GOUT

Definition Heterogeneous group of diseases involving : An elevated serum urate concentration (hyperuricemia) Recurrent attacks of acute arthritis in which monosodium urate monohydrate crystals are demonstrable in synovial fluid leukocytes Aggregates of sodium urate monohydrate crystals (tophi) deposited chiefly in and around joints, which sometimes lead to deformity and crippling Renal disease involving glomerular, tubular, and interstitial tissues and blood vessels Uric acid nephrolithiasis Hyperuricemia : serum uric acid >7mg% (males) and >6mg% (females)

Epidemiology Prevalence of hyperuricemia 2.3 – 41.4% in various populations. 2.3 – 41.4% in various populations. Corresponds with serum creatinine /BUN levels, body weight, height, age, blood pressure, and alcohol intake. (Taiwan) Corresponds with serum creatinine /BUN levels, body weight, height, age, blood pressure, and alcohol intake. (Taiwan) Body bulk (as estimated by body weight, surface area, or body mass index) has proved to be one of the most important predictors of hyperuricemia in people of widely differing races and cultures. Body bulk (as estimated by body weight, surface area, or body mass index) has proved to be one of the most important predictors of hyperuricemia in people of widely differing races and cultures. Incidence of Gout Varies depending on population studied – 1.8 /1000 – 3.2/1000 Varies depending on population studied – 1.8 /1000 – 3.2/1000 RR for blacks slightly higher (1.3) RR for blacks slightly higher (1.3)

1977 ACR criteria for acute gout The presence of characteristic urate crystals in the joint fluid, or a tophus proved to contain urate crystals by chemical means or polarized light microscopy, or the presence of 6 of the following 12 clinical, laboratory, and radiographic phenomena: 1. More than one attack of acute arthritis 2. Maximum inflammation developed within 1 day 3. Monoarthritis attack 4. Redness observed over joints 5. First metatarsophalangeal joint painful or swollen 6. Unilateral first metatarsophalangeal joint attack 7. Unilateral tarsal joint attack 8. Tophus (proven or suspected) 9. Hyperuricemia 10. Asymmetric swelling within a joint on x ray/exam 11. Subcortical cysts without erosions on x ray 12. Monosodium urate monohydrate microcrystals in joint fluid during attack 13. Joint fluid culture negative for organisms during attack

Classification of Hyperuricemia and Gout Primary Hyperuricemia and Gout with No Associated Condition Uric acid undersecretion(80%–90%) Idiopathic Idiopathic Urate overproduction (10%–20%) Idiopathic HGPRT deficiency HGPRT deficiency PRPP synthetase overactivity PRPP synthetase overactivity Secondary Hyperuricemia and Gout with Identifiable Associated Condition Secondary Hyperuricemia and Gout with Identifiable Associated Condition Uric acid undersecretion Uric acid undersecretion Renal insufficiency Renal insufficiency Polycystic kidney disease Polycystic kidney disease Lead nephropathy Lead nephropathy Drugs(Diuretics,Salicylates (low dose), Pyrazinamide, Ethambutol,Niaci n, Cyclosporine, Didanosine ) Drugs(Diuretics,Salicylates (low dose), Pyrazinamide, Ethambutol,Niaci n, Cyclosporine, Didanosine ) Urate overproduction Myeloproliferative/ Lymphoproliferative diseases / Hemolytic anemias/ Polycythemia vera/Other malignancies Myeloproliferative/ Lymphoproliferative diseases / Hemolytic anemias/ Polycythemia vera/Other malignancies Psoriasis/Glycogen storage disease Psoriasis/Glycogen storage disease Dual mechanism Dual mechanism Obesity, ETOH,Hypoxemia and hypoperfusion Obesity, ETOH,Hypoxemia and hypoperfusion

Outcomes in Gout Clinical outcomes 60% of untreated gout have attacks within 1 yr, 78% have recurrence in 2 yrs, only 7% have no attacks in 10 yrs. 60% of untreated gout have attacks within 1 yr, 78% have recurrence in 2 yrs, only 7% have no attacks in 10 yrs. Chronic tophaceous gout develops after yrs of untreated gout. Chronic tophaceous gout develops after yrs of untreated gout. Incidence decreased from 14% in 1949 –> 3% in 1972.(Oduffy et al)------’colchicine’ effect’ Incidence decreased from 14% in 1949 –> 3% in 1972.(Oduffy et al)------’colchicine’ effect’ Hyperuricemia control superior to self medication alone. Hyperuricemia control superior to self medication alone. Humanistic outcomes Treatment outcomes decrease QOL in pts with gout. Treatment outcomes decrease QOL in pts with gout. Adherence to allopurinol only 56%. (Riedel et al, managed care study) Adherence to allopurinol only 56%. (Riedel et al, managed care study) Economic outcomes Direct burden annually is 27.4 million USD. (men only) Direct burden annually is 27.4 million USD. (men only) Patients with acute gout miss 3-5 days of work annually. Patients with acute gout miss 3-5 days of work annually. Average cost-effectiveness ratio for patients using urate-lowering drugs is $487 to $983 compared with a cost of $5070 to $6571 for those not using these agents. Average cost-effectiveness ratio for patients using urate-lowering drugs is $487 to $983 compared with a cost of $5070 to $6571 for those not using these agents.

Diagnosis Clinical : In men, initial attack monoarticular – 1 st MTP joint(50% of cases) In men, initial attack monoarticular – 1 st MTP joint(50% of cases) Other jts involved – instep/knees/wrists/ olecranon bursa. Often begins at night. Usually abrupt, severely painful. Other jts involved – instep/knees/wrists/ olecranon bursa. Often begins at night. Usually abrupt, severely painful. Later attacks – polyarticular, assoc with systemic signs., most often initial presenting complaint in women. (hands/tarsal jts/knees) Later attacks – polyarticular, assoc with systemic signs., most often initial presenting complaint in women. (hands/tarsal jts/knees) Precipitants – Minor trauma, ETOH, diuretic Rx, Surgery, severe medical illness, hypouricemic Rx. Precipitants – Minor trauma, ETOH, diuretic Rx, Surgery, severe medical illness, hypouricemic Rx. Tophi – Classically, helix/ antihelix,but rare ; more common, hands, feet, olecranon bursa. Complications : ulceration/infection. Tophi – Classically, helix/ antihelix,but rare ; more common, hands, feet, olecranon bursa. Complications : ulceration/infection. Laboratory:- GOLD STANDARD SF Analysis – WBC ct – /ml SF Analysis – WBC ct – /ml MSU crystals- needle shaped, negatively birefringent. MSU crystals- needle shaped, negatively birefringent. Serum Uric acid level – important in monitoring treatment.(42% - normal levels) Serum Uric acid level – important in monitoring treatment.(42% - normal levels) 24 hr uric acid collection –useful in young pts with gout/ + fam h/o 24 hr uric acid collection –useful in young pts with gout/ + fam h/o

Diagnosis Radiologic X RAY : Punched out erosions – only 45% of pts have them, takes 6 yrs to develop Martel’s sign CT/MRI/US/Bone scan Sensitive, non specific

Treatment Acute gouty arthritis: Anti- inflammatory drugs ( if s.creat < 2mg/dl, no PUD) Anti- inflammatory drugs ( if s.creat < 2mg/dl, no PUD) Colchicine preferred in pts without confirmed diagnosis of gout. Colchicine preferred in pts without confirmed diagnosis of gout. Endpoints – improvement in jt symptoms/ GI symptoms/ 10 doses taken. NSAIDs if diagnosis confirmed. Any NSAID can be used. NSAIDs if diagnosis confirmed. Any NSAID can be used. Newer agents – Etoricoxcib 120 OD comparable to indomethacin 50 TID. In c/o renal failure /PUD - IM ACTH, oral /iv prednisone. In c/o renal failure /PUD - IM ACTH, oral /iv prednisone. Avoid adjusting dosage of urate lowering agents. Avoid adjusting dosage of urate lowering agents. Prophylaxis : Only indicated if patient is started on urate lowering Rx. Only indicated if patient is started on urate lowering Rx. Colchicine( 1-3 pills a day)/ NSAID( in colchicine intolerant). Colchicine( 1-3 pills a day)/ NSAID( in colchicine intolerant). Does not alter crystal deposition and development of tophi. Does not alter crystal deposition and development of tophi. Continue till serum urate levels stabilize and no attacks for 3 – 6 mths. Continue till serum urate levels stabilize and no attacks for 3 – 6 mths. If long term prophylactic colchicine given, check CBC,CK every 6 mths. If long term prophylactic colchicine given, check CBC,CK every 6 mths.

Treatment (contd) Control of hyperuricemia Differing opinions regarding initiation esp. around 1 st attack. Differing opinions regarding initiation esp. around 1 st attack. Clear evidence if erosions + on X-ray / chronic tophaceous gout/ >2 gout attacks per year. Clear evidence if erosions + on X-ray / chronic tophaceous gout/ >2 gout attacks per year. Goal : s. urate levels < 6 mg%. Goal : s. urate levels < 6 mg%. Serial s. uric acid at least once every 6 mths upon initiation. Serial s. uric acid at least once every 6 mths upon initiation. Choice of agents : Choice of agents : Xanthine oxidase inhibitor Uricosuric agents. Equal efficacy in pts with normal renal function and who excrete < 800 mg/day of uric acid.

Treatment (contd) Xanthine oxidase inhibitors Allopurinol- only prescription drug available. Allopurinol- only prescription drug available. Renally excreted, therefore adjust dose if s.creat > 2mg% or CrCl 2mg% or CrCl <50 Usually DOC in most patients. Usually DOC in most patients. S/E – GI / rash / sarcoid like reaction/Allopurinol hypersensitivity syndrome S/E – GI / rash / sarcoid like reaction/Allopurinol hypersensitivity syndrome Drug interaction – esp. with 6 MP/azathioprine/ warfarin/theophylline. Drug interaction – esp. with 6 MP/azathioprine/ warfarin/theophylline. Desensitization protocols exist. Desensitization protocols exist. Oxypurinol – possible option Oxypurinol – possible option Uricosuric agents Indications – no h/o renal calculi, pts <60 yrs, U.A excretion < 800 mg/d Indications – no h/o renal calculi, pts <60 yrs, U.A excretion < 800 mg/d CI - + nephrolithiasis, renal insufficiency CI - + nephrolithiasis, renal insufficiency Limit ASA to 81 mg/day Limit ASA to 81 mg/day Probenecid/ Benzbromarone Probenecid/ Benzbromarone

Treatment (contd) Adjuvant Rx Control obesity,ETOH intake, hyperlipidemia,HTN Control obesity,ETOH intake, hyperlipidemia,HTN Losartan / fenofibrate – weakly uricosuric Losartan / fenofibrate – weakly uricosuric Diet – moderation in purine intake. Makes a difference of up to 1mg % in s. uric acid. Diet – moderation in purine intake. Makes a difference of up to 1mg % in s. uric acid. Beer, other alcoholic beverages. Beer, other alcoholic beverages. Anchovies, sardines in oil, fish roes, herring. Anchovies, sardines in oil, fish roes, herring. Yeast. Yeast. Organ meat (liver, kidneys, sweetbreads) Organ meat (liver, kidneys, sweetbreads) Legumes (dried beans, peas) Legumes (dried beans, peas) Meat extracts, consommé, gravies. Meat extracts, consommé, gravies. Mushrooms, spinach, asparagus, cauliflower Mushrooms, spinach, asparagus, cauliflower

Treatment (contd) Newer agents PEG- uricase PEG- uricase Febuxostat Febuxostat Asymptomatic hyperuricemia Investigate cause Investigate cause No recommendations for Rx. No recommendations for Rx.