gouty arthritis seminar presentation best slide

it's best slide on gouty arthritis from epidemiology to management

1. Gouty Arthritis “ I have been shot, beaten up, stabbed and thrown out of a helicopter, but non of that compared to gout” US veteran, 2001 By : Dr. Yemisrach Kifle (IMR - 2) Moderator: Dr. B irhanu Demelash (Internist, Consultant Rheumatologist) May , 20 22 G.C.

2. Outline Introduction Epidemiology and risk factors P athogenesis Clinical stages or phases Clinical manifestations Work up and Diagnosi s Differential diagnosis Classification criteria Treatment Complications, prognosis

3. History First identified by the Egyptians in 2640 B.C Hippocratus later recognized podagra in the 5 th century BC… unwalkable disease Galen, the first to describe tophi 6 centuries later Derived from the word “ gutta ”.. drop..medieval belief that an excess of one of the four humors, would under certain circumstances drop or flow in to the joint causing pain and inflammation Disease of the kings, arthritis of the rich

4. Introduction Metabolic disorder that results from the response to deposition of MSU crystal in joints, bones and soft tissues Characterized b y t h e extracellular fluid urate saturation, which is reflected in the blood by hyperuricemia Hyperuricemia: a serum urate concentration in excess of urate solubility ( > 6.8mg per dl) A necessary but not sufficient precondition for the development of gout Results from either overproduction or under excretion of uric acid

5. Epidemiology More common in men tends to occur earlier in life in men than women Men at 4 th to 5 th decades of life Women at 6 th to 7 th decades Population based studies from Asia, Europe and North America have reported incidence ranges between 0.6 and 2.9 per 1000 person years, and prevalence between 0.68-3.9% in adults Prevalence is higher among african americans than caucasians , possibly reflecting the increased prevalence of hypertension Both the incidence & prevalence of the disease appear to be increasing. Why? Increased longevity and age associated metabolic, cardiovascular and renal diseases, use of diuretics

6. rare in children, except Inherited defects in enzymes of purine metabolism .... leading to a marked hyperuricemia due to urate overproduction or Diseases with greatly increased rates of cell proliferation, or Due to severely impaired renal uric acid clearance, as in familial juvenile hyperuricemic nephropathy

7. Risk factors Non-modifiable risk factors Male gender Advanced age, menopause Ethnicity (more common blacks) Multiple genetic mutation & polymorphism Modifiable risk factors Obesity (extra tissue increases the production of uric acid) Dietary habits (red meat, sea food, alcohol/beer, sugar-sweetened beverages (fructose rich) HTN, hyperlipidemia CKD Drugs Aspirin (low dose) Chemotherapeutic cytotoxics Diuretics, ACEi Pyrazinamide, Ethanol, Levodopa, Nicotinic acid, Cyclosporine & tacrolimus Protective factors Higher consumption of dairy products , coffee, vitamin c => decrease the risk Losartan => increase uric acid excretion High dose ASA: uricosuric Fenofibrate: uricosuric

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9. Uric acid metabolism

10. Renal Handling of Urate Three major urate transporters URAT1/SLC22A12 (SLC = Solute carrier) Urate-monocarboxylate exchanger; Reabsorbs urate at the apical membrane. GLUT9/SLC2A9 Urate uniporter Reabsorbs urate at the basolateral membrane. ABCG2/BCRP Apical ATP-binding cassette transporter G2 functions as a urate extrusion pump. Tubular and intestinal urate transport

11. Pathophysiologic mechanisms Involves a number of complex interacting processes Factors that result in hyperuricemia Physiologic, metabolic, and other characteristics responsible for crystal formation Acute inflammatory response to MSU crystals Immune mechanisms that mediate resolution of acute inflammation Chronic imnflammatory processes and the effectsof crystals and immune cells on osteoclasts, osteoblasts, and chondrocytes that contribute to tophi, bone erosions and joint injury

12. Pathogenesis… hyperuricemia

13. O v e r p r oduct i on 2 enzyme abnormalities Phosphoribosyl pyrophosphate(PRPP) synthesase overactivity Key determinant of purine synthesis and uric acid production Hypoxanthine guanine phospho ribosyl transferase (HGPRT) deficency Leads to increased metabolism of guanine and hypoxanthine to uric acid

14. Underexcretion

15. Crystal formation : Urate concentration (at 37ºC, > 6.8mg/dl) Specific components of cartilage or joint fluid... such as protein polysaccharides, proteoglycans, & glycosaminoglycans influence urate solubility Low temperature , Intraarticular dehydration , Na+ increase nucleation Cation (K+, Cu2+, Mg+) reduce nucleation

16. Alcohol and gout Gout is related not only to the amount of alcohol intake but also to different beverages Beer>>>spirits>>wine high in purines…increased production of uric acid Inhibition of renal excretion of urate by lactic acid

17. Clinical stages o f gout The 4 classic stages in the natural history of progressive urate crystal deposition are: Asymptomatic hyperuricemia Gout flares Intercritical gout Chronic gouty arthritis and tophaceous gout

18. The clinical stages of gout can be regarded as emerging sequentially (but with some overlapping) Th clinical severity often parallels the frequency of gout flares and the eventual development of chronic gouty arthropathy and tophaceous gout. The interval from the first gout flare to the onset of chronic gouty arthritis or detectable tophi averaged: 10 to 12 years Clinical stages of gout…

19. Clinical manifestation s 1 . Gout flares Abrupt and rapid onset Maximal severity - usually reached within 12 to 24 hours. Attack often come at night or early morning Typically monoarticular (80%) at early times, often occurring in the lower extremities MTP joint is first affected in 50% cases, podagra Others commonly affected joints: ankle, heel, knee, wrist and hands Pts may experience polyarticular flares, which are more likely to occur in pts with more longstanding disease Affected joints are red, hot, swollen and exquisitely tender Attacks resolve within days to weeks without treatment Resolution may be accompanied by desquamation of the skin overlying the affected joint.

20. Gout flares

21. Factors provoking gout flares May provoke disturbances in ECF urate concentrations or may increase the proinflammatory activities of cells interacting with MSU crystals deposited in tissues or in ECF Trauma, surgery Dehydration , life style factors Drugs affecting serum urate concentrations eg , thiazide and loop diuretics, low-dose aspirin

22. Local anatomic factors Locally elevated urate concentrations in conjunction with repeated joint microtrauma, prior degenerative change, or reduced temperature in poorly perfused distal tissues OA related changes in IP joints (Heberden's and Bouchard's nodes) may predispose these joints to develop coexisting gout, particularly in older individuals with CKD or in those receiving diuretic therapy. Factors provoking gout flares …

23. I nitiation of UL therapy disrupts the physical state and/or surface chemical composition of preformed crystal deposits initiating IL- 1-mediated acute inflammatory responses emanating from activation of TLRs and the formation of NALP3 inflammasomes …resulting oin a flare a s a result, anti-inflammatory prophylaxis is usually given to prevent this complication Provoking factors..continued

24. 2. Intercritical gout Asymptomatic period b/n attacks Intervals between gout flares are of variable duration. Most untreated pts will experience a second episode within 2 yrs Some pts evolve to chronic polyarticular gout without pain free intercritical episodes

25. If untreated ; recurrent gout flares occur with Shorter asymptomatic periods Prolonged and disabling, Polyarticular, and May be associated with fever In general, initial intercritical period Provides an opportunity to establish the diagnosis of gout (Hx, PEx, joint fluid analysis, imaging) Also a time during which important patient education and counseling regarding the management of hyperuricemia and gout can take place . 2. Intercritical gout

26. 3. Chronic tophaceous gout Gouty tophi are foreign body granulomas surrounding deposits of MSU crystals in the tissue Characterized by chronic inflammatory and often destructive changes in the surrounding connective tissue Occur at synovium based structures such as bursae and tendons Tophi are often visible and/or palpable and typically not painful Location: along the helix of the ears, fingers, toes, prepatellar bursa, along the olecranon, including articular structures, tendons, or bursas They may attenuate the skin, revealing a yellow or white color Rarely, a cr ea my discharge may be present

27. May extend beyond the confines of a single joint, producing generalized enlargement of a digit due to the presence of tophi and/or the inflammation itself. DDx: Dactylitis seen PsA, sarcoidosis. Expansive & destructive changes mistaken for osteomyelitis Have sometimes led to erroneous amputation of involved digits Plain radiograph of the foot demonstrating features consistent with gout. There is soft tissue swelling & extensive erosions involving the first MTP joint, as well as calcifications within a tophus. Chronic tophaceous gout

28. Early-Onset Gout Between 3% and 6% of patients with gout have symptom onset before age 25. Early-onset gout represents a special subset of cases that generally have a genetic component, show a more accelerated clinical course , and require more aggressive antihyperuricemic therapy. In large epidemiologic studies of classic gout, a family history of gout and/or nephrolithiasis is present in 25% to 30% of cases. In early-onset gout, the incidence of family history is approximately 80%. In this younger group, detailed questioning about the kindred over several generations may yield enough information to suggest a mode of inheritance (X-linked or autosomal dominant or recessive

29. Gout in Organ Transplantation Patients Hyperuricemia develops in 75% to 80% of heart transplant recipients who routinely take cyclosporine to prevent allograft rejection. A slightly lower frequency (approximately 50%) of kidney and liver transplant recipients develop hyperuricemia Presumably because lower doses of cyclosporine are used in these individuals . Whereas asymptomatic hyperuricemia progresses to clinical gout in only 1 in 30 subjects in the general population, cyclosporine-induced hyperuricemia leads to gout in 1 in every 6 patients (18).

30. Gout in Women Unlike most other rheumatic conditions, gout is less common in women than in men. In most large reviews, women account for no more than 5% of all people with gout Conditions that are much more commonly associated with gout in postmenopausal women than with gout in men include diuretic use (95%), hypertension (73 %), renal insufficiency (50%), and preexisting joint disease , such as osteoarthritis (20 ). Premenopausal gout has a strong hereditary component.Most women who develop gout before menopause have hypertension and renal insuffi ciency . The rare woman with premenopausal gout and normal renal function should be evaluated for the autosomally inherited familial juvenile hyperuricemic nephropathy or the even more rare non–X-linked inborn errors of purine metabolism

31. Normouricemic Gout The most frequent explanations for apparent gout with normal levels of uric acid are that (1 ) gout is not the correct diagnosis ( 2) the patient actually is chronically hyperuricemic but the serum urate is normal at the time it is measured

32. Several articular conditions can mimic gout closely including crystalline arthropathies of calcium pyrophosphate dehydrate ( pseudogout ) basic calcium (apatite ) liquid lipid Infection Sarcoidosis trauma , The clinical suspicions of gout should be confirmed by crystal analysis of synovial fl uid . Without this confi rmation,the diagnosisremains in question.

33. CLINICAL ASSOCIATIONS Renal Disease The only consistent visceral damage caused by hyperuricemia is its effect on the kidneys. Three forms of hyperuricemia-induced renal disease are recognized, including ( 1) chronic urate nephropathy ( 2) acute uric acid nephropathy ( 3) uric acid nephrolithiasis

34. Hypertension Hypertension is present in 25% to 50% of people with gout , and 2% to 14% of people with hypertension have gout Obesity Hyperlipidemia Serum triglycerides are elevated in 80% of people with gout. The association between hyperuricemia and serum cholesterol is controversial

35. Work up Synovial fluid analysis Gross appearance Effusions appear cloudy due to the increased numbers of leukocytes Large amounts of crystals occasionally produce a thick pasty or chalky joint fluid Cell count Leukocyte counts are elevated from 2000 to 60,000/μL Neutrophil predominant Polarized light microscopy MSU crystals - Sens: 85% and spec: 100%

36. Nonspecific cha nges of inflammation Neutrophilic leukocytosis and elevation of the ESR or CRP Serum urate level difficult to interpret during a gout flare Normal to low values: 12 to 43% of pts with gout flares An elevated serum urate (≥ 6.8 mg/dL) only supportive The most accurate time for assessment of serum urate (& establishment of a baseline value) is after > 2 wks of a gout flare completely subsides 24-h urine collection for uric acid Excretion of >800mg/24 hr on a regular diet suggests that causes is overproduction of purines Urinalysis, SCr , liver function tests and serum lipids should be obtained Blood tests

37. I m ag i ng Plain radiography Typical changes are not usually detectable at the time of the first gout flare. More specific gouty lesions - "overhanging edges " of bone Associated with bone erosions due to tophi Occur with more chronic disease.

38. Ultrasonography Findings can strongly and independently support the diagnosis of gout May be useful in the early detection and monitoring of therapy Important diagnostic features Double contour sign (DCS) Hyperechoic linear density overlying the surface of joint hyaline cartilage Sen - 83 % and spe - 76 % Hyperechoic cloudy area (HCA)... aka ‘Wet clumps of sugar’ appearances Tophaceous-appearing deposits in joints or tendons Hyperechoic & hypoechoic heterogeneous material with an anechoic rim Sen - 46 % and spe - 95 % I m ag i ng

39. This longitudinal dorsal ultrasound scan of the second MCP joint shows thickened synovium with hyperechoic deposits (arrow) indicative of urate crystal deposition. The double contour sign at the metacarpal head (arrowhead) represents crystal deposition on the articular cartilage surface. Imaging..ultrasonography

40. MRI Not part of any routine evaluation recommended when Tendon sheath involvement must be evaluated To r/o Osteomyelitis Tophi usually have low signal intensity on T1W On T2W: intermediate signal intensity Presence of inflammation results in increased perilesional signal intensity. Tophus size can be estimated on MRI Coronal T1W MRI of the same foot demonstrates a hypointense periarticular mass medial to the MTP joint, compatible with a tophus (straight arrow). The erosions at the head of the first metatarsal and base of the proximal phalanx are much more apparent (curved arrow). Imaging

41. Imaging… Dual-energy computed tomography (DECT) It is a good noninvasive alternative to synovial fluid aspiration Roles: Specifically identify urate deposits in articular & periarticular locations Distinguish b/n crystal deposition diseases (urate vs Ca deposition) Quantifying the volume of urate crystals/ tophus size

42. Diagnosis of Gout (flare) P referred approach is based upon the identification of intracellular MSU crystals on polarizing light microscopy of an affected joint. When this is not feasible, a diagnosis may be made based upon clinical features, including the History Physical Examination Laboratory and Imaging studies

43. The most validate one is the Janssens clinical prediction rule Score < 4: Probability of gout is low; consider alternative Dx Score > 4 and < 8: Probability of gout is intermediate Score > 8: Probability of gout is high Validated only for the Dx of gout flare setting Its application to Dx pts in intercritical period awaits validation. Diagnosis..continued

44. Classification criteria for gout - 2015 ACR/EULAR The criteria permit characterization of an individual as having gout regardless of whether the pt is currently experiencing an acute symptomatic episode and regardless of any comorbidities. This classification criteria are also not intended to characterize the severity of disease , but only its presence. Additionally, classification criteria should be applied only to the intended population—those who meet the entry criteria

45. Entry criteria for having gout: at least one episode of swelling, pain, or tenderness in a peripheral joint or bursa with either the Presence of MSU crystals in a symptomatic joint, bursa, or tophus or Without positive synovial fluid findings (whether or not arthrocentesis has been attempted) in individuals with a sufficient number and type of a series of well-defined clinical and imaging findings . Score > 8 out of 23 are required for classification of as gout However, a negative search for MSU crystals reduces the calculated score . Classification criteria for gout - 2015 ACR/EULAR

46. Differential diagnosis A wide variety of conditions result in acute monoarthritis Ddx of a gout flare : Septic arthritis Trauma CPPD Cellulitis Ddx of a tophaceous gout : RA, Dactylitis , osteomyelitis

47. DDx: Gout vs Pseudo gout

48. Treatment: Gout flares Goal Prompt & safe termination of pain and disability General principles Early treatment (preferably with in several hrs of symptoms onset and continue on Rx for the duration of the flare) Duration of therapy Cessation of Rx - usually within 2 to 3 days of complete resolution of the flare May range from a few days to several weeks

49. G out flare prophylaxis Continue low dose anti- inflammatory agents during the early months of ULT Aim - to reduce the risk of additional flares, which are often seen early in the course of ULT Continue ULT during flares In pts already on ULT... continue without interruption No benefits of stopping & later re- initiation after a period of flare Tophaceous gout no difference in Rx of flares Indication for initiation of long term ULT Comorbidities General principles..continued

50. Anti-inflammatory agents , including systemic and intraarticular GCs, NSAIDs, and colchicine Each are effective for the Rx of the gout flare No single best agent for all pts with flare Choice is based on specific features of the individual pt and the flare history Factors affecting the choice Patient related medical factors Pt’s gout history DDx of flare symptoms Characteristics of gout flare Drug availability and cost and clinician experiences Patient preferences Initial treatment: Gout flares

51. Oral glucocorticoids In pts who are not candidates for IA GC injection & those who have contraindications to NSAIDs. Initial dose: 30 to 40 mg of prednisone given once daily or divided and given as BID basis Duration: until flare resolution begins, and then taper the dose, usually over 7 to 10 days. They can be used in pts with moderate to severe renal insufficiency. Less preferred in pts with frequent recurrent flares ..... to avoid excessive total glucocorticoid dosing over time Caution: if fever, chills, other systemic symptoms, if dx of gout is not supported

52. As alternative to GCs Naproxen: 500mg Po BID, or Indomethacin: 50mg Po TID Particularly in pt < 60 yrs who lacks renal, CV or active GI disease Pt should not be Rx with > 1 NSAIDs at a time Different NSAIDs appear comparably effective when used at full doses Dose can be reduced after a significant decrease in symptoms has occurred NSAIDs

53. CKD with CrCl < 60 Active duodenal or gastric ulcer CVDs - HF or poorly controlled HTN In pts with multiple risks for or established ASCVDs, the use of NSAIDs are associated with increase the risk of MI, stroke and HF Existing NSAID allergy Ongoing Rx with anticoagulants - combined risk of bleeding is high (here opt for Colchicine or GCs) Hyperkalemia, poorly controlled HTN ASA: not used for flare Rx , no need to discontinue low dose ASA being used for AS CVD prophylaxis Contraindications for NSAIDS

54. Colchici ne Reasonable alternative to GCs and NSAIDs Effective when taken within 24 hr s onset of symptom Dose and administration: Initial dose (first day): 1.2mg Po, followed in 1 hr with a single dose of 0.6mg (ACR, EULAR) Day 2 and thereafter: 0.6 mg once or twice daily until flare resolves Continue for 2 to 3 days after flare resolves A dverse effects: diarrhea and abdominal cramping Less common adverse effects: reversible peripheral neuropathy, organ failure, myopathy, cytopenia Contraindications: severe renal and hepatic impairment, medications that inhibit CYT PR450

55. Parentral GCs In pts who are unable to take medications orally In low risk pts for joint infections, one or two actively inflamed joints: IA GCs Options: Triamcinolone acetonide 40 mg for a large joint ( eg , knee), 30 mg for a medium joint ( eg , wrist, ankle, elbow), and 10 mg for a small joint) or Equivalent doses of methylpred Caution: if fever, chills, other systemic symptoms, if dx of gout is not supported

56. Parentral GCs In pts who are unable to take medications orally If more than two joints are involved, or joints inaccessible to injection: IV or IM GCs M ethylprednisolone 20 mg IV BID Stepwise reduction by half of each dose when improvement begins and transition to oral GCs when feasible IM GC injection - reported effective Triamcinolone acetate: 40 to 60 mg once or twice (at intervals of atleast 48 hrs )

57. Initial combination therapy In severe polyarticular flares, particularly in pts who have previously responded only partially to monotherapy Combine IA GCs with 1 or 2 oral agents (e.g, colchicine + NSAIDs or oral glucocorticoids in the same doses used for oral monotherapy). Persistent symptoms Mgt depends upon the prior therapy & pt’s comorbidities. Useful interventions More prolonged Rx courses than usual, Switching or combining agents, and Use of IL-1 inhibitors

58. Long-Term Management Goal s to prevent recurrent gout flares prevent damage to joints and other tissues from urate crystal deposition improve the quality of life Strategies Use of urate lowering drug s Lifestyle modifications

59. Indications for ULT Recurrent gout flares ( > 2 flare a year), Tophi (detected by PEx or imaging), Radiographic changes of arthropathy Stage 3 or worse CKD ( weak) Kidney stones/nephrolithiasis ( weak) Target: ACR guidelines recommend a target serum urate of < 6 mg/ dL for all pts on ULT A lower target of < 5mg/ dL is recommended for pts with tophaceous or severe disease, as this concentration is associated with more rapid tophus regression.

60. Time of initiations in acute flares Traditionally, ULT has been commenced at least 2 wks after an acute flare. But, studies have shown that starting ULT during a gout flare does not prolong the flare, provided that the acute episode is adequately treated. Gout flares after starting ULT Can be precipitated by the introduction of intensive ULT What to do? Careful education of the pts about this possibility Use of anti-inflammatories to prevent flares in the early phase of ULT is crucial. Anti-inflammatory prophylaxis is recommended for 3- 6 months Low dose colchicine is the preferred option

61. Urate Lowering Drugs There are 3 main classes: Drugs that inhibit urate production (xanthine oxidase inhibitors) - allopurinol and febuxostat Drugs that normalise renal urate excretion (uricosurics) - probenecid , benzbromarone, sulfinpyrazone & the newer URAT1 and OAT4 inhibitor lesinurad ; and Drugs that catalyse the conversion of urate to the more water soluble and readily excretable allantoin (recombinant uricases) - pegloticase and rasburicase

62. Serum urate monitoring Determine two to four weeks on a given dose before considering dose adjustment Repeat after 3 months after the goal has been achieved Every six months for one year then annually

63. Allopurinol Often used as a first-line therapy Initial dose At a low dose: 100 mg daily in a pt with CrCl >60 mL/minute (max: 800mg po/day) Then, dose titration q2-4 wks to reach and maintain the target Adverse effects: rare May precipitate gout flares Leukopenia or thrombocytopenia, and diarrhea (3 -5% of pts ) Rash, hypersensitivity, and severe cutaneous reactions – especially in pts with HLA-B*5801-positive DRESS syndrome

64. Drug interactions Azathioprine and 6-MP It can potentiate 6--MP & azathioprine, which are metabolized in part by xanthine oxidase Thus allopurinol should generally be avoided in pts on these agents In pts with severe gout who otherwise require allopurinol, reduce AZA dose (by at least 50%) . A possible alternative: MMF Alkylating agents – like Cyclophosphamide, BM suppression Ampicillin – Ampicillin-induced rash reported (25%) Allopurinol

65. F ebu x o s ta t Not a purine-base analog unlike allopurinol Initial dosing dosing: 40 and 80 mg Po per day Titration : every 2 to 4 weeks At 40 mg daily, it is also an alternative XOI for use in pts with reduced renal function A daily dose of 40 mg febuxostat = 300mg Allopurinol in reducing serum urate Adverse effects Cardiovascular and hepatic abnormalities Drug reactions Decreased metabolism of AZA, 6-MP, and theophylline Should be avoided when the pt is on one of these three drugs

66. ll FAST trial (November 9, 2020) doi.o r g /10.1016/S0140- 6736(20)32234-0 Interpretation: Febuxostat is non-inferior to allopurinol therapy with respect to the primary cardiovascular endpoint, and its long-term use is not associated with an increased risk of death or serious adverse events compared with allopurinol

67. Uricosuric drugs Indications Pts with relative renal underexcretion of uric acid (low to normal) are potentially candidates responsible for at least 85 to 90 % of pts with 1 o or 2 o hyperuricemia Monotherapy with this group drugs should be avoided in those with a history of nephrolithiasis to avoid renal stone recurrence conditionally recommended against checking urinary acid levels prior to prescribing. conditionally recommended against to alkalinize the urine of patients receiving uricosuric medications

68. Uricosuric drugs Probenecid: Initial dose - 250 mg twice daily; Increments in dose are titrated based on serum urate level Usual maintenance dose of 500 to 1000 mg 2x or 3x times daily Max. effective dose is 3 g/day. Benzbromarone Starting dose of 50 mg/day and increase to a maximum of 200 mg/day in 50 mg/day increments 100 mg/day is commonly used

69. Sulfinpyrazone Started at a dose of 50 mg twice daily Increments over several weeks to 100 to 200 mg three or four times daily as needed. The maximum effective dose of sulfinpyrazone is 800 mg/day. Lesinurad Taken in a single dose of 200 mg once daily Always combined with an XOI, either allopurinol or febuxostat. It inhibits transporter proteins URAT1 and organic anion transporter 4 (OAT4), which are involved in urate reabsorption in the kidney. Uricosuric drugs

70. Combination of ULT If target serum urate range is not attained with maximal allopurinol doses (but tolerate the drug), allopurinol in combination with a uricosuric agent (such as probenecid) is preferred to an alternative drug - febuxostat, particularly in pts at high risk of CVD

71. Urate oxidase (Uricases) Recombinant forms of uricase Uricase (urate oxidase) is the enzyme that catalyzes conversion of urate to a more soluble purine degradation product, allantoin . Uricase is present in most mammals but is absent in humans Pegloticase Used for refractory hyperuricemia in pts with severe and chronic gout

72. Rasburicase (Elitek) Indicated for the prevention of acute uric acid nephropathy in pts with high risk for Not approved to be used in gout Urate oxidase ( Uricases )

73. Management of Gout in advanced CKD NSAIDs should be avoided Prophylactic therapy: colchicine Particular caution should be taken Clearance of colchicine is reduced in pts with CKD, increasing the risk of neuromyopathy Colchicine (for prophylaxis) 0.6 mg once daily at aCrCl of 35 to 49 mL/minute and 0.6 mg every 2 to 3 days at a CrCl of 10 to 34 mL/minute . Colchicine (for flare) CrCl > 30: no dose adjustment is needed CrCl < 30: Consider alternate therapy; if not - give 1.2mg at first sign of flare, then 0.6mg in 1 hr and never repeat with in 14 days CrCl < 10: contraindication (colchicine is not dialyzable)

74. Febuxostat Effective in safely reducing the serum urate in pts with moderate to severe renal impairment (eGFR 15 to 50) Allopurinol Stage 3 or more severe CKD (eGFR <60/min) Initiate at a dose not exceeding 1.5 mg per mL/minute of eGFR. Titrated q4 wks to achieve and maintain the same target serum urate goal as in pts with normal renal function ULT in advanced CKD

75. Switching to New ULT Strat egy

76. Managing concurrent medications Pts with gout receiving HCT switch to alternate antihypertensive therapy regardless of disease activity (conditionally recommendation). Losartan has been conditionally recommended as an antihypertensive agent when feasible. For pts with gout receiving low-dose aspirin therapy for appropriate indications, it has been conditionally recommended against stopping this medication, regardless of disease activity. For pts receiving cholesterol-lowering therapy, it has been conditionally recommended against to add or switch to fenofibrate , regardless of disease activity .

77. Lifestyle Management Limit intake of alcohol, purine, and high fructose corn syrup, regardless of disease activity (conditional recommendation). Adding vitamin C supplements to pts’ daily diet , regardless of disease activity. Weight loss (using any program) has been recommended for pts with gout who are overweight or obese, regardless of disease activity

78. Complications of gout Severe degenerative arthritis Secondary infections Urate or uric acid nephropathy Increased susceptibility to infection Nerve or spinal cord impingement Fractures in joints with tophaceous gout

79. Prognosis Dramatic change, following long term ULT Unsatisfactory outcomes<5% Factors include non adherence, intolerance, failure to titrate doses, drug-drug interactions, inadequate monitoring of serum urate levels

80. References Uptodate (2021 online) ACR 2012/2020 guideline for gout Primer on the Rheumatologic Disease R h eumatología Hochberg 2019 EULAR 2016 recommendations for gout Harrison’s Principle of IM (2 1st ed) 84

81. Thank you