It's challenging to treat patients with gout who also have chronic kidney disease. Here's a review of literature on how to proceed. This happens to be my second PRA convention presentation.

1. ISSUES IN THE ARTHRITIDES
Gout, Tophi and
Kidney Disease
SIDNEY ERWIN T. MANAHAN, MD, FPCP
Rheumatologist
18th PRA Annual Meeting
February 5, 2011

2. Session Objectives
• Define Complicated Gouty Arthritis
• Discuss the Management of Gout in the
Background of Chronic Kidney Disease
• Enumerate Novel Therapies for Gout

3. Prevalence of Gout in the PH
1.8
FACTORS
1.6
• Obesity
1.4 • Aging Population
1.2
• Kidney Failure and Hypertension
• Thiazides and Aspirin
1 • Beer Consumption
0.8
0.6
0.4
Manahan L, et al Rheum Int 1985
Dans LF, et al J Rheum 1997
0.2
Dans LF, et al. PJIM 2006
Edwards NL Arth Rheum 2008
0
COPCORD 1985 COPCORD 1997 NNHeS 2003

4. Relationship between Gout & CKD
Frequency Annual
Time Period
Male Female Flares
Renal Function
>2 years
15.4% 4.1% 2.0 + 4.2
pre-HD
Inflammatory
Cytokines <2 years
7.7% 0.6% 1.9 + 6.6
pre-HD
<2 years
3.4% None 0.2 + 0.7
Acute Gout post HD
>2 years
1.2% None 0.1 + 0.6
post HD
Iwao O, et al. Int Med. 2005
Schreider O, et al. Nephro Dial Trans. 2000

5. Complicated Gout
Risk Factors for Complications
 SUA 11 + 2 mg/dl  Upper extremity involvement
 Early Onset Gout  Polyarticular flares
 Flares >4/ year  Prolonged steroid use
 Long periods of untreated gout Nakayama A, et al. 1984; Raso AA, et al. 2009
Vazques Mellado J, J Rheum 1999

6. Complicated Gout
Treatment Failure Gout (TFG)
Symptomatic Gout
• Intolerance to urate lowering therapies (ULT)
• Refractory to maximal doses of ULT
Features
• Presence of complications
• Impaired QOL and chronic disability
• Significant co-morbid conditions
• Polypharmacy and drug interactions
Edwards HL, Arth Rheum 2008
Terkeltaub R. Arth Res Ther 2009.

7. Gout in Renal Disease
Terminate attacks
• Steroids
• ACTH
• Colchicine
• NSAIDs / COXIBs
Prevent flares
• Colchicine
• NSAID
Prevent/ Reverse complications
• Urate Lowering Therapies
El-Zawawy H, Mandell BF, Cleveland Clin J Med. 2010

8. Steroids in Gout
Indications
• Acute Gout
• Not for Prophylaxis
Recommended Doses
• Prednisone 20-50 mg over mean of 10 days
• Prednisone 30 mg single dose on Day 1, taper dose by 5 mg
daily and discontinue by Day 7
Li-Yu J, et al. Phil J Int Med 2008
• ACTH 25 IU IM for monoarthritis
• ACTH 40 IU IM for polyarthritis
El-Zawawy H, Mandell B. Cleveland Clin J Med 2010

9. Colchicine in Gout
Indications
• 6 months from achieving target SUA
• Attacks continue
• Persistent tophi
Recommended Doses
Crea Cl > 50 ml/min 0.6 – 1.8 mg/day
35-49 ml/min 0.6 mg/day
10-34 ml/min 0.6 mg q 2-3 days
< 10 ml/min CAUTION
Monitor CK-MM, LFTs if CrCl < 50 ml/min
Wallace S, et al. J Rheumatol 1991
El-Zawawy H, Mandell B. Cleveland Clin J Med 2010

10. Colchicine in Gout
Contraindications
• Creatinine Clearance < 10 ml/min
• Patients undergoing hemodialysis
• Significant hepatic disease
• Combined hepatic and renal disease
Drug Interactions
• Macrolides (i.e. Clarithromycin)
• Statins (i.e Pravastatin)
• Ketoconazole
• Cyclosporin
El-Zawawy H, Mandell B. Cleveland Clin J Med 2010

11. Preventing Complications
Target Serum uric acid <6 mg/dl
Li Yu J, Salido E, et al. PJIM. 2008;
Zhang W, Doherty M, et al. Ann Rheum Dis. 2006
Benefits of Achieving Target SUA
• Reduction in flares
• Reduction in tophus size
• Retarded decline in GFR
Li Yu J, Salido E, et al. PJIM. 2008;
Zhang W, Doherty M, et al. Ann Rheum Dis. 2006;
Li Yu J, et al. J Rheum 2001; Shoji A, et al. Arth Rheum 2004;
Gibson T, et al. Ann Rheum Dis 1982

12. Reversing Complications
P – 63 CTG patients treated with ULT
I – Allopurinol, Benzbromarone or both
M – Observational study
Average SUA Levels Rate of Tophus Reduction
6.1 – 7.0 mg/dl 0.53 + 0.59 mm/mo
5.1 – 6.0 mg/dl 0.77 + 0.41 mm/mo
4.1 – 5.0 mg/dl 0.99 + 0.50 mm/mo
<4.0 mg/dl 1.52 + 0.67 mm/mo
Perez Ruiz F, et al. Arthritis Rheum 2002

13. Reversing Complications
Target SUA 3-5mg/dl in those with
massive or numerous tophi
Schumacher HR, Am J Med. 1996
Perez Ruiz F, et al. Arth Rheum. 2002
Jordan K, et al. Rheumatol 2007
Herschfield M. Curr Opin Rheum 2009
Diseases Associated with
Increased Uric Acid Reduced Uric Acid
Gout Multiple Sclerosis
Kidney Disease Parkinson’s Disease
Hypertension Alzheimer’s Disease
Cardiovascular Dse Optic Neuritis
Kutzing M, et al. J Pharma Exp Therap 2008

14. Urate Lowering Therapies
Uricosurics
• Probenecid
• Sulfinpyrazone
• Benzbromarone
ULT Indications • RDEA594
• At least 2 Gout Flares
• Tophaceous Deposits
XO Inhibitors
• Arthropathy
• Allopurinol
• Nephrolithiases
• Febuxostat
• Difficult to treat attacks
Urate Oxidase
• Rasburicase
• Pegloticase

15. Allopurinol in Renal Disease
Maximum Recommended Allopurinol
Decline in Renal Function Dose Based on Crea Clearance
Crea Cl (ml/min) Dose
0 100 mg q 3 days
Inc Allopurinol Half-life 10 100 mg q 2 days
20 100 mg/day
40 150 mg/day
Dec Oxypurinol Clearance 60 200 mg/day
80 250 mg/day
100 300 mg/day
120 350 mg/day
Increase in Adverse Events
Hande KR, et al. Am J Med, 1984

16. Allopurinol in Renal Disease
P – 120 Gout patients receiving Allopurinol
I – Allopurinol in prescribed renally-adjusted doses vs
Allopurinol in higher than usual doses
O – Incidence of Adverse Events
M – Retrospective
CONCLUSION
Frequency of adverse events were
SIMILAR between groups
Vasquez-Mellado J, et al.Ann Rheum Dis 2002

17. Allopurinol in Renal Disease
P – 250 Gout patients with Crea Cl 12-130 ml/min
I – (A) Allopurinol in prescribed renally-adjusted doses vs.
(B) Allopurinol in higher than usual doses
O – Incidence of Adverse Events
No. of pateints achieving SUA <6mg/dl
M – Retrospective
RESULTS/ CONCLUSIONS
• 4 had hypersensitivity reactions
• 19% of Group A achieved target SUA
• 38.1% of Group B achieved target SUA
Dalbeth N, et al. J Rheum 2006
Perez Ruiz F, et al. J Clin Rheum 1999

18. Allopurinol in Renal Disease
Patients achieving SUA <6mg/dl
Study
Normal Renal Failure
FACT 2005 53/251 (21%) -----
APEX 2008 60/268 (22%) 0/10
CONFIRMS 2010 106/254 (42%) 212/501 (42%)
CONCLUSION
• Adherence to renal-dosing guidelines lead to SUB-OPTIMAL
treatment of hyperuricemia

19. Allopurinol in Renal Disease
Treat to Max
Allopurinol based
on Renal Function
TREAT
TO
TARGET
RECOMMENDATION
• Initial dose of Allopurinol based on Crea Clearance
• Titrate up by 50-100 mg/day every 2-4 weeks
• Target SUA 3-5 mg/dl

20. GOUT, TOPHI AND KIDNEY DISEASE
NEW DRUGS IN GOUT

21. Febuxostat: A Novel XOI
• Non-purine Xanthine Oxidase Inhibitor
• Commercial availability
– 2008 Europe
– 2009 United States
• Clinical Trials
– Febuxostat against Allopurinol Controlled Trial (FACT), 2005
– Allopurinol and Placebo-Controlled Efficacy Study of
Febuxostat (APEX), 2008
– Comparing Efficacy And Safety of Daily Febuxostat and
Allopurinol in Patients with Gout (CONFIRMS), 2010
– Febuxostat Open Label Clinical Trial of Urate Lowering
Efficacy and Safety (FOCUS), 2009

22. Febuxostat
Patients achieving SUA < 6mg/dl for 3 consecutive months
Study FEBUXOSTAT
ALLOP
40mg 80mg 120mg 240mg
FACT 2005 53% 62% 21%
APEX 2008 76% 87% 94% 41%
CONFIRMS 2010 45.2% 67.1% 42.1%
CONFIRMS RD 49.7% 71.6% 42.3%
FOCUS 2009 100% 82% 81%
OBSERVATION: Patients receiving Febuxostat were able to achieve
SUA <4 mg/dl and 5 mg/dl.
Becker M, et al. NEJM 2005; Schumacher HR, et al. Arth Rheum 2008
Becker M, et al. Arth Res Ther 2010; Schumacher HR, et al. Rheum 2009

23. Febuxostat
Patients suffering a gout flare
Study FEBUXOSTAT
ALLOP
40mg 80mg 120mg 240mg
FACT 2005 64% 70% 64%
APEX 2008 10-15%
CONFIRMS 2010 <5% <5% <5%
CAVEAT: Similar proportions of patients between groups
experienced gout flares during treatment.
Becker M, et al. NEJM 2005; Schumacher HR, et al. Arth Rheum 2008
Becker M, et al. Arth Res Ther 2010; Schumacher HR, et al. Rheum 2009

24. REDUCTION IN TOPHUS SIZE
• FACT and APEX – no statistically significant difference in
mean reduction of tophus size in between groups
Becker M, et al. NEJM 2005; Schumacher HR, et al. Arth Rheum 2008
Becker M, et al. Arth Res Ther 2010; Schumacher HR, et al. Rheum 2009

25. Febuxostat
ADVERSE EVENTS
Study FEBUXOSTAT
ALLOP
40mg 80mg 120mg 240mg
FACT 2005 25% 24% 23%
(4%) (8%) (8%)
APEX 2008 68% 68% 73% 75%
(4%) (3%) (4%) (3%)
CONFIRMS 2010 56.7% 54.2% 57.3%
(2.5%) (3.7%) (4.1%)
ADVERSE EVENTS – abnormal LFT, diarrhea and rashes
SERIOUS AE – abnormal LFT, cardiovascular events
Becker M, et al. NEJM 2005; Schumacher HR, et al. Arth Rheum 2008
Becker M, et al. Arth Res Ther 2010; Schumacher HR, et al. Rheum 2009

26. Uricase
• Concept of using urate oxidase (uricase) since 1981
• Concerns regarding uricase development
– Short half-life
– Risk of immunologic reactions
– G6 PD Deficiency

27. Pegloticase
RESPONSE TO ADMINISTRATION
• DOSE: 8 mg infused over 2 hours q 2-4 weeks
• All patients achieve SUA<2mg/dl after 1st infusion
• Persistent Responders
– Sustained reduction in SUA <6mg/dl
• Transient Responders
– Initial SUA <6mg/dl but later increased to >6mg/dl
– Infusion reactions
– Development of Anti-pegloticase IgM and IgG
– Coincided with 3rd or 4th infusion
Reinders M, et al. Ther Clin Risk Mngt. 2010

28. Pegloticase
Gout Outcome and Urate Therapy (GOUT)
TREATMENT FAILURE GOUT
• >3 flares in previous 18 months
• >1 tophus
• Documented arthropathy
• SUA >8 mg/dl
• Contra-indications to Allopurinol
• Failure to achieve target SUA with maximum
medically appropriate doses of Allopurinol

29. Pegloticase
Reduction in SUA <6mg/dl
Treatment GOUT 1 GOUT 2 Combined
8mg q 2 weeks 46.5% 38.1% 42.3%
8 mg q 4 weeks 19.5% 48.8% 34.5%
Placebo 0 0 0
Treatment Flares Tophus
8mg q 2 weeks 77% 40.4%
8 mg q 4 weeks 81% 21.2%
Placebo 54% 0

30. Pegloticase
Adverse Events
Treatment SAE IR Abs
8mg q 2 weeks 24% 26% 88%
8 mg q 4 weeks 23% 41% 89%
Placebo 12%
Most Common Adverse Events
• Flares
• Infusion Reactions
Other Concerns
• Higher rate of serious adverse events
• Infusion reactions
• Immunogenicity

32. RDEA594
• Uricosuric drug
• Selectively inhibits URAT1
• Maintains efficacy even in
moderate renal insufficiency
• Enhances urate lowering effects of
Febuxostat and Allopurinol
• No identified adverse events in
Phase II and case series

33. COMBINATION THERAPY
ALLOPURINOL Combination of Allopurinol and Sulfinpyrazone
Serum Urate Production • Diminution of SUA
Urine Urate Excretion • Rapid softening & dissolution of tophi
• Cessation of renal stone formation
Kuzell W, et al. Ann Rheum Dis 1966
URICOSURICS Combination of Allopurinol and Benzbromarone
Urine Urate Excretion • Lowered SUA in patients with renal
dysfunction
• Lower doses of both drugs were used
• Reduced serum Oxypurinol levels
Urine Urate Excretion
Ohno I, et al. Nippon Jinzo Gakkai. 2008
Serum Urate Production

35. Biologics in Gout
• P – 10 Patients with Treatment Failure Gout
• I – Rilonacept 320 mg SC initially then 160 mg SC q weekly
• M – Proof of Concept Study
Terkeltaub R, et al. Ann Rheum Dis 2009

36. PROPOSED APPROACH TO
Gout Patients with
Indication for ULT URATE LOWERING
THERAPY IN GOUT
Start ALLOPURINOL
TREATEMENT FAILURE (TF) to Allopurinol
and Titrate up
Intolerance/ ADR Shift to
to Allopurinol FEBUXOSTAT ??Consider
Combination Tx
Start Sulfinpyrazone and
Titrate up
INTOLERANCE or Consider Tophi-Debulking Therapy
TF to Sulfinpyrazone with Pegloticase
Adapted from Terkeltaub R. Nat Rev Rheum 2010

37. Summary
• Defined Complicated Gouty Arthritis as
– Presence of Complications
– Treatment Failure Gout
• Managing Gout in Patients with Chronic Kidney Disease
– Reviewed Treatment Goals
– Discussed Differences in Medications used
• Enumerated Novel Therapies for Gout
• Proposed an Algorithm to Treat Gout/ Hyperuricemia

38. Thank You!
Philrheumajr.blogspot.com