Overview of Serum Uric Acid Treatment Targets in Gout: Why Less Than 6 mg/dl?

Postgraduate Medicine ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20 Overview of Serum Uric Acid Treatment Targets in Gout: Why Less Than 6 mg/dl? Gary Ruoff & N. Lawrence Edwards To cite this article: Gary Ruoff & N. Lawrence Edwards (2016) Overview of Serum Uric Acid Treatment Targets in Gout: Why Less Than 6 mg/dl?, Postgraduate Medicine, 128:7, 706-715, DOI: 10.1080/00325481.2016.1221732 To link to this article: https://doi.org/10.1080/00325481.2016.1221732 Accepted author version posted online: 10 Aug 2016. Published online: 25 Aug 2016. Submit your article to this journal Article views: 1273 View related articles View Crossmark data Citing articles: 2 View citing articles Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalinformation?journalcode=ipgm20

POSTGRADUATE MEDICINE, 2016 VOL. 128, NO. 7, 706 715 http://dx.doi.org/10.1080/00325481.2016.1221732 CLINICAL FEATURE REVIEW Overview of Serum Uric Acid Treatment Targets in Gout: Why Less Than 6 mg/dl? Gary Ruoff a and N. Lawrence Edwards b a Department of Family Practice, Michigan State University, Kalamazoo, MI, USA; b Department of Medicine, University of Florida, Gainesville, FL, USA ABSTRACT Gout is a progressive, painful, debilitating form of inflammatory arthritis. It is caused by factors that elevate the concentration of serum uric acid (sua), leading to hyperuricemia (sua >6.8 mg/dl). Continued elevated sua can result in monosodium urate (MSU) crystal deposition in joints and soft tissues, and can cause acute and chronic inflammation. The prevalence of hyperuricemia and gout has increased over the last few decades, likely due to an aging population, changes in lifestyles and diet, and an increase in gout-associated comorbidities. Untreated or improperly treated gout can lead to chronic manifestation of the disease, including persistent inflammation, increased number of flares, development of tophi, and structural joint damage. Data show that even when patients are asymptomatic, ongoing inflammation and subsequent damage occurs locally at the joint and systemically. The aim of long-term treatment of gout is to reduce sua levels to <6 mg/dl, which is below the saturation point of MSU (6.8 mg/dl), to inhibit formation of new crystals and to promote dissolution of existing crystals. Gout treatment should improve disease outcomes by eliminating gout flares, inducing longterm resolution of tophi, and more effectively managing comorbidities, many of which are associated with hyperuricemia. A number of studies have demonstrated that treating to the target of <6 mg/dl, by using effective therapies to lower sua, results in reduction in the incidence of gout flares as well as shrinkage and eventual disappearance of tophi. Gout is often poorly managed due to a number of factors including lack of physician and patient adherence to treatment guidelines. Patients need to be educated about their diagnosis and management of the disease, such as the influence of diet and the importance of compliance with long-term treatment. With treatment, regular sua monitoring, and patient adherence, gout is a curable disease. ARTICLE HISTORY Received 4 March 2016 Accepted 4 August 2016 Published online 26 August 2016 KEYWORDS Gout; serum uric acid; monosodium urate; inflammatory arthritis; treatment guidelines; hyperuricemia; joint damage; joint erosion; MSU crystals; tophi Methods PubMed and Google Scholar databases were searched to identify clinical trials and review articles on the epidemiology, disease mechanism, history, clinical presentation, and treatment and management of gout. The search also identified previously recommended guidelines which were incorporated into the review. Search terms included, but were not limited to, gout, hyperuricemia, treatment guidelines, American College of Rheumatology (ACR), European League Against Rheumatism (EULAR), comorbidity, flare, adherence, epidemiology, serum uric acid (sua), monosodium urate (MSU), tophi, joint damage, joint erosion, <6 mg/dl, MSU crystal formation, and individual drug names and classes of treatments of interest. Both authors actively participated in the drafting and editing of the paper and offered comprehensive discussions regarding the content. Gout background and epidemiology Gout is a progressive, painful, debilitating form of inflammatory arthritis that has been affecting man since antiquity [1 3]. It is caused by factors that elevate the concentration of sua, leading to hyperuricemia [2,4]. Continued elevated sua can result in MSU crystal deposition throughout the body, including joints, soft tissues, cartilage, and organs (e.g. kidneys) [5]. MSU crystals trigger the periodic occurrence of painful, acute, inflammatory flares [1,2]. If hyperuricemia persists, the acute gout flares may be superseded by long-term, chronic, tophaceous gout with bone and cartilage destruction [1,2]. Gout is one of the most common forms of inflammatory arthritis among men. In the USA, about 8.3 million adults (4%) are affected by gout and 43.3 million (21%) by hyperuricemia [6]. Both occur with greater frequency in adults than other wellknown, chronic, joint- or pain-related debilitating diseases such as fibromyalgia (5.0 million) [7], rheumatoid arthritis (1.5 million) [8], and psoriatic arthritis (0.5 million) [9]. Gout and other crystal arthropathies accounted for 1.5% of the 1.2 million nonfederal, short-stay hospitalizations in 2007 [1]. All-cause medical expenditures in persons with gout are estimated to total about $11,663 per person per year, and the direct burden for new gout in the USA may be greater than $27 million per year [1,10]. In addition, gout is a source of significant personal burden for patients. Among those with inadequately controlled gout, the condition is associated with significant functional disability, loss of work productivity, reduction in social activity, and poor health-related quality of life [11 13]. In fact, the work loss CONTACT N. Lawrence Edwards larry.edwards@medicine.ufl.edu Department of Medicine, University of Florida, 1600 SW Archer Road, Room 4102, Gainesville, FL 32610-0277, USA 2016 Informa UK Limited, trading as Taylor & Francis Group

POSTGRADUATE MEDICINE 707 observed with gout is similar to that seen with rheumatoid arthritis [8,11]. The prevalence of gout and hyperuricemia has increased considerably over the last 25 years [6,14]. This increase may be due to an aging population, changes in lifestyle and diet (e.g. higher intake of fructose-containing soft drinks and alcoholic beverages, such as beer), and an increasing prevalence of comorbidities associated with hyperuricemia and gout, such as obesity, hypertension, widespread use of thiazide diuretics, and chronic kidney disease (CKD) [14 17]. Other factors associated with hyperuricemia and gout include metabolic syndrome, congestive heart failure, and organ transplantation [18]. In fact, evidence suggests that increased sua levels may play a role in the development of metabolic syndrome, type 2 diabetes, and hypertension [19]. A history of gout is also an independent risk factor for cardiovascular disease, possibly due to increased systemic inflammation [20]. Use of sua-lowering therapy improved blood pressure and had a cardiovascular protective effect [19]. Hyperuricemia has also been shown to be predictive of CKD; however, it is unclear whether elevated sua levels have a causal role in the development of kidney disease [20]. Similarly, the precise role of uric acid in the development of cardiovascular disease is not clear [19]. Furthermore, age and genetic factors can predispose an individual to developing gout. Genetic variation in solute carrier family 2 member 9 (SLC2A9) and 11 (SLC22A11); solute carrier family member 17, member 1 (SLC17A1); coding PDZ domaincontaining 1 (PDK-Z1); and ATP-binding cassette, subfamily G, member 2 (ABCG2) have been implicated in increasing the risk of gout [21,22]. Asymptomatic hyperuricemia can begin during puberty in boys, but is usually delayed until menopause in women [3]. Estrogen has a uricosuric effect, making the disease less common among premenopausal women [14,23]. Gout commonly develops in men between 40 and 60 years of age after many (approximately 20 30) years of hyperuricemia [3]. Before the age of 65 years, men have a fourfold greater incidence of gout than women (about 4 per 1000 persons in men compared with 1 per 1000 persons in women) [23,24]. After 65 years of age, prevalence increases for both men and women at a more comparable rate, with incidence about threefold higher in men [24]. Presentation and characterization of gout Classically, gout has been described as occurring in three stages: asymptomatic hyperuricemia, acute intermittent gout (flares), and advanced or chronic gout (Figure 1) [25,26]. A recent modification of this staging, however, has been proposed by Dalbeth and Stamp (2014) that includes four stages, with the period of asymptomatic hyperuricemia subdivided into two separate stages: Stage A (hyperuricemia without detectable MSU crystal deposition); Stage B (hyperuricemia with MSU crystal deposition but no signs or symptoms of gout); Stage C (MSU crystal deposition with prior or current symptoms of a gout flare); and Stage D (advanced gout requiring a specialist s intervention) [27]. Hyperuricemia is defined as sua levels >6.8 mg/dl (404 µmol/l) and no symptoms from crystal deposition [28,29]. Of note, each laboratory calculates its own sua threshold for hyperuricemia, often defined as the mean sua plus 2 standard deviations for their local healthy population, and calculated separately according to sex [30,31]. Therefore, an sua level in what an individual laboratory considers the normal range may still reflect levels in joint tissues that are above the point for MSU crystal formation [31]. The rate at which a person progresses from asymptomatic hyperuricemia to chronic advanced gout varies by individual and is dependent upon numerous factors, the most important of which is the degree of increase in the concentration of sua (Figure 2) [3,32,33]. Of all patients with asymptomatic hyperuricemia, only about 15 20% will develop gout [3]. In these patients, MSU Figure 1. Diagram showing the path from hyperuricemia to structural joint damage. Long-standing hyperuricemia may lead to monosodium urate (MSU) deposits. Hyperuricemia is typically asymptomatic and is often associated with subclinical inflammation and bone erosion. Crystal shedding into the joint can cause Intermittent, acute inflammation and a gout flare-up. Continued crystal deposition can result in chronic manifestation of the disease, including persistent inflammation, increased number of flares, development of tophi, and structural joint damage. Adapted from Adv Ther, A review of uric acid, crystal deposition disease, and gout, volume 32, 2015, Perez-Ruiz F, et al, Figure 1: Diagram showing the path from hyperuricemia to structural joint damage on page 32, with permission of Springer ( 2014) [26].

708 G. RUOFF AND N. L. EDWARDS Etiology Figure 2. Five-year cumulative incidence of gout according to sua level in men in the Normative Aging Study [33]. Reproduced with permission from Roddy E and Doherty M: Arthritis Res Ther 2010;12(6):223. [32]. crystal deposition, subclinical inflammation, and bone erosion can occur [3,18,26,33,34]. The MSU crystals form small lattice structures on the surface of synovial lining and cartilage [3]. The fact that not all patients with hyperuricemia develop gout suggests that other factors may contribute to the formation of crystals and the ability of formed crystals to trigger flares [26]. MSU deposition is a precursor to gout, but it is unclear whether MSU crystals in patients with asymptomatic hyperuricemia predict development of clinically apparent gout [26]. After a prolonged period of hyperuricemia, the shedding of asymptomatic, preformed crystals from the cartilage surface into the joint triggers inflammation characteristic of an acute flare [26,34]. The first manifestation of acute gout is an attack of synovitis typically affecting a single peripheral joint, most often the first metatarsophalangeal joint [35]. Other joints commonly affected include the ankles, knees, mid-tarsal joints, fingers, elbows, and wrists [35,36]. Acute attacks are characterized by the sudden onset of extreme pain, which typically takes less than 24 h to peak in intensity (Table 1) [35,36]. Flares are also associated with swelling, heat, tenderness, and erythema [35,36]. Acute gouty flares are self-limiting, with symptoms resolving in about 2 weeks [26,36]. Although acute flares appear episodic in nature, ongoing damage during intercritical asymptomatic periods occurs due to continuing MSU crystal deposition and inflammation [26,37,38]. This continuing damage may not be apparent in normal plain radiographs; however, the destructive arthropathy can be detected by more advanced imaging procedures, such as dual-energy computed tomography (DECT), computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound (Figure 3) [39,40]. Untreated or improperly treated crystal deposition can lead to chronic manifestation of the disease, including persistent inflammation, increased number of flares, development of tophi, and structural joint damage [26]. Tophi can cause chronic inflammation and erosive arthritis [16]. Chronic gout typically develops after 10 or more years of acute episodic gout, and is apparent when the pain-free intermittent periods disappear [3]. Hyperuricemia is the most important risk factor for gout [33,34]. In vitro, at 37 C and ph 7.4, levels of uric acid above 6.8 mg/dl result in crystal formation and aggregation [41 43]. Solubility of a substance (a solute) is a measure of how well one substance dissolves into another (Figure 4). A solute can fully dissolve in a solution that contains less than the maximum amount of solute that can be dissolved. A saturated solution contains as much solute as it possibly can dissolve, and a supersaturated solution contains more solute than can be dissolved, resulting in crystal formation. As sua levels rise, the blood and body fluids become supersaturated, causing crystals to form in synovial fluids, soft tissues, and organs [5,43,44]. Crystal deposition is reversible, and crystals can dissolve when the concentration of sua is reduced to levels <6 mg/dl [43,45]. The importance of maintaining sua levels below 6.8 mg/dl is made evident by the observation that the incidence of gout increases with higher levels of sua, starting at between 6.0 and 6.9 mg/dl (Figure 2) [3,32,33]. One study found that the annual incidence of gouty arthritis for patients with sua >9 mg/dl was 4.9%, compared with 0.5% for urate levels of 7.0 8.9 mg/dl and 0.1% for urate levels <7.0 mg/dl [33]. Another study found that the 5-year incidence rate of gout was 0.6% in patients with sua levels <7 mg/dl and about 30% for patients with sua levels >10 mg/dl [46]. Uric acid levels are controlled by the rate of urate production and the elimination of urate via the kidneys and the gastrointestinal tract. In about 90% of patients with hyperuricemia, sua levels are elevated mainly due to inefficient renal excretion rather than overproduction of uric acid [3]. About one-third of uric acid comes from exogenous sources, such as diet (alcohol/beer, red meat, seafood) [47,48]. The other twothirds derive from endogenous production via the degradation of purines, such as DNA and RNA [48,49]. In humans, urate is produced by the conversion of hypoxanthine to xanthine, which is subsequently converted to uric acid by an enzyme called xanthine oxidase [3]. Most mammals possess an additional enzyme, uric acid oxidase, that converts uric acid into a soluble end product called allantoin that is readily eliminated in urine [3]. The ability of humans and other higher primates to make uric acid oxidase was lost during evolution, and consequently, humans are prone to uric acid accumulation [3]. The gastrointestinal tract eliminates about 20% of urate, while the rest is excreted by the kidney [50]. The majority of uric acid (about 98 99%) circulates in the blood as ionized urate, and due to the high concentration of sodium in the extracellular compartment, urate is primarily present as MSU [15,51]. Guideline recommendations for sua levels The primary aim of treatment for gout is to lower sua [52]. Several guidelines, such as those published by the ACR [53] and EULAR [31,54] (plus others, such as the American Society of Clinical Rheumatologists [ASCR] [28], the 3Es [Evidence, Expertise, Exchange] Initiative [55], Japanese Society of Gout and Nucleic Acid Metabolism [JSGNM] [56], and the Dutch College of General Practitioners [DCGP] [57]) recommend a

POSTGRADUATE MEDICINE 709 Table 1. The ACR/EULAR gout classification criteria (reproduced with permission from Neogi et al. [36]. Steps Categories Score* Step 1: Entry criterion (only apply criteria below to those meeting this entry criterion) At least one episode of swelling, pain, or tenderness in a peripheral joint or bursa Step 2: Sufficient criterion (if met, can classify as gout without applying criteria below) Presence of MSU crystals in a symptomatic joint or bursa (i.e., in synovial fluid) or tophus Step 3: Criteria (to be used if sufficient criterion not met) Clinical Pattern of joint/bursa involvement during symptomatic episode(s) ever Ankle or mid-foot (as part of monoarticular or oligoarticular episode without involvement of the first metatarsophalangeal 1 joint Involvement of the first metatarsophalangeal joint (as part of monoarticular or oligoarticular episode) Characteristics of symptomatic episode(s) ever Erythema overlying affected joint (patient reported or physician observed) One characteristic 1 Cannot bear touch or pressure to affected joint Two characteristics 2 Great difficulty walking or inability to use affected joint Three characteristics 3 Time course of episode(s) ever (presence [ever] of 2, irrespective of antiinflammatory treatment) Time to maximal pain <24 h One typical episode 1 Resolution of symptoms in 14 d Recurrent typical episodes 2 Complete resolution (to baseline level) between symptomatic episodes Clinical evidence of tophus Draining or chalk-like subcutaneous nodule under transparent skin, often with overlying vascularity, located in typical locations: joints, ears, olecranon bursae, finger pads, tendons (e.g. Achilles) Laboratory Serum urate : measured by the uricase method. Ideally should be scored at a time when the patient was not receiving uratelowering therapy and it was >4 weeks from the start of an episode (i.e. during intercritical period); if practicable, retest under those conditions. The highest value irrespective of timing should be scored Present 4 <4 mg/dl (<0.24 μmol/l) 6 <8 mg/dl (0.36 <0.48 μmol/l) 8 <10 mg/dl (0.48 <0.60 μmol/l) 10 mg/dl ( 0.60 μmol/l) Synovial fluid analysis of a symptomatic ever joint or bursa MSU negative 2 Imaging # Imaging evidence of urate deposition in symptomatic (ever) joint or bursa: ultrasound evidence of double-contour sign or DECT demonstrating urate deposition** Present (either modality) 4 Imaging evidence of gout-related joint damage: conventional radiography of the Present 4 hands and/or feet demonstrates at least one erosion DECT: dual-energy computed tomography; MSU: monosodium urate. *The higher the score, the greater likelihood of gout. A web-based calculator can be accessed at http://goutclassificationcalculator.auckland.ac.nz, and through the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) websites. Symptomatic episodes are periods of symptoms that include any swelling, pain, and/or tenderness in a peripheral joint or bursa. If serum urate level is <4 mg/dl (<0.24 mmol/l), subtract 4 points; if serum urate level is 4 mg/dl to <6 mg/dl ( 0.24 <0.36 mmol/l), score this item as 0. Should be assessed by a trained observer. If polarizing microscopy of synovial fluid from a symptomatic (ever) joint or bursa by a trained examiner fails to show MSU crystals, subtract 2 points. If synovial fluid was not assessed, score this item as 0. # If imaging is not available, score these items as 0. Hyperechoic irregular enhancement over the surface of the hyaline cartilage that is independent of the insonation angle of the ultrasound beam (note: falsepositive double-contour sign [artifact] may appear at the cartilage surface but should disappear with a change in the insonation angle of the probe). **Presence of color-coded urate at articular or periarticular sites. Images should be acquired using a DECT scanner, with data acquired at 80 kv and 140 kv and analyzed using gout-specific software with a two-material decomposition algorithm that color-codes urate. A positive scan is defined as the presence of colorcoded urate at articular or periarticular sites. Nail bed, submillimeter, skin, motion, beam hardening, and vascular artifacts should not be interpreted as DECT evidence of urate deposition. Erosion is defined as a cortical break with sclerotic margin and overhanging edge, excluding distal interphalangeal joints and gull wing appearance. 2 4 2 3 4 target sua level of <6 mg/dl (360 µmol/l). In some cases, a lower target (<5 mg/dl) may be recommended to more rapidly improve gout signs and symptoms in patients with more severe disease [53,54]. In contrast, the British Society of Rheumatology recommends the lower (<5 mg/dl) sua target for all patients with gout [58]. The idea behind treating to a target of <6 mg/dl and achieving lifelong maintenance of this level is to lower the concentration of sua well below its saturation point and to provide some margin to accommodate the influence of natural fluctuations in uric acid levels. Lower sua levels also increase the resolution rate of tophaceous deposits (Figure 5) [59]. Gout treatment should improve disease outcomes by eliminating gout flares, inducing long-term resolution of tophi, and more effectively managing comorbidities, many of which are associated with hyperuricemia [31,53]. There is growing evidence of the association of gout with several chronic diseases, including cardiovascular disease, and data exist that indicate gout treatment may improve some of these comorbidities [60,61]. The ACR recommends both nonpharmacologic and pharmacologic approaches to treatment after first establishing the diagnosis of gout (Figure 6) [53]. Patient education is an important component of treatment and should include information on lifestyle adjustments, treatment objectives, and management of comorbidities [52,53]. Patients should be encouraged to lose weight and be cautioned about consumption of excessive amounts of foods with high purine content, such as organ meats, shell fish, and alcohol (especially beer), as well as foods containing high fructose corn syrup, all of which could trigger a flare [14,20]. However, diet change

710 G. RUOFF AND N. L. EDWARDS Figure 3. Dual-energy computed tomography (DECT) images of ankle and foot (a, b) showing MSU crystal deposition in green color (arrows) and corresponding CT images (c, d) showing erosions (arrowheads). Reproduced with permission from Chowalloor PV, et al: Ther Adv Musculoskelet Dis 2014;6(4):131-43. [40]. Figure 4. Solubility of a substance (a solute) is the amount of that substance that will dissolve in a given amount of solvent; or it is a measure of how well one substance dissolves into another. A solute can fully dissolve in a solution that has less than the maximum amount of solute that can be dissolved. A saturated solution contains as much solute as it possibly can dissolve. A supersaturated solution contains more solute than can be dissolved, increasing the potential for crystal formation. alone, although beneficial, is rarely sufficient to lower sua levels to the degree necessary to prevent acute or chronic disease [52,62]. Physicians should consider all causes of hyperuricemia both exogenous and endogenous for all gout patients, and evaluate certain disorders that are associated with hyperuricemia and gout, such as obesity, metabolic Figure 5. Mean serum urate levels versus velocity of tophi reduction. Reproduced with permission from Perez-Ruiz F, et al: Arthritis Rheum 2002;47 (4):356-60. [59]. syndrome, type 2 diabetes, hypertension, and CKD [52,53]. The ACR treatment guidelines also advocate consideration of the removal or replacement of nonessential prescription drugs (e.g. thiazide and loop diuretics, niacin, and calcineurin inhibitors), when appropriate, which are known to elevate sua [53]. Following these initial steps, ACR recommends that a patient be evaluated for the use of urate-lowering therapy (ULT). A patient is considered a candidate if he/she has at least one of the following: tophus or tophi (verified by clinical examination or imaging study); 2 gout flares per year; stage 2 or worse CKD; or past urolithiases [53]. If pharmacologic ULT is

POSTGRADUATE MEDICINE 711 Figure 6. Baseline ACR recommendations and overall strategy for treating and managing patients with gout. Data from Khanna D, et al: Arthritis Care Res (Hoboken) 2012;64(10):1431-46. [53]. indicated, the patient should be treated to achieve an sua target of <6 mg/dl [53]. First-line pharmacologic therapies are xanthine oxidase inhibitors (e.g. allopurinol or febuxostat), or if necessary due to poor tolerability or contraindications, an alternative therapy (e.g. probenecid) can be used instead [53]. If needed, ACR guidelines recommend the addition of probenecid to a xanthine oxidase inhibitor [53]. Pegloticase can be considered if treatment goals are not achieved and there is continuing disease activity [53]. If the target level of <6 mg/dl is not achieved, the dose of the ULT should be increased [53]. When ULT is started, anti-inflammatory prophylactic treatment should also be initiated to reduce the increased risk of acute gouty attacks during the early phase (first 6 months) of treatment [53]. Nonsteroidal anti-inflammatory drugs and low-dose colchicine are options for prophylactic therapy [53]. Once the sua target of <6 mg/dl is achieved continuously [53], the dose of ULT should be maintained indefinitely with ongoing monitoring of sua levels twice yearly [53]. Anti-inflammatory prophylaxis should be maintained for at least 6 months after the target is achieved, or 3 months after achieving target sua in patients without tophi, or 6 months in patients with tophi [53]. It may be necessary to reduce sua levels to <5 mg/dl for patients with advanced disease and tophaceous deposits [53]. After all symptoms have resolved, ACR guidelines recommend continuing all measures and therapies needed to keep the patient s sualevels<6mg/dl[53]. In patients with more advanced disease, the primary care provider (PCP) may consider referral to a specialist, such as a rheumatologist, for cases of unclear etiology of hyperuricemia, refractory signs and symptoms of gout, lack of tolerability to standard therapy, or difficulty in reaching the sua level target goal of <6 mg/dl [53]. Reasoning behind the sua target goal of <6 mg/dl For patients whose sua levels are not lowered sufficiently, gout will continue to be a chronic, progressive disease [26]. Achieving a lower level of sua can help prevent further MSU crystal deposition, inhibit tophi formation, and accelerate tophi dissolution [59] (Table 2). Halting crystal formation and dissolving existing crystals is the only way to permanently stop the signs and symptoms of gout, and potentially cure the disease [59]. Undertreatment can have significant consequences for a patient, including increased number and frequency of flares, diminished quality of life and productivity,

712 G. RUOFF AND N. L. EDWARDS Table 2. Why keep serum uric acid levels <6 mg/dl? Keeping the levels of sua <6 mg/dl, which is below the saturation concentration of 6.8 mg/dl, can help: Prevent MSU crystal formation Prevent inflammation Reduce progressive debilitating joint and tissue damage Reduce the amount of crystals in the body Reduce the likelihood of flares Reduce tophus formation Prevent gouty arthritis Increase dissolution of tophi Keeping levels of sua sufficiently below the saturation concentration of 6.8 mg/dl will mitigate fluctuations in sua levels due to physiologic and natural factors Halting crystal formation and eliminating existing crystals, together, is the only way to stop signs and symptoms of gout MSU: monosodium urate; sua: serum uric acid. and increased use of systemic steroids and nonsteroidal antiinflammatory drugs [20]. Inadequate or delayed treatment and the failure to reduce sua levels <6 mg/dl can result in increased crystal deposition and development of comorbidities, which can in turn result in more severe disease that is more difficult to treat and manage [20,26,63]. Imaging studies have found a close relationship between features of structural joint damage and crystal deposition, with MSU crystals frequently observed within the areas of bone erosion [40]. This close relationship between joint damage and MSU crystal formation emphasizes the need to reduce sua levels before structural damage occurs [26]. A number of studies found that patients experienced fewer flares and better therapeutic outcomes when their sua levels remained at <6 mg/dl [45,64 68]. In one prospective study, sustained reduction of sua levels <6 mg/dl over a 5-year period with long-term febuxostat therapy resulted in nearly complete elimination of gout flares in all patients (N = 116) and total dissolution of tophi in 69% of the patients who had palpable tophi at baseline (Figure 7) [64]. A prospective study of patients with MSU crystal-confirmed gout (N = 18) found that lowering sua to levels <5 mg/dl resulted in disappearance of MSU crystals [66]. The time required for disappearance ranged from 3 to 33 months, and disappearance of crystals took longer in patients who had gout for a longer duration [66]. A retrospective study of 267 patients found that the use of ULT and significant lowering of sua levels reduced the risk of a gout attack over a 3-year period [65]. Another retrospective study, which assessed gout outcomes over a 10-year period in patients with crystal-confirmed gout (N = 38), found that almost half of patients who maintained their sua levels 6 mg/dl for more than 12 months had no gout attacks for 2 or more years [45]. They also found that urate crystal deposition in knees and joint fluids were depleted in more than half (56%) of patients who maintained their sua 6 mg/dl [45]. The effect of reducing sua levels on radiographic changes is less clear. A retrospective study that assessed management of gout over a 10-year period found that tophaceous resorption correlated with serum levels 6 mg/dl [67]. However, they found no correlation between sua levels and radiographic changes [67]. Similarly, another study in patients with early gout treated for 2 years with febuxostat found that treatment greatly reduced synovitis but did not alter joint erosion scores [69]. In contrast, an exploratory study, which evaluated radiographic changes following intensive sua-lowering therapy with pegloticase in patients with severe chronic gout, found that sustaining sua levels <1 mg/dl for 1 year resulted in improvement in structural changes, particularly bone erosion, suggesting that some structural damage may be reversible [68]. A key difference in these studies is the Figure 7. Percentage of patients who required treatment for flares while receiving a maintenance dose of febuxostat to keep sua levels <6 mg/dl. Reproduced with permission from Schumacher HR, Jr., et al: Rheumatology (Oxford) 2009;48(2):188-94. [64].

POSTGRADUATE MEDICINE 713 degree of uric acid suppression by different medical regimens, and this is the likely explanation for the different outcomes. Although the disease is well understood, with good treatment options available, gout is often poorly managed [28,70]. Challenges of treating and managing gout include physician adherence to recommended guidelines when prescribing, and patient adherence to their prescribed treatment regimens [71,72]. In a retrospective study of 9482 patients with gout enrolled in managed care, only 18% of patients who filled at least two prescriptions were compliant with their allopurinol therapy throughout a 2-year study period [73]. Another study found that of 4166 patients who initiated ULT for gout, more than 50% were nonadherent with their treatment, particularly younger patients (<50 years of age), patients with fewer comorbidities, and those with no visits to a healthcare provider prior to gout [72]. These findings point out the importance of proactive education of patients about their disease [74]. Patient education has been found to improve adherence, reduce the number of attacks, and improve the number of patients who reach sua target levels [74]. Rheumatologists and PCPs have also been found to have less than optimal overall adherence to treatment guidelines, particularly for first-line ULT and length of prophylactic treatment [71,75]. For example, a comprehensive quantitative survey that assessed adherence of US PCPs (n = 120) and rheumatologists (n = 71) to the ACR guidelines found that 53.7% of PCPs and 35.3% of rheumatologists had low adherence to treatment recommendations (defined as following 4 out of 8 ACR treatment recommendations), and even among highly adherent PCPs and rheumatologists, only 36.4% and 35.2%, respectively, were adherent to the initial ULT dose [71]. Conclusions Gout is a chronic, pervasive disease characterized by underlying hyperuricemia that results in recurrent flares and MSU crystal deposition. Even when patients are asymptomatic and free from flares, ongoing inflammation and subsequent damage occur locally at the joint and systemically [26,76]. Several guidelines recommend targets for sua levels <6 mg/dl to prevent MSU crystal deposition, reduce the overall volume of crystals in the body, and dissolve tophi [31,53,56 58,77]. Halting crystal formation and hastening dissolution of existing crystals are key to preventing the long-term negative effects of gout on a patient s health and quality of life [2,52]. Importantly, only by keeping the sua level <6 mg/dl can disease progression be halted and therapeutic outcomes improved [13,59,64,65,78,79]. While hyperuricemia is defined at sua >6.8 mg/dl, the target goal of <6 mg/dl provides a necessary margin to mitigate the effects of fluctuations in factors that can influence the concentration and solubility of sua. Physician and patient education is also key for properly managing the disease to ensure medication compliance and regular (6 12 months) monitoring of sua levels. About two-thirds of gout patients in the USA are diagnosed and managed by PCPs [80,81]. Hence, these healthcare professionals can make a significant impact on treating this disease by ensuring that after gout diagnosis more patients receive optimal care [28]. With proper titration and dosing of medication, regular sua monitoring, and patient compliance, gout is a curable disease [59,82]. The old treat-to-symptoms approach for managing gout is in large part responsible for the historically poor management of this disease. By contrast, the treat-to-target recommendation of guidelines from multiple professional organizations [28,31,53 55,58,77] is based on clear and consistent demonstration that this approach improves long-term outcomes in this common disease. Funding This study was funded by AstraZeneca. Declaration of interest Support for this paper was provided by AstraZeneca Pharmaceuticals, and editorial assistance was provided by Charlotte Singh, MD, CMPP, and Elizabeth Goodwin, PhD, of The Lockwood Group. NL Edwards has been a consultant for Takeda, AstraZeneca, Crealta/Horizon, and CymaBay Pharmaceuticals. G Ruoff has served on the advisory boards and speakers bureaus for Takeda, Endo, and Cephalon. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. References 1. CDC. 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