11.30.09(c): crystalline arthritis
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Author(s): Seetha Monrad, M.D., 2009 License: Unless otherwise noted, this material is made available under the terms of the Creative Commons Attribution–Noncommercial–Share Alike 3.0 License: http://creativecommons.org/licenses/by-nc-sa/3.0/
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Crystalline Arthritis
Seetha Monrad M.D.
Fall 2009
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What is gout?
• Disease state arising from the deposition of monosodium urate crystals in assorted tissues, with accompanying inflammatory and/or degenerative consequences – In joints -> inflammatory arthritis – In soft tissue -> tophi – In kidneys -> nephrolithiasis, nephropathy
• Most common inflammatory arthritis in men >40
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Purine metabolism
Cecil Medicine, 23rd ed.
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Endogenous purine synthesis, tissue nucleic acid breakdown
Dietary purines
Total Body Urate Pool
Men: 1200 mg
Women: 600 mg
Renal excretion (>2/3)
Intestinal uricolysis (<1/3)
Normal uric acid metabolism
Normal serum urate levels (+2)
Men: 5.0 mg/dL, Women: 4.0 mg/dL
S. Monrad
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Renal handling of uric acid
Normal: 500-800 mg/ 24 hours
Teng, Drugs, 2006
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Hyperuricemia
• Serum uric acid >6.8 mg/dL • Caused by uric acid overproduction and/or
underexcretion • Total body urate pool >2000 mg ->
becomes insoluble – Non-tophaceous gout: 2-4 g – Tophaceous gout: 10-1000 g
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Uric acid overproduction • 10% of cases • 24 hour urinalysis >1000
mg/d • Causes
– Genetic • Glucose-6-phosphatase
deficiency (glycogen storage disease type I)
• Hypoxanthine guanine phosphoribosyltransferase deficiency (HGPRT)
• PRPP-synthetase superactivity
Cecil Medicine, 23rd ed.
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Uric acid overproduction
• Causes (con’t) – Excessive purine intake – Ethanol – Drugs: nicotinic acid, warfarin, chemotherapy (tumor
lysis) – Obesity – Malignancies (myeloproliferative, lymphoproliferative) – Psoriasis – Hemolytic anemia – Tissue destruction (hypoxia, ischemia, trauma)
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Uric acid underexcretion
• 90% of cases • <500 mg/d excretion • Causes
– Genetic (polycystic kidney disease, etc.) – Decreased GFR – Organic acidosis – Lead nephropathy – Drugs
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Drugs • Cyclosporin
– Reduced GFR – Reduces urate secretion
• Aspirin – Low dose (eg. 81 mg):
inhibits urate secretion – High dose (>3g):
decreases tubular reabsorption
• Diuretics – Volume depletion ->
increased reabsorption – Thiazides interfere with
secretion Teng, 2006
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Ethanol • Overproduction
– High purines (especially beer)
– Produces excess AMP -> metabolized into uric acid
• Underexcretion – Dehydration – Organic acids ->
overwhelm urate transporter
Torpedo Extra IPA by Milletre, Flickr.com
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Hyperuricemia is NOT Gout
• Hyperuricemia present in 5-10% of adult men
• 80% of hyperuricemic patients do not develop gout
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Is hyperuricemia bad? • Hyperuricemia is associated with hypertension, renal disease,
metabolic syndrome, cardiovascular disease • Studies are beginning to suggest that uric acid is an independent
risk factor for these conditions and may be involved in their pathogenesis – An elevated uric acid level consistently predicts the development of
hypertension. – An elevated uric acid level is observed in 25–60% of patients with
untreated essential hypertension and in nearly 90% of adolescents with essential hypertension of recent onset.
– Raising the uric acid level in rodents results in hypertension with the clinical, hemodynamic, and histologic characteristics of hypertension.
– Reducing the uric acid level with xanthine oxidase inhibitors lowers blood pressure in adolescents with hypertension of recent onset
• However, currently not sufficient evidence to support treatment of asymptomatic hyperuricemia
Feig et al, NEJM, 2008
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Epidemiology of gout
• Most common inflammatory arthritis in men>40
• Total prevalence ~3%; 6-9% if >80
• U.S. incidence may be rising (>2 fold)
Arromdee, Drugs, 2002
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3 phases of gout
• Asymptomatic hyperuricemia • Acute gout flares • Chronic (tophaceous) gout
Primer, 2008
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Acute gout “The victim goes to bed and sleeps in good health. About 2 o'clock in the morning, he is awakened by a severe pain in the great toe; more rarely in the heel, ankle or instep. This pain is like that of a dislocation, and yet the parts feel as if cold water were poured over them. Then follows chills and shiver and a little fever. The pain which at first moderate becomes more intense. With its intensity the chills and shivers increase. After a time this comes to a full height, accommodating itself to the bones and ligaments of the tarsus and metatarsus. Now it is a violent stretching and tearing of the ligaments-- now it is a gnawing pain and now a pressure and tightening. So exquisite and lively meanwhile is the feeling of the part affected, that it cannot bear the weight of bedclothes nor the jar of a person walking in the room.”
Thomas Sydenham
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The Gout by James Gillray, Crankyprofessor.com
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Acute gout • 4th-6th decade (men); later in
women • Sudden onset, rapid escalation • 1st MTP (podagra)
– 50% have as first attack – 90% will have eventually
• Other lower extremity joints • Systemic symptoms • Extraarticular (bursitis,
tenosynovitis) • Triggered by: trauma, surgery,
sepsis, overindulgence (alcohol, purine-rich foods), drugs
Clinical Slide Collection on the Rheumatic Diseases, American college of Rheumatology, 1972-2004
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Intercritical gout
• Asymptomatic periods between acute flares
• Body urate load still increasing • Joints still with MSU crystals
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Chronic gout
• Chronic destructive arthritis
• Flares become polyarticular, additive, ascending
• Can be mistaken for rheumatoid arthritis
Rheumatology Image Bank
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Tophaceous gout
Rheumatology Image Bank American College of Rheumatology
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Source Undetermined
Rheumatology Image Bank
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American College of Rheumatology
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Rheumatology Image Bank
Rheumatology Image Bank
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Source Undetermined
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Renal Disease
• Acute uric acid nephropathy (tumor lysis syndrome)
• Chronic urate nephropathy (tubulointerstitial disease) – MSU deposition in renal medulla – Not seen in the absence of gouty arthritis
• Uric acid nephrolithiasis – 10-25% of gout patients – Increased non-urate nephrolithiasis as well
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Diagnosis: Arthrocentesis
• Can be performed even if not in acute attack
• Inflammatory joint fluid, sometimes septic appearing
Source Undetermined
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American College of Rheumatology American College of Rheumatology
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Source Undetermined
Source Undetermined
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American College of Rheumatology
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Serum uric acid
• If high, suggestive but not diagnostic • Up to 1/3 of patients having an acute gout
attack may have a uric acid <7 • 24 hour urine collections for uric acid
– Difficult to perform – May be useful in select cases (young patient,
history of urolithiasis)
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Treatment
Asymptomatic hyperuricemia
Acute gout Chronic gout
No treatment Antiinflammatory Preventative Uric acid lowering
therapy
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Acute treatment
• NSAIDs • Steroids
– Intraarticular – Oral/IV
• ACTH • Anakinra
• Colchicine – Never IV – Used prophylactically
in intercritical periods – Toxicities: diarrhea
(common), neuromyopathy, bone marrow suppression, hematologic abnormalities
– Not dialyzable
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Lowering uric acid • Adjust offending
medications (ex. diuretics)
• Weight loss • Dietary adjustments
– Less meat, seafood – Less alcohol (particularly
beer) – Less fructose containing
soft drinks – ?More dairy
• Purine rich foods – Beer, other alcoholic
beverages. – Anchovies, sardines in oil,
fish roes, herring – Yeast – Organ meat (liver, kidneys,
sweetbreads) – Meat extracts, consomme,
gravies – Mushrooms, spinach,
asparagus, cauliflower, legumes (dried beans, peas) less associated with gout
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Indications for uric acid lowering medication
• Tophaceous gout • Erosive gout • Unacceptably frequent attacks (>3-4/year) • Nephrolithiasis • Serum uric acid >12 with other risk factors for
gout or nephrolithiasis
• Goals: lower serum urate <6.0 (<5.0 if tophi) • Should not be initiated during an acute flare
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Treating undersecretion: uricosurics
• Suppress URAT1 -> decreases tubular reabsorption
• Probenecid • (sulfinpyrazone, benzbromarone) • Others: losartan, fenofibrate • Limitations:
– Require adequate GFR – Increases risk of uric acid stone formation/ urinary
crystallization – Numerous drug-drug interactions (ampicillin,
salicylates, indomethacin, heparin, etc.)
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Treating overproduction
Source Undetermined
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Allopurinol
• Purine analog of xanthine • Competitive xanthine oxidase inhibitor • Active metabolite = oxypurinol • Potentiates azathioprine and warfarin • Side effects:
– Rash/toxic epidermolysis/Stevens Johnson syndrome
– GI intolerance/liver enzyme elevation – Cytopenia
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Allopurinol hypersensitivity syndrome
• Idiosyncratic; usually develops within first 3 months of initiation
• Fever, rash, hepatitis, interstitial nephritis, myocarditis, rhabdomyolysis, eosinophilia
• Incidence ~0.4%, mortality 25% • Arellano, et al. 1993: ~75% of patients
developing syndrome were receiving allopurinol for asymptomatic hyperuricemia
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Renal dosing?
• Guidelines for dose adjustment in patients with renal insufficiency to minimize toxicity
• However, – Unclear if this is successful – Results in significant undertreatment of gout
• Recommend carefully advancing allopurinol as high as needed to lower serum urate
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Other urate lowering therapies
• Febuxostat – Non-purine selective xanthine oxidase inhibitor – Hepatically metabolized -> ?safer in renal
insufficiency – Side effects: transaminitis
• Uricase – Converts uric acid to allantoin – Prevents/manages tumor lysis syndrome – Infusion reactions; anti-uricase antibodies
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Special instances of gout
• Organ transplant patients on cyclosporine – More likely to develop rapidly, be tophaceous,
involve atypical joints – Steroid use may mask acute attacks despite
accumulation of total body urate load • Gout in young men (<25) or
premenopausal women: likely genetic
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CPPD disease • Calcium pyrophosphate deposition disease
– Pseudogout – Also pseudo-septic, pseudo-RA, pseudo-OA
• Associated with aging • Also associated with
– Hemochromatosis – Hyperparathyroidism – Hypomagnesemia/hypophosphatemia – Gout – Trauma – Hypothyroidism
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Pseudogout
• Acute inflammatory attacks • Asymptomatic in between • Flares involve large joints: knees,
shoulders, wrists, ankles • Also can involve MCPs • May take longer to reach peak intensity,
longer to subside than gout • Not due to uric acid
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Diagnosis
• Joint aspiration – Crystals more
rhomboid – Weakly positive
birefringence
Source Undetermined
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Chondrocalcinosis
Rheumatology Image Bank
Rheumatology Image Bank
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CPPD arthritis
Kelley’s Textbook of Rheumatology (Both Images)
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CPPD arthritis
Source Undetermined
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Management of pseudogout
• NSAIDs • Steroids • ?Colchicine • Treat associated disorders
(hemachromatosis, hyperparathyroidism)
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Other crystals: Hydroxyapatite
American College of Rheumatology
Source Undetermined
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Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicy
Slide 5: Cecil Medicine, 23rd ed. Slide 6: Seetha Monrad Slide 7: Teng, Drugs, 2006 Slide 9: Cecil Medicine, 23rd ed. Slide 12: Teng, 2006 Slide 13: Torpedo Extra IPA by Milletre, Flickr.com, http://www.flickr.com/photos/71781509@N00/3252864721 Slide 15: Feig et al, NEJM, 2008 Slide 16: Arromdee, Drugs, 2002 Slide 17: Primer, 2008 Slide 18: Thomas Sydenham Slide 19: The Gout by James Gillray, Crankyprofessor.com, http://www.crankyprofessor.com/archives/001383.html Slide 20: Clinical Slide Collection on the Rheumatic Diseases, American college of Rheumatology, 1972-2004,
http://www.msnbc.msn.com/id/27848025/ Slide 22: Rheumatology Image Bank, http://images.rheumatology.org/ Slide 23: Rheumatology Image Bank, http://images.rheumatology.org/ ; American College of Rheumatology Slide 24: Source Undetermined; Source Undetermined Slide 25: American College of Rheumatology Slide 26: Rheumatology Image Bank, http://images.rheumatology.org/ Slide 27: Source Undetermined Slide 29: Source Undetermined Slide 30: American College of Rheumatology; American College of Rheumatology Slide 31: Source Undetermined; Source Undetermined; Source Undetermined Slide 32: American College of Rheumatology Slide 39: Source Undetermined Slide 47: Source Undetermined Slide 48: Rheumatology Image Bank, http://images.rheumatology.org/ Slide 49: Kelley’s Textbook of Rheumatology (Both Images) Slide 50: Source Undetermined Slide 52: American College of Rheumatology; Source Undetermined