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Management of Acute Gout

Management of Acute Gout. John J. Cush, MD Presbyterian Hospital of Dallas. Who Manages Acute Gout. Rheumatologists:musculoskeletal medicine specialists Tends to see minority of Gout patients, often those with severe, recalcitrant, chronic disease

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Management of Acute Gout

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  1. Management of Acute Gout John J. Cush, MD Presbyterian Hospital of Dallas

  2. Who Manages Acute Gout • Rheumatologists:musculoskeletal medicine specialists • Tends to see minority of Gout patients, often those with severe, recalcitrant, chronic disease • Compared with RA (similar prevalence), far fewer gout patients are seen/followed by rheumatologists • Rheum referral more accurate dx, shorter Sx duration (3.1day), shorter hospitalization (7.4 days), lower hospitalization costs ($5995 less). Solomon DH. Ann Int Med 12:52, 1997 • Primary Care and Emergency Dept Physicians • First line for acute gouty attacks • Education is needed to optimize outcomes and limit toxicity • Survey in Mexico shows significant drug misuse by non-rheumatologists (GP,IntMed,Ortho) Rev Invest Clin 55:621,2003 • Survey of N.Zealand Rheums and GPs: differences in NSAID, colchicine, allopurinol use. Stuart RD N Z Med J 104:115,1991

  3. Gout • Disorder of urate metabolism, results in deposition of monosodium urate (MSU) crystals in joints and soft tissues. • 1st described 5th century BC – Hippocrates described gout as “the king of diseases and the disease of kings” • Burden: In 1981, 37 million lost work days in US* • 2003 Kim et al estimates the annaul cost of Acute Gout is $27,378,494 in the USA (underestimate: women excluded & not all indirect and intangible costs included) * Roubenoff et al

  4. NHANES III 1988-94 (2.7%) (5.6%) National Health Intv Survey (&PE) = 17,030 men/women

  5. Prevalence of Gout NHANES III 1988-94

  6. Gout • Acute: intermittent/recurrent, LE, ascending, inflammatory mono/oligoarthritis, “Podagra” • Intercritical gout: between attacks • Tophaceous gout: chronic, accumulation of MSU crystals as “tophi” (may look like RA) • Asymptomatic hyperuricema: elevated uric acid without evidence of gout, nephrolithiasis. Higher levels increase risk of these diseases • Renal: nephrolithiasis, gouty nephropathy, uric acid nephropathy

  7. Acute (Classic) Gout • Acute, severe onset of pain, warmth, inflammation, Limited motion  cant walk, cant put sheet on it. • Podagra (50-90%): pain, swelling warmth in 1st MTP • Joints: MTP, tarsus, ankle, knee • Associated with fever, leukocytosis, high ESR or C-reactive protein levels. • Initially monarthritis (80-90%) and with repeated attacks ascends from the lower extremity (initial polyarthritis in elderly, women, myeloproliferative disorders, CyA) • Precipitants: stress, trauma, excess alcohol, infection, surgery, drugs • Chronology: untreated attacks last 7-14 days. Acute gout risk of repeat attack estimated to be 78% w/in 2 yrs

  8. Natural Hx of Acute AttackBellamy N, et al. Br J Clin Pharmacol 24:33-6, 1987 • 11 volunteers with acute podagra studied • 2 withdrew on day 4 for severe pain • 9 remaining showed improvement • Pain by day 5 • Swelling by day 7 • Tenderness improved in 7/9 by day 7 (2 persisted) • But only 3 noted resolution of pain during 7d study • Implications for clinical trial endpoints? • Pain improvement/resolution by day 3-5 • Resolution of symptoms, return to normal activity

  9. Acute Gout • Laboratory Findings • 40-49% will have normal uric acid levels • Leukocytosis common • ESR and CRP elevated • No indices of chronic inflammatory disease (alb, Hgb) • Measureable elevations in IL-6 and IL-1 • Radiographic findings • Soft tissue swelling (Opacities = tophi) • Normal Joint space and Normal ossification • Erosions: nonarticular, punched out, Sclerotic margins, overhanging edge

  10. Gouty Tophi • Incidence has decreased over last few decades • Seen in 25-50% of untreated patients (after 10-20yrs) • Location: Olecranon, bursae, digits, helix of ear • Damages bone, periarticular structures and soft tissues • Palpable measure of total body urate load • Other Extraarticular Complications • Renal • Uric acid calculi (seen in10-15% of gout pts) • Chronic urate nephropathy (in those with tophi) • Acute uric acid nephropathy (in pts undergoing chemotherapy) • Hypertensive Renal disease is the most common cause of renal disease in gout

  11. Uric Acid • Random hyperuricemia ≠ gout (likely CRI, diuretic use) • Acute attack: Urate levels may be normal, low or high • 40-49% of acute gouty attacks normouricemic • Mechanism: increased excretion of uric acid • Probably mediated by IL-6, inflammation • Urano W, et al. J Rheumatol 29:1950-3, 2002 • Schlesinger N, et al. J Rheumatol 24: 2265-6, 1997 • Negative association between Gout – RA • Few reports of both coexisting in literature • RF preferentially binds MSU coated with IgG and inhibited neutrophil chemiluminescence (RF may block interaction of crystal bound IgG and Fc recpt)

  12. Diagnosis of Gout • 1977 ARA criteria: Urate crystals*: IA or Tophus • Any 6 of following: > 1 attack acute arthritis; Max. inflammation w/in 1day; Erythema over joint; Podagra; hx podagra; Unilateral tarsal involvement; Tophus; Hyperuricemia; Asymmetric swelling on xray; subcortical cyst w/o erosion; c/s neg. inflam arthritis • Practical Approach: Acute or recurrent inflammatory monarthritis/oligoarthritis • With evidence of MSU crystal identification OR • One of the following: • History of recurrent, intermittent similar attacks • Evidence of hyperuricemia • Xray evidence of antecedent gouty damage * Wallace et al 1977 (sensitivity 84.4%, specificity 100%)

  13. Overview: Gout Management • Acute Rx: NSAIDs > steroids > colchicine (oral only) • Steroids: PO, IM, intraarticular • Chronic Rx: colchicine, probenecid, allopurinol • > 2-3 attacks/year  initiate prophyllaxis (cost effective) • Probenecid: uricosuric, promotes excretion • Don’t use w/ CRI, nephrolithiasis, Tophaceous gout • Colchicine: (diarrhea) decr. PMN motility, activity • Allopurinol: decrease formation- use w/ CRF, renal stones, Tophaceous gout, Uric acid > 11 * * Adjust dose for renal insufficiency

  14. Benefit Risk Limitations of Current Gout Drugs • NSAIDs • Colchicine • Allopurinol • Sulfinpyrazone ?Elderly ?Renal insufficiency ?Peptic Ulcer disease ?Hepatic dysfunction Need for Safer Agents

  15. Acute Gout Management • Confirm Diagnosis • Prevention: diet, weight reduction, avoid alcohol diuretic • FDA approved therapies: indomethacin, naproxen, sulindac, colchicine, allopurinol, sulfinpyrazone • Unapproved for Acute Gout: • Variety of NSAIDs • Corticotrophin, corticosteroids: for monarticular attacks (IA), polyarticular attacks (IM, PO), when NSAID contraindicated. ACTH has been used since 1949 and may be superior to indomethacin in some trials. • AVOID Uricosuric drugs: Probenecid, Sulfinpyrazone • (PotentiaL adjunctive agents: losartan (24%↑), fenofibrate • Fenofibrate lowers Urate 19%, increases excretion 36%

  16. Acute Gout Management • Regional Differences • NSAIDs Preferred: USA, Canada, N. Zealand, Australia • Colchicine Preferred: France, EU (diagnostic?) • Colchicine + NSAID in 32% • Minority use uricosurics (or test 24hr urine urate) • Duration of Therapy: 7-30 days • No formal guidelines advocated or studied

  17. Acute Gout Management * or equivalent antiinflammatory dose

  18. no yes no yes # Joints Involved? 1 >1 NSAIDs Contraindicated? • Renal insufficiency • Peptic ulcer disease • Congestive heart failure • NSAID intolerance NSAIDs Antiinflamatory doses Treatment Acute Gout Corticosteroids Are Corticosteroids Contraindicated? Oral Colchicine Intraarticular PO Steroid Oral or Intraarticular Steroid Lipsky PE, Alarcon GS, Bombardier C, Cush JJ, Ellrodt AG, Gibofsky A, Heudebert G, Kavanaugh AF, et al. Am J Med 103(6A):49S-85S, 1997

  19. Colchicine • Alkaloid of the Colchicum species • Antiinflammatory effects mediated by ability to inhibit microtubule and PMN activity • PK: mean terminal ½ life: 9hrs (IV 19 min – 16 hours). Tightly binds microtubules (PMNs). Concentrates liver, spleen & intestine. • Excreted in urine and bile. Undergoes enterohepatic recirculation • Undergoes demethylation by CYP 3A4 (interacts with cimetadine, terfenidine, EES, ketoconazole, diltiazem, nifedipine, cyclosporine, statins • May cross placent. + found in breast milk • Off label indications: gout, pseudogout, amyloidosis, familial mediterranean fever, hepatic cirrhosis, dermatitis herpetiformis, Behcets, Sweets syndrome • Biologic effects: Binds tubules, inhibits cell migration, adherence, degranulation. Inhibits IL-8, ICAM, E-selectin, L-Selectin., IL-1. Also decreases insulin, thyroid, TSH, amylase, catecholamine synthesis, lysosomal hydrolase release, fibroblast proliferation

  20. Colchicine Advantages • Long history of use (acute and chronic Rxs) • Diagnositic specificity (96%); Sensitivity (70%) • Faster onset 6-12 hours (IV) • Corticosteroids 12-24 hrs; NSAIDs: 24-48 hours • Tx surgical (NPO) patients, NSAID intolerant/contraindic. • Cost ! • Yu T. 20 yrs retrospective study 540 pts (518M) • Results: Excellent 82%, Satisfactory 12%, Poor 5% • Few were intolerant • No cases of renal or hematologic toxicty w/ chronic use • Semin Arthritis Rheum 12:256-64, 1982

  21. Clinical Trials in Gout • 1939 Lockie: colchicine in gout (75) vs other(50) • ALL gout responded (none of the other) • Criteria for response not noted • 1967 Wallace 120 pts w/ arthritis • 58 acute gout (urate + recurrent arthritis) 15 tophi • Colchicine orally (61 pts) or IV (59 pts) • Criteria: Major resolution joint inflamm w/in 48 hrs and no worsening in 7 days • Responders: Gout 76% vs Other 2/62 (3.2%)

  22. Colchicine Dosing • PO: 1.2 mg initially then 0.6 mg q 1-2 hours till GI Sx and/or better (max 6 mg) • Ahern et al. Placebo controlled trial shows colchicine 64% respond within 48 hrs (23% placebo same). Significant differences 18-36 hrs. Colchicine diarrhea developed @ median 24 hours (mean 6.7 mg) • GI toxicity in 80% of pts w/in 48 hrs. Toxicity before improvement. • Acute use reserved for when NSAIDs/Steroids contraindicated • Wortman RL 2004 Prefers Colchicine when dx Gout not established • When to use IV Colchicine? If rapid response, oral use precluded, NSAIDs or steroids contraindicated • Problem is that there is no warning GI symptoms (as with PO). • Toxicity depends on total dose over time, size of single dose • Rec: 1) 2 mg initially, followed by 1 mg IV q 6 (max 4-5 mg); 2) 2 mg as single IV dose; or 3) 3 mg IV as single IV dose • Death: 2% reported by Roberts et al. • 20 deaths by Bonnel et al from ODS/FDA

  23. Carr AA. Colchicine toxicity. Arch Int Med 115:29, 1965 • Ellwood MG, Self poisoning with colchicine. Postgrad Med 47:129, 1971 • Baum J, Colchicine use as a suicidal drug by females. J Rheumatol 7:124, 1980 • Ferranini E, Marrow aplasia following colchicine in gout. Clin Exp Rheum 2:173,1984 • Pasero G. Colchicine: should we still use it? Clin Exp Rheumatol 2:103-4, 1984 • Roberts WN. Colchcine in acute gout: reasses risk/benefits. JAMA 257:1920-2, 1987 • Wallace SL. Systemic toxicity assoc with the IV colchicine. J Rheum 15:495, 1988 • Hoffman RS. Outpatient colchicine poisoning. Del Med J. 65: 257-60, 1993 • Lee BI. Colchicine myopathy with cyclosporine. J Korean Med Sci 12:160, 1997 • Dawson TM. Colchicine induced rhabdomyolysis. J Rheumatol 24:2045, 1997 • Maldonado MA, IV colchicine:retro analysis hosp patient. Clin Exp Rheum 15:487, 1997 • Mullins ME. Fatal CVS collapse after acute colchicine. J Toxicol Clin Tox 38:51, 2000 • Goldbart A. Fatal colchicine intox in a child. Eur J Pediatr 159:895, 2000 • Mullins ME. Troponin I cardiac toxicity w/ colchicine. Am J Emerg Med 18:743, 2000 • Sanchez Munoz LA, Acute colchicine poisoning. An Med Intern 17:109, 2000 • Dogukan A. Fatal colchicine intoxication w/ CAPD. Clin Nephrol 55:181, 2001 • Dixon AJ. Colchicine neutropenia, not overdose. Ann Pharmacother 35:192, 2001 • Bonnel RA. Deaths assoc w/ IV colchicine. J Emerg Med 22:385-7, 2002 • Jones GR. LC-MS analysis of colchicine fatality. J Anal Toxicol 26:365-9, 2002 • Maxwell MJ, Accidental colchicine overdose. Emerg Med J 19:265-7, 2002 • Debie K, Colchcine induced rhatbomyolysis in CHF. Acta Cardiol 58: 561, 2003 • Phanish MK, Colchicine induced rhabdomyolysis. Am J Med 114 (2) 2/1/03 • Asuvdevan AR, Colchicine induced rhabdomyolysis. Am J Med 115 (3) 8/15/03 Colchicine Serious Toxicity, Suidice, & Death

  24. Deaths associated with IV Colchicine • Since 1990, AERS reports 90 deaths associated with IV colchicine use (429 allopurinol) • Bonnel RA, et al. J Emerg Med 22:385-7, 2002 • 20 deaths 1983-2000 (13 AERS, 7 literature) • 8F:11M; 17 gout pts (ages 50-91 yrs), 2 FMF(21,31) • All exceed rec. dose (2-4 mg). Range 5.5-19 mg • Adverse effects: thrombocytopenia (8), leukopenia (8), pancytopenia (3), agranulocytosis (2), aplastic anemia (2), acute renal failure (6), and DIC (4) • Death within 1-40 days; 80% showed BM depression • 13 risk factors: age > 65 yrs, preexisting medical cond, concomitant NSAIDs, recent oral colchicine use • Warnings, precautions, contraindications, dosing NOT followed or were misinterpreted

  25. IV Colichicine Toxicity • Acute Toxicity • Local irritation  skin necrosis with extravasation • Tightness in the chest, difficulty swallowing, abdominal pain, nausea, vomiting, diarrhea,arthralgia, myalgia, myopathy, cyanosis, severe shock, hematuria, oliguria, ascending paralysis, delerium • Labs: thrombocytopenia, leukopenia, pancytopenia, agranulocytosis, aplastic anemia, acute renal failure, and DIC (4) • Fatalities with as little as 1 mg IV • Rhabdomyolysis: ESRD, 2 mos, other drugs • @ risk: Elderly, renal failure, those taking colchicine po & IV, Cyclosporine, grapefruit juice, statins

  26. Colchicine Intoxication *Ben-Chetrit E, Levy M. Sem AR 28:48,1998

  27. Colchicine:Guidelines for Use • IV colchicine should be severely restricted if not banned • Removed from licenced clinical use in Great Britain • Removed from hospital formulary in many Hospitals • Single IV dose < 2-3 mg and cumulative doses < 4-5 mg/7days • Give via established intravenous catheter • Following IV use, no PO colchicine for at least 7days • Give REDUCED (<50%) doses in CRI, liver disease, elderly, prior PO colchicine therapy • Lower Doses in elderly (2gm max) and pts w/ renal failure • Contraindicated: pregnancy, combined renal and hepatic disease, Creat Clearance <10cc/min, extrahepatic biliary obstruction

  28. Treatment of IV Colchicine Toxicity • Avoidance/prevention through intelligent use • Drug cessation • Not dialyzable (has occurred in pts on dialysis) • Cytopenias Rx: with growth factors • Rhabdomyolysis: fluids, alkalinzation of urine • Experimental : Fab’ anti-colchicine Abs

  29. Corticosteroids in Acute Gout • Benefits: equal to NSAIDs, less toxic acutely, benefits of local use and aspiration (nonstandard dosing, forms, routes – po, IM, SC, IV) • Often given w/ CHF, CRI, hx of GI bleed or Monarticular Gout • Toxicity: hyperglycemia, hypokalemia, fluid retention, rebound flare • Prednisone: 30-50 mg 3-7d then tapered over 10-14 days (rebound?) • ACTH IM 40-80 U; Triamcinolone acetonide 60 mg;betamethasone 7

  30. NSAIDs in Acute Gout • FDA approval:indomethacin, naproxen, sulindac • Tested: etodolac, flurbiprofen, meclofenamic acid, indoprofen, carprofen, phenylbutazone, piroxicam, isoxicam, fentiazac, ketorolac, etoricoxib • Benefits • Faster onset of relief (compared with colchcine) • Within 2-4 hours for indomethacin • Less toxic (when prescribed appropriately); better tolerated • Widespread use and familiarity • Cost

  31. Etoricoxib vs Indomethacin in Acute GoutDailch D, et al. Am Pain Society 2004 • Combined analyses of 2 prior studies • N = 339 (Etor 178 vs Ind 161 for 6 weeks) • 1o Outcome: Joint pain on days 2-5 (VAS) • 2o Outcome: Pt/MD global response, Tender Jt Etoricoxib Indocin Moderate Pain reduced 1.14 0.99 Severe Pain reduced 2.0 2.06 AE: dizziness 2.8% 14.3% HTN 5.6% 8.7% Diarrhea 2.8% 4.3% Headache 1.1% 6.2%

  32. Analgesics in Acute Gout • Conventional thought: control inflammation yields control of pain • Pain is the Dominant Symptom in Acute gout • Trials • Topical Ice: Schlesinger 2002 • RCT 19 pts: all recv colchcine + pred, ½ recv Ice packs. Local ice associated with less pain, swelling • Ketorolac • Shresta Am J Emerg Med 12:454, 1994 • OL 9pts: Pain VAS improved >80% by 90 minutes • Shresta Ann Emerg Med 26:682, 1995 • DBRCT 20pts: Pain improved 59-68% in 2hrs. “Some rebound in ketorolac group by 6 hours”

  33. Acute Gout: Open-Label Clinical Trials

  34. Trial Issues: Acute Gout • Diagnosis: by crystal Identification, ARA criteria, other • Disease duration? ; > 1 yr. • Duration of attack? 18 hours, 5-7 days • Con Meds • NSAIDs, Pain meds – discontinued/held • Steroids: disallowed • Allopurinol: +/- continuation • Time of assessments • Q 30”, Q 6h x 48 hrs, Days 1,2, 3,4,6,7, longer? • Primary Outcomes: pain VAS, Joint scores, Global Responses • Seconday: Global responses, serum urate, CRP/ESR, toxicity, time to resolution, need for rescue therapy • Rescue? Acetaminophen, narcotics, steroids

  35. Suggested Trial Design • ICH guidelines appropriate (300-600 for 6mo;>100 1 yr) • Randomized, active control (IND, colchicine) • DX: Gout by ARA criteria or + crystal identification? • Acute Gout attack < 3 days • Trial Length: < 2 weeks • Visit Frequency: according to desired/expected onset of effect and/or complete resolution. (eg, 0, 1d, 3d, 7d, 14d) • Longer: to assess rebound, toxicity, QOL, return to work • Inclusion: 18, Dx Gout, Acute attack, Mono-, Oligoarthritis, Activity (3/4 Cardinal signs inflammation) • Exclusion • Polyarthritis, Alcohol excess, CRI, ASA(81,325), CyA, RA, Transplant, active infection, Dietary restriction,uncontrolled HTN • ?? Diuretics, obesity, DM, CHF, tophi, Kidney stones, narcotics, anticoagulants, NSAID, allopurinol, probenecid, sulfinpyrazone, Hospitalized/Immobilized, Unwilling, Involved in litigation

  36. Suggested Trial Design • Primary Outcomes: Patient derived • Pain (Pt self-reported >> MD Tender Joint score) • Eg, use of real time PDA-assisted data capture • Secondary Outcomes: Pt & MD derived • Global assess. (0-4, mild, mod, severe, extreme) • Global response to drug • Complete resolution of symptoms • Time to symptom resolution • Index Joint Score (tender, swollen, erythema, warmth) • Swollen joint score, Tender Joint scores • Need for rescue analgesics • ESR/CRP, Uric acid • Functional measures (ie, 50 ft. walk time) • Safety/Toxicity w/ comparator

  37. Gout Quotes • “King of diseases and the disease of kings” • Hippocrates 450 BC • “Love and gout are incurable” 1623 Meridia • “A disease of ancient and distinguished lineage” • G Rodnan 1980 • “The best medicine for rheumatism is to thank the lord it aint gout” Josh Billings~1850 • “Among all the diseases that infest our human bodies, there is not one known hitherto, that more deservedl is called opprobrium Medicorum, the Reproach of Physicians, than the Gout” - John Marten, 1713

  38. REFERENCES • Arromdee E, et al. J Rheumatol 29:2403-6, 2002 • Kim KY, et al. Clin Therapeutics 25:1593, 2003 • Ahern MJ, et al. Aust NZ J Med 17: 301, 1987 • Roubenoff R, et al. JAMA 266:2004-7, 1991 • Wallace SL, et al. ARACriteria. Arth Rheum 20:895, 1977 • Roberts WN, et al. JAMA 257:1920-2, 1987 • Wallace SL, et al. J Rheum 15:495, 1988 • Bonnel RA, et al. J Emerg Med 22:385-7, 2002 • Emmerson BT. N Engl J Med 334:445, 1996 • Wortmann RL. Curr Rheumatol Rep 6:235-9, 2004 • Schumacher HR, et al. BMJ 324:1488, 2002 • Lally EV, et al. Gout/women.Arch Int Med 146:2221,1986 • Rott KT, Agudelo CA. JAMA 289:2857, 2003 • Terkeltabu RA. Gout. N Engl J Med 349:1647, 2003

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