2. TXF-00099 Caveat on urate levels Serum uric acid level may be normal at the time of an acute attack. Normal level does not rule out gout. May be better to recheck the level after 2 weeks

3. TXF-00099

6. Resolve the acute flare rapidly NSAIDs Corticosteroids Colchicine Remember that above may all be limited by comorbidities !! Antiinflammatories do not treat the underlying disease.

7. TXF-00099

16. Long term approach

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18. Allopurinol Purine “backbone” xanthine oxidase inhibitor FDA approved in 1966, most widely used urate- lowering drug for the last four decades. Basis for the 1988 Nobel Prize in Physiology and Medicine. Starting dose of 50-100mg daily and slowly titrate; consider prophylaxis against flare. Some studies suggested that only 21% of patients on 300mg achieved urate level < 6.0.

19. TXF-00099 New and Emerging Gout Meds febuxostat– oral nonpurine xanthine oxidase inhibitor FDA approved in 2009 for gout and hyperuricemia pegloticase – PEGylated uricase; not yet FDA approved-- for advanced tophaceous gout, administered intravenously.

20. TXF-00099 Febuxostat FDA approved doses are 40mg and 80mg. Published RCT looked at higher doses as well. Compared to allopurinol, was as good or superior in achieving goal of sUA <6.0. Significant reduction in gout flares and tophi when sUA goal is maintained.

21. TXF-00099 Febuxostat A Allopurinol has a purine backbone. Febuxostat is a non-purine xanthine oxidase inhibitor.

22. TXF-00099 Febuxostat Primarily excreted by the liver, only 3% by the kidney; no dosage reduction required for renal impairment. Mild transaminase elevations observed, similar to that of allopurinol. Contraindicated with use of 6-MP, azathioprine, theophylline In RCT a higher rate of CV and thromboembolic events noted (0.14 / 100 pt-years > allopurinol), but a causal relationship not identified

23. TXF-00099 Febuxostat Primarily excreted by the liver, only 3% by the kidney; no dosage reduction required for renal impairment. Mild transaminase elevations observed, similar to that of allopurinol. Contraindicated with use of 6-MP, azathioprine, theophylline In RCT a higher rate of CV and thromboembolic events noted (0.14 / 100 pt-years > allopurinol), but a causal relationship not identified

24. TXF-00099 Febuxostat In general 40mg (starting dose) not inferior to 300mg allopurinol. 80 mg dose produced higher rate of achieving target sUA level of <6.0 and reduction of flares 5-year findings (FOCUS) showed sustained effect with maintenance of sUA < 6.0 and nearly complete suppression of flares

25. TXF-00099 References (febuxostat) Becker, M.A., et al. NEJM.353:2450, December 8, 2005 {“FACT trial”} Schumacher, H.R., et al. Rheum. 48; (2),188- 194. {“FOCUS” 5-year findings} Becker, M.A, et al. Arthr & Rheum, 52; (3), 916-923. Schumacher, H.R., et al. A&R (Arthr Care & Research). 59; (11), 1540-1548.

26. TXF-00099 Thank you !!