1. GOUT Wayne Blount, MD, MPH Professor, Emory Univ. S.O.M.

2. OBJECTIVES Identify diagnostic criteria for gout Identify diagnostic criteria for gout Identify 3 treatment goals for gout Identify 3 treatment goals for gout Name the agents used to treat the acute flares of gout and the chronic disease of gout Name the agents used to treat the acute flares of gout and the chronic disease of gout

3. Why Worry About Gout ? Prevalence increasing Prevalence increasing May be signal for unrecognized comorbidities : ( Not to point of searching) May be signal for unrecognized comorbidities : ( Not to point of searching) Obesity (Duh!) Metabolic syndrome DMHTN CV disease Renal disease

4. URATE, HYPERURICEMIA & GOUT Urate: end product of purine metabolism Urate: end product of purine metabolism Hyperuricemia: serum urate > urate solubility (> 6.8 mg/dl) Hyperuricemia: serum urate > urate solubility (> 6.8 mg/dl) Gout: deposition of monosodium urate crystals in tissues Gout: deposition of monosodium urate crystals in tissues

5. HYPERURICEMIA & GOUT Hyperuricemia caused by Hyperuricemia caused byOverproductionUnderexcretion No Gout w/o crystal deposition No Gout w/o crystal deposition

6. THE GOUT CASCADE Urate Urate OevrproductionUnderexcretion OevrproductionUnderexcretion Hyperuricemia Hyperuricemia ________________________________________ ________________________________________ SilentGoutRenalAssociated SilentGoutRenalAssociated Tissue manifestationsCV events & Tissue manifestationsCV events & Deposition mortality Deposition mortality

7. GOUT: A Chronic Disease of 4 stages Asymptomatic hyperuricemia Asymptomatic hyperuricemia Acute Flares of crystallization Acute Flares of crystallization Intervals between flares Intervals between flares Advanced Gout & Complications Advanced Gout & Complications

8. ACUTE GOUTY FLARES Abrupt onset of severe joint inflammation, often nocturnal; Abrupt onset of severe joint inflammation, often nocturnal; Warmth, swelling, erythema, & pain; Possibly fever Untreated? Resolves in 3-10 days Untreated? Resolves in 3-10 days 90% 1 st attacks are monoarticular 90% 1 st attacks are monoarticular 50% are podagra 50% are podagra

9. SITES OF ACUTE FLARES 90% of gout patients eventually have podagra : 1st MTP joint 90% of gout patients eventually have podagra : 1st MTP joint

10. Sites Can occur in other joints, bursa & tendons Can occur in other joints, bursa & tendons

11. INTERVALS SANS FLARES Asymptomatic Asymptomatic If untreated, may advance If untreated, may advance Intervals may shorten Intervals may shorten Crystals in asx joints Crystals in asx joints Body urate stores increase Body urate stores increase

12. FLARE INTERVALS Silent tissue deposition & Hidden Damage Silent tissue deposition & Hidden Damage

13. ADVANCED GOUT Chronic Arthritis Chronic Arthritis X-ray Changes X-ray Changes Tophi Develop Tophi Develop Acute Flares continue Acute Flares continue

14. ADVANCED GOUT Chronic Arthritis Chronic Arthritis Polyarticular acute flares with upper extremities more involved Polyarticular acute flares with upper extremities more involved

15. TOPHI Solid urate deposits in tissues Solid urate deposits in tissues

16. TOPHI Irregular & destructive Irregular & destructive

17. TOPHI RISK FACTORS Long duration of hyperuricemia Long duration of hyperuricemia Higher serum urate Higher serum urate Long periods of active, untreated gout Long periods of active, untreated gout

18. RADIOLOGIC SIGNS

19. X-RAYS

20. X-RAYS

21. DIAGNOSING GOUT Hx & P.E. Hx & P.E. Synovial fluid analysis Synovial fluid analysis Not Serum Urate Not Serum Urate

22. SERUM URATE LEVELS Not reliable Not reliable May be normal with flares May be normal with flares May be high with joint Sx from other causes May be high with joint Sx from other causes

23. GOUT RISK FACTORS Male Male Postmenopausal female Postmenopausal female Older Older Hypertension Hypertension Pharmaceuticals: Pharmaceuticals: Diuretics, ASA, cyclosporine

24. GOUT RISK FACTORS Transplant Transplant Alcohol intake Alcohol intake Highest with beer Not increased with wine High BMI (obesity) High BMI (obesity) Diet high in meat & seafood Diet high in meat & seafood

25. SYNOVIAL FLUID ANALYSIS (Polarized Light Microscopy) The Gold standard The Gold standard Crystals intracellular during attacks Crystals intracellular during attacks Needle & rod shapes Needle & rod shapes Strong negative birefringence Strong negative birefringence

26. SYNOVIAL FLUID

27. DIFFERENTIAL DIAGNOSIS Pseudogout: Chondrocalcinosis, CPPD Pseudogout: Chondrocalcinosis, CPPD Psoriatic Arthritis Psoriatic Arthritis Osteoarthritis Osteoarthritis Rheumatoid arthritis Rheumatoid arthritis Septic arthritis Septic arthritis Cellulitis Cellulitis

28. Gout vs. CPPD Similar Acute attacks Similar Acute attacks Different crystals under Micro; Different crystals under Micro; Rhomboid, irregular in CPPD

29. Gout vs CPPD

30. RA vs Gout Both have polyarticular, symmetric arthritis Both have polyarticular, symmetric arthritis Tophi can be mistaken for RA nodules Tophi can be mistaken for RA nodules

31. RA vs Gout

32. REDNECK MEDICAL TERMS “BENIGN” : WHAT YOU BE AFTER YOU BE EIGHT “BENIGN” : WHAT YOU BE AFTER YOU BE EIGHT

33. TREATMENT GOALS Rapidly end acute flares Rapidly end acute flares Protect against future flares Reduce chance of crystal inflammation Prevent disease progression Prevent disease progression Lower serum urate to deplete total body urate pool Correct metabolic cause

34. ENDING ACUTE FLARES Control inflammation & pain & resolve the flare Control inflammation & pain & resolve the flare Not a cure Not a cure Crystals remain in joints Crystals remain in joints Don’t try to lower serum urate during a flare Don’t try to lower serum urate during a flare Choice of med not as critical as alacrity & duration EBM Choice of med not as critical as alacrity & duration EBM

35. Acute Flare Med Choices NSAIDS NSAIDS Colchicine Colchicine Corticosteroids Corticosteroids

36. MED Considerations NSAIDS : NSAIDS : Interaction with warfarin Contraindicated in: Renal disease PUD GI bleeders ASA-induced RAD

37. MED Considerations Colchicine : Colchicine : Not as effective “late” in flare Drug interaction : Statins, Macrolides, Cyclosporine Contraindicated in dialysis pt.s Cautious use in : renal or liver dysfunction; active infection, age > 70

38. MED Considerations Corticosteroids : Corticosteroids : Worse glycemic control May need to use mod-high doses

39. TREATMENT GOALS Rapidly end acute flares Rapidly end acute flares Protect against future flares Reduce chance of crystal inflammation Prevent disease progression Prevent disease progression Lower serum urate to deplete total body urate pool Correct metabolic cause

40. PROTECTION VS. FUTURE FLARES Colchicine : 0.5-1.0 mg/day Colchicine : 0.5-1.0 mg/day Low-dose NSAIDS Low-dose NSAIDS Both decrease freq & severity of flares Both decrease freq & severity of flares Prevent flares with start of urate-lowering RX Prevent flares with start of urate-lowering RX Best with 6 mos of concommitant RX Best with 6 mos of concommitant RXEBM Won’t stop destructive aspects of gout Won’t stop destructive aspects of gout

41. TREATMENT GOALS Rapidly end acute flares Rapidly end acute flares Protect against future flares Reduce chance of crystal inflammation Prevent disease progression Prevent disease progression Lower serum urate to deplete total body urate pool Correct metabolic cause

42. PREVENT DISEASE PROGRESSION Lower urate to < 6 mg/dl : Depletes Lower urate to < 6 mg/dl : Depletes Total body urate pool Deposited crystals EBM RX is lifelong & continuous RX is lifelong & continuous MED choices : MED choices : Uricosuric agents Xanthine oxidase inhibitor

43. PREVENT THIS

44. URICOSURIC AGENTS Probenecid, (Losartan & fenofibrate for mild disease) Probenecid, (Losartan & fenofibrate for mild disease) Increased secretion of urate into urine Increased secretion of urate into urine Reverses most common physiologic abnormality in gout ( 90% pt.s are underexcretors) Reverses most common physiologic abnormality in gout ( 90% pt.s are underexcretors)

45. XANTHINE OXIDASE INHIBITOR Allopurinol : Allopurinol : Blocks conversion of hypoxanthine to uric acid Blocks conversion of hypoxanthine to uric acid Effective in overproducers Effective in overproducers May be effective in underexcretors May be effective in underexcretors Can work in pt.s with renal insufficiency Can work in pt.s with renal insufficiency

46. WHICH AGENT ? AllopurinolUricosuric Issue in renal disease X X Drug interactions X X Potentially fatal hypersen- sitivity syndrome X sitivity syndrome X Risk of nephrolithiasis X Mutiple daily dosing X

47. WHICH AGENT Base choice on above considerations & whether pt is an overproducer or underexcretor : Need to get a 24-hr. urine for urate excretion: Base choice on above considerations & whether pt is an overproducer or underexcretor : Need to get a 24-hr. urine for urate excretion: < 700 --- underexcretor (uricosuric) > 700 --- overproducer (allopurinol)

48. NEW AGENTS RX gaps : RX gaps : Can’t always get urate < 6 Can’t always get urate < 6 Allergies Allergies Drug interactions Drug interactions Allopurinol intolerance Allopurinol intolerance Worse Renal disease Worse Renal disease

49. URICASE ENZYMES (Stay Tuned) Catabolize urate to allantoin: Catabolize urate to allantoin: More soluble, excretable form Currently approved for hypoeruricemia in tumor lysis syndrome Currently approved for hypoeruricemia in tumor lysis syndrome Some concerns: fatal immunogenicity & unknown long-term effects Some concerns: fatal immunogenicity & unknown long-term effects

50. CASE STUDIES

51. CASE J.F. CASE J.F. 80 YO W F c/o acute overnight pain & swelling in R knee 80 YO W F c/o acute overnight pain & swelling in R knee PE: 5’1’’ & 180 lbs PE: 5’1’’ & 180 lbs R knee swollen, warm & erythematous PMH : HTN x 5 yrs PMH : HTN x 5 yrs Meds: HCTZ (25 QD) & ASA Meds: HCTZ (25 QD) & ASA SH : 20 PY smoker; 5 wine drinks/wk SH : 20 PY smoker; 5 wine drinks/wk

52. WHAT ARE J.F.’s RISK FACTORS FOR GOUT ? A. HTN A. HTN B. SMOKER B. SMOKER C. HCTZ C. HCTZ D. ASA D. ASA WINE CONSUMPTION WINE CONSUMPTION OBESITY OBESITY AGE AGE POSTMENOPAUSAL POSTMENOPAUSAL

53. HOW WOULD YOU DX GOUT ? A. HX & PE COMPATIBLE A. HX & PE COMPATIBLE B. CHECK SERUM URATE LEVEL B. CHECK SERUM URATE LEVEL ASSESS SYNOVIAL FLUID ASSESS SYNOVIAL FLUID TRIAL OF COLCHICINE TRIAL OF COLCHICINE CHECK X-RAYS CHECK X-RAYS

54. IF YOU DX GOUT, WHAT RX TODAY? (& Why?) A. MOTRIN A. MOTRIN B. INDOCIN B. INDOCIN C. PREDNISONE C. PREDNISONE D. ALLOPURINOL D. ALLOPURINOL E. PROBENECID E. PROBENECID F. COLCHICINE F. COLCHICINE

55. NEXT STEP FOR J.F. ? A. Modify risk factors A. Modify risk factors B. Give refills to rx next flare B. Give refills to rx next flare C. Start colchicine to prevent flares C. Start colchicine to prevent flares D. Check serum urate level D. Check serum urate level E. Start allopurinol E. Start allopurinol F. Start probenecid F. Start probenecid

56. CASE M.B. CASE M.B. 56 YO W M c/o hand stiffness & growths 56 YO W M c/o hand stiffness & growths PE : 6’2’’ & 205 lbs PE : 6’2’’ & 205 lbs Multiple tophi; chronic arthritis PMH : DM x 8 yrs; gout x4 yrs, but no flares x 3 yrs, lost 20# on Atkins diet PMH : DM x 8 yrs; gout x4 yrs, but no flares x 3 yrs, lost 20# on Atkins diet Meds: Glyburide; colchicine (0.6 mg TID) Meds: Glyburide; colchicine (0.6 mg TID) Labs: Creat.= 2.0; Urate = 11.4 Labs: Creat.= 2.0; Urate = 11.4

57. IN WHAT STAGE OF GOUT IS M.B. ? A. Doesn’t have gout A. Doesn’t have gout B. ASX. Hyperuricemia B. ASX. Hyperuricemia C. Interflare period C. Interflare period D. Advanced Gout D. Advanced Gout

58. WOULD YOU CHANGE MD’S RX ? No – Not gout No – Not gout No – No flare x 3 yrs. No – No flare x 3 yrs. Yes - Increase colchicine Yes - Increase colchicine Yes – Add allopurinol Yes – Add allopurinol Yes – Add benemid Yes – Add benemid

59. WHAT OTHER ISSUES WOULD YOU CONSIDER ? Renal dysfunction Renal dysfunction Weight Weight DM DM Glyburide Glyburide Diet Diet

60. CONCLUSIONS Gout is chronic with 4 stages Gout is chronic with 4 stages Uncontrolled gout can lead to severe disease Uncontrolled gout can lead to severe disease Separate RX for flares & preventing advancement Separate RX for flares & preventing advancement Many meds for flares Many meds for flares Treating the disease requires lowering urate Treating the disease requires lowering urate Get a 24-hr urine for urate excretion Get a 24-hr urine for urate excretion

61. QUESTIONS QUESTIONS