The Management of Gout and Hyperuricemiadbm

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  • Uric acid will precipitate in crystalline form at a uric acid concentration above 6.8 mg/dL at a pH of 7.4 and a body temperature of 98.6°F.
  • Gout is mediated by the supersaturation and crystallization of uric acid within the joints. The amount of urate in the body depends on the balance between dietary intake, synthesis, and excretion. Hyperuricemia results from the overproduction of urate (10%), from underexcretion of urate (90%), or often a combination of the two. Approximately one third of urate elimination in humans occurs in the gastrointestinal tract, with the remainder excreted in the urine.
  • Rationale Metabolic Syndrome Comorbidities such as hypertension, hypertriglyceridemia, hypercholesterolemia, diabetes, and obesity are associated with a higher risk of gout. 30 A large cohort study (N = 12 179 men) conducted in Taiwan demonstrated that all features of metabolic syndrome increase the risk for gout in patients of all ages (Table 3). 31 Cardiovascular Disease Research until 2006 strongly suggested that hypertension and coronary heart disease increased the risk of developing gout. 12 Subsequent studies underscored the interplay of cardiovascular disease (CVD) and gout. The Health Professionals Follow-up Study, which followed 51 297 men for 12 years, showed that those with hypertension had more than twice the risk of developing gout (relative risk [RR], 2.31 [95% CI, 1.96–2.72]). 32   Chronic Kidney Disease Patients with CKD often present with gout because poor kidney function leads to insufficient urate clearance.(Table 4) Conversely, patients with hyperuricemia may also be at greater risk for developing renal disorders. 33 Medication Singh et al 30 determined that thiazide and loop diuretics were associated with an increased risk of incident gout and gout flares. As more patients are using low-dose aspirin to prevent CVD, results of 2 studies mentioned by Singh et al about this medication are of interest. 34, 35 Accordingly, low doses (1–2 g/day) of aspirin cause retention of UA, while high doses (> 3 g/day) are uricosuric. 34   Risk Factors in Women The hormonal changes associated with menopause put women at risk of gout. 30 When 92 535 women were followed for 16 years as part of the Nurses’ Health Study, 1703 developed gout. 36 In this study, menopause increased the risk of gout with an age-adjusted RR of 1.33 (95% CI, 1.08–1.63) and a multivariate-adjusted RR of 1.26 (95% CI, 1.03–1.55). 36  
  • A 32 ounce serving of coca cola increases sUA 2.5mg/dL
  • During the 12 years of the study, we documented 730 confirmed new cases of gout. The multivariate relative risk of gout among men in the highest quintile of meat intake, as compared with those in the lowest quintile, was 1.41 (95 percent confidence interval, 1.07 to 1.86; P for trend=0.02), and the corresponding relative risk associated with seafood intake was 1.51 (95 percent confidence interval, 1.17 to 1.95; P for trend=0.02). In contrast, the incidence of gout decreased with increasing intake of dairy products; the multivariate relative risk among men in the highest quintile, as compared with those in the lowest quintile, was 0.56 (95 percent confidence interval, 0.42 to 0.74; P for trend <0.001). The level of consumption of purine-rich vegetables and the total protein intake were not associated with an increased risk of gout. Fish increased risk of gout, more notable in those WITHOUT obesity.
  • Rationale Signs and symptoms such as painful joint, swelling, severely painful attacks of sudden onset, and remission within 2 weeks are of limited diagnostic value due to their poor specificity for gout. 12 Results by Janssens et al 19 suggest similar limitations for the clinical criteria “overlying erythema” and “development of severe pain within one day.” Although these criteria had a high sensitivity for gout (ie, using these criteria would result in a high likelihood that patients with gout would be identified), they showed poor specificity (ie, many patients with inflammatory joint conditions other than gout would be incorrectly identified as having gout) (Table 3).   Rapid onset of severe pain, swelling, and erythema that is self-limiting, while indicative of crystal associated synovitis, appears to have limited diagnostic value on a definitive diagnosis of gout (Figure 2, Table 3). Women may present with atypical signs and symptoms of gout. A systematic review of literature indicated that women were an average of almost older than men when experiencing their first gout attack and presented less frequently than men with metatarsophalangeal (MTP1) involvement. 20 Instead, polyarticular gout affecting the ankles or joints of the fingers and upper limbs was more common in females. 20 Therefore, it is prudent to consider gout as a possible diagnosis in postmenopausal women with acute arthritis, especially in areas of prior osteoarthritis and in the ankle.
  • Rationale Elevated SUA levels are a significant risk factor for gout. Persistence of hyperuricemia at levels higher than a serum saturation of 6.8 mg/dL leads to deposits of urate on articular cartilage. Although hyperuricemia can remain silent for years and does not always progress to clinically recognizable gout, 21 higher SUA levels are associated with greater risk for developing gout. However, SUA is not always a reliable diagnostic tool for gout. Flares (termed mobilization flares) may occur during the implementation of urate-lowering therapy (ULT) as urate levels drop. Also, normal levels of SUA are also sometimes present during acute flares due to an increase in renal urate excretion that has been linked to increases in cytokines and other inflammatory stimuli. 23, 24 Also, address the concept of “normal” SUA, as commercial lab “normal ranges” for SUA are the normative distributions in their database, and for clinical relevance a “normal uric acid” is a level below the solubility level  
  • 36 36 Include information on more/less common in slide notes
  • Rationale Patients with suspected gout who present with fever, feel as if they may have influenza or their test findings show an elevated white blood cell count should be suspected of having sepsis. In these patients, synovial fluid aspiration can correctly identify septic arthritis. 25, 27 In patients suspected of sepsis, culture of the synovial fluid should be performed, even if MSU was identified.
  • Rationale Based on data from case-control studies and reviews of case-control studies, EULAR recommended the detection of MSU in affected tissue as the diagnostic gold standard for symptomatic gout, despite interobserver variability. 12 However, the routine demonstration of MSU for the diagnosis of gout may not be feasible in busy PCP practices. 21, 22 This is not problematic in patients presenting with the typical signs and symptoms of gout, particularly in the presence of podagra, because clinical criteria can be used to make a working diagnosis of gout (Figure 2).  
  • Rationale According to EULAR recommendations, MSU crystals have been identified in aspirated synovial fluid during intercritical periods. 12 However, although MSU eventually disappeared from synovial fluid of all study participants in one trial, MSU clearance required 3 to 33 months. 26
  • Although the intercritical periods between flares are symptom-free, urate crystals continue to deposit in joints, reflecting the progressive effects of the disease. 1,4-6 Once crystals form, they stay in the joints and can cause disease progression 3,6 In a study by Pascual et al, urate crystals were found in 34 of 48 (71% [CI, 56% to 83%]) asymptomatic, but previously inflamed, knees from patients with gout who were receiving urate-lowering agents 3 Median sUA level for treated patients was 351 μ mol/L (interquartile range 280 to 422 μ mol/L); 27% had sUA levels >416 μ mol/L 3 Crystals were found in all samples from patients not receiving urate-lowering therapy (n=43; 100% [95% CI, 92% to 100%]); 91% had an sUA level >416 μ mol/L 3 The presence or absence of crystals was directly correlated with the time elapsed since the last gout attack 3 A previous study from Pascual revealed low-grade inflammation persists in synovial joints during the intercritical period, which may lead to disease progression even in the absence of flares 2 References McCarthy GM, Barthelemy CR, Veum JA, Wortmann RL. Influence of antihyperuricemic therapy on the clinical and radiographic progression of gout. Arthritis Rheum. 1991;34:1489-1494. Pascual E. Persistence of monosodium urate crystals and low-grade inflammation in the synovial fluid of patients with untreated gout. Arthritis Rheum. 1991;34:141-145. Pascual E, Batlle-Gualda E, Martínez A, Rosas J, Vela P. Synovial fluid analysis for diagnosis of intercritical gout. Ann Intern Med . 1999;131:756-759. Pascual E, Pedraz T. Gout. Curr Opin Rheumatol. 2004;16:282-286. Schumacher HR. The pathogenesis of gout. Clev Clin J Med. 2008;75(suppl 5):S2-S4. Wortmann RL, Kelley WN. Gout and hyperuricemia. In: Harris ED Jr, Budd RC, Genovese MC, et al, eds. Kelley’s Textbook of Rheumatology. 7th ed. Philadelphia, PA: Elsevier Saunders; 2005:1402-1429.
  • Rationale Although the examination of synovial fluid is not routinely required for the correct diagnosis of gout in patients with the typical presentation of gout, a confirmation is appropriate when synovial fluid is already available. In patients using a hospital-based rheumatology service, joint aspiration resulted in a definite diagnosis of gout, septic arthritis, or pseudogout in 44% (n = 38) of 86 procedures. 25
  • Rationale The identification of patients with hereditary gout is necessary for tailoring ULT appropriately. Familial juvenile hyperuricemic nephropathy, an autosomal dominant disorder disease that can affect both men and women, is characterized by frequent but not universal hyperuricemia, frequent gout, slowly progressive renal disease, and low fractional excretion of UA (fractional excretion of UA, 5.1% ± 1.6%) relative to glomerular filtration rate. 28, 29 Less frequently, P-ribosyl-PP synthetase super activity leads to gross overproduction of UA and therefore to gout, kidney stones, or acute renal failure in men or women. 28 Only men are at risk for young onset gout caused by the absence of hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Deficiency in HGPRT is associated with Lesch-Nyhan syndrome, which expresses with severe neurologic manifestations, a tendency for self-mutilation, and UA over-excretion that may lead to crystal-caused obstructive uropathy. 28 Medications that may be introduced in the next 3 to 5 years may necessitate a change in this recommendation, and thus it is important to remain current with the literature.
  • Rationale Nephrolithiasis is sometimes associated with gout. Overproduction of UA leads to the development of UA-containing stones. Because uricosuric therapy for gout can promote renal lithiasis in some patients, appropriate patient selection for uricosuric therapy depends on a thorough evaluation of risk factors. Patients with gout who already present with renal stones may have an associated defect in urinary acidification. They should be referred to a nephrologist to undergo a lithogenic workup.
  • Rationale A number of imaging techniques have been proposed for the diagnosis and assessment of disease severity in patients with gout. The EULAR team concluded that radiography played only a limited role in gout diagnosis, mostly in patients with chronic, advanced, or severe disease.
  • The advanced gout stage is often referred to as chronic tophaceous gout to indicate the presence of this clinical manifestation, which will remain unresolved in the absence of urate-lowering therapy. Tophi are characterized by solid urate deposits in connective tissues that produce irregular nodularities and joint destruction. In addition, the skin overlying the tophi may become ulcerated and exude a white, chalky material. Shown here are some common sites of tophi, including dermal tophi on the finger, periarticular tophi on the hands, and tophi on the helix of the ear. The patient who was experiencing the intradermal tophi on the knees was diagnosed and treated by multiple generalists and specialists for osteoarthritis. This photo was taken during his self-referred first visit to a rheumatologist and reinforces the point that gout is a disease that is under-recognized. 1 The patient with polyarticular involvement of his hands had been misdiagnosed and treated for rheumatoid arthritis for 8 years. 2 The tophi exhibited on this slide are clinically apparent, but this may not always be the case, as was seen in the previous case study examples of the tophi that formed in the bone of the knee and the palm of the hand. 1. Patient case study courtesy of Brian Mandell, MD, PhD, Cleveland Clinic. 2. Patient case study courtesy of N. Lawrence Edwards, MD, University of Florida.
  • Demonstrated here are the radiographic changes seen with advanced gout. The deposition of urate, and resultant gouty erosion, is associated with bony sclerosis, in contrast to the osteopenia seen in rheumatoid arthritis.
  • Many physicians follow 3 treatment goals for controlling and treating gout. Understanding these 3 treatment goals and associated medications is vital for proper control and treatment of gout in patients. When a patient presents with an acute attack, the first goal is to control the inflammation and pain as soon as possible. Another goal of treatment is to protect against further attacks by administering medications that will reduce the chance of inflammation, occurring due to the deposited crystals. The underlying cause of the disease, however, is hyperuricemia. Until the elevated serum urate is controlled in a given patient, the total body urate pool will continue to expand, resulting in further formation and deposition of urate crystals. This will occur regardless of whether or not the crystal-induced inflammation is prevented.
  • Nonpharmacologic Measures Gout is associated with a number of risk factors that should be minimized with weight-control measures and dietary changes to create the best environment possible for the pharmacologic management of the disease. Gout-specific risk factors, such as SUA levels, the clinical phase of the disease, and general risk factors, including a patient’s lifestyle, overall health, and use of medications guide the individual aspects of gout management in each patient (Table 5). 37 Significant challenges to the effective management of patients with gout include patient nonadherence to necessary lifestyle changes and to long-term use of prescribed medications, such as ULT. Therefore, patient education explaining key issues of gout therapy should begin after an initial gout attack. Research has shown that adherence to gout therapy is low. 38-40 Patient education will be essential to improved adherence.
  • Rationale Significant challenges to the effective management of patients with gout include patient nonadherence to necessary lifestyle changes and to long-term use of prescribed medications, such as ULT. Therefore, patient education explaining key issues of gout therapy should begin after an initial gout attack. Research has shown that adherence to gout therapy is low. 38-40 Patient education will be essential to improved adherence. www.gouteducation.org
  • Rationale The strong positive correlations between SUA/gout and hypertension, 41-45 CVD, 46-49 stroke, 48, 50 cardiovascular mortality, 31, 48, 51-56 type 2 diabetes mellitus, 57-60 metabolic syndrome, 47, 61-63 and kidney disease 64, 65 have been established with numerous large cohort study results (Tables 3, 4). The EULAR management recommendations suggest addressing the comorbidities that are commonly seen to promote global patient care and gout management. 11 However, this can be particularly challenging because many of the typical comorbidities seen in the context of gout result in contraindications to the very medications required for the treatment of the disease (Table 6).
  • Rationale Quick initiation (within 12–24 hours after onset of an acute attack) of anti-inflammatory therapy is essential for achieving optimal treatment results. A 2006 Cochrane systematic review demonstrated the efficacy of colchicine in the treatment of acute gout. 66 Nonsteroidal anti-inflammatory drugs that are currently approved for the management of acute gout are indomethacin, sulindac, and naproxen. 21 Colchicine must be used with caution in patients taking calcineurin inhibitors. Due to possibly serious toxicity in these patients, it has been recommended that colchicine not be prescribed for older adults with creatinine clearances of < 30 mL/min. 11 Nonsteroidal anti-inflammatory drugs must be used with caution in patients with hypertension, CVD, renal insufficiency, peptic ulcer disease, and other comorbidities and are contraindicated in renal transplant patients. Glucocorticoids may the best choice for these patients. A systematic review found 3 studies exploring the use of systemic corticosteroids in 148 patients, including 74 patients with acute gout. 67 (Tables 7, 8). When prescribing an NSAID or corticosteroids, it is essential to consider existing comorbidities.  
  • Rationale Colchicine was approved in 2009 by the FDA for the prophylaxis and the treatment of patients with acute gout attack. A multicenter RCT with 185 patients experiencing acute gout attacks was conducted to compare colchicine efficacy at the traditional high dose (1.2 mg followed by 0.6 mg every hour for 6 hours, resulting in a total dose of 4.8 mg) with a low-dose regimen consisting of 1.2 mg followed by 0.6 mg in 1 hour (resulting in a total colchicine dose of 1.8 mg). 68 Significantly ( P = 0.034 for the high dose, and P = 0.005 for the low dose) more patients responded to colchicine than to placebo. 68 The high- and low-dose regimens were of equal efficacy. The low-dose colchicine regimen was associated with a lower rate (36.5%) of AEs compared with the traditional high-dose regimen (76.9%) and did not significantly differ from that of patients in the placebo group (27.1%). 68 The intensity of AEs tended to be mild-to-moderate in the low-dose group and severe in the high-dose group. Based on this study and expert experience, only the low-dose colchicine regimen is recommended for treating patients experiencing acute gout attacks.   The colchicine dose must be adjusted in patients with renal insufficiency, and colchicine is contraindicated in patients taking P-glycoprotein or strong CYP3A4 inhibitors (clarithromycin, erythromycin, cyclosporine, ketoconazole, fluconazole, verapamil, natural grapefruit juice, and St. John’s wort. 21, 69, 70 Concomitant use of statins may increase the risk of myopathy. 69, 71 Recent case reports describe serious interaction with colchicine and atorvastatin, 72, 73 clarithromycin, 74-76 disulfiram, 77 pravastatin, 78 and simvastatin. 79 Severe toxicities include blood dyscrasias, neuromuscular disorders, and fatal drug overdoses. 21 Colchicine poisoning should be suspected in patients with the typical toxidrome (gastroenteritis, hypotension, lactic acidosis, and prerenal azotemia). Untreated colchicine poisoning is associated with a high rate of fatality. Timely recognition is associated with the likelihood of complete recovery. 69  
  • Patients with acute gout (N=184) Inclusion criteria included patients with gout diagnosis by ACR criteria and ≥ 2 gouty attacks in the 12 months prior to therapy. Exclusion criteria included the chronic use of NSAIDs or analgesics, Creatinine clearance <60 mL/min, > 2 gouty attacks per month, or >12 attacks in 6 mo prior to study During a pre-flare phase patients were screened, randomized, and given sealed study drug Patients who flared were to call Flare Call Center (open 24 hours a day) and were instructed to take study medication if: Pain ≥4 (0-10 scale) Presence of all 4 cardinal inflammatory signs (redness, swelling, tenderness, and warmth) Flare started no later than 12 hours prior No prohibited medications were started since randomization No significant change in medical history since randomization Patients seen by investigator ASAP and followed until flare resolved
  • Both colchicine regimens were significantly more effective than placebo, with 17 responders (32.7%) in the high dose group, 28 responders (37.8%) in the low-dose group, and 9 responders (15.5%) in the placebo group ( P 0.034 and P 0.005, respectively, versus placebo). Most rescue medications used in this trial were NSAIDs, with indomethacin predominating. Rescue medication was taken within the first 24 hours by 23 patients (31.1%) in the low-dose colchicine group, 18 patients (34.6%) in the high-dose colchicine group, and 29 patients (50.0%) in the placebo group. These patients were considered non-responders. Compared with patients receiving placebo, significantly fewer patients in the low-dose colchicine group (odds ratio [OR] 0.45 [95% CI 0.22–0.92], P 0.027) took rescue medication prior to hour 24. Fewer patients in the high-dose colchicine group than in the placebo group (OR 0.53 [95% CI 0.25–1.14]) took rescue medication prior to hour 24, although the difference did not reach statistical significance ( P 0.103).
  •   A total of 147 treatment-emergent adverse events (TEAEs) were reported: 85 TEAEs by 76.9% (40/52) of patients in the high-dose colchicine group, 34 TEAEs by 36.5% (27/74) of patients in the Low-dose colchicine group, and 27 TEAEs by 27.1% (16/59) of patients in the placebo group. There were approximately twice as many patients randomized to the high-dose colchicine group with TEAEs as compared to either the Low-dose colchicine group or placebo. The incidences in the Low-dose colchicine group and placebo were similar. Most events were mild to moderate in intensity, with all but one of the severe events occurring in the high-dose colchicine group. Serious adverse events (SAEs) ws determined by patient self-assessment. There were no treatment-emergent SAEs or discontinuations due to adverse events. Diarrhea, nausea, and vomiting occurred more frequently in patients randomized to the high-dose colchicine group compared to the other two treatment groups. Gastrointestinal adverse events were the most common TEAEs in all treatment groups. There appeared to be a dose-response relationship for diarrhea and vomiting which only occurred amongst patients randomized to the high-dose colchicine group. The only other adverse events that occurred in 2 or more patients randomized to colchicine (and more common than those patients randomized to placebo) were fatigue, gout, and pharyngolaryngeal pain.
  • Rationale Although intra-articular aspiration may be of benefit during acute attacks, no research is reported in the literature that supports this practice. Intra-articular injection of a long-acting steroid has demonstrated efficacy in relieving the pain of an acute attack, but there is no recent published evidence (Table 7). 11
  • Rationale According to prescribing information, ULT is indicated for the treatment of patients with signs and symptoms of gout, such as acute gout attacks, tophi, joint destruction, and UA lithiasis and/or nephropathy. 80 Urate-lowering therapy is also indicated for the chronic management of hyperuricemia in patients with gout. 81 The appropriate point to begin therapy for any individual remains a decision to be made by PCPs and their patients considering individual needs and preferences. Urate-lowering therapy is associated with the possibility of significant side effects and is therefore never indicated for patients with asymptomatic hyperuricemia. 80, 81 In addition, it should never be started or discontinued during an acute gout attack.
  • Rationale Serum uric acid levels of < 6.0 mg/dL are necessary to clear urate and MSU from affected tissues. Several large studies have shown the benefit of this target SUA level. 82-85 Serum uric acid levels of ≥ 6.0 mg/dL were correlated with increased likelihood of experiencing an acute gout attack when compared with the risk associated with SUA levels below that cutoff. 82, 84 The correlation of lower SUA levels and successful treatment of patients with gout led to the concept of “treating to target,” which means that ULT is prescribed as necessary to achieve the beneficial target SUA level of 6 mg/dL, rather than treating to a specific urate-lowering drug dose calibrated to renal function. 86, 87
  •   Rationale The initiation of ULT in a patient with gout may precipitate an acute gout attack (called mobilization flare), which makes prophylactic treatment a necessary and integral part of chronic gout management. 86 Prophylactic therapy should be initiated ≥ 2 weeks prior to initiating ULT. Any sudden increase or decrease in SUA may trigger a gout flare. Mobilization flares are due to the sudden fall of SUA associated with effective ULT. However, when health care professionals or patients do not expect such a flare, they may attribute it to the worsening of gout rather than the first sign of successful therapy. In addition, UA-lowering therapy, once initiated, should be titrated to achieve a target SUA. Furthermore, discontinuing ULT due to a mobilization flare will further destabilize the patient’s condition. It is essential to anticipate a mobilization flare after initiating ULT and to prepare patients to manage them. 21 Based on RCTs, EULAR investigators recommended the use of low-dose colchicine (0.5–1.0 mg/day) for the prophylaxis against mobilization flares. Nonsteroidal anti-inflammatory drugs were recommended based on non-RCTS. 11 In 2009, colchicine gained FDA approval for use in the prophylaxis of mobilization flares. The dosing schedule is 0.6 mg once or twice per day, with a maximum daily dose of 1.2 mg. 71 Reduced dosing is recommended for patients with renal impairment. Colchicine is the only agent FDA approved for prophylaxis. 83, 96, 103 ACR 2011 Update: Wason et al 103 evaluated the pharmacokinetics (PK) of colchicine in subjects aged 60 years to determine if older subjects require dose adjustments when prescribed colchicine. Thirty-eight subjects (aged 18–30 [n = 20], and ≥ 60 [n = 18] years) received a single oral 0.6-mg dose of colchicine after a 10-hour fast. Following administration of a single 0.6-mg dose of colchicine, there were no significant differences in PK parameters between young and older adults, including those with mild decreases in renal function estimated by creatinine clearance, suggesting there is no need to modify the dose of colchicine based on age alone. 104 Wason et al 104 also obtained single-dose pharmacokinetic (PK) data in healthy subjects and subjects with varying degrees of renal impairment to allow predictions of colchicine steady-state concentrations following currently recommended dose of colchicine for gout flare prophylaxis (0.6 mg twice daily). Based on these data, for the prophylaxis of gout flares, no dosing adjustments are needed for patients with normal renal function or mild impairment (creatinine clearance > 50 mL/min). For patients with moderate and severe renal failure (creatinine clearance < 50 mL/min), it is recommended that the colchicine dose be reduced 50% (ie, for those patients requiring 0.6 mg twice daily, the dose should be decreased to 0.6 mg once a day, and for those requiring 0.6 mg once a day, the dose should be decreased to 0.3 mg/day).  
  • Rationale The only uricosuric agent available in the United States is probenecid, which impedes UA reabsorption in the distal nephron, a process mediated by the proteins urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9). 101 Probenecid may not be effective in patients with chronic renal insufficiency, particularly in those with glomerular filtration rates of ≤ 30 mL/min. 102 Probenecid is contraindicated in patients with known blood dyscrasias or renal lithiasis. 102 Probenecid therapy is typically started at a dose of 250 mg per day (one half tablet) twice per day for 1 week, followed by 500 mg (1 tablet) twice per day thereafter. In patients with renal impairment, doses may be increased every 4 weeks as tolerated to doses, usually not exceeding 2000 mg, as needed to achieve and maintain SUA levels of < 6.0 mg/dL. When beginning probenecid therapy, patients need to be instructed to increase their fluid intake and use a product to alkalinize their urine. 102
  • Rationale Allopurinol gained FDA approval in 1964 as the first xanthine oxidase inhibitor; febuxostat entered the US market in 2009. Based on evidence from RCTs, the EULAR committee concluded that allopurinol was a cost-effective option for long-term ULT in patients with chronic gout. 11 Large clinical trials have shown that febuxostat is an effective therapy in the management of patients with chronic gout. 88 Gaffo and Saag 88 concluded that there was moderate evidence suggesting that febuxostat treatment could help reduce gout flares and the number and size of tophi, and clear evidence that febuxostat effectively reduces SUA and compares favorably with allopurinol (Table 7). Febuxostat doses do not need to be adjusted in patients with gout and mild-to-moderate renal 89 or hepatic 90 impairment.   Approximately 2% of patients treated with allopurinol demonstrate allopurinol hypersensitivity syndrome. 80 This may affect elderly patients especially, and those with underlying renal impairment or other risk factors. 91 The syndrome is an immune-mediated severe reaction, which may be limited to severe cutaneous reactions such as toxic epidermal necrolysis or Stevens-Johnson syndrome, but also may include eosinophilia, leukocytosis, fever, and hepatitis. 92 Allopurinol hypersensitivity syndrome can lead to death in up to 20% of affected patients. 88 Many but not all of the affected patients recovered after withdrawal of allopurinol and treatment with prednisone.  
  • Rationale In a dose-escalation trial, increasing allopurinol dose from 300 mg to 600 mg per day enabled 78% of patients with gout to achieve SUA levels of 5.5 mg/dL. 93 Thus, doses of > 300 mg per day may be required to achieve optimal therapeutic result. 92, 94 The FDA dosing guide lists 200 to 300 mg per day as typical doses for patients with mild gout, and doses of 400 to 600 mg per day for patients with moderately severe tophaceous disease. 80, 92 ACR 2011 UPDATES Paisansinsup and Schousboe 95 identified 551 patients who had allopurinol prescribed between January 1, 2004 and December 31, 2010, who had serum creatinine measured while on allopurinol, and had complete covariate data. Of the 551 patients, 342 (61.5%) were prescribed doses that exceeded those recommended for their levels of renal function; 65 patients (11.7%) had a minor adverse drug reaction, and none had a major adverse drug reaction to allopurinol. The risk of having adverse drug reactions to allopurinol was not increased in patients exposed to allopurinol higher doses as described in study. These results support the strategy of titrating doses of allopurinol to attain a therapeutic goal of UA < 6 mg/dL to achieve adequate clinical control of gout. 95
  • Rationale Febuxostat efficacy and safety have been compared with those of allopurinol in several phase 3 trials. 96-100 Febuxostat doses of 80,120, and 240 mg were given to patients with renal impairment (serum creatinine level of > 1.5 to < 2.0 mg/dL) and without renal impairment. Allopurinol was given at the dose of 300 mg to patients without renal impairment; doses were reduced to 100 mg for patients with renal impairment. In all trials, more of the participants receiving febuxostat reached the target SUA levels (< 6.0 mg/dL) versus those receiving allopurinol. Thus, febuxostat is an effective alternative to allopurinol, particularly for patients with reduced renal function. 98-100
  • SES: Really should be referenced.
  • The CONFIRMS study evaluated efficacy in 1483 patients with renal impairment (ie, baseline estimated ClCr <90 mL/min). In this study among patients with mild to moderate renal impairment, ULORIC 40 mg and 80 mg were superior in achieving the primary efficacy endpoint (sUA <6.0 mg/dL at the final visit) [ULORIC PI 2008 Section 14.1 C] Allopurinol patients (n=145) with estimated ClCr ≥ 30mL/min and ClCr ≤59/min were dosed at 200 mg daily [ULORIC PI 2008 Section 14.1 C] No dose adjustment in ULORIC treated subjects [ULORIC PI 2008 Section 2.2 A] Moderately renally impaired defined as baseline estimated ClCr of 30 mL/min to 59 mL/min [F-GT06-153 2008 5] Mildly renally impaired defined as estimated ClCr of 60 mL/min to 89 mL/min [F-GT06-153 2008 5] ULORIC (febuxostat) [package insert]. Takeda Pharmaceuticals America, Inc.; 2008.
  • Rationale The progression of gout to a deforming, disabling disease is the result of the failure of the patients to respond to ULT, their intolerance to available medications, or the presence of comorbidities that contraindicate treatment with approved agents. 107 Patients with refractory gout may be helped by pegloticase, a pegylated uricase that gained FDA approval for the management of refractory chronic gout in 2010. Pegloticase is given by intravenous infusion at 2-week intervals. 106 It may rapidly resolve tophi and control chronic synovitis in patients with severe gout. The pegloticase package insert includes warnings for anaphylaxis, infusion reactions, gout flares, and congestive heart failure; patients should be monitored closely for all 4 reactions. 108
  • The Management of Gout and Hyperuricemiadbm

    1. 1. Enhanced Subspecialist Deck: Recommendations for the Diagnosis and Management of Gout and Hyperuricemia
    2. 2.  ThisCME activity is intended for practicing physicians, and other health care providers who may treat patients who have Gout and Hyperuricemia. There is no fee for participation in this CME activity. This program is made possible through aneducational grant from Savient Pharmaceuticals, Inc. and URL Pharma, Inc.
    3. 3. AccreditationThis activity has been planned and implemented inaccordance with the Essential Areas and policies of theAccreditation Council for Continuing Medical Education(ACCME) through the joint sponsorship of UHS-PEP ofVirginia Commonwealth University Health System andMiller Professional Group. UHS-PEP is accredited by theACCME to provide continuing medical education forphysicians.
    4. 4. Disclosure of Significant Relationships with Relevant Commercial Interests Neither VCU nor Miller Professional Group has any commercial interests relevant to the content of this activity. The content of this CME activity will not contain discussion of off-label uses. Please consult the product prescribing information for full disclosure of labeled uses.
    5. 5. DISCLOSURES of FACULTY CONFLICTS OF INTEREST These members of the faculty and /or VCU UHS-PEP faculty and staff disclose the following relevant relationships to commercial interests: Thomas Adamson, III, MD is a member of the Speaker’s Bureau for Warner Chilcott and Pfizer; and participated in a one-time speaking even for Interpace BioPharma. Herb Baraf, MD is a member of the Speaker’s Bureau for Savient and Takeda and is an Investigator for Savient, Takeda, Ardea, Metabollix and Regeneron; and is a Consultant for Savient. Howard Blumstein, MD is a member of the Speaker’s Bureau for Abbott, UCB, Warner Chilcott and Genentech. Alan Brown, MD is a member of the Speaker’s Bureau for Takeda. Paul Doghramji, MD is a member of the Speaker’s Bureau and a Consultant for URL. N. Lawrence Edwards, MD is a Consultant for Takeda, Savient, Novartis, Ardea and Regeneron. Alan Epstein, MD is a member of the Speaker’s Bureau for Takeda and HGS. Madelaine Feldman, MD has no relationships to report. Germano Guadagnoli, MD is a member of the Speaker’s Bureau for Pfizer, Amgen, Takeda, URL and Savient. Max Hamburger, MD is a member of the Speaker’s Bureau for Amgen, BMS, Genentech and UCB; is a Consultant for Amgen and BMS; and has obtained Med Ed grants on behalf of 3 rd parties from Abbott, Amgen, BMS, Centocor, Genentech and UCB. Miller Professional Group (MPG), a medical education and communications company, owned by a family member; has been the recipient of CME grants from Abbott, Amgen, BMS, Centocor, Crescendo, Genentech, Biogen Idec, Roche, and URL. Joseph Huffstutter, MD is a member of the Speaker’s Bureau for Takeda, HGSI and Savient. Richard Jimenez, MD is a member of the Speaker’s Bureau for Takeda. Joseph Lieberman III, MD has no relationships to report. Kenneth Miller, MD has no relationships to report. Eric Mizuno, MD has no relationships to report.
    6. 6. DISCLOSURES of FACULTY CONFLICTS OF INTEREST Alan Morton, DO is a member of the Speaker’s Bureau for Pfizer, Amgen, UCB, URL, BMS, Takeda, Genentech, Abbott, Warner Lambert and Savient; and is a Consultant for Pfizer, Amgen, URL, BMS, Savient and Novartis. David Mount, MD has no relationships to report. Richard Pope, PA-C is a member of the Speaker’s Bureau for Takeda and URL. Gregory Schimizzi, MD has no relationships to report. Paul Schulman, MD has no relationships to report. Katy Setoodeh, MD is a member of the Speaker’s Bureau for Amgen and HGS. Evan Siegel, MD is a member of the Speaker’s Bureau for Amgen and Abbott. John Skosey, MD is a Stockholder in Amgen and TheraTest Laboratories and is a Director of TheraTest Laboratories. Michael Weitz, MD is a member of the Speaker’s Bureau for Savient.All conflicts of interest due to reported relationships above have been resolved according to VCU’s Policy on Conflict of Interest and the Standards for Commercial Support of the ACCME.All presenting faculty affirm that they will employ the best available evidence from all sources to support any clinical recommendations made in their presentations.
    7. 7. After Participating in the Educational Activity, Attendees should be able to:• Describe the patho-physiology of hyperuricemia and gout• Describe recent advances in the understanding of the epidemiology of gout and hyperuricemia, and the relationship between hyperuricemia, risk factors and co-morbidities• Apply recommended guidelines for correctly diagnosing gout and hyperuricemia• Manage gout and hyperuricemia in accordance with recommended guidelines and incorporate data on efficacy and safety – Manage the acute attack – Implement prophylaxis and urate lowering therapy – Management of chronic hyperuricemia – Manage the refractory or challenging patient
    8. 8. Updating the EULAR 2006 Guidelines- Methods• A multidisciplinary team with members specializing in rheumatology, nephrology, cardiology, primary care, and allied health reviewed the diagnostic and management recommendations published by EULAR in 2006. 11, 12• The EULAR evidence hierarchy for diagnosis and management of gout was based primarily on study design.• The revised recommendations are based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach 13 as an evidence- based strategy for rating quality of evidence and grading the strength of recommendations formulated for use in clinical practice.
    9. 9. Strength of Recommendation• Strength-of-recommendation scores express expert experience and consensus.• Each team member rated the strength of each agreed-on recommendation on 2 scales: • a categorical scale (as fully, strongly, moderately, weakly, or not recommended) • a visual analog scale (VAS) ranging from 60 (weak recommendation) to 100 (strong recommendation).• Based on categorical data, the percentage of strongly and fully recommended scores was calculated for each recommendation.• Analysis of continuous data resulted in a mean VAS score with 95% confidence intervals for each recommendation.
    10. 10. The numbered recommendations in this presentation were taken with permission from:2011 Recommendations for the Diagnosis and Management of Gout and Hyperuricemia Postgraduate Medicine Volume 123 Issue 6 Supplement 1 Hamburger et al
    11. 11. Sir Thomas Sydenham: Description of Acute Gout: 1848The victim goes to bed and sleeps in good health. About twoo’clock in the morning he is awakened by a severe pain in the great toe; morerarely in the heel, ankle or instep. This pain is like that of a dislocation. ...Then it is a violent stretching and tearing of the ligaments. … now it is agnawing pain and now a pressure and tightening.… He cannot bear the weight of bedclothes nor the jar of a person walking inthe room. The night is passed in torture, and perpetual change of posture; thetossing about of the body being as incessantas the pain of the tortured joint. Sydenham T. The Works of Thomas Sydenham, MD Translated by RG Latham. Vol II London: Sydenham Society; 1848:1224.
    12. 12. A Renaissance for Uric Acid? Increasing incidence of gout Mapping/characterization of genes associated with hereditary hyperuricemic nephropathy, uric acid stones, hyperuricemia, and gout Evolving associations with hyperuricemia: – Kidney stones – Insulin resistance syndrome / metabolic syndrome – Hypertension, renal disease – Prognosis of vascular disease, heart failure, stroke – Protection from Parkinson’s, multiple sclerosis, AD
    13. 13. Gout• Gout: Acute arthritis, typically very severe• Most common form of inflammatory joint disease.• Disease Process • Urate: End product of purine metabolism • Blood level of urate > physiologic limit of solubility (6.8mg/dL): Tissue crystallization • Sodium in tissues: Conversion of urate to monosodium urate (MSU) • Inflammatory response to the presence of MSU crystals: Acute Gout
    14. 14. Gout - a Progressive and Disabling Disease One Chronic Disease - 4 Stages Asymptomatic asymptomatic Gout2 hyperuricemia hyperuricemia1 Gout sUA ≥ 7 mg/dl Acute flares Intercritical Persistent or Chronic Period Progressive gout Arthropathy and Tophi ~32million in US ~8 million ~5 million ~300-800k Progression to Intermittent Increasing Chronic gout: 20 – 30% inflammatory frequency and synovitis arthritis duration of attacks Visible tophi Necessary but Polyarticular not sufficient First MTP Joint presentation for gout Disease Progression1. Zhu Y, et al. Arth. & Rheumatism. 2010 ;62(10 suppl.):S5662. Zhu Y, et al. Arth. & Rheumatism. 2010 ;62(10 suppl.):S901-2
    15. 15. Level Stages of GoutPain Years Asymptomatic Acute Gout with Advanced Gout Hyperuricemia Intercritical
    16. 16. Classification of Patients with Gout and Hyperuricemia • >90% are Under-excretors • Enhanced net proximal tubular reabsorption of urate • Renal insufficiency • Medications impairing renal urate clearance • <10% are Over-producers: de novo increased purine biosynthetic rateScott JT, Pollard AC Ann Rheum Dis 1970:29:397-400
    17. 17. Pathogenesis of HyperuricemiaChoi, H. K. et. al. Ann Intern Med 2005;143:499-516 (reprinted with permission)
    18. 18. Purine Total Body Uric Purine Sources Acid Pool EliminationEndogenouspurinesynthesis Miscible urate pool Renal 500 mg excretion 600 mgTissuenucleic acids 1200 mg SUA x Blood Volume 200 mg Intestinal Dietary 100 mg uricolysis purines Sources and distribution of uric acid
    19. 19. Purine Total Body Uric Purine Sources Acid Pool EliminationEndogenouspurinesynthesis Miscible urate pool Miscible urate pool Renal 300 500 mg excretion 600 mgTissuenucleic acids 1200 mg 2000 mg Intestinal Dietary 200 mg 300 mg 100 mg uricolysis purines Insoluble urate pool 1 to >100 grams
    20. 20. Consequences of Expanded Urate Pools Asymptomatic Miscible urate pool Miscible urate pool hyperuricemia Hypertension, 1200 mg ? kidney & heart 2000 mg disease Renal Manifestations Insoluble urate pool Gouty arthritis 1 to >40 grams Urate tophi
    21. 21. URIC ACID AND THE KIDNEY
    22. 22. Overview Pathways for proximal tubular urate absorption and secretion; relevance to hyperuricemia Genetics of renal urate transport – Renal hypouricemia – Hyperuricemia and gout – new genetic factors Hyperuricemia and renal disease – Familial hyperuricemic nephropathy – Nephrolithiasis and gout – Progression of CKD – Management issues for gout in CKD
    23. 23. Pathophysiology of Renal Urate Transport Renal under-excretion is the dominant mechanism for hyperuricemia in gout. Genetic syndromes of renal hyper/hypouricemia. – Renal hypouricemia – deficiency in the absorptive transporters URAT1 and GLUT9 – Familial hyperuricemic nephropathy – mutations in uromodulin – Genetic variation in urate transporters and associated proteins are the dominant contributor to genetic risk of hyperuricemia and gout Strong correlation between proximal tubular reabsorption of Na+-Cl- and urate → hyperuricemia in volume depletion, hypouricemia in SIADH. Indirect evidence for regulation of renal urate reabsorption by: – Insulin – Angiotensin-II – PTH
    24. 24. Renal Processes
    25. 25. Renal Transport of UrateProximal Tubule Peritubular Renal Proximal Nephron Interstitium Tubular Epithelium Lumen MRP4 Urate Urate OAT1 UAT OAT3 Urate Anions ABCG2 Urate NTP1 SECRETION Na+ OAT4 Anions REABSORPTION OAT10 Urate Anions URAT1 L-GLUT9 Urate Urate S-GLUT9 Urate To Blood To Urine Edwards NL, ACP Medicine, 2012
    26. 26. Proximal Urate Absorption
    27. 27. Proximal Urate SECRETION
    28. 28. Inhibition AND Activation of Urate Exchange by the Same Anions
    29. 29. TAKE HOME MESSAGES: Proximal Tubular Apical Absorption URAT1, OAT4, and OAT10 function as apical, absorptive urate:anion exchangers The Na+-anion transporters SLC5A8 and SLC5A12 activate urate absorption via “trans-stimulation” of apical urate exchange. Many of the “trans-activating” anions can also “cis-inhibit”. The four-component model is imperfect – Anti-uricosurics ↑ absorption, versus ↓ secretion
    30. 30. Genome-Wide Association Studies Have RevealedMultiple Genetic Contributors to Variation in Urate  SLC2A9 – encodes GLUT9, involved in urate absorption  ABCG2 – apical urate secretory transporter: loss of function → hyperuricemia  SLC17A1/A3 – apical urate secretory transporters: loss of function → hyperuricemia  SLC16A9 – MCT9 – solute transporter, mechanism of hyperuricemia unknown  GCKR – regulator of glucokinase – contributes to risk of metabolic syndrome  SLC22A11 – encodes OAT4, absorptive urate transporter  SLC22A12 – encodes URAT1, absorptive urate transporter  PDZK1 – scaffolding protein for URAT1, OAT4, SLC5A8/A12, etc. Most of this genetic variation affects net renal urate excretion
    31. 31. Gout and Chronic Kidney Disease CKD complicates the management of acute gout and urate-lowering therapy. Gout is much less common in ESRD/dialysis, but can resume or emerge after transplant. Lowering urate in gout patients can ↑ GFR, ? partially secondary to ↓ in NSAID use. Evolving interest in the role of urate in CKD and hypertension Inhibition of xanthine oxidase (XO) also exerts urate-independent effects on kidney and vasculature.
    32. 32. Gout and Transplantation 2-13% of renal transplants may develop new-onset gout; ~1/3 asymptomatic hyperuricemia. New-onset gout is associated with graft loss. Treatment issues – Post transplant gout tends to be highly tophaceous. – Risk of gout with CsA >>> than with tacrolimus. – Allopurinol ↑↑ effect of azathioprine, but has less effect on MMF. • Xanthine Oxidase inhibitors are contraindicated with allopurinol – CsA ↑ risk of myoneurotoxicity from colchicine.
    33. 33. Diagnostic Recommendations
    34. 34. Diagnostic Recommendation: Assess for Risk FactorsRisk factors for gout should be assessed, including features ofthe metabolic syndrome (obesity, hyperglycemia,hyperlipidemia, and hypertension), chronic kidney disease(CKD), medications, family history, and lifestyle. (#10) • Strength of recommendation: 97 (95% CI, 96–98) • Highly or strongly recommend: 100% • Quality of evidence: Moderate, grade 2 recommendation
    35. 35. Risk Factors & Co-Morbid Conditions Risk Factors Co-Morbid Conditions Modifiable1-6 Non-modifiable Metabolic Syndrome7(63%) • Obesity • Age • Hypertension • Serum urate • Gender • Diabetes Mellitus • High-fructose corn syrup – Male • Obesity • Purine-rich diets – Postmenopausal Cardiovascular Disease – Meats (organ meats), females • Myocardial Infarction Seafood • Peripheral artery disease • Alcohol consumption • Congestive heart failure • Medications Impaired Renal Function8-11 – Diuretics, Low-dose aspirin, (10 -50%) Cyclosporine, Ethambutol1. Bieber JD, Terkeltaub RA. Arthritis & Rheumatism. 2004;50(8):2400-2414 7. Choi et al. Arthritis Rheum. 2007;57:1092. Wallace KL et al. J Rheumatol. 2004;31:1582-1587. 8. Keenan RT, et al. Am. J. Med. 2010:Article in Press.3. Weaver AL. Cleveland Clinic Journal of Medicine. 2008;75(Sup 5):S9-S12. 9. KRYSTEXXA™ (pegloticase) for intravenous infusion, Briefing4. Choi HK et al. Arch Intern Med. 2005;165:742-748. Document for Arthritis Advisory Committee.5. Williams. Am J Clin Nutr. 2008;87:1480. 10. Becker MA, et al. New Engl. J. Med. 2005;353(23):2450-2461.6. Smith RG. US Pharm. 2009;34(5):40-47. 11. Zhu Y, et al. Arth. & Rheumatism. 2010 ;62(10 suppl.):S365
    36. 36. Risk Factors for Development of Gout: Diet • Risk from caffeine : 5+ caffeinated beverages/day ↓ risk of gout • Risk from alcohol intake: Beer>liquor>wine • High meat consumption: ↑ risk of gout • High seafood consumption: ↑ risk of gout • High dairy consumption: ↓ risk of gout • High consumption of purine-rich vegetables or total protein: no associationChoi HK, Willett W, Curhan G. Arthritis Rheum 2007;56(6):2049-2055Choi HK, Atkinson K, Karlson EW, Willet W Curhan G. Lancet 2004:363:1277-1281.Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. NEJM 2004;350:1093-1101..
    37. 37. Dietary Purine Intake and Serum Uric Acid Levels • Severe reduction in dietary purine intake can accomplish no more than a 1 mg/dl decrease in serum uric acid. • Exception: Reduction of dietary fructose • Only carbohydrate that influences purine metabolism • Implicated in insulin resistance, metabolic syndrome and obesity • An apple a day? Ingestion of 5 apples=35% increase in serum uric acid within 6 hoursChoi HK, Atkinson K, Karlson WE, Willett W, Curhan G. NEJM 2004;350:1093-1101Choi HK, Atkinson, K, Karlson WE, Willett W, Curhan G. Lancet 2004;353: 1277-1281Lotito SB, Frei B Free Radic Biol Med. 2004;37:251-8
    38. 38. Medications Affecting Urate Excretion • Thiazides and loop diuretics • Low dose aspirin • Cyclosporin A • Anti-tuberculous medications • pyrazinamide and ethambutol • Niacin • PTH therapyGonzalez EB, Miller ST, Agudelo CA. Drugs Aging 1994;4:128-134.
    39. 39. Secondary Causes of Gout and Hyperuricemia Due to Uric Acid Overproduction • Myeloproliferative syndromes • Lymphoproliferative disorders • Malignancy • Hemolytic anemias • Exfoliative psoriasis • Tumor lysis syndrome • Hyperparathyroidism • Genetic disorders • Deficient hypoxanthine-guanine phosphoribosyl transferase • Glycogen storage diseases
    40. 40. Hyperuricemia: Cardiovascular Risk Factor? • Chronic inflammation associated with chronic gout • Stronger risk factor in those already at high risk for cardiovascular disease Bickel C, et al. Am J Cardiol 2002; 29:12-17.Culleton BF, et al. Ann Int Med 1999;131:7-13. Niskanen LK, et al. Arch Int Med 2004;164:1546-1551.Fang J, Alderman M. JAMA 2000;283:2404-2410.
    41. 41. Hyperuricemia and Hypertension• Co-occurrence of hypertension with hyperuricemia• Hyperuricemia predicts development of hypertension, in many but not all studies• ULT of hypertensive hyperuricemia in adolescents → ↓ bp• Animal models – uricase inhibition → ↑ bp/renin• In vitro effects of uric acid on endothelial and VSM cells; intracellular pro-oxidant effect
    42. 42. Acute Gout• Acute arthritis, typically monoarticular and very severe • Inflammatory response to the presence of monosodium urate (MSU) crystals • Urate: end product of purine metabolism• Most common form of inflammatory joint disease in men*• Crystallization occurs when the blood level of urate> physiologic limit of solubility: 6.8mg/dl* Terkeltaub RA. N Eng J Med 2003; 349:1647-1655
    43. 43. Diagnostic Recommendation: Know the Clinical Picture of GoutIn acute monoarticular attacks of the lower extremities,the rapid development of severe pain, swelling, andtenderness that reaches its maximum within 6 to 12 hours,especially with overlying erythema, is highly suggestive ofcrystal inflammation, though not specific for gout. (#1)• Strength of recommendation: 93 (95% CI, 91–94)• Highly or strongly recommend: 96%• Quality of evidence: Moderate, grade 1 recommendation
    44. 44. Diagnostic Recommendation:Normal Serum Uric Acid Levels Don’t Confirm or Exclude Gout While being the most important risk factor for gout, serum uric acid (SUA) levels do not confirm or exclude gout, as many people with hyperuricemia do not develop gout, and SUA levels may be normal during acute attacks. (#3) Elevated IL-6 levels are uricosuric, contributing to a drop in SUA during acute attack • Strength of recommendation: 80 (95% CI, 79–81) • Highly or strongly recommend: 47% • Quality of evidence: Low, Grade 2 recommendation
    45. 45. Common Sites of Acute Gout Attacks Olecranon Bursa ElbowGout flares or attacks can occurin bursae, tendons, Wrist and joints Fingers 1st MTP Knee (eventually affected in ~ 90% of individuals Ankle Subtalar with gout) Midfoot
    46. 46. Precipitating Factors• Trauma, including surgery• Diuretics-other medications• Dehydration or volume depletion for any reason• Sudden rise or fall in SUA• Dietary indiscretion• Low temperature of affected limb• Alcohol: Beer > Liquor > Wine
    47. 47. Special Considerations for Diagnosing Gout• Look for gout, even if • Serum uric acid levels are normal • The symptoms present in a woman • The attack is polyarticular and chronic • The involved joint is atypical• Don’t diagnose based on response to treatment: • Other types of acute arthritis may also respond to colchicine
    48. 48. Differential Diagnosis of Gout• Septic Joint• Trauma, Hemarthrosis• Pseudogout (CPPD/chondrocalcinosis) Rheumatoid or psoriatic arthritis Acute bursitis, tendonitis
    49. 49. Diagnostic Recommendation: Gout and Infection May CoexistGout and sepsis may coexist; therefore, when septic arthritis issuspected, Gram staining and culture of synovial fluid shouldstill be performed, even if MSU crystals are identified. (#6) • Strength of recommendation: 92 (95% CI, 91–93) • Highly or strongly recommend: 95% • Quality of evidence: Very low, grade 1 recommendation
    50. 50. Diagnostic Recommendation: A Clinical Diagnosis Alone May Suffice• Although only the demonstration of MSU crystals in synovial fluid or tophus aspirates constitutes a definite diagnosis of gout……• a clinical diagnosis alone is a reasonable alternative in patients with the typical presentation of gout. (#2) • Strength of recommendation: 90 (95% CI, 89–91) • Highly or strongly recommend: 90% • Quality of evidence: Moderate, grade 1 recommendation
    51. 51. Diagnostic Recommendation:Crystal Identification May Establish Diagnosis When the diagnosis is in doubt, identification of MSU crystals from asymptomatic joints may allow definite diagnosis during intercritical periods.(#5) • Strength of recommendation: 85 (95% CI, 84–86) • Highly or strongly recommend: 65% • Quality of evidence: Very low, grade 2 recommendation
    52. 52. Mono-sodium Urate Crystals during Intercritical Periods • MSU Crystals persist in joints during intercritical periods1,3 • Low-grade inflammation often persists during intercritical periods2,4 • Persistent MSU crystals and low-grade inflammation can lead to progressive disease1-41. Pascual E, Batlle-Gualda E, Martínez A, Rosas J, Vela P. Synovial fluid analysis for diagnosis of intercritical gout. Ann Intern Med. 1999;131:756-759. 2Pascual E. Persistence of monosodium urate crystals and low-grade inflammation in the synovial fluid of patients with untreated gout. ArthritisRheum. 1991;34:141-145. Pascual E, Pedraz T. Gout. Curr Opin Rheumatol. 2004;16:282-286. Schumacher HR. The pathogenesis of gout. Clev ClinJ Med. 2008;75(suppl 5):S2-S4.
    53. 53. Analysis of Synovial Fluid 2• Synovial fluid (SF) crystal analysis requires a polarized light microscope* • All monosodium urate crystals (MSU) birefringent • 1/5 calcium pyrophosphate dihydrate (CPPD) crystals birefringent • Always culture SF • Infected joints may also contain MSU and CPPD crystals* • Search for MSU and CPPD crystals in all undiagnosed joint effusions* * Pascual et al. Clin Rheum. 2004;50:2400-2414.
    54. 54. Diagnostic Recommendation:Look For Crystals in Available Synovial FluidIn available synovial fluid samples obtained fromundiagnosed inflamed joints, a routine search for MSUcrystals is recommended. (#4)• Strength of recommendation: 82 (95% CI, 81–82)• Highly or strongly recommend: 53%• Quality of evidence: Very low, grade 2 recommendation
    55. 55. Diagnostic Recommendation:When to Measure Renal Uric Acid Excretion: Rarely Assessment of renal uric acid (UA) excretion is rarely necessary in patients with gout. It should, however, be considered in those with early onset gout (aged < 25 years) or a family history of early onset gout. (#7) • Strength of recommendation: 87 (95% CI, 86–88) • Highly or strongly recommend: 80% • Quality of evidence: Very low, grade 2 recommendation
    56. 56. Uric Acid Nephrolithiasis 5-10% of stones in the U.S. are uric acid stones; varies from 4% (Sweden) to 40% (Israel). Associated with obesity, metabolic syndrome, and type II DM; the “gouty diathesis”. Yu and Gutman reported a 15-22% prevalence of stones in gout, versus 12% lifetime risk in the general population. Prevalence of reported gout with stones is 13.9%, but including subclinical stone disease prevalence may be as high as 39%.
    57. 57. Risk Factors for Uric Acid Stones Low urinary pH – Idiopathic uric acid nephrolithiasis – Gout – Obesity, type II DM Volume depletion Hyperuricemic hyperuricosuria – Congenital enzyme defects – Myeloproliferative disorders Normal/hypouricemic hyperuricosuria – Uricosuric medications – Renal hypouricemia Liebman et al, Curr Rheum Reports, 2007
    58. 58. Diagnostic Recommendation:Do Lithogenic Workup in Patients with Stones Patients with gout have a high incidence of renal stones(>20%) and those with stones should have a lithogenic workup.(#8) • Strength of recommendation: 88 (95% CI, 87–89) • Highly or strongly recommend: 80% • Quality of evidence: Very low, grade 2 recommendation
    59. 59. Uric Acid Stones - Evaluation Standard chemistries, including Ca/Phosphate/PTH Stone analysis 24 hour urine evaluation wrt volume, pH, other lithogenic substrates (calcium, etc.) Noncontrast helical CT re stone burden, imaging characteristics, etc.
    60. 60. Uric Acid Stones – Management Increase fluid intake to > 2 liters/day Urinary alkalinization – typically with K-citrate Moderation of animal protein intake Xanthine oxidase inhibitors for hyperuricosurics Avoid uricosuric agents
    61. 61. Diagnostic Recommendation:Little Role for Radiographs in Diagnosis of Acute Gout Radiographs may be useful for differential diagnosis and may show typical features in gout. They are not useful in confirming the diagnosis of early or acute gout and should only be performed if a fracture is suspected.(#9) • Strength of recommendation: 91 (95% CI, 90–92) • Highly or strongly recommend: 89% • Quality of evidence: Very low, grade 2 recommendation
    62. 62. Advanced Gout: Clinically Apparent Tophi 1 2 1 31. Photos courtesy of Brian Mandell, MD, PhD, Cleveland Clinic. 3. ACR Clinical Slide Collection on the Rheumatic Diseases, 1998.2. Photo courtesy of N. Lawrence Edwards, MD, University of Florida.
    63. 63. Advanced Gout: Radiographic Changes • The characteristic gouty erosion is both destructive and hypertrophic, leading to “overhanging edges.” • The joint space is often preserved until very late in the disease process.Photo courtesy ACR Clinical Slide Collection on the Rheumatic Diseases, 1998.
    64. 64. Ultrasound in the Diagnosis of GoutA NormalB Gouty Arthritis “Double Contour Sign”
    65. 65. ManagementRecommendations
    66. 66. Gout Treatment Goals• Terminate the acute attack as rapidly as possible • Colchicine, NSAIDs, or Corticosteroids (Oral, Intra-articular)• Protect against further attacks • Reduce the chance of crystal-induced inflammation • Decrease the chances of joint destruction and other long-term complications• Treat hyperuricemia and prevent disease progression • Long-term correction of the metabolic problem • Lower serum uric acid sufficiently to deplete the total body urate pool. Target: Serum uric acid < 6.0 mg/dl.
    67. 67. Approach to Gout ManagementControlling Pain and Inflammation Reducing Urate BurdenAcute Flare AntiinflammatoryPain ProphylaxisNSAIDsColchicineGlucocorticoidsIL-1 inhibitors Optimal Pharmacologic Gout Management Edwards NL, Crystal-Induced Joint Disease in ACPMedicine Textbook, 2012
    68. 68. Management Recommendation: Optimize Treatment Outcomes Optimal treatment of gout requires both nonpharmacologic andpharmacologic modalities and should be tailored according to: • Specific risk factors (levels of serum urate, previous attacks, radiographic signs) • Clinical phase (acute gout, intercritical gout, or advanced [ie, chronic tophaceous] gout) • General risk factors (age, sex, obesity, diet, alcohol consumption, urate- elevating drugs, drug interactions, renal function, and comorbidities) (#1) • Strength of recommendation: 97 (95% CI, 96–98) • Highly or strongly recommend: 100% • Quality of evidence: Very low, grade 1 recommendation
    69. 69. Management Recommendation: Importance of Patient EducationPatient education pertaining to beneficial lifestyle changes,compliance with long-term therapy, and the prevention offlares early in the course of ULT are core aspects of goutmanagement. (#2) • Strength of recommendation: 94 (95% CI, 93–95) • Highly or strongly recommend: 96% • Quality of evidence: Very low, grade 1 recommendation
    70. 70. Management Recommendation:Address Modifiable Risk Factors and Comorbidities Associated modifiable comorbidities and risk factors such as hyperlipidemia, hypertension, hyperglycemia, obesity, and smoking should be addressed as an important part of the management of patients with gout. (#3) • Strength of recommendation: 96 (95% CI, 95–97) • Highly or strongly recommend: 100% • Quality of evidence: Moderate, grade 1 recommendation
    71. 71. Management Recommendation: Colchicine, NSAIDs, and Corticosteroids Useful for Acute Attacks• In patients with acute gout; oral colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), and glucocorticoids may be used as first-line treatments.• The choice will depend on patient and physician preference, with consideration of comorbidities (especially a history of CKD and gastrointestinal disease).• It may be necessary to continue treatment for an additional 7 to 10 days.(#4) • Strength of recommendation: 97 (95% CI, 96–98) • Highly or strongly recommend: 100% • Quality of evidence: Low, grade 1 recommendation
    72. 72. Other Options for Acute Gouty Inflammation• Other choices • IA, IM or IV glucocorticoids • Off Label: ACTH gel s.c. • Off Label: IL-1 inhibitors • Topical ice Terkeltaub R. AR&T, 2009
    73. 73. IL-1 Inhibitors (not FDA approved) Anakinra Canakinumab Rilonacept
    74. 74. A Pilot Study of IL-1 Inhibition by Anakinra in Acute Gout 10 patient pilot, open-labeled trial of anakinra in patients who had failed other anti-inflammatory therapy for acute gout. “All patients responded rapidly to the drug, with the most rapid onset observed within 24 hours. In all patients, subjective symptoms of gout were greatly relieved by 48 hours after the first injection.” “No side-effects were observed during the study period.”So A, DeSmedt T, Revaz S, Tschopp J. Arthritis Research & Therapy 2007, 9: R28 (doi:10.1186/ar2143)
    75. 75. TLR2/4 MSU Crystals CD14 Synovial Fluid MyD88 NFκB Mediated Cell Activation NALP3 Endothelium/ Pro-IL1ß Gene Transcription Leukocyte Pro-caspace 1 ASC Pro-IL1β IL-1R Caspace 1 IL-1β Endothelial Activation Monocyte Leukocyte MigrationEdwards NL. Crystal-Induced Joint Disease, ACP Medicine Textbook, 2012 Reproduced with permission Edwards ML
    76. 76. Canakinumab (ACZ885) Relieves Pain andControls Inflammation Rapidly in Patients withDifficult-to-Treat Gouty Arthritis.  Purpose: Compare effect of IL-1β inhibition with Cannukinumab (CAN) to triamcinolone acetonide (TA) in the treatment of acute gout flare.  Methods: Patient with gouty flares who have contraindications to NSAIDs a/o colchicine given 1 subcut dose of CAN or 1 IM dose of TA. Primary outcome: pain intensity at 72 hr post dose.  Results: Pain reduction at 72 Cannukinumab 150 Triamcinolone 40 mg hours mg s.c. IM >75% 78% 45% >50% 96% 61% So A, et al. Abstract #145, ACR Annual Meeting, 2010
    77. 77. Conclusion: Cannukinumab vs Triamcinolone Cannukinumab 150 mg sc is superior to IM triamcinolone 40 mg for pain relief in acute gouty flares. Markers of inflammation were suppressed by Cannukinumab but not triamcinolone for 8 weeks after injection.
    78. 78. Rilonacept and Gout Flare Prevention  Conclusions: Phase III trial of IL-1 blockade with Rilonacept demonstrated a marked reduction in acute gout flares during the first 16 weeks of urate-lowering-therapy initiation and escalation. Incidence of AEs similar in PLO and RIL groups with no serious AEs
    79. 79. Management Recommendation: Low Dose Colchicine is Effective and Best Tolerated• For acute gout, low-dose colchicine (ie, 1.2 mg administered as soon as possible, followed by 0.6 mg 1 hour later) is effective and well tolerated.• Colchicine should be continued (QD-BID as tolerated)for an additional 7 to 10 days or until the flare is resolved.• High-dose colchicine is not indicated and should not be prescribed. (#5) • Strength of recommendation: 93 (95% CI, 92–94) • Highly or strongly recommend: 90% • Quality of evidence: Very low, grade 1 recommendation
    80. 80. AGREE: Trial in Acute Gout • Pivotal phase-3 trial examining the efficacy and safety of colchicine • One of 17 clinical studies submitted to the FDA by URL Pharma • Primary end point: 50% pain reduction at 24 hours without the use of rescue medication R High-dose colchicine1 1(n=52) High-dose colchicine (n=52) A (4.8 mg: 1.2 mg, then 0.6 mg/h ××6) (4.8 mg: 1.2 mg, then 0.6 mg/h 6) N D O Low-dose colchicine1 1(n=74) Low-dose colchicine (n=74) Patients with acute gout M (1.8 mg: 1.2 mg, then 0.6 mg in 11 (1.8 mg: 1.2 mg, then 0.6 mg in h) h) (N=184) I Z E Placebo Placebo D (n=58) (n=58) 1 24 Hours1. Terkeltaub RA, et al. Arthritis Rheum 2010; 62:1060-1068. (Colchicine delivered as COLCRYS)
    81. 81. AGREE: Responder Analysis at 24 Hours* 40 * 38% † 33% 30 20 15% 10 0 Low-dose High-dose Placebo (n=74) (n=52) (n=58) *A responder is defined as a patient who achieved a ≥ 50% reduction in pain score and did not take rescue medication prior to the 24-hour post dose assessment.* P=0.034 versus placebo.†P=0.034 versus placebo.
    82. 82. AGREE: Adverse Events 90 High-dose (n=52) Low-dose (n=74) 80 * * * Placebo (n=59) 70 60 50 40 30 % * * w E A P d h n e a o v s * r t f i 20 10 0 AEs GI AEs Diarrhea Nausea Vomiting Severe AEs Severe diarrhea*P ≤0.05 vs low-dose and placebo.Terkeltaub RA, et al. Arthritis Rheum 2010; 62:1060-1068.
    83. 83. NSAIDs• Equivalent efficacy in gout amongst all NSAIDs• Relatively contra-indicated in many common comorbid conditions • Peptic ulcer disease • Cardiovascular disease and hypertension • GI bleeds • Aspirin- or NSAID-induced asthma • Renal dysfunction • Postoperative patients • Warfarin• Consider using PPI for gastric protection
    84. 84. Corticosteroids• Effective as oral, intramuscular, or intra-articular agents• Worsening of glycemic control in diabetics• Infection risk• Steroid “rebound” acute attack may recur if treatment not followed by NSAID or colchicine• All side effects likely minimized by intra-articular
    85. 85. Management Recommendation:Intra-articular Steroids May Be EffectiveFor an acute attack, after sufficient precautions have beentaken, intra-articular aspiration and injection of a long-acting steroid is an effective and generally well-toleratedtreatment. (#6)Rebound may occur and supplemental anti-inflammatorytherapy is often needed • Strength of recommendation: 95 (95% CI, 93–96) • Highly or strongly recommend: 85% • Quality of evidence: Very low, grade 1 recommendation
    86. 86. Management Recommendation: Indications for ULTUrate-lowering therapy is indicated in patients with any ofthe following: recurrent attacks (> 1 attack per year),chronic arthropathy, tophaceous deposits, nephrolithiasis,or radiographic changes of gout.Once initiated, ULT is considered a lifelong treatmentrecommendation. (#7) • Strength of recommendation: 97 (95% CI, 96–98) • Highly or strongly recommend: 95% • Quality of evidence: Low, grade 1 recommendation
    87. 87. Management Recommendation: Goals of ULTThe therapeutic goal of ULT is to prevent acute flares,prevent the development of tophi, help dissolve tophi, andprevent the development of chronic gouty arthropathy.This is achieved by maintaining an SUA level of < 6.0mg/dL, well below the saturation point for MSU of 6.8mg/dL. (#8) • Strength of recommendation: 97 (95% CI, 96–98) • Highly or strongly recommend: 100% • Quality of evidence: Low, grade 1 recommendation
    88. 88. Urate Lowering Treatments • Urostatic agents: Xanthine oxidase inhibitors • Allopurinol • Febuxostat (Uloric ™) • Uricosuric Agents • Contraindicated in over-producers • Probenecid • Sulfinpyrazone • Enzymatic-uricase • Pegloticase (Krystexxa ™) • Medications that incidentally lower SUA • Losartan • Fenofibrate
    89. 89. Urate Lowering Therapy Important Considerations• Prophylaxis against gout flares • Duration of therapy – • Increased risk of flares with indefinite urate lowering therapy • Colchicine or NSAIDs; • Lifelong risks of ULT sometimes glucocorticoids • Adherence is often sub-• Treating to target optimal • serum urate to <6 mg/dl • May be<4mg/dl in patients with tophi • Uncertainty in chronic• DON’T TREAT ASSYMPTOMATIC kidney disease HYPERURICEMIA• Patient education
    90. 90. Protect Against Acute Attacks While Implementing Urate Lowering Therapy • Abrupt reduction in uric acid may cause acute attack • Do not implement urate lowering therapy without prophylaxis • Co-administer prophylactic agent prior to initiating urate lowering therapy (usually 2 weeks before) • Warn patient of potential for attacks, even in face of optimum treatment • Continue prophylactic therapy • Colchicine 0.6 mg once or twice daily – Or NSAID • Duration: 6 months until after last attack and tophi if present have resolvedBorstad GC, et al. J Rheumatol 2004;31:2429-2432.
    91. 91. Management Recommendation: Colchicine Is First Choice for Prophylaxis• Prophylaxis against acute attacks during the first 6 to 12 months of ULT can be achieved by colchicine (given as tolerated, 0.6 mg once or twice daily) or an NSAID (with gastroprotection if indicated).• Prophylaxis should be initiated 2 weeks prior to the implementation of ULT.• The choice for prophylaxis should include an analysis of the comorbidities of the patient as well as the risks and benefits of the agent, which are shown below.• Nonsteroidal anti-inflammatory drugs are currently not FDA approved for prophylaxis. (#13) • Strength of recommendation: 97 (95% CI, 96–98) • Highly or strongly recommend: 100% • Quality of evidence: Very low, grade 1 recommendation The expert panel recommends that colchicine be considered as the first choice for prophylaxis. Nonsteroidal anti-inflammatory drugs and corticosteroids are alternatives if colchicine is not tolerated or is not effective. Colchicine is the only FDA approved medication for prophylaxis.
    92. 92. Management Recommendation: Probenecid• Probenecid, a uricosuric agent, can be used as an alternative to a xanthine oxidase inhibitor (XOI) in patients with normal renal function, but is relatively contraindicated in patients with nephrolithiasis and ineffective in the presence of renal insufficiency.• Probenecid can be used together XOI, if necessary, to achieve the target goal of lowering SUA to < 6.0 mg/dL.• Dosing may begin at 500 mg daily, with titration monthly up to a maximum of 3 g per day in divided doses. (#12) • Strength of recommendation: 93 (95% CI, 92–94) • Highly or strongly recommend: 90% • Quality of evidence: Very low, grade 1 recommendation
    93. 93. Management Recommendation: Xanthine Oxidase Inhibitors• The xanthine oxidase inhibitors (allopurinol and febuxostat) are the agents of choice for ULT to reach the therapeutic target SUA level of < 6.0 mg/dL.• The dose should be titrated to optimize safety and minimize the chance of precipitating an acute flare.• Serum uric acid should be monitored to ascertain the achievement and maintenance of this goal.• Appropriate laboratory monitoring for toxicity is indicated.(#9) • Strength of recommendation: 95 (95% CI, 94–96) • Highly or strongly recommend: 100% • Quality of evidence: Low, grade 1 recommendation
    94. 94. The Target Level of SUA Saturation of uric acid occurs at >6.8 mg/dL at pH 7.4 and body temp 98.6. Achieving SUA of <6 mg/dL results in: ↓ MSU crystals in joints ↓ frequency of flares/attacks ↓ tophus size Lower target SUA levels are appropriate in patients with, tophaceous disease. Median dose to goal for allopurinol is ~380 mg/day.
    95. 95. Management Recommendation: Allopurinol• Allopurinol should be started at a low dose (100 mg daily) and increased by 100 mg every 2 to 4 weeks (to a maximum allowable dose of 800 mg/day) as necessary to achieve the target SUA goal of < 6.0 mg/dL.• If allopurinol toxicity occurs, it should be stopped immediately.• Other treatment options include febuxostat or probenecid. (#10) • Strength of recommendation: 95 (95% CI, 94–96) • Highly or strongly recommend: 100% • Quality of evidence: Moderate, grade 1 recommendation
    96. 96. Allopurinol • Administered as a daily dose of 50 to 800 mg daily • Divide dose when >300mg daily • Initiate at 50 mg/day in patients with renal insufficiency • Titrate until Serum Uric acid < 6.0 mg/dl. It is commonly underdosed • Get baseline laboratory tests • Measure uric acid every month while titrating for 1st 3 months • Monitor toxicity with exam, LFTs, RFTs, every 3-6 months while titrating • CBC with manual differential to look for eosinophils • About 2% incidence of mild allergic rash • 0.4% incidence of severe reactions-20-25% mortality with allopurinol hypersensitivity syndrome • Steven Johnson Syndrome • Toxic epidermal necrolysis • Hepatitis • Interstitial nephritis • Reaction risk greatest in renal insufficiency and diureticsHande,KR, et al Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med 1984;76: 47-56Stamp,L, et al, the optimal use of allopurinol: An audit of allopurinol use in South Aukland. Aust NZ J Med 2000;30: 567-72
    97. 97. Dosing Above >300mg Allopurinol89% of 90 patients reached goal with > recommendeddosing Arthritis Rheum. 2011 Feb;63(2):412-21
    98. 98. Allopurinol Hypersensitivity AHS occurs in ~0.4% of patients on allopurinol, with ~20% fatality. Renal dysfunction thought to be a risk factor, but there is minimal evidence that reduction in CKD dose affects incidence of AHS. Molecular case control study suggests marked ↑ risk for those with HLA-B*5801, i.e. immune factors may be > [oxypurinol]. Dose reduction in CKD is associated with ↓ success in achieving target urate.
    99. 99. Allopurinol Dose in CKDHande et al, Am. J. Med., 76, 1984 → Allopurinol: Drug info, “UpToDate”, 2007
    100. 100. Conclusions: Renally-Adjusted Allopurinol Dosing Allopurinol dosing in CKD has not traditionally been based on achieving a target SUA. There is minimal evidence that dose reduction of allopurinol in CKD affects risk of AHS. Problem: scant safety data for allopurinol dosing >300mg/d, vs. the impediments (cost, insurance approval, etc.) to using febuxostat. Febuxostat, however, does not cause an equivalent to AHS… Recommendation is to SLOWLY ↑ dose, with low-dose colchicine for flare prophylaxis.
    101. 101. Management Recommendation: Febuxostat• Febuxostat should be started at 40 mg daily and may be increased to 80 mg after at least 2 weeks of treatment, if necessary to achieve the target SUA goal of < 6.0 mg/dL.• If toxicity occurs, febuxostat should be stopped immediately.• Other treatment options include allopurinol or probenecid.• However, allopurinol and febuxostat should not be coadministered. (#11) • Strength of recommendation: 97 (95% CI, 96–98) • Highly or strongly recommend: 100% • Quality of evidence: Low, grade 1 recommendation
    102. 102. Febuxostat vs Allopurinol Phase 3 Clinical Trial Primary End Points Randomized, double-blind, 52-week, multicenter trial of 760 90 patients 80 Primary end points Subjects with SUA <6.0 mg/dL, % 70 * * 60 50 * Last 3 SUA <6.0 mg/dL Week 52 SUA <6.0 mg/dL 40 * 30 *P<.05 for each 20 febuxostat group vs allopurinol group. 10 0 Febuxostat 120 Febuxostat Allopurinol mg 80 mg 300 mgBecker et al. ACR/ARHP Program Book Supplement. 2004;L18.Bec
    103. 103. CONFIRMS Efficacy in Renally Impaired Subjects Proportion of Subjects With Mild-to-Moderate Renal Impairment With sUA <6 mg/dL at Final Visit * 80 ** 72% 70 50% * 60% of Subjects 50 42% 40 Febuxostat Febuxostat 30 80 mg Allopurinol 40 mg 300/200 mg 20 (n=479) (n=503) (n=501) 10 0 *p<.05 vs allopurinol. **p<.05 vs ULORIC 40 mg. Renal impairment was defined as baseline estimated CL cr <90 mL/min.
    104. 104. Enzymatic Uricolytic Drugs• Uricase (urate oxidase) catalyzes uric acid to allantoin • Allantoin is more soluble than uric acid • Humans and other higher primates lack this enzyme• Fast-acting, potent decrease in serum urate and in tophi• Native and recombinant bacterial uricases are available outside the U.S. for intravenous use • To treat tumor lysis syndrome • Not indicated for treatment of gout.• Significant incidence of allergic reactions: all uricase of non-human origin
    105. 105. Effect of Urate-Lowering Therapy on the Velocity of Size Reduction of Tophi in Chronic Gout Perez-Ruiz F, Calabozo M, Pijoan JI, et al . Arthritis Rheum 47: 356-360, 2002
    106. 106. Uricase EnzymesUricase (uric acid oxidase) catalyzes the conversion of uric acid to allantoin: A more soluble, readily excretable form Uricase Uricase OH OH H2O + O2 H2O2 + CO2 N N OH HO N OH N H OH N N N N OH OH HO N N H HO N N N H H Allantoin Uric acid
    107. 107. Management Recommendation: Pegloticase• For patients who have refractory gout and/or resistant tophaceous disease, pegloticase is another treatment option. Pegloticase is administered by infusion and has a significant risk profile.• Patients who may be candidates should be referred to health care professionals with expertise in the use of pegloticase. • Strength of recommendation: 95 (95% CI, 93–95) • Highly or strongly recommend: 82% • Quality of evidence: Very low, grade 2 recommendation
    108. 108. Ideal Candidate for Pegloticase Indication: – gout refractory to conventional therapy occurs in patients who have failed to normalize serum uric acid and whose signs and symptoms are inadequately controlled with xanthine oxidase inhibitors at the maximum medically appropriate dose or for whom these drugs are contraindicated*. – *From Krystexxa Product Information Sheet
    109. 109. Ideal Candidate for Pegloticase Tophaceous disease, or Chronic synovitis, or Repetitive and frequent attacks of gout, or Unresponsive to standard ULT with one or more of the above issues De-bulking agent
    110. 110. Pegloticase Resolution of TophiBaseline Week 15 Sundy and Hershfield, unpublished data
    111. 111. Phase 3 Trials 2 double blind replicate trials in 212 patients – 2:2:1 randomization • q2 vs q4 vs placebo – 6 months RCT and 2 year OLE
    112. 112. Phase Three Trial
    113. 113. Risks Gout flares Infusion related events (reactions) Anaphylaxis
    114. 114. Adverse Events
    115. 115. Primary Endpoint– Proportion of patients maintaining plasma uric acid <6mg/dL in 80% of determinations during month 3 and month 6
    116. 116. Infusion Reaction Relationship to SUA< 6mg/dL or >6 mg/dL Among patients with SUA <6 mg/dL, fewer than 1 in 100 infusions were accompanied by signs or sx of an infusion reaction; placebo treated patients had a 0.4% incidence in the RCT
    117. 117. Most Common Signs and Symptoms of Infusion Reactions to Pegloticase
    118. 118. Management of Infusion-Related Events in RCT All reactions resolved with supportive measures – slowing or stopping the infusion and/or other interventions that included • antihistamines • fluids • corticosteroids • analgesics • Epinephrine: wheezing, lip swelling of “infusion reaction without BP change - 1 each
    119. 119. Management of Infusion-Related Events in Phase 3 In the clinical studies no patient with an infusion related event required resuscitation, intubation, mechanical ventilatory support, pressors or hospitalization There was no shock among patients meeting definition of anaphylaxis There were no infusion-related deaths
    120. 120. Infusion Reaction Summary Risk of reaction and anaphylaxis is higher in patients who have lost a therapeutic response (and will not benefit from additional rx). Risk of reaction is low (under 1% of infusions) when SUA is <6 mg/dL. Risk of reaction during rx can be mitigated: – routine SUA measurement prior to each infusion – stopping pegloticase treatment in patients with pre- infusion SUA >6 mg/dL. All reactions resolved with conservative measures
    121. 121. January 25, 2011 May 3, 2011
    122. 122. Secondary Endpoints Tophus resolution Reduction in gout flares Reduction in tender and swollen joint counts Improvement in quality of life (SF-36) Improvement in functional status (HAQ-DI)
    123. 123. Tophus Resolution
    124. 124. Tophus Resolution26 March 2007 26 September 2007
    125. 125. Reduction in Gout Flares
    126. 126. Radiographic Outcomes No data was collected in the phase 3 program Radiographic scoring system recently proposed for gout* Virtually no data on radiographic outcomes in gout*Dalbeth, et. al., Arthritis Care and Research, Vol 57, No. 6. August 2007
    127. 127. Radiographic OutcomesBaraf, Matsumoto et al, A&R 2008
    128. 128. Radiographic OutcomesBaraf, Matsumoto et al, A&R 2008
    129. 129. Management Recommendation: When to ReferConsiderations for referring a patient with gout to a rheumatologist or nephrologist include: • Confirmation of diagnosis, particularly in patients with atypical presentation • Management of refractory cases when • An SUA level < 6.0 mg/dL cannot be achieved • Recurrent flares occur despite apparent adequate treatment • A patient presents with persistent and/or extensive tophaceous disease • Management of patients with nephrolithiasis • Consideration for complex treatment options (#16) • Strength of recommendation: 94 (95% CI, 93–95) • Highly or strongly recommend: 100% • Quality of evidence: Very low, grade 1 recommendation
    130. 130. Treatment Pearls• Treat associated co-morbidities and • Uricosurics useful in allopurinol allergic address risk reduction behavior patients with normal renal function, under-excretion, and no history of• Initiate urate lowering therapy (ULT) nephrolithiasis in patients with two or more attacks a year • Uricosurics – not indicated in overproducers• Do not start ULT during an acute attack • Use concomitant prophylaxis when initiating ULT to prevent treatment induced attacks• Do not discontinue ULT if patient on ULT has an acute attack • Measure serum uric acid levels• Allopurinol is drug of choice for initial • every 3-6 months. Adjust ULT medications until a target uric acid • of <6 mg/dl is obtained Cannella AC, Mikuls TR. Res and Staff Phys 2005:51:21-28.
    131. 131. TAKE HOME MESSAGES: Gout and CKD The kidney plays a dominant role in gout; SUA reflects the net balance of urate reabsorption and secretion across the renal proximal tubule. Diuretic Rx ↑ SUA by multiple mechanisms. High prevalence of both CKD and renal stones in patients with gout. Think of FJHN in patients with a family history of gout and CKD. The target SUA in CKD is no different than in patients with normal renal function.
    132. 132. TAKE HOME MESSAGES: Gout Rx in CKD Dose reduction in allopurinol in CKD → ↓↓ likelihood of reaching SUA goal. In CKD, > recommended allopurinol dosage appears to be safe without ↑ risk of AHS. However, minimal safety data for >300 mg/day. Low-dose colchicine for acute gout and renally-adjusted colchicine for ULT prophylaxis → expanded utility in CKD. High incidence of tophaceous gout in renal transplantation → consider pegloticase.
    133. 133. Should Nephrologists Take a More Active Role in Gout? High prevalence of CKD in gout. Increasing evidence of a role for hyperuricemia in progressive CKD. WRT dose titration of ULT, there is a built-in frequency of Nephrology follow-up in patients with CKD III or worse. Minimal extra effort in achieving SUA goal along with bp and proteinuria goals, PTH/calcium/phosphate/vitD goals, iron goals, etc.
    134. 134. Summary Points - 1• Data continue to support the decision to diagnose gout using clinical characteristics rather than mandating crystal identification.• Although studies have shown that SUA levels of > 6.0 mg/dL are a significant risk factor for gout,82-85 they are always a reliable diagnostic tool because approximately 14% of patients with acute gout presented with SUA levels of < 6.0 mg/dL. 109 Conversely, some people with high SUA may never develop gout. Serum uric acid should be used in combination with clinical criteria and response to gout treatment to arrive at a diagnostic decision.• Research has focused on the interaction of gout with typically associated risk factors and comorbid conditions. Strong associations have been demonstrated between gout and metabolic syndrome,110-112 CVD,32, 33, 50, 113 and CKD.33• Reference numbers are those from PostGraduate Medicine Reference
    135. 135. Summary Points - 2• The use of nonpharmacologic measures in the treatment of patients with gout, particularly dietary aspects, has become more sophisticated. 114• Gout therapy relies on good patient education. Patients need to understand that gout treatment requires a lifelong commitment. Patients also need to know that the initiation of ULT results in acute gout attacks (mobilization flares) and that these attacks are a sign of effective therapy. Finally, they need to understand the importance of adhering to prophylaxis regimens.• For effective management of an acute gout attack, treatment should begin within hours of first symptoms. Low-dose colchicine (1.2 mg as soon as possible, followed by 1 dose of 0.6 mg 1 hour later, for a total dose of 1.8 mg) is as effective and better tolerated than high-dose colchicine (1.2 mg followed by 0.6 mg every hour for 6 hours, resulting in a total dose of 4.8 mg).68
    136. 136. Summary Points - 3• The benefits of reaching a target SUA level of < 6.0 mg/dL have been confirmed. For most patients, a target SUA between 5.0 and 6.0 mg/dL is safe and effective. Patients with incapacitating, severe, tophaceous gout may require SUA levels of < 4.0 mg/dL to see improvement.87,115, 116• Allopurinol has been found to be safe and more effective at higher doses. It should be started at a low dose of 100 mg per day but can (with appropriate monitoring) be titrated up to 800 mg per day as necessary for a patient to achieve the target SUA level of 6.0 mg/dL.92-94 It has been recommended that patients with renal impairment receive lower doses but recent studies report that this might not be required clinical practice.
    137. 137. Summary Points - 4• For patients who have not responded to or were not eligible to receive allopurinol, febuxostat (also a xanthine oxidase inhibitor with a slightly different mechanism of action) can be prescribed at unchanged doses for patients with mild-to-moderate renal or hepatic impairment.89, 90 Intravenous pegloticase is indicated for patients with refractory and/or resistant tophaceous gout.108• Timely referral from primary care to rheumatology or nephrology may be the best option for patients with an uncertain diagnosis or in cases of severe disease.

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