56 yr. old white woman complains of new onset left ankle pain and swelling for 6 days.

Case 3 - Acute L AnkleCOMPLAINT

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.

Case 3 - Acute L AnkleHISTORY

All joints were normal, except the left ankle.

Left ankle - moderate warmth, erythema, tenderness and swelling present.

Case 3 - Acute L AnkleEXAMINATION

Glucose = 244 mg/dl Creatinine = 2.4 mg/dl Uric acid = 6.7 mg/dl WBC = 13,000/mm3 ESR = 88 mm/hr.

Case 3 - Acute L AnkleINVESTIGATIONS

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

Case 3 - Acute L Ankle

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

Case 3 - Acute L AnkleADDITIONAL

INVESTIGATIONS

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

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

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?

Is the Frequency Increasing?Author Population

1st Era

Incidence rate

2nd Era

Incidence rate

NHIS Self-report(prevalence)

1969

5/1000

1996

9.4/1000

ArromdeeRochester

MN1977-78

45/100,000

1995-96

62.3/100,00

Wallace Wortmann

USA Managed

Care

1990

2.9/1000

1999

5.2/1000

Testing? Increasing life-span? Insulin resistance? Obesity?

Prevalence of GoutAge (years) Men 3.4 Million

Population %Women 1.7 Mill Population %

20-29 0.2 0.6

30-39 2.1 0.1

40-49 2.2 0.6

50-59 5.7 2.3

60-69 9.1 3.5

70-79 10.8 4.7

>80 8.6 5.6

NHANES III 1988-94

Serum Uric Acid & Incidence of Gout*Serum Urate

mg/dlGout

Incidence/yr/10005 year

cummulative

< 7.0 0.8 5

7.0 – 7.9 0.9 6

8.0 – 8.9 4.1 9.8

> 9.0 49 (4.9%) 220 (22%)

*Campion EW et al (1963-87) Am J Med 82:421-26, 1987

National Health Intv Survey (&PE) = 17,030 men/women

(2.7%)(5.6%)

NHANES III 1988-94

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

Low Purine Diet High Purine Diet

Cereals, bread, pasta

Milk, dairy products, eggs

Sugar, gelatin

Butter, margarine, fats

Fruit, peanut butter

Lettuce, tomato, greens

All Meats, Anchovies

Seafood, herring, sardines

Yeast, beer, alcohol, sweetbreads

Beans, peas, lentils, oatmeal, spinach, asparagus, cauliflower, mushrooms

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

Associations: Hypertension Obesity Diabetes Renal insufficiency Diuretics/congestive heart

failure Alcohol consumption Lead exposure Family history

Gout Epidemiology

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

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.

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

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

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

Comparison of Gout FormsCLASSIC 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

* Adapted from Rott KT, Agudelo CA. JAMA 289:2857, 2003

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

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

Gout: Xray Changes•Soft tissue swelling•Opacities = tophi•Nl Joint space•Nl ossification•Erosions: punched out

Sclerotic marginsOverhanging edge

Treatment Acute Gout

NSAIDs Contraindicated? Renal insufficiency Peptic ulcer disease Congestive heart failure NSAID intolerance

Are Corticosteroids Contraindicated?

1. NSAIDsAntiinflamatory

doses

2.Corticosteroids

3.Oral Colchicine

Oral orIntraarticular

Steroid

no

# Joints Involved?

yes

no

yes

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

IntraarticularPO Steroid

>11

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

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) 8/15/03C

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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

Treatment of Interval Gout

Number of

Gouty Attacks per Year

Hx of nephrolithiasis?

ObserveEducateRx Acute

Attack

AllopurinolTherapy

(colchicine duringInitiation)

Uricosuric(Probenecid)

Colchicine duringinitiation

<2

no

no

yes

yes

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

Can pt. Stop Alcohol, Diuretics, Weight Loss?

>2 yes

Tophi present?

Serum urate > 11?

Serum Creat > 2.0?

Uric acid >650mg/24h?

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

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

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?

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?

RED FLAG CONDITIONS

FRACTURE

SEPTIC ARTHRITIS

GOUT/PSEUDOGOUT

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.

CALCIUM PYROPHOSPHATE CRYSTAL DEPOSITION DISEASE (CPPD)

OA and aging. hyperparathyroidism hypophosphatasia hypomagnesemia hypothyroidism hypocalciuric

hypercalcemia hemochromatosis hemosiderosis

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

CPPD - Dx & Rx

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

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

Indications for Arthrocentesis and Joint Injection

Osteoarthritis with pain RA - focal pain/swelling Acute gouty attack Acute bursitis (r/o

septic) Tendinitis Early adhesive

capsulitis Reflex sympathetic

dystrophy

Monarthritis (acute/chronic)

Suspected infection or crystal-induced arthritis

New monarthritis in old polyarthritis

Joint effusion and trauma

Intrarticular therapy Arthrography Uncertain diagnosis

Contraindications to Corticosteroid Injections

Suspicion of infected joints or bursae Overlying cellulitis Neuropathic (Charcot) joints Referred pain Known bacteremia Thrombocytopenia (platelets < 50K) Coagulopathy - anticoagulant therapy Uncontrolled diabetes (?) Lack of response to previous injection Prosthetic joints Inaccessible joints (SI, hip, etc)

Synovial Fluid AnalysisType I Type II Type III Type IV

Noninflamatory Inflammatory Septic Hemorrhagic

Appearance Straw Yellow Purulent Bloody

Clarity Clear Cloudy Opaque Opaque

Viscosity Normal Decreased Decreased Variable

Cell # 200 –2000 2000-75,000 > 60,000 RBC > WBC

PMN% < 25% > 60% > 80%

Examples OA, Trauma, AVN, SLE

RA, Gout, viral Reiters, Tbc

Bacterial Crystal

Trauma, FX, Hemophilia,

PVS

Leave needle in place, change syringes

Knee Joint Injection

A Moran – Cush Video Exclusive

“I’ve seen the needle and the damage done...”

- Neil Young “Harvest” 1972

Complications Allergic reactions: iodine, lidocaine adhesives Vasovagal episodes Local ecchymosis Corticosteroid crystal-induced synovitis Depigmentation of overlying skin Subcutaneous atrophy at injection site Rare: skin/joint infection, hemarthrosis,

calcification or rupture of periarticular structures