2. Gouty Arthritis Dr.noori rheumatologist

3. Gout: Definitions  Gout is a disease characterized by hyperuricemia and monosodium urate deposition in the body  Gouty arthritis is joint inflammation caused by monosodium urate crystals in the synovial fluid and/or joint tissues

4.  ) Gout is a metabolic disease that most often affects middle-aged to elderly men and postmenopausal women. It results from an increased body pool of urate with hyperuricemia. It typically is characterized by episodic acute and chronic arthritis caused by deposition of MSU crystals in joints and connective tissue tophi and the risk for deposition in kidney interstitium or uric acid nephrolithiasisn.

5. Women represent only 5–20% of all patients with gout. Premenopausal gout is rare; it is seen mostly in individuals with a strong family history of gout. Kindreds of precocious gout in young females caused by decreased renal urate clearance and renal insufficiency have been described. Most women with gouty arthritis are postmenopausal and elderly, have osteoarthritis and arterial hypertension that cause mild renal insufficiency, and usually are receiving diuretics.

6. URATE, HYPERURICEMIA & GOUT  Urate: end product of purine metabolism  Hyperuricemia: serum urate > urate solubility (> 6.8 mg/dl):urate>7 men/urate>6 women  Gout: deposition of monosodium urate crystals in tissues

7. HYPERURICEMIA & GOUT  Hyperuricemia caused by Overproduction Underexcretion  No Gout w/o crystal deposition

8. Gout: Pathophysiology  Uric acid: overproduction vs. underexcretion  Mechanisms of urate “production”  cellular nucleoproteins/nucleotides (~ 66%)  diet (~33%)  Mechanisms of urate excretion  kidney (~66%)  gut (~33%)

9. Renal Excretion of Uric Acid  Completely filtered by the glomerulus  Completely (essentially) reabsorbed in the proximal tubule  Approximately 50% is secreted back into the tubule in the descending loop  Approximately 80% (of the 50% now in the loop) is reabsorbed in the ascending loop

10. Gout: Clinical Manifestations  Acute gouty arthritis  Intercritical gout  Chronic tophaceous gout  Miscellaneous other (e.g., gouty nephropathy)

11. Stages of Classic Gout  Asymptomatic hyperuricemia  Very common biochemical abnormality  Defined as 2 SD above mean value  Majority of people with hyperuricemia never develop symptoms of uric acid excess  Acute Intermittent Gout (Gouty Arthritis)  Episodes of acute attacks. Symptoms may be confined to a single joint or patient may have systemic symptoms.  Intercritical Gout  Symptom free period interval between attacks. May have hyperuricemia and MSU crystals in synovial fluid  Chronic Tophaceous Gout  Results from established disease and refers to stage of deposition of urate, inflammatory cells and foreign body giant cells in the tissues. Deposits may be in tendons or ligaments.  Usually develops after 10 or more years of acute intermittent gout.

12. Asymptomatic Hyperuricemia  Hyperuricemia alone does NOT make a diagnosis of gout -only a subset of people with hyperuricemia will develop gout -probability of gout increases with higher uric acid levels  Asymptomatic hyperuricemia generally requires no treatment

13. ASYMPTOMATIC  A- meaning without indicates that there are no symptoms associated  Patient will be unaware of what is happening  Gout can only be determined with the help of a physician

14. Management of Asymptomatic Hyperuricemia  Determine the cause  Address contributing factors  Hypertension  Obesity  Alcoholism  Hyperlipidemia  At this time, specific urate-lowering drugs are not indicated

15. Clinical Course of Classic Gout

16. The first episode of acute gouty arthritis frequently begins at night with dramatic joint pain and swelling. Joints rapidly become warm red, and tender, with a clinical appearance that often mimics that of cellulitis. Early attacks tend to subside spontaneously within 3–10 days, and most patients have intervals of varying length with no residual symptoms until the next episode. Several events may precipitate acute gouty arthritis: dietary excess, trauma, surgery, excessive ethanol ingestion, hypouricemic therapy, and serious medical illnesses such as myocardial infarction and stroke.

17. The metatarsophalangeal joint of the first toe often is involved, but tarsal joints, ankles, and knees also are affected commonly. Especially in elderly patients or in advanced disease, finger joints may be involved. Inflamed Heberden's or Bouchard's nodes may be a first manifestation of gouty arthritis

19. Presenting Symptoms  Systemic: fever rare but patients may have fever, chills and malaise  Musculoskeletal: Acute onset of monoarticular joint pain. First MTP most common. Usually affected in 90% of patients with gout. Other joints knees, foot and ankles. Less common in upper extremities  Postulated that decreased solubility of MSU at lower temperatures of peripheral structures such as toe and ear  Skin: warmth, erythema and tenseness of skin overlying joint. May have pruritus and desquamation  GU: Renal colic with renal calculi formation in patients with hyperuricemia

20. Acute Gouty Arthritis: Diagnosis  Observation of monosodium urate crystals in synovial fluid leukocytes  Monosodium urate crystals are  needle-shaped  negatively birefringent

21. ACUTE gout  Sever and sudden onset  Involve one or a few joints  Frequently starts nocturnally  Joint is warm, red, and tender

23. Laboratory Diagnosis diagnosis ideally should be confirmed by needle aspiration of acutely or chronically involved joints or tophaceous deposits. Acute septic arthritis, several of the other crystalline-associated arthropathies, palindromic rheumatism, and psoriatic arthritis may present with similar clinical features. During acute gouty attacks, needle-shaped MSU crystals typically are seen both intracellularly and extracellularly.With compensated polarized light these crystals are brightly birefringent with negative elongation.

24. Synovial fluid leukocyte counts are elevated from 2000 to 60,000/ L. Effusions appear cloudy due to the increased numbers of leukocytes. Large amounts of crystals occasionally produce a thick pasty or chalky joint fluid. Bacterial infection can coexist with urate crystals in synovial fluid; if there is any suspicion of septic arthritis, joint fluid must be cultured

27. SYMPTOMS  Joint pain Joint pain  Affects one or more joints : hip, knee, ankle, foot, shoulder, elbow,wrist, hand, or other joints  Great toe, ankle and knee are most common  Swelling of Joint  Stiffness  Warm and red  Possible fever  Skin lump which may drain chalky material Skin lump

30. Synovial Fluid Findings  Needle shaped crystals of monosodium urate monohydrate that have been engulfed by neutrophils

32. Diagnosis  Definitive diagnosis only possible by aspirating and inspecting synovial fluid or tophaceous material and demonstrating MSU crystals  Polarized microscopy, the crystals appear as bright birefringent crystals that are yellow (negatively birefringent)

36. Diagnosis  Definitive diagnosis only possible by aspirating and inspecting synovial fluid or tophaceous material and demonstrating MSU crystals  Polarized microscopy, the crystals appear as bright birefringent crystals that are yellow (negatively birefringent)

37. Serum uric acid levels can be normal or low at the time of an acute attack, as inflammatory cytokines can be uricosuric and effective initiation of hypouricemic therapy can precipitate attacks. This limits the value of serum uric acid determinations for the diagnosis of gout. Nevertheless, serum urate levels are almost always elevated at some time and are important to use to follow the course of hypouricemic therapy.

38. Acute Gouty Arthritis: Precipitating Factors  Surgery  Alcohol  Fluctuation of uric acid level  initiation of therapy to lower uric acid level  diuretics (esp. hydrochlorothiazide)  aspirin  low doses raise uric acid levels  high doses lower uric acid levels

39. Differential Diagnosis  Trauma  Infections  septic arthritis, gonococcal arthritis, cellulitis  Inflammatory  Rheumatic arthritis, Reiter’s syndrome, Psoriatic arthritis  Metabolic  pseudogout  Miscellaneous  Osteoarthrtis

40. Predisposing Factors  Heredity  Drug usage  Renal failure  Hematologic Disease  Trauma  Alcohol use  Psoriasis  Poisoning  Obesity  Hypertension  Organ transplantation  Surgery

41. Less commonly, chronic gouty arthritis will be the only manifestation, and, more rarely, the disease will manifest only as periarticular tophaceous deposits in the absence of synovitis

42.  Prevalence increasing  May be signal for unrecognized comorbidities : ( Not to point of searching) Obesity (Duh!) Metabolic syndrome DM HTN CV disease Renal disease

43. INTERCRITICAL  More concentration of uric acid crystals TTypically no need for drug intervention at the time.

44. CHRONIC GOUT

45. Chronic Gout-Radiographic Features

46. Chronic Tophaceous Gout

47. CHRONIC GOUT

48. Chronic Tophaceous Gout

49. Questions?

53. Chronic Tophaceous Gout

57. CHRONIC  Continuous or persistent over a long period of time  Treatment required  Not easily or quickly resolved

59. Diagnostic Studies  Uric Acid  Limited value as majority of hyperuricemic patients will never develop gout  Levels may be normal during acute attack  CBC  Mild leukocytosis in acute attacks, but may be higher than 25,000/mm  ESR  mild elevation or may be 2-3x normal  24hr urine uric acid  Only useful in patients being considered for uricosuric therapy or if cause of marked hyperuricemia needs investigation  Trial of colchicine  Positive response may occur in other types of arthritis to include pseudogout.

60. A 24-h urine collection for uric acid can, in some cases, be useful in assessing the risk of stones, elucidating overproduction or underexcretion of uric acid, and deciding whether it may be appropriate to use a uricosuric therapy (.Excretion of >800 mg of uric acid per 24 h on a regular diet suggests that causes of overproduction of purine should be considered. Urinalysis, serum creatinine, hemoglobin, white blood cell (WBC) count, liver function tests, and serum lipids should be obtained because of possible pathologic sequelae of gout and other associated diseases requiring treatment and as baselines because of possible adverse effects of gout treatment.

61. MEDS- Decreased Urate Pool  High dose Salicylate  Losartan  Fenofibrate  Amlodipine  Vitamin C  Probenecid, sulfinpyrazone, benzbromarone  Allopurinol, uricase, febuxostat

62. Diagnostic Studies  Uric Acid  Limited value as majority of hyperuricemic patients will never develop gout  Levels may be normal during acute attack  CBC  Mild leukocytosis in acute attacks, but may be higher than 25,000/mm  ESR  mild elevation or may be 2-3x normal  24hr urine uric acid  Only useful in patients being considered for uricosuric therapy or if cause of marked hyperuricemia needs investigation  Trial of colchicine  Positive response may occur in other types of arthritis to include pseudogout.

63. Diagnosing Gout  X-rays  Arthrocentesis- extraction of joint fluid  Examination of joint  Patient medical history

64. Radiographic Features Early in the disease radiographic studies may only confirm clinically evident swelling. Cystic changes, well-defined erosions with sclerotic margins (often with overhanging bony edges), and soft tissue masses are characteristic features of advanced chronic tophaceous gout. Ultrasound, CT and MRI are being studied and are likely to become more sensitive for early changes

66. RADIOLOGIC SIGNS

68. X-RAYS

70. Complications  Renal Failure  ARF can be caused by hyperuricemia, chronic urate nephropathy  Nephrolithiasis  Joint deformity  Recurrent Gout

71. Questions?

72. Treatment Goals  Gout can be treated without complications.  Therapeutic goals include  terminating attacks  providing control of pain and inflammation  preventing future attacks  preventing complications such as renal stones, tophi, and destructive arthropathy

73. Treatment: Gout Acute Gouty Arthritis The mainstay of treatment during an acute attack is the administration of anti-inflammatory drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, or glucocorticoids. NSAIDs are used most often in individuals without complicating comorbid conditions. Both colchicine and NSAIDs may be poorly tolerated and dangerous in the elderly and in the presence of renal insufficiency and gastrointestinal disorders. Ice pack applications and rest of the involved joints can be helpful.

74. The end

75. . Colchicine given orally is a traditional and effective treatment if used early in an attack. One useful regimen is one 0.6-mg tablet given every 8 h with subsequent tapering. This is generally better tolerated than the formerly advised hourly regimen. The drug must be stopped promptly at the first sign of loose stools, and symptomatic treatment must be given for the diarrhea. Intravenous colchicine has been taken off the market. NSAIDs given in full anti-inflammatory doses are effective in 90% of patients, and the resolution of signs and symptoms usually occurs in 5–8 days. The most effective drugs are any of those with a short half-life and include indomethacin, 25–50 mg tid; naproxen, 500 mg bid; ibuprofen, 800 mg tid; and diclofenac, 50 mg tid

76. Hypouricemic Therapy Ultimate control of gout requires correction of the basic underlying defect: the hyperuricemia. Attempts to normalize serum uric acid to <300–360 mol/L (5.0– 6.0 mg/dL) to prevent recurrent gouty attacks and eliminate tophaceous deposits entail a commitment to long-term hypouricemic regimens and medications that generally are required for life

77. Colchicine given orally is a traditional and effective treatment if used early in an attack. One useful regimen is one 0.6-mg tablet given every 8 h with subsequent tapering. This is generally better tolerated than the formerly advised hourly regimen. The drug must be stopped promptly at the first sign of loose stools, and symptomatic treatment must be given for the diarrhea. Intravenous colchicine has been taken off the market. NSAIDs given in full anti-inflammatory doses are effective in 90% of patients, and the resolution of signs and symptoms usually occurs in 5–8 days. The most effective drugs are any of those with a short half-life and include indomethacin, 25–50 mg tid; naproxen, 500 mg bid; ibuprofen, 800 mg tid; and diclofenac, 50 mg tid. Glucocorticoids given IM or orally, for example, prednisone, 30–50 mg/d as the initial dose and gradually tapered with the resolution of the attack, can be effective in polyarticular gout. For a single joint or a few involved joints intraarticular triamcinolone acetonide, 20–40 mg, or methylprednisolone, 25–50 mg, have been effective and well tolerated. Based on recent evidence on the essential role of the inflammasome and interleukin 1 (IL-1 ) in acute gout, anakinra has been used and other inhibitors of IL-1 are under investigation. Hypouricemic Therapy Ultimate control of gout requires correction of the basic underlying defect: the hyperuricemia. Attempts to normalize serum uric acid to <300–360 mol/L (5.0– 6.0 mg/dL) to prevent recurrent gouty attacks and eliminate tophaceous deposits entail a commitment to long-term hypouricemic regimens and medications that generally are required for life Colchicine given orally is a traditional and effective treatment if used early in an attack. One useful regimen is one 0.6-mg tablet given every 8 h with subsequent tapering. This is generally better tolerated than the formerly advised hourly regimen. The drug must be stopped promptly at the first sign of loose stools, and symptomatic treatment must be given for the diarrhea. Intravenous colchicine has been taken off the market. NSAIDs given in full anti- inflammatory doses are effective in 90% of patients, and the resolution of signs and symptoms usually occurs in 5–8 days. The most effective drugs are any of those with a short half-life and include indomethacin, 25–50 mg tid; naproxen, 500 mg bid; ibuprofen, 800 mg tid; and diclofenac, 50 mg tid. Glucocorticoids given IM or orally, for example, prednisone, 30–50 mg/d as the initial dose and gradually tapered with the resolution of the attack, can be effective in polyarticular gout. For a single joint or a few involved joints intraarticular triamcinolone acetonide, 20–40 mg, or methylprednisolone, 25–50 mg, have been effective and well tolerated. Based on recent evidence on the essential role of the inflammasome and interleukin 1 (IL- 1 ) in acute gout, anakinra has been used and other inhibitors of IL- 1 are under investigation.

78. SERUM URATE LEVELS  Not reliable  May be normal with flares  May be high with joint Sx from other causes

79. Hypouricemic Therapy Ultimate control of gout requires correction of the basic underlying defect: the hyperuricemia. Attempts to normalize serum uric acid to <300–360 mol/L (5.0–6.0 mg/dL) to prevent recurrent gouty attacks and eliminate tophaceous deposits entail a commitment to long-term hypouricemic regimens and medications that generally are required for life.

80. Hypouricemic therapy should be considered when, as in most patients, the hyperuricemia cannot be corrected by simple means (control of body weight, low-purine diet, increase in liquid intake, limitation of ethanol use, decreased use of fructose-containing foods and beverages, and avoidance of diuretics

81. the decision to initiate hypouricemic therapy usually is made taking into consideration the number of acute attacks (urate lowering may be cost-effective after two attacks), serum uric acid levels [progression is more rapid in patients with serum uric acid >535 mol/L (>9.0 mg/dL)], the patient's willingness to commit to lifelong therapy, or the presence of uric acid stones. Urate- lowering therapy should be initiated in any patient who already has tophi or chronic gouty arthritis. Uricosuric agents such as probenecid can be used in patients with good renal function who underexcrete uric acid, with 177 mol/L (2 mg/dL

82. Benzbromarone is another uricosuric drug that is more effective in patients with renal failure. Some agents used to treat common comorbidities, including losartan, fenofibrate, and amlodipine, have some mild uricosuric effects.

83. The xanthine oxidase inhibitor allopurinol is by far the most commonly used hypouricemic agent and is the best drug to lower serum urate in overproducers, urate stone formers, and patients with renal disease. It can be given in a single morning dose, 100–300 mg initially and increasing up to 800 mg if needed. In patients with chronic renal disease, the initial allopurinol dose should be lower and adjusted depending on the serum creatinine concentration; for example, with a creatinine clearance of 10 mL/min, one generally would use 100 mg every other day. Doses can be increased gradually to reach the target urate level of 6 mg/dL; however, more studies are needed to provide exact guidance.

84. Toxicity of allopurinol has been recognized increasingly in patients who use thiazide diuretics and patients allergic to penicillin and ampicillin. The most serious side effects include life-threatening toxic epidermal necrolysis, systemic vasculitis, bone marrow suppression, granulomatous hepatitis, and renal failure. Patients with mild cutaneous reactions to allopurinol can reconsider the use of a uricosuric agent, undergo an attempt at desensitization to allopurinol, or take febuxostat, a new, chemically unrelated specific xanthine oxidase inhibitor

85. Febuxostat is approved at 40 or 80 mg once a day and does not require dose adjustment in mild to moderate renal disease. Patients can also pay increased attention to diet and should be aware of new alternative agents (see below). Urate-lowering drugs are generally not initiated during acute attacks but after the patient is stable and low-dose colchicine has been initiated to decrease the risk of the flares that often occur with urate lowering. Colchicine anti-inflammatory prophylaxis in doses of 0.6 mg one to two times daily should be given along with the hypouricemic therapy until the patient is normouricemic and without gouty attacks for 6 months or as long as tophi are present.

87. Colchicine should not be used in dialysis patients and is given in lower doses in patients with renal disease or with P gylcoprotein or CYP3A4 inhibitors such as clarithromycin that can increase toxicity or colchicine. Pegloticase is a new urate- lowering biologic agent that can be effective in patients allergic to or failing xanthine oxidase inhibitors. New uricosurics are undergoing investigation.

88. “Disease of Kings”  ORGAN MEATS  WILD GAME  SEAFOOD  LENTILS  PEAS  ASPARAGUS  YEAST  BEER Rich foods have a higher concentration of protein. This could cause major problems for a person afflicted with gout.

89. Newer Therapies  Uricase  Enzyme that oxidizes uric acid to a more soluble form  Natural Uricase from Aspergillus flavus and Candida utilis under investigation  Febuxostat  New class of Xanthine Oxidase inhibitor  More selective than allopurinol  Little dependence on renal excretion  Losartan  ARB given as 50mg/dL can be urisuric. When given with HCTZ, it can blunt the effect of the diuretic and potentiate its antihypertensive action  Fenofibrate  Studies note when used in combo with Allopurinol produced additional lowering of the urate