Best Tophi Picture

I think this is the best tophi picture. Because it shows successful tophi treatment. Most tophi photographs are horrible. But I think you should know the dangers of untreated gout.

Despite the advances in science that mean we can now control gout, there is a tiny minority who cannot tolerate common uric acid-lowering treatment. If you do not get uric acid to safe concentration, you are doomed to the continuous growth of tophi. So, you might treat the pain, but can you control the gout?

Pain relief without uric acid control means more and more uric acid crystals that will eventually show themselves as gouty tophi.

Continue reading about the best tophi picture

Uricase

Uricase is not a gout treatment. It is an enzyme that converts uric acid to allantoin. Allantoin is much more soluble than uric acid, and passes harmlessly from the body.

Unfortunately, during evolution, humans have lost the ability to produce uricase (also called urate oxidase)[1]. Scientists will argue about the reasons for this. However, we can do nothing about the reasons, though we might be able to do something about the loss of uricase.

The Loss Of Uricase

Uricase is not totally lost to us. The bacteria that keep our digestive system working do produce uricase. However, it is not clear if this plays a part in removing uric acid from our bodies.

There is significant research in the 1950s, 1960s, and 1970s to try to understand the complex uric acid pathways[2-5]. The general consensus from that research is that

Two thirds of the uric acid is normally excreted through the kidney while one third gains entrance to the gut where it undergoes uricolysis.

Uricolysis is the process of breaking down uric acid to other compounds. Once assumed to be down to bacteria in the gut, this was discounted as early as 1953 when Wyngaarden wrote:

these results argue against the active participation of intestinal bacteria in uricolysis in man.

Given the significance of one third of uric acid excretion not passing through the kidneys, the term extra-renal excretion was introduced to gout studies. In recent years, researchers have discovered a genetic role in extra-renal excretion[6].

Ichida and colleagues progress the identification of genetic involvement by suggesting a new way to classify gout, which could have a significant impact on future treatment. They argue that the traditional division of gout patients into over-producers and under-excreters of uric acid requires refinement.

Under excreters remains valid, but they argue that over-producers should be renamed kidney-overload (or renal overload type to use their term). Kidney-overload would then have two subgroups: genuine overproduction; and extra-renal excretion impairment.

This may seem like semantics, but it is important, because the cause of excess uric acid can help to determine the treatment. In this case, it could influence new treatments that encourage uric acid excretion through pathways other than the kidneys.

This reminds me of a low-profile study that I saw some time ago. In September 2008, a paper was presented at the Third China-Russia International Symposium on Pharmacology titled: “Montmorillonite promotes diffusion, prevents absorption of uric acid and
decrease uric acid level in the serum.”

That research has been translated to two or three similar published articles, but I do not have access to the full text. This is in the category of “further research required,” but initial findings look promising. The paper concludes:

CONCLUSION: MMT can promote diffussion of uric acid from blood vessel to intestine, prevent absorption of uric acid in intestinal tract and decrease uric acid level in the serum.

Now, this has little to do with uricase, but it is relevant that it points to a genetic advantage indicating that we could forgo uricase because we developed other ways to excrete excess uric acid. Unfortunately, some people have a weakness with this. Montmorillonite is an untested potential remedy, but science has also developed ways to replace uricase.

Uricase Replacements

Uricase does not exist in humans, so scientists have had to prepare it from other sources. This led to the early discovery that most humans cannot tolerate uricase as a treatment. A great deal of time, effort, and money has been spent refining uricase into an acceptable treatment.

There are currently two replacement uricase products available, though neither are without problems.

Rasburicase sold as Elitek and Fasturtec

Pegloticase sold as Krystexxa

Detailed pages for these uricase-based gout treatments are coming soon. If you want to be informed when they are available, please see my Gout Info Update Service.

Although not directly uricase related, if you want to try the Montmorillonite treatment, you should discuss it with your doctor. Montmorillonite is widely available as Calcium Bentonite.

If you cannot respond to allopurinol or Uloric (febuxostat), and probenecid is only suitable for under-excreters, then Krystexxa could be good for your gout. This is best administered by a rheumatologist with experience in this new gout treatment.

Flagged For Review

Please note that this information about uricase is flagged for review. I am gathering more recent information at Improving Uricase Information. Please see that discussion for my latest information about uricase and gout.

Uricase Converts Uric Acid image
How will you get rid of excess uric acid?

Leave Uricase to browse other gout medications to avoid gout by lower uric acid


Uricase References

  1. Title: Loss of urate oxidase activity in hominoids and its evolutionary implications. Author(s): Oda M, Satta Y, Takenaka O, Takahata N. Published: Mol Biol Evol. 2002 May;19(5):640-53. Uric Acid & Evolution
  2. Title: Uricolysis in normal man. Author(s): WYNGAARDEN JB, STETTEN D Jr. Published: J Biol Chem. 1953 Jul;203(1):9-21.
  3. Title: Role of the intestinal tract in the elimination of uric acid. Author(s): Sorensen L B. Published: Arthritis Rheum. 8, 694–706 (1965).
  4. Title: The study of human intermediary purine metabolism and its regulation. Author(s): Seegmiller J E. Published: Proc R Soc Med. 1966 April; 59(4): 292–302.
  5. Title: Origin and extrarenal elimination of uric acid in man. Author(s): Sorensen LB, Levinson DJ. Published: Nephron. 1975;14(1):7-20.
  6. Title: Decreased extra-renal urate excretion is a common cause of hyperuricemia. Author(s): Ichida K, Matsuo H, Takada T, Nakayama A, Murakami K, Shimizu T, Yamanashi Y, Kasuga H, Nakashima H, Nakamura T, Takada Y, Kawamura Y, Inoue H, Okada C, Utsumi Y, Ikebuchi Y, Ito K, Nakamura M, Shinohara Y, Hosoyamada M, Sakurai Y, Shinomiya N, Hosoya T, Suzuki H. Published: Nat Commun. 2012 Apr 3;3:764. Gout Causes: 3 Types Not 2

Uricase Document History

Uricase Document Revision HistoryTo read the document revision history for this page, please click the GoutPal History image on the right.

Do you have general comments or opinions about the content of this page? Then, join the discussion at Improving Uricase Information. But, if you have personal questions about your gout, please ask in the gout forums.

Krystexxa (pegloticase)

Krystexxa (a brand of the generic pegloticase) is a new type of gout treatment, delivered intravenously, which provides a form of uricase.

Unlike other gout medications to avoid gout by lowering uric acid, Krystexxa actually breaks down uric acid to allantoin and other soluble compounds that are easily excreted by the body. As such, it is the fastest way to remove tophi and other uric acid deposits.

Krystexxa Background

This background to Krystexxa is summarized from “Long-term safety of pegloticase in chronic gout refractory to conventional treatment,” which I have reviewed on my Krystexxa Safety page.

The report emphasizes the need for improvements in gout medication. From the 8 million American gout patients, almost a quarter million fail to achieve safe uric acid levels with allopurinol or Uloric (febuxostat).[1] This is because of intolerance to medication, unsuitability due to other health problems, or simple failure to lower uric acid adequately.[2-4]

Safe uric acid lowering is essential. Without it, gout patients risk:

  • More gout attacks
  • More gouty joints
  • Joint destruction and deforming tophi
  • Chronic pain
  • Impaired mobility
  • Poor quality of life

Attempts have been made to reintroduce uricase which has been lost from humans during evolution. Unfortunately, our immune systems see uricase as an invader and develop antibodies against it, reducing its effectiveness.

To counteract the immune system, uricase has been combined with genetically altered ethylene glycol. This medication was initially named PEG-uricase, then registered with the generic name, pegloticase. Pegloticase was approved in the USA in 2010, and marketed as Krystexxa.[5-7]

Krystexxa is taken intravenously, working directly on uric acid dissolved in the blood to convert it to harmless allantoin. With uric acid reduced well below the crystallization point, 6.8mg/dl, uric acid crystals dissolve. This lowers uric acid deposits in tophi, reducing there size, and generally treating the symptoms of gout.[8-9]

Licensing applications included 2 6-month Randomized Controlled Trials (RCTs) which demonstrated the effectiveness and safety of pegloticase.[8] Pegloticase trials were either every 2 weeks or every 4 weeks, with both doses achieving significant uric acid reduction, but not without problems. Though all gout patients achieved lower uric acid levels, some (labeled non-responders) showed reduced effectiveness after the first dose. Also, Infusion-related Reactions (IRs) caused 10% of 2-weekly, and 13% of 4-weekly to withdraw from the trials.[8]

Krystexxa (pegloticase)
Krystexxa (pegloticase) image shows colored uricase surrounded by gray PEG strands. Krystexxa lowers uric acid by converting it to more soluble compounds.

Krystexxa Dosing

Krystexxa is a highly specialized gout treatment with limited distribution. Approved treatment centers must receive information packs from Savient, the manufacturers of Krystexxa. Doctors who prescribe Krystexxa should explain the patients guidelines to the gout patient. This should be done for each course of treatment, as guidelines may change between treatments.

Krystexxa History

Krystexxa Side-effects

Please see the Krystexxa Safety Report

Krystexxa: Next Steps

If you cannot tolerate allopurinol or Uloric (febuxostat), arrange to see a rheumatologist about Krystexxa.

If you have used Krystexxa, please share your experiences in the gout forum.

Leave Krystexxa to browse other Uricase pages.


Krystexxa References

  1. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007–2008. Arthritis Rheum 2011;63:3136–41.
  2. Edwards NL. Treatment-failure gout: a moving target (editorial). Arthritis Rheum 2008;58:2587–90. Treatment Failure Gout
  3. Brook RA, Forsythe A, Smeeding JE, et al. Chronic gout: epidemiology, disease progression, treatment and disease burden. Curr Med Res Opin 2010;26:2813–21.
  4. Doghramji PP, Edwards NL, McTigue J. Managing gout in the primary care setting: what you and your patients need to know. Am J Med 2010;123:S2.
  5. Sherman MR, Saifer MG, Perez-Ruiz F. PEG-uricase in the management of treatment-resistant gout and hyperuricemia. Adv Drug Deliv Rev 2008;60:59–68.
  6. Krystexxa® (pegloticase) Injection, for intravenous infusion. Prescribing information. East Brunswick, NJ: Savient Pharmaceuticals, 2010.
  7. Schlesinger N, Yasothan U, Kirkpatrick P. Pegloticase. Nat Rev Drug Discov 2011;10:17–18.
  8. 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. JAMA 2011;306:711–20.

Krystexxa Safety

Krystexxa (generic name is pegloticase) has been available to gout patients in America for 2 years, and conditions of it’s license require significant safety monitoring and reporting.

This is a layman’s review of the 2012 Krystexxa safety report. You should note that there are associated changes to labeling. I will report on revised Krystexxa labels in due course.

Krystexxa Safety Report

This is a review of:

Title:
Long-term safety of pegloticase in chronic gout refractory to conventional treatment.
Authors:
Becker MA, Baraf HS, Yood RA, Dillon A, Vázquez-Mellado J, Ottery FD, Khanna D, Sundy JS
Published:
Ann Rheum Dis. 2012 Dec 11

Krystexxa Safety Report Introduction & Objectives

The report introduces pegloticase with some background information. I have summarized this information in my Krystexxa Introduction, so I will not repeat it here, though references are included below for completeness.

Pegloticase is a form of uricase, that was granted a licence to be sold as Krystexxa in 2010. Approval for Krystexxa was subject to ongoing safety studies. This report continues the initial 6 month Randomized Control Trials with an additional 2.5 years of study (Open Label Extension) to provide a three year review.[17]

In Open Label Extension studies, the patient knows what they are being treated with, compared to Randomized Control Trials where the patient and doctor are unaware if the treatment is placebo or medicine.

Krystexxa Safety Report Methods

Gout patients who had taken part in the Randomized Control Trials that supported the license application were eligible to take place in the Open Label Extension. They received infusions of 8mg pegloticase every 2 or 4 weeks. Patients were monitored primarily for:

  • Safety, with special interest in gout attacks and Infusion Reactions
  • Side Effects (Adverse Events) evaluated and vital signs measured prior to each 2 or 4 weekly pegloticase infusion

They were also monitored for:

  • Durability of pegloticse treatment responses
  • Plasma Uric Acid and Serum Uric Acid measured every 12 weeks
  • Serum assessed for immune reaction every 12 weeks
  • Gout attacks evaluated each visit
  • Tophus burden evaluated every 24 weeks by a centralreader using digital photographs

Krystexxa Safety Report Results

151 gout patients entered the Open Label Extension, including 2 who had received 4 weekly pegloticase in the Randomized Control Trials but continued observaion only without further treatment. A further 27 stopped treatment due to side effects, and 13 stopped treatment because the pegloticase infusion no longer reduced uric acid.

Of the total 37 months covered by the trials, patients remained in the trials for an average of 25 months, including a no-treatment observation period at the end of the trial up to 6 months.

The report includes extensive statistical analysis and observation. The important data about side effects in the 149 patients who were treated with pegloticase is:

  1. 106 (71%) Gout attack
  2. 65 (44%) Infusion Reaction
  3. 29 (20%) Joint pain
  4. 27 (18%) Upper respiratory tract infection
  5. 26 (17%) Pain in exremity
  6. 25 (17%) Back pain
  7. 22 (15%) Diarrhea
  8. 21 (14%) Peripheral edema (swelling/puffiness)
  9. 20 (13%) Urinary tract infection
  10. 17 (11%) Nausea
  11. 16 (11%) Headache
  12. 15 (10%) Fatigue
  13. 15 (10%) Sinusitis
  14. 15 (10%) Sore nose/throat

The most important aspect of the study is whether pegloticase achieves a uric acid level below 6mg/dL. Patients who did are labeled responders. Patients who failed to achieve below 6mg/dL are labeled non-reponders. The results are complicated, because responders can stop responding during the treatment. The data presented in the study is difficult to interpret absolutely, as different benefits accrue on a case-by-case basis. For example, a patient might enjoy a few weeks of rapid tophi resolution followed by a move towards no further effectiveness. 2-weekly treatment achieved better results than 4-weekly.

The gout patients who had visible tophi generally achieved good reduction rates. Again, various statistics across different sub-groups produce complex statistics. Each patient was assessed on up to 5 tophi, and 185 of a total 302 tophi in the study were completely resolved (61%).

The study contains information on gout attacks. As with all other types of uric acid lowering treatment, gout attacks were noticed most in the first 3 months of treatment.

Krystexxa Safety Report Discussion & Conclusion

Given that all patients had no other treatment options, long-term pegloticase was “safe and generally well tolerated”. The study showed that most Infusion Reactions occurred in patients who failed to reduce uric acid below 6mg/dL, and so it recommends that pegloticase treatment ceases if target uric acid levels are not achieved.

The authors note the general limitation of potential bias in Open Label Extension studies.[19] They also note the limitation from earlier Randomized Control Trials of separate groups of 2 weekly and 4 weekly treatment. Most patients ended with the 2 weekly treatment.

In summary, the safety profile of pegloticase in the OLE study was consistent with that observed in the RCTs [Randomized Control Trials][17] with no evidence of new safety concerns related to long-term exposure. Efficacy findings further demonstrated that clinical improvements were durable and probably progressive during long-term therapy in patients with persistent goal range urate-lowering responses to pegloticase.

Krystexxa Safety: Next Steps

If you have any questions, opinions, or experiences of Krystexxa, especially safety issues, please share them in the gout forums.

Leave Krystexxa Safety to browse other Krystexxa pages.


Krystexxa Safety Report References

  1. Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout. Part II: management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2006;65:1312–24.
  2. Hamburger M, Baraf HS, Adamson TC III.et al. Recommendations for the diagnosis and management of gout and hyperuricemia. Postgrad Med 2011;123(6 Suppl 1):3–36.
  3. Li-Yu J, Clayburne G, Sieck M, et al. Treatment of chronic gout. Can we determine when urate stores are depleted enough to prevent attacks of gout? J Rheumatol 2001;28:577–80.
  4. Pascual E, Sivera F. Time required for disappearance of urate crystals from synovial fluid after successful hypouricaemic treatment relates to the duration of gout. Ann Rheum Dis 2007;66:1056–8.
  5. Perez-Ruiz F, Lioté F. Lowering serum uric acid levels: what is the optimal target for improving clinical outcomes in gout? Arthritis Rheum 2007;57:1324–8.
  6. Shoji A, Yamanaka H, Kamatani N. A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy. Arthritis Rheum 2004;51:321–5.
  7. Becker MA, Schumacher HR, MacDonald PA, et al. Clinical efficacy and safety of successful longterm urate lowering with febuxostat or allopurinol in subjects with gout. J Rheumatol 2009;36:1273–82.
  8. Perez-Ruiz F, Calabozo M, Pijoan JI, et al. Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout. Arthritis Rheum 2002;47:356–60.
  9. Jordan KM, Cameron JS, Snaith M, et al. British Society for Rheumatology and British Health Professionals in Rheumatology guidelines for the management of gout. Rheumatology (Oxford) 2007;46:1372–4.
  10. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007–2008. Arthritis Rheum 2011;63:3136–41.
  11. Edwards NL. Treatment-failure gout: a moving target (editorial). Arthritis Rheum 2008;58:2587–90. Treatment Failure Gout
  12. Brook RA, Forsythe A, Smeeding JE, et al. Chronic gout: epidemiology, disease progression, treatment and disease burden. Curr Med Res Opin 2010;26:2813–21.
  13. Doghramji PP, Edwards NL, McTigue J. Managing gout in the primary care setting: what you and your patients need to know. Am J Med 2010;123:S2.
  14. Sherman MR, Saifer MG, Perez-Ruiz F. PEG-uricase in the management of treatment-resistant gout and hyperuricemia. Adv Drug Deliv Rev 2008;60:59–68.
  15. Krystexxa® (pegloticase) Injection, for intravenous infusion. Prescribing information. East Brunswick, NJ: Savient Pharmaceuticals, 2010.
  16. Schlesinger N, Yasothan U, Kirkpatrick P. Pegloticase. Nat Rev Drug Discov 2011;10:17–18.
  17. 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. JAMA 2011;306:711–20.
  18. Richette P, Bardin T. Gout. Lancet 2010;375:318–28.
  19. Day RO, Williams KM. Open-label extension studies: do they provide meaningful information on the safety of new drugs? Drug Safety 2007;30:93–105.

How Is Your Krystexxa?

Krystexxa, the intravenous uric acid lowering developed as pegloticase, has been around a few months now.

At least one patient, or rather his wife, has reported good initial results in the gout forum and has promised to keep us updated with progress. Any new treatment is always interesting, and people want to know more about it.

The scientists get to have their say in the professional publications, but much more important, is the way treatments affect gout sufferers. Now, gout patients have a chance to tell their story.

A leading health magazine is was looking for Krystexxa patients to interview. Please note that this no longer applies.

Of course, I would be delighted if you could also share your experiences about Krystexxa, or any other gout treatment in the gout treatment forum.

Leave this Krystexxa article to browse more Krystexxa guidelines.