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,

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-5-

phosphate overproduction

AMP-deaminase def.

Secondary Glycogen storage disease type II (G6PD), type III, V, VII Hereditary fructose intolerance Lymphoproliferative and

myeloproliferative 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 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 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

( 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

Heberden’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 nephropathy

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.