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Disease Transmission and Context (1).ppt
- 1. GOUT HOSPITAL PRACTICE SUBMITTED TO-Prof. IGOR YATSKOV SUBMITTED BY- KAIS AHAMAD GROUP – LA2 –CO-173(2)
- 2. Gout • Chronic heterogeneousdisorder of urate metabolism • Results in deposition of monosodium urate crystals in the joints and soft tissues, with accompanying inflammation and degenerative consequences • Most common form of inflammatory joint disease in men aged ≥40 years • This disorder can be progressive through four stages if undertreated 1. Asymptomatic hyperuricemia 2. Acute gout 3. Intercritical gout 4. Chronic tophaceous gout
- 3. Hallmarks of Gout •Group of conditions which may be characterized by – An elevation of serum uric acid (usually) – Recurrent attacks (flares) of an acute inflammatory arthritis with monosodium urate crystals demonstrated in synovial fluid leukocytes – Bone and joint destruction in some cases – Aggregates of uric acid crystals (tophi) in and around joints, soft tissues, and various organs – Tophus in bone leading to erosions in some cases – Kidney disease and stones
- 4. Hyperuricemia Biologically significant hyperuricemia(≥6.8 mg/dL) is less than laboratory defined hyperuricemia (≥8.0 mg/dL) Underexcretion Silent tissue deposition Urate Hyperuricemia ≥6.8 mg/dL Overproduction Associated cardiovascular events and mortality Renal manifestations Gout Endogenous purine synthesis Dietary purines Tissue nucleic acids The Hyperuricemia Cascade
- 5. Hyperuricemia and Gout Serumurate levels in 1515 men and 1670 women aged ≥30 in Taiwan 1991-1992 Normative Aging Study:1858 previously healthy men (average initial age 42) followed for 14.9 years Cumulative incidence of gout, % 0 1 2 3 4 5 6 Years 10 5 15 20 25 30 Initial urate n ≥9.0 94 7.0-8.9 666 <7.0 898 Serum urate, mg/dL Many patients fit biological definition for hyperuricemia Distribution, % Urate crystallizes at a level of 6.8 mg/dL 40 35 30 25 20 15 10 5 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Males Females Over time, high serum urate levels lead to gout
- 6. Evolution from Hyperuricemiato Gout • Over time, untreated, chronic hyperuricemia increases body urate stores, advancing the severity of the disease – Flares last longer – Flares occur more often – Intercritical segments (flare free periods) decrease – Persistent pain and stiffness occur Time: 2. Acute flares 4. Chronic polyarthropathy with tophus formation 1. Asymptomatic hyperuricemia Pain Levels 3. Painless intercritical segments Body Urate Pool
- 7. Properly Lowering SerumUrate s Acute Flares • 86% (71/81) of patients who had serum urate <6.0 mg/dL did not experience an acute flare during the study period . Average serum urate during the whole investigation period, mg/dL Incidence of recurrent gouty attacks > 1 year after each patient visit, % 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0 Observed Logistic regression
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- 9. Common Sites ofAcute Flares Midfoot Gout can occur in bursae, tendons, and joints Olecranon Bursa Elbow Wrist Knee Ankle Subtalar 1st MTP (eventually affected in ~90% of individuals with gout) Fingers
- 10. Intervals Between 1st &2nd Acute Flares Majority experience second acute flare within 1 year of first gout flare 62% 16% 6% 5% 4% 7% Within 1 yr 1-2 yrs 2-3 yrs 3-5 yrs After 10 yrs No 2nd in more than 10 yrs
- 11. Advanced Chronic Tophaceous Gout •Tophi can be seen clinically, with obvious deformity demonstrated in hands and foot • Tophi may be associated with bony destruction as seen on the x-ray on right
- 12. Largely Non-Specialist Care •The majority of individuals with gout are treated by primary care physicians, not specialists • Many gout-related visits are based on acute exacerbations of the disease • The diagnostic terms “acute gout” and “chronic gout” with and without “tophi” are commonly documented in primary care medical records • / Distribution of Office Visits (1999-2003) • Frequent Low Back Pain Rheumatologist (3%) Primary Care Provider or PCP (74%) Other (22%) • Osteoarthritis Rheumatologist (7%) PCP (52%) Other (40%) • Osteoporosis Rheumatologist (5%) PCP (79%) Other (15%) • Gout Rheumatologist (12%) PCP (80%) Other (8%) • Rheumatoid Arthritis Rheumatologist 52%) PCP (31%) Other (17%)
- 13. Changing Treatment Landscape Current •Allopurinol • Uricosurics • Symptomatic relief In Development • Uricosurics • Selective xanthine oxidase inhibitor • Pegylated uricase enzyme • IL-1 receptor antagonists • URAT1 Transporter Inhibitor IL-1 = Lnterleukin-1 URAT1 = urate transporter 1
- 14. Synoviocytes phagocytose uratecrystals and then secrete inflammatory mediators, which attract and activate polymorphonuclear leukocytes (PMN) and mononuclear phagocytes (MNP) (macrophages). Drugs active in gout inhibit crystal phagocytosis and polymorphonuclear leukocyte and macrophage release of inflammatory mediators. PG, prostaglandin; IL-1, interleukin-1; LTB4, leukotriene B4. 14
- 15. Drugs Capable ofInducing Hyperuricemia and Gout: •Diuretics •Ethanol •Ethambutol •Nicotinic acid •Pyrazinamide •Cytotoxic drugs •Salicylates (<2 g/day) •Levodopa •Cyclosporine 15
- 16. Signs and Symptoms Acuteattack: •Acute arthritis •The metatarsophalangeal joint of the first toe often involved •Nocturnal excruciating pain, swelling, redness and tenderness Chronic: •Nonsymmetric synovitis •Chronic gouty arthritis •Periarticular tophaceous deposits 16
- 17. The aims oftreatment are to: 1.Decrease the symptoms of an acute attack 2.Decrease the risk of recurrent attacks 3.Lower serum urate levels The substances available for these purposes are: 1.Drugs that relieve inflammation and pain (NSAIDS, colchicine, glucocorticoids,) 2.Drugs that prevent inflammatory responses to crystals (colchicine, NSAIDS and Interleukin-1 inhibitors) 3.Drugs that act by inhibition of urate formation (allopurinol, febuxostat) or to augment urate excretion (probenecid) 4.Converts uric acid to allantoin, which is then excreted (Pegloticase and rasburicase ) 17
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- 19. Treatment of acutegout • Acute gouty attacks can result from a number of conditions, including excessive alcohol consumption, a diet rich in purines, or kidney disease. • The mainstay of treatment during an acute attack is the administration of anti-inflammatory drugs such as NSAIDs, colchicine or glucocorticoids. • NSAIDs are used most often in individuals without complicating comorbid conditions. • The most effective drugs are indomethacin, naproxen, ibuprofen, diclofenac and celecoxib. 19
- 20. Treatment of acutegout • Acute gouty attacks can result from a number of conditions, including excessive alcohol consumption, a diet rich in purines, or kidney disease. • Glucocorticoids is given i.m. or orally (prednisone). • For a single joint or a few involved joints, intraarticular triamcinolone acetonide or methyl prednisolone have been effective and well tolerated. Note: Aspirin is contraindicated, because it competes with uric acid for the organic acid secretion mechanism in the proximal tubule of the kidney. 20
- 21. Treatment of chronicgout • Treatment strategies for chronic gout include the use of uricosuric drugs that increase the excretion of uric acid, thereby reducing its concentration in plasma, and the use of allopurinol, which is a selective inhibitor of the terminal steps in the biosynthesis of uric acid. • Uricosuric agents are first-line agents for patients with gout associated with reduced urinary excretion of uric acid. • Allopurinol is preferred in patients with excessive uric acid synthesis, with previous histories of uric acid stones, or with renal insufficiency. 21
- 22. Colchicine • Colchicine iscurrently used for prophylaxis of recurrent attacks and will prevent attacks in more than 80 percent of patients. Pharmacokinetics: Colchicine is administered orally, followed by rapid absorption from the GI tract. • Colchicine is recycled in the bile and is excreted unchanged in the feces or urine. • Use should be avoided in patients with a creatinine clearance of less than 50 mL/min. 22
- 23. • Colchicine modulatesmultiple pro- and antiinflammatory pathways associated with gouty arthritis. • Colchicine prevents microtubule assembly and thereby disrupts inflammasome activation, microtubule-based inflammatory cell chemotaxis, generation of leukotrienes and cytokines, and phagocytosis. 23
- 24. Colchicine Adverse effects: • Nausea •Vomiting • Abdominal pain • Diarrhoea Chronic administration may lead to:- • myopathy, neutropenia, aplastic anaemia and alopecia. • The drug should not be used in pregnancy, and it should be used with caution in patients with hepatic, renal, or cardiovascular disease. • The fatal dose has been reported as low as 7 to 10 mg. 24
- 25. Uricosuric agents • Bothprobenecid and sulfinpyrazone inhibit the secretion as well as the reabsorption of urate and, if given in subtherapeutic doses, can actually increase plasma urate concentrations. • The maintenance of adequate urine flow and alkalinization of the urine during the first several days of uricosuric therapy further diminish the possibility of uric acid stone formation. Note- In addition, probenecid can inhibit the tubular secretion of other organic acids; thus, increased plasma concentrations of penicillins, cephalosporins, sulfonamides, and indomethacin can occur. 25
- 26. Uricosuric agents Adverse effects: •Gastrointestinalirritation •Rash and hypersensitivity •Precipitation of acute gouty arthritis •Stone formation. Of the two agents, probenecid is the most frequently used uricosuric as sulfinpyrazone is associated with more severe adverse effects. Contraindication: •Allergic to uricosuric drugs •In patients with impaired renal function (a creatinine •Clearance <50 ml/min) •A history of renal calculi •In patients who are overproducers of uric acid For such patients, allopurinol should be used. 26
- 27. Allopurinol • Allopurinol inhibitsxanthine oxidase and prevents the synthesis of urate from hypoxanthine and xanthine. • It is used to treat hyperuricemia in patients with gout and to prevent it in those with hematological malignancies about to undergo chemotherapy (acute tumor lysis syndrome). • Even though underexcretion rather than overproduction is the underlying defect in most gout patients, allopurinol remains effective therapy. 27
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- 29. Allopurinol Drug Interactions: (a) Allopurinolinhibits the degradation of 6- mercaptopurine and azathioprine: their doses should be reduced to 1/3rd, but not that of thioguanine, because it follows a different metabolic path(S-methylation). (b) Probenecid given with allopurinol has complex interaction; while probenecid shortens t1/2 of alloxanthine, allopurinol prolongs t1/2 of probenecid. (c) Allopurinol can potentiate warfarin and theophylline by inhibiting their metabolism. (d) A higher incidence of skin rashes has been reported when ampicillin is given to patients on allopurinol. 29
- 30. Allopurinol Therapeutic Uses: • Allopurinolis available for oral use and provides effective therapy for the primary hyperuricemia of gout and the hyperuricemia secondary to polycythemia vera, myeloid metaplasia, other blood dyscrasias, or acute tumor lysis syndrome. • In the management of gout, it is customary to antecede allopurinol therapy with colchicine and to avoid starting allopurinol during an acute attack of gouty arthritis. • Fluid intake should be sufficient to maintain daily urinary volume of more than 2 liters; slightly alkaline urine is preferred. 30
- 31. Allopurinol Adverse Effects: Allopurinol istolerated well by most patients. • The most common adverse effects are hypersensitivity reactions that may occur after months or years of medication. • Cutaneous reaction: Predominantly, a pruritic, erythematous, or maculopapular eruption. Occasionally, the lesion is urticarial or purpuric. • Rarely, toxic epidermal necrolysis or Stevens-Johnson syndrome (SJS) occurs, which can be fatal. – The risk for SJS is limited primarily to the first 2 months of treatment. Fever, malaise, and myalgias also may occur. 31
- 32. Febuxostat • Febuxostat isa non-purine-selective inhibitor of xanthine oxidase. It works by non-competitively blocking the molybdenum pterin center which is the active site on xanthine oxidase. • It is used in the treatment of chronic gout and hyperuricemia. • Side effects-nausea, diarrhea, arthralgia, headache, increased hepatic serum enzyme levels and rash. 32
- 33. Drugs Increasing Metabolism •Urate oxidase (uricase) metabolizes insoluble uric acid to soluble allantoin in the birds. • This enzyme is absent in humans. • Recombinant urate oxidase is now available as rasburicase. • Pegloticase is another similiar drug that is pegylated to increase duration of action. • Pegloticase and rasburicase are administered by i.v. route and are indicated only in patients with chronic gout refractory to other treatments. 33
- 34. Interleukin-1 inhibitors • Drugstargeting the IL-1 pathway, such as anakinra, canakinumab, and rilonacept, are used for the treatment of gout. • These agents may provide a promising treatment option for acute gout in patients with contraindications to, or who are refractory to, traditional therapies like NSAIDs or colchicine. • A recent study suggests that canakinumab, a fully human anti- IL- 1β monoclonal antibody, can provide rapid and sustained pain relief at a dose of 150 mg subcutaneously 34
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