Rheumatology E-learning. University of Szeged Department of Rheumatology and Immunology

Transcription

1 Rheumatology E-learning University of Szeged Department of Rheumatology and Immunology

2 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

3 Gouty arthritis Chronic tophaceous gout Acute gouty attack

4 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

5 The source of uric acid in the body Endogenous pathway (80%) - liver 1. Nucleic acid-breakdown 2. de novo purinnukleotide synthesis Adenin AMP Exogeous pathway (20%) Small intestinal epithelium (nucleotides from food) Guanin GMP Inosin-monophosphate (IMP) Hypoxantin Xantin Uric acid Xantinoxidase Xantinoxidase Uricase not present in humans

6 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-phosphatepirophosphokinase) Amidophosphoribosil-transferase 3. Salvage-mechanisms AMP, GMP, IMP + phosphoribosil-pirophosphate (PRPP) adenin, guanin Hypoxantin-guanin-phosphoribosil-transferase (HGPRT)

7 Causes of hyperuricaemia Mechanism: Overproducers (10%) Underexcretors (90%) Aetiology: Primary (10%) Secondary (90%) Normal serum uric acid levels: μmol/l (2-6 mg/dl) (females) μmol/l (3-7 mg/dl) (males)

8 Primary hyperuricaemias PRPP synthetase increased activity X-linked disease Increased production of PRPP increased supply of adenineand 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, choreoathethosis, chronic urate nephropathy Decreased uric acid clearance Hereditary renal tubular deficiency of unknown background

9 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 purinnucleotide synthesis, increased renal Na + uric acid reabsorption (Na-H exchange ) Obesity (mixed aetiology)

10 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, tubulointerstitial 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

11 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 monosodiumurate crystals + 2)inflammation Precipitation: urate concentration, ph, temperature

12 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

13 Activation of the innate immune system Neutrophil granulocyte oxidative burst enzymes, ROI, prostaglandins Chemokines Inflammasome hyperactivation IL-1β overproduction Autoinflammatory syndrome

14 Gout - epidemiology Prevalence: 5/1000 in men, 2/1000 in women Peak incidence: Men: years Women: years Younger age: hereditary cause Older age: association with other diseases (renal failure, diuretics, malignancy)!

15 Triggering factors of a gouty attack Hyperuricaemia # gout Gouty arthritis = 1) precipitation of monosodiumurate 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)

16 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

17 Acute gouty arthritis

18 Acute gouty arthritis

19 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 (juxtaarticular) or in soft tissues (subcutaneous, ear, occasionally in viscers)

20 Gout tophi, deforming arthritis

21 Tophaceous gout

22 Chronic olecranon bursitis in gout

23 Chronic olecranon bursitis in gout

24 Subcutaneous tophi

25 Chronic tophaceous gout

26 Tophi on the ear

27 Chronic tophus with subcutaneous fistula formation

28 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?

29 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

30 Intracellular urate crystals Light microscopy Polarisation microscopy

31 Intra-articular urate crystals polarisation microscopic image

32 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.

33 Gout radiographic changes in the feet Arrow: soft tissue calcification Punched out erosions + soft tissue calcification

34 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)

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36 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)!!!

37 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

38 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)