Karim Richard Masri , Kevin Winterling , Brian Lamoreaux 
1. Bon Secours Rheumatology Center, Richmond, Va 2. Horizon Therapeutics Plc, Deerfield, Il
Background/Objective: Pegloticase is a PEGylated uricase biologic for uncontrolled gout, but not all patients complete a full therapy course due to anti-drug antibody (ADA) development. ADAs to pegloticase can cause loss of urate-lowering efficacy (from increased drug clearance) and infusion reactions . Prospective  and retrospective  case series indicate that administering the immunomodulator methotrexate can markedly improve the proportion of pegloticase responders from 42% in the phase 3 clinical trials  to 80%-100%. However, certain considerations with methotrexate use including significant renal or hepatic disease may not be as restricting with leflunomide. This study examined pegloticase response rate in uncontrolled gout patients co-treated with pegloticase and leflunomide.
Methods: Patients included in this retrospective study were co-treated with biweekly pegloticase (8 mg infusion) and daily leflunomide (20 mg oral). Demographic, disease, pegloticase/leflunomide treatment, and safety (adverse events [AEs], laboratory testing) parameters were examined. Prior to each infusion, patients were administered a standard prophylactic infusion regimen (IV methylprednisolone [125 mg] the day of infusion and either oral fexofenadine (60 mg, 8 patients) or diphenhydramine (25 mg, 2 patients) the night before and morning of infusion). Patients were considered treatment responders if they received at least 12 pegloticase infusions and had a serum uric acid level (sUA) below 6 mg/dL at infusion 12.
Results: 10 patients (5 male) were included. Comorbidities included chronic kidney disease (90%), hypertension (70%), diabetes mellitus (60%), obesity (60%), congestive heart failure (50%), and coronary artery disease (20%). Mean patient age was 72.7 ± 12.5 years and baseline sUA was 7.1 ± 2.4 mg/dL. Seven patients (70%) were responders and had received 26.6 ± 14.0 infusions (range: 13-55 infusions, infusion 12 sUA: 0.9 ± 1.5 mg/dL). Three patients were lost to follow-up or discontinued therapy. Three patients (30%) experienced AEs. One patient had worsening of cardiac and renal disease (deemed unrelated to co-therapy) and 3 gout flares, 1 patient had wooziness/loss of consciousness (reaction to methylprednisolone prior to pegloticase infusion), and 1 patient had 2 mild, transient rises in liver enzymes.
Conclusion: Results of this proof-of-concept study suggest that leflunomide can safely be used to increase the proportion of pegloticase responders in patients with uncontrolled gout, presumably through ADA attenuation. Other immunomodulators, particularly methotrexate, have also been shown to be useful, but it is important to have several options for this heterogenous patient population with a high incidence of comorbidities.
References:  Lipsky PE, et al. Arthritis Res Ther 2014;16:R60.  Botson J, Peterson J. Ann Rheum Dis 2019;78:A1289.  Albert J, et al. Arthritis Rheumatol 2019;71.  Sundy JS, et al. JAMA 2011;306:711-20.  Liu Z, et al. Sci Rep 2015;5:14325.  Yang C, et al. PloS One 2017;12:e0177249.
Disclosures: K. R. Masri is a consultant and paid speaker for Horizon and a current stock holder. K. Winterling and B. LaMoreaux are employees of and hold stock in Horizon.