Tophi start as nonvisible clusters of uric acid crystals that can deposit almost anywhere, and, as with some other inflammatory diseases, damage can occur independently of pain.9,11-14

Aggregated neutrophil extracellular traps (aggNETs) develop from gout flares and lead to pain resolution despite ongoing crystal deposition and bone erosion.11,19

Animated images throughout this experience were adapted with permission from Schett G et al. RMD Open. 2015;1:e000046.11
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The urate burden may be greater than it appears

Advanced imaging techniques make it possible to see the true extent of urate deposits or crystals.4,20,37

Recent studies using these advanced techniques show that patients with chronic gout have extensive urate deposits that can’t be seen by traditional clinical examination.4,20

An imaging study by Choi et al (N=20) found 4x more tophi on dual-energy computed tomography (DECT) scan vs thorough clinical exam.20

Radiograph may appear normal. DECT scan shows evidence of urate burden.37

Green areas in DECT scan indicate deposited urate.
Images have been adapted with permission from Desai MA et al. RadioGraphics. 2011;31(5):1365-1375.

Crystal deposition

Nonvisible clusters of uric acid crystals can deposit almost anywhere.11

Inflammatory
response
with pain

Urate crystals cause macrophages to release cytokines, triggering the recruitment of neutrophils.11

NEUTROPHIL NETosis AND DNA EXTRUSION

Neutrophils at the attack site ingest uric acid crystals and then undergo NETosis. During NETosis, neutrophils extrude their DNA over the crystals.11

NEUTROPHIL NETosis AND DNA EXTRUSION

Neutrophils at the attack site ingest uric acid crystals and then undergo NETosis. During NETosis, neutrophils extrude their DNA over the crystals.11

Formation of aggNETs
and pain resolution

DNA extruded during NETosis densely packs uric acid crystals and cytokines, leading to the formation of aggNETs, which are responsible for the rapid resolution of inflammation and pain11,18

Formation of aggNETs
and pain resolution

DNA extruded during NETosis densely packs uric acid crystals and cytokines, leading to the formation of aggNETs, which are responsible for the rapid resolution of inflammation and pain11,18

Development
of tophi

The aggNET process results in tophaceous material.11

Normal process
of bone remodeling

In normal bone, osteoclasts and osteoblasts work in conjunction to achieve homeostasis in the process of bone remodeling.19

Localized bone erosion

Tophi often directly overlay bone, reducing osteoblast viability and increasing osteoclast formation and activity. This results in an imbalance, leading to bone erosion independent of pain.11,19

Visible and nonvisible tophi have been associated
with structural joint damage9,14,19,37

Crystal deposition & bone erosion CAN CONTINUE INDEPENDENT of pain

An sUA of 6 mg/dL is not low enough for many patients with gout.23

DUAL-ENERGY COMPUTED TOMOGRAPHY (DECT) AND ULTRASOUND SCANNING STUDIES FOUND NONVISIBLE TOPHI IN THE MAJORITY OF PATIENTS4,10

Pie chart

DECT scan

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

Pie chart

Ultrasound

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

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.

DECT scans use a standard energy x-ray beam and a second low energy beam25

The low energy beam excites elemental electrons at a different wavelength to produce a second superimposed image over the original x-ray image.

Object
X-ray tube
X-ray tube
Detector
Detector

DECT imaging can show the extent of urate deposition in people with established gout, including at unsuspected sites25

Precise 3-D rendering of joint and soft tissue tophaceous deposits and erosions

Can detect “pseudogout”41,42

Can detect axial and sacroiliac urate38

Macrophage-uric acid crystal interaction and inflammatory response

The inflammatory response recruits neutrophil to gout attack site.

Adapted with permission from Schett G et al. RMD Open. 2015;1:e000046.11

An sUA of 6 mg/dL is not low enough for many patients with gout23

The 2012 American College of Rheumatology Guidelines recommend lowering the sUA level sufficiently to durably improve the signs and symptoms of gout, which may require a therapeutic sUA level of <5 mg/dL.23

SOLUBILITY OF URIC ACID: LOWERING sUA LEVEL IS NECESSARY TO BEGIN DEPLETION OF URATE BURDEN24,25

sUA LEVEL (mg/dL) IMPACT ON URATE BURDEN
6.0-6.826 Slows progression of gout; urate burden remains essentially unchanged24
4.1-5.9 Begins to slowly dissolve visible and nonvisible tophi24
0-4.0 Potential to resolve tophi and reduce the urate burden faster24,25
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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.
  37. Desai MA, Peterson JJ, Garner HW, Kransdorf MJ. Clinical utility of dual-energy CT for evaluation of tophaceous gout. RadioGraphics. 2011;31(5):1365-1375.
  38. Zhu J, Li A, Jia E, et al. Monosodium urate crystal deposition associated with the progress of radiographic grade at the sacroiliac joint in axial SpA: a dual-energy CT study. Arthritis Res Ther. 2017 May 2;19(1):83.
  39. Paparo F, Zampogna G, Fabbro E, et al. Imaging of tophi with an extremity-dedicated MRI system. Clin Exp Rheumatol. 2011;29(3):519-526.
  40. Dalbeth N, Clark B, Gregory K, et al. Mechanisms of bone erosion in gout: a quantitative analysis using plain radiography and computed tomography. Ann Rheum Dis. 2009;68(8):1290-1295.
  41. Miksanek J, Rosenthal AK. Curr Rheumatol Rep. 2015 March;17(3): 20. doi:10.1007/s11926-015-0496-1.
  42. Kim H-R, Lee J-H, Kim NR, Lee S-H. Korean J Intern Med. 2014;29:404-405.
For U.S. Healthcare Professionals  |  Patient Site

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.