Crystal-Induced Arthritis

1. Crystal-Induced Arthritis “All the Pearls in 50 Minutes” Gerald F. Falasca, M.D. Johnson City, TN March 27, 2012

2. The risk factors for gout were known to the ancients.

3. Ben Franklin (1706 -1790) "Be temperate in wine, in eating, girls, and sloth, or the Gout will seize you and plague you…" -- Franklin

4. MAJOR ARTHRITOGENIC CRYSTALS • Monosodium urate • Calcium pyrophosphate dihydratte • Hydroxyapatite • Corticosteroid esters • Calcium oxalate

5. MAJOR ARTHRITOGENIC CRYSTALS • Monosodium urate • Calcium pyrophosphate dihydratte • Hydroxyapatite • Corticosteroid esters • Calcium oxalate

6. Underexcretors (80%) Male gender Postmenopausal females Obesity, metabolic synd. Ethanol Renal insufficiency Plumbism Medications (see separate) Dehydration/low flow Filipino ancestry Fructose ingestion Uromodulin kidney dis. Overproducers (20%) Ethanol High cell turnover states (psoriasis, myeloprolif. disorders) Excessive purine ingestion PRPP overactivity (x-linked) HGPRT underactivity (x-linked) Beta aldolase deficiency Sarcoidosis B12 deficiency Down syndrome Glycogen storage dis. 3, 5, 7 Fever, post-op state Risk Factors for Gout

7. Obesity, metabolic syndrome Ethanol Diuretics Fructose ingestion Excessive purine ingestion Risk Factors for Gout

8. Hyperuricemia and Gout • Dairy consumption is protective. • Estrogen protective (suppresses URAT1, the proximal renal tubule epithelial cell anion exchanger ). • Beer much worse than wine.

9. Overproducers • 15-20% of gouty patients are overproducers. • Distinguished by 24 hour uric acid excretion: • > 800 mg/d on regular diet. • > 600 mg/d on purine-free diet.

10. Diuretics (loop and thiazide types) Low-dose aspirin Cyclosporine, tacrolimus Ethanol Ethambutol Pyrazinamide Ritonavir, darunavir, didanosine Levodopa Nicotinic acid, niacin Pancreatic enzymes Rituximab Basiliximab Teriparatide Filgrastim Sildenafil Diazoxide Cytotoxic chemotherapy Drugs Associated with Hyperuricemia

11. Diuretics (loop and thiazide types) Low-dose aspirin Cyclosporine, tacrolimus Ethanol Ethambutol Pyrazinamide Ritonavir, darunavir, didanosine Levodopa Nicotinic acid, niacin Pancreatic enzymes Rituximab Basiliximab Teriparatide Filgrastim Sildenafil Diazoxide Cytotoxic chemotherapy Drugs Associated with Hyperuricemia

12. Hyperuricemia & Gout

13. Hyperuricemia and Gout • Hyperuricemia (>7.0 mg/dl) in 5% - 8% of male population. • Most (about ⅔) are forever asymptomatic. • 80% of gouty patients have uric acid < 9 mg/dl. • Above 10 mg/dl, risk rises rapidly. • Gout is the most common cause of monarthritis in middle-aged and elderly men (8% yearly prevalence).

14. Who Almost Never Gets Gout? • Pre-pubertal children • Pre-menopausal women • Look for enzyme defects in these patients. • Look for familial kidney disease

15. Ethanol Cessation of ethanol Purine overindulgence Surgery Trauma Overexercise Fasting Fever Provocative Factors“Adding Insult to Injury”

16. The Fructose Connection • Fructose raises uric acid levels in minutes. • Biggest source of fructose: high fructose corn syrup. • Sucrose does not seem to raise uric acid.

17. Link to Cardiovascular Dis. • In experimental models, hyperuricemia causes: • Hypertension • Reduced perfusion • Endothelial dysfunction • Renal dysfunction • Reversible with hypouricemics

18. Frequent Clinical Associations with Gout • Hypertension • Diabetes • Hyperlipidemia • Obesity • Ethanol – the fuel

19. Gout & Kidney Disease • Stones - Uric acid and calcium • Urate nephropathy - chronic interstitial disease, not well defined. • Uric acid nephropathy – acute tubular deposition of uric acid, with renal failure, not seen in gout.

20. Uromodulin-associated kidney disease AKA: • Familial medullary cystic kidney disease, type 2. • Familial juvenile hyperuricemic nephropathy. • Uromodulin storage disease.

21. Uromodulin (cont’d) • Uromodulin (Tamm-Horsfall protein) accumulates in the thick ascending portion of Loop of Henle. • Reduced excretion of uric acid. • No renal deposition of urates. • Autosomal dominant.

22. A Typical Attack of Gout • Lasts several days to several weeks. • May spread from joint to joint. • Often accompanied by fever, leukocytosis. • Gets worse as the years go on. • Pain appears last, disappears first. • Petite attacks occur (lasting hours).

24. Causes of Podagra • MSU • CPPD • Hydroxyapatite • Septic • Psoriatic, Reiter’s • Rheumatoid

34. Radiographic Hallmarks of Gout • Overhanging edges • Punched out lesions with sclerotic borders. • Preservation of joint space (till late) • Degenerative changes

37. The “Double Contour Sign” of Gout. Filippucci E, Grassi W Department of Rheumatology, University of Ancona, Italy

39. The Three Phases of Gout Treatment • Treat acute attack • Prevent new attacks • Reduce uric acid level (sometimes)

40. Phase 1 - Termination • NSAID • Colchcine • Intra-articular steroids • Systemic steroids • IL-1 inhibitors

41. NSAIDs • Treatment of choice in otherwise healthy patient. • Avoid in renal insufficiency and in peptic ulcer disease. • Avoid salicylates (these cause swings in serum uric acid).

42. Intra-Articular Steroids • One or a few joints. • Not useful for polyarticular or soft-tissue gout. • Make sure infection not present.

43. Oral Colchicine • 1.2 mg followed by 0.6 mg 2 hrs later. • Loading dose same in renal insufficiency. • Maintenance (preventive) dose 0.6 mg qd or bid. • 0.3 mg 2-3 times per week in dialysis patients (preventive).

44. Systemic Steroids • Polyarticular attacks or fever. • Longstanding attacks (>3-5 days). • Need divided doses. • Taper over 7-10 days. • Start prophylactic agent (colchicine) as soon as possible.

45. Anakinra (Off-Label) • Effective for acute attack in studies. • Best in pts who cannot take steroids or colchcine. • Expensive but 1 week of treatment may be affordable. • Not for preventive use. • Other interleukin-1 inhibitors currently in trials (rilonacept & canakinumab)

46. Adjunctive Measures • Rest • Ice • Elevation • Analgesics • Anti-motility agents (if using colchicine or indomethacin) • Continue hypouricemic agent if patient has been taking it.

47. Phase 2 - Preventive Therapy • Colchicine or NSAID. • Always use when beginning a hypouricemic drug. • Continue several weeks to years (depending on tophi, serum uric acid). • Always use before surgery in previously gouty patient.

48. Phase 3 - Hypouricemic Therapy • Not every patient needs it. • May not need it in: • Very elderly • Non-compliant • Infrequent attacks and no tophi • May exacerbate attacks early on

49. Goals of Hypouricemic Treatment • Aim for serum uric acid under 6, preferably near 5 for some chronic gouty patients. • But remember: • allopurinol toxicity more likely with higher dose. • More likely with renal insufficiency.

50. Hypouricemic Agents • Allopurinol • Febuxostat • Probenecid • Pegloticase • Losartan (off-label) • High-dose salicylates (off-label) • Vitamin C (off-label)