Pegloticase
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Chronic gout refractory to conventional therapy — patients who have failed to normalise 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 | Adults | Biologic urate-lowering therapy; infusion q2 weeks | FDA Approved |
Pegloticase (Krystexxa) received initial FDA approval in 2010 as a PEGylated recombinant mammalian uricase for treatment-failure gout. It catalyses the oxidation of uric acid to allantoin, an inert, water-soluble metabolite readily excreted by the kidneys. Pegloticase is not recommended for the treatment of asymptomatic hyperuricaemia. The 2020 ACR guideline conditionally recommends pegloticase for patients with refractory gout who have failed or cannot tolerate oral urate-lowering therapies. The current PI recommends co-administration with oral methotrexate 15 mg weekly to reduce immunogenicity and improve response rates. Patients must discontinue all oral urate-lowering agents before starting pegloticase, as these may mask the SUA rise that signals loss of therapeutic response and increased infusion reaction risk.
Dosing
Adult Dosing
| Component | Dose & Regimen | Notes |
|---|---|---|
| Pegloticase | 8 mg IV infusion every 2 weeks | Infuse over ≥120 minutes; do not administer as IV push or bolus; optimal treatment duration not established Available as RTU 8 mg/50 mL vial or To-be-Diluted 8 mg/mL (1 mL) vial |
| Methotrexate co-therapy (recommended) | 15 mg PO weekly | Start MTX with folic acid or folinic acid supplementation ≥4 weeks before first pegloticase infusion; continue throughout treatment Pegloticase alone may be used if MTX is contraindicated or not clinically appropriate |
| Pre-infusion medications | Antihistamines + corticosteroids | Administer before each infusion to reduce anaphylaxis and infusion reaction risk Acetaminophen may also be included per institutional protocol |
| Gout flare prophylaxis | Colchicine or NSAID | Start ≥1 week before first infusion; continue for ≥6 months Low-dose prednisone (≤10 mg/day) may be added at prescriber discretion |
Monitor serum uric acid levels before each infusion. A rising SUA above 6 mg/dL reflects the development of anti-drug antibodies and predicts loss of efficacy and increased infusion reaction risk. Discontinue pegloticase if SUA levels increase to above 6 mg/dL at 2 consecutive visits. Do not use oral urate-lowering agents concurrently, as they mask this safety signal.
In the MIRROR RCT, methotrexate co-therapy increased 6-month sustained urate-lowering response from 38.5% (pegloticase alone) to 71%, while reducing the infusion reaction rate from 30.6% to 4.2%. This represents a paradigm shift in pegloticase prescribing. MTX reduces immunogenicity by suppressing anti-pegloticase antibody formation. The current PI recommends co-administration with MTX unless contraindicated.
Pharmacology
Mechanism of Action
Pegloticase is a recombinant uricase (urate oxidase) produced in a genetically modified strain of Escherichia coli and conjugated to monomethoxypoly(ethylene glycol) (mPEG) of 10 kDa. Humans lack a functional uricase gene due to evolutionary mutations, making uric acid the end-product of purine metabolism. Pegloticase restores the enzymatic conversion of uric acid to allantoin, a highly water-soluble metabolite that is readily excreted by the kidneys. This results in rapid and profound urate lowering, often achieving SUA levels <1 mg/dL. PEGylation prolongs the circulating half-life and reduces immunogenicity of the uricase protein, though anti-PEG and anti-uricase antibodies still develop in the majority of patients treated with monotherapy.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Administration | IV infusion over ≥120 minutes; dose-proportional Cmax following single infusions of 0.5–12 mg | Must be administered in a healthcare setting prepared for anaphylaxis; never as IV push or bolus |
| Distribution | Large molecule (~540 kDa); predominantly intravascular distribution expected | PEGylation extends residence in circulation |
| Metabolism | Proteolytic degradation typical of PEGylated proteins; not metabolised by CYP enzymes | No CYP-mediated drug interactions expected |
| Elimination | Mean t½ ~6–14 days (variable; measured as uricase enzyme activity); clearance accelerated by anti-drug antibodies | Patients who develop high-titre antibodies have faster clearance, loss of efficacy, and rising SUA |
In pivotal monotherapy trials, 92% of patients developed anti-pegloticase antibodies. High-titre antibodies were associated with treatment failure (loss of SUA lowering) and a dramatically higher infusion reaction rate (53% vs 6% in patients with undetectable/low titres). Anti-PEG antibodies may also theoretically cross-react with other PEGylated therapeutics. Methotrexate co-therapy significantly reduces antibody formation, which is the rationale for the current PI recommendation of MTX co-administration.
Side Effects
| Adverse Effect | Incidence (q2wk) | Placebo | Clinical Note |
|---|---|---|---|
| Gout flares | 74% (first 3 months; decreases to 41% in months 4–6) | 51% | Due to rapid urate mobilisation from tissue deposits; prophylaxis essential; not a reason to discontinue |
| Infusion reactions | 26% | 5% | Higher in patients with high anti-pegloticase antibody titres (53%); reduced to ~4% with MTX co-therapy |
| Nausea | 12% | 0% | May be related to infusion or premedication |
| Contusion or ecchymosis | 11% | 2% | Often related to concomitant medications (anticoagulants, insulin injections) rather than pegloticase directly |
| Adverse Effect | Incidence (q2wk) | Placebo | Clinical Note |
|---|---|---|---|
| Nasopharyngitis | 7% | 5% | Common upper respiratory symptoms |
| Constipation | 6% | 5% | Similar rate to placebo |
| Chest pain | 6% | 0% | Distinguish from infusion reaction or cardiac event; cardiovascular evaluation if concerning |
| Vomiting | 5% | 0% | May be related to infusion or premedication |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Anaphylaxis (BOXED WARNING) | 6.5% (q2wk monotherapy); reduced with MTX co-therapy | Generally within 2 hours of infusion; may occur with any infusion including the first; delayed reactions reported | Stop infusion immediately; treat per anaphylaxis protocol; do not rechallenge after anaphylaxis |
| Severe infusion reactions | Subset of 26% overall IR rate | During or shortly after infusion | Slow or stop infusion; treat symptoms; may restart at slower rate for non-severe reactions (~75% resolved with this approach) |
| Haemolysis / methemoglobinaemia (G6PD deficiency) | Expected in G6PD-deficient patients | Hours to days after infusion | CONTRAINDICATED in G6PD deficiency; screen high-risk populations before initiating; do not administer |
| Heart failure exacerbation | Reported during pre-marketing trials | Variable | Monitor patients with CHF closely; causal relationship not established |
Drug Interactions
No formal drug interaction studies with pegloticase have been conducted. As a PEGylated protein, pegloticase is not metabolised by cytochrome P450 enzymes, so CYP-mediated interactions are not expected. The key interactions are pharmacodynamic in nature.
Monitoring
- Serum Uric AcidBefore every infusion
RoutineCritical safety biomarker. SUA >6 mg/dL suggests anti-drug antibody development. Discontinue pegloticase if SUA >6 mg/dL at 2 consecutive visits. Keep samples on ice at 4°C to prevent ex vivo urate degradation. - G6PD StatusOnce, before first infusion
RoutineScreen patients at higher risk (African, Mediterranean, or South Asian ancestry). Pegloticase is contraindicated in G6PD deficiency due to risk of haemolysis and methemoglobinaemia from hydrogen peroxide generated during urate oxidation. - Infusion MonitoringDuring and for ≥1 hour after each infusion
RoutineObserve for signs of anaphylaxis and infusion reactions (urticaria, dyspnoea, chest discomfort, haemodynamic instability). Ensure resuscitation equipment and trained personnel available. - MTX Monitoring (if co-administered)Baseline; regularly during treatment
RoutineCBC with differential, LFTs, renal function per standard MTX monitoring. Screen for hepatitis B and C before initiating MTX. Monitor for infections, myelosuppression. - Gout FlaresEach visit
Trigger-basedFlares are expected, especially in the first 3 months. Ensure flare prophylaxis is in place. Do not discontinue pegloticase for gout flares. - Cardiovascular StatusBaseline; clinical vigilance
Trigger-basedHeart failure exacerbation reported during trials. Monitor patients with CHF closely. Differentiate chest pain from infusion reactions versus cardiac events.
Contraindications & Cautions
Absolute Contraindications
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency — pegloticase generates hydrogen peroxide during urate oxidation; G6PD-deficient patients cannot adequately neutralise this oxidant stress, leading to haemolysis and methemoglobinaemia.
- History of serious hypersensitivity reaction, including anaphylaxis, to pegloticase or any of its components.
Use with Caution
- Congestive heart failure — heart failure exacerbation reported during clinical trials; causal relationship not established but close monitoring warranted.
- Concurrent immunosuppression — patients already on immunosuppressants require careful assessment before adding MTX co-therapy.
- Pregnancy — no adequate human studies; animal studies (rats and rabbits at doses up to 50–75 times MRHD) showed no structural abnormalities but decreased fetal/pup body weights at high doses.
- Lactation — unknown whether pegloticase is excreted in human milk; use only if benefit outweighs risk.
- Paediatric patients — safety and efficacy have not been established.
- Prior pegloticase monotherapy failure — retreatment with MTX co-therapy after prior monotherapy failure shows lower response rates (9%) due to established anti-drug antibodies; initiate immunomodulation before first pegloticase exposure for best results.
Anaphylaxis and infusion reactions have been reported during and after administration of pegloticase. In pre-marketing monotherapy trials, anaphylaxis occurred in 6.5% (8/123) of patients receiving pegloticase every 2 weeks, with no cases in placebo. Anaphylaxis may occur with any infusion, including the first, and generally manifests within 2 hours. Delayed hypersensitivity reactions have also been reported. Pegloticase must be administered in healthcare settings by healthcare providers prepared to manage anaphylaxis. Patients must be pre-medicated with antihistamines and corticosteroids and closely monitored during and after each infusion. Risk is higher in patients who have lost therapeutic response (SUA >6 mg/dL).
Patient Counselling
Purpose of Therapy
Pegloticase is a biologic infusion therapy used for severe gout that has not responded to other uric acid-lowering medicines. It works by converting uric acid into a harmless substance (allantoin) that the body can easily eliminate. It is given as an IV drip every two weeks in a clinic or infusion centre, and is typically prescribed alongside weekly oral methotrexate to improve its effectiveness.
What to Expect
Each infusion takes at least two hours, and you will be monitored afterwards. You will receive medicines before each infusion (antihistamines and a steroid) to reduce the risk of allergic reactions. Blood tests for uric acid are taken before each infusion to ensure the medicine is still working.
Sources
- Krystexxa (pegloticase) Prescribing Information. Amgen Inc. FDA (2022 label)Current PI with MTX co-therapy recommendations, boxed warning for anaphylaxis/infusion reactions, adverse reaction Table 1 and Table 2, and immunogenicity data.
- 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. doi:10.1001/jama.2011.1169GOUT1/GOUT2 pivotal trials: 42% responders (q2wk) vs 0% placebo at 6 months in treatment-failure gout; established efficacy and safety profile for FDA approval.
- Botson JK, Tesser JRP, Bennett R, et al. Pegloticase in combination with methotrexate in patients with uncontrolled gout: a multicenter, open-label study (MIRROR). J Rheumatol. 2021;48(5):767–774. doi:10.3899/jrheum.200460MIRROR open-label trial: 79% (11/14) responders with MTX co-therapy at 6 months; 1 mild infusion reaction (7.1%); no anaphylaxis.
- Botson JK, Saag K, Peterson J, et al. A randomized, placebo-controlled study of methotrexate to increase response rates in patients with uncontrolled gout receiving pegloticase (MIRROR RCT). Arthritis Rheumatol. 2023;75(2):293–304. doi:10.1002/art.42320MIRROR RCT: MTX co-therapy increased 6-month sustained response from 38.5% to 71%; IR rate 4.2% vs 30.6%; pivotal data supporting current PI recommendation for MTX co-administration.
- Becker MA, Baraf HS, Yood RA, et al. Long-term safety of pegloticase in chronic gout refractory to conventional treatment. Ann Rheum Dis. 2013;72(9):1469–1474. doi:10.1136/annrheumdis-2012-201795Open-label extension safety data from the pivotal GOUT1/GOUT2 trials demonstrating sustained efficacy and consistent safety profile with longer-term treatment.
- Lipsky PE, Calabrese LH, Kavanaugh A, et al. Pegloticase immunogenicity: the relationship between efficacy and antibody development in patients treated for refractory chronic gout. Arthritis Res Ther. 2014;16(2):R60. doi:10.1186/ar4497Key immunogenicity analysis: 92% developed anti-pegloticase antibodies; high titres associated with loss of response and 53% IR rate vs 6% in low-titre patients.
- Sundy JS, Ganson NJ, Kelly SJ, et al. Pharmacokinetics and pharmacodynamics of intravenous PEGylated recombinant mammalian urate oxidase in patients with refractory gout. Arthritis Rheum. 2007;56(3):1021–1028. doi:10.1002/art.22403Phase I/II PK-PD study: dose-proportional exposure; established 8 mg dose; demonstrated profound SUA lowering.
- Baraf HSB, 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. doi:10.1097/RHU.0000000000000200Detailed analysis of infusion reactions from GOUT1/GOUT2 trials; ~75% resolved by slowing or restarting infusion; correlation with anti-drug antibody titres.
- FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology guideline for management of gout. Arthritis Care Res. 2020;72(6):744–760. doi:10.1002/acr.24180Current ACR guideline conditionally recommending pegloticase for treatment-failure gout refractory to other urate-lowering therapies.
- 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. doi:10.1186/ar4318Demonstrated significant tophus reduction with pegloticase in responders from GOUT1/GOUT2 and open-label extension.
- Botson JK, Saag K, Peterson J, et al. A randomized, double-blind, placebo-controlled multicenter efficacy and safety study of methotrexate to increase response rates in patients with uncontrolled gout receiving pegloticase: 12-month findings. Arthritis Rheumatol. 2023;75(11):2066–2074. doi:10.1002/art.42615MIRROR RCT 12-month data: sustained efficacy of MTX co-therapy; continued tophus resolution through week 52; no new safety signals.
- Padda IS, Bhatt R, Patel P, et al. Pegloticase. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; Updated February 28, 2024. NCBI BookshelfComprehensive peer-reviewed clinical summary covering indications, dosing, PK, adverse effects, and monitoring of pegloticase.