Pathophysiology of gout

INTRODUCTION — Gout is a disease that occurs in response to the presence of monosodium urate (MSU) crystals in joints, bones, and soft tissues. It may result in one or a combination of acute arthritis (a gout flare), chronic arthritis (chronic gouty arthritis), and tophi (tophaceous gout) [1,2].

Hyperuricemia (typically defined as serum urate concentration >6.8 mg/dL) is a common and necessary pathogenic factor in the development of gout, but it is insufficient to explain clinical expression of either self-limited gout flares, chronic gouty arthritis, or tophaceous gout [3]. These clinical manifestations also require MSU crystal formation and deposition in tissues and acute and/or chronic inflammatory responses to the presence of such crystals.

The pathophysiologic mechanisms of MSU crystal deposition, acute crystal-induced inflammation, and chronic destructive lesions of joints and bones associated with collections of MSU crystals (tophi) will be reviewed here. The clinical features, diagnosis, and treatment of gout flares; the prevention of recurrent gout flares; asymptomatic hyperuricemia; and associated renal diseases are discussed elsewhere. (See "Clinical manifestations and diagnosis of gout" and "Treatment of gout flares" and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout" and "Asymptomatic hyperuricemia" and "Kidney stones in adults: Uric acid nephrolithiasis" and "Uric acid kidney diseases".)

PATHOPHYSIOLOGIC MECHANISMS — A number of complex interacting processes are responsible for the pathophysiology of gout. These include:

●Metabolic, genetic, and other factors that result in hyperuricemia (see 'Hyperuricemia and gout' below)

●Physiologic, metabolic, and other characteristics responsible for crystal formation (see 'Hyperuricemia and gout' below and 'Crystals' below)

●Cellular and soluble inflammatory and innate immune processes and characteristics of monosodium urate (MSU) crystals themselves that promote the acute inflammatory response to MSU crystals (see 'Acute inflammation' below and 'Initiation of acute MSU crystal-induced inflammation' below and 'Amplification of acute MSU crystal-induced inflammation' below)

●Immune mechanisms and other factors that mediate the resolution of acute inflammation (see 'Resolution of acute MSU crystal-induced inflammation' below)

●Chronic inflammatory processes and the effects of crystals and immune cells on osteoclasts, osteoblasts, and chondrocytes that contribute to the formation of tophi and to bone erosion, cartilage attrition, and joint injury (see 'The tophus' below and 'Joint damage in gout' below)

HYPERURICEMIA AND GOUT — Hyperuricemia is a necessary predisposing factor for gout, but the majority of people with hyperuricemia never develop gout [3-6]. Pathways to hyperuricemia have been identified to be renal underexcretion of urate, extrarenal underexcretion of urate, and overproduction of urate [7], with the cause of hyperuricemia in an individual reflecting the combined effect of these pathways. Individual differences in the formation of monosodium urate (MSU) crystals [8] and/or in inflammatory responses to those crystals play a role in whether a person with hyperuricemia will develop gout [9]. Multiple risk factors are associated with the development of hyperuricemia [10], which can be caused by impairment of renal and gut urate excretion and overproduction of urate [7,11]. The causes of hyperuricemia and the normal mechanisms of urate handling are discussed in detail separately. (See "Asymptomatic hyperuricemia" and "Urate balance".)

A causative relationship among hyperuricemia, deposition of monosodium urate (MSU) crystals, and gout was proposed by Garrod in the mid-19^th century [12]. Freudweiler established in 1899 that injection of tophaceous material caused inflammation, further supporting the validity of the concept of gout as an MSU crystal deposition disease [13]. MSU crystals were identified in synovial fluid from patients with a gout flare using compensated polarized microscopy in 1961 [14], which was followed soon after by the observation that injection of MSU crystals into normal joints produced an acute inflammatory arthritis [15].

Risk factors associated with the development of gout appear to mediate their effects, at least in part, through promoting saturation of extracellular fluid urate levels, a biochemical state confirmed by measurement of serum or plasma urate. Both non-modifiable and modifiable risk factors have been recognized. Non-modifiable risk factors include male sex, advanced age, and ethnicity (eg, Pacific Islanders). Associations of >200 genetic loci with hyperuricemia have been established by genome-wide association studies (GWAS) [16-18]; single nucleotide polymorphism (SNP) analyses at these loci have identified polymorphic alleles that also alter gout risk [19]. These loci are dominated by renal and gut urate transporters, in particular SLC2A9 (GLUT9), ABCG2, SLC22A11/A12 (URAT1/OAT4), SLC22A9 (OAT7), and SLC17A1-4 (NPT1-4). These control renal and gut excretion of urate, with individual variability contributed to by inherited genetic variations that largely mediate their effects by controlling gene expression. Modifiable risk factors for gout include obesity, alcohol-containing beverages (especially beer and distilled spirits), sodas and fruit juices high in fructose or sucrose content, hypertension, thiazide or loop diuretic use, chronic kidney disease, postmenopausal and organ transplant recipient status, and use of certain medications (eg, cyclosporine A or low-dose aspirin, although cardioprotective aspirin doses of only 81 to 325 mg/day do not warrant discontinuation).

Lead toxicity has been associated with gout since the 1700s, but the mechanism has been a matter of debate [20]. Some evidence has suggested that blood lead levels widely considered to be within an acceptable range may be associated with an increased prevalence of gout [21]. These findings need confirmation, and it is unknown whether interventions to lower lead levels will reduce risk. Coffee consumption [22] and cigarette smoking [23] are both associated with reduced risk of gout.

Dietary exposures are important in triggering gout in the presence of MSU crystal deposition [24,25]. However, there is little evidence for a significant causal role of overall diet in causing hyperuricemia [26,27], suggesting that gout-associated dietary exposures play a role in the progression from hyperuricemia to gout, for example as specific triggers of gout flares. (See "Urate balance", section on 'Hyperuricemia' and "Asymptomatic hyperuricemia", section on 'Epidemiology' and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Management principles and initial postdiagnostic assessment'.)

The importance of an increased capacity for MSU crystal formation in patients with gout, although unexplained, is supported by the observation that MSU crystals are frequently found in synovial fluid from uninflamed joints of gout patients [28], but are found less commonly, in about one-third of people, in synovial fluids from non-gouty hyperuricemic individuals [29,30]. It is not known whether the presence of crystals in the latter case indicates a greater risk for later development of clinical gout [31]. Higher levels of urate in the blood are clearly associated with a greater risk for developing gout [3,5,6], but not necessarily more severe gout. Obesity and ethanol ingestion further increase the risk for gout at any given level of hyperuricemia [32]. Among people with an established history of gout, consumption of alcohol or intermittent use of diuretics appear to acutely increase the risk of a gout flare [24,33].

Several clinical features of gout remain incompletely understood, but may relate in part to the concentration of urate and the solubility of MSU; these features include the predilection of gout for the first metatarsophalangeal (MTP) joint; the precipitation of gout flares by trauma, surgery, or the initiation of urate-lowering therapy [34-37]; and the spontaneous resolution of flares (see 'Resolution of acute MSU crystal-induced inflammation' below). Plausible though unproven explanations for the frequent involvement of the first MTP include relative coolness of the feet (reducing the solubility of MSU); the repeated microtrauma to which the MTP joint is subjected [38], possibly altering components of the tissue matrix; and differential reabsorption into the joint of exuded solvent (joint fluid) and solute (urate) from the periarticular area when weightbearing is replaced by recumbency [39].

CRYSTALS — The solubility of monosodium urate (MSU), which is reduced by lower temperatures, is determined by its concentration together with factors that influence nucleation and growth of crystals [8]. These elements explain, at least in part, why hyperuricemia is necessary but not sufficient for the development of gout and the increased risk of gout that is associated with increasing urate concentration.

●Urate concentration – The solubility of MSU in physiologic saline at 37ºC, about 7 mg/dL (416 micromol/L), is approximately the same concentration above which patients are at risk of developing gout [4,5]. Measurements of MSU solubility in plasma and serum have varied more widely than those in saline, although the average value is similar. Specific components of cartilage or joint fluid, including protein polysaccharides, aggregated and non-aggregated proteoglycans, and glycosaminoglycans influence urate solubility [8].

●Temperature – The solubility of MSU falls rapidly with decreasing temperature [40]. Noninflamed synovial fluid is significantly cooler than serum, being 90 to 91ºF (32ºC) in the knee [41], so the upper limit of urate solubility in tissue of a given joint could be considerably less than 7 mg/dL (416 micromol/L).

●Nucleation and growth – Both nucleation rates and subsequent growth rates of MSU crystals are directly proportional to the degree of MSU supersaturation [42]. Solubility is a thermodynamic parameter determined when a fluid is in equilibrium with a solid phase. Supersaturation may persist if nucleation and growth of MSU crystals do not occur. Indeed, urate has been noted to remain in solution indefinitely at a concentration of 84 mg/dL (5 mmol/L) [43]. Ions (K+, Cu2+, Mg+) reduce nucleation, and albumin, globulins (particularly gamma-globulin), and type 1 collagen all increase nucleation. Synovial fluid from people with gout enhances MSU crystal formation [8].

INFLAMMATION

Acute inflammation — Multiple cellular- and fluid phase-based mechanisms of innate immune activation by monosodium urate (MSU) crystals are recognized as critical to the development of the signs and symptoms of gout flare [44,45]. Inflammatory responses to crystal deposition and release, and the phagocytosis of MSU crystals by neutrophils and a variety of other cells all contribute to the inflammatory response, which is highly variable between individuals [9].

An intense inflammatory response initiated in the synovium by MSU crystal deposition, or by release of MSU crystals from preformed deposits, is characteristic of a gout flare. Synovial lining cell hyperplasia and infiltration by neutrophils, monocytes/macrophages, and lymphocytes are major histologic features of this process [46]. The predominance of neutrophils and neutrophil phagocytosis of MSU crystals in the synovial fluid aspirated from a joint affected by a gout flare, which is the accepted hallmark for definitive diagnosis of gout [47], focused attention on inflammatory processes mediated by neutrophils in the pathogenesis of the gout flare. This view was also supported by suppression of acute MSU crystal-induced inflammation in experimental animals rendered neutropenic prior to MSU crystal joint injection and restoration of the inflammatory response to injection after neutrophil repletion [46].

The identification of multiple additional events that precede or accompany neutrophil activation has contributed to further understanding of the complex processes involved in initiation and amplification of MSU crystal-induced inflammation. As an example, synovial cells, monocytes, and endothelial cells all phagocytose MSU crystals and release proinflammatory cytokine and chemokine mediators, and phagocytosis of MSU crystals by synovial lining cells, some of which have the phenotypic characteristics of macrophages, precedes the influx of neutrophils into the joint in vivo [48-51]. Potentially significant are ex vivo experimental data that soluble urate can prime a toll-like receptor (TLR)-dependent enhanced inflammatory response from human peripheral blood mononuclear cells [52] by a pathway involving mammalian target of rapamycin (mTOR) signaling that inhibits autophagy [53].

The NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome is central to the production of bioactive interleukin (IL) 1 beta [54]. Two signals are required for activation of the NLRP3-inflammasome (figure 1). The first is phagocytosis of MSU crystals and the second a poorly understood signal via TLRs, which is amplified by molecules such as lipopolysaccharide and long chain fatty acids. Collectively, these signals lead to inflammasome activation, requiring a wide array of molecules, including stressed mitochondria. The nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB) pathway is activated, and transcription of IL1B is promoted in a nucleotide-binding oligomerization domain-containing protein 2 (NOD2)-dependent process. The various components of the NLRP3 inflammasome are recruited, including the NLRP3 protein, the ASC adaptor, and procaspase-1. CARD8 is a negative regulator of inflammasome activation. The inflammasome is activated upon conversion of procaspase-1 to caspase-1 and produces bioactive IL-1 beta by proteolytic cleavage of inactive pro-IL-1 beta. Soluble urate is able to prime this response [52]. IL-1 beta binds to its receptor (IL-1R1) and induces secondary inflammatory mediators (prostaglandins, cytokines, chemokines) with the resultant recruitment of neutrophils that produce reactive oxygen species and proteases resulting in fulminant joint inflammation.

Study of MSU crystal-induced inflammation has revealed the importance of processes activating the innate immune system that are shared with rare inherited disorders, such as the cryopyrin-associated periodic syndromes (CAPS) [55] (see "Cryopyrin-associated periodic syndromes and related disorders", section on 'Pathogenesis'). Some studies have shown that MSU crystals derived from urate released from cells undergoing "sterile" cell death can also serve as a danger signal, activating both innate and adaptive immune responses [44,56-58]. Understanding the primacy and interactions of pro- (and anti-) inflammatory processes induced by MSU crystals and how environmental factors, including comorbidities, affect (and are affected by) these processes remains a work in progress. Still, considerable insight has been gained in identifying mediators of the sequential events in acute gouty inflammation: initiation, amplification, and resolution.

Initiation of acute MSU crystal-induced inflammation — The initiation of the acute inflammatory response to MSU crystals is affected by properties of the crystals themselves and proteins coating the crystals, cell-mediated mechanisms including signaling via membrane receptors, assembly and activation of the inflammasome, and the release of multiple cytokines.

Certain properties of MSU crystals, including size, electrostatic charge, state of aggregation, and the presence and nature of proteins coating the crystals, may impart or restrain the proinflammatory potential of MSU crystals deposited in the joint. For example, MSU crystals derived from tophi produce more inflammation than synthetic crystals, a difference that is eliminated by protease treatment of tophi [59]. Binding of immunoglobulin G (IgG) to MSU crystals results in an increased release of superoxide and lysosomal enzymes from human neutrophils in vitro compared with protein-free, crystal-induced release of these substances [60-62]. Although these findings imply an amplification rather than initiation phase effect for crystal-IgG binding, reduction in the inflammation potential of MSU crystals bound by lipoproteins (particularly those containing apolipoprotein B [ApoB]) prior to injection in animal models [63] suggests that lipoprotein binding to crystals contributes to the resolution of the gout flare (see 'Resolution of acute MSU crystal-induced inflammation' below) and, perhaps, to the absence of MSU crystal-induced flares in the joints of gout patients in whom MSU crystals without evidence of inflammation persist over the course of many months or years [64].

MSU crystal cell-mediated interactions supporting or essential for the initiation phase of MSU crystal-induced acute inflammation include membrane signaling through TLR-2 and TLR-4 [65]; and expression of MyD88 [66], an adaptor protein (CD14) shared by TLR-2 and TLR-4 [67], and TREM-1 (triggering receptor expressed on myeloid cells 1) [68]. Conflicting data have been presented regarding the necessity of one or more of these mechanisms [65,67-69], although a central role for resident macrophages in the initiation of acute MSU crystal-induced inflammation is widely acknowledged. Little is known about specific triggers of TLR-mediated activation of the NLRP3-inflammasome, although C16:0 (palmitic acid) has been demonstrated as a trigger [70].

Monocytes and synoviocytes release IL-1, IL-6, IL-8, and tumor necrosis factor (TNF) in response to MSU crystals in vitro [48,71-73], and increased levels of IL-6, IL-8, and TNF alpha are found in gouty tissues in vivo. Identification of the assembly and activation of the NLRP3 NOD-like receptor protein 3 inflammasome, with consequent caspase-1-catalyzed pro-IL-1 beta processing and release of IL-1 beta from macrophages and activated monocytes [54] has clarified the sequence of molecular events related to initiation and amplification of MSU crystal-induced inflammation [54,74]. Recruitment and activation of neutrophils, monocytes, dendritic cells [44], and other inflammatory cells appear to be dependent upon locally produced cytokines [75-77], and IL-1 beta is a cytokine critical for initiation of gouty inflammation. Rodents deficient in IL-1 receptors do not mount as vigorous an inflammatory response as wild-type animals to injected MSU crystals [75,76], and clinical trials showing the efficacy of IL-1 beta antagonists in treatment and/or prophylaxis of gout flares support a role for IL-1 beta mediation in the gout flare [37,78]. The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) showed that the IL-1 beta neutralizing monoclonal antibody canakinumab reduces incident gout [79].

An additional mechanism potentially germane to the clinically observed enhanced frequency of acute inflammatory response to MSU crystals by increasing soluble urate, nutritional stressors, alcohol excess, and specific comorbidities (such as obesity and metabolic syndrome) is suggested by in vitro and in vivo studies in mice [80]. These studies examined regulation of the activity of adenosine monophosphate-activated protein kinase (AMPK), a metabolic biosensor with anti-inflammatory properties. Suppression and activation of AMPK alpha1 phosphorylation respectively enhanced or suppressed MSU crystal-induced IL-1 beta and CXCL1 release. Enhanced phosphorylation also promoted the macrophage antiinflammatory (M2) phenotype and inhibited NLRP3 gene expression and activation of caspase-1 and IL-1 beta. In addition, exposure of bone marrow-derived macrophages to colchicine, at concentrations (10 micromolar) achievable in humans during gout flare prophylaxis, was associated with each of the above antiinflammatory responses. Prior research has established that hyperuricemia, alcohol consumption, nutritional stressors, obesity, and metabolic syndrome decrease tissue AMPK activity [81-85]. Thus, the experimental results described [80] are consistent with the view that AMPK activity limits MSU crystal-induced inflammation and mediates at least some of the antiinflammatory effects of colchicine in macrophages.

Amplification of acute MSU crystal-induced inflammation — Neutrophils provide a central cellular mechanism for amplification of acute gouty inflammation, a role accurately reflected both by the synovial histology and the leukocyte profile of synovial fluid aspirated at clinical presentation of the human gout flare. Neutrophil recruitment to the joint requires cellular and fluid phase proinflammatory processes, such as mast cell degranulation, activation of the complement cascade, and expression of endothelium-derived selectins, which play their major roles in the neutrophil-centered amplification of inflammation.

Activation of the endothelium of blood vessels adjacent to the joint is mediated by MSU crystal-induced participation of activated resident macrophages, chondrocytes, mast cells, and dendritic cells, and by activation of both classical and alternative complement pathways [45,86,87]. Endothelial cell activation results in vascular dilatation and increased vascular permeability; the activation of endothelial cells also results in the elaboration of adhesion molecules, including E-selectin, intercellular adhesion molecule-1 (ICAM), and vascular cell adhesion molecule-1 (VCAM) on the endothelial cells [88]. As a consequence, neutrophils in the circulation undergo tethering, rolling, and adhesion to the endothelium, leading to their traversal of the vessel wall. Subsequently, extravasated cells follow the concentration gradients of chemotactic molecules to the site of inflammation [87,88]. The major chemotactic molecule involved in MSU crystal-induced inflammation is IL-8, with leukotriene B4, IL-1, and complement fragment C5a also contributing [87,89].

Neutrophils are involved in a positive feedback loop of inflammation. Once in the inflamed joint, some neutrophils are subject to either crystal phagocytosis-induced degranulation or direct crystal lysis of lysosomal or cell membranes [45], with the release of further inflammatory mediators (prostaglandin E2, nitric oxide, leukotriene B4 [LTB-4], reactive oxygen species, S100A8, S100A9, IL-1 , and IL-8), as well as mediators of pain and tissue damage. Since most neutrophils in synovial fluid during a gout flare do not contain detectable MSU crystals, it seems likely that such cells may contribute to gouty inflammation in ways that do not require crystal phagocytosis, such as by downregulation of negative regulators of neutrophil activation like myeloid inhibitory C-type lectin-like receptor (MICL), which results in IL-1 beta-independent increases in IL-8 production [90]. Neutrophils activated by MSU crystals also recruit and activate monocytes/macrophages to express proinflammatory molecules, including IL-1, IL-6, IL-8, TNF-alpha, cyclooxygenase (COX)-2 [45], and LTB-4 [91].

MSU crystal activation of fluid phase inflammatory/nociception mediator systems includes the classical and alternative complement pathways [87,89,92]; formation of the complement membrane attack complex [87], which activates endothelial cells to produce the potent neutrophil chemotaxin, IL-8 [89]; the kallikrein-kininogen pathway (the product, bradykinin, contributing to vascular endothelial cell activation); prostaglandins; and substance P and LTB4 [91], which are nociceptor sensitizers that result in the heightened pain associated with a gout flare. The cellular biology and intracellular signaling mechanisms involved in neutrophil chemotaxis and activation in response to crystals are complex, involving transcriptionally and post-transcriptionally determined changes in the actions of kinases, phospholipases, chemoattractants, adhesion molecules, and other factors.

Resolution of acute MSU crystal-induced inflammation — The mechanisms by which a typical gout flare resolves even without treatment within a few days to several weeks are uncertain, but serial analysis of synovial fluid during a gout flare has shown the emergence of increased levels of some negative regulators of inflammation in the course of flare resolution; changes in the physical properties of the crystals may also play a role. The resolution phase of acute gouty inflammation is mediated by aggregated neutrophil extracellular trap structures (NETs) [93]. The NET structures contain chromatin and enzymes from neutrophil granules. The NETs occur after neutrophils undergo an oxidative burst with the resultant NETs binding and degrading chemokines and cytokines via serine protease activity. This disrupts neutrophil recruitment and activation. That tophi share features with aggregated NETs suggests that NET activity plays a role in the formation of the tophus [93].

In the synovial fluid, negative regulatory factors include antiinflammatory cytokines, transforming growth factor (TGF) beta-1, IL-1 receptor antagonist, IL-10, and soluble TNF receptor-I/II [94,95]; in synovial fluid cells, levels of cytokine-inducible SH2 (src homology 2 domain)-containing protein (CIS), and suppressors of cytokine signaling 3 (SOCS3) are upregulated [95]. Other mechanisms implicated in suppressing crystal-induced inflammation include inactivation of inflammatory mediators, deactivation or altered maturation of inflammatory cells, phagocytic disposal of apoptotic neutrophils, and enhanced expression of melanocortin 3 receptors [96] and the peroxisome proliferator-activated receptor gamma (PPAR gamma) [97]. IL-37 exerts potent antiinflammatory effects by suppressing production of IL-1 beta via binding the IL-18 receptor [98] and can limit the inflammatory response to MSU crystals [99]. Recombinant IL-37 suppresses experimental MSU crystal-induced inflammation [100].

Dissolution of MSU crystals by products of phagocytes, including superoxide, or sequestration of crystals in the synovium could serve to turn off inflammation [101], but resolution of a gout flare appears to occur even in the ongoing presence of intracellular crystals. However, the physical properties of crystals may change with inflammation. Indeed, neutrophil-derived products remove IgG from MSU crystals, thereby making them less inflammatory [102]. Perhaps of greater importance is the observation that increasing amounts of antiinflammatory ApoB bind to MSU crystals over the course of a flare [103].

Chronic inflammation: Tophaceous gout and joint damage

The tophus — Tophi are deposits of MSU crystals surrounded by granulomatous inflammation; the tophus is a complex but organized and dynamic chronic inflammatory tissue response to MSU crystal deposition. Both innate immunity and adaptive immunity participate. The correlated expression of both pro- and antiinflammatory factors in these lesions suggests cyclic processes of tophus inflammation and resolution and of tissue remodeling, with NETs likely to play an integral role in the formation of the tophus.

Tophi are most often found in proteoglycan-rich articular, periarticular, and subcutaneous areas, including joints, bone, cartilage, tendons, and skin. Uncommonly, tophi may be found in parenchymal organs as well. The tissue reaction to a tophus is generally chronic inflammatory in type and involves both innate and adaptive immunity. Although clinical signs of acute inflammation sometimes occur in tophi, this is unusual. Some patients with tophaceous gout also present with evidence of chronic synovitis (chronic gouty arthritis).

Tophi surgically obtained from 12 established gout patients were analyzed by quantitative immunohistochemistry [104]. The coronal zone of the tophus (immediately surrounding a mass of MSU crystals and, in turn, surrounded by a fibrovascular zone) contains substantial numbers of CD68+ mononuclear macrophages, and lesser numbers of multinucleated CD68+ cells and plasma cells. Few neutrophils are present. CD20+ B cells are present in small numbers in the fibrovascular zone, and both mast cells and T cells are found in modest numbers in both coronal and fibrovascular zones. Of note, IL-1 beta is frequently expressed by CD68+ cells in the corona, and the number of mononuclear cells expressing the proinflammatory cytokine IL-1 beta correlates with the number expressing the antiinflammatory cytokine TGF beta-1.

Visible or palpable tophi are usually noted among patients who have had repeated gout flares, often over many years. Little is known about host risk factors for the formation of tophi; however, there is some evidence for genetic risk factors playing a role [105,106]. Tophi and ensuing tophaceous joint damage may develop, however, in joints that have never been the sites of a gout flare. In addition, microscopic examination of synovium from patients with gout flares who do not have clinically detectable tophi can show micro-tophi containing only a thin rim of fibrocytes [107]. Although unsubstantiated, the initiation of a gout flare may begin with the release of MSU crystals from micro-tophi into the synovial fluid or may actually begin in the tissue. The latter mechanism is consistent with the clinical observation that joint fluid obtained shortly after the onset of symptoms is sometimes free of crystals, while a repeat aspiration a day or more later is floridly positive [108]. It is tempting to ascribe the posttraumatic gout flare to this mechanism.

Joint damage in gout — The histological and immunohistochemical study of the damaging effects of MSU crystal deposits have been substantially aided by the advent of newer imaging modalities (such as ultrasonography, dual-energy computed tomography [DECT], and magnetic resonance imaging [MRI]), which have highlighted the close relationship between MSU crystal deposits and the development of bone and cartilage erosions [109]. Tophi contribute to bone erosion and joint damage in gout [110], and a role for activated osteoclasts in gouty bone erosion is suggested by the observation that MSU crystal deposits are surrounded by osteoclast-like cells at the interface of a tophus and bone [111]. MSU crystals do not directly stimulate osteoclast formation but may activate osteoclastogenesis by altering the ratio of receptor activator of nuclear factor kappa B ligand (RANKL) to osteoprotegerin (OPG) in stromal cells such as osteoblasts [111,112].

In addition, T cells expressing RANKL are present in the tophus, providing an alternative mechanism for disordered osteoclastogenesis [113]. MSU crystals also compromise the viability, function, and differentiation of osteoblasts in primary culture [114,115], and osteoblasts are scarce at the tophus-bone interface [116]. These effects may reflect crystal activation of osteoblast phagocytosis and NLRP3-inflammasome-dependent autophagy, with associated functional dedifferentiation in these cells [115]. The expression of matrix metalloproteinases in response to MSU crystals in tophi may also contribute to cartilage and bone matrix damage in tophaceous gout [116,117].

MSU crystals also provoke negative effects on chondrocyte and cartilage viability and function [109,118]. Human chondrocytes, isolated or in cartilage explants, undergo increasing cell death in response to exposure to increasing doses of MSU-crystals [118], and chondrocyte production of cartilage matrix is also impaired by culture in the presence of crystals, as assessed by collagen, aggrecan, and versican gene expression. Examination of joints with extensive tophaceous deposits can show no intact hyaline cartilage, with only residual fragments of degenerate cartilage surrounded by tophaceous material [109]. Finally, chondrocyte exposure to MSU crystals appears to upregulate the inflammatory milieu associated with tophi [109].

SUMMARY

●Hyperuricemia is caused by absolute or relative impairment of renal and gut urate excretion and/or overproduction of urate. In some affected individuals, a period of hyperuricemia leads to monosodium urate (MSU) crystal deposition, reaction to which can result in the acute and/or chronic inflammation associated with the signs and symptoms of gout. Hyperuricemia is a necessary predisposing factor for gout, but the majority of hyperuricemic patients never develop gout. Individual differences in the formation of MSU crystals and/or in inflammatory responses to those crystals may play a role in whether a person with hyperuricemia will develop gout. (See 'Hyperuricemia and gout' above.)

●Risk factors associated with the development of hyperuricemia and gout include non-modifiable risk factors such as male sex, advanced age, ethnicity, and multiple genetic variations; and, particularly for the progression from hyperuricemia to gout, modifiable risk factors such as obesity, diets rich in meat and seafood content, alcohol-containing beverages (especially beer and distilled spirits), sodas and fruit juices high in fructose or sucrose content, hypertension, chronic kidney disease, thiazide or loop diuretic use, postmenopausal and organ transplant recipient status, use of certain medications (low-dose aspirin or cyclosporine A), and toxin exposure (eg, lead). Individual dietary triggers of gout play a role in the progression from hyperuricemia to gout. Obesity and ethanol ingestion further increase the risk for gout at any given level of hyperuricemia. Among persons with an established history of gout, consumption of alcohol or intermittent use of diuretics appear to acutely increase the risk of a gout flare. (See 'Hyperuricemia and gout' above.)

●The solubility of MSU in saline at 37°C, approximately 7 mg/dL (416 micromol/L), is approximately the same concentration above which patients are at risk of developing gout. The solubility of MSU falls rapidly with decreasing temperature. There are specific cartilage and joint factors that influence urate solubility and MSU crystal nucleation. Both nucleation rates and subsequent growth rates of MSU crystals are directly proportional to the degree of MSU supersaturation. (See 'Crystals' above.)

●Phagocytosis of MSU crystals by neutrophils plays a readily observable central role in amplifying the acute inflammation of a gout flare, but neutrophil recruitment to the joint requires earlier local cellular and fluid phase events in the synovium and joint vasculature. These events initiate innate immune system-mediated inflammation and include activation of resident synovial phagocytes (including monocytes/macrophages, mast cells, endothelial cells, and dendritic cells) and of the NOD-like receptor protein 3 (NLRP3) inflammasome, which leads to cellular processing of pro-interleukin (IL) 1 and elaboration of the key cytokine IL-1 beta. Release of IL-6, IL-8, tumor necrosis factor (TNF)-alpha, and additional proinflammatory molecules also supports MSU crystal-induced inflammation. (See 'Acute inflammation' above and 'Initiation of acute MSU crystal-induced inflammation' above and 'Amplification of acute MSU crystal-induced inflammation' above.)

●Neutrophils respond to MSU crystal phagocytosis with a respiratory burst and release of lysosomal enzymes, superoxide anion, leukotriene B4, and IL-1 and additional cytokines and chemokines. The cellular biology and intracellular signaling mechanisms involved in neutrophil chemotaxis and activation in response to crystals are complex, involving transcriptionally and post-transcriptionally determined changes in the actions of kinases, phospholipases, chemoattractants, adhesion molecules, and other factors. (See 'Acute inflammation' above and 'Initiation of acute MSU crystal-induced inflammation' above and 'Amplification of acute MSU crystal-induced inflammation' above.)

●Even without treatment, a typical gout flare resolves within a few weeks. There are many feedback mechanisms that tend to limit inflammatory states and that are likely to play a role in limiting the duration of a gout flare. Examples are neutrophil extracellular traps (NETs, which may play a role in formation of tophi) and IL-37. (See 'Resolution of acute MSU crystal-induced inflammation' above.)

●Tophi are deposits of MSU crystals surrounded by granulomatous inflammation. They are most often found in proteoglycan-rich tissues (joints, bone, cartilage, tendons, and skin), but may (uncommonly) be found in parenchymal organs as well. The tissue reaction to a tophus is generally chronic inflammatory in type; both innate immunity and adaptive immunity participate. The immunohistopathology of tophi suggests that the tophus is an organized and dynamic chronic inflammatory tissue response to MSU crystal deposition. Although clinical signs of acute inflammation sometimes occur in tophi, this is unusual. (See 'The tophus' above.)

●The pathophysiology of joint damage in gout involves chronic MSU crystal-induced inflammation, which may never have been punctuated by a gout flare. Interactions between the inflammatory components of crystalline tophaceous deposits and homeostatic processes dependent on the viability and function of osteocytes and chondrocytes may underlie the development of joint damage in gout. (See 'Joint damage in gout' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Paul Monach, MD, and Michael A Becker, MD who contributed to earlier versions of this topic review.