Case 3 - Acute L Ankle COMPLAINT

1. Case 3 - Acute L AnkleCOMPLAINT • 56 yr. old white woman complains of new onset left ankle pain and swelling for 6 days.

2. Case 3 - Acute L AnkleHISTORY • Complains of difficulty walking and warmth over the ankle. • Self-treated with rest, elevation and taking "6 aspirins daily". • Denies trauma, fever, or prior episodes joint swelling. • Past history: NIDDM, coronary artery disease, and CHF. • Medications: Digoxin, furosemide, KCL, glyburide and aspirin.

3. Case 3 - Acute L AnkleEXAMINATION • All joints were normal, except the left ankle. • Left ankle - moderate warmth, erythema, tenderness and swelling present.

4. Case 3 - Acute L AnkleINVESTIGATIONS • Glucose = 244 mg/dl • Creatinine = 2.4 mg/dl • Uric acid = 6.7 mg/dl • WBC = 13,000/mm3 • ESR = 88 mm/hr.

5. Case 3 - Acute L Ankle What diagnostic test(s) are warranted? • Joint aspiration • Radiographs of ankles and feet • MR image of the lumbosacral spine • Rheumatoid factor • Repeat serum uric acid • None of the above

6. Case 3 - Acute L AnkleADDITIONAL INVESTIGATIONS • Synovial Fluid Analysis Amount aspirated: 10 ml Appearance: Cloudy, yellow WBC count: 34,000 cells/mm3 (89% PMNs) Gram stain/Culture: negative Crystals: negatively birefringent MSU crystals

7. 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 annual cost of Acute Gout is $27,378,494 in the USA (underestimate: women excluded & not all indirect and intangible costs included) * Roubenoff et al

8. Gout • Primary gout: from purine metabolism abnormalities (HGPRT defic. or PRPP synthetase) or from idiopathic decreased renal excretion of urate. • Secondary gout: neoplasms, Alcohol, lymphoproliferative disease, chronic renal failure, psoriasis, or drug therapy (eg, diuretics, ethanol, cytotoxics). • Most patients are Underexcreters rather than Overproducers

12. Gout Epidemiology • Men: onset is 40-50 yrs (most common inflammatory arthritis in men) • Women: peak onset is post-menopausal • Less than have 15% onset prior to menopause • Prevalence influenced by hormonal, geographic, racial, genetic, dietary, background conditions: • Males > Females. Estrogen is uricosuric • Populations: Maori, Tokelauan migrants, Filipinos, Taiwan males, etc (genetics or dietary) • renal transplant (2-13%); HTN (RR 2.7+) • Seasonal:Gout more often in spring (possibly summer) • Is the frequency of gout increasing over time?

13. Is the Frequency Increasing? Testing? Increasing life-span? Insulin resistance? Obesity?

14. Prevalence of Gout NHANES III 1988-94

15. Serum Uric Acid & Incidence of Gout* *Campion EW et al (1963-87) Am J Med 82:421-26, 1987

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

17. Diet and Gout • Survey of 47150 males over 12 yrs. (w/ no hx Gout). Identified 730 new cases of gout • Comparing highest and lowest quintiles: RR • Meat intake 1.41 (1.07-1.86) • Seafood intake 1.51 (1.17 – 1.95) • Dairy products 0.56 (0.42-0.74) • Purine Vegetables and protein intake were not associated with increased risk of gout Choy HK. NEJM 350:1093, 2004

18. Alcohol and Gout • Choy HK. Lancet 363:1277-81, 2004 • Surveys of 47150 males over 12 yrs( w/ no hx Gout) • Identified 730 incident cases RR • Relative Risk: 10-15 g/d 1.32 15-30 g/d 1.49 30-50g/d 1.96 >50g/d 2.53 Beer 1.49 per 12oz serving Wine 1.04 per 4 oz serving

19. Gout Epidemiology Associations: • Hypertension • Obesity • Diabetes • Renal insufficiency • Diuretics/congestive heart failure • Alcohol consumption • Lead exposure • Family history Precipitants: • Alcohol • Hospitalization (fever,Poly) • Surgery: joint replacement, carpal tunnel release • Drugs: Diuretics, ASA, IV NTG, PZA, GCSF, CyA • Total parenteral nutrition • Septic arthritis, reactive arthritis, lupus, elderly

20. Saturnine Gout • Saturnine gout: gout due to chronic lead intoxication, either from occult or occupational exposure or the ingestion of moonshine. • This account for <5% of cases and is due to lead induced tubulointerstitial renal damage. • Saturnine gout should be expected when the magnitude of hyperuricemia exceeds the reduction in glomerular filtration.

21. Gout • Acute: intermittent/recurrent, LE, ascending, inflammatory mono/oligoarthritis, “Podagra” • Atypical Gout: affects elderly women w/ OA • Intercritical (interval) 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

23. Acute (Classic) Gout • Precipitants: stress, trauma, excess alcohol, infection, surgery, drugs • 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 • Assoc. w/ fever, leukocytosis, high ESR or CRP • Initially monarthritis (80-90%) and with repeated attacks ascends from the lower extremity • (initially a polyarthritis: in elderly, women, myeloproliferative disorders, CyA) • Chronology: untreated attacks last 7-14 days. Acute gout risk of repeat attack estimated to be 78% w/in 2 yrs

24. 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

25. CLASSIC GOUT Any age Mostly Men Acute onset Monarthritis Asymmetric Lower extremity Rarely tophi 1st seen Mis-Dx cellulitis, Septic jt ATYPICAL GOUT Elderly patients Women > Men Insidious, chronic Polyarthritis Symmetric or asymmetric Upper and lower extrem. Tophic common Mis-Dx: RA, OA, infx Comparison of Gout Forms * Adapted from Rott KT, Agudelo CA. JAMA 289:2857, 2003

29. 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: Renal manifestations • 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

30. Assessment of Gout • Laboratory Findings • Acute gout: 40-49% have normal uric acid levels • >90% will be hyperuricemic during intercritical period • 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

31. Gout: Xray Changes • Soft tissue swelling • Opacities = tophi • Nl Joint space • Nl ossification • Erosions: punched out Sclerotic margins Overhanging edge

32. no yes no yes # Joints Involved? 1 >1 NSAIDs Contraindicated? • Renal insufficiency • Peptic ulcer disease • Congestive heart failure • NSAID intolerance 1. NSAIDs Antiinflamatory doses Treatment Acute Gout 2.Corticosteroids Are Corticosteroids Contraindicated? 3.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

33. 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

34. 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

35. 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

36. Number of Gouty Attacks per Year <2 no yes yes >2 yes no Observe Educate Rx Acute Attack Treatment of Interval Gout Can pt. Stop Alcohol, Diuretics, Weight Loss? Hx of nephrolithiasis? Allopurinol Therapy (colchicine during Initiation) Tophi present? Serum urate > 11? Serum Creat > 2.0? Uric acid >650mg/24h? Uricosuric (Probenecid) Colchicine during initiation 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

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

38. Gout Review • Demographics: males and postmenopausal females. Incidence rises when uric acid >9.0 • Clinical: exquisite tenderness, red, warm, fever, attacks last 7-14 days • Labs: High WBC, ESR, uric acid may be normal in 40% of acute attacks. • Renal function? 24 hr. uric acid excretion • Dx: Hx Plus synovial fluid (inflammatory) crystals (negatively birefringent) or ^uric acid or Xray proof. • Differential Dx: septic arthritis, pseudogout, Reiters

39. 55 yr. old “dude” with Oligoarthritis • Acute onset (3 wks) of Oligoarthritis: knee and ankle • Inflammatory Sxs? fever, 1 hr AM stiffness • PMHx: EtOH abuse • Exam: T=100.2F, Swollen/warm Left knee and ankle. 2+ L knee effusion. • Differential Diagnosis? • Tests? • Procedures?

40. 55 yr. old “dude” with Oligoarthritis • Acute onset (3 wks) of Oligoarthritis: knee and ankle • Inflammatory Sxs? fever, 1 hr AM stiffness • PMHx: EtOH abuse • Exam: T=100.2F, Swollen/warm Left knee and ankle. 2+ L knee effusion. • ESR=112, Uric acid=7.5, negative RF & ANA • XRAY L Knee: STS, Ca++ of Menisci, -erosion • Procedures?

41. RED FLAG CONDITIONS • FRACTURE • SEPTIC ARTHRITIS • GOUT/PSEUDOGOUT

42. CALCIUM PYROPHOSPHATE CRYSTAL DEPOSITION DISEASE (CPPD) • Synonyms: Pseudogout, chondrocalcinosis, pyrophosphate arthropathy • Chondrocalcinosis: calcification of articular cartilage. • Chronic CPPD: damage associated with intra-articular deposition of CPPD crystals. • Pseudogout: acute synovitis with intra-articular CPPD crystal deposition. Pseudogout is the most common form of CPPD.

43. CALCIUM PYROPHOSPHATE CRYSTAL DEPOSITION DISEASE (CPPD) • OA and aging. • hyperparathyroidism • hypophosphatasia • hypomagnesemia • hypothyroidism • hypocalciuric hypercalcemia • hemochromatosis • hemosiderosis

45. CPPD - Dx & Rx • Pseudogout: self-limited acute monarticular attacks w/ swelling lasting from 1 day to 4 weeks . Knee>wrist > shoulder >ankle. Fever may occur • Chronic CPPD: women. symmetric polyarthritis affecting the knees or hands • Chondrocalcinosis:usually incidental radiographic finding. • Labs: normal uric acid, high ESR & + WBC • Diagnostic Tests: Synovial fluid inflammatory w/ intracellular crystals, weakly positive birefringence. • Rx: NSAIDs • Intraarticular steroids • Colchicine prophyllaxis

47. Synovial Fluid Analysis • Visual inspection (color, clarity, hemorrhagic) • Viscosity - incr w/ normal (noninflam) SF (long “string sign”) - decreased with inflammatory SF (loss of string sign) • Place in tubes: EDTA (purple)-cell count.; Na heparin (green)-Crystals • Cell Count and Differential • noninflammatory: WBC < 2000/mm3 (PMNs < 75%) • inflammatory: WBC = 2000 - 75,000/mm3 (PMNs > 75%) • septic: WBC > 60,000/mm3 (PMNs >80%) • GC may have WBC from 30K - 75K

49. Synovial Fluid Analysis • Analyze SF immediately by “wet prep” • If cannot, refrigerate @ 4oC. • Delay will lower WBC counts and increase artifacts • MSU crystals will persist for days/weeks. CPPD crystals will decrease over time (days/weeks) • Do not do protein or glucose - no predictive value • No value to SF urate, RF, ANA, LE cells, complement, LDH • Gram stain, c/s, Tbc, fungal, cryptococcal Ag as indicated • Use Thayer-Martin media if gonococcal infx is suspected • Low Yield Tap Visually inspect, assess viscosity, perform SF culture, do “wet prep” to assess the # and type of cell

50. Indications for Arthrocentesis and Joint Injection • Monarthritis (acute/chronic) • Suspected infection or crystal-induced arthritis • New monarthritis in old polyarthritis • Joint effusion and trauma • Intrarticular therapy • Arthrography • Uncertain diagnosis • Osteoarthritis with pain • RA - focal pain/swelling • Acute gouty attack • Acute bursitis (r/o septic) • Tendinitis • Early adhesive capsulitis • Reflex sympathetic dystrophy