Gout- Treatment Updates. Harinder Singh, MD Rheumatology Mercy Internal Medicine Clinic Mason City, IA

Transcription

1 Gout- Treatment Updates Harinder Singh, MD Rheumatology Mercy Internal Medicine Clinic Mason City, IA

2 Gout

3 Outline of purine metabolism: (1) amidophosphoribosyltransferase (2) hypoxanthine-guanine phosphoribosyltransferase (3) phosphoribosylpyrophosphate (PRPP) synthetase (4) adenine phosphoribosyltransferase, (5) adenosine deaminase, (6) purine nucleoside phosphorylase, (7) 5 -nucleotidase (8) xanthine oxidase.

4 Classification of Hyperuricemia and Gout Primary Hyperuricemia and Gout with No Associated Condition Uric acid undersecretion(80% 90%) Idiopathic Urate overproduction (10% 20%) Idiopathic HGPRT deficiency PRPP synthetase overactivity Secondary Hyperuricemia and Gout with Identifiable Associated Condition Uric acid undersecretion Renal insufficiency Polycystic kidney disease FJHN Drugs Urate overproduction Lymphoproliferative disorders Hemolytic anemias Polycythemia vera Psoriasis Dual mechanism Hypoxemia and hypoperfusion

5 1977 ACR criteria for acute gout The presence of MSU crystals Or 6/12 of following: 1. More than one attack of acute arthritis 2. Maximum inflammation developed within 1 day 3. Monoarthritis attack 4. Redness observed over joints 5. First metatarsophalangeal joint painful or swollen 6. Unilateral first metatarsophalangeal joint attack 7. Unilateral tarsal joint attack 8. Tophus (proven or suspected) 9. Hyperuricemia 10. Asymmetric swelling within a joint on x ray/exam 11. Subcortical cysts without erosions on x ray 12. Joint fluid culture negative for organisms during attack 1/10 patients who meet 6/12 criteria have pseudogout and not Gout. Sensitivity 70%; Specificity 79% (Malik et al 2009)

6 Acute Gout Treatment Goals Severity Determination NSAIDS Corticosteroids

7 COLCHICINE 1500 BC 18 th century st use of Colchicine described in Egyptian literature Colchicum autumnale is brought to America by Benjamin Franklin Colchicine is first isolated 1938 Food Drug & Cosmetic act 1960s FDA begins to evaluate the safety and efficacy of older drugs FDA approves Col-Probenecid (0.5 mg/500 mg) (Watson Lab.) for Gout Orphan drug act Waxman-Hatch Act 2009 Colchicine becomes Colcrys

8 COLCHICINE AHERN Trial AGREE Trial Colchicine Dose 1 mg followed by 0.5 mg q2h until relief or GI toxicity Vs Placebo 1.2 mg po; then 0.6 mg at 1 hr 1.2 mg po; then 0.6 mg q 1 h times 6 doses Vs Placebo q 1hr times 6 doses Patients Included N=43 N=74 N=52 (40 placebo) Mean colchicine dose 6.7 mg 1.8 mg 4.8 mg Diarrhea (%) % 77% Pain Decrease Vs Placebo at 24/48 hrs Yes * Yes* (38%) Yes * (36%) Conclusion: Low Dose colchicine as effective as high dose with less GI toxicity; * p<0.05 Ref: Ahem etal; Aust NZ J Med 1987; 17: Terkeltaub et al; A & R 2010; 62:

9 About Allopurinol & Uricosurics Indication Dosing Intolerance Allopurinol Hypersensitivity Reaction HLA-B5801 Uricosurics Gout Prophylaxis

10 FEBUXOSTAT Potent non-purine inhibitor of xanthine oxidase Feb 2009 FDA approved Available under trade name Uloric While both allopurinol and febuxostat are hepatically metabolized, only allopurinol s main metabolite, oxypurinol, is renally excreted Indication Side-effects

11 Study designs of the FACT, APEX, and CONFIRMS studies Study Study drugs doses & Randomization Study duration Prophylaxis Primary efficacy variable Results Comments FACT (n = 760) FBXT: 80, 120 ALPN: 300 Randomz: 1:1:1 52 wks Colch 0.6 mg qd Or Naproxen 250 mg bid For 8 wks Proportion of subjects in each treatment group with last 3 monthly sua levels <6.0 mg/dl FBXt 80/ 120=50% ALPN=21% -CKD not included --Drop out rate higher in both FBX groups --Full dose ALPN not employed APEX (n = 1,072) FBXT: 80,120,240 ALPN: 300/100 Placebo Randmz: 2:2:1:2:1 28 wks Colch 0.6 mg qd Or Naproxen 250 mg bid For 8 wks Proportion of subjects in each treatment group with last 3 monthly sua levels <6.0 mg/dl FBX 80, 120 or 240 mg qd showed significantly greater SUA lowering efficacy than ALPN 100/300 mg qd - Insufficient dose of ALPN used CONFIRMS (n = 2,269) FBXT: 40,80 ALPN: 300/200 Randmz: 1:1:1 24 wks Colch 0.6 mg qd Or Naproxen 250 mg bid For 24 wks Proportion of subjects in each treatment group with last 3 monthly sua levels <6.0 mg/dl -FBXT 40=45% -FBXT 80=86%, -ALLP =42%. -In pts with CrCl ml/m: -FBXT 40=50% -FBXT 80=72% -ALPN =42% % Gout flares in all grps -Discontinuation rate 16-20% in all groups --CVD events FBXT 40 (0%); FBXT 80 (0.4%) ALPN (0.4%) Were statist NS

12 PEGLOTICASE Treatment Group N Number (%) Met Response Criteria P- Value Trial 1 Pegloticase 8mg q2wk (47%) <0.001 Pegloticase 8mg q4wk 41 8 (20%) Placebo 20 0 (0%) Trial 2 Pegloticase 8mg q2wk (38%) <0.001 Pegloticase 8mg q4wk (49%) <0.001 Placebo 23 0 (0%)

13 PEGLOTICASE Q 2 weeks Q monthly Placebo N=85 N=84 N=43 Infusion Reactions 22 (26%) 35 (42%) 2 (5%) Anaphylaxis 3 (4%) 2 (2%) 0

14 PEGLOTICASE Infusion reactions do not decrease with time Antibodies to PEG present in 26% patients at beginning of study; At completion, 92% had antibodies Develop of anti-pegloticase antibody associated with loss of SUA response Most infusion reactions occurred after loss of serum uric acid treatment effect Increased titre of antibodies: Increased risk of Infusion Reactions <1% Infusion Reactions in subsets whose SUA <6 mg% Cardiovascular: Chest pain (9.5%); CHF exacerbations possible 4 deaths in PEGloticase group were related to cardiac arrest, cardiac arrhythmias, sepsis and renal failure. Caution in cardiac patients. Available under trade name Krystexxa Current ACR position on Pegloticase

15 J Inflamm Res. 2011; 4:

16 Rilonacept IL-1 inhibitor Feb 2008: FDA approved for treatment Familial Cold Autoinflammatory syndrome & Muckle-Wells syndrome Available under trade name Arcalyst Currently not approved by FDA for Gout Rilonacept in preventing Gout Flares-Trial: 16 weeks qweekly sq Rilonacept (320 mg, then 160 mg weekly) Vs placebo. Every pt received allopurinol (300 mg/d, titrated to SUA<6) The mean number of gout flares per patient through week 12 (primary efficacy endpoint) in the Rilonacept group was 0.15 [6 flares] Vs 0.79 [33 flares] in placebo group ( P=0.001). The proportion of patients with flares was lower with Rilonacept relative to placebo (14.6% versus 45.2%; P=0.004). (Schumacher HR et al. Arthritis Rheum Jan 4)

17 Canakinumab Human monoclonal antibody that neutralizes IL-1 beta activity June 2009: FDA approved for treatment Familial Cold Autoinflammatory syndrome & Muckle-Wells syndrome Available under trade name Ilaris Currently not approved by FDA for Gout Small studies have shown efficacy in acute Gout Single dose of Canakinumab im mg doses resulted in greater improvement in pain at 48 hrs Vs Triamcinolone acetonide 40 mg im Canakinumab normalized CRP at 1 wk but triamcinolone did not. (So A. Arthritis Rheum 62(10): )

18 Anakinra in Gout Recombinant human IL-1 receptor antagonist Nov 2001: FDA approved for moderate-severe Rheumatoid arthritis Available under trade name Kineret Currently not approved by FDA for Gout Studies in Gout are restricted to small case series in 10 or fewer pts In one series, pts with h/o recurrent gouty arthritis or tophaceous gout received anakinra 100 mg/d sq for 3 days. All pts responded rapidly to Rx. Mean decrease in pain rating by 79% by day 3 of Rx. (So A etal. Arthritis Res Ther 9(2):R28) Another case series of 10 pts also reported favorable short term response. Recurrent flare in 9 of 10 pts after Rx stopped. (Chen K etal. Semin Arthritis Rheum 40(3): )

19 American College of Rheumatology preliminary Recommendations for Acute Gout management Hospital Pt- NPO? I.a. steroid I.v. methylprednisone mg/kg. Repeat as needed ACTH units sq No consensus on Ketorolac IL-1 antagonist in Rx resistant cases

20 American College of Rheumatology preliminary Recommendations for Acute Gout management Refractory Gout? <20% response in 24 hrs Or < 50% response in 48 hrs Consider alternate Dx Consider alternate monotherapy Add Combination monotherapy If still no response, consider trial of IL-1 antagonist