Antigout drugs

Gout -> hyperuricemia -> urate crystals within joint -> immune response with IL-1B via NOD-like receptors pyrin domain containing protein 3 (NLRP3)

Xanthine Oxidase Inhibitors

Azathioprine and 6-mercaptopurine are both metabolized by xanthine oxidase, therefore using any xanthine oxidase inhibitor such as allopurinol or febuxostat can cause severe agranulocytosis or pancytopenia.

Allopurinol

Patch testing 0% in DRESS, including allopurinol and oxypurinol.

HLA-B*58:01 main risk allele

Other risk factors, CKD, thiazide

Median time to onset of delayed reaction is 3 weeks.

Allopurinol hypersensitivity reactions, 1 in 1000.

Slow or gradual reintroduction protocols for patients with history of non-severe delayed reactions. May be successful in large part because patients lose drug allergy over time since their index reaction.

delayed T cell mediated

An estimated 2% of patients receiving allopurinol therapy, particularly those with chronic kidney disease, may experience a maculopapular exanthem.

Febuxostat

Inhibits NLRP3 inflammasome in vitro.

Superior SUA lowering compared to allopurinol.

Structurally distinct from allopurinol. Safe to use as alternative in individuals who have had allopurinol hypersensitivity reactions.

Uricosuric Drugs

Probenecid

Main target of inhibition is URAT1 in the proximal convuluted tubule.

Can be used as monotherapy or combination with XOI.

Lower potentcy than other ULTs.

Stage III or > CKD relative contraindication.

Nephrolithiasis

Urciases

Pegloticase

A recombinant uricase conjugated with PEG, created by a genetically altered variant of Escherichia coli.

A tetrameric protein of four identical chains (~300 amino acids), approximately 10 of the 30 lysine residues of in each chain are PEGlyated. Each about 225 ethylene oxide units each ~10 kDA PEG (means PEG 10000)

Catalyzes uric acid to the water-soluble easily excreted metabolite allantoin.

Longer half-life than rasburicase due to being PEGylated (instead of 8 hours ->10 to 12 days)

Infusion Reactions/Anaphylaxis (Black-box warning)

CARPA anti-PEG IgM infusion reactions

IgE-mediated anti-PEG IgE = anaphylaxis

No dose adjustment based on renal function.

Contraindicated in G6PD deficiency.

“Stopping rules” whereby pegloticase therapy discontinued if pre-infusions serum uric acid level >= 6 mg/dL.

• Development of antidrug antibodies is related to incidence of infusion reactions and loss of efficacy.

immediate IgE-mediated -> serum tryptase, skin testing sIgE

MIRROR-RCT is underway to test whether combining pegloticase with methotrexate reduces immunogenicity.