Gout Flashcards
Overview of gout
Gout is a chronic inflammatory arthritis that results from monosodium urate (MSU) crystal deposition in tissues or joints resulting from supersaturation of uric acid in extracellular fluids
- gout is a disorder of uric acid metabolism
- hyperuricemia = serum uric acid > 2SD above the mean (>7 mg/dL for men, >6 mg/dL for women)
- hyperuricemia is a precursor to gout –> not everyone who has hyperuricemia has gout
Clinical manifestations of gout
- gouty arthritis –> recurrent attacks of articular and per-articular inflammation
- tophus –> accumulation of MSU deposits in joints, bone, soft tissues and cartilage
- gouty nephrolithiasis –> uric acid calculi in urinary tract
- gouty nephropathy –> interstitial nephropathy with renal function impairment
Epidemiology
- increases with age - presents early in men than women (estrogen might be protective)
- most common cause of inflammatory arthritis in men >40 yrs old
- prevalence is on the rise in both sexes –> affects 8.3 million US adults >20 years
Risk factors and comorbidities
Comorbitiies –> HTN, CV disease, chronic kidney disease, DB mellitus, dyslipidemia, metabolic syndrome
Demographics –> advanced age, male gender, postmenopausal women
Lifestyle
- obesity
- idet
- ETOH
- high fructose corn syrup
Meds
- thiazides/furosemids
- low dose ASA
- cyclosporine
- nicotinic acid
- levodopa
Pathopys
hypoxanthin is converted to xanthine by xanthine oxidase
- xanthine converted to uric acid by xanthine oxidase
***allopurinole and febuxostat inhibit xanthine oxidase and block uric acid formation
- uric acid is normally excreted in the urine and feces –> supersaturation of monosodium urate cystals leads to precipitation of crystals and deposition in the tissues
Renal handling of urate - molecular mechanisms
Uric acid transporter (URAT1) –> receptor on luminal side of PCT epithelial cell
- major determinant of urate reabsorption
Organic acid transporters (OAT1 and 3) –> receptors located on interstitial side of PCT
- regulate transport of urate into the blood
Inflammatory response in gout
Pathophys
- phagocytosis of crystals by synoviocytes and neutrophils
- stimulation of chemotactic factors and cytokines (IL1, IL6 and TNF), prostaglandins, leukotrienes, and oxygen radicals
- activation of complement and lysosomal enzyme release
Inflammatory response
- IgG- dependent complement activation via classical and alternative pathways
- crystal associated polypeptides which activate clotting cascade –> transient fibrinogen elevation
- PMNs phagocytose MSU crystals, which cause cell lysis and release of lysosomal enzymes
- monocyte and macrophage interaction with MSU crystals cause release of pro-inflammatory cytokines, O2, LTB4, PGs and lysosomal proteases
- IL1 may account for systemic features of gout
IL1 and gout
Inflammasome - a multi-protein complex expressed in myeloid cells that is activated by infection, stress, etc., and is responsible for maturation of IL1 and activation of inflammatory processes
- IL1B produced by macrophages, monocytes + dendritic cells
- the innate immune system recognizes MSU crystals via TLRs 2 + 4 on the cell surface
- binding MSU to TLR generates reactive oxygen species which stimulate the cryopyrin NALP3 inflammasome
- this results in the processing and maturation of pro-IL-1B and secretion of mature IL-1B
Stages of gout
- Asymptomatic hyperuricemia
- Acute intermittent gout (acute flare)
- Intercritical gout
- Advanced gout
Stage 1: Asymptomatic hyperuricemia
- Hyperuricemia is a necessary precursor to gout
- Hyperuricemia is NOT gout
- –> Elevated serum urate
- –> No history of gout
- –> No clinical signs or symptoms
- No indication for pharmacologic treatment
- Few progress to gout
- Consider non-pharmacologic therapy, ie lifestyle modification
- –> weight loss
- –> reducing consumption of red meat and other high purine foods
- –> reduce alcohol consumption
- –> increase consumption of low fat dairy
- –> vit C supplements
Stage 2: Acute gout flare
Acute inflammation, rapid development of intense pain, swelling, tenderness and overlying erythema
- Often occurs at night or early morning
- Monoarticular ~90% of first attacks
- Podagra ~50% of first attacks –> instep, ankles, heels, knees, wrists, fingers and elbows too
- In advanced disease, attacks may be polyarticular, atypical, and more frequent –> non-articular sites- olecranon bursa, Achilles
Stage 3: Intercritical gout
Symptom free periods between flares
- urate crystals may still be identified –> previously inflamed joints and uninvolved/asymptomatic joints
- crystals remaining in joint may lead to:
- –> chronic, low grade inflammation
- –> risk of recurrent attacks
- –> devt of tophi
Stage 4: Advanced gout
- Persistent, destructive arthritis w/ chronic symptoms
- Results from established disease
- Usually develops after 10 or more years of acute intermittent gout
- Tophaceous deposits may become clinically apparent
- Intercritical periods no longer pain free –> persistent pain, swelling, deformities
- May be confused with rheumatoid arthritis
Diagnosis
- Identification of MSU crystals in synovial fluid or tissue (e.g., tophus)
- –> Polarized light microscopy
- Radiographic erosions typical of gout may be suggestive i.e. “rat bite”
- Synovial fluid is inflammatory i.e. 10-100,000 cells/mm3, but not specific
- Bacterial infections can co-exist with gout; always send fluid for gram stain and culture
Cyclosporine induced gout
- Occurs in 10% of transplant patients treated with cyclosporine, almost exclusively males
- Frequently complicated by calculi and tophi
- Associated with hyperuricemia, renal insufficiency, and diuretic use
- Cyclosporine-induced tubular defect in urate secretion
Saturnine gout
- lead poisoning inhibits excretion of the waste product urate and causes a predisposition for gout
- environmental –> moonshine, high lead content in food
- occupational exposures –> painter, plumber, pipefitters, mechanics, etc
Relationship of gout to sUA level
- annual incidence of gout directly correlates with serum uric acid concentration
- above 6.8 mg/dL urate precipitates as MSU crystals, leading to gout flare and tophus formation
Principles of gout treatment
- cost effective after 1st attack and cost-saving after 2nd attack
- target is to reduce SUA below 6 mg/dl –> precipitates at 6.8
- –> reduction in number of attacks
- –> fewer crystals in joints
- –> reduction in size of tophi
Acute rx
- NSAIDS
- steroids
- colchicine (oral)
- IL1 inhibitors
Chronic –> if more than 2-3 attacks/year, initiate prophylaxis
- colchicine
- allopurinol
- febuxostat
- probenecid (fallen out of favor, very contraindicated in renal insufficiency)
NSAIDS
- first line therapy for acute gout attack
- may be used for prophylaxis when starting maintenance therapy
- indomethacin used more often, but no good data to show that it is more efficacious than other NSAIDs
- use is often limited by renal impairment, GI intolerance, fluid retention and hepatotoxicity
Caution in elderly patients and those with renal impairment
Colchicine
- FDA approved for use in gout in 2009
- used for both acute and chronic therapy
- most effective in first 12-24 hours of attack
- binds to tubulin dimers
- decreased leukocyte phagocytosis, adherence, chemotaxis and release of lysosomal enzymes from PMNs
- should be continued for at least 3-6 months following initiation of uric acid lowering therapy
Adverse effects
- narrow therapeutic window
- diarrhea
- myonecross
- caution in renal failure
IL-1Ra receptor antagonist
Anakinra –> very effective in tx of acute attacks; used off label
- rationale –> role of inflammasome in pathogenesis of acute gout attack
- inflammasome - a multi-protein complex expressed in myeloid cells that is activated by infection, stress, etc - responsible for the maturation of IL1 and activation of inflammatory processes
Allopurinol
Used for maintenance therapy
- hypoxanthine analogue –> inhibits xanthine oxidase through competitive and non-competitive inhibition depending on concentration
- allopurinol metabolite, oxypurinol (xanthine analog) can reduce uric acid concentrations in plasma, urine, and dissolve or prevent formation of uric acid
- decreases serum uric acid and dissolves tophi
- max urate lowering effects seen within 14 days
Caution –> concomitant use with azathioprine and 6MP can lead to pancyotopenie due to shared metabolism by xanthine oxidase
Allopurinol hypersensitivity syndrome
DRESS syndrome –> drug reaction, eosinophilia, systemic symptoms
- 2% of all allopurinol users develop cutaneous rash
- risk of hypersensitivity related to starting dose
- occurs in 1/260
- 20% mortality
- life threatening toxicity –> vasculitis, rash, eosinophilia, hepatitis, progressive renal failure
Treatment –> early recognition, withdrawal of drug, supportive care
- oxypurinol is the allopurinol metabolite produced by xanthine oxidase –> cleared by the kidney and accumulates in patients with renal failure
- increased oxypurinol related to risk of allopurinol hypersensitivity syndrome
Febuxostat
Maintenance therapy
- non-purine selective XO inhibitor
- inhibits both oxidized and reduced forms of XO
- decreases serum uric acid and dissolves tophi
- option in chronic gout patients with allopurinol allergy or inadequate response to allpurinol
Adverse effects
- caution with hepatic impairment, diarrhea, arthralgia
Probenecid
Maintenance therapy
- promotes renal uric acid excretion
- competitively inhibits organic anion transporter through URAT1 exchanger
Adverse effects
- multiple drug interactions
- not effective with poor kidney function
- cannot use in patients with renal stones
- has largely fallen out of favor
Drugs that convert uric acid to allantoin
Allantoin = metabolite of uric acid that humans do not normally produce
- uricase –> catalyzes conversion of uric acid to allantoin
- rasburicase –> FDA approved for prevention of tumor lysis syndrome
- PEGylated uricase –> FDA approved for tx of chronic refractory gout
Pegloticase
Maintenance therapy
- PEGylated uric acid enzyme indicated for chronic refractory gout
- contains recombinant mammalian urate oxidase (uricase)
- converts uric acid to allantoin, which is water soluble and renally excreted
- 8 mg infusion every 2 weeks
Caution
- screen for G6PD deficiency
- anaphylaxis/infusion reaction (dyspnea, wheezing, urticaria)
- no use with CHF
- stop use if serum uric acid levels rise above 6
Calcium pyrophosphate dihydrate deposition disease (CPPD)
- CPPD is calcium salt deposited in cartilage
- CPPD release into joint causes acute painful arthritis, called pseudogout
- most chondrocalcinosis is asymptomatic
- caused by an abnormality in inorganic pyrophosphate (Ppi) metabolism –> leads to progressive osteoarthritis
- X rays will show chondrocalcinosis –> linear or punctate calcification of fibrocartilage or hyaline cartilage
- common sites = meniscus, TFC cartilage of wrist, symphysis pubis, glenoid rim, hip, annulus fibrosis
- demnonstration of CPPD crystals in synovial fluid by compensated polarized light microscopy –> weakly positive birefringent rhomboid shaped crystals, classically blue
CPPD management
Treatment
- NSAIDS
- colchicine
- intraarticular steroids
- low dose oral steroid
Prevention - oral colchicine
Milwaukee shoulder syndrome
- deposition of hydroxyapatite crystals
- crystal deposition activates enzymes which lead to joint destruction and rotator cuff disruption
- Xray shows erosion of hymeral head, cartilage, capsule and bursae
- seen in females in fifth/sixth decade
- diagnosis with arthrocentesis and alizarin red staining
calcium oxalate arthropathy
Acute mono- or oligoarthritis involving knees, elbows, or ankles
- chronic , rheumatoid-like polyarthritis with flexor tenosynovitis
- poorly responsive to colchicine or NSAIDs
- mildly inflammatory synovial fluid with calcium oxalate crystals
- peri-articular and soft tissue calcification with arterial calcification on x ray
