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Guideline for gout management (Arthritis)

Introduction
the deposition of monosodium urate ( MSU ) crystals in the joints and soft tissues. Incidence: 0.1%

Introduction
Crystal-Induced Arthritis Characteristic
Prevalence

Gout
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

Pseudogout
<1 case per 1000 individuals; increases with age

Crystals Chemistry Appearance Articular involvement Most frequently affected joints Monosodium urate Negatively birefringent; needle-shaped Monoarticular > oligoarticular; polyarticular < 30% First MTP joint initially 50% eventuall 90% Ankles, knees, other Hyperuricemia*, obesity, hypertension, hyperlipidemia, alcohol ingestion, lead ingeation, hereditary enzyme defect (rare) Acute attacks: NSAIDs, corticosteroids, colchicine Chronic management Urate-lowering agents, colchicine Calcium pyrophosphate dihydrate Weakly positively birefringent; linear or rhomboidal Monoarticular > oligoarticular Knee, wrist other

Predisposing conditions/risk factors

Hypothyroidism, hemochromatosis, OA, chronic renal insufficiency, diabetes, hyperparathyroidism, hereditary (rare) Acute attacks: NSAIDs, corticosteroids, colchicine Chronic management NSAIDs colchicine

Therapeutic options

*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 Secondary Hypertension Idiopathic Hyperparathyroidism Myxoedema Familial juvenile Downs syndrome gouty nephropathy Increased level of organic level

Lead nephropathy Sarcoidosis Bartters syndrome Beryllium poisoning Drug: diuretics, B-blocker, ACEI, salicylates (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-5phosphate overproduction AMP-deaminase def. Secondary

Glycogen storage disease type II (G6PD), type III, V, VII Hereditary fructose intolerance Lymphoproliferative and myeloproliferative diseases ( leukemia, Hodgkins dz, lymphosarcoma, myeloma, PV, Waldenstroms macroglobulinemia ) Cytotoxic drugs Carcinomatosis Gauchers 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 CRP 90% of first attacks are monoarticular with first metatarsophalangeal joint, known as podagra. Left untreated, the symptoms are selflimiting but may take up to 21 week to subside.

Intercritical Gout
After 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
Can present at any age, including patients older than 60 years Predominantly men Monarthritis

Atypical Gout
Observed in elderly patients Diagnosed in as many women as men Polyarthritis

Asymmetric
Usually in lower extremity Tophi rare at presentation Acute Can be misdiagnosed as cellulitis or infection

Symmetric or asymmetric
Any joint, upper or lower extremity Tophi common at presentation Chronic but can have acute flareups Chronic form can be misdiagnosed as rheumatoid arthritis or osteoarthritis: acute flare-ups can be misdiagnosed as cellulitis or infection

Complication of gout
Joint: destruction Soft tissue nerve entrapment syndrome: CTS, tarsal tunnel syndromes kidney: uric acid calculi(10-15%), chronic urate nephropathy, and acute uric acid nephropathy Heart: ischemic heart disease

Criteria for clinical diagnosis


American Rheumatism Association sub-committe on classification criteria for gout 1977

presence of characteristic urate crystals in the joint fluid Tophus proved to contain urate crystals by negative polarized light microscopic study If 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 diagnosis
Acute
Infective arthritis Bursitis, cellulitis, tenosynovitis Other crystal arthropathy

( pseudogout, apatite or brushite arthritis or periarthritis ) Traumatic arthritis Hemoarthrosis RA with palindromic onset Reactive arthritis Spondarthritis with peripheral involvement Psoriatic arthritis Sarcoid arthritis Rheumatic fever

Chronic Nodular rheumatoid arthritis Psoriatic arthritis Osteoarthritis with Heberdens and Bouchards 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


Trauma unusual physical exercise Surgery Severe systemic illness Severe dieting Dietary excess Alcohol Drugs ( diuretics, initiation of uricosuric or allopurinol therapy, initiation of B12 therapy in pernicious anemia, cytotoxic drug therapy )

Physical examination
Vital sign Body weight and body height General appearance: Cushingnoid Consciousness HEENT Chest ( CV ) Abdomen Extremity -- 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 treatment
Indication: 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
Acute therapy/ prophylaxis NSAIDs

Adverse Events
Dose-dependent gastropathy, nephropathy, liver dysfunction, central nervous system dysfunction. May cause fluid overload in patients with congestive heart failure. Less GI toxicity than conventional NASIDs renal effecect similar to conventional NSAIDs

Contraindications
Peptic ulcer disease or bleeding ASA- Or NSAID-induced asthma, urticaria, or allergic-type reactions.

Regimen
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. Etoricoxise 120 mg/d (available outside the United States)

Cox-2 selective inhibitors (etoricoxib)

Cautious use in patients with advanced renal disease, history of ischemic heart disease, or history of NSAID-induced asthma. Use cautiously in renal or hepatic dysfunction.

Colchicine

Dose-dependent GI symptoms, neuromyopathy; improve IV dosing can cause bone narrow suppression, renal failure, paralysis, and death. Fluid detention, impaired Wound healing, psychosis Hyperglycemia hypothalamus Pituitary axis suppression Osteoporosis, potential for Rebound inflammation.

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. 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.

Corticosteroids

Table III. (Continued)


Agent
ACTH

Adverse Events
Fluid retention, hypokalemia relapse of gout, worse diabetes control

Contraindications

Regimen
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. 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. Rash, headache, and GI symptoms, bone narrow suppression, minor hypersensitive. Possesses inherent antiplatelet activity. 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.

Probenecid

Sulfinpyrazone

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.

Consider acquired causes of hyperuricemia associated with normal urinary acid excretion Obesity Ethanol Drugs Salicylates(low dose) Diuretics Pyrazinamide Ethambutol Nicotinic acid Laxative abuse(alkalosis) Cyclosporine If positive Correct underlying cause if possible and / or appropriate Hyperuricemic Symptoms Treat Asymptomatic Routine medical management Renal insufficiency Polycystic kidney disease Lead nephropathy Hypothyroidism Hyperparathyroidism Diabetic ketoacidosis Lactic acidosis Starvation Dehydration If negative Salt restriction Diabetes insipidus Bartters syndrome Sarcoidosis Downs syndrome Toxemia of pregnancy Hypoxemia Chronic beryllium disease

Consider secondary causes of hyperuricemia associated with elevated uric acid production
Myeloproliferative diseases Lymphoproliferative diseases Myeloproliferative diseases Lymphoproliferative Hemolytic anemias Polycythemia vera Obesity Ethanol Fructose (large doses) Tissue necrosis Exercise Convulsions Drugs 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 Treat Close follow-up of renal function Routine medical management It positive and patient is asymptomatic and not in clinical setting for acute uric acid nephropathy 24-hour urine uric acid >1100 mg/day <1100 mg/day

If positive and hyperuricemic symptoms Treat

Cause of hyperuricemia is not discermible


Symptomatic Treat Asymptomatic Serum urate >11 mg/dl 24-hour urine uric acid >1100 mg/day Serum urate <11 mg/dl

Routine medical management

<1100 mg/day

Follow renal Function closely

Routine medical management

Low Purine Diet


On 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 Beverages Peas, beans, spinach, lentils. Alcohol, beer, and beer products.

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