Tophi start as nonvisible clusters of uric acid crystals that can deposit almost anywhere.9

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THE POTENTIAL FOR GOUT DISEASE PROGRESSION IN THE ABSENCE OF PAIN11-13

Tophi start as nonvisible clusters of uric acid crystals that can deposit almost anywhere, and, like some other inflammatory diseases, damage can occur independently of pain9,11-17

Gout flare cycle of aggregated neutrophil extracellular traps (aggNETs) development, pain resolution, and ongoing crystal deposition11

Progression of gout diagram Progression of gout diagram

Adapted with permission from Schett G, et al. RMD Open. 2015;1:(suppl 1):e000046 and McQueen FM. Nat Rev Rheumatol. 2012;8(3):173-181.

Nonvisible cluster of uric acid crystals11

Urate crystals can trigger recruitment of neutrophils, which then undergo NETosis (a type of cell death)11

During NETosis, neutrophils extrude their DNA over the crystals leading to the formation of aggNETs11,18

The aggNET process results in tophaceous materials, and it is the mechanism responsible for the rapid resolution of inflammation and pain11,18

Tophi often directly overlay bone, reducing osteoblast viability and increasing osteoclast formation and activity. This results in an imbalance that causes bone erosion19

Urate crystals

Neutrophils

Monocytes

Cytokines

Osteoblast

Osteoclast

Dual-energy computed tomography (DECT) and ultrasound scanning studies found nonvisible tophi in the majority of patients4,10

DECT scan

Pie chart

In a prospective DECT study, Bongartz et al demonstrated urate crystal deposition in 95% of patients with gout (N=40)10

Patient population specifically excluded those with visible tophi10

Ultrasound

Pie chart

Thiele et al found ultrasound evidence of tophi in all patients with gouty hands and feet (N=23)4a

oNonvisible tophi: 59% (13/22)

oVisible tophi: 41% (9/22)

0% (0/23) of patients in the control group had evidence of tophi

aTophi status for 1 patient was not recorded to be either nonvisible or visible.

THE LEVEL OF URATE CRYSTAL BURDEN MAY NOT BE VISUALLY APPARENT4,10,20

A separate DECT scanning study by Choi et al found that the urate burden was more than expected from physical examination20

Patients’ tophus volume ranged from 0.63 cm3 to 249.13 cm3 (slightly larger than a baseball), with a mean of 40.20 cm3 (about the size of a golf ball). Only joints were scanned.20

DECT scans of hands, elbows, knees, and feet DECT scans of hands, elbows, knees, and feet DECT scans of hands, elbows, knees, and feet DECT scans of hands, elbows, knees, and feet DECT scans of hands, elbows, knees, and feet DECT scans of hands, elbows, knees, and feet DECT scans of hands, elbows, knees, and feet DECT scans of hands, elbows, knees, and feet

Images used with permission of Choi HK et al. Ann Rheum Dis. 2012;71:1466-1471.

4x

more urate deposits were found using DECT vs through clinical examination.20*

*In a study evaluating the utility of DECT scanning in assessing urate deposits in gout patients (N=20).20

Urate crystal deposition is systemic and can accumulate almost anywhere in the body, including joints, tendons, and organs9,21

Comparison of clinical examination of a hand and a DECT scan of the same hand
Comparison of clinical examination of a hand and a DECT scan of the same hand

Deposition of monosodium urate crystals detected using DECT (displayed in green). Images courtesy of Dr Jurgen Rech. Individual patient presentations may vary.

CHRONIC INFLAMMATION INDUCED BY URATE CRYSTAL DEPOSITION CAN LEAD TO JOINT DAMAGE5,19

Imaging highlights the links between urate crystal deposition, tophus formation, the resulting inflammation, and bone erosion5,19

Ultrasound of bone erosion

T1-weighted coronal image showing multiple erosions, with a large lesion at the distal ulna (circle).19

Ultrasound of bone erosion

T1-weighted axial image confirming erosion and tophus.19

Images used with permission of McQueen F et al. Rheumatology. 2014;53:95-103.19 Individual presentation may vary.

In an ultrasound study, bone erosions adjacent to tophaceous material were seen in 65% of metatarsophalangeal joints and 25% of metacarpophalangeal joint4

Patients both with and without visible tophi were found to have bone erosions

Cartilage damage and loss are also observed around tophi22

MRI scans have shown that cartilage damage is predominantly focal and related to sites of tophi

oIn addition to tophi, cartilage damage was associated with synovitis and bone erosion

Tophus infiltration into bone may be accompanied by damage to the overlying cartilage

Based on an uncontrolled MRI imaging study of wrists in 40 gout patients.

References
  1. Baraf HS, Becker MA, Gutierrez-Urena SR, et al. Tophus burden reduction with pegloticase: results from phase 3 randomized trials and open-label extension in patients with chronic gout refractory to conventional therapy. Arthritis Res Ther. 2013;15(5):R137.
  2. Sundy JS, Baraf HS, Yood RA, et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA. 2011;306(7):711-720.
  3. KRYSTEXXA [prescribing information]. Horizon Pharma Rheumatology LLC. September 2016.
  4. Thiele RG, Schlesinger N. Diagnosis of gout by ultrasound. Rheumatology (Oxford). 2007;46(7):1116-1121.
  5. Rees F, Hui M, Doherty M. Optimizing current treatment of gout. Nat Rev Rheumatol. 2014;10(5):271-283.
  6. Naredo E, Uson J, Jiménez-Palop M, et al. Ultrasound-detected musculoskeletal urate crystal deposition: which joints and what findings should be assessed for diagnosing gout? Ann Rheum Dis. 2014;73(8):1522-1528.
  7. Dalbeth N, House ME, Horne A, Taylor WJ. Reduced creatinine clearance is associated with early development of subcutaneous tophi in people with gout. BMC Musculoskelet Disord. 2013;14:363.
  8. Dalbeth N, Pool B, Gamble GD, et al. Cellular characterization of the gouty tophus: a quantitative analysis. Arthritis Rheum. 2010;62(5):1549-1556.
  9. Doghramji PP, Wortmann RL. Hyperuricemia and gout: new concepts in diagnosis and management. Postgrad Med. 2012;124(6):98-109.
  10. Bongartz T, Glazebrook KN, Kavros SJ, et al. Dual-energy CT for the diagnosis of gout: an accuracy and diagnostic yield study. Ann Rheum Dis. 2015;74(6):1072-1077.
  11. Schett G, Schauer C, Hoffmann M, Hermann M. Why does the gout attack stop? A roadmap for the immune pathogenesis of gout. RMD Open. 2015;1:(suppl 1):e000046.
  12. Edwards NL. Gout A. Clinical features. In: Klippel JH, Stone JH, Crofford LJ, White PH, eds. Primer on the Rheumatic Diseases. 13th ed. New York, NY: Springer; 2008:241-249.
  13. Edwards NL. Crystal-induced joint disease. In: Nabel EG. ACP Medicine: A Publication of the American College of Physicians. Hamilton, Ontario: Decker Intellectual Properties; 2012:1-16.
  14. Yu KH, Lien LC, Ho HH. Limited knee joint range of motion due to invisible gouty tophi. Rheumatology (Oxford). 2004;43(2):191-194.
  15. Dalakas MC. Inflammatory muscle diseases. N Engl J Med. 2015;372:1734-1747.
  16. Ianuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med. 2007;357:2153-2165.
  17. Parsad K, Rath D, Kundu BK. Arthritis Robustus: review of a case of an "abnormal" rheumatoid. Springerplus. 2014 Oct 16;3:606.
  18. Rada B. Neutrophil extracellular traps and microcrystals. J Immunol Res. 2017;2017:2896380.
  19. McQueen FM, Doyle A, Reeves Q, et al. Bone erosions in patients with chronic gouty arthropathy are associated with tophi but not bone oedema or synovitis: new insights from a 3 T MRI study. Rheumatology (Oxford). 2014;53(1):95-103.
  20. Choi HK, Al-Arfaj AM, Eftekhari A, et al. Dual energy computed tomography in tophaceous gout. Ann Rheum Dis. 2009;68(10):1609-1612.
  21. Park JJ, Roudier MP, Soman D, Mokadam NA, Simkin PA. Prevalence of birefringent crystals in cardiac and prostatic tissues, an observational study. BMJ Open. 2014;4(7):e005308.
  22. Popovich I, Dalbeth N, Doyle A, Reeves Q, McQueen FM. Exploring cartilage damage in gout using 3-TMRI: distribution and associations with joint inflammation and tophus deposition. Skeletal Radiol. 2014;43(7):917-924.
  23. Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012;64(10):1431-1446.
  24. Perez-Ruiz F. Treating to target: a strategy to cure gout. Rheumatology (Oxford). 2009;48(suppl 2):ii9–ii14.
  25. Araujo EG, Bayat S, Petsch C, et al. Tophus resolution with pegloticase; a prospective dual-energy CT study. RMD Open. 2015;1(1):e000075.
  26. Schumacher HR, Becker MA, Wortmann RL, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum. 2008;59(11):1540-1548.
  27. Data on file. Horizon Pharma Rheumatology LLC; 2016.
  28. Baraf HS, Yood RA, Ottery FD, Sundy JS, Becker MA. Infusion-related reactions with pegloticase, a recombinant uricase for the treatment of chronic gout refractory to conventional therapy. J Clin Rheumatol. 2014;20(8):427-432.
  29. McDonagh EM, Thorn CF, Callaghan JT, Altman RB, Klein TE. PharmGKB summary: uric acid-lowering drugs pathway, pharmacodynamics. Pharmacogenet Genomics. 2014;24(9):464–476.
  30. Terkeltaub R, Bushinsky DA, Becker MA. Recent developments in our understanding of the renal basis of hyperuricemia and the development of novel antihyperuricemic therapeutics. Arthritis Res Ther. 2006;8(suppl 1):S4.
  31. Yood RA, Ottery FD, Irish W, Wolfson M. Effect of pegloticase on renal function in patients with chronic kidney disease: a post hoc subgroup analysis of 2 randomized, placebo-controlled, phase 3 clinical trials. BMC Res Notes. 2014;7:54.
  32. Levey AS, Bosch JP, Lewis JB, et al. Ann Intern Med. 1999;130(6):461-470.
  33. Levey AS, Stevens LA, Schmid CH, et al; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) [published correction appears in Ann Intern Med. 2011;155(6):408]. Ann Intern Med. 2009;150(9):604-612.
  34. Michels WM, Grootendorst DC, Verduijn M, et al. Clin J Am Soc Nephrol. 2010;5(6):1003-1009.
  35. Poggio ED, Wang X, Greene T, et al. J Am Soc Nephrol. 2005;16(2):459-466.
  36. Bleyer AJ, Wright D, Alcorn H. Pharmacokinetics and pharmacodynamics of pegloticase in patients with end-stage renal failure receiving hemodialysis. Clin Nephrol. 2015;83(5):286-292.
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Indications and Usage

KRYSTEXXA® (pegloticase) is indicated for the treatment of chronic gout in adult patients who have failed to normalize serum uric acid and whose signs and symptoms are inadequately controlled with xanthine oxidase inhibitors at the maximum medically appropriate dose or for whom these drugs are contraindicated.

Important Limitations of Use: KRYSTEXXA is not recommended for the treatment of asymptomatic hyperuricemia.

Important Safety Information

WARNING: ANAPHYLAXIS AND INFUSION REACTIONS

Anaphylaxis and infusion reactions have been reported to occur during and after administration of KRYSTEXXA. Anaphylaxis may occur with any infusion, including a first infusion, and generally manifests within 2 hours of the infusion. However, delayed-type hypersensitivity reactions have also been reported. KRYSTEXXA should be administered in healthcare settings and by healthcare providers prepared to manage anaphylaxis and infusion reactions. Patients should be premedicated with antihistamines and corticosteroids. Patients should be closely monitored for an appropriate period of time for anaphylaxis after administration of KRYSTEXXA. Monitor serum uric acid levels prior to infusions and consider discontinuing treatment if levels increase to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed.

CONTRAINDICATIONS: G6PD DEFICIENCY ASSOCIATED HEMOLYSIS AND METHEMOGLOBINEMIA

Screen patients for G6PD deficiency prior to starting KRYSTEXXA. Hemolysis and methemoglobinemia have been reported with KRYSTEXXA in patients with G6PD deficiency. Do not administer KRYSTEXXA to these patients.

INDICATIONS AND USAGE

KRYSTEXXA® (pegloticase) is indicated for the treatment of chronic gout in adult patients who have failed to normalize serum uric acid and whose signs and symptoms are inadequately controlled with xanthine oxidase inhibitors at the maximum medically appropriate dose or for whom these drugs are contraindicated.

Important Limitations of Use: KRYSTEXXA is not recommended for the treatment of asymptomatic hyperuricemia.

IMPORTANT SAFETY INFORMATION

WARNING: ANAPHYLAXIS AND INFUSION REACTIONS

Anaphylaxis and infusion reactions have been reported to occur during and after administration of KRYSTEXXA. Anaphylaxis may occur with any infusion, including a first infusion, and generally manifests within 2 hours of the infusion. However, delayed-type hypersensitivity reactions have also been reported. KRYSTEXXA should be administered in healthcare settings and by healthcare providers prepared to manage anaphylaxis and infusion reactions. Patients should be premedicated with antihistamines and corticosteroids. Patients should be closely monitored for an appropriate period of time for anaphylaxis after administration of KRYSTEXXA. Monitor serum uric acid levels prior to infusions and consider discontinuing treatment if levels increase to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed.

The risk of anaphylaxis and infusion reactions is higher in patients who have lost therapeutic response.

Concomitant use of KRYSTEXXA and oral urate-lowering agents may blunt the rise of sUA levels. Patients should discontinue oral urate-lowering agents and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA.

In the event of anaphylaxis or infusion reaction, the infusion should be slowed, or stopped and restarted at a slower rate.

Inform patients of the symptoms and signs of anaphylaxis, and instruct them to seek immediate medical care should anaphylaxis occur after discharge from the healthcare setting.

CONTRAINDICATIONS: G6PD DEFICIENCY ASSOCIATED HEMOLYSIS AND METHEMOGLOBINEMIA

Screen patients for G6PD deficiency prior to starting KRYSTEXXA. Hemolysis and methemoglobinemia have been reported with KRYSTEXXA in patients with G6PD deficiency. Do not administer KRYSTEXXA to these patients.

GOUT FLARES

An increase in gout flares is frequently observed upon initiation of anti-hyperuricemic therapy, including treatment with KRYSTEXXA. If a gout flare occurs during treatment, KRYSTEXXA need not be discontinued. Gout flare prophylaxis with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended starting at least 1 week before initiation of KRYSTEXXA therapy and lasting at least 6 months, unless medically contraindicated or not tolerated.

CONGESTIVE HEART FAILURE

KRYSTEXXA has not been studied in patients with congestive heart failure, but some patients in the clinical trials experienced exacerbation. Exercise caution when using KRYSTEXXA in patients who have congestive heart failure and monitor patients closely following infusion.

ADVERSE REACTIONS

The most commonly reported adverse reactions in clinical trials with KRYSTEXXA are gout flares, infusion reactions, nausea, contusion or ecchymosis, nasopharyngitis, constipation, chest pain, anaphylaxis and vomiting.

Please see Full Prescribing Information and Medication Guide for more information.

INDICATIONS AND USAGE

KRYSTEXXA® (pegloticase) is indicated for the treatment of chronic gout in adult patients who have failed to normalize serum uric acid and whose signs and symptoms are inadequately controlled with xanthine oxidase inhibitors at the maximum medically appropriate dose or for whom these drugs are contraindicated.

Important Limitations of Use: KRYSTEXXA is not recommended for the treatment of asymptomatic hyperuricemia.

IMPORTANT SAFETY INFORMATION

WARNING: ANAPHYLAXIS AND INFUSION REACTIONS

Anaphylaxis and infusion reactions have been reported to occur during and after administration of KRYSTEXXA. Anaphylaxis may occur with any infusion, including a first infusion, and generally manifests within 2 hours of the infusion. However, delayed-type hypersensitivity reactions have also been reported. KRYSTEXXA should be administered in healthcare settings and by healthcare providers prepared to manage anaphylaxis and infusion reactions. Patients should be premedicated with antihistamines and corticosteroids. Patients should be closely monitored for an appropriate period of time for anaphylaxis after administration of KRYSTEXXA. Monitor serum uric acid levels prior to infusions and consider discontinuing treatment if levels increase to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed.

The risk of anaphylaxis and infusion reactions is higher in patients who have lost therapeutic response.

Concomitant use of KRYSTEXXA and oral urate-lowering agents may blunt the rise of sUA levels. Patients should discontinue oral urate-lowering agents and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA.

In the event of anaphylaxis or infusion reaction, the infusion should be slowed, or stopped and restarted at a slower rate.

Inform patients of the symptoms and signs of anaphylaxis, and instruct them to seek immediate medical care should anaphylaxis occur after discharge from the healthcare setting.

CONTRAINDICATIONS: G6PD DEFICIENCY ASSOCIATED HEMOLYSIS AND METHEMOGLOBINEMIA

Screen patients for G6PD deficiency prior to starting KRYSTEXXA. Hemolysis and methemoglobinemia have been reported with KRYSTEXXA in patients with G6PD deficiency. Do not administer KRYSTEXXA to these patients.

GOUT FLARES

An increase in gout flares is frequently observed upon initiation of anti-hyperuricemic therapy, including treatment with KRYSTEXXA. If a gout flare occurs during treatment, KRYSTEXXA need not be discontinued. Gout flare prophylaxis with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended starting at least 1 week before initiation of KRYSTEXXA therapy and lasting at least 6 months, unless medically contraindicated or not tolerated.

CONGESTIVE HEART FAILURE

KRYSTEXXA has not been studied in patients with congestive heart failure, but some patients in the clinical trials experienced exacerbation. Exercise caution when using KRYSTEXXA in patients who have congestive heart failure and monitor patients closely following infusion.

ADVERSE REACTIONS

The most commonly reported adverse reactions in clinical trials with KRYSTEXXA are gout flares, infusion reactions, nausea, contusion or ecchymosis, nasopharyngitis, constipation, chest pain, anaphylaxis and vomiting.

Please see Full Prescribing Information and Medication Guide for more information.