Rheumatology E-learning

University of Szeged

Department of Rheumatology and Immunology

The definition of gout

Arthritis urica: an acute inflammatory process elicited by the precipitation of uric acid cristals inside the joint or in other soft tissues

Known also in ancient times

Famous people with gout: Henry VIII, Louis XIV, Thomas Jefferson, Alfred Tennyson, Charles V (German and Spanish Emperor), Hungarian king Mathias,

„Disease of the kings”

Gouty arthritis

Acute gouty attack

Chronic tophaceous gout

The history of gout

First signs of gout: Egyptian mummies 2000 B.C.

First description: Hippokrates – podagra (pain in the foot)

1679: Leuwenhook describes the needle-shaped crystals obtained from tophi

1600s: precise description of gout by Thomas Sydenham (a gout sufferer)

1776: the first characterisation of uric acid

Early 1800s: first use of colchicum as a treatment. Colchicum autumnale: meadow saffran, a flower from the coasts of the Black Sea

1861: Alfred Garrod connects uric acid with gout

1963: introduction of allopurinol

The source of uric acid in the body

Endogenous pathway

(80%) - liver

1. Nucleic acid-breakdown

2. de novo purin-

nukleotide synthesis

Exogeous pathway (20%)

Small intestinal epithelium

(nucleotides from food)

Adenin Guanin

AMP GMP

Inosin-monophosphate (IMP)

Hypoxantin

Xantin

Uric acidXantin-

oxidase

Xantin-

oxidase

Uricase – not present in humans

The pathways of endogenous uric

acid formation

1. DNA, RNA breakdown: Nucleotides → nukleosides → AMP, GMP

Depends upon cell-turnover (tumor, psoriasis, increase in basal metabolism /stress, physical strain, infection/, fasting

2. De novo nucleotide synthesis Ribose-5-P → phosphoribosil-pirophosphate (PRPP) → IMP → AMP, GMP

PRPP synthetase (Ribose-phosphate-

pirophosphokinase) Amidophosphoribosil-transferase

3. Salvage-mechanisms AMP, GMP, IMP + phosphoribosil-pirophosphate (PRPP) → adenin, guanin

Hypoxantin-guanin-phosphoribosil-transferase (HGPRT)

Causes of hyperuricaemia

Mechanism:

Overproducers (10%)

Underexcretors (90%)

Aetiology:

Primary (10%)

Secondary (90%)

Normal serum uric acid levels:

120-360 μmol/l (2-6 mg/dl) (females)

180-420 μmol/l (3-7 mg/dl) (males)

Primary hyperuricaemias

PRPP synthetase increased activity X-linked disease

Increased production of PRPP → increased supply of adenine-and guanine nucleotide constituents

Gouty arthritic and urinary stone attacks in early adulthood

HGPRT deficiency X-linked disease

Loss of feedback inhibition of amidophosphoribosil transferase → increased de novo purin synthesis

Lesch-Nyhan syndrome – gout, mental retardation, choreo-athethosis, chronic urate nephropathy

Decreased uric acid clearance Hereditary renal tubular deficiency of unknown background

Secondary hyperuricaemias –

overproduction of uric acid

Haematological malignancies, cell destruction (trauma, cancer), cytotoxic drugs, psoriasis

Increased consumption of foods with high uric acid content (cocoa, chocolate, liver, meat, pea, lentil, beer)

Fasting

Fever, stress, infection

Alcohol (mixed aetiology) – increased purin-nucleotide synthesis, increased renal Na + uric acid reabsorption (Na-H exchange )

Obesity (mixed aetiology)

Secondary hyperuricaemias –

decreased excretion of uric acid Metabolic syndrome

Hyperinsulinism – increased Na-H exchange in the proximal tubules –increased uric acid reabsorption

Very frequent association with obesity, hypertension, diabetes, hyperlipidaemia, atherosclerosis

Acute or chronic renal insufficiency Dehydration, other causes of acute renal failure

Chronic tubulo-interstitial diseases (polycystic kidney disease, tubulo-interstitial nephritis, hyperparathyreoidism, lead intoxication)

Acidosis Alcohol, lactate acidosis, ketoacidosis… Increased Na-H exchange in the

proximal tubules – increased uric acid reabsorption

Drugs Diuretics (thiazide and furosemide)

Cyclosporin

Low dose aspirin

Hyperuricaemia and gout

Hyperuricaemia # gout

In one survey: the five-year cumulative incidence rates of gouty arthritis 2.0 percent for a serum urate level of 8.0 mg per dL

(475 µmol per L) or lower,

19.8 percent for urate levels from 9.0 to 10.0 mg per dL (535 to 595 µmol per L)

30 percent for a serum urate level higher than 10 mg per dL (595 µmol per L).

Gouty arthritis = 1) precipitation of monosodium-urate crystals + 2)inflammation

Precipitation: urate concentration , pH ↓, temperature ↓

Inflammation in gouty arthritis

Urate crystals are phagocyted by neutrophils and macrophages

Neutrophil activation: Proteases, reactive oxigen species, leukotrienes,

prostanoids

IL-1, TNF-α, IL-6

Macrophage activation: Chemokines, TNF-α, IFN-γ

Crystals activate the NALP3 inflammasome

„autoinflammatory disease”

Activation of the innate immune system

Neutrophil granulocyte „oxidative burst” –enzymes, ROI, prostaglandins

Chemokines

Inflammasome hyperactivation → IL-1βoverproduction

„Autoinflammatory syndrome”

Gout - epidemiology

Prevalence: 5/1000 in men, 2/1000 in

women

Peak incidence:

Men: 30-50 years

Women: 45-60 years

Younger age: hereditary cause

Older age: association with other diseases

(renal failure, diuretics, malignancy)!

Triggering factors of a gouty attack

Hyperuricaemia # gout

Gouty arthritis = 1) precipitation of monosodium-

urate crystals + 2)inflammation

Precipitation:

Urate concentration - excessive eating, fasting,

dehydration, infection, chemotherapy

pH ↓- alcohol, lactate acidosis, ketoacidosis

temperature ↓- typical onset of symptoms at night and

presentation at acral body parts (toe, finger, elbow,

ear)

Acute gouty arthritic attack

Very acute onset

Very painful swelling, redness, tenderness

I. MTP joint > ankle, knee> other foot joints >

upper extremity

Fever, subfebrility may be present

Spontaneous resolution within 5-8 days

Acute gouty arthritis

Acute gouty arthritis

Chronic gout

The attacks tend to occur more frequently,

resolve more slowly, and involve more and more

joints

Chronic joint damage develops (chronic pain,

loss of range of motion, contracture,

radiographic bone destruction

Tophus formation (monosodium-urate crystal

containing nodules around the joints (juxta-

articular) or in soft tissues (subcutaneous, ear,

occasionally in viscers)

Gout – tophi, deforming arthritis

Tophaceous gout

Chronic olecranon bursitis in gout

Chronic olecranon bursitis in gout

Subcutaneous tophi

Chronic tophaceous gout

Tophi on the ear

Chronic tophus with subcutaneous

fistula formation

The kidney in gout

1. Sodium-urate urinary stones

2. Acute urate nephropathy (during excessive cell destruction e.g. chemotherapy) – acute renal failure, acute tubular obstruction and necrosis

3. Chronic urate nephropathy: signs of chronic tubulo-interstitial damage

Frequent differential-diagnostic question: Chronic renal insufficiency → secondary

hyperuricaemia?

or Chronic hyperuricaemia → chronic urate

nephropathy?

Diagnosis of gout

Absolute proof: the demonstration of urate crystals in the synovial fluid

Probable diagnosis:

typical clinical picture

Hyperuricaemia – but: serum urate levels are often normal during gouty attack

Chronic tophaceous gout

typical radiographic pictures

rarely a differential diagnosis from rheumatoid arthritis or spondylarthropathies may be challenging

Intracellular urate crystals

Light microscopy Polarisation microscopy

Intra-articular urate crystals –

polarisation microscopic image

Radiographic hallmarks of advanced,

tophaceous gout

.

The simultaneous

occurrence of erosions (1),

enlargement of

the width of joints (2),

overhanging edges (3a,

3b), and sclerotic,

degenerative changes in

the wrist.

Gout – radiographic changes in the feet

Punched out

erosions + soft

tissue

calcification

Arrow: soft tissue

calcification

The treatment of gout

Treatment of acute attacks

Prevention of subsequent attacks and

chronic bone and joint destruction

The evaluation and treatment of associated

diseases (METABOLIC SYNDROME)

Dietary treatment of gout High purin content

Best to avoid: Anchovies, sardines, herring, mussels, codfish, scallops, trout, haddock,

veal, venison, turkey, high fructose-content juices and sodas and alcoholic beverages

Moderate purin content

May eat occasionally: Asparagus, beef, bouillon, chicken, crab, duck, ham, kidney beans,

lentils, lima beans, mushrooms, lobster, oysters, pork, shrimp, spinach

Low purin content

No limitation: Coffee, fruits, breads, grains, macaroni, cheese, eggs, milk products,

sugar, tomatoes and green vegetables (including lettuce and excluding vegetables listed above

MODERATE CALORY INTAKE (IF OBESITY), APPROPRIATE SUGAR (IF DIABETES) OR CHOLESTEROL (IF HYPERCHOLESTEROLAEMIA, ATHEROSCLEROSIS)!!!

Chronic maintainance drug therapy of

gout (hypouricaemic therapy)

Allopurinol Xanthin-oxidase inhibitor

Decreases hepatic uric acid production (xantin and hypoxantin are more soluble)

Dose: 100 mg/day → 600 mg/day

Reduced doses in renal and hepatic insufficiency!

Occasionally severe allergic reactions (erythroderma, toxic epidermal necrolysis, „allopurinol hypersensitivity syndrome”: fever, generalised rash, systemic vasculitis, hepatic and renal failure, eosinophilia)

Febuxostate More effective, better pharmacokinetics, less side

effects

Indicated in cases of allopurinol-allergy

Further drugs to treat

hyperuricaemia/gout

Uricosuric agents Sulfinpyrazone

Less effective

Urate stones – for prevention, urine alkalinisation is important!

Uricase Rasburicase (recombinant uricase enzyme)

Interleukine-1 antagonist biological therapies Canakinumab, rilonacept

Indications for urate lowering treatment: repeated gouty attacks, tophaceous gout, repeated urinary stone formation, urate nephropathy, prophylaxis during chemotherapy (→ hyperuricaemia without the above symptoms: no treatment is indicated)