Guideline for gout management
高雄長庚醫院風濕過敏免疫科高雄長庚醫院風濕過敏免疫科
(Arthritis)
Introduction
the deposition of monosodium urate ( MSU ) crystals in the joints and soft tissues.
Incidence: 0.1%
IntroductionCrystal-Induced Arthritis
Characteristic Gout Pseudogout
Prevalence 1.5 to 2.6 cases per 1000 individuals; increases with age in men and postmenopausal women; 15/1000 at age 58; men:28/1000, women:11/1000
<1 case per 1000 individuals; increases with age
Crystals
Chemistry Monosodium urate Calcium pyrophosphate dihydrate
Appearance Negatively birefringent; needle-shaped Weakly positively birefringent; linear or rhomboidal
Articular involvement Monoarticular > oligoarticular; polyarticular < 30%
Monoarticular > oligoarticular
Most frequently affected joints First MTP joint
- initially 50%
- eventuall 90%
Ankles, knees, other
Knee, wrist other
Predisposing conditions/risk factors Hyperuricemia*, obesity, hypertension, hyperlipidemia, alcohol ingestion, lead ingeation, hereditary enzyme defect (rare)
Hypothyroidism, hemochromatosis, OA, chronic renal insufficiency, diabetes, hyperparathyroidism, hereditary (rare)
Therapeutic options Acute attacks:
- NSAIDs, corticosteroids, colchicine
Chronic management
- Urate-lowering agents, colchicine
Acute attacks:
- NSAIDs, corticosteroids, colchicine
Chronic management
- NSAIDs colchicine
*Drugs associated with hyperuricemia include diuretios, low-dose salicylates, nicotinic acid, oyclosporine, ethanol and ethambutol.
Adapted from Am J Med 1997; 103 : 68S.
De novo and salvage pathways in purine metabolism. Phosphoribosyl pyrophosphate amidotransferase (AMPRT) catalyzes the committed step of de novo purine nucleotide synthesis. Hypoxanthine phosphoribosyltransferase (HPRT) and adenine phosphoribosyltransferase (APRT) are responsible for recycling purine bases into nucleotides. 5-phosphoribosyl-1-pyrophosphate (PRPP) levels regulate all of these reactions. Uricase (UC) prevents the buildup of uric acid in mice, but not in humans. Other important enzymes in the salvage pathway are adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP), guanase (GA), and xanthine oxidase (XO).
Clinical course
4 clinical phases if untreated:
asymptomatic hyperuricemia,
acute/recurrent gout,
intercritical gout,
chronic tophaceous gout
Asymptomatic Hyperuricemia
elevated urate levels without symptoms of gout, nephrolithiasis, or kidney stones. Hyperuricemia is defined:
>7 mg/dL (0.42mmol/L) in men and postmenopausal women
>6 mg/dL (0..36mmol/L) in premenopausal women. urate <7 mg/dL 0.1% annual incidence of gout
urate >=9 mg/dL 4.9% annual incidence.the clustering of glucose intolerance, central obesity, dyslipidemia, hypertension, and increased prothrombotic and antifihrinolytic factors in an individual.
Cause of hyperuricemia-- decreased renal excretion
Primary Idiopathic Familial juvenile
gouty nephropathy
Secondary Hypertension Hyperparathyroidism Myxoedema Down’s syndrome Increased level of organic level Lead nephropathy Sarcoidosis Bartter’s syndrome Beryllium poisoning Drug: diuretics, B-blocker, ACEI, sa
licylates (low dose), PEA, EMB, cyclosporin, nicotinic acid
Chronic renal failure Volume depletion NDI
Cause of hyperuricemia-- increased uric acid production
Primary Idiopathic HPRT def. PPRT overactivity Ribose-5-phosphat
e overproduction AMP-deaminase de
f.
Secondary Glycogen storage disease type II (G6PD), type III, V, VII Hereditary fructose intolerance Lymphoproliferative and myelopr
oliferative diseases ( leukemia, Hodgkin’s d’z, lymphosarcoma, myeloma, PV, Waldenstrom’s macroglobulinemia )
Cytotoxic drugs Carcinomatosis Gaucher’s disease Chronic hemolytic anemia Severe exfoliative psoriasis
Acute/Recurrent Gout
symptoms: sudden onset of severe pain, inflammation, limited range of motion, and warmth at the affected joint(s).slight fever, leukocytosis, elevation of ESR, and elevation of CRP90% of first attacks are monoarticular with first metatarsophalangeal joint, known as podagra. Left untreated, the symptoms are self-limiting but may take up to 21 week to subside.
Intercritical GoutAfter recovery from an acute gout flare, the patient enters an asymptomatic phase of the disease. This interval between gout flares: as intercritical or interval gout.Later, recurrence of acute gout may become more frequent and polyarticular involvement.
Chronic Tophaceous Gout
Tophi are usually present after 10 to 20 years of inadequately treated chronic gout.Visible tophi occur in 12% of patients after 5 years of gout and in 55% of patients after 20 years. most common sites of tophaceous gout: olecranon bursae (elbow) and the joints of the hand and feet.
Other sites: the helix of the ear, the Achilles tendons, and the knees.
Table. Characteristics of Classic Gout vs Atypical Gout
Classic Gout Atypical Gout
Can present at any age, including patients older than 60 years
Observed in elderly patients
Predominantly men Diagnosed in as many women as men
Monarthritis Polyarthritis
Asymmetric Symmetric or asymmetric
Usually in lower extremity Any joint, upper or lower extremity
Tophi rare at presentation Tophi common at presentation
Acute Chronic but can have acute flare-ups
Can be misdiagnosed as cellulitis or infection
Chronic form can be misdiagnosed as rheumatoid arthritis or osteoarthritis: acute flare-ups can be misdiagnosed as cellulitis or infection
Complication of gout
Joint: destructionSoft tissuenerve entrapment syndrome: CTS, tarsal tunnel syndromeskidney: uric acid calculi(10-15%), chronic urate nephropathy, and acute uric acid nephropathyHeart: ischemic heart disease
Criteria for clinical diagnosisAmerican Rheumatism Association sub-committe on classification criteria for gout 1977
presence of characteristic urate crystals in the joint fluidTophus proved to contain urate crystals by negative polarized light microscopic studyIf none of above, diagnosis is 6/12 clinical, radiographic, and laboratory criteria include:
1. more than one attack of acute arthritis 2. Maximum inflammation within 24 hours 3. Attack of monoaricular arthritis 4. Joint redness observed 5. first MTP joint painful or swollen 6. Unilateral attack involving first MTP 7. Unilateral attack involving tarsal joint 8. Suspected tophus 9. Hyperuricemia 10. Asymmetric swelling within a joint ( roentgenogram ) 11. Subcortical bone cysts without erosions ( roentgenogram ) 12. Negative synovial culture during attack of joint inflammation
Differential diagnosisAcute Infective arthritis Bursitis, cellulitis, tenosynovitis Other crystal arthropathy ( pseudo
gout, apatite or brushite arthritis or periarthritis )
Traumatic arthritis Hemoarthrosis RA with palindromic onset Reactive arthritis Spondarthritis with peripheral invol
vement Psoriatic arthritis Sarcoid arthritis Rheumatic fever
Chronic Nodular rheumatoid
arthritis Psoriatic arthritis Osteoarthritis with H
eberden’s and Bouchard’s nodes
Sarcoid arthritis xanthomatosis
History taking
Age of onset
Involving joints
Frequency of attack
Family hx
Previous treatment and other medication
Associated medical hx: 4H ( hypetension, hyperglycemia, hyperlipidemia, and hyperuricemia )
Events provoking acute gouty arthritis
Traumaunusual physical exerciseSurgerySevere systemic illnessSevere dietingDietary excessAlcoholDrugs ( diuretics, initiation of uricosuric or allopurinol therapy, initiation of B12 therapy in pernicious anemia, cytotoxic drug therapy )
Physical examination
Vital signBody weight and body heightGeneral appearance: Cushingnoid …ConsciousnessHEENTChest ( CV )AbdomenExtremity
-- PE of joint: appearance, joint effusion, ROM -- location of tophi -- sign of neuropathy -- muscle power, DTR…
Diagnostic evaluation
CBC/DC
Glucose, Na/K, Ca/P, uric acid, AST/ALT/ALP, HDL-cholesterol electrophoresis
U/A, 24hr uric acid(U)
Synovial study
Special investigation
-- EKG, CXR, joint radiography
-- skeleto-muscular ultrasound examination
Long-term treatmentIndication:
1. Recurrent attacks 2. Evidence of tophi or chronic gouty arthritis 3. Associated renal disease 4. Patient is young with high serum UA and FH of renal or heart disease 5. Normal serum UA cannot be achieved by life-style modifications
Medication: 1. Allopurinol 2. Uricosuric agents: probenecid or sulfinpyrazone 3. benzbromarone
Indications for Antihyperuricemic Therapy in Gout
•Frequent and disabling attacks of acute gouty arthritis
•Clinical or radiographic signs of chronic gouty joint disease•The presence of tophaceous deposits in soft tissues or subchondral bone
•Gout with renal insufficiency
•Recurrent nephrolithiasis•Serum urate levels persistently in excess of 13 mg/dL in men or 10 mg/dL in women
•Urinary uric acid excretion exceeding 1100 mg/day•Impending cytotoxic chemotherapy or radiotherapy for lymphoma or leukemia
Table III. Main medications used in the treatment and prophyaxis of gout.1-8,13,81
Agent Adverse Events Contraindications Regimen
Acute therapy/
prophylaxis
NSAIDs
Dose-dependent gastropathy, nephropathy, liver dysfunction, central nervous system dysfunction. May cause fluid overload in patients with congestive heart failure.
Peptic ulcer disease or bleeding ASA- Or NSAID-induced asthma, urticaria, or allergic-type reactions.
Indomethaction 50mg TID for 2 to 3 days, then tapered over 5 to 7 days; naproxen 750 mg, followed by 250mg TID, then tapered over 5 to 7 days, sulindac 200mg BID, then tapered over 5 to 7 days. Prophylaxis low daily doses.
Cox-2 selective inhibitors (etoricoxib)
Less GI toxicity than conventional NASIDs renal effecect similar to conventional NSAIDs
Cautious use in patients with advanced renal disease, history of ischemic heart disease, or history of NSAID-induced asthma.
Etoricoxise 120 mg/d (available outside the United States)
Colchicine Dose-dependent GI symptoms, neuromyopathy; improve IV dosing can cause bone narrow suppression, renal failure, paralysis, and death.
Use cautiously in renal or hepatic dysfunction.
1.2mg initially then 0.6mg every 1 to 2 hours until pain relief or abdominal discomfort/diarrhea develops (do not exceed 4 mg/d). Prophylaxis 0.6 to 1.2 mg/d.
Corticosteroids Fluid detention, impaired Wound healing, psychosis
Hyperglycemia hypothalamus
Pituitary axis suppression
Osteoporosis, potential for
Rebound inflammation.
Intra-articular; methylprednisolone 10 to 20mg for a small joint; 20 to 10 mg for large joint. IM: triamcinolone acetonide 60mg repeat after 24 hours if necessary. PO: prednisone 30 to 60mg QD, then tapered over 7 to 10 days.
Table III. (Continued)
Agent Adverse Events Contraindications Regimen
ACTH Fluid retention, hypokalemia relapse of gout, worse diabetes control
40 to 80 IU IM, repeat every 12 hours as necessary.
Orate-lowering therapy
Allopuriol Rash, GI symptoms, headache, urticaria, and intestinal nephritis; rare potentially fatal hypersensitivity syndrome, reduces orate levels in over producers and underexcretors.
Probenecid Rash, headache, and GI symptoms; rare nephritic syndrome, hepatic necrosis, aplastic anemia and hemolytic anemia. Reduced orate levels in underexcretors.Potential for numerous drug interactions because of interference with excretion of many medications.
Renal dysfunction (CrCI <50mL/min) or renal calculi
250mg BID for 1 to 2 weeks↑ ny500mg increments every 1 to 2 weeks until satisfactory control is achieved or maximal dose 3 g.
Sulfinpyrazone Rash, headache, and GI symptoms, bone narrow suppression, minor hypersensitive. Possesses inherent antiplatelet activity.
Renal dysfunction (CrCI <50mL/min) or renal calculi
50mg BID;↑ to 300 to 400 mg/d in 2 to 3 divided doses maximum dose 800 mg/d.
Hyperuricemic Symptoms
Asymptomatic
Consider acquired causes of hyperuricemia associated with normal urinary acid excretion
ObesityEthanolDrugs Salicylates(low dose) Diuretics Pyrazinamide Ethambutol Nicotinic acid Laxative abuse(alkalosis) Cyclosporine
Renal insufficiencyPolycystic kidney diseaseLead nephropathyHypothyroidismHyperparathyroidismDiabetic ketoacidosisLactic acidosisStarvationDehydration
Salt restrictionDiabetes insipidusBartter’s syndromeSarcoidosisDown’s syndromeToxemia of pregnancyHypoxemiaChronic beryllium disease
If positiveIf negative
Correct underlying cause if possible and / or appropriate
Consider secondary causes of hyperuricemia associated with elevated uric acid production
Treat Routine medical management
Myeloproliferative diseasesLymphoproliferative diseasesMyeloproliferative diseasesLymphoproliferativeHemolytic anemiasPolycythemia veraObesityEthanolFructose (large doses)Tissue necrosisExerciseConvulsionsDrugs Cytotoxic agents B12 (patients with pernicious anemia) Pancreatic extract
If positive and clinical setting for acute uric acid nephropathy; Myelo-or lymphoproliferative disorder, solid tumor with anticipated cytotoxic and/ or radiation therapy, inherited disorders with overproduction of uric cid, or rhabdomyolysis
It positive and patient is asymptomatic and not in clinical setting for acute uric acid neph
ropathy
24-hour urine uric acid
>1100 mg/day <1100 mg/day
Close follow-up of renal function
Routine medical management
Treat
If positive and hyperuricemic symptoms
Treat
Cause of hyperuricemia is not discermible
Symptomatic Asymptomatic
Serum urate>11 mg/dl
Serum urate<11 mg/dl
24-hour urine uric acid
Routine medical management
>1100 mg/day <1100 mg/day
Follow renal Function closely
Routine medical management
Treat
Low Purine DietOn a strict low purine diet, protein is derived principally from eggs and cheese. Grains, most vegetables, fruits and nuts are acceptable.
The following should be AVOIDED:
Animal-based proteins:
Meats, poultry, seafood,
Liver, kidney, heart, gizzard, sweetbreads,
Meat extracts, yeast extract.
Vegetables Peas, beans, spinach, lentils.
Beverages Alcohol, beer, and beer products.
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