HLA-B27, axial spondyloarthritis and survival.

INTRODUCTION: Ankylosing spondylitis (AS), and carriage of HLA-B27 gene in otherwise healthy individuals, are reportedly associated with increased mortality. We evaluated this hypothesis, using data from both a 35-year AS follow-up study and UK Biobank data. METHODS: In 1985, 363 members of the Swiss AS Patient Society and 806 relatives were screened clinically and then radiographically for AS/axial spondyloarthritis (axSpA). Life expectancy was analysed in 377 axSpA patients having available pelvic radiographs and HLA-B27 status, comparing with matched Swiss population data. Survival in relation to HLA-B27 status in the general population was studied in UK Biobank European-ancestry participants (n=407 480, n=30 419 deaths). RESULTS: AS patients have increased standardised mortality rate (SMR) compared with the general population (1.37, 95% CI 1.11 to 1.62). This increase was significant for HLA-B27-positive AS (SMR 1.38, 95% CI 1.11 to 1.65). Shortened life expectancy was observed among both HLA-B27-positive AS women (SMR 1.77, 95% CI 1.09 to 2.70) and men (SMR 1.31, 95% CI 1.02 to 1.59). Patients with non-radiographic axSpA (nr-axSpA) had significantly lower SMR: 0.44 (95% CI 0.23 to 0.77), compared with the general population. In the UK Biobank European-ancestry population cohort, HLA-B27 carriage was not significantly associated with any change in mortality (HR 1, 95% CI 0.97 to 1.1, p=0.349, adjusted by sex), in either males (HR 1, 95% CI 0.98 to 1.1, p=0.281) or females (HR 0.96, 95% CI 0.9 to 1, p=0.232), and no increase in vascular disease mortality was observed. DISCUSSION: AS patients, but not nr-axSpA patients, have a significantly shortened life expectancy. Increased mortality is particularly significant among women with HLA-B27-positive AS. HLA-B27 carriage in the European-ancestry general population does not influence survival, or the risk of death due to vascular disease.

Factors predicting axial spondyloarthritis among first-degree relatives of probands with ankylosing spondylitis: a family study spanning 35 years.

OBJECTIVE: Factors predicting axial spondyloarthritis (axSpA) among first-degree relatives (FDRs) of ankylosing spondylitis (AS) patients need to be defined. We investigated the predictive value of the probands' HLA-B27 and radiographic sacroiliitis status on disease occurrence among their FDR. We also assessed the predictive value of features of the clinical history, including chronic inflammatory back pain (CIBP) and acute anterior uveitis (AAU), among the FDR and how they can be used to improve classification and diagnosis of axSpA. METHODS: In 1985, we studied 363 AS probands and 806 FDR who underwent rheumatologic examination, completed questionnaires, provided blood samples for HLA-typing and underwent radiography of sacroiliac joints. At follow-up in 2018-2019, 125 patients and 360 FDR were available for study, and completed a postal questionnaire about axSpA features. FDRs were asked to report whether after 1985 they had been diagnosed by Swiss rheumatologists as having axSpA. RESULTS: Among HLA-B27(+) FDR, axSpA occurred in 25.4%-26.3%, independent of the radiographic sacroiliitis status of the proband. AAU occurred in 13/34 (38.2%) FDR with axSpA vs 29/251 (11.6%) FDR without axSpA (p=0.00004, OR=4.74 95% CI 2.15 to 10.47). The presence of CIBP at baseline did not predict later occurrence of axSpA but combining CIBP and pain/discomfort at the thoracic spine and at anterior (ventral) chest wall ever, assessed at follow-up in 2018-2019, provided 83.1% sensitivity and 87.2% specificity for current axSpA. CONCLUSION: Occurrence of AAU among FDR of axSpA probands should prompt screening for axSpA. Moreover, co-occurrence of CIBP and pain/discomfort in the thoracic spine and at anterior chest wall as a three-question tool may further enhance clinical suspicion of axSpA among these FDR.

The ASAS Criteria for Axial Spondyloarthritis: Strengths, Weaknesses, and Proposals for a Way Forward.

Classification criteria should facilitate selection of similar patients for clinical and epidemiologic studies, therapeutic trials, and research on etiopathogenesis to enable comparison of results across studies from different centers. We critically appraise the validity and performance of the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial spondyloarthritis (axSpA). It is still debatable whether all patients fulfilling these criteria should be considered as having true axSpA. Patients with radiographically evident disease by the ASAS criteria are not necessarily identical with ankylosing spondylitis (AS) as classified by the modified New York criteria. The complex multi-arm selection design of the ASAS criteria induces considerable heterogeneity among patients so classified, and applying them in settings with a low prevalence of axial spondyloarthritis (SpA) greatly increases the proportion of subjects falsely classified as suffering from axial SpA. One of the unmet needs in non-radiographic form of axial SpA is to have reliable markers that can identify individuals at risk for progression to AS and thereby facilitate early intervention trials designed to prevent such progression. We suggest needed improvements of the ASAS criteria for axSpA, as all criteria sets should be regarded as dynamic concepts open to modifications or updates as our knowledge advances.

Determinants of the prevalence of gout in the general population: a systematic review and meta-regression.

Studies on the occurrence of gout show a large range in estimates. However, a clear insight into the factors responsible for this variation in estimates is lacking. Therefore, our aim was to review the literature on the prevalence and incidence of gout systematically and to obtain insight into the degree of and factors contributing to the heterogeneity. We searched MEDLINE, EMBASE, and Web of Science (January 1962 to July 2012) to identify primary studies on the prevalence and incidence of gout in the general population. Data were extracted by two persons on sources of clinical heterogeneity, methodological heterogeneity, and variation in outcome reporting. Meta-analysis and meta-regression analysis were performed for the prevalence of gout. Of 1,466 articles screened, 77 articles were included, of which 71 reported the prevalence and 12 the incidence of gout. The pooled prevalence (67 studies; N = 12,226,425) based on a random effects model was 0.6% (95% CI 0.4; 0.7), however there was a high level of heterogeneity (I(2) = 99.9%). Results from a mixed-effects meta-regression model indicated that age (p = 0.019), sex (p < 0.001), continent (p < 0.001), response rate (p = 0.016), consistency in data collection (p = 0.002), and case definition (p < 0.001) were significantly associated with gout prevalence and jointly accounted for 88.7% of the heterogeneity. The incidence in the total population ranged from 0.06 to 2.68 per 1,000 person-years. In conclusion, gout is a common disease and the large variation in the prevalence data on gout is explained by sex, continent on which the study was performed, and the case definition of gout.

The Gout Assessment Questionnaire 2.0: cross-cultural translation into Dutch, aspects of validity and linking to the International Classification of Functioning, Disability and Health.

OBJECTIVES: The Gout Assessment Questionnaire 2.0 (GAQ2.0) is a disease-specific patient-reported outcome measure for gout that distinguishes five different subscales and comprises overall 31 questions. The aims of this study were to translate the GAQ2.0 into Dutch and to test clinimetric properties. METHODS: Recommendations for translation and cross-cultural adaptation were followed and no cultural adaptations were needed. The resulting Dutch GAQ2.0 was administered to patients registered at the rheumatology outpatient clinic diagnosed with gout. Internal consistency was tested using Cronbach's α, reliability using intraclass correlation coefficient (ICC), content validity by linkage to the International Classification of Functioning, Disability and Health (ICF) and construct validity by correlating the subscales of the GAQ2.0 with the HAQ disability index (HAQ-DI) and 36-item Short Form Health Survey (SF-36). RESULTS: A total of 126 patients [106 (84%) male, mean age 66.6 years (s.d. 10.4), mean disease duration 11.2 years (s.d. 10.6)] completed a number of questionnaires, including the GAQ2.0, HAQ-DI and SF-36, and underwent a clinical examination. Internal consistency was sufficient (Cronbach's α = 0.83-0.94), except for the subscale gout medication side effects (Cronbach's α = 0.51). Test-retest reliability was good (ICCs 0.73-0.86) for all subscales, but moderate for the subscale unmet gout treatment need (ICC 0.56). Gout impact (GI) subscale scores showed only weak to moderate correlations with HAQ-DI and SF-36, but stronger emphasis on the emotional consequences of gout. Also, it correlated better with gout-specific outcomes such as the number of gout flares and pain. CONCLUSION: The Dutch GAQ2.0 shows sufficient evidence of validity to assess disease-specific functioning and health in patients with gout and seems to capture different aspects than those represented in the HAQ and SF-36.

The cross-sectional association between uric acid and atherosclerosis and the role of low-grade inflammation: the CODAM study.

OBJECTIVES: The aims of this study were to investigate (i) associations between uric acid and prevalent cardiovascular disease (CVD), ankle-arm blood pressure index (AAIx) and carotid intima-media thickness (CIMT) in the total population and in predefined subgroups according to glucose metabolism status and (ii) the extent to which these associations are explained by low-grade inflammation. METHODS: Cross-sectional analyses were conducted among 530 individuals [60.6% men, mean age 58.9 years (s.d. 6.9), 52.6% normal glucose metabolism (NGM)] at increased risk of CVD from the Cohort of Diabetes and Atherosclerosis Maastricht study. A low-grade inflammation score was computed by averaging the z-scores of eight inflammation markers [CRP, TNF-α, IL-6, IL-8, serum amyloid A, intercellular adhesion molecule 1 (ICAM-1), ceruloplasmin and haptoglobin]. RESULTS: After adjustment for traditional CVD risk factors, plasma uric acid (per s.d. of 81 µmol/l) was associated with CVD in individuals with NGM [odds ratio (OR) = 1.66, 95% CI 1.06, 2.58] but not with disturbed glucose metabolism (DGM) (OR = 0.81, 95% CI 0.55, 1.19, P interaction = 0.165). Uric acid was associated with CIMT in the total population (ß = 0.024, 95% CI 0.007, 0.042) and slightly more strongly in individuals with NGM (ß = 0.030, 95% CI 0.006, 0.054) than DGM (ß = 0.018, 95% CI -0.009, 0.044, P interaction = 0.443). There was no association between uric acid and AAIx in any group (P interaction = 0.058). Uric acid was associated with low-grade inflammation in the total population (ß = 0.074, 95% CI 0.013, 0.134, P interaction = 0.737). Adding low-grade inflammation to the models did not attenuate any of the associations. CONCLUSION: The associations for uric acid with CIMT, and with CVD in NGM only, were not explained by low-grade inflammation. A difference in the strength of the associations between individuals with NGM and DGM was suggested.

Physical functioning in patients with ankylosing spondylitis: comparing approaches of experienced ability with self-reported and objectively measured physical activity.

BACKGROUND: Physical functioning can be assessed by different approaches that are characterized by increasing levels of individual appraisal. There is insufficient insight into which approach is the most informative in patients with ankylosing spondylitis (AS) compared with control subjects. OBJECTIVE: The objective of this study was to compare patients with AS and control subjects regarding 3 approaches of functioning: experienced ability to perform activities (Bath Ankylosing Spondylitis Functional Index [BASFI]), self-reported amount of physical activity (PA) (Baecke questionnaire), and the objectively measured amount of PA (triaxial accelerometer). METHODS: This case-control study included 24 AS patients and 24 control subjects (matched for age, gender, and body mass index). Subjects completed the BASFI and Baecke questionnaire and wore a triaxial accelerometer. Subjects also completed other self-reported measures on disease activity (Bath AS Disease Activity Index), fatigue (Multidimensional Fatigue Inventory), and overall health (EuroQol visual analog scale). RESULTS: Both groups included 14 men (58%), and the mean age was 48 years. Patients scored significantly worse on the BASFI (3.9 vs 0.2) than their healthy peers, whereas PA assessed by Baecke and the accelerometer did not differ between groups. Correlations between approaches of physical functioning were low to moderate. Bath Ankylosing Spondylitis Functional Index was associated with disease activity (r = 0.49) and physical fatigue (0.73) and Baecke with physical and activity related fatigue (r = 0.54 and r = 0.54), but total PA assessed by accelerometer was not associated with any of these experience-based health outcomes. CONCLUSIONS: Different approaches of the concept physical functioning in patients with AS provide different information. Compared with matched control subjects, patients with AS report more difficulties but report and objectively perform the same amount of PA.

Heterogeneity of axial spondyloarthritis: genetics, sex and structural damage matter.

OBJECTIVE: Axial spondyloarthritis (axSpA) comprises both radiographic and non-radiographic disease. However, the paucity of specific objective measures for the disease and current classification criteria showing suboptimal specificity contribute to disease heterogeneity observed in clinical practice and research. We used a historical cohort of patients with axSpA to assess sources of heterogeneity. METHODS: The study involved 363 axSpA probands recruited from membership of the Swiss Ankylosing Spondylitis Patient Society. Participants underwent examination by a rheumatologist, completed questionnaires and provided blood samples for HLA typing. Patients underwent radiography of sacroiliac joints and were categorised according to the New York (NY) criteria (ankylosing spondylitis (AS) or non-radiographic axSpA (nr-axSpA)) and HLA-B27 status. Genetic characterisation by single nucleotide polymorphism microarray was performed and AS polygenic risk scores (PRS) were calculated. RESULTS: Considerable heterogeneity was observed. The male to female ratio for AS (NY+) was 3:1, but 1:1 for nr-axSpA. For HLA-27(+) AS, the ratio was 2.5:1, but nearly 1:1 for HLA-B27(-) disease. Women with nr-axSpA had strikingly lower mean PRS and lower HLA-B27 prevalence than men with nr-axSpA or NY(+) male and female patients with AS. PRS was able to distinguish male but not female patients with nr-axSpA from related healthy first-degree relatives. Radiographic sacroiliitis was strongly associated with HLA-B27, especially in men. CONCLUSION: Women clinically diagnosed with axSpA but without radiographic sacroiliitis as a group have a disease that is distinct from AS by the modified New York criteria overall and from nr-axSpA in men. Given the high degree of heterogeneity, stratified or adjusted analysis of effectiveness studies is indicated, taking genetics, sex and radiographic damage (sacroiliitis) into account.

Recurrence of axial spondyloarthritis among first-degree relatives in a prospective 35-year-follow-up family study.

OBJECTIVE: The lifetime recurrence rate (RR) of axial spondyloarthritis (axSpA) among first-degree relatives (FDR) and the effect of proband's gender, HLA-B27 and radiographic status is unclear. Our 35-year-follow-up family study has enabled these issues to be addressed. METHODS: In 1985, 363 ankylosing spondylitis (AS) probands (members of the Swiss AS Patient Society) and 806 FDR recruited into the study, completed questionnaires regarding axSpA manifestations, underwent a physical examination and most also underwent pelvic radiography and HLA-B27 typing. At follow-up in 2018-2019, of the former participants whose current addresses could be retrieved, 162 had died and 485 (125 patients with AS plus 360 FDR) completed a postal questionnaire. RESULTS: At follow-up, 48 of 177 HLA-B27(+) FDR had developed axSpA, an RR of 27.1% (95% CI 20.6% to 33.7%). 27/148 (18.2%) children of AS probands (modified New York (mNY) criteria) were affected versus 2/50 (4.0%) children of non-radiographic axSpA probands (p=0.0138, OR=5.36; 95% CI 1.23 to 23.40). Children of female probands were more often affected (12/22; 54.5%) than of male probands (15/78; 19.2%) (p=0.0003; OR=4.89; 95% CI 1.96 to 12.23). This increased risk applies equally to sons and daughters. CONCLUSION: The lifetime RR of axSpA for HLA-B27(+) FDR is substantial (27.1%), and disease severity (as defined by radiographic sacroiliitis by the mNY criteria) is an additional risk factor. Affected mothers pass on the disease significantly more often to their offspring than do affected fathers. These findings may lead to better assessment of lifetime risk for axSpA in the offspring. Moreover, investigation of this gender effect may uncover additional putative disease susceptibility factors.

Large epidemiologic studies of gout: challenges in diagnosis and diagnostic criteria.

Large epidemiologic studies of gout can improve insight into the etiology, pathology, impact, and management of the disease. Identification of monosodium urate monohydrate crystals is considered the gold standard for diagnosis, but its application is often not possible in large studies. Therefore, under such circumstances, several proxy approaches are used to classify patients as having gout, including ICD coding in several types of databases or questionnaires that are usually based on the existing classification criteria. However, agreement among these methods is disappointing. Moreover, studies use the terms acute, recurrent, and chronic gout in different ways and without clear definitions. Better definitions of the different manifestations and stages of gout may provide better insight into the natural course and burden of disease and can be the basis for valid approaches to correctly classifying patients within large epidemiologic studies.

Axial spondyloarthritis: concept, construct, classification and implications for therapy.

The axial spondyloarthritis (axSpA) disease concept has undergone substantial change from when the entity ankylosing spondylitis was defined by the modified New York criteria in 1984. Developments in imaging, therapy and genetics have all contributed to changing the concept of axSpA from one of erosions in the sacroiliac joints to a spectrum of disease with and without changes evident on plain radiographs. Changes to the previously held concept and construct of the disease have also necessitated new classification criteria. The use of MRI, primarily of the sacroiliac joints, has substantially altered the diagnosis and differential diagnosis of axSpA. Many in the axSpA community believe that the current classification criteria lack specificity, and the CLASSIC study is underway to examine this area. Although much about the evolving axSpA disease concept is universally agreed, there remains disagreement about operationalizing aspects of it, such as the requirement for the objective demonstration of axial inflammation for the classification of axSpA. New imaging technologies, biomarkers and genetics data will probably necessitate ongoing revision of axSpA classification criteria. Advances in our knowledge of the biology of axSpA will settle some differences in opinion as to how the disease concept is applied to the classification and diagnosis of patients.

Evaluation of patients with a recent clinical fracture and osteoporosis, a multidisciplinary approach.

The aetiology of osteoporotic fractures is multifactorial, but little is known about the way to evaluate patients with a recent clinical fracture for the presence of secondary osteoporosis. The purpose of this study was to determine the prevalence of contributors to secondary osteoporosis in patients presenting with a clinical vertebral or non-vertebral fracture. Identifying and correcting these contributors will enhance treatment effect aimed at reducing the risk of subsequent fractures. In a multidisciplinary approach, including evaluation of bone and fall-related risk factors, 100 consecutive women (n = 73) and men (n = 27) older than 50 years presenting with a clinical vertebral or non-vertebral fracture and having osteoporosis (T-score < or =-2.5) were further evaluated clinically and by laboratory testing for the presence of contributors to secondary osteoporosis. In 27 patients, 34 contributors were previously known, in 50 patients 52 new contributors were diagnosed (mainly vitamin D deficiency in 42) and 14 needed further exploration because of laboratory abnormalities (mainly abnormal thyroid stimulating hormone in 9). The 57 patients with contributors were older (71 vs. 64 yrs, p < 0.01), had more vertebral deformities (67% vs. 44%, p < 0.05) and a higher calculated absolute 10-year risk for major (16.5 vs. 9.9%, p < 0.01) and for hip fracture (6.9 vs. 2.4%, p < 0.01) than patients without contributors. The presence of contributors was similar between women and men and between patients with fractures associated with a low or high-energy trauma. We conclude that more than one in two patients presenting with a clinical vertebral or non-vertebral fracture and BMD-osteoporosis have secondary contributors to osteoporosis, most of which were correctable. Identifying and correcting these associated disorders will enhance treatment effect aimed at reducing the risk of subsequent fractures in patients older than 50 years.

Ankylosing spondylitis and symptom-modifying vs disease-modifying therapy.

The main objectives of medical therapy in ankylosing spondylitis (AS) are to relieve pain, stiffness and fatigue and to prevent structural damage. The Assessment in Ankylosing Spondylitis Working Group has proposed different domains with specific instruments to assess the efficacy of therapeutic agents classified as symptom-modifying and disease-controlling antirheumatic drugs. Non-steroidal antiinflammatory drugs (NSAIDs) are still the first-line treatment in the management of AS, and they are effective in controlling symptoms such as pain and stiffness and maintaining mobility in many patients. A recent randomized trial suggested that the progression of radiological damage occurs less on continuous use of celecoxib compared with on-demand use. If such findings were confirmed by other studies, the therapeutic value of NSAIDs in AS may extend beyond symptom control. However, for each individual patient, the expected advantages of treatment with NSAIDs should be weighted against any possible gastrointestinal and cardiovascular disadvantages. Disease-modifying antirheumatic drugs (DMARDs) are widely used for second-line therapy in AS, but the evidence for their efficacy is poor. The term 'DMARD' has been borrowed from rheumatoid arthritis, and none of the DMARDs have been shown to prevent or significantly decrease the rate of progression of structural damage which is required to be qualified as a disease-controlling antirheumatic drug for AS. Sulphasalazine is the most extensively studied DMARD and studies suggest some degree of clinical benefit confined to peripheral joint involvement, but no evidence of benefit in axial disease. Methotrexate, which is the gold standard DMARD in rheumatoid arthritis, does not seem to have a substantial therapeutic effect in AS on axial or peripheral joint involvement. Leflunomide appears to exert little beneficial effect, if any, even on peripheral joint involvement. There is also good evidence that local therapy with corticosteroids is effective and may be used in selected patients. Oral corticosteroids may be somewhat effective in relieving the symptoms of AS, but this has not been formally studied. Small studies have reported favourable results with intravenous methylprednisolone pulse therapy, but the effect is temporary. Pamidronate and thalidomide have been used in some preliminary trials but need further studies to assess their potential role in treating AS patients resistant or intolerant to other forms of treatment. Treatment with tumour necrosis factor blockers is not discussed in this review.

The burden of ankylosing spondylitis.

The acute as well as chronic clinical features of ankylosing spondylitis (AS) are a burden to the patient and society. Apart from the axial and articular manifestations, extraarticular AS-related comorbidities such as uveitis, inflammatory bowel disease, and psoriasis contribute to the burden of the disease. In addition, a large proportion of patients have osteoporosis or osteopenia, which may be associated with fractures and contribute to kyphosis. All these features result in decreased quality of life. Moreover, patients with AS have an increased mortality rate. The impact of this disease also can be seen in various aspects of workforce participation, from requiring more assistance at paid work to withdrawal from the workforce. Further, patients with AS and, subsequently, society are affected by substantial healthcare costs related to medications and healthcare provider expenses. Early diagnosis and management of patients will likely prevent functional disability and improve patient outcomes.

Knowledge, illness perceptions and stated clinical practice behaviour in management of gout: a mixed methods study in general practice.

The objective of the present study is to explore knowledge, illness perceptions and stated practice behaviour in relation to gout in primary care. This is a mixed methods study among 32 general practitioners (GPs). The quantitative assessment included the Gout Knowledge Questionnaire (GKQ; range 0-10; better) and Brief Illness Perceptions Questionnaire (BIPQ; nine items, range 0-10; stronger). Structured individual interviews obtained further qualitative insight into knowledge and perceptions, in the context of daily practice. Among 32 GPs, 18 (56.3 %) were male, mean age 44.4 years (SD 9.6) and mean working experience 17.1 years (SD 9.7). Median score [interquartile ranges (IQR)] on the GKQ was 7.8 [6.7-8.9] and 9.0 [8.0-10.0], when presented as open or multiple-choice questions, respectively. The BIPQ (median; [IQR]) revealed that gout was seen as a chronic disease (8.0; [7.0-9.0]), affecting life and emotions moderately (6.5; [5.0-7.0]), having many severe symptoms (8.0; [7.0-9.0]) and in which treatment could be very helpful (8.0; [7.0-9.0]). Further interviews revealed large variation in specific aspects of knowledge and about gaps concerning indications for uric acid-lowering therapy (UALT), duration of UALT, target serum uric acid (sUA) level or duration of prophylactic treatment. Finally, patients' adherence was not checked systematically. Specific knowledge gaps and discrepancies between perceptions and stated practice behaviour were identified, which might hamper effective management of this well-treatable disease. Improving evidence on the rationale and effectiveness of treatment targets and adherence interventions, tailoring guidelines to general practice and intensification of implementation of guidelines in primary health care seem to be needed.

Cost of illness and determinants of costs among patients with gout.

OBJECTIVE: To estimate costs of illness in a cross-sectional cohort of patients with gout attending an outpatient rheumatology clinic, and to evaluate which factors contribute to higher costs. METHODS: Altogether, 126 patients with gout were clinically assessed. They completed a series of questionnaires. Health resource use was collected using a self-report questionnaire that was cross-checked with the electronic patient file. Productivity loss was assessed by the Work Productivity and Activity Impairment Questionnaire, addressing absenteeism and presenteeism. Resource use and productivity loss were valued by real costs, and annual costs per patient were calculated. Factors contributing to incurring costs above the median were explored using logistic univariable and multivariable regression analysis. RESULTS: Mean (median) annual direct costs of gout were €5647 (€1148) per patient. Total costs increased to €6914 (€1279) or €10,894 (€1840) per patient per year when adding cost for absenteeism or both absenteeism and presenteeism, respectively. Factors independently associated with high direct and high indirect costs were a positive history of cardiovascular disease, functional limitations, and female sex. In addition, pain, gout concerns, and unmet gout treatment needs were associated with high direct costs. CONCLUSION: The direct and indirect costs-of-illness of gout are primarily associated with cardiovascular disease, functional limitations, and female sex.