Guideline For Gout Management

Guideline for gout management (Arthritis) 高雄長庚醫院風濕過敏免疫科

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

Introduction Crystal-Induced Arthritis

Characteristic Prevalence

Gout

Pseudogout

1.5 to 2.6 cases per 1000 individuals; <1 case per 1000 individuals; increases increases with age in men and with age postmenopausal women; 15/1000 at age 58; men:28/1000, women:11/1000

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, Hypothyroidism, hemochromatosis, OA, hyperlipidemia, alcohol ingestion, lead chronic renal insufficiency, diabetes, ingeation, hereditary enzyme defect (rare) 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.

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  Down’s syndrome  Increased level of organic level gouty nephropathy  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-5phosphate 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 CRP 90% 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 flareups

Can be misdiagnosed as cellulitis or Chronic form can be misdiagnosed infection 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 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 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

Adverse Events

Contraindications

Regimen

Acute therapy/ prophylaxis NSAIDs

Dose-dependent gastropathy, Peptic ulcer disease or bleeding nephropathy, liver dysfunction, ASA- Or NSAID-induced asthma, central nervous system urticaria, or allergic-type reactions. dysfunction. May cause fluid overload in patients with congestive heart failure.

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

Colchicine

Dose-dependent GI symptoms, Use cautiously in renal or hepatic neuromyopathy; improve IV dysfunction. dosing can cause bone narrow suppression, renal failure, paralysis, and death.

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.

Cautious use in patients with Etoricoxise 120 mg/d (available advanced renal disease, history of outside the United States) ischemic heart disease, or history of NSAID-induced asthma.

Table III. (Continued) Agent ACTH

Adverse Events

Contraindications

Fluid retention, hypokalemia relapse of gout, worse diabetes control

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.

Probenecid

Rash, headache, and GI symptoms; Renal dysfunction (CrCI rare nephritic syndrome, hepatic <50mL/min) or renal calculi necrosis, aplastic anemia and hemolytic anemia. Reduced orate levels in underexcretors.Potential for numerous drug interactions because of interference with excretion of many medications.

Sulfinpyrazone

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

250mg BID for 1 to 2 weeks↑ ny500mg increments every 1 to 2 weeks until satisfactory control is achieved or maximal dose 3 g.

Renal dysfunction (CrCI 50mg BID;↑ to 300 to 400 <50mL/min) or renal calculi mg/d in 2 to 3 divided doses maximum dose 800 mg/d.

Consider acquired causes of hyperuricemia associated with normal urinary acid excretion Renal insufficiency Polycystic kidney disease Lead nephropathy Hypothyroidism Hyperparathyroidism Diabetic ketoacidosis Lactic acidosis Starvation Dehydration

Obesity Ethanol Drugs 　 Salicylates(low dose) 　 Diuretics 　 Pyrazinamide 　 Ethambutol 　 Nicotinic acid 　 Laxative abuse(alkalosis) 　 Cyclosporine

If negative

If positive

Consider secondary causes of hyperuricemia associated with elevated uric acid production

Correct underlying cause if possible and / or appropriate Hyperuricemic Symptoms Treat

Salt restriction Diabetes insipidus Bartter’s syndrome Sarcoidosis Down’s syndrome Toxemia of pregnancy Hypoxemia Chronic beryllium disease

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

Asymptomatic Routine medical management

If positive and hyperuricemic symptoms Treat

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

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

Cause of hyperuricemia is not discermible Symptomatic Treat

Asymptomatic Serum urate >11 mg/dl 24-hour urine uric acid

>1100 mg/day Follow renal Function closely

Serum urate <11 mg/dl Routine medical management

<1100 mg/day 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

Peas, beans, spinach, lentils.

Beverages

Alcohol, beer, and beer products.