Gout: A Clinical Update Peng Thim Fan, MD, FACP Clinical Professor of Medicine Division of Rheumatology David Geffen School of Medicine at UCLA Why talk about Gout? Large increase in gout in the last 20 years - 200-300% in the last 30 years 1.56 million men, 550,000 women (1992 self-reported) 3 million self-reported A&R 1/08 Recent estimate 8.3 million Now the most common inflammatory arthritis in men 7 Why talk about Gout? Aging population contributes to problem Polypharmacy, co-morbidities, reduced drug clearance, increased toxicity profile Wide use of diuretics in patients with renal insufficiency and/or congestive heart failure Altered dietary trends, rising prevalence of obesity, metabolic syndrome, end-stage renal disease Transplant patients - cyclosporine Renewed interest because of new and effective medications US Gout Population: 2009 Estimated number of affected persons in the US 8.3 million 1 2.8 million 2 200 500,000 3 60 180,000 (1 3%) 4 Patients with Gout Treated With Allopurinol or Febuxostat 1. NHANES 2007-8 2. Halpern R, et al. Curr Med Res Opin. 2009,25:1711-1719. 3. Harris Interactive poll: A Survey of Patients with Gout, 2006 Poor Urate Control / Progressive Symptoms Chronic Gout Refractory to Conventional Therapy* Populations at risk: The risk of gout is a consequence of hyperuricemia Risk of initial gout attack: Serum urate 7.0 to 8.9 mg/dl* Annual attack rate 0.1% 5-year incidence 3% Serum urate > 9.0 mg/dl Annual incidence 4.9% 5-year incidence 22% After the first attack of gout the risk is of future attacks is higher Why is Gout Less Common in Women? Adult men reach maximal serum urate at puberty and the level rises little with age Average 5-6 mg/dl Women have lower serum urate before menopause related to fractional urate excretion due to estrogen Average 1.0 to 1.5 mg/dl lower than males After menopause with loss of estrogenic influence serum urate rapidly catches up with men Risk of gout is 6x higher than before menopause One-third of new cases of gout after age 65 are women Punzi L, So A. Curr Med Res Opin 2013;Suppl 3: 3-8
Populations at risk: Pacific Islanders Hawaii, Tahiti, New Zealand Maori, Filippino High prevalence in the Hmong people Minnesota, Central California (onset age 37; mean uric acid 9.1 mg/dl) Defect is underexcretion by the kidneys 1. Krishna, J Rheum 2008;35:498 2. Maloney, J Urol 2005;173:2001 3. Wahedduddin, J Clin Rheum 2010;16:262 Clinical Setting of Typical Gout 40-year-old male History of CHD, hypertension, hypercholesterolemia Several episodes of pain in his left foot and ankle in the past lasting several days Severe pain and swelling in the left big toe since yesterday morning* Erythema and swelling left first MTP joint Clinical Setting of Typical Gout Risk of gout attacks at night and early morning is 2.4 x higher than daytime 724 patients internet study Possible reasons Nocturnal dehydration Lower body temperature dip in cortisol level Sleep apnea with nucleotide turnover generates purines Choi et al. Arth Rheum 2015; 67:555-62 Clinical Setting of Typical Gout First attack monoarticular 80% Great toe joint affected 75% Polyarticular gout 40% (with full examination) Lawry GV 2nd, Fan PT, Bluestone R. Medicine 188;67:335 Great toe Forefoot Ankle Heel Knee Wrist Finger Elbow Risk Factors and Co-morbidities Coronary heart disease Hypertension Hyperlipidemia Obesity* Anemia (<13.5 m; <12 w)** Recent weight gain of 30 lbs High alcohol consumption particularly beer and distilled spirits High fructose corn syrup in soft drinks increases risk Increases AMP degradation to ATP Diet drinks are safe Is cane sugar safe? What tests should we perform? CBC with differential Comprehensive metabolic panel BUN, creatinine Liver function tests Glucose ESR, C-reactive protein Uric acid Uric acid normal (< 7.0 mg/dl) in up to 50% during acute attack! Repeat serum urate in 2 weeks after acute attack * Campion EW. Am J Med 1987;82:421
Are Radiographs of Any Use? Well-marginated punched out bone erosions confirm gout Strongly indicate tophi Amorphous calcium deposits and often fine stippled calcification, usually around the sesamoid bones suggest a different diagnosis Calcific periarthritis Periosteal bone reaction suggests osteomyelitis or psoriatic dactylitis Is Joint Fluid Examination Necessary? Examination of joint fluid under polarized light is the BEST way to diagnose gout Serum urate is normal in 50% during acute gout, 30% even in polyarticular gout Negatively birefringent crystals under a first-order compensator Hydroxyapatite shows up as amorphous globules with variable birefringence What if you cannot get joint fluid? Our patient s presentation is classic Reasonable to treat as gout If he does not respond to an NSAID in 3 days send him to a rheumatologist or orthopedic surgeon for joint aspiration Treatment for Acute Gout Start with rapidly-acting NSAID: indomethacin 100mg then 50mg q8h x 3-4 days Reduce to 50mg twice a day for 1 week Other rapidly acting NSAID may work as well: ibuprofen, naproxen, diclofenac Avoid long-acting NSAIDs: piroxicam, oxaprozin COX-2 inhibitors may work: etoricoxib Add PPI if GI history Even under ideal conditions between 100,000 to 300,000 of 5 million cases in the US will be treatment failures Treatment for Acute Gout Colchicine 1mg followed by 0.6mg hourly x 6 may work Predictably causes diarrhea, vomiting or both A better scheme is 1.2mg at diagnosis followed by 0.6mg 1 hour later and then no more colchicine for 24 hours * Avoid IV colchicine (not available anymore) * Terkeltaub RA, Furst DE, Bennett K, et al. Arthritis Rheum 2010; 62:1060. Treatment for Acute Gout Intra-articular corticosteroid or systemic works well Prednisone 30mg daily x 5 days Rebound of gout does NOT occur Useful in patients with creatinine > 2.0 mg/dl Or surgical patients Don t start urate-lowering treatment during an acute attack of gout (? Dogma) Taylor TH, Mecchella JN, Larson RJ, et al. Initiation of allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial. Am J Med 2012; 125:1126.
Are there Effective Non-drug Options? For first attack, treat pain and swelling 10-lb weight loss effective if overweight Strict purine diet is unpalatable with poor long-term compliance lowers serum urate by only 1 mg/dl Reasonable option Switch to low-fat dairy products Eat less red meat and fish Restrict calories, use complex CHO, reduce sat fat Are there Effective Non-drug Options? 2 glasses of wine a day NOT associated with risk Change diuretic treatment for hypertension to alternative agent; losartan has uricosuric effect HCTZ: serum urate by 0.8 mg/dl; less if renal compromise 81mg enteric-coated aspirin daily OK: raises serum urate by 0.3 mg/dl Supplemental vitamin C at 1500mg/d lowers gout risk 50% When should we start urate-lowering? Excessive intake Endogenous overproduction Underexcretion (90%) (10%) HYPERURICEMIA Tissue deposition Gout Renal Stones CV events Do people with gout have kidney stones? NHANES III (2002): 10 million people had kidney stones (5.7% of popn); 5.1 million (2.7%) reported gout Of those with stones 8.6% had a history of gout 13.9% of patients with gout reported kidney stones RR after all adjustments for stones in gout patients was 1.49 (1.04 2.14) Kramer HM, Curhan G Am J Kidney Dis. 2002;40(1):37. Health Professionals Follow-up Study (2003): patients with stones not at higher risk for gout RR 1.05 (0.54 2.07) Kramer HJ, Choi HK, et al. Kidney Int. 2003;64(3):1022. When should we start urate-lowering? Gout: Metabolic Disease of Purine Metabolism If serum urate is not lowered 62% another attack in next year 78% within 2 years 93% within 10 years If urate level > 9.0 mg/dl then 80% recurrent attack in the next 12 months If urate level is below 6.0 mg/dl 86% have no recurrence within 1 year and maintained during 3 years Hypoxanthine Purines 1 Cell breakdown & diet xanthine oxidase allopurinol 2 febuxostat Xanthine Conventional Therapy xanthine oxidase allopurinol 2 febuxostat Uric Acid probenecid 2 Arthritis Care & Research Volume 51, Issue 3, pages 321-325, 3 JUN 2004 DOI: 10.1002/art.20405 http://onlinelibrary.wiley.com/doi/10.1002/art.20405/full#fig1 1. Becker M, Jolly M. In: Koopman WJ, Moreland LW (eds). A Textbook of Rheumatology. 15th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:2303-2339. 2. Hochberg M, Silman A, Smolen J, Weinblatt M, Weisman, M in Rheumatology. 5 th ed. Philadelphia, PA: Elsevier; 2011:1867-1874. Urinary Excretion
How should we lower serum urate? Probenecid 250mg twice a day for 1 month then increase to 500-1000mg twice a day over next 2 months Encourage fluid intake Maximum 1500mg twice a day Each aspirin tablet of 325mg will nullify the effect of 500mg of probenecid Not effective if creatinine clearance is under 50 ml/min Do not use urinary uric acid > 800mg / 24 hours Avoid in patients with sulfa allergy May be used together with a xanthine oxidase inhibitor for additive effect add to allopurinol or febuxostat How should we lower serum urate? Allopurinol Start with 100mg daily and increase every 2-4 weeks to maximum 800mg daily Even though allopurinol is eliminated by renal excretion higher doses of 600-800mg daily are safe in CKD Get urate below 6 mg/dl: don t stop at 300mg/d!!! At 300mg daily only 9% of patients with urate >10 mg/dl achieves a serum urate < 6.0 mg/dl Allopurinol Side Effects Rash, diarrhea, drug fever, leukopenia, thrombocytopenia 5% Allopurinol hypersensitivity syndrome is very rare but 25% mortality Severe rash, fever, hepatitis, eosinophilia, acute renal failure Reported in patients with renal insufficiency started on allopurinol 300mg daily More common in asymptomatic hyperuricemia Allopurinol Side Effects HLA-B*5801 allele present in 100% of Han Chinese with Stevens-Johnson syndrome or toxic epidermal necrolysis Confirmed in Koreans but association not seen in Japanese population Perform HLA-B*5801 in Han Chinese, Thai, and Koreans with CKD 3 or worse Hung, PNAS 2005; 102:4134 How should we lower serum urate? Febuxostat non-purine xanthine oxidase inhibitor 40mg once daily is recommended starting dose after 2 weeks increase to 80mg daily if serum uric acid is >6 mg/dl T ½ is 5-8hrs, only 3% excreted by the kidneys, extensively metabolized by the liver: no adjustment for renal insufficiency Do not use together with allopurinol no additive benefit How should we lower serum urate? Always provide anti-inflammatory prophylaxis for 6 months when starting a urate lowering agent
Strategy for Successful Long-term Treatment Wait a month before lowering uric acid (? Dogma) Check uric acid at least twice a year Always give a prophylactic agent: colchicine 0.6 mg once or twice a day for 6 months beyond reaching target urate of 6.0 mg/dl Colchicine 0.6mg daily may reduce CV events by 49% and all-cause mortality by 73%. (Solomon. Ann Rheum Dis 2015doi:10.1136/annrheumdis-2015-207984 ) NSAIDs may be used; short-term prednisone trial for flares Pegloticase: Mechanism of Action Hypoxanthine Purines 1 Cell breakdown & diet xanthine oxidase 2 Xanthine xanthine oxidase 2 Urate Pegloticase + Uricase H 2 O + O 2 H 2 O 2 Allantoin Use combination allopurinol and probenecid for tophaceous gout Newer agents febuxostat novel non-purine xanthine oxidase inhibitor IV polyethylene glycol uricase (pegloticase) 8mg IV q2w Urinary Excretion 1. Becker M, Jolly M. In: Koopman WJ, Moreland LW (eds). A Textbook of Rheumatology. 15th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:2303-2339. 2. Hochberg M, Silman A, Smolen J, Weinblatt M, Weisman, M in Rheumatology. 5 th ed. Philadelphia, PA: Elsevier; 2011:1867-1874. 3. KRYSTEXXA (pegloticase) Full Prescribing Information. Savient Pharmaceuticals, Inc. September 2010. 4. Hershfield MS, et al. Proc Natl Acad Sci. U S A. 2010;107:14351-14356. Urinary Excretion Pegloticase: For Chronic Tophaceous Gout Indicated for patients who failed or are intolerant to allopurinol and febuxostat Given at 8mg every 2 weeks as an IV infusion over 120 minutes Risk of infusion reaction and anaphylaxis can be reduced if treatment is stopped for patients who do not achieve a serum uric acid of < 6mg/dl either once or 2 consecutive infusions Should not be used with other urate-lowering therapy High risk of gout flares needs prophylaxis with colchicine or NSAID Leisured: A URAT1 Inhibitor Outcomes Uric Acid <6 mg/dl Febuxostat 40 mg/d 67% Febuxostat 80 mg/d 56% Febuxostat 40 mg/d + lesinurad 400 mg/d Febuxostat 40 mg/d + lesinurad 600 mg/d Febuxostat 80 mg/d + lesinurad 400 mg/d Febuxostat 80 mg/d + lesinurad 600 mg/d 100% 82% 100% 100% 100% 100% 100% 100% Uric Acid < 5 mg/dl Fleischmann R et al Rheumatology 2014;53:2167-2174 Should we treat asymptomatic hyperuricemia? Make sure it is asymptomatic! No renal stones, gouty tophi, suspicious gout history If truly asymptomatic: don t treat.? Treat if significant renal impairment? Treat if uric acid level is >11 mg/dl or 24-hour urine urate >1000mg Still controversial how much hyperuricemia contributes to hypertension, CAD or diabetes Hyperuricemia 1. co-factor in Na+ sensitive hypertension J Hyp 2008. 2. Independent risk factor for CVD. Should we treat asymptomatic hyperuricemia? Allopurinol halves the incidence of non-fatal acute MI Spanish study of 3171 non-fatal acute MI 18525 controls Current use allopurinol- risk was 0.82% Controls 1.03% RR 0.52 (0.33 to 0.83) Men 0.44; women 0.90 ns. Only seen with doses 300mg/d and >180 days 33% of patients had uric acid but not gout 54% had gout In patients who had previous MI RR 0.16 De Abajo F, et al. Heart online Jan 2015
Gout: The future Understanding gout Recognition of Pathogens by Toll-like Receptors Bacteria Yeast Viruses Protozoa Uropath Gram -ve Gram +-ve Mycobacteria All All RSV All T. cruzi. bacteria LPS PGN lipoproteins CpG Flagellin Zymosan protein poly-c ssrna GPI anchors lipoproteins GIPLs Host Hsp60 FN frags TLR-4/4 TLR-2/6 TLR-6/1 TLR-9/? TLR-5/? TLR11 TLR-2/? TLR-4/4 TLR-3/? TLR-7/8 TLR-2/? TLR-4/4 MyD88 NFĸB JNK p38 TLRs mediate innate immune response Found on macrophages, neutrophils and dendritic cells Recognize distinct pathogen-associated molecular patterns conserved in microbes, eg, lipopolysacharides, lipoproteins,viral ds RNA Stimulate NF-κB associated cytokines, eg, TNF, IL-1, IL-8 via activation of stress kinases Shares signaling apparatus with IL-1R adapter protein MyD88 MSU crystals activate complement and generates the C5b-C9 membrane attack complex C5 is cleaved on crystal surface C5a generated promotes the C5b-C9 Membrane attack complex Endothelial cells activated IL-8 release Liu-Bryan R, Terkeltaub R. Arthritis Rheum 2006; 54:383 IL-1 inhibitors very effective in treating Gout Anakinra IL-1R antagonist 100mg SQ daily x 3d Canakinumab mab to IL-1β single 150mg SQ Rilonacept traps IL-1 single 320mg SQ Canakinumab is the most effective, better than a single triamcinolone acetonide injection of 40mg IM But 5000x more expensive!! Sivera F1, Wechalekar MD, Andrés M, Buchbinder R, Carmona L. Cochrane Database Syst Review September 2014 References 1. Mikuls TR, Farrar JT, Bilker WB, et al. Gout epidemiology: results from the UK General Practice Research Database, 1990-1999. Ann Rheum Dis 2005; 64:267. 2. Becker MA, Chohan S. We can make gout management more successful now. Curr Opin Rheumatol 2008; 20:167. 3. Nakayama DA, Barthelemy C, Carrera G, et al. Tophaceous gout: a clinical and radiographic assessment. Arthritis Rheum 1984; 27:468. 4. Lawry GV 2nd, Fan PT, Bluestone R. Polyarticular versus monoarticular gout: a prospective, comparative analysis of clinical features. Medicine (Baltimore) 1988; 67:335. References 1. Wallace KL, Riedel AA, Joseph-Ridge N, Wortmann R. Increasing prevalence of gout and hyperuricemia over 10 years among older adults in a managed care population. J Rheumatol 2004; 31:1582. 2. Roddy E, Zhang W, Doherty M. The changing epidemiology of gout. Nat Clin Pract Rheumatol 2007; 3:443. 3. Smith E, Hoy D, Cross M, et al. The global burden of gout: estimates from the Global Burden of Disease 2010 study. Ann Rheum Dis 2014; 73:1470. 4. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008. Arthritis Rheum 2011; 63:3136.
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