GOUT! (And Calcium Crystal Diseases)

1. GOUT!(And Calcium Crystal Diseases) Michael Pillinger, MD Division of Rheumatology NYU School of Medicine

2. What Is Rheumatology? Rheuma (Greek)--flowing In ancient Greek and medeval medicine it was believed that certain liquids, or humors, could flow through the body and needed to be in balance.

3. Arthritis Involves the Influx of Something Into a Joint--Andrew Boorde, 16th C “The rheumatic humor, produced in the head, is viscous. Descending from the head to the inferior parts, it causes many infirmities. If it, in contrast to the coleric humor, causes joint disease, the affected parts become swollen and red, with engorged vessels.” --Andrew Boorde, MD, 1547

4. Arthritis Can Be Part of a Systemic Disease--Guillaume de Baillou, 16th C “What arthritis is in a joint, that is exactly what rheumatism is in the whole body.” --Guillaume de Baillou, MD, (1558-1616)

5. Rheumatic Diseases: Multiple Targets, Multiple Mechanisms

6. Acute Monoarticular Arthritis

7. Neutrophils in Synovial Fluid

8. Uric Acid Crystals--Scanning EM

9. Charles V (1500-1558) -Last of the Holy Roman Emporers -United most of Europe into a single large empire HAD GOUT!!!

10. Charles V--The Pediatric Record A young man does not take the gout until [around the time] he indulges in coition; a woman does not take the gout, unless her menses be stopped. Eunichs do not take the gout. --Hippocrates, MD--ca. 400 B.C. The first references to Charles V’s arthritic pain were made when he was 28 years of age --Ordi et al, NEJM

11. Age, Sex Hormones and Uric Acid Levels

12. The Stages of Gout 1) Asymptomatic hyperuricemia

13. The Uric Acid Pool:A Balance of Formation and Excretion

14. Charles V--The Dietary History “The Emporer had a voracious appetite, especially for meat.” -Ordi et al, NEJM

15. 2 1 1 0.5 0 0 Low Low Med Med High High Dietary Intake and Risk of Gout Meat Intake Dairy Intake Relative Risk of Gout Relative Risk of Gout Meat Intake Dairy Intake

16. Supersize Me!

17. Gout is ON the Rise! All patients Gout Incidence/ 100,000 Age > 80 years Gout Prevalence % 1994 2008 1977- 1978 1995- 1996 J. Rheum 2002; 29:2403-2406 Zhu et al, ACR Abstract 2010 #2154

18. A Second Opinion--Diet and Gout “'Most of the time, acute attacks are not related [exclusively] to diet,” said Dr. Steven Abramson. "Most of the time, [gout occurs] because the body doesn't handle uric acid as well as it should." --Newsday

19. The Uric Acid Pool:A Balance of Formation and Excretion

20. Purine Metabolism

21. Purine Metabolism Made Ridiculously Simple! Ribose-5-P PRPP Synthase Purines ATP, ADP, AMP HGPR Transferase (purine salvage) Xanthine Xanthine Oxidase Uric Acid

22. Uricase Allantoic Acid (highly soluble!) Purine Metabolism Made Ridiculously Simple! Ribose-5-P PRPP Synthase Purines HGPR Transferase (purine salvage) Xanthine Xanthine Oxidase Uric Acid

23. Mechanisms of Uric Acid Overproduction • Abnormal purine metabolism • Increased production (PRPP synthase up) • Decreased salvage (HGPRTdown) • Increased cell (and purine) turnover • Myelo- and lymphoproliferative malignancies • Hemolytic anemias • Chemotherapy with tumor lysis

24. The Uric Acid Pool:A Balance of Formation and Excretion

25. Renal Urate Excretion: The Old Model

26. Urate Excretion by the Kidney: Multiple Transporters in the Proximal Tubule Manage Urate

27. Genetics of Hyperuricemia: Separated At Birth? Henry VIII Charles V

28. Mechanisms of Uric Acid Underexcretion Primary Underexcretion -Renal Tubular Defects Secondary Underexcretion -Glomerular insufficiency -Counter-ion promotion of uric acid retention Lactic and ketoacidosis Drugs

29. Drugs Causing Hyperuricemia • Salicylates (low dose) • Diuretics • Pyrazinamide • Ethambutol • Nicotinic acid • Alcohol

30. Alcohol and Hyperuricemia • Increased ATP consumption • Increased lactate production • Ketoacidosis • Increased purine consumption • Diuresis and dehydration • Moonshine (lead) nephropathy

31. Charles V: A Drinking History “Charles liked to drink large quantities of beer and wine, and he even ordered a specially designed four-handled drinking mug.”

32. Consequences of Hyperuricemia For most patients-- NONE (Maybe…..)

33. Incidence of Acute Gout Rises with Serum Urate Concentration 5 4 Annual Incidence of Gout (Percent) 3 2 1 0 ≤7.0 7.1-8.9 >8.9 Serum Urate Concentration (mg/dl)

34. The Stages of Gout 1) Asymptomatic hyperuricemia 2) Acute gouty arthritis

35. Sydenham On Gout “The victim goes to bed and sleeps in good health. About two o'clock in the morning he is awakened by a severe pain in the great toe; more rarely in the heel, ankle or instep. The pain is like that of a dislocation, and yet the parts feel as if cold water were poured over them. Then follows chills and shivers, and a little fever. The pain, which was at first moderate, becomes more intense. With its intensity, the chills and shivers increase. After a time this comes to its height, accommodating itself to the bones and ligaments of the tarsus and metatarsus. Now it is a violent stretching and tearing of the ligaments--now it is a gnawing pain, and now a pressure and a tightening. So exquisite and lively meanwhile is the feeling of the part affected that it cannot bear the weight of the bedclothes nor the jar of a person walking in the room. The night is passed in torture, sleeplessness, turning of the part affected and perpetual change of posture.”--Thomas Sydenham, 1683

36. What REALLY Causes Gout?

37. Acute Gout--First Metatarsophalangeal Joint

38. Acute Gout--First MTP--With Desquamation

39. Spontaneous Precipitation (? Acute Hyperuricemia?) Formation of Urate Crystals in the Synovial Fluid Release from Cartilaginous Deposits (?Trauma?) Free-floating Urate Crystals

40. Initiation of Inflammation by Urate Crystals Urate Crystal Activation of Synovial Macrophages -Activation of complement C5a (direct and indirect pathways) -Activation of other serum factors Il-1, TNF-a, IL-8 production -Upregulation of PMN integrins -PMN activation Upregulation of Endothlial Cell ICAMs and Selectins.

41. ASC Cardinal The Inflammasome-A Central Mediator of Gout Inflammation Monosodium Urate Crystals NLRP3 Inflammasome Caspase-1 Pro-caspase-1 IL-1β TNF, IL-6 Pro-IL-1β IL-1β IL-1β Receptor TNF, IL-6 Nucleus Macrophage

42. Rolling Tight Adhesion Selectin (shed after neutrophil activation) Selectin (activated by chemoattractants) Integrin-CD11b/CD18 (upregulated and activated by cytokines) ICAM Integrin (CD11b/ CD18, inactive) Complement activation C5a Cytokines (IL-1, TNF-a, etc) Macrophage Crystal Inflammation: Neutrophil Adhesion, Diapedesis, Chemotaxis Sialylated Glycoprotein Endothelial Cells Basement Membrane

43. Diapedesis Complement activation C5a Chemotaxis Phagocytosis Degranulation O2- Generation Inflammation: Neutrophil Adhesion, Diapedesis, Chemotaxis Rolling Tight Adhesion Endothelial Cells Basement Membrane Macrophage Crystal

44. Jailbreak: Neutrophils Escape the Bloodstream and Flee to a Gouty Joint!

45. Neutrophils and Endothelium:A Vascular Love Affair

46. Effect of Urate Crystals on Neutrophils in the Acute Gouty Joint PMN Activation PMN Lysis Urate Crystal Ingested by PMN -Production of IL-1, IL-8, LTB4 -Superoxide anion generation -Degranulation (Protease Release) -Production of LTB4 -Protease Release Further Inflammation and Joint Damage

47. Acute Gout of the Wrist

48. Acute Polyarticular Gout-First MTP, Ankle

49. Acute Polyarticular Gout--First MTP Left Foot, Midfoot of Right Foot

50. Acute Polyarticular Gout--Fingers