure (7.7% vs 6.6%) and stroke (4.1% vs 3.3%). Conclusions: The occurrence of most comorbidities was significantly increased at first diagnosis of gout in both sexes. Women were older at diagnosis and had higher occurrence of most comorbidities, including obesity and diuretic use, factors that increase serum urate, and this needs to be taken into account when starting and optimizing urate lowering therapy. These sex differences were attenuated when standardizing for age and the occurrence of cardiovascular diseases was actually higher in men. Keywords: Gout, Comorbidity, Epidemiology, Gender, Urate lowering treatment * Correspondence: email@example.com Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Grona Straket 12, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Drivelegka et al. Arthritis Research & Therapy (2018) 20:108 Page 2 of 10 Background Using healthcare register data in the Western Swed- Gout is the most common form of inflammatory ish Health Care Region (VEGA) to identify cases and arthritis and is caused by deposition of monosodium population registers to identify matched controls, and urate (MSU) crystals in peripheral joints and sur- linking these groups to several national registers, this rounding tissues as a result of chronic elevation of study aimed to: examine the occurrence of several co- serum urate (SU) levels. The incidence and preva- morbidities at the time of first diagnosis of gout com- lence of gout are increasing in many parts of the pared with matched controls, overall and by sex; and world and the prevalence is > 1% in North America examine the crude and age-standardized prevalence of and Europe . these comorbidities in men and women with gout at Gout has been linked with an increased occurrence first diagnosis. of several comorbidities, which all may influence the overall effect on quality of life and increased mortality Methods [2–4]. Some of these comorbidities, such as use of di- Study design uretics [5, 6], renal disease [7–14], obesity [15, 16], We conducted a population-based and register-based transplantation [17–20], psoriasis [21, 22] and alcohol case–control study using register data from 1 January overconsumption [23, 24], have also been suggested 2000 through 31 December 2012 comparing patients at to increase SU levels and hence be part of the causal the time of first gout diagnosis to matched general pathway for developing hyperuricemia and clinical population controls. gout. Epidemiological studies examining the relation- Ethical approval for the study was granted from the ship between gout and risk for cardiovascular diseases Ethical Review Board of Gothenburg, Sweden. Informed (CVD) overall and in men and women separately re- consent from the patients was not needed as the study port conflicting findings, with a significant association only involved quality register linkage and no actual reported by some studies [3, 4, 25, 26], but not others handling of patients. [27–29]. There is only limited evidence for positive associations with cerebrovascular disease [30–33]or Setting peripheral vascular disease (PVD) [34, 35]. According to Statistics Sweden, in 2016 the population of Current clinical guidelines and management pathways Sweden was 9,995,153 and in Västra Götaland, a county in endorsed by the European League against Rheumatism the western part of Sweden, where the study was conducted, , American College of Rheumatology  and British the population was 1,671,783 (http://www.scb.se/hitta-statis- Society for Rheumatology  agree on the importance tik/statistik-efter-amne/befolkning/befolkningens-samman- of assessing comorbidities before deciding to initiate sattning/befolkningsstatistik/). treatment of gout with urate lowering therapy (ULT). In Swedish health care is public and tax funded. Health addition, there are also results supporting the need for and demographic information on all inhabitants is higher doses of ULT if patients have comorbid condi- recorded in a series of different healthcare registers. tions, such as renal disease, use of diuretics or obesity Linkage of data from these registers is possible using the . This effect of decreased eGFR and diuretic use is 10-digit personal identification number automatically probably explained by their ability to increase SU levels assigned to all Swedish residents . and not by any effect on the dose–response relationship between given allopurinol dose and change in urate Data sources levels . The Western Swedish Health Care Region (VEGA) was It is well known that several comorbidities occur more used to identify cases with gout. This register contains commonly in patients with gout compared to the general information back to 2000 about all healthcare contacts population [20, 41–43], although there are relatively few at inpatient and outpatient specialty clinics, as well as at population representative studies from Europe . primary care clinics, and includes the date of visit and Furthermore, the timing of comorbidity occurrence rela- diagnoses given by the treating physician according to tive to gout diagnosis has not always been addressed. In the Swedish version of the International Statistical particular, there are very few studies examining the Classification of Diseases (ICD). Since 1997, the 10th prevalence of comorbidities in patients with gout by sex version of ICD (ICD-10) is used in Sweden. The vast [44–47] and none of them have presented results at the majority of patients with gout are treated by general time of gout diagnosis. If such differences between sexes practitioners. were found, they could indicate that pathological path- The Swedish Prescribed Drug Register (PDR) (http:// ways differ in importance in men and women. In www.socialstyrelsen.se/register/halsodataregister/lakeme- addition, such differences could be of importance to take delsregistret) contains information about all prescribed into consideration when initiating and dosing ULT . drugs dispensed by Swedish pharmacies since July 2005. Drivelegka et al. Arthritis Research & Therapy (2018) 20:108 Page 3 of 10 This register was used to determine the exposure of pa- according to ATC codes in the PDR), comorbidities tients and controls to treatment with diuretics within were defined as the presence of at least one visit to a 6 months prior to first diagnosis of gout, as well as to physician in primary or specialized care with a corre- support the obesity and hypertension diagnoses. The sponding ICD-coded diagnosis (Additional file 1: Anatomical Therapeutic Chemical Classification System Table S1). Treatment with diuretics (including thia- (ATC codes) was used to identify the medical treatments zide, loop and thiazide-related diuretics) was defined (Additional file 1: Table S1). as having dispensed a prescription of these agents Demographic data were obtained from Statistics Sweden within 6 months prior to first diagnosis of gout. (http://www.scb.se/en/), which holds data on immigration, emigration and residency. Data on education level were Comparison by sex retrieved from the Longitudinal Integration Database for We compared demographic characteristics and pattern Health Insurance and Labor Market Studies (LISA), which of comorbidities separately in men and women, with is administered by Statistics Sweden and holds annual reg- their respective controls. isters on all individuals 16 years of age and older. Vital status on 31 December 2012 was determined via Statistical analysis the Cause-of-death Register (https://www.socialstyrelsen. Data are expressed as mean ± SD for continuous vari- se/register/dodsorsaksregistret), which provides informa- ables and number and percentages for categorical var- tion on the date and cause(s) of death for all residents iables. The prevalence of a specific comorbidity was since 1961. calculated by dividing the number of subjects diag- nosed with that comorbidity prior to the date of first Study populations gout diagnosis of the index patient as numerator (for We identified all patients who attended any inpatient, both cases and controls) by the total number of patients outpatient or primary care clinic between 1 January with gout or controls as denominator. Prevalence ratios 2000 and 31 December 2012. In this study we in- (PRs) and 95% confidence intervals (CIs) were used cluded all patients who had received their first ICD- to estimate the association between gout and each coded diagnosis corresponding to gout (Additional coexisting medical condition. In a sensitivity analysis, file 1: Table S1) between 1 January 2006 and 31 only cases with two or more visits with an ICD- December 2012. This time period was chosen in coded diagnosis of gout  were included and order to be able to link our data to the PDR and to compared with their matched controls. In the sex-- be able to define these cases as incident. Cases with a stratified analyses we compared both the crude and diagnosis of gout before that period, cases receiving standardized prevalence for each comorbidity. ULT before gout diagnosis and cases aged < 20 years Standardization was done by the indirect method, were excluded (Fig. 1). Up to five general population with the Swedish census population in 2012 as the comparators, alive and without gout by the time of standard population. Nonoverlapping 95% CIs were the index patients’ firstgoutdiagnosis were identified considered statistically significant for all comparisons. for each gout patient and matched by year of birth, All analyses were conducted using SAS software, ver- sex and county from the population register held by sion 9.3 (SAS Institute Inc. Cary, NC, USA). Statistics Sweden. Results Comorbidities and medication of interest Population We classified comorbidities into two diagnostic cat- A total of 14,113 individuals who received their first egories: comorbidities which have been ‘suggested to ICD-coded gout diagnosis between 1 January 2006 and increase the SU level’ and consequently increase the 31 December 2012 were identified and matched to risk for clinical gout (psoriasis, transplantation, renal 65,782 general population comparator subjects (Fig. 1). disease, use of diuretics, obesity and alcoholism); and There were 4600 women and 9513 men matched to ‘other comorbidities’, such as diabetes, hypertension, 22,052 and 43,730 controls, respectively (Table 1). coronary heart disease (CHD), congestive heart failure Women were approximately 6 years older than men at (CHF), atrial fibrillation (AF), stroke, thromboembol- the time of gout diagnosis and had lower education level ism, PVD and chronic obstructive pulmonary disease (Table 1). (COPD), in which the causal relationship to urate levels and clinical gout is not clear. With the excep- Prevalence of comorbidities in the study population tions of hypertension and obesity (based on both ICD Comorbidities suggested to increase SU level codes and/or ever previously dispensed prescription At the time of gout diagnosis, 59.1% of gout cases had at of antihypertensive or anti-obesity drugs respectively least one comorbidity of this category, which was 2.1- Drivelegka et al. Arthritis Research & Therapy (2018) 20:108 Page 4 of 10 2000–2012 1 ICD code for gout N= 32,999 Emigrated before gout diagnosis N= 151 First gout diagnosis st before Jan 1 2006 N= 12.805 Urate lowering therapy before gout diagnosis N= 5906 Age <20 years N= 24 1 ICD code for gout First gout diagnosis after l st Jan 1 2006 N = 14.113 Gout cases Controls Matched on sex, birth year and county N= 14.113 N= 65.782 Swedish prescribed drug register Cause-of-death register Statistics Sweden - LISA Fig. 1 Study design. ICD International Statistical Classification of Diseases, LISA Longitudinal Integration Database for Health Insurance and Labor Market Studies fold higher than in controls (27.7%) (Table 1). Exposure Other comorbidities to diuretics (43.7%), renal disease (11.8%) and obesity At the time of gout diagnosis, the overall proportion of (10.4%) were the most frequent of these comorbidities in patients having at least one comorbidity of this category gout patients and were 2.3–2.7-fold more common in was 71.8% in comparison to 51.3% of the controls gout patients at diagnosis vs matched controls (Table 1). (Table 1). All cardiovascular diseases were both common The proportions of individuals having undergone organ and highly associated with gout at the time of gout diag- transplantation and those having diagnosed alcoholism nosis (Table 1), with hypertension being the most fre- and to a lesser extent psoriasis were also more common quent in both gout patients (67.0%) and controls (44.3%) in gout patients compared to controls (Table 1). (Table 1). Drivelegka et al. Arthritis Research & Therapy (2018) 20:108 Page 5 of 10 Table 1 Demographic characteristics of the study population and prevalence (95% CI) of comorbidities in gout cases at the time of first diagnosis and statistical comparisons between all gout patients and controls Gout cases Controls PR (95% CI) (total p value (total gout cases – gout cases – total controls) total controls) Men (N = 9513) Women (N = 4600) Total (N = 14,113) Men (N = 43,730) Women (N = 22,052) Total (N = 65,782) Age at diagnosis (years), mean (SD) 65.3 (14.9) 71.1 (15.1) 67.2 (15.2) 64.4 (14.6) 70.7 (15.0) 66.5 (15.0) Level of education, N (%) ≤ 9 years 3560 (37.4) 2169 (47.2) 15,531 (35.5) 9419 (42.7) 10–12 years 4047 (42.6) 1655 (36.0) 17,349 (39.7) 7699 (34.9) > 12 years 1766 (18.6) 690 (15.0) 10,254 (23.5) 4509 (20.5) Comorbidities, total (%) 74.4 81.2 76.6 52.8 61.3 55.7 Comorbidities suggested to increase 52.2 62.8 59.1 25.7 31.7 27.7 SU level (%) Psoriasis, PR (95% CI) 3.6 (3.3–4.0) 4.0 (3.4–4.6) 3.7 (3.4–4.1) 2.7 (2.5–2.8) 2.8 (2.6–3.0) 2.7 (2.6–2.8) 1.4 (1.3–1.5) < 0.001 Organ transplantation, PR (95% CI) 1.1 (0.9–1.3) 1.2 (0.9–1.5) 1.1 (1.0–1.3) 0.4 (0.3–0.5) 0.5 (0.4–0.5) 0.4 (0.4–0.5) 2.8 (2.3–3.4) < 0.001 Renal disease, PR (95% CI) 12.2 (11.5–12.9) 11.1 (10.1–12.1) 11.8 (11.3–12.4) 5.1 (4.9–5.3) 3.4 (3.2–3.6) 4.5 (4.4–4.7) 2.6 (2.5–2.8) < 0.001 Use of diuretics, PR (95% CI) 39.1 (37.8–40.4) 53.4 (51.3–55.5) 43.7 (42.7–44.8) 15.8 (15.5–16.2) 24.3 (23.6–25.0) 18.7 (18.4–19.0) 2.3 (2.3–2.4) < 0.001 Obesity, PR (95% CI) 9.5 (8.9–10.1) 12.2 (11.2–13.2) 10.4 (10.0–11.0) 3.5 (3.3–3.7) 4.8 (4.5–5.1) 3.9 (3.8–4.1) 2.6 (2.5–2.8) < 0.001 Alcoholism 5.1 (4.6–5.5) 1.8 (1.5–2.2) 4.0 (3.7–4.3) 2.9 (2.7–3.1) 0.9 (0.8–1.1) 2.2 (2.1–2.3) 1.8 (1.6–2.0) < 0.001 Other comorbidities (%) 69.3 76.9 71.8 48.4 57.3 51.3 Diabetes, PR (95% CI) 14.9 (14.1–15.7) 18.3 (17.1–19.6) 16.0 (15.4–16.7) 9.5 (9.2–9.8) 8.6 (8.2–9.0) 9.2 (9.0–9.4) 1.7 (1.7–1.8) < 0.001 Hypertension, PR (95% CI) 64.5 (62.9–66.1) 72.3 (69.9–74.8) 67.0 (65.7–68.4) 41.4 (40.8–42.0) 50.2 (49.3–51.1) 44.3 (43.8–44.9) 1.5 (1.5–1.6) < 0.001 Coronary heart disease, PR (95% CI) 19.5 (18.6–20.4) 18.2 (17.0–19.5) 19.1 (18.4–19.8) 13.7 (13.3–14.0) 11.8 (11.4–12.3) 13.0 (12.8–13.3) 1.5 (1.4–1.5) < 0.001 Congestive heart failure, PR (95% CI) 16.2 (16.1–17.8) 21.4 (20.1–22.8) 18.4 (17.7–19.1) 6.5 (6.3–6.8) 7.7 (7.3–8.1) 6.9 (6.7–7.1) 2.7 (2.5–2.8) < 0.001 Atrial fibrillation, PR (95% CI) 18.6 (17.7–19.5) 19.0 (17.8–20.3) 18.7 (18.0–19.5) 7.5 (7.3–7.8) 7.7 (7.3–8.1) 7.6 (7.4–7.8) 2.5 (2.4–2.6) < 0.001 Stroke, PR (95% CI) 8.3 (7.7–8.9) 9.4 (8.6–10.3) 8.7 (8.2–9.2) 6.9 (6.6–7.1) 7.9 (7.5–8.3) 7.2 (7.0–7.4) 1.2 (1.1–1.3) < 0.001 Thromboembolism, PR (95% CI) 9.7 (9.1–10.4) 13.6 (12.6–14.7) 11.0 (10.5–11.6) 5.4 (5.2–5.6) 7.3 (7.0–7.7) 6.0 (5.8–6.2) 1.8 (1.7–1.9) < 0.001 Peripheral vascular disease, PR 4.5 (4.1–5.0) 5.5 (4.8–6.2) 4.8 (4.5–5.2) 2.2 (2.0–2.3) 2.6 (2.4–2.8) 2.3 (2.2–2.4) 2.1 (1.9–2.3) < 0.001 (95% CI) Chronic obstructive pulmonary disease, 4.9 (4.5–5.4) 6.5 (5.8–7.3) 5.5 (5.1–5.9) 2.3 (2.1–2.4) 3.2 (3.0–3.4) 2.6 (2.5–2.7) 2.1 (1.9–2.3) < 0.001 PR (95% CI) CI confidence interval, PR prevalence ratio, SD standard deviation, SU serum urate Drivelegka et al. Arthritis Research & Therapy (2018) 20:108 Page 6 of 10 Comparison by sex levels did not differ substantially (overlapping 95% CIs) and were numerically similar in men and women, with the Crude prevalence At the time of first gout diagnosis, all exception of a slightly higher prevalence (but overlapping comorbidities were more frequent in cases compared to 95% CIs) for diagnosed obesity and use of diuretics in controls both overall and stratified by sex (Table 1). women. All comorbidities, except for alcoholism, renal disease On the other hand, the age-standardized prevalence for and CHD, had higher point prevalence in women com- other comorbidities such as CHD, CHF and AF was sig- pared to men, with nonoverlapping 95% CIs for use of nificantly higher in men (nonoverlapping 95% CIs) com- diuretics (53.4% vs 39.1%), obesity (12.2% vs 9.5%), dia- pared to that for women, whereas the age-standardized betes (18.3% vs 14.9%), hypertension (72.3% vs 64.5%), prevalence for thromboembolism and COPD was signifi- CHF (21.4% vs 16.2%), thromboembolism (13.6% vs 9.7%) cantly higher in women (nonoverlapping 95% CIs). and COPD (6.5% vs 4.9%). In men, only diagnosed alco- holism (5.1% vs 1.8%) was significantly more common. Sensitivity analyses To assess the robustness of the results we also calcu- Age-standardized prevalence The higher age of women lated the prevalence of the various comorbidities, de- at diagnosis (71.1 years compared to 65.3 years in men) fining gout by a stricter definition of having had two was taken into account in two separate analyses. or more visits to a physician with gout over time. First, the PRs for comorbidities were calculated by sex The prevalence of comorbidities when using the stric- for each comorbidity (Fig. 2) compared to age-matched ter case definition was overall similar to that in the controls. The pattern of PRs was overall similar for men main analyses (Additional file 2:Table S2). and women, although there were slightly higher PRs (nonoverlapping 95% CIs) for men for diagnosed hyper- Discussion tension and use of diuretics, and for women with regard In this large, population-based study of patients with to diagnosed renal disease and diabetes compared to the gout, recruited from both primary and specialized health opposite sex (Fig. 2). care, we found that both comorbidities suggested to Second, we compared the age-standardized prevalence increase SU level and other comorbidities were more of comorbidities in men and women with gout (Table 2). common in gout cases vs population-based controls, In these analyses, comorbidities suggested to increase SU both overall and for men and women separately. All Fig. 2 Prevalence rates (95% CIs) of comorbidities in cases and controls for men and women at first gout diagnosis. CI confidence interval, COPD chronic obstructive pulmonary disease, PR prevalence ratio Drivelegka et al. Arthritis Research & Therapy (2018) 20:108 Page 7 of 10 Table 2 Age-standardized prevalence (95% CI) of comorbidities in men and women with gout at the time of first diagnosis Gout cases (N = 14,113) Men 95% CI Women 95% CI (N = 9513), (N = 4600), prevalence (%) prevalence (%) Comorbidities suggested to increase SU level Psoriasis 3.7 2.8–4.5 3.3 2.6–4.1 Organ transplantation 1.3 0.8–1.8 1.8 0.9–2.6 Renal disease 8.2 7.4–9.0 8.3 6.8–9.8 Use of diuretics 21.9 20.9–22.8 24.1 22.7–25.6 Obesity 10.2 8.9–11.6 12.5 10.8–14.3 Alcoholism 5.5 4.7–6.3 3.5 2.1–4.8 Other comorbidities Diabetes 8.7 8.1–9.3 9.9 8.9–10.9 Hypertension 40.1 38.6–41.6 39.4 36.9–41.9 Coronary heart disease 9.4 9.0–9.9 6.4 5.8–7.0 Congestive heart failure 7.7 7.3–8.1 6.6 6.0–7.1 Atrial fibrillation 9.0 8.4–9.5 6.0 5.4–6.5 Stroke 4.1 3.7–4.5 3.3 2.8–3.7 Thromboembolism 5.2 4.8–5.6 6.6 5.8–7.5 Peripheral vascular disease 2.1 1.9–2.3 2.1 1.7–2.5 COPD 2.4 2.1–2.6 3.1 2.6–3.5 CI confidence interval, COPD chronic obstructive pulmonary disease, SU serum urate comorbidities, except for alcoholism, were or tended to Other studies that have examined sex differences in be more frequent in women than in men at the time of occurrence of comorbidities by sex differ to some extent first gout diagnosis. When standardizing for age, these from ours. One previous study on established gout by sex differences were attenuated, and diagnoses of CVD Harrold et al. from 2017  showed, in line with the were actually more prevalent in men. Since gout may be present study, that women had higher prevalence of diagnosed several years after the first attack , both obesity, hypertension and diabetes mellitus and were hyperuricemia and gout may have been present for a more likely to take diuretics compared to men, although considerable time before and a causal relation to CVD this study was based on a smaller sample of patients or other comorbidities is not possible to deduce from identified from an American network of rheumatolo- the present study. Regarding occurrence of comorbidi- gists. In another previous American study  based on ties suggested to increase SU level, there were only 6133 patients diagnosed with gout as part of their health minor sex differences after age standardization, which insurance plans, all evaluated comorbidities (obesity was suggests large similarities in the pathophysiologic path- not included) were more frequent in women with gout ways leading to gout in men and women. compared to men. On the other hand, these studies The prevalence of some comorbidities in our study, showed that women had higher prevalence of kidney such as hypertension, CHF, diabetes, PVD and renal dis- disease compared to men, which is not confirmed in our ease, was higher than that in the study by Kuo et al. study. One possible explanation could be that our study , despite the fact that both studies are register based, is conducted at the time of first diagnosis of gout, include a large group of patients and report occurrence whereas the previous studies examined prevalent gout, of comorbidities at the time of first gout diagnosis. The and that the mean age of our male patients was 5 and prevalence of psoriasis, however, was almost the same in 7 years higher respectively than in the two previous both studies. Possible explanations, apart from the dif- studies. There is also one small clinical study by De ferent geographical setting, could be that the mean age Souza et al.  based on only 58 patients that showed of gout patients in our study was 5 years higher and that no differences in the occurrence of comorbidities be- our study had a slightly higher proportion of women tween women and men, which could be explained by the (32.6% vs 27.5%), who were found to have higher occur- small sample size of the study. We have also shown that rence of associated comorbidities than men. thromboembolism and COPD were more frequent in Drivelegka et al. Arthritis Research & Therapy (2018) 20:108 Page 8 of 10 women with gout compared to men. The association be- toward a higher prevalence of obesity and use of di- tween these comorbidities and gout has not been studied uretics, factors that increase urate levels in serum, before. The higher prevalence in women might suggest these comorbidities should be considered when initi- some differences in pathophysiologic pathways or risk ating and adjusting ULT in women. profile between men and women, but it is not possible Some possible limitations should be acknowledged. to study the underlying mechanisms in the present The identification of gout patients was based on ICD study. codes, which may have led to some misclassification Regarding CVD, we found a higher occurrence in bias. However, according to a previous validation men compared to women, when adjusting for age. study , a more strict definition of gout requiring Current literature on risk for cardiovascular events in one or more visits with an ICD-coded gout diagnosis men and women with gout reports conflicting results. by a rheumatologist or two or more visits in primary In line with the present study that showed higher care was found to have a high positive predictive prevalence of CHD and CHF in men, when we stan- value for fulfilling the various classification criteria for dardized for age, Krishnan et al.  showed that gout. The comorbidity pattern of gout cases in the men with hyperuricemia had an increased risk for present study was very similar to the comorbidity myocardial infarction in a controlled trial examining pattern of those fulfilling the stricter case definition the efficacy of risk reduction in men at high risk for (Additional file 2: Table S2), suggesting similar valid- vascular events. Results from the Framingham study ity for both case definitions. Regarding definition of  showed an increased risk for CHD and angina in comorbidities, the validity of ICD codes in the men with gout, but not in women, independently of Swedish national patient registry is generally very high other cardiovascular risk factors. Choi and Curhan  , although not all diagnoses used in this study showed in a large prospective study that men with have been validated. There is, thus, a possible risk for gout had higher overall mortality compared to men underestimation of some comorbidities, in particular without gout. In contrast, De Vera et al. ina obesity and alcoholism, when ICD codes are used for population-based cohort showed higher risk for myo- definitions. However, there is no reason to believe cardial infarction in women compared to men, and that such underestimation would be of different mag- Clarson et al.  in a population representative co- nitude in cases compared to controls and in women hort in the UK showed that female patients with gout compared to men. Smoking, which is a major risk were at greater risk for any vascular event compared factor for CVD, could not be taken into account be- to men with gout. These discrepancies could be cause of a lack of data. Finally, the study was per- explained by differences between studies in study formed in the western part of Sweden, which may design, sample size and selection of the study population. hamper generalizability. However, according to previ- Regarding potential explanatory mechanisms for higher ous reports, the sociodemographic distribution and frequency of CVD in men, we showed that other conven- healthcare seeking in this region are very similar to tional risk factors for CVD, such as obesity, hypertension Sweden as a whole [52, 53]. or diabetes, were not higher in men, although smoking This study has also several strengths. First, it is a and dyslipidemia could not be taken into account due to population-based study, including all gout cases in lack of data. the region, which reduces the risk of selection bias. A previous study by Wright et al.  showed that Second, patients were identified from both primary obesity, use of diuretics and, to a lesser extent, renal and specialized health care, which covers all of the disease had a significant influence on plasma urate con- different phenotypes of gout, from mild to severe centrations and allopurinol daily maintenance dose. disease. Third, several unrelated independent data According to this study, dose requirements to achieve sources were used. For instance, case identification treatment goals for SU were found to increase by 2-fold and information regarding medication or education to over 3-fold with increasing total body weight and level were retrieved from completely independent were 1.25–2 times higher in those taking diuretics, sources. Fourth, the study includes a large number whereas renal function had a relatively modest impact of subjects with gout and controls, which generates on the required allopurinol dose. Another study  statistically robust estimates for the occurrence of suggests that the effect of decreased eGFR and diur- the various comorbidities. etic use is explained by their ability to increase SU levels and not by any effect on the dose–response re- Conclusions lationship between the given allopurinol dose and the This large, population-based study shows that all change in urate levels. Considering that women in patients with gout have higher occurrence of many our study and previous studies haveatrend comorbid conditions at the time of first diagnosis, Drivelegka et al. Arthritis Research & Therapy (2018) 20:108 Page 9 of 10 compared to matched controls from the general Received: 7 February 2018 Accepted: 18 April 2018 population. The majority of these comorbidities are more common in women than in men with gout. In particular, the higher occurrence of diuretic use and References 1. Kuo CF, Grainge MJ, Zhang W, Doherty M. Global epidemiology of obesity in women may need to be taken into account gout: prevalence, incidence and risk factors. Nat Rev Rheumatol. 2015; when initiating ULT. 11(11):649–62. 2. Kuo CF, Yu KH, See LC, Chou IJ, Tseng WY, Chang HC, et al. Elevated risk of mortality among gout patients: a comparison with the national population Additional files in Taiwan. Joint Bone Spine. 2011;78(6):577–80. 3. 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