key: cord-337487-1lbopaso
authors: Hansildaar, Romy; Vedder, Daisy; Baniaamam, Milad; Tausche, Anne-Kathrin; Gerritsen, Martijn; Nurmohamed, Michael T
title: Cardiovascular risk in inflammatory arthritis: rheumatoid arthritis and gout
date: 2020-09-01
journal: Lancet Rheumatol
DOI: 10.1016/s2665-9913(20)30221-6
sha: 
doc_id: 337487
cord_uid: 1lbopaso

The increased risk of cardiovascular morbidity and mortality in rheumatoid arthritis and gout has been increasingly acknowledged in past decades, with accumulating evidence that gout, just as with rheumatoid arthritis, is an independent cardiovascular risk factor. Although both diseases have a completely different pathogenesis, the underlying pathophysiological mechanisms in systemic inflammation overlap to some extent. Following the recognition that systemic inflammation has an important causative role in cardiovascular disease, anti-inflammatory therapy in both conditions and urate-lowering therapies in gout are expected to lower the cardiovascular burden of patients. Unfortunately, much of the existing data showing that urate-lowering therapy has consistent beneficial effects on cardiovascular outcomes in patients with gout are of low quality and contradictory. We will discuss the latest evidence in this respect. Cardiovascular disease risk management for patients with rheumatoid arthritis and gout is essential. Clinical guidelines and implementation of cardiovascular risk management in daily clinical practice, as well as unmet needs and areas for further investigation, will be discussed.

Cardiovascular disease is the most frequent cause of death worldwide. The 2017 Global Burden of Disease Study showed that 17·8 million people died of cardiovascular disease globally, accounting for 21% of all deaths. 1 Well established, traditional risk factors for cardiovascular dis ease comprise age, sex, race, hypertension, diabetes, smok ing, and hyperlipidaemia, all of which are included in various prediction models. However, over the past 20 years several nontraditional risk factors, such as chronic inflam mation, have emerged as amplifiers of cardiovascular disease risk. 2 Rheumatoid arthritis is the most common auto immune arthritis, with a prevalence of up to 1%, 2 and is char acter ised by a symmetrical polyarthritis with pos sible sys temic manifestations. Rheumatoid arthritis is an accepted independent risk factor for cardiovascular disease, driven by the underlying chronic inflammatory pro cess. However, traditional cardiovascular risk factors remain important. 3 Gout is the most common crystalinduced, auto inflammatory joint disease with a prevalence of between 0·1% and 10·0%. 4 Gout occurs when monosodium urate crystals are deposited in joints and soft tissues. Hyperuricaemia-defined by a serum urate concentra tion above the saturation point (ie, ≥0·41 mmol/L [≥6·8 mg/dL])-results predominantly from reduced renal excretion of uric acid, which is a consequence of genetics, comorbidities, and therapies. A continuum has been sug gested, from asymptomatic hyperuricaemia to asympto matic subclinical crystal deposition detectable only by ultrasound or dualenergy CT, to the clinical inflammatory state of gout flares, to chronic gouty arthritis with tophi and gouty bone erosions. 5 If not treated adequately, gout is a debilitating disease with systemic manifestations, such as monosodium urate crystal deposition in organs and worsening of cardiorenal function. 6, 7 In addition to gout flares, patients with gout frequently have a high burden of cardiovascular comorbidities, which might explain, in part, the high cardiovascular mortality when compared with the general population. 8 During the past 20 years, gout has been shown to be an independent cardiovascular risk factor, with higher cardiovascular mortality than in the general population. 9 In this Review, we will discuss epidemiological data on cardiovascular disease in rheumatoid arthritis and gout, not only for atherosclerotic disease but also for venous thrombotic disease and heart failure, as clinical and subclinical prevalence of the two diseases is higher than previously thought. The underlying pathophysiology of increased cardiovascular risk relevant to inflammatory arthritis, as well as the observed effect of antiinflammatory and disease modifying treatments such as uratelowering therapies in gout, will be reviewed and discussed. Increased cardiovascular risk in patients with inflam matory arthritis necessitates cardiovascular risk assess ment and current management guidelines and their practical implications will be discussed. Finally, we con sider topics that need further research with the aim to decrease the cardiovascular burden of patients.

Patients with rheumatoid arthritis have up to a twotimes higher risk of developing atherosclerotic cardiovascular disease than the general population, similar to patients with diabetes. 10 The risk of ischaemic heart disease is increased in patients with early rheumatoid arthritis and symptom duration of less than 1 year, and probably even in the subclinical stage. 11 The risk of cerebrovascular incidents is increased by about 50% (relative risk 1·48, 95% CI 0·70-3·12), whereas the risk of myocardial infarction is doubled (relative risk 2·00, 1·23-3·29). 11 Moreover, patients with rheu matoid arthritis have almost twice the risk of developing congestive heart failure (rate ratio 1·7, 95% CI 1·3-2·1), including both heart failure with preserved ejection fraction and heart failure with reduced ejection fraction. 12 

Several factors contribute to increased cardiovascular risk, including comorbidities such as diabetes, dyslipidae mia, and hypertension; 13 albeit the data for hypertension are somewhat conflicting. 14 Lipids seem to have paradoxi cal associations with cardiovascular risk in rheumatoid arthritis. During active disease, low total cholesterol and LDL cholesterol are associated with increased cardio vascular risk (the socalled lipid paradox). 15 Effective anti rheumatic therapies resulting in reduced disease activity of rheumatoid arthritis reverse the cholesterol reduction, thus leading to increased lipid concentra tions, 16 and lipid concentrations in well controlled rheumatoid arthritis are generally stable and similar to those in the general population. 11, 15, 17 Furthermore, patients with rheu ma toid arthritis also have more than a two times increased risk of venous thrombotic disease compared with the general population (cumulative inci dence of 6·7% [SE 1·7] vs 2·8% [1·1], p=0·005). 18 Studies show that allcause mortality among patients with rheumatoid arthritis was 54% higher than in the general population, primarily because of cardiovascular disease (32%), 19 with a median shortened life expectancy of 6-7 years. 20 In one study, the estimated standardised cardiovascularmortality ratio was 1·2 (95% CI 1·05-1·43), 21 which is substantially less than reported in earlier studies. The improvement in cardiovascular mortality in patients with rheumatoid arthritis over the past 20 years could be attributed to the early initiation of more effective anti rheumatic treatments (conventional synthetic and biologi cal diseasemodifying antirheumatic drugs [DMARDs]). 22 Decreased disease activity following effec tive therapy is associated with a lower cardiovascular risk, and vice versa, whereas cardiovascular risk remains unchanged in patients who do not respond to biological DMARDs. 23 However, it should be noted that about 50% of increased cardiovascular disease risk in patients with rheuma toid arthritis is associated with traditional cardiovascular risk factors. 24

A large retrospective database study in the UK (8386 patients with gout vs 39 766 without gout) showed that the prevalence of hypertension in patients with gout at baseline was twice as high compared with the control group (36% vs 17%). Patients were also more often obese (60% vs 44%) and hyperlipidaemic (6% vs 3%) with more prevalent use of statins (34% vs 26%). 25 A high prevalence of these traditional risk factors was also seen in the large National Health and Nutrition Examination Survey 2007-08, including 7·7 million US patients with gout. Moreover, the National Health and Nutrition Examination Survey showed that 26% of patients with gout had diabetes compared with almost 8% in the nongout population (OR 2·36, 95% CI 1·5-3·7). 26 In a large retrospective Dutch cohort of primary care patients with gout, 796 (30%) of 2655 patients already had established cardiovascular disease at cohort entry compared with 1557 (20%) of 7891 in the nongout control group. After 3 years of followup, 154 (8%) of 1859 patients with gout had developed cardiovascular disease, compared with 318 (5%) of 6334 in the nongout control group. 13 There was an even higher incidence of cardiovascular disease (47%) in patients managed by rheumatologists, possibly explained by a higher portion of severe gout seen in this setting. 8 Gout is an independent risk factor for cardiovascular disease; however, the strength of the association of hyper uricaemia and gout with other traditional cardio vascular risk factors makes distinguishing the isolated influence of gout on that risk difficult. 27 Although atherosclerotic disease, hypertension, and chronic kidney disease are associated with elevated serum urate concentrations, the causal relationship and direction of association between urate and these disorders is still under debate. 28 29, 30 In the past decade, several observational studies have suggested an association between hyperuricaemia, gout, and congestive heart failure. A crosssectional study of 15 722 patients in the USA found the prevalence of congestive heart failure to be 10% in patients with gout versus 2% in patients without gout. 31 Another study in patients with coronary artery disease showed that patients with gout had a higher prevalence of congestive heart failure (500 [36%] of 1406) than those without gout (3847 [25%] of 15 795). 32 Furthermore, individuals with asymptomatic hyperuricaemia already have an increased risk of con gestive heart failure, 33, 34 and there appears to be a linear relationship with serum urate concentrations.

Gout increases the risk of mortality from cardiovascular disease (hazard ratio [HR] 1·29, 95% CI 1·14-1·44). 35 During a mean followup of 4 years among 706 patients with gout, 38 (59%) of 64 deaths had a cardio vascular attribution. 36 Looking for trends and possible improvement of cardiovascular mortality in gout, analysis of a medical record database representative of the UK compared cumulative mortality rates of individuals with gout versus nongout between 1999-2006 and 2007-14. The investi gators found that the high mortality in patients with gout remained unchanged, whereas mortality rates for rheumatoid arthritis have improved over the same time period. This mortality gap might be related to suboptimal gout care (insufficient allocation of medication, insufficient treat ment, and low drug adherence), as well as insufficient management of cardiovascular comorbidities. Gout speci fic character istics that are associated with high cardio vascular risk are elevated serum urate concentrations (>0·55 mmol/L [>9·1 mg/dL]), longer disease duration (≥2 years), oligo articular or polyarticular disease, and Review joint damage and tophi, which all reflect a more severe disease state. 8

Although rheumatoid arthritis and gout have different pathogenic stimuli (not known for rheumatoid arthritis; monosodium urate crystal deposition for gout), different immune pathways (eg, antibodymediated in rheumatoid arthritis; interleukin [IL]1 driven in gout flares), and in most cases different clinical presentation (more chronic symmetric synovitis in rheumatoid arthritis; mostly mono arthritic gout flares with asymptomatic periods), imaging studies have shown that in gout, subclinical inflamma tion and synovitis are present, even during asymptomatic periods. 37 Importantly, persistent inflammation is known to be a key mechanism in the development of cardiovascular disease. 38, 39 Cardiovascular disease in patients with gout and rheumatoid arthritis can be divided into three main categories: atherosclerosis, thromboembolism, and cardiac dysfunction (figure 1). The pathophysiological mechanisms of these diseases are different. However, the inflammatory processes of gout and rheumatoid arthritis in the develop ment of cardiovascular diseases partly overlap.

Postulated shared mechanisms of rheumatoid arthritis and gout are systemic inflammation, reactive oxygen species (ROS)induced oxidative stress, and endothelial dysfunction, all of which lead to atherosclerosis (figure 2).

The pathways of inflammation in rheumatoid arthritis and gout share some components of the innate and adaptive immune system, including activated neutrophils. Exaggerated neutrophil activation has been linked to auto immunity and autoinflammation in rheumatoid arthritis and gout. One of the supposed links is the formation of neutrophil extracellular traps (NETs). NETosis involves a neutrophil cell death process in which DNA is extruded, together with cytoplasmic and granular contents, to trap and eliminate extracellular pathogens and neutralise inflammatory cytokines. This process, which was first described in gout by Schauer and col leagues, 40 could explain the selflimiting character of gout flares. Extra cellular DNA exerts cytotoxic and pro thrombotic effects and might be a causal link between inflammation and coagulation. Moreover, complexes of presumably NET borne DNA stimulate vascular plasma cytoid dendritic cells, with a strong interferon type 1 response, promoting atherogenesis. 41 NETs might also directly cause endothelial dysfunction by activation and induction of damage to endothelial cells, illustrated by the establishment of NETs in atherosclerotic lesions and arterial thrombi in humans. 42 In addition to neutrophils, different proinflammatory cytokines play a central role in the pathogenesis of rheumatoid arthritis and gout. In rheumatoid arthritis, the reason for immune system activation has not been completely elucidated. However, proinflammatory cyto kines, such as tumour necrosis factor (TNF), IL6, and IL1, are important in the inflammatory process. In gout, the central inflammatory pathogenic process is assumed to be hyperuricaemia, leading to monosodium urate crystal deposition. 43 These crystals provoke a host response, result ing in recurrent gout flares by acting as a danger signal for the innate immune system through activation of the NLRP3 inflammasome with the immedi ate release of mature IL1β by resident macrophages, as well the release of other cytokines. 44 The NLRP3 inflammasome has an important role in the initiation of a gout flare. Inflam masome activity causes oxidative stress, mito chondrial dysfunction, endoplasmic reticulum stress, and lysosome rupture, which are all important events in atherogenesis and could lead to atherosclerotic plaque instability and ultimately rupture. 42 ROS are a group of small reactive species that play crucial roles in the regulation of biocellular processes. The balance between ROS and antioxidant species is essential 

to maintain cellular homoeostasis. Hence, an imbalance in oxidant and antioxidant mechanisms leads to a state of oxidative stress. In several chronic diseases, including rheumatoid arthritis, there is abundant oxidative stress. 45 Although essential for vascular homoeostasis, an excess of ROS might lead to vascular injury. Vascular injury being the result of a complex cascade, including oxidative modification of lipoproteins, endothelial activation, and leucocyte migra tion and differentiation resulting in accelera tion of atherogenesis. 46 Oxidative stress might also link gout with cardiovascular disease. Although soluble urate has antioxidant properties, during urate generation the catalytic enzyme xanthine oxidase produces substantial amounts of ROS that affect biocellular mechanisms. There is some experimental evidence that in patients with gout, higher activity of xanthine oxidoreductase (XO) is associ ated with larger amounts of ROS. Indirectly, it was shown that inhibiting endotheliumbound XO resulted in reduced ROS with favourable effects on vascular function. 47, 48 Endothelial dysfunction is a maladaptive state with disruption of vascular homoeostasis resulting from a proinflammatory state. By expressing adhesion molecules and inflammatory cytokines, endothelial cells amplify an inflammatory cascade facilitating monocyte infiltration in the subendothelial layer. LDL cholesterol accumulates in the subendothelial space and is oxidised, which is essential for the development of atherosclerotic plaques. 46 Endo thelial dysfunction is the earliest phenomenon in the development of atherosclerosis and was first described in rheumatoid arthritis in 2002; 49 it has been observed in patients with early rheumatoid arthritis without traditional risk factors and in those with longstanding disease. In rheumatoid arthritis, systemic inflammation with pro inflammatory mediators, such as IL1β and TNF, is assumed to play a role in the development of endothelial dysfunction, as shown in rodent models. 50 Impaired endotheliumdependent arterial responsive ness has been observed in patients with untreated gout, compared with individuals without gout, with the degree of impairment related to both serum urate and high sensitive Creactive protein concentrations. 51 There are published case series and case reports of urate crystal deposition in the spine and solid organs in histological samples fixed with alcohol (no dissolution of crystals). 52 A current observational study investi gated alcoholfixed specimens of coronary arteries from explanted hearts with polarisation microscopy and detected strongly birefringent urate crystals in about 10% of coronary arteries. 53 Whether or not crystal deposition in the vessels with subsequent local inflammation con tributes to a higher cardiovascular risk in these patients is not known.

The immune system and coagulation system are linked to increased activity of the fibrinolytic system in patients with inflammatory joint diseases. Tissue factor initiates the extrinsic coagulation cascade and is found on extravascular cells, such as monocytes and neutrophils. Creactive protein, TNF, IL6, and com ple ment activation might amplify tissue factor synthesis in monocytes and endo thelial cells, and high concen trations of tissue factor have been found in patients with rheumatoid arthritis, particularly in those with a high disease activity. 54 Conse quently, increased concentrations of coagulation factors were shown in patients with rheumatoid arthritis. 54 The role for TNF seems plausible, as in the general population this cytokine might induce an imbalance between clotting and fibrinolysis, resulting in a hypercoagu lable state. Further more, a role for IL6 was suggested by a randomised trial in patients with rheumatoid arthritis that showed that IL6 receptor blockade reduced coagulation activation parameters by more than 40% compared with placebo. 55 To date, data on the role of cytokines in the develop ment of thromboembolism in gout are not available and observational data suggests that gout is an independent risk factor for the development of deep vein thrombosis and pulmonary embolism. 56 In addition to extensive neutrophil activation in gout, increased platelet reactivity has been detected. This finding might serve as one explanation for a prothrombotic state and association with thromboembolism in gout. 57

Initially, cardiac dysfunction in patients with rheumatoid arthritis was assumed to be secondary to ischaemic heart disease. However, the incidence of congestive heart failure (heart failure with preserved ejection fraction and heart failure with reduced ejection fraction) cannot be explained by atherosclerotic disease alone. A casecontrol study showed that patients with rheumatoid arthritis had a rapidly increasing risk of developing nonischaemic conges tive heart failure after clinical onset. 58 Congestive heart failure was seen more frequently in patients with rheuma toid arthritis compared with patients with osteo arthritis (adjusted risk 3·9% [95% CI 3·4-4·3] for rheumatoid arthritis vs 2·3% [1·6-3·3] for osteoarthritis). 59 Patients with rheumatoid arthritis treated with TNF blocking agents had significantly less congestive heart failure than those who were not receiving antiTNF treatment. 59 Another study found an increased prevalence of heart failure with preserved ejection fraction in patients with rheumatoid arthritis, which correlated primarily with disease activity and with antiinflammatory treat ments (ie, conventional synthetic DMARDs and biological DMARDs). 60 In addi tion, patients with rheumatoid arth ritis are susceptible to more rapid subclinical changes in diastolic func tion than are the general population. 61 Altogether, these studies suggest that systemic inflam matory activity and cardiac dys function cannot be attrib uted to athero sclerosis alone.

Chronic systemic inflammation has two distinct path ways in the development of cardiac dysfunction ( figure 3) . First, chronic systemic inflammation leads to myo cardial Review remodelling, and, specifically, to diastolic dysfunc tion. This process starts with inflammationinduced microvascular dysfunction, 63 leading to deposition of collagen with subsequent stiffness and hypertrophy of cardio myocytes and a decreased ability of the myocardium to contract and relax, which might evolve into heart failure with preserved ejection fraction. 64 Second, systemic inflam mation and traditional cardiovascular risk factorinduced coronary microvascular dysfunction and activation lead to athero sclerosis with ischaemic heart disease. This ischaemia leads to autophagy, apoptosis and necrosis of cardio myocytes, and collagen deposition in the interstitial space giving rise to systolic ventricular dysfunction. In severe cases, heart failure with reduced ejection fraction might develop. 62 Several studies have assessed the effect of anti inflammatory therapy on cardiac function in rheumatoid arthritis, and a systematic review revealed that biological DMARD therapy probably has favourable effects on cardiac dysfunction in rheuma toid arthritis. 65 Remarkably, the pathogenesis of cardiac dysfunction in hyperuricaemia and gout has not been adequately investigated to date. 66 Previous studies showed an associ ation between serum urate concentration and inflamma tion, thus suggesting a comparable pathogenesis with rheumatoid arthritis. 67 Furthermore, increased serum urate concentration and higher activity of ROSgenerating XO in gout might lead to endothelial dysfunction with decreased nitric oxide production. 68 Hypertension might also have a causal role because gout and hyperuricaemia are independent predictors of developing hyperten sion. One interventional study assessing uratelowering therapy in patients with heart failure did not find signifi cant beneficial effects of allopurinol, probably because there was already advanced structural myocardial damage and multimor bidity in the patient population. 69 Studies with early urate lowering inter ventions are needed to answer the ques tion of whether, and to what extent, urate concentration and the associated inflam ma tion in gout con stitutes an independent risk factor for cardiac dysfunction. 70

Most nonsteroidal antiinflammatory drugs (NSAIDs), including the cyclooxygenase inhibitors, are associated with about a twotimes increased cardiovascular risk. 71 The excep tion is probably naproxen, although the pub lished literature is conflicting in this respect. 72 Cardio vascular risk is associated with COX2 selectivity, and the lower COX2 selectivity of naproxen than of other NSAIDs (eg, cyclooxygenase inhibitors) is assumed to translate into a lower cardiovascular risk. 73 In clinical practice, weighing the benefits of these drugs against cardiovascular risk is often difficult. The first risk model that could aid in clinical decision making regarding the use of these drugs was published in 2019. 74 This model was based on the Precision trial, 75 a large randomised controlled trial in which patients with osteoarthritis or rheumatoid arthritis were random ised to naproxen, ibuprofen, or celecoxib. 75 A major toxicity risk calculator was developed from easily accessible cardiovas cular risk factors (ie, age, gender, diabetes, cardio vascular disease, hypertension, current smoking, statin use, serum creatinine, rheumatoid arth ritis, and haemato crit) to calculate a 1year risk score yielding three risk categories: low (<1%), inter medi ate (1-4%), or high risk (>4%). However, external validation is necessary before such a calculator can be implemented in daily clinical practice.

There has been a longstanding debate on whether steroids (eg, low dose of prednisolone, <10 mg daily) have unfavourable cardiovascular effects in an inflammatory situation. This effect is suggested by observational studies, but these data are confounded by indication because of high disease activity and should therefore be inter preted with caution. 76 Hopefully this debate can be settled by the Gloria trial (NCT02585258), a multicentre, 2year trial assessing the safety and effectiveness of a daily 5 mg dose of prednisolone versus a matching placebo added to standard of care in older patients (aged ≥65 years) with rheumatoid arthritis. Systemic inflammation with elevated concentrations of circulating cytokines, such as IL-6 and TNF, induce oxidative stress and endothelial activation. Consequently, presentation of adhesion molecules (VCAM-1 and E-selectin) by endothelial cells leads to monocyte infiltration in the myocardium. These monocytes produce TGF-β, resulting in the differentiation of fibroblasts into myofibroblasts, with subsequent deposition of collagen in the interstitial space. In addition, intracellular oxidative stress results in disrupted crosstalk between endothelial cells and cardiomyocytes, leading to stiffness and hypertrophy of cardiomyocytes with a subsequent decreased ability to contract and relax. These processes ultimately lead to preclinical diastolic ventricular dysfunction, which might evolve into heart failure with preserved ejection fraction. Ischaemia, mostly secondary to atherosclerosis, leads to autophagy, apoptosis, and necrosis of cardiomyocytes, and deposition of collagen in the interstitial space. This condition can give rise to systolic ventricular dysfunction, which in severe cases can lead to heart failure with reduced ejection fraction. Adapted from Paulus and Tschöpe, 62 

One of the first studies suggesting that cardiovascular mortality risk in rheumatoid arthritis could be reduced by methotrexate was published in 2002. 77 Of 1240 patients with rheumatoid arthritis with a mean followup of 6 years, 191 (15%) patients had died, 84 (44%) of which were cardiovascular deaths. Methotrexate use was associ ated with a 70% reduction in cardiovascular mortality (HR 0·3, 95% CI 0·2-0·7). Methotrexate also has favourable effects on nonfatal cardiovascular events, with metaanalysis showing a risk reduction of 28% in comparison with treatment without methotrexate. 78 Other conventional synthetic DMARDs, such as sulfasalazine, might also have favourable cardio vascular effects. 79 In addition to beneficial effects on the lipid profile, hydroxychloroquine has been associated with a reduc tion in cardiovascular events in patients with rheumatoid arthritis. 80 The recent association of highdose hydroxy chloroquine with QT prolongation in patients with COVID19 has raised questions about the use of hydroxy chloroquine in patients with rheumatoid arthritis. 81 As such, it is important to note that disease activity of rheumatoid arthritis itself is associated with QT prolonga tion. 82 Furthermore, there have been no published reports indicating that the use of hydroxychloquine in patients with rheumatoid arthritis is associated with an increased risk for QT prolongation. Hence, there is no indication to restrict the use of hydroxychloroquine in people with rheumatoid arthritis to require baseline electrocardiograms.

The first largescale investigation that compared the effect of antiTNF agents versus conventional synthetic DMARDs on cardiovascular mortality in patients with rheu matoid arthritis found an adjusted HR for death of 0·65 (95% CI 0·46-0·93). 83 The risk of acute coro nary syndrome in rheumatoid arthritis was studied in 7704 patients from a Swedish registry (32 621 patientyears) compared with the general population; 84 the HR for acute coronary syndrome was 2·0 (95% CI 1·8-2·3) for patients who were previously untreated with biolo gics and 1·6 (1·4-1·9) for patients using TNF inhibitors.

A metaanalysis of 28 studies with 236 525 patients with rheumatoid arthritis investigated the reduction in cardio vascular events with methotrexate and TNF inhibitors in comparison with patients previously untreated with these agents. 85 5410 cardiovascular events were observed and the relative risk was 0·72 (95% CI 0·57-0·91) for metho trexate and 0·70 (0·54-0·90) for TNF inhib itors. Hence, favourable cardiovascular effects might be mediated through an overall reduction in inflammation and are not drug specific.

In 2017, Janus kinase (JAK) inhibitors were suggested to be associated with an increased risk of thromboembolic disease 86 and concerns have been reported by the US Food and Drug Administration (FDA) about the safety of tofacitinib. These concerns emerged from a postmarketing trial evalu ating the safety of tofacitinib at two doses (5 mg twice daily and 10 mg dose twice daily) versus a control group given a TNF inhibitor. 87 There was an increased inci dence of pulmonary embolism and an increased overall mortality in patients taking 10 mg tofacitinib twice daily. 88 Subse quently, a warning was issued indicating that tofacitinib 10 mg twice daily is contraindicated in patients who have an increased thromboembolic risk. In view of these events, it is important that the prescribed dose for the treatment of rheumatoid arthritis is restricted to 5 mg twice daily. The trial programme for baricitinib, the other JAK inhibitor currently licensed for rheumatoid arth ritis, identified more thromboembolic events in the 4 mg group in comparison with the placebo group, 89 and as a result the 4 mg dose was not approved in the USA. By contrast, a warning was issued in Europe, indicating that the 4 mg dose should not be used in patients with rheumatoid arthritis with an increased risk of venous thrombo embolism. Further studies are needed to investi gate and to differentiate between the potential adverse effect of JAK inhibitors and the hypercoagulable character of rheumatoid arthritis.

Firstline treatment of gout flares is usually with an NSAID or cyclooxygenase inhibitor. The duration of treatment, in general, is short, as gout flares in the early stages of disease are often limited to a few days. Whether or not this treatment increases cardiovascular risk is not known. Furthermore, there are no data on the cumulative yearly dose of NSAID or cyclooxygenase inhibitor intake for patients with recurrent gout flares, as these drugs are often available without prescription. In advanced gout in particular, chronic use of these drugs might be relevant with respect to adverse cardiovascular effects.

Colchicine is frequently used for treatment of acute gout flares and is also given as a lowdose regimen to prevent gout flares during initiation of uratelowering therapy. Colchicine was first used as an antiinflammatory treatment in cardiovascular disease. A 2018 narrative review showed that colchicine has beneficial effects on athero sclerosis with plaque stabilisation, reduction of cardiovascular damage, and reduction in recurrence of acute coronary syndromes. 90 Colchicine might also have protective effects in stable coronary artery disease. 91 Two retrospective cohort studies in patients with gout showed a lower incidence of combined cardiovascular out comes in patients treated with colchicine. 92, 93 By contrast, a trial showed that shortterm lowdose colchicine does not improve endothelial function in patients with coronary artery disease. 94 However, an exploratory analysis indicated that endothelial function was significantly improved in the subgroup of patients with leucocyte activation, further indicating the important role of inflammation in athero sclerosis. 94 Ongoing trials, such as the COLCOT trial (NCT02551094), will hopefully settle the debate about the efficacy of lowdose colchicine for secondary preven tion in patients with coronary disease. In patients with gout, more research is needed to establish the effects of colchicine on cardiovascular risk.

Gout flares that do not respond to NSAIDs, cyclo oxygenase inhibitors, or colchicine are frequently treated with steroids, either systemically or by intraarticular injec tion. As data on patients with gout are scarce, one can only speculate as to whether the typically short treatment duration has any unfavourable cardiovascular effects.

In 2013, the antiIL1β antibody canakinumab was approved by the FDA and the European Medicines Agency for gout inflammation refractory to conven tional antiinflam matory treatment. 95 A 2019 trial of the IL1 receptor antagonist, anakinra, showed efficacy in controlling inflammation during gout flare without cardio vascular safety issues. 96 The CANTOS trial, 97 which investi gated antiinflammatory therapy with canakinumab for secon dary cardiovascular prevention in patients with myocar dial infarction, showed only a modest decrease in recurrent cardiovascular events (about 15%) compared with placebo, and this result was independent of lipid lowering effects. Whether patients with gout had a cardio vascular bene fit from IL1βblocking therapy was not answered by this trial.

In patients with diagnosed gout, uratelowering therapy with a treattotarget strategy to reduce serum urate below 0·36 mmol/L (6 mg/dL) is an essential therapeutic intervention recom mended by current gout guidelines. 98 The efficacy of a treattotarget approach on regression of tophi, frequency of gout flares, and MRIdetected synovitis has been shown. 99 To reach the serum urate target, patients could be treated with uratelowering drugs such as XO inhibitors (eg, allopurinol), uricosurics (and combination with XO inhibitors-eg, benzbromaron), or a recombinant uricase (eg, rasburicase). Uratelowering therapy should, in theory, reduce the risk of cardiovascular disease in gout. This therapy could decrease the risk by directly lowering urate concentration or indirectly through XO inhibition, with a subsequent reduc tion in oxidative stress and improvements in endothelial function.

A systematic review and metaanalysis of randomised controlled trials 100 revealed that uratelowering therapy with allopurinol, a purine XO inhibitor, lowered the incidence of major cardiovascular events (OR 0·65, 95% CI 0·41-1·05), total cardiovascular events (OR 0·57, 0·46-0·72), myocardial infarction or the need of urgent revas cularisation (OR 0·38, 0·17-0·83), and new or worsening hyper tension (OR 0·32, 0·18-0·58) in patients with various cardiovascular conditions versus the control group, but did not affect overall or cardiovascular mortality. These effects were not observed with nonpurinelike XO inhib itors, such as febuxostat. 100 However, febuxostat lowered the composite event rate (cerebral, cardiovascular, and renal events, as well as all deaths) in patients with hyper uricaemia who were at risk of cerebral, cardio vascular, or renal disease compared with a nonfebuxostat group (HR 0·75, 95% CI 0·59-0·95). 101 In a systematic review and metaanalysis in patients with gout uratelowering therapy with an XO inhibitor was not shown to reduce cardiovascular events compared with placebo. 102 In addition, another systematic review and metaanalysis showed that there was no significant association between allcause mortality and allopurinol use in patients with gout, albeit the number of studies was small. 103 Finally, a trial of nurseled gout care in a primary care setting consisting of extensive patient education and involvement, as well as a treattotarget strategy, was shown to be superior in reach ing a serum urate con centration of less than 0·36 mmol/L (6 mg/dL) compared with standard care (95% vs 30%, risk ratio 3·18, 95% CI 2·42-4·18, p<0·0001). 104 Fewer deaths were observed in the nurseled care group, but numbers were too small to draw firm con clusions. To date, data regarding the effect of uricosurics or uricase treatment on cardiovascular risk in gout are absent. In general, available evidence is not sufficient to draw definite conclusions and further studies are needed.

In 2019, the FDA issued a public safety alert with a warning of increased risk of death with febuxostat compared with allopurinol. 105 This warning was based on results from the CARES trial. Although febuxostat was shown to be noninferior to allopurinol for the primary outcome (a composite of death and major cardiovascular events; HR 1·03, upper limit of the onesided 98·5% CI 1·23, p=0·002 for noninferiority), the incidence of secondary outcome measures, including death from any cause (HR 1·22, 95% CI 1·01-1·47) and cardiovascular death (HR 1·34, 1·03-1·73), was significantly higher with febuxostat than with allopurinol. 106 Definite conclusions from this trial are difficult to draw: first, no significant difference was observed in the primary outcome of the trial, second, there was a very high rate of discontinuation of therapy, with the majority of deaths occurring after stopping the drug, and finally, a control group without a XO inhibitor was absent. 106 The FDA therefore first mandated febuxostat not to be used in patients with cardio vascular disease but thereafter restricted the approved use to patients who could not be treated effectively or had severe sideeffects with allopurinol. Important data will come from the FAST trial, comparing the cardiovascular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia (EUDRACT number: 2011-001883-23, ISRCTN72443728).

The recognition of an increased cardiovascular disease risk in arthritis prompted the European League Against Rheumatism (EULAR) to set out evidencebased recom mendations for the management of cardiovascular disease risk in inflammatory arthritis, and these guidelines were updated in 2017. 107 Rheumatoid arthritis is also now accepted as an independent cardiovascular disease risk factor by the European Society of Cardiology guidelines. 108 To reduce the risk of cardiovascular disease in patients with rheumatoid arthritis, optimal disease control is neces sary, and cardio vascular disease management should be the responsibility of the rheumatologist. Risk assessment Review should be done at least once every 5 years, and should be reassessed following major changes in DMARD therapy. Cardiovascular risk management is also important for patients with gout, since gout is associated with a high rate of traditional cardiovascular risk factors and is also considered an independent risk factor for cardiovascular disease and associated mortality. In the 2016 update of EULAR's evidencebased recommendations for the management of gout, two overarching principles were that every patient with gout should receive advice regarding lifestyle and that they should be screened for cardiovascular comorbidities and cardiovascular risk factors. How ever, no specific recommenda tions for cardiovascular risk management were given. 109 This omission was one of the main reasons for the assembly of a EULAR taskforce to develop recommenda tions for the management of athero sclerotic cardiovascular risk in rheu matic and musculo skeletal diseases, including sys temic lupus erythematosus, antiphospholipid syn drome, vasculitis, and gout. 110

In Europe, the Systematic Coronary Risk Evaluation calculator is used for cardiovascular disease risk pre diction. This model estimates the 10year risk of cardio vascular mortality and includes age, gender, smoking status, total cholesterol to HDL cholesterol ratio, and systolic blood pressure. However, Systematic Coronary Risk Evaluation was developed solely for the general popula tion and therefore underestimates the cardio vascular risk in patients with rheumatoid arthritis. To correct for this underestimation, EULAR recommends use of a multi plication factor of 1·5. 107 Importantly, EULAR advises screening for cardiovascular disease risk in all patients with inflammatory arthritis and states that the rheumatol ogist is responsible for its initiation. Subse quently, several prediction models for cardiovascular disease risk, such as QRISK3, have incorporated rheu matoid arthritis in their risk model. 111 The Expanded Risk Score in rheumatoid arthritis is derived from the CORRONA registry and includes rheumatoid arthritis specific features (laboratory data are not needed). 74 This risk score appears to perform as well as QRISK3. 112 The

The table shows the characteristics of these algorithms. Thus far, no goutspecific cardiovascular risk scores have been developed, probably because of an absence of con sistent data on cardiovascular outcomes.

Statins reduce cholesterol concentrations and cardio vascular disease in patients with rheumatoid arthritis to a similar extent as in the general population. Furthermore, statins are not associated with more adverse events in comparison to the general population. The TRACE RA study compared the effect of 40 mg atorvastatin with placebo in patients with rheumatoid arthritis and found a significant reduction in LDL cholesterol in the atorvastatin group. 113 In this group, LDL concentrations were similar to those observed in the general population. A risk reduction of 34% in major cardiovascular events compared with placebo was observed, although this difference did not reach statistical significance possibly due to a lower than expected event rate. Furthermore, statins have anti inflammatory properties that might translate into further reductions in cardiovascular disease risk as well as a modest reduction in rheumatic disease. A metaanalysis has shown the pleiotropic effects of statins, with a decline in inflammation markers (oestrogen receptor, Creactive protein), proinflammatory cytokines (TNF, IL1, and IL6), and fewer tender and swollen joints. 114 The EULAR recommendations for gout advise syste matic screening and care in terms of cardiovascular diseases and risk factors. 98 This strategy can be complicated because many drugs targeting comorbidities can aggravate hyperuricaemia and gout by lowering renal excretion of uric acid-eg, antihypertensive drugs such as β blockers, nonlosartan angiotensin 2 receptor blockers, thiazides, and loop diuretics. 115 This is also true for lowdose aspirin, but as the effect is very modest, use of lowdose aspirin for cardioprotective reasons should not be precluded in highrisk patients with gout. 116 Statins (atorvastatin and simvastatin), and also fenofibrate, have uratelowering effects by increasing renalurate excre tion. 117 

The effects of dietary measures in rheumatoid arthritis are still uncertain because of an absence of adequately powered studies. Observational studies show that diet, exercise, and stress are associated with outcomes such as inflammation or disease activity. Therefore, EULAR recom mends a general healthy lifestyle for all patients with rheumatoid arthritis, defined as a healthy diet (Mediterranean), regular exercise, and smoking cessation. Exercise improves cardiorespiratory fitness and decreases cardiovascular risk in patients with rheumatoid arthritis. 120 There is lowtomoderate quality evidence for beneficial effects of weight loss with respect to lowering serum uric acid, achieving serum uric acid targets, and preventing flares in patients with gout. 121 The EULAR guideline recom mends that patients with gout receive advice regarding lifestyle that includes avoidance of alcohol and sugar sweetened drinks, and discourages excessive intake of meat and seafood (purinelow diet). In addition to purines, the intake of fructose is also associated with an increase in uric acid production and should be avoided.

Guidance on smoking cessation is similar to the general population as smoking has multiple adverse effects, such as increasing the risk of cardiovascular disease, respir atory disease, and cancer. Smoking also seems to have a pathogenic role in rheumatoid arthritis, promoting disease activity and reducing response to antirheumatic therapy. In contrast to rheumatoid arthritis, a relationship between smoking and the development of gout has not been found. 122

Many studies have indicated poor adherence to cardio vascular disease risk, management in rheumatoid arth ritis. For example, in a crosssectional study 282 (71%) of 400 patients with rheumatoid arthritis had hypertension, of which 171 (61%) were treated with antihypertensive medications. Moreover, despite treatment, many of these patients had suboptimal blood pressure. 123 Also, hyper cholesterolaemia is under diagnosed and undertreated in patients with rheumatoid arthritis. 124 Notwithstanding guidelines for the implementation of cardiovascular risk, management in clinical practice is often difficult. 125 Nevertheless, successful implementation of cardiovascular disease risk management was shown in a Dutch programme for cardiovascular disease care. 126 This programme included a collaboration between primary care and secondary care professionals with a shared laboratory system for primary care physicians and rheumatologists, in which primary care physicians received reimbursement for additional costs from health care insurance companies. Lipid screening (as a proxy for cardiovascular disease risk management) was done in 454 (72%) of 600 patients with rheumatoid arthritis and increased to almost 90% after primary care physicians were sent reminder letters. Implementation of cardiovas cular risk management for patients with gout has not been syste matically studied and to what extent it has been applied in either primary or secondary care is unknown.

Unfortunately, despite several guidelines for cardiovas cular disease risk management, implementation in daily clinical practice is still poor. A study in the UK confirmed this in a group of 673 patients with gout in primary care. Monitoring of lipids (34 [5%]), blood pressure (178 [26%]), and glucose (43 [6%]) within 1 month after their first gout consultation was infrequently recorded. 127 This finding indicates the urgent unmet need for optimisation of cardiovascular risk management in these patients. At the same time, we should not forget that patients often also have other comorbid conditions. Optimal preven tive treatment requires attention to these comorbidities, which are commonly seen in inflammatory arthritis and include osteoporosis, fatigue, and depression. The rationale is that the underlying mechanisms of these common comor bidities, particularly in rheumatoid arth ritis, overlap. In our view, such a multi morbidity, holistic approach is the optimal way to achieve substantial improvement in the quality of life of these patients. Lastly, further randomised controlled trials with cardiovascular end points are needed, especially in gout, to ascertain optimal serum urate concentrations to improve the cardiovascularrisk profile. Another relevant question is whether early uratelowering therapy-in case of asympto matic hyper uricaemia and evidence of crystal deposi tion by ultrasound or dual energy CT-has favourable cardio vascular effects, as shown for early treat ment intervention in patients with rheumatoid arthritis.

Rheumatoid arthritis and gout-two inflammatory joint diseases with different underlying causes-are associated with about a 50-70% increased risk of cardiovascular disease compared with the general population. These patients not only have inflammation of joints but also experience systemic effects, including cardiovascular and haematological manifestations. Different underlying pathophysiological mechanisms, such as systemic inflam mation, elevated oxidative stress, endothelial dysfunction, and changes in lipid profiles, might contribute to a substantially higher cardiovascular risk in these patients. The increased cardiovascular risk includes not only a higher rate of ischaemic cardiovascular disease but also subclinical heart failure, which seems far more prevalent than previously thought. Early therapeutic intervention with current antirheumatic treatment in rheumatoid arthritis has shown favourable effects on cardiovascu lar disease risk. Unfortunately, in gout, evidence that uratelowering therapy has consistent beneficial effects Review on cardiovascular outcomes is still scarce. Following the recognition that inflammation has an important causative role for cardiovascular risk in gout, anti inflammatory therapy and uratelowering therapies are expected to reduce the cardiovascular burden of these patients. Therefore, optimal antiinflammatory control of patients with rheumatoid arthritis and effective urate lowering therapy in patients with gout are the main treatment goals to date. In addition to adequate control of disease activity, attention of the treating physician should be given to the treatment of concomitant cardio vascular diseases and management of risk factors-eg, adequate control of hypertension and dislipidaemia. For individual cardio vascular risk estimation in patients with rheumatoid arthritis and gout, the use of estab lished cardiovascular risk scores (eg, Systematic Coronary Risk Evaluation) could be implemented in daily assess ments. The inclu sion of a multiplication factor for gout in cardiovascular risk scores, as already accepted for rheumatoid arthritis, should be considered.

All authors searched and screened references. The figures were constructed by MB and DV. The drafts were cowritten by RH, DV, MB, AKT, MG, and MTN. All authors contributed to the final writing and editing of the submitted manuscript.

DV has received speaker fees from Novartis. AKT has received speaker fees from BerlinChemie Menarini, Novartis, and Pfizer; personal fees and nonfinancial support from AstraZeneca; and personal fees from Grünenthal, outside the submitted work. MG has received speaker fees from Sobi and Roche, and research support from BerlinChemie Menarini and Grünenthal. MTN received consulting fees from AbbVie, Celgene, Celltrion, Eli Lilly, Janssen, and Sanofi; speakers fees from AbbVie, BristolMyers Squibb, Eli Lilly, Roche, and Sanofi; and research funding from AbbVie, BristolMyers Squibb, Celgene, Eli Lilly, Janssen, MSD, Mundipharma, Novartis, Pfizer, Roche, and Sanofi. All other authors declare no competing interests.

We followed the main steps in writing a narrative review, and MTN formulated cardiovascular research questions addressing epidemiological and pathophysiological aspects of rheumatoid arthritis and gout, cardiovascular effects of drug treatment, and management of cardiovascular risk. References for this Review were identified through searches of PubMed with the terms "rheumatoid arthritis", "gout", "hyperuricemia", "gouty", "arthritis, "gouty", "atherosclerosis", "cardiovascular disease", "cardiovascular event", "myocardial ischemia", "cerebrovascular disease", "stroke", "angina pectoris", "coronary disease", "coronary artery disease", "coronary arterial disease", "peripheral artery disease", "peripheral arterial disease", "congestive heart failure", "cardiac dysfunction", and "cardiovascular risk management" from Jan 1, 1998, to April 1, 2019. Articles were also identified through searches of the authors' own files. Only papers published in English were reviewed. The final reference list was generated on the basis of originality and relevance to the broad scope of this Review.

2 van der Woude D, van der Helmvan Mil AHM. Update on the epidemiology, risk factors, and disease outcomes of rheumatoid arthritis

Cardiovascular disease in patients with rheumatoid arthritis

Global epidemiology of gout: prevalence, incidence and risk factors

Hyperuricaemia and gout: time for a new staging system

Gout as a systemic disease. Manifestations, complications and comorbidities of hyperuricaemia

Hyperuricaemia and CrystalAssociated Disease Network (GCAN) consensus statement regarding labels and definitions of disease states of gout

Crystalproven gout and characteristic gout severity factors are associated with cardiovascular disease

Association between gout and allcause as well as cardiovascular mortality: a systematic review

Rheumatoid arthritis versus diabetes as a risk factor for cardiovascular disease: a crosssectional study, the CARRE Investigation

Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis

The risk of congestive heart failure in rheumatoid arthritis: a populationbased study over 46 years

Gout and rheumatoid arthritis, both to keep in mind in cardiovascular risk management: a primary care retrospective cohort study

Hypertension in rheumatoid arthritis

Changes in lipid levels with inflammation and therapy in RA: a maturing paradigm

Lipid paradox in rheumatoid arthritis: the impact of serum lipid measures and systemic inflammation on the risk of cardiovascular disease

Influence of glucocorticoids and disease activity on total and high density lipoprotein cholesterol in patients with rheumatoid arthritis

Noncardiac vascular disease in rheumatoid arthritis: increase in venous thromboembolic events

How many life years are lost in patients with rheumatoid arthritis? Secular causespecific and allcause mortality in rheumatoid arthritis, and their predictors in a longterm Australian cohort study

Trend in and predictors for cardiovascular mortality in patients with rheumatoid arthritis over a period of 15 years: a prospective cohort study

Decreased cardiovascular mortality in patients with incident rheumatoid arthritis (RA) in recent years: dawn of a new era in cardiovascular disease in RA?

Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to antitumor necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register

Impact of risk factors associated with cardiovascular outcomes in patients with rheumatoid arthritis

Increased risk of vascular disease associated with gout: a retrospective, matched cohort study in the UK clinical practice research datalink

Comorbidities of gout and hyperuricemia in the US general population: NHANES 2007-2008

Uric acid and cardiovascular events: a mendelian randomization study

No causal effects of serum urate levels on the risk of chronic kidney disease: a mendelian randomization study

Uric acid is a strong risk marker for developing hypertension from prehypertension: a 5year Japanese cohort study

Elevated serum uric acid increases risks for developing high LDL cholesterol and hypertriglyceridemia: a fiveyear cohort study in Japan

Independent and conjoint associations of gout and hyperuricaemia with total and cardiovascular mortality

Association of gout with longterm cardiovascular outcomes among patients with obstructive coronary artery disease

Uric acid and risk of heart failure: a systematic review and metaanalysis

Gout and the risk for incident heart failure and systolic dysfunction

Increased cardiovascular mortality associated with gout: a systematic review and metaanalysis

Tophaceous gout and high level of hyperuricaemia are both associated with increased risk of mortality in patients with gout

The burden of subclinical intraarticular inflammation in gout

Inflammation, oxidative stress and lipids: the risk triad for atherosclerosis in gout

Inflammation beyond the joints: rheumatoid arthritis and cardiovascular disease

Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines

Neutrophil extracellular traps in atherosclerosis and atherothrombosis

Presence of luminal neutrophil extracellular traps in atherosclerosis

Monosodium urate crystals generate nucleaseresistant neutrophil extracellular traps via a distinct molecular pathway

Gout is a chronic inflammatory disease in which high levels of interleukin8 (CXCL8), myeloidrelated protein 8/myeloidrelated protein 14 complex, and an altered proteome are associated with diabetes mellitus and cardiovascular disease

Increased reactive oxygen species formation and oxidative stress in rheumatoid arthritis

Oxidative stress in atherosclerosis

Xanthine oxidase induces foam cell formation through LOX1 and NLRP3 activation

Monosodium urate crystals induce oxidative stress in human synoviocytes

Endothelial dysfunction in rheumatoid arthritis: mechanistic insights and correlation with circulating markers of systemic inflammation

Impaired arterial responsiveness in untreated gout patients compared with healthy nongout controls: association with serum urate and Creactive protein

The anatomical pathology of gout: a systematic literature review

Prevalence of birefringent crystals in cardiac and prostatic tissues, an observational study

Thromboembolic and cardiovascular risk in rheumatoid arthritis: role of the haemostatic system

Effect of interleukin6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomised

Trends of venous thromboembolism risk before and after diagnosis of gout: a general populationbased study

Increased platelet reactivity as measured by plasma glycoprotein VI in gout

Association between rheumatoid arthritis and risk of ischemic and nonischemic heart failure

Heart failure in rheumatoid arthritis: rates, predictors, and the effect of antitumor necrosis factor therapy

Increased prevalence of diastolic heart failure in patients with rheumatoid arthritis correlates with active disease, but not with treatment type

Fiveyear changes in cardiac structure and function in patients with rheumatoid arthritis compared with the general population

A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation

Coronary microvascular function and cardiovascular risk factors in women with angina pectoris and no obstructive coronary artery disease: the iPOWER study

Cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction

The effect of biological DMARDs on the risk of congestive heart failure in rheumatoid arthritis: a systematic review

Impact of comorbidities on gout and hyperuricaemia: an update on prevalence and treatment options

Uric acid in chronic heart failure: a marker of chronic inflammation

Uric acidinduced Creactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells

Effects of xanthine oxidase inhibition in hyperuricemic heart failure patients: the Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (EXACTHF) study

The role of uratelowering treatment on cardiovascular and renal disease: evidence from CARES, FAST, ALLHEART, and FEATHER studies

Cardiovascular safety of nonsteroidal antiinflammatory drugs: network metaanalysis

Risk of acute myocardial infarction with NSAIDs in real world use: Bayesian metaanalysis of individual patient data

Clinical pharmacology and cardiovascular safety of naproxen

Derivation and validation of a major toxicity risk score among nonsteroidal antiinflammatory drug users based on data grom a randomized controlled trial

Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis

Confounding by indication probably distorts the relationship between steroid use and cardiovascular disease in rheumatoid arthritis: results from a prospective cohort study

Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study

Protective effects of methotrexate against ischemic cardiovascular disorders in patients treated for rheumatoid arthritis or psoriasis: novel therapeutic insights coming from a metaanalysis of the literature data

Diseasemodifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study

Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis: a systematic review and metaanalysis

QT prolongation, torsades de pointes, and sudden death with short courses of chloroquine or hydroxychloroquine as used in COVID19: a systematic review

Marked QTc prolongation and torsades de pointes in patients with chronic inflammatory arthritis

Treatment with TNF blockers and mortality risk in patients with rheumatoid arthritis

The risk of acute coronary syndrome in rheumatoid arthritis in relation to tumour necrosis factor inhibitors and the risk in the general population: a national cohort study

The effects of tumour necrosis factor inhibitors, methotrexate, nonsteroidal antiinflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta analysis

Olumiant clot signal echoes Xeljanz experience

FDA responds to safety signal reported in required postmarketing trial for Xeljanz

Restrictions in use of Xeljanz while EMA reviews risk of blood clots in lungs

Cardiovascular safety during treatment with baricitinib in rheumatoid arthritis

The beneficial therapy with colchicine for atherosclerosis via antiinflammation and decrease in hypertriglyceridemia

Colchicine in stable coronary artery disease

Colchicine use is associated with decreased prevalence of myocardial infarction in patients with gout

Effects of colchicine on risk of cardiovascular events and mortality among patients with gout: a cohort study using electronic medical records linked with Medicare claims

Effect of shortterm colchicine treatment on endothelial function in patients with coronary artery disease

Canakinumab for the patient with difficulttotreat gouty arthritis: review of the clinical evidence

Anakinra for the treatment of acute gout flares: a randomized, doubleblind, placebocontrolled, activecomparator, noninferiority trial

Antiinflammatory therapy with canakinumab for atherosclerotic disease

updated European League Against Rheumatism evidencebased recommendations for the diagnosis of gout

What is the evidence for treattotarget serum urate in gout?

Xanthine oxidase inhibitors for prevention of cardiovascular events: a systematic review and metaanalysis of randomized controlled trials

Febuxostat for Cerebral and cardiorenovascular events prevention study

Cardiovascular effects of uratelowering therapies in patients with chronic gout: a systematic review and metaanalysis

Mortality in patients with gout treated with allopurinol: a systematic review and metaanalysis

Efficacy and costeffectiveness of nurseled care involving education and engagement of patients and a treattotarget uratelowering strategy versus usual care for gout: a randomised controlled trial

FDA adds boxed warning for increased risk of death with gout medicine uloric (febuxostat)

cardiovascular safety of febuxostat or allopurinol in patients with gout

EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update

European guidelines on cardiovascular disease prevention in clinical practice: the sixth Joint Task Force of the European Society of Cardiology and other societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR)

updated EULAR evidencebased recommendations for the management of gout

EULAR recommendations for cardiovascular risk management in rheumatic and musculoskeletal diseases (including SLE and the antiphospholipid syndrome)

Development and validation of QRISK3 risk prediction algorithms to estimate future risk of cardiovascular disease: prospective cohort study

The Expanded Risk Score in Rheumatoid Arthritis (ERSRA): performance of a diseasespecific calculator in comparison with the traditional prediction scores in the assessment of the 10year risk of cardiovascular disease in patients with rheumatoid arthrit

A Multicenter, randomized, placebocontrolled trial of atorvastatin for the primary prevention of cardiovascular events in patients with rheumatoid arthritis

The impact of statins therapy on disease activity and inflammatory factor in patients with rheumatoid arthritis: a metaanalysis

Antihypertensive drugs and risk of incident gout among patients with hypertension: population based casecontrol study

Lowdose aspirin use and recurrent gout attacks

Effect of fenofibrate on uric acid and gout in type 2 diabetes: a posthoc analysis of the randomised, controlled FIELD study

Impact of statin therapy on plasma uric acid concentrations: a systematic review and metaanalysis

Statin use and mortality in gout: a general populationbased cohort study

Individualised aerobic and resistance exercise training improves cardiorespiratory fitness and reduces cardiovascular risk in patients with rheumatoid arthritis

Weight loss for overweight and obese individuals with gout: a systematic review of longitudinal studies

Association between smoking and gout: a metaanalysis

Prevalence and associations of hypertension and its control in patients with rheumatoid arthritis

Marked underdiagnosis and undertreatment of hypertension and hypercholesterolaemia in rheumatoid arthritis

Suboptimal cardiovascular risk management in rheumatoid arthritis patients despite an explicit cardiovascular risk screening programme

Implementation of the EULAR cardiovascular risk management guideline in patients with rheumatoid arthritis: results of a successful collaboration between primary and secondary care

Prescription and comorbidity screening following consultation for acute gout in primary care