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Recent therapy for Gouty Arthritis 경희의료원 류마티스내과 홍승재 case M/48 CC : pain in right big toe Onset : 3 days ago, abruptly severe pain Trauma Hx (-) Medical Hx : self analgesics, temporary effect 2 times pain Hx. of big toe but spontaneous subside Q1. 이와 같은 증상을 보일 때, 가장 먼저 의심할 수 있는 질병은? ① Spondyloarthropathy ② Gout ③ Rheumatoid arthritis ④ Broken toe P/E : BMI 31 kg/m2 with central obesity Office worker, few exercise Diet : mainly red meat, white breads, rice, pasta, potato etc. Alcoholic Hx. : Beer or non-diet soda/freq. Asthma Hx. of childhood : intermittent dyspnea or development wheezing at current Family Hx. : Gout (father, retirement state) Q2. 앞서 보인 환자의 임상 소견 중 통풍의 위험 인자가 아닌 것은? ① Diet ② Asthma ③ Alcohol consumption ④ Body Weight What are the Risk Factors for Gout? 1. Genetic Factors genetic variation within SLC2A9 1q21 region of chromosome 1 4q25 region of chromosome 4 estrogen receptor gene thymine-adenine repeat polymorphism at chromosome 6q25.1 Updated urate transport model in human proximal tubule incorporating the newly discovered urate transporters by GWAS genome-wide association studies (GWAS) Curr Opin Rheumatol.2010 Mar;22(2):144-51 What are the Risk Factors for Gout? 2. Hyperuricemia Hyperuricemia : SU>6.8 mg/dL, limit of urate solubility in serum Associated with gout and increases the risk for crystal deposition due to urate supersaturation Asymptomatic hyperuricemia = hyperuricemia without gout Becker and Jolly, Rheum Dis Cilin North AM 2006;32:275-93 Plug & Martinez, Curr Opin Rheumatol 2008;20:187-91 Novak et al, Curr Med Res Opin 2007;23:623-30 Hyperuricemia results Predominantly from: Decreased renal uric acid excretion Alone or in combination with: Increased uric acid synthesis hyperuricemia without gout → direct positive association between SU and future risk of developing Gout Arthritis & Rheumatism 2007;57(7):1324–1328 What are the Risk Factors for Gout? 3. Medications aspirin : high doses (>3 g/day, uricosuric) : low doses (1-2 g/day, retention of uric acid) diuretics : increased risk of gout Ritonavir, Tacrolimus… 4. Metabolic Syndrome obesity hyperinsulinemia hypertension 5. Diet and Alcohol Medications as a risk for Gout Current Opinion in Rheumatology 2011, 23:192–202 Prevalence of the metabolic syndrome according to presence of gout in adults in the US Prevalence estimates of comorbidities among individuals with gout Current Opinion in Rheumatology 2010, 22:165–172 Q3. 다음 음식 중 통풍 발생의 protective factor인 것은? ① Beer ② Dairy products ③ Red meat ④ Seafood Lifestyle risk factors of hyperuricemia and gout Current Opinion in Rheumatology 2010, 22:165–172 Gout risk and a healthy eating pyramid Current Opinion in Rheumatology 2010, 22:165–172 Life-style modification – dietary: Low purine diets are not palatable and not effective Long term dietary recommendations should take metabolic syndrome into account and be planned appropriately Diet becomes high in carbohydrate and saturated fats Increased serum urate Increased risk of insulin resistance syndrome Restrict purine intake BUT High serum insulin levels Low purine diet Reduced renal excretion of urate Increased serum urate Choi et al, Am J Med; 120: 442-7 Q4. acute gout에서 가장 흔히 침범하는 관절은? ① Acetabulofemoral joint ② First metatarsophalangeal (MTP) joint ③ Radiocarpal joint ④ Third metacarpophalangeal (MCP) joint Potential evaluations in a patient presenting with gout symptoms Clinical Family history Past history of similar events Medication history Diet, alcohol use Metabolic syndrome Past urolithiasis Radiographic Conventional radiographs of involved joints Ultrasonographic examination of involved joints Examination Evaluate all joints Vital signs Look for tophi Bursae, tendons Laboratory CBC ESR and/or CRP Urinalysis Biochemistry LFTs, Cr(eGFR), serum urate Am J Manag Care 2005;11:S435-42 Synovial fluid analysis for crystals 2 to 20 microns length, needle shaped monosodium urate (MSU) crystals under compensated polarized light microscopy “U pay peb” Joint aspiration: Ideal vs practical Ideal : Aspirated synovial fluid Practical : primary care physicians & patients are reluctant to do routinely Practical recommendation 1. reasonable doubt → aspirate the joint Especially gout or septic arthritis 2. preliminary 1977 ACR criteria or EULAR ladder for acute gout Ann Rheum Dis 2002; 61: 493-8 Ann Rheum Dis 2006; 65: 1301-11 ACR preliminary criteria for the diagnosis of gout ~11% patients with suspected gout will undergo joint aspiration, the ACR produced a set of clinical diagnostic criteria Six or more of the minor criteria or 1 of the major criteria (tophus or MSU crystals in synovial fluid) are needed for gout diagnosis >1 attack of acute arthritis Maximum inflammation developing within 1 day Monoarthritis If septic arthritis is Redness over joint suspected, carry out Painful or swollen 1st MTP joint joint aspiration Unilateral attack on 1st MTP joint immediately Unilateral attack of tarsal joint If pseudogout is Tophus (proven or suspected) suspected, also aspirate the joint Asymmetric swelling within joint on radiograph Subcortical cysts without erosions on radiograph Joint fluid culture negative for organisms during attack Monosodium urate monohydrate microcrystals in joint fluid during BMJ 2006; 332: 1315-9 attack Arthritis Rheum 1977; 20: 895-900 EULAR: Composite diagnostic ladder of gout A composite approach can provide a more definite diagnosis of gout The probability of gout in a patient with “a rapidly painful, swollen tender joint” is only 0.63%, but with “erythema” this rise to 1.53% and to over 99% if a full range of parameters are present Ann Rheum Dis 2006; 65(10): 1301-11 Q5. 통풍 관절염이 의심되는 환자에서 관절 상태를 보기 위한 검사로 적절하지 않은 것은? ① Ultrasound ② CT/MRI ③ Arthroscopy ④ Plain film X-ray Plain radiographs of chronic gout Current Opinion in Rheumatology 2009, 21:124–131 Gout by ultrasound Rheumatology 2007;46:1116–1121 Dorsal Lo Plantar Lo Medial Lo Sagittal MRI scan of the 5th MTPJ with severe tophaceous gout large tophus with low signal on T1 variable signal on the short tau inversion recovery sequence image patchy enhancement of the tophus with contrast Current Opinion in Rheumatology 2009, 21:124–131 Dual-energy CT imaging of tophi in gout multiple urate deposits urate crystal tophi Nat Rev Rheumatol.2010 Jan;6(1):30-8. Laboratory investigations to consider for gout patients Test Clinical comment Serum urate Level may be normal in an acute gout attack in up to 40~50% of patients Complete blood count Exclude myeloproliferative disorders Increased WBC may suggest possible septic arthritis Renal function Hyperuricemia occurs in approximately 50% of patients with CKD Fasting lipids, glucose and thyroid function Hyperlipidemia, DM, hypothyroidism associated with gout Urinary uric acid excretion Uricosurics contraindicated in uric acid overproducers BMJ 2006;332:1315-9 Q6. 통풍과 감별해야 할 질병 중, 즉각적인 치료를 필요로 하는 것은? ① Pseudogout ② Rheumatoid arthritis ③ Osteoarthritis ④ Septic arthritis Major consideration for differential diagnosis in gout Gout & pseudogout Septic arthritis Involved joints • 1st MTP, knee • Knee Synovial WBC • 2,000~75,000/mm3 • >100,000/mm3 Synovial fluid • Crystal examination Radiologic findings • Swelling • Gram stain/culture(+) • Effusion, normal at early stage Major consideration for differential diagnosis in gout Gout Pseudogout Sex ratio (M:F) 2-7:1 1:4 Frequent age 40-50 65-75 Frequent joint 1st MTP jt Knee Serum uric acid High Normal Radiology Erosion Chondrocalcinosis Crystal MSUM CPPD Morphology Needle Small rod-like Birefringence Strong, negative Weak, positive Q7. 이 환자에서 급성발작을 완화하기 위한 1차 선택약은? ① ACTH ② NSAIDs ③ Colchicine ④ Intra-articular glucocorticoids Therapeutic choices: Acute gout Treat at earliest signs of an attack NSAIDs and colchicine do not prevent MSU tissue deposits and damage NSAIDs Mainstay acute attack High dose first 24-48 hours : Taper dose until dose subside Caution – CHF, CKD, anticoagulation therapy, ↓hepatic function Corticosteroids Useful in CKD or if NSAIDs/ colchicine contraindicated Concern re-worsening glycemic control in diabetes Colchicine Oral, 0.6mg tid for 1-2 days Diarrhea and nausea Avoid in renal/hepatic impairment Multiple drug interactions Used less commonly due to drug toxicity Other Options Synthetic ACTH IL-1 inhibitors : canakinumab, rilonacept, anakinra Am J Manag Care 2005;11:S451-8 Pharmacologic Management Options for Acute Gout Attacks. N Engl J Med.2011 Feb 3;364(5):443-52 Mechanisms of Inflammation in Gout N Engl J Med.2011 Feb 3;364(5):443-52 일주일 후 재방문 NSAID 사용 후 pain과 swelling 감소 WBC, ESR/CRP 감소 LFTs, BUN/Cr 정상, serum urate 7.5 mg/dL Plain film X-ray: diffuse soft tissue swelling Q8. 다음 중 이 환자의 재발을 막기 위해 가장 중요한 치료는? ① Lower WBC and CRP levels to within normal range ② Ensure patient loses weight ③ Reduce serum urate level to ≤ 6.0 mg/dL ④ No action required at this time Treatment options for therapeutic goal Treatment of acute flares NSAIDs Acute Colchicine gout Prednisolone Intra-articular corticosteroids Adrenocorticotropic hormone IL-1 inhibitors (canakinumab, rilonacept, anakinra) Prophylaxis against acute flares NSAIDs Colchicine IL-1 inhibitors (canakinumab, rilonacept, anakinra) Urate-lowering therapy for chronic gout Xanthine oxidase inhibitors (allopurinol, febuxostat) Uricosuric agents (probenecid, sulfinpyrazone, benzbromarone) Pegloticase Chronic Gout Nat Rev Rheumatol.2011 Feb;7(2):77-8 환자는 allopurinol 처방받아 복용시작함 100 mg once daily로 시작 4개월에 걸쳐 300 mg once daily까지 증량 요산 농도가 낮아지며 급성 발작이 발생할 수 있 어 예방적으로 NSAID도 함께 사용 4개월 후 재방문 그 사이 몇 차례 gout attack 발생 등과 하지에 rash 발생 serum urate < 6.0 mg/dL CrCl 56 mg/day Q9. 이 환자에게 allopurinol을 사용하 면서 발생할 수 있는 문제점은? ① Hypersensitivity ② Drug interaction ③ Poor patient compliance ④ All of the above Allopurinol dose guidelines Allopurinol FDA-approved at doses up to 800mg once daily EULAR and FDA guidelines: Start at 100mg once daily to avoid gout flares Increase by 100mg once daily q 1~4 weeks until target serum urate level reached Divided allopurinol dose to bid at >300mg once daily FDA/NIH web page Ann Rheum Dis 2006; 35: 1251-60 Q10. Allopurinol에 반응하지 않는 환자 의 경우 다음 중 어떤 요산 강하제를 사 용할 수 있는가? ① Probenecid ② Rasburicase ③ Febuxostat ④ All of the above Treatment options – Chronic gout Hypouricemic agent • allopurinol, febuxostat Uricosuric agent • probenecid, sulfinpyrazone, benzbromarone Uricase • uricozyme, rasburicase, pegloticase Pathways of uric acid metabolism and renal elimination, and primary therapeutic sites of actions of gout medications Allopurinol, Febuxostat rasburicase, pegloticase probenecid, benzbromarone, RDEA594 Nat Rev Rheumatol.2011 Feb;7(2):77-8 Lancet.2011 Jan 8;377(9760) :165-77 Therapeutic algorithm for s-urate lowering in gout Nat Rev Rheumatol.2011 Feb;7(2):77-8 PEG-uricase : Puricase ® Pegylated recombinant porcine-like uricase Decrease immunogenicity relative to nonPEGylated uricase such as rasburicase Assessed in clinical trials in patients with treatment failure gout due to: Uncontrolled hyperuricemia and ongoing symptoms of gout despite ULT Dose limiting adverse reaction to other ULTs Optimal duration of therapy not yet determined Curr Rheumatol Rep 2007; 9: 258-64 Febuxostat : Adenuric® (EU), Uloric ® (US) Oral, once daily, selective xanthine oxidase inhibitor Minimal effect on other enzymes involved in purine or pyrimidine metabolism Primarily metabolized by oxidation and glucuronidation in the liver Minimal renal component of drug clearance Mild / moderate renal and hepatic impairment has little effect on PK or PD Ann Pharmacother 2006; 40: 2187-94 FACT study: SU at last 3 visits 762 patients with gout and serum urate >8.0mg/dL received febuxostat 80mg or 120mg qd or allopurinol 300mg qd for 52weeks Prophylaxis against gout flares with naproxen or colchicine during weeks 1-8 *** (n=251) (n=255) *** (n=250) FDA approved dose ***p<0.001, febuxostat vs allopurinol N Eng J Med 2005; 353: 2450-61 APEX study: Allopurinol and placebocontrolled efficacy study of febuxostat 28 week phase III randomized, double blind trial 1067 patients with gout and hyperuricemia (sUA>8mg/dL) including those with renal impairment * * FDA approved dose * n= 134 262 269 134 268 Higher proportions of patients with renal impairment achieved serum urate < 6.0mg/dL in febuxostat group vs allopurinol Arthritis Rheum 2008;59:1540-8 FOCUS study: Reduction from baseline SU at final visit n=116; 59 patients completed 5 years of study Reduction from baseline SUA (%) FDA approved dose n= 6 41 11 Rheumatology 2009; 48: 188-94 CONFIRMS trial: The urate-lowering efficacy and safety of febuxostat of the hyperuricemia of gout 6 months randomized, double blind trial 2269 patients with gout and hyperuricemia (sUA>8mg/dL) including those with renal impairment subgroup achieving sUA <6.0 mg/dL at Final Visit a: P<0.001 Urate-lowering efficacy of febuxostat 80mg exceeded that of febuxostat 40mg and allopurinol (300/200mg). In subjects with mild/moderate renal impairment, both febuxostat doses were more efficacious than allopurinol and equally safe Arthritis Res Ther.2010;12(2):R63. Apr 6. IL-1 inhibition : anakinra and rilonacept Ann Rheum Dis 2009;68;1517-1519 Pharmacologic Management Options for Hyperuricemia Therapy in Gout Pharmacologic Management Options for Hyperuricemia Therapy in Gout Update on gout: new therapeutic strategies and options The prevalence of gout has approximately doubled in the past two decades, along with increases in its severity, treatment complexity and refractoriness These advances have the potential to improve risk stratification for patients with incident gout and to optimize urate-lowering therapy via pharmacogenomics Evolution in the evidence base for allopurinol, colchicine and oral glucocorticosteroid administration has validated improved and costeffective treatment strategies for most patients Febuxostat and biologic agents in development (interleukin 1 inhibitors and pegloticase) represent substantial therapeutic advances, particularly for severe, treatment-refractory gout, and patients with comorbidities or intolerance to other drugs Nat. Rev. Rheumatol. 6, 30–38 (2010) Changing points of Harrison 18th (gout part) Radiographic Features : Ultrasound, CT and MRI are being studied and are likely to become more sensitive for early changes. Treatment: Gout, Acute Gouty Arthritis : One useful regimen is one 0.6mg tablet given every 8 h with subsequent tapering. Intravenous colchicine has been taken off the market….The most effective drugs are any of those with a short half-life and include indomethacin, 25– 50mg tid; naproxen, 500mg bid; ibuprofen, 800mg tid; and diclofenac, 50mg tid. Glucocorticoids given IM or orally..... Based on recent evidence on the essential role of the inflammasome and interleukin 1 (IL-1) in acute gout, anakinra has been used and other inhibitors of IL-1 are under investigation. Changing points of Harrison 18th (gout part) Treatment: Gout, Hypouricemic Therapy : the hyperuricemia cannot be corrected by simple means (… decreased use of fructose-containing foods and beverages…). Probenecid…increased gradually as needed up to 3g per day to maintain a serum uric acid level <360mol/L (6mg/dL)….Patients with mild cutaneous reactions to allopurinol can reconsider the use of a uricosuric agent or take febuxostat, a new, chemically unrelated specific xanthine oxidase inhibitor. Febuxostat is approved at 40 or 80 mg once a day and does not require dose adjustment in mild to moderate renal disease…..Colchicine should not be used in dialysis patients and is given in lower doses in patients with renal disease or with P gylcoprotein or CYP3A4 inhibitors such as clarithromycin that can increase toxicity or colchicine. Pegloticase is a new urate-lowering biologic agent that can be effective in patients allergic to or failing xanthine oxidase inhibitors. New uricosurics are undergoing investigation.