Orthopaedic Refrat

Gouty Arthritis

Arrange by: Redya Ayu T. G9911112120

Tutor: Dr. Tangkas Sibarani, SpOT, FICS

Orthopaedic and Traumatology Department of Sebelas Maret University Moewardi Hospital / Prof. Dr. R. Soeharso Orthopaedic Hospital Surakarta 2012

LEGALLY SHEET Refrat with title Gouty Arthritis is arranged to fulfil the requirement in Orthopaedic and Traumatology Department Sebelas Maret University, Moewardi Hospital/Prof. Dr. R. Soeharso Orthopaedic Hospital Surakarta by:

Redya Ayu T. G9911112120

Has been approved by Tutor of Orthopaedic and Traumatology Department in Prof. Dr. R. Soeharso Orthopaedic Hospital Surakarta.

Surakarta, 7th June 2012 Tutor

Dr. Tangkas Sibarani, SpOT, FICS

CHAPTER 1 PREFACE

The term gout, represents a group of heterogeneous metabolic dysfunctions characterized by deposition of monosodium urate crystals in the tissue from hyperuricemic body fluids. It can present as acute monoarthritis, chronic tophaceous arthritis, urate nephropathy and urolithiasis. The classical presentation is in form of acute monoarthritis usually involving first metatarso-phalangeal jojnt, however, untreated patients may acquire polyarticular course and may develop tophi. Gout is the single most common cause of inflammatory arthritis in males above the age of 40 years. Though hyperuricemia is the single most important risk factor for the causation of gout, the epidemiology of gout and hyperuricemia are different. Hyperuricemia is arbitarily defined as serum or plasma urate concentration >7 mg/dl in males and >6 mg/dl in females. At this concentration of urate, the limit of solubility of MSU in plasma at 37C is exceeded. The risk of gouty arthritis and renal stones increases inproportion to serum urate concentrations. The five year cumulative incidence rates of gouty arthritis for serum urate level of 8 mg/dl has been reported to be 2% as compared to 19.8% for urate levels 9-1 0 mg/dl and 30% for> 10 mg/dl. Serum urate level increases sharply at pubelty in males and at menopause in females. The precise incidence and prevalence rate ofgout is difficult to determine because of remitting and relapsing nature of the disease, propensity to misdiagnosis (over diagnosis by patients), changing life styles, eating habits and longevity of life in different population worldwide. Various risk factors which predisposes to gout are obesity, alcohol intake, hypeltension, renal insufficiency, diuretics use, family history of gout and environmental or occupational exposure to lead.

CHAPTER II Book Review

I.

Definition Gouty arthritis is an inflammatory condition associated with debilitating clinical symptoms, functional impairments, and a substantial impact on quality of life. This condition is initially triggered by the deposition of monosodium urate crystals into the joint space. This causes an inflammatory cascade resulting in the secretion of several proinflammatory cytokines and neutrophil recruitment into the joint. While generally effective, currently available agents are associated with a number of adverse events and contraindications that complicate their use. Based on our increased understanding of the inflammatory pathogenesis of gouty arthritis, several new agents are under development that may provide increased efficacy and reduced toxicity.1 Gouty Arthritis is a defect in the ability of the body to rid itself of excess uric acid, thus causing uric acid crystals to lodge in the collagen tissue matrices throughout portions of the body, especially near the joints, or at other locations where a supersaturated solution of poorly dissolved uric acid will easily fall out of solution, near cooler portions of the body.2

II.

Pathogenesis a. Clinical Principles The overall disease burden of gout is substantial and may be increasing. As more scientific data on the modifiable risk factors and comorbidities of gout become available, integration of these data into gout care strategies may become essential. Hyperuricemia and gout are associated with the insulin resistance syndrome and related comorbid conditions. Lifestyle modifications that are recommended for gout generally align with those for major chronic disorders (such as the insulin resistance syndrome, hypertension, and cardiovascular disorders); thus, these measures may be doubly beneficial for many patients with gout and particularly for individuals with these comorbid conditions. Effective management of risk factors for gout and careful selection of certain therapies for comorbid conditions (such as hypertension or the insulin resistance syndrome) may also aid gout care.

The urateanion exchanger URAT1 (urate transporter-1) is a specific target of action for both antiuricosuric and uricosuric agents. The long-term health effect of hyperuricemia (beyond the increased risk for gout) needs to be clarified, including any potential consequences associated with the chronic hyperuricemia that anti-inflammatory treatment does not correct. b. Pathophysiologic Principles A direct causal relationship exists between serum urate levels and the risk for gout. Lifestyle factors, including adiposity and dietary habits, appear to contribute to serum uric acid levels and the risk for gout. Urate is extensively reabsorbed from the glomerular ultrafiltrate in the proximal tubule via the brush-border urateanion exchanger URAT1. Sodiumdependent reabsorption of anions increases their concentration in proximal tubule cells, resulting in increased urate exchange via URAT1, increased urate reabsorption by the kidney, and hyperuricemia. Genetic variation in renal urate transporters or upstream regulatory factors may explain the hereditary susceptibility to conditions associated with high urate levels and a patients particular response to medications; these transporters may also serve as targets for future drug development. Urate crystals are able to directly initiate, to amplify, and to sustain an intense inflammatory attack because of their ability to stimulate the synthesis and release of humoral and cellular inflammatory mediators. Cytokines, chemokines, proteases, and oxidants involved in acute urate crystalinduced inflammation also contribute to the chronic inflammation that leads to chronic gouty synovitis, cartilage loss, and bone erosion.

Gout is a type of inflammatory arthritis that is triggered by the crystallization of uric acid within the joints and is often associated with hyperuricemia. Acute gout is typically intermittent, constituting one of the most painful conditions experienced by humans. Chronic tophaceous gout usually develops after years of acute intermittent gout, although tophi occasionally can be part of the initial presentation. In addition to the morbidity that is attributable to gout itself, the disease is associated with such conditions as the insulin resistance syndrome, hypertension, nephropathy, and disorders associated with increased cell turnover. The overall disease burden of gout

remains substantial and may be increasing. The prevalence of self-reported, physician-diagnosed gout in the Third National Health and Nutrition Examination Survey was found to be greater than 2% in men older than 30 years of age and in women older than 50 years of age. The prevalence increased with increasing age and reached 9% in men and 6% in women older than 80 years of age. Furthermore, the incidence of primary gout (that is, patients without diuretic exposure) doubled over the past 20 years, according to the Rochester Epidemiology Project. Dietary and lifestyle trends and the increasing prevalence of obesity and the metabolic syndrome may explain the increasing incidence of gout.

ABSENCE OF URICASE IN HUMANS Humans are the only mammals in whom gout is known to develop spontaneously, probably because hyperuricemia only commonly develops in humans. In most fish, amphibians, and nonprimate mammals, uric acid that has been generated from purine metabolism undergoes oxidative degradation through the uricase enzyme, producing the more soluble compound allantoin. In humans, the uricase gene is crippled by 2 mutations that introduce premature stop codons. The absence of uricase, combined with extensive reabsorption of filtered urate, results in urate levels in human plasma that are approximately 10 times those of most other mammals (30 to 59 _mol/L). The evolutionary advantage of these findings is unclear, but urate may serve as a primary antioxidant in human blood because it can remove singlet oxygen and radicals as effectively as vitamin C. Of note,levels of plasma uric acid (about 300 _M) are approximately 6 times those of vitamin C in humans. Other potential advantages of the relative hyperuricemia in primate species have been speculated. However, hyperuricemia can be detrimental in humans, as demonstrated by its proven pathogenetic roles in gout and nephrolithiasis and by its putative roles in hypertension and other cardiovascular disorders.

THE ROLE OF URATE LEVELS Uric acid is a weak acid (pKa, 5.8) that exists largely as urate, the ionized form, at physiologic pH. As urate concentration increases in physiologic fluids, the risk for supersaturation and crystal formation generally increases. Population studies indicate a direct positive association between serum urate levels and a future risk for gout. Conversely, the use of antihyperuricemic medication is associated with an 80%

reduced risk for recurrent gout, confirming the direct causal relationship between serum uric acid levels and risk for gouty ar thritis. The solubility of urate in joint fluids, however, is influenced by other factors in the joint. Such factors include temperature, pH, concentration of cations, level of articular dehydration, and the presence of such nucleating agents as nonaggregated proteoglycans, insoluble collagens, and chondroitin sulfate. Variation in these factors may account for some of the difference in the risk for gout associated with a given elevation in serum urate level. Furthermore, these factors may explain the predilection of gout in the first metatarsal phalangeal joint (a peripheral joint with a lower temperature) and osteoarthritic joints (degenerative joints with nucleating debris) and the nocturnal onset of pain (because of intra-articular dehydration).

Urate Balance The amount of urate in the body depends on the balance between dietary intake, synthesis, and the rate of excretion. Hyperuricemia results from urate overproduction (10%), underexcretion (90%), or often a combination of the two. The purine precursors come from exogenous (dietary) sources or endogenous metabolism (synthesis and cell turnover).

The Relationship between Purine Intake and Urate Levels The dietary intake of purines contributes substantially to the blood uric acid. For example, the institution of an entirely purine-free diet over a period of days can reduce blood uric acid levels of healthy men from an average of 297 _mol/L to 178 _mol/L. The bioavailable purine content of particular foods would depend on their relative cellularity and the transcriptional and metabolic activity of the cellular content. Little is known, however, about the precise identity and quantity of individual purines in most foods, especially when cooked or processed. When a purine precursor is ingested, pancreatic nucleases break its nucleic acids into nucleotides, phosphodiesterases break oligonucleotides into simple nucleotides, and pancreatic and mucosal enzymes remove phosphates and sugars from nucleotides. The addition of dietary purines to purinefree dietary protocols has revealed a variable increase in blood uric acid levels, depending on the formulation and dose of purines administered. For example, RNA has a greater effect than an equivalent amount of

DNA, ribomononucleotides have a greater effect than nucleic acid, and adenine has a greater effect than guanine. A recent large prospective study showed that men in the highest quintile of meat intake had a 41% higher risk for gout compared with the lowest quintile, and men in the highest quintile of seafood intake had a 51% higher risk compared with the lowest quintile. Correspondingly, in a nationally representative sample of men and women in the United States, higher levels of meat and seafood consumption were associated with higher serum uric acid levels. However, consumption of oatmeal and purinerich vegetables (for example, peas, beans, lentils, spinach, mushrooms, and cauliflower) was not associated with an increased risk for gout. The variation in the risk for gout associated with different purine-rich foods may be explained by varying amounts and type of purine content and their bioavailability for metabolizing purine to uric acid. At the practical level, these data suggest that dietary purine restriction in patients with gout or hyperuricemia may be applicable to purines of animal origin but not to purine-rich vegetables, which are excellent sources of protein, fiber, vitamins, and minerals. Similarly, implications of the recent finding in the management of hyperuricemia or gout were consistent with the new dietary recommendations for the general public, with the exception of the guidelines for fish intake. Thus, among patients with gout or hyperuricemia, the use of plant-derived _-3 fatty acids or supplements of eicosapentaenoic acid and docosahexaenoic acid instead of fish consumption could be considered to provide the benefit of these fatty acids without increasing the risk for gout.

PURINE METABOLISM AND GOUT The vast majority of patients with endogenous overproduction of urate have the condition as a result of salvaged purines arising from increased cell turnover in proliferative and inflammatory disorders (for example, hematologic cancer and psoriasis), from pharmacologic intervention resulting in increased urate production (such as chemotherapy), or from tissue hypoxia. Only a small proportion of those with urate overproduction (10%) have the well-characterized inborn errors of metabolism (for example, superactivity of 5-phosphoribosyl-1-pyrophosphate synthetase and deficiency of hypoxanthine guanine phosphoribosyl transferase). Conditions associated with net adenosine triphosphate (ATP) degradation lead to accumulation of adenosine diphosphate (ADP) and adenosine monophosphate

(AMP), which can be rapidly degraded to uric acid. For example, ethanol administration has been shown to increase uric acid production by net ATP degradation to AMP (41, 44). In addition, decreased urinary excretion as a result of dehydration and metabolic acidosis may contribute to the hyperuricemia that is associated with ethanol ingestion. Recently, a large-scale prospective study confirmed that the effect of ethanol on urate levels can be translated into the risk for gout (31). Compared with abstinence, daily alcohol consumption of 10 to 14.9 g increased the risk for gout by 32%; daily consumption of 15 to 29.9 g, 30 to 49.9 g, and 50 g or greater increased the risk by 49%, 96%, and 153%, respectively. Furthermore, the study also found that this risk varied according to type of alcoholic beverage: Beer conferred a larger risk than liquor, whereas moderate wine drinking did not increase risk. Correspondingly, a national U.S. survey demonstrated parallel associations between these alcoholic beverages and serum urate levels. These findings suggest that certain nonalcoholic components that vary among these alcoholic beverages play an important role in urate metabolism. Ingested purines in beer, such as highly absorbable guanosine, may produce an effect on blood uric acid levels that is sufficient to augment the hyperuricemic effect of alcohol itself, thereby producing a greater risk for gout than liquor or wine. Whether other nonalcoholic offending factors exist remains unclear, particularly in regard to beer; instead, protective factors in wine may be mitigating the alcohol effect on the risk for gout. Fructose is the only carbohydrate that has been shown to exert a direct effect on uric acid metabolism. Fructose phosphorylation in the liver uses ATP, and the accompanying phosphate depletion limits regeneration of ATP from ADP. The subsequent catabolism of AMP serves as a substrate for uric acid formation. Thus, within minutes after fructose infusion, plasma (and later urinary) uric acid concentrations are increased. In conjunction with purine nucleotide depletion, rates of purine synthesis de novo are accelerated, thus potentiating uric acid production. Oral fructose may also increase blood uric acid levels, especially in patients with hyperuricemia or a history of gout. Fructose has also been implicated in the risk for the insulin resistance syndrome and obesity, which are closely associated with gout. Furthermore, hyperuricemia resulting from ATP degradation can occur in acute, severe illnesses, such as the adult respiratory distress syndrome,myocardial infarction, or status epilepticus .

ADIPOSITY, INSULIN RESISTANCE, AND GOUT Increased adiposity and the insulin resistance syndrome are both associated with hyperuricemia. Body mass index, waist-to-hip ratio, and weight gain have all been associated with the risk for incident gout in men. Conversely, small, open-label interventional studies showed that weight reduction was associated with a decline in urate levels and risk for gout. Reduced de novo purine synthesis was observed in patients after weight loss, resulting in decreased serum urate levels. Exogenous insulin can reduce the renal excretion of urate in both healthy and hypertensive persons. Insulin may enhance renal urate reabsorption through stimulation of the urateanion exchanger urate transporter-1 (URAT1) or through the sodium-dependent anion cotransporter in brush-border membranes of the renal proximal tubule. Because serum levels of leptin and urate tend to increase together, some investigators have also suggested that leptin may affect renal reabsorption. Finally, in the insulin resistance syndrome, impaired oxidative

phosphorylation may increase systemic adenosine concentrations by increasing the intracellular levels of coenzyme A esters of long-chain fatty acids. Increased adenosine, in turn, can result in renal retention of sodium, urate, and water.

RENAL TRANSPORT OF URAT Renal urate transport is typically explained by a 4-component model: glomerular filtration, a near-complete reabsorption of filtered urate, subsequent secretion, and postsecretory reabsorption in the remaining proximal tubule. The urate secretion step was incorporated into the model to explain the potent antiuricosuric effect of pyrazinamide. However, direct inhibition of proximal tubular urate secretion by pyrazinoate, the relevant metabolite, has never been demonstrated. Indeed, pyrazinamide has no effect in animal species that eliminate urate through net secretion, and direct effects of the drug on human urate secretion are largely unsubstantiated. Rather, studies utilizing renal brush-border membrane vesicles have shown that pyrazinoate activates the reabsorption of urate through indirect stimulation of apical urate exchange. Similar mechanisms underlie the clinically relevant hyperuricemic effects of lactate, ketoacids, and nicotinate.

URATE CRYSTALINDUCED INFLAMMATION Urate crystals are directly able to initiate, to amplify, and to sustain an intense inflammatory attack because of their ability to stimulate the synthesis and release of humoral and cellular inflammatory mediators. Urate CrystalInduced Cell Activation and Signaling Urate crystals interact with the phagocyte through 2 broad mechanisms. First, they activate the cells through the conventional route as opsonized and phagocytosed particles, eliciting the stereotypical phagocyte response of lysosomal fusion, respiratory burst, and release of inflammatory mediators. The other mechanism involves the particular properties of the urate crystal to interact directly with lipid membranes and proteins through cell membrane perturbation and cross-linking of membrane glycoproteins in the phagocyte. This interaction leads to the activation of several signal transduction pathways, including G proteins, phospholipase C and D, Src tyrosine kinases, the mitogenactivated protein kinases ERK1/ERK2, c-Jun Nterminal kinase, and p38 mitogen-activated protein kinase. These steps are critical for crystalinduced interleukin (IL)8 expression in monocytic cells, which plays a key role in the neutrophil accumulation that is discussed later in this review. Crystal-Induced Cellular Response Cellular kinetic analyses using experimental animal models of gout indicate that monocytes and mast cells participate during the early phase of inflammation, whereas neutrophil infiltrates occur later during inflammation. Phagocytes from noninflamed joints may contain urate crystals, and most of these phagocytes are macrophages. The state of differentiation of mononuclear phagocytes determines whether the crystals will trigger an inflammatory response. In less differentiated cell lines, synthesis of tumor necrosis factor (TNF) and endothelial cell activation occurred after urate crystal phagocytosis, whereas well-differentiated macrophages failed to induce TNF-_ synthesis or to activate endothelial cells. Similarly, freshly isolated human monocytes lead to a vigorous response by induction of TNF-_, IL-1_, IL-6, IL-8, and cyclooxygenase-2 secretion, whereas human macrophages differentiated in vitro for 7 days failed to secrete cytokines or to induce endothelial cell activation.

These findings indicate that monocytes play a central role in stimulating an acute attack of gout, whereas differentiated macrophages play an anti-inflammatory role in terminating an acute attack and preserving the asymptomatic state.

Recent advances in the understanding of acute gouty attack are illustrated (left). The attack is primarily neutrophil-dependent and initiated by the capacity of urate crystals to activate complements and to stimulate synovial lining cells and resident inflammatory cells to induce a variety of inflammatory mediators. As depicted (right), self-resolution of acute gout is mediated by several mechanisms, including coating of monosodium urate crystals with proteins and clearance by differentiated macrophages, neutrophil apoptosis, clearance of apoptotic cells, inactivation of inflammatory mediators, and the release of anti-inflammatory mediators. Dots represent humoral inflammatory mediators, including cytokines and chemokines. Apo B _ apolipoprotein B; Apo E _apolipoprotein E; C1q, C3a, C3b, C5a, C5b-9 _ complement membrane attack complex; IL _ interleukin; LDL _ low-density lipoprotein; LTB4 _ leukotriene B4; MCP-1 _ monocyte chemoattractant protein-1/CCL2; MIP-1 _ macrophage inflammatory protein-1/CCL3; MMP-3 _ matrix metalloproteinase-3; NO _ nitrous oxide; PAF _ platelet-activating factor; PGE2 _ prostaglandin E2; PLA2 _ phospholipase A2; PPAR-_ _ peroxisome proliferator-activated receptor-_ ligand; PPAR_ _ peroxisome proliferator-activated receptor-_ ligand; TGF-_ _ transcriptio growth factor-_; TNF-_ _ tumor necrosis factor-_; S100A8/A9 _ myeloid-related protein; sTNFr _ soluble tumor necrosis factor receptor.

SPONTANEOUS RESOLUTION OF ACUTE GOUT The self-limited nature of acute gout is thought to involve several mechanisms. Clearance of urate crystals by differentiated macrophages in vitro has been linked to inhibition of leukocyte and endothelial activation. Neutrophil apoptosis and other apoptotic cell clearance represent a fundamental mechanism in the resolution of acute inflammation. Furthermore, transforming growth factor becomes abundant in acute gouty synovial fluid and inhibits IL-1 receptor expression and IL-1 driven cellular inflammatory responses. Upregulation of IL-10 expression has been shown to limit experimental urateinduced inflammation and may function as a native inhibitor of gouty inflammation. Similarly, urate crystals induce peroxisome proliferatoractivated receptor-_ (PPAR-_) expression in human monocytes and promote neutrophil and macrophage apoptosis (156). Research has yet to determine if the PPAR-_based therapy currently available for type 2 diabetes would also be useful in gout management.

Inactivation of inflammatory mediators by proteolytic cleavage, crossdesensitization of receptors for chemokines, release of lipoxins, IL-1 receptor antagonist, and other anti-inflammatory mediators all facilitate the resolution of acute gout. increased vascular permeability allows the entry of large molecules (such as apolipoproteins B and E and other plasma proteins into the synovial cavity, which also contributes to the spontaneous resolution of acute flares.

CHRONIC GOUTY ARTHRITIS Chronic gouty arthritis typically develops in patients who have had gout for years. Cytokines, chemokines, proteases, and oxidants involved in acute urate crystal induced inflammation also contribute to the chronic inflammation, leading to chronic synovitis, cartilage loss, and bone erosion. Even during remissions of acute flares, low-grade synovitis in involved joints may persist with ongoing intra-articular phagocytosis of crystals by leukocytes. Tophi on the cartilage surface, which can be observed through arthroscopy, may contribute to chondrolysis despite adequate treatment of both hyperuricemia and acute gouty attacks. Adherent chondrocytes phagocytize microcrystals and produce active metalloproteinases. Furthermore, crystal chondrocyte cell membrane interactions can trigger chondrocyte activation, gene expression of IL-1_ and inducible nitric oxide synthase, nitric oxide release, and the overexpression of matrix metalloproteinases that leads to cartilage destruction. The crystals can also suppress the 1,25-dihydroxycholecalciferol induced activity of alkaline phosphatase and osteocalcin. Thus, crystals can reduce the anabolic effects of osteoblasts, thereby contributing to damage to the juxta-articular bone.2,3,4,7

Low-level inflammation persists during the remissions of acute flares. Cytokines, chemokines, proteases, and oxidants involved in acute inflammation contribute to chronic inflammation leading to chronic synovitis, cartilage loss, and bone erosion. Monosodium urate (MSU) crystals are able to activate chondrocytes to release interleukin-1, inducible nitric oxide synthetase, and matrix metalloproteinases, leading to cartilages destruction. Similarly, MSU crystal activation of osteoblasts, release of cytokines by activated osteoblast, and decreased anabolic

function contribute to the juxta-articular bone damage seen in chronic MSU inflammation. IL _ interleukin; iNOs _ inducible nitrous oxide synthase; MMP-9 _ matrix metalloproteinase-9; PGE2 prostaglandin E2.

III.

Clinical Presentation on Gout

The natural history of gout is comprised of 4 phases (a) asymptomatic hyperuricemia, (b) acute gouty arthritis, (c) intercritical gout and (d) chronic gout. Asymptomatic hyperuricemia remains so in most of the patients and in remainder it ends with the first attack of acute arthritis. Usually it takes 20 years of sustained hyperuricemia to present as acute gouty arthritis and 10-40% patients will have renal col ic before first articular event. Diagnosis of gout should be reserved for increased uric acid and arthritis but not for increased uric acid and renal stones or arthralgias. Acute gouty arthritis typically presents as monoarthritis in 85-90% cases with first metatarsophalangeal (MTP) involvement at presentation in more than 50% cases. Around 30% of cases present with first attack at other sites such as other parts offoot, ankle, knee, hand and shoulder. Acute attacks are precipitated by trauma, surgery, acute illness, alcohol and drugs (diuretics, cyclosporine, TV heparin). Joints invloved in decreasing frequency are : ankle, heel, knee, wrist, elbow, fingers. Shoulder, hip, spine, sacroiliac and temporomandibularjoints are seldom involved. First MTPjoint involvement occurs in around 90% of patients with gout at some time during the course of illness. The classical description of Sydenham's describing the explosive onset of arthritis at night with features of inflammation and severe pain lasting few hours of days is valid till date. Usually, there are no sequelae of an acute attack. Occasionally, it can present as soft tissue involvement mimicking cellulitis in form of bursitis and tenosynovitis. Polyarticular presentation at the onset may occur in around 10% of patients with gout and may occur in upto 40% of patients during long term followup. The polyarticular involvement is usually symmetrical and ascending type with involvement of hand joints. It is usually seen in eldery males and postmenopausal 'females, particularly those taking diuretics. Tntercritical gout is the asymptomatic period in between the attack of acute gouty arthritis. Most of the patients will have second attack within 6 months to 2 years. The frequency of attacks increases with time in untreated patients. however, the onset of attacks are 58 less explosive. Though, recovery following an attack is complete, arthritis typically evolves into

oligo-or polyarticular involvement with severe disease which lasts longer and abates more gradually. Chronic gout is characterized by 01 igo-or polyarticular involvement with no pain free period. Much of the disability is due to tophi which may produce destructive deforming arthritis and non healing ulcers. The classic locations for tophi are joints of hands or feet, helix of ear, the olecranon bursa, and the achilles tendon. Before the advent of uric acid lowering drugs, 60% of the patients with untreated gout, used to develop tophi after 10 years . Rate of formation of tophi depends upon the degree and duration of hyperuricemia and severity of renal disease. Tophi at initial presentation is unusual in the primary gout but can occur in gout secondary to myleproliferative diseases, glycogen storage diseases, Lesch-Nyhan syndrome, allograft recipients on cyclosporine and patients on diuretics. Tophaceous gout is often associated with early age of onset, frequent acute attacks, high serum uric acid levels, polyarticular involvement at onset and renal dysfunction. However, with the use of uric acid lowering drugs and the ability to control hyperuricemia, incidence of tophi has decreased from 53% to 17%. Another series has reported the incidence of tophaceous gout to as low as 3%. However, the prevalence oftophaceous gout remain high in untreated patients.4

IV.

Diagnosis The diagnosis of gout is not always easy to make. The original American College of Rheumatology criteria have been shown to have limited validity (sensitivity, 0.80; specificity, 0.64; positive predictive value, 0.80; and negative predictive value, 0.65). More recently, the European League Against Rheumatism (EULAR) also developed recommendations.

Visualization of crystals The gold standard for making a diagnosis of gouty arthropathy is visualization of negatively birefringent, needle-shaped crystals. This is done with arthrocentesis and analysis of synovial fluid (SF) or tophus aspirate and identification of monosodium urate (MSU) crystals, particularly intracellular crystals in neutrophils. MSU crystals also may be identified in SF obtained from asymptomatic joints, especially the knees and the first metatarsophalangeal (MTP) joints. Of note, acute gouty arthritis may coexist with another joint disease, such as septic arthritis or pseudogout. Therefore, arthrocentesis should be performed in almost all

circumstances. Serum uric acid (SUA) levels may be obtained during an acute attack (a high SUA level supports the possibility that a patient has gout). However, SUA levels may be paradoxically low during an acute attack (because of an increase in renal excretion); they typically are highest about 2 weeks after.

Previously proposed criteria A thorough history helps distinguish an acute gout attack from other causes of acute arthritis. Previously proposed clinical, radiographic, and laboratory criteria include the following: Identification of MSU crystals from the SF of the affected joint. Negative Gram stain and culture results from the SF. A history of 1 or more episodes of monarticular arthritis, followed by intercritical periods free of symptoms. Maximum inflammation within 12 to 24 hours after the onset of the attack. Rapid resolution of synovitis after colchicine(Drug information on colchicine) or NSAID therapy. Unilateral first MTP joint attack (podagra), especially if it is the first event. Hyperuricemia. Subcortical bone cysts on plain radiographs.

Natural history The natural history of gout may be translated into 3 clinical periods. They are: (1) asymptomatic hyperuricemia; (2) episodes of acute attacks of gout, with asymptomatic intervals (intercritical gout); and (3) chronic gouty arthritis. Chronic hyperuricemia. This is the most important risk factor for gout. The risk of acute gout rises with the SUA concentration. In patients with SUA concentrations of 6.1 mg/dL (540 mol/L) or higher, the cumulative incidence of gouty arthritis is 22% after 5 years.6,9 However, many persons with high SUA levels do not ever have gout, indicating that factors other than hyperuricemia play a role in the development of clinical symptoms.

Acute gouty arthritis. Episodes of acute gouty arthritis often begin at night or in the early morning; pain and swelling escalate rapidly. The joint quickly becomes

warm, red, and tender (calor, rubor, dolor, et tumor), potentially mimicking cellulitis or even a septic joint. Acute attacks typically affect the first MTP joint (up to 50% of first-time attacks), but tarsal joints, ankles, knees, elbows, and interphalangeal (IP) joints all are frequently affected. Rarely, the initial attack is polyarticular

(3% to 14% of cases); acute attacks infrequently affect the shoulders or hips. In most cases, unmanaged gout resolves within a few days. Most patients have a second attack within 6 months to 2 years, although only a single episode occurs in some. Subsequent attacks often last longer than the initial attack, and they are more likely to affect proximal joints, including the knees and carpal and IP joints.

Chronic gouty arthritis. When left unmanaged, acute attacks of gout can lead to chronic gout. This condition is characterized by chronic destructive polyarticular involvement with low-grade joint inflammation, joint deformity, and tophiMSU crystals surrounded by chronic mononuclear and giant-cell reactions. Tophaceous gout develops within 5 years of the onset of gout in 30% of untreated patients. Tophi often are seen in the helices of the ears, over the olecranon processes, on the Achilles tendons, within and around the toe or finger joints, around the knees, and within the prepatellar bursae. The skin overlying the tophus may ulcerate and extrude white, chalky material composed of MSU crystals. Tophi are painless and rarely become infected.

Imaging

Radiographs of joints affected by acute gout attacks typically are not useful for the diagnosis of acute gout. However, they may show evidence of chronic disease. Musculoskeletal ultrasonography (MSUS) continues to gain popularity in the evaluation of various musculoskeletal diseases, including crystal-induced arthropathy. MSUS has the capacity to visualize intra-articular crystal deposits with a characteristic hyperechoic enhancement of the outer surface of the hyaline cartilage (the double contour sign). Although MSUS may be useful in the diagnosis of gout, it has limitations, paramount of which is the inability to differentiate between the type of crystal deposition and the presence or absence of infection.

CT and MRI may be useful in confirming the presence of erosion and tophi. Since the use of both imaging modalities has increased, the prevalence of axial skeleton gout also has increased.8

V.

Treatment Acute gout Phagocytosis of MSU crystals is the inciting factor of acute gouty arthritis. The urate crystals are recognized as foreign and taken up by macrophages, inciting an inflammatory response (activation of the NLRP3 inflammasome). This activation triggers a cascade that results in the release of interleukin (IL)-1 and other inflammatory cytokines. The release of the cytokines rapidly ignites a broader inflammatory response and the infamous redness, pain, and swelling of an acute gout flare. The goal of therapy for acute gout is to stop this inflammatory process. Therefore, the faster the attack is recognized and medications (including NSAIDs, colchicine, corticosteroids, and even IL-1 inhibitors) are administered, the quicker and easier the attack is to abate. For most patients, NSAIDs are the preferred agent for managing acute gout. All NSAIDs appear to be equally effective when used at a full anti-inflammatory dose. The most frequently used regimens are ibuprofen, 800 mg tid; naproxen, 500 mg bid; and indomethacin, 50 mg tid. Having adequate dosing and duration is important. Treatment should be continued until the flare has resolved and then reduced in tapered doses for at least 2 or 3 days after all overt signs of inflammation are gone. NSAIDs have the advantage of acting as an analgesic as well as an anti-inflammatory, but they may be somewhat contraindicated in patients who have hypertension, congestive heart failure (CHF), renal insufficiency, gastritis/ulcers, and a number of other conditions.

Colchicine. To maximize response time while minimizing adverse effects, some clinicians managing acute gout add an intermediate dosing regimen of colchicine (0.6 mg every 6 to 8 hours) to their patients' NSAID regimens. The use of a proton pump inhibitor can improve GI tolerance of NSAIDs and reduce the likelihood of gastric bleeding, but it may not avoid other concerns. Although colchicine has been used for gout management since the 6th century ad, only 1 year has passed since its FDA approval for acute and chronic gout. As a result, dosing guidelines and the evidence basis for colchicine in acute gout management have advanced. Historically, colchicine has been given orally or intravenously. Oral colchicine is taken every 1 to 2 hours for acute gout flares until toxicity occurs. When the first signs and symptoms associated with toxicity occurincluding diarrhea, nausea, and vomitingdosing is stopped. Intravenous dosing bypasses the GI tract and therefore is associated with less GI intolerance but at the risk of severe cytopenia, acute renal failure, and disseminated intravascular coagulopathy. The high-dose oral regimen has fallen out of favor; intravenous colchicine was taken off the market in 2008. The low-dose colchicine regimen has been found to be as effective as the high-dose colchicine regimen and much less toxic. In a large, randomized, controlled, multicenter trial that compared low-dose and extended-dose colchicine regimens, the results strongly supported the use of 1.2 mg within 12 hours of the onset of the attack, followed by 0.6 mg 1 hour later. Corticosteroids. These potent anti-inflammatory agents can be highly effective at abrogating acute gout. Intra-articular corticosteroids may be particularly useful in managing acute gout in a single joint or bursa and in cases in which the systemic corticosteroid load needs to be minimized. Care must be taken to rule out infection before injecting corticosteroids into the joint; this may mean performing joint aspiration and injection separately, an approach that patients do not always appreciate. Both oral and intravenous corticosteroids are very effective, especially in patients who are experiencing polyarticular attacks or have contraindications to colchicine and NSAIDs. Most rheumatologists prescribe about 40 mg/d of prednisone with a slow taper (similar to management of an acute asthma attack) to avoid rebound attacks after corticosteroid withdrawal. Although treatment periods with oral corticosteroids

typically are fairly brief (less than a week), potential contraindicationssuch as diabetes mellitus, hypertension, and heart failurestill must be considered. Adrenocorticotropic hormone (ACTH). A single intramuscular injection of depot ACTH gel (25 to 80 IU) repeated 24 to 72 hours later, if needed, also is a very powerful anti-inflammatory, and it may be more effective than oral corticosteroids. ACTH stimulates the adrenal cortex to produce corticosteroids, and it may suppress the acute inflammatory response by activating melanocortin receptor 3. However, access to ACTH gel in the United States currently is limited. New therapies. Acute gout therapy has not changed for decades, but there are medications on the horizon that may come to fruition. Development of potential new therapies has capitalized on evolving understanding of the pathophysiology of the inflammatory response in acute gout. Targeting the secretory product of the inflammasome, a pilot study of 10 patients with chronic refractory gouty inflammation given the soluble IL-1 receptor antagonist anakinra (100 mg/d SC for 3 days) suggested good overall responses, although results of larger randomized, controlled trials are needed. Rilonacept, a soluble IL-1 receptor-Fc fusion protein, and canakinumab, a fully human monoclonal antiIL-1 antibody, have shown promising results both as treatment for patients with acute, difficult-to-manage gout attacks and prevention of recurring attacks.

Chronic gout

The goals of chronic gout treatment are to eliminate the recurrence of acute attacks and to decrease or eliminate the tophus burden in the joints and soft tissues. These goals are achieved by lowering the SUA level to less than 6 mg/dL.

The first step in managing gout is patient education. SUA levels may be lowered modestly (by 1 or 2 mg/dL) with lifestyle changes, such as weight loss, avoidance of purine-rich foods (organ meats, shellfish, beer), avoidance of processed foods that have high-fructose sweeteners, elimination or reduction of alcohol consumption (beer and liquor), and even increased intake of vitamin C. Medications also may play a role in gout management by raising or lowering SUA concentrations with stimulation or inhibition of the urate transporter URAT1 in the proximal tubule of the kidney, respectively. The use of diuretic drugs (eg, thiazides and loop diuretics) increases the risk of gout attacks, and the occurrence of arthritis shortly after the start of SUA-lowering therapy is well established. In contrast, some medications (eg, losartan) inhibit URAT1 and subsequently lower SUA levels. Although lifestyle interventions and daily low-dose colchicine or NSAID prophylaxis may be all that is needed in some patients with early mild gout, such interventions typically do not replace the need for SUA-lowering drug therapy to prevent frequent attacks (more than 2 per year). SUA-lowering agents frequently used to manage chronic gout include purine and nonpurine inhibitors of xanthine oxidase (allopurinol, febuxostat) and uricosuric agents (probenecid, sulfinpyrazone, benzbromarone). Also, new medications on the horizon may be used instead of or in addition to those already approved for use in chronic gout. Allopurinol, the most frequently used SUA-lowering agent in the treatment of patients with gout, is FDA-approved for doses up to 800 mg/d. In clinical practice, nonadherence with allopurinol treatment was elucidated to be a problem in about 50% of patients in the first year of therapy. Allopurinol is widely underdosed in clinical practicethe vast majority of allopurinol prescriptions are for 300 mg/d,30 even though higher doses often are required to achieve an SUA target level (lower than 6 mg/dL). Such dosing practices stem from limited 30-year-old data about potentially serious adverse effects in patients with chronic kidney disease (CKD). The adverse effects, which include rash, cytopenia, and fever, are uncommon. Although most serious adverse effects of CKD occur within the first 6 to 8 weeks of allopurinol use, long-term monitoring is required. Daily doses ranging from 600 to 1000 mg can be used safely in patients with CKD.

The EULAR currently recommends dose adjustment in patients with CKD. A good rule to follow is to start with a lower dose, then titrate to the dose until the target SUA level is achieved, all the while monitoring the patient for signs and symptoms of hypersensitivity. Interactions with other medications can occur. For example, azathioprine is metabolized by xanthine oxidase; concomitant use of the drugs can raise azathioprine levels and result in bone marrow toxicity. Consequently, use of the drugs together is discouraged. Febuxostat is a potent, nonpurine, selective inhibitor of xanthine oxidase.32 More significantly, it is primarily metabolized by the liver. Dosing is limited to 40 or 80 mg/d, making dose adjustment unnecessary in patients with mild to moderate kidney impairment.33 Febuxostat also does not affect pyrimidine metabolism, and in contrast to allopurinol, it does not have the potential to contribute to certain drug toxicities. The results of clinical trials unequivocally established the superiority of febuxostat over 300 mg/d of allopurinol in achieving an SUA target level of lower than 6 mg/dL and reducing tophaceous deposits in most of the patient population that was studied.8

SURGICAL THERAPY FOR GOUT The use of surgical intervention for gout dates back to the time of Hippocrates, when relief from severe pain was provided by burning the painful tophus with crude flax. Before the introduction of effective urate lowering therapy in the management of gout, surgery was frequently used for cosmetic reasons or for removal of large deposits of sodium urate. Tophi are characteristically deposited in articular and periarticular structures, and have a predilection for avascular structures. Nerves, blood vessels and muscles are not usually involved. Straub et al condensed and reclassified the earlier indications of Linton and Talbot for surgery ingout into four main categories: 1) functional: excision to permit wearing of shoes and clothing, restoration of motion, and stabilization of joints; 2) symptomatic: control of drainage and infection, reduction of pain and decompression of nerves; 3) cosmetic restoration and 4) metabolic: decrease of total body urate. The role of surgery for gout is now generally limited to the complications of tophaceous disease which include infection, nerve compression due to mass effect of the tophus, joint deformity and intractable pain. Tophaceous gout may compress peripheral nerves, the cauda equina or the spinal cord in which case prompt surgical intervention is needed to prevent permanent neurological impairment. In a retrospective analysis of 45 patients who underwent surgery for gouty tophi, sepsis control in infected or ulcerated tophi was the main indication for surgery (51%), followed by mechanical problems caused by foot, elbow and hand tophi (27%). Four percent of patients underwent tophus surgery mainly for pain control. Recurrence of tophi is unpredictable. In the series of Straub, 36 procedures were performed and tophi recurred in only 3 cases. However, few clinical trials address the long term efficacy of surgery in the management of tophaceous disease. It is universally recommended that before surgery is considered for the treatment of gout, optimal uratelowering medical therapy should be employed to reduce the size of tophi.5,6,7,9

REFERENCES

1. Aggarwal. 2012. Gouty Arthtritis. India : JBJS , Department of Medicine Gour, Jammu 2. Choi, Hyon k. 2008. Pathogenesis of Gout. USA : Physiology in medicine 3. Fabio, Anthony. 2012. Gouty Arthtritis. USA : The Arthtritis Thrust of America 4. Gonzales, Emilio. 2012. An Update on the Pathology and Clinical Management of Gouty Arthritis. USA : NCBI (National Library of Medicine National Institutes of Health) 5. Imon SR, Alaranta H, Fischer R, et all. Kinesiology. In: Simon SR,eds. Orthopaedics basic science. American Academy of Orthopaedic Surgeons, Ohio.1994, 583-92. 6. Larmon, William. 1985. The journal of Bone and Joint Surgery.USA 7. Rajendra, Marwah. 2011. Comorbidities in Gouty Arthritis. USA : Journal of innergative medicine 8. Underwood, Martin. 2006. Diagnosis and Management of Gout. London: BMJ, Department of General Practice and Primary care, Centre for gealth sciences, University of London 9. Woughter, Harold. 1995. Surgery of Tophaceous Gout. USA