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.6,8-11

Aggregated neutrophil extracellular traps (aggNETs) develop from gout flares and lead to pain resolution despite ongoing crystal deposition and bone erosion.8,12

Animated images throughout this experience were adapted with permission from Schett G et al. RMD Open. 2015;1:e000046.8
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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.1,13,14

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.1,13

An imaging study by Choi et al (N=20) found 4x more tophi on dual-energy computed tomography (DECT) scan vs thorough clinical exam.13

Radiograph may appear normal. DECT scan shows evidence of urate burden.14

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.8

Inflammatory
response
with pain

Urate crystals cause macrophages to release cytokines, triggering the recruitment of neutrophils.8

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.8

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.8

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 pain.8,19

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 pain.8,19

Development
of tophi

The aggNET process results in tophaceous material.8

Normal process
of bone remodeling

In normal bone, osteoclasts and osteoblasts work in conjunction to achieve homeostasis in the process of bone remodeling.12

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.8,12,20-24

Visible and nonvisible tophi have been associated
with structural joint damage6,11,12,14

Crystal deposition & bone erosion CAN CONTINUE INDEPENDENT of pain

An sUA of 6 mg/dL is not low enough for many patients with gout.27

DUAL-ENERGY COMPUTED TOMOGRAPHY (DECT) AND ULTRASOUND SCANNING STUDIES FOUND NONVISIBLE TOPHI IN THE MAJORITY OF PATIENTS1,7

Pie chart

DECT scan

In a prospective DECT study, Bongartz et al demonstrated urate crystal deposition in 95% of patients with gout (N=40)7

Patient population specifically excluded those with visible tophi7

Pie chart

Ultrasound

Thiele et al found ultrasound evidence of tophi in all patients with gouty hands and feet (N=23)1,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 beam15

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 sites15

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

Can detect “pseudogout”16,17

Can detect axial and sacroiliac urate18

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:e000046.8

An sUA of 6 mg/dL is not low enough for many patients with gout27

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.27

SOLUBILITY OF URIC ACID: LOWERING sUA LEVEL IS NECESSARY TO BEGIN DEPLETION OF URATE BURDEN15,27-29

sUA LEVEL (mg/dL) IMPACT ON URATE BURDEN
6.0-6.8 Slows progression of gout; urate burden remains essentially unchanged
4.1-5.9 Begins to slowly dissolve visible and nonvisible tophi
0-4.0 Potential to resolve tophi and reduce the urate burden faster
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References
  1. Thiele RG, et al. Rheumatology (Oxford). 2007;46(7):1116-1121.
  2. Rees F, et al. Nat Rev Rheumatol. 2014;10(5):271-283.
  3. Naredo E, et al. Ann Rheum Dis. 2014;73(8):1522-1528.
  4. Dalbeth N, et al. BMC Musculoskelet Disord. 2013;14:363.
  5. Dalbeth N, et al. Arthritis Rheum. 2010;62(5):1549-1556.
  6. Doghramji PP, et al. Postgrad Med. 2012;124(6):98-109.
  7. Bongartz T, et al. Ann Rheum Dis. 2015;74(6):1072-1077.
  8. Schett G, et al. RMD Open. 2015;1:(suppl 1):e000046.
  9. Edwards NL. Gout A. Clinical features. Primer on the Rheumatic Diseases. 13th ed. New York, NY: Springer; 2008:241-249.
  10. Edwards NL. ACP Medicine. 2012:1-14.
  11. Yu KH, et al. Rheumatology (Oxford). 2004;43(2):191-194.
  12. McQueen FM, et al. Rheumatology (Oxford). 2014;53(1):95-103.
  13. Choi HK, et al. Ann Rheum Dis. 2009;68(10):1609-1612.
  14. Desai MA, et al. RadioGraphics. 2011;31(5):1365-1375.
  15. Araujo EG, et al. RMD Open. 2015;1(1):e000075.
  16. Miksanek J, et al. Curr Rheumatol Rep. 2015;17(3):20.
  17. Kim H-R, et al. Korean J Intern Med. 2014;29:404-405.
  18. Zhu J, et al. Arthritis Res Ther. 2017 May 2;19(1):83.
  19. Rada B. J Immunol Res. 2017;2017:2896380.
  20. Chhana A, et al. Ann Rheum Dis. 2011;70(9):1684–1691.
  21. Chhana A, et al. Rheum Dis Clin North Am. 2014;40(2):291-309.
  22. Dalbeth N, et al. Arthritis Rheum. 2008;58(6):1854-1865.
  23. Sapsford M, et al. Rheumatology. 2017;56(1):129-133.
  24. Schlesigner N, et al. Ann Rheum Dis. 2010;69(11):1907-1912.
  25. Paparo F, et al. Clin Exp Rheumatol. 2011;29(3):519-526.
  26. Dalbeth N, et al. Ann Rheum Dis. 2009;68(8):1290-1295.
  27. Khanna D, et al. Arthritis Care Res (Hoboken). 2012;64(10):1431-1446.
  28. Perez-Ruiz F. Rheumatology (Oxford). 2009;48(suppl 2):ii9–ii14.
  29. Schumacher HR, et al. Arthritis Rheum. 2008;59(11):1540-1548.
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.