Management of Acute Gout

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Management of Acute Gout

• John J. Cush, MD
• Presbyterian Hospital of Dallas

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Who Manages Acute Gout

• Rheumatologistsmusculoskeletal 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 1252, 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 55621,2003
• Survey of N.Zealand Rheums and GPs differences
  in NSAID, colchicine, allopurinol use. Stuart RD
  N Z Med J 104115,1991

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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
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NHANES III 1988-94
(2.7)
(5.6)

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

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Prevalence of Gout

• NHANES III 1988-94

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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

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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

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Natural Hx of Acute AttackBellamy N, et al. Br J
Clin Pharmacol 2433-6, 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

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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

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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

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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 291950-3, 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)

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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)
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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
• Dont 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
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Limitations of Current Gout Drugs

• NSAIDs
• Colchicine
• Allopurinol
• Sulfinpyrazone

?Elderly ?Renal insufficiency ?Peptic Ulcer
disease ?Hepatic dysfunction
Need for Safer Agents
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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

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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

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Acute Gout Management
or equivalent antiinflammatory dose
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Treatment Acute Gout

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

NSAIDs Antiinflamatory doses
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
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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

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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 12256-64, 1982

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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)

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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 _at_ 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

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• Carr AA. Colchicine toxicity. Arch Int Med
  11529, 1965
• Ellwood MG, Self poisoning with colchicine.
  Postgrad Med 47129, 1971
• Baum J, Colchicine use as a suicidal drug by
  females. J Rheumatol 7124, 1980
• Ferranini E, Marrow aplasia following colchicine
  in gout. Clin Exp Rheum 2173,1984
• Pasero G. Colchicine should we still use it?
  Clin Exp Rheumatol 2103-4, 1984
• Roberts WN. Colchcine in acute gout reasses
  risk/benefits. JAMA 2571920-2, 1987
• Wallace SL. Systemic toxicity assoc with the IV
  colchicine. J Rheum 15495, 1988
• Hoffman RS. Outpatient colchicine poisoning. Del
  Med J. 65 257-60, 1993
• Lee BI. Colchicine myopathy with cyclosporine. J
  Korean Med Sci 12160, 1997
• Dawson TM. Colchicine induced rhabdomyolysis. J
  Rheumatol 242045, 1997
• Maldonado MA, IV colchicineretro analysis hosp
  patient. Clin Exp Rheum 15487, 1997
• Mullins ME. Fatal CVS collapse after acute
  colchicine. J Toxicol Clin Tox 3851, 2000
• Goldbart A. Fatal colchicine intox in a child.
  Eur J Pediatr 159895, 2000
• Mullins ME. Troponin I cardiac toxicity w/
  colchicine. Am J Emerg Med 18743, 2000
• Sanchez Munoz LA, Acute colchicine poisoning. An
  Med Intern 17109, 2000
• Dogukan A. Fatal colchicine intoxication w/ CAPD.
  Clin Nephrol 55181, 2001
• Dixon AJ. Colchicine neutropenia, not overdose.
  Ann Pharmacother 35192, 2001
• Bonnel RA. Deaths assoc w/ IV colchicine. J Emerg
  Med 22385-7, 2002
• Jones GR. LC-MS analysis of colchicine fatality.
  J Anal Toxicol 26365-9, 2002

Colchicine Serious Toxicity, Suidice, Death
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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 22385-7, 2002
• 20 deaths 1983-2000 (13 AERS, 7 literature)
• 8F11M 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

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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
• _at_ risk Elderly, renal failure, those taking
  colchicine po IV, Cyclosporine, grapefruit
  juice, statins

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Colchicine Intoxication
Ben-Chetrit E, Levy M. Sem AR 2848,1998
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ColchicineGuidelines 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 4-5 mg/7days
• Give via established intravenous catheter
• Following IV use, no PO colchicine for at least
  7days
• Give REDUCED (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 extrahepatic biliary obstruction

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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

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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
  mgbetamethasone 7

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NSAIDs in Acute Gout

• FDA approvalindomethacin, 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

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Etoricoxib vs Indomethacin in Acute Gout Dailch
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

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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 12454, 1994
• OL 9pts Pain VAS improved 80 by 90 minutes
• Shresta Ann Emerg Med 26682, 1995
• DBRCT 20pts Pain improved 59-68 in 2hrs. Some
  rebound in ketorolac group by 6 hours

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Acute Gout Open-Label Clinical Trials
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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

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Suggested Trial Design

• ICH guidelines appropriate (300-600 for 6mo100
  1 yr)
• Randomized, active control (IND, colchicine)
• DX Gout by ARA criteria or crystal
  identification?
• Acute Gout attack
• Trial Length
• 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

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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

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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 Billings1850
• 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

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• Roberts WN, et al. JAMA 2571920-2, 1987
• Wallace SL, et al. J Rheum 15495, 1988
• Bonnel RA, et al. J Emerg Med 22385-7, 2002
• Emmerson BT. N Engl J Med 334445, 1996
• Wortmann RL. Curr Rheumatol Rep 6235-9, 2004
• Schumacher HR, et al. BMJ 3241488, 2002
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