Urate-lowering therapy, serum urate, inflammatory biomarkers, and renal function in patients with gout following pegloticase discontinuation.

BACKGROUND/PURPOSE: Little is known about long-term clinical outcomes or urate-lowering (ULT) therapy use following pegloticase discontinuation. We examined ULT use, serum urate (SU), inflammatory biomarkers, and renal function following pegloticase discontinuation. METHODS: We conducted a retrospective analysis of gout patients who discontinued pegloticase using the Rheumatology Informatics System for Effectiveness (RISE) registry from 1/2016 to 6/2022. We defined discontinuation as a gap ≥ 12 weeks after last infusion. We examined outcomes beginning two weeks after last dose and identified ULT therapy following pegloticase discontinuation. We evaluated changes in lab values (SU, eGFR, CRP and ESR), comparing on- treatment (≤ 15 days of the second pegloticase dose) to post-treatment. RESULTS: Of the 375 gout patients discontinuing pegloticase, median (IQR) laboratory changes following discontinuation were: SU: +2.4 mg/dL (0.0,6.3); eGFR: -1.9 mL/min (- 8.7,3.7); CRP: -0.8 mg/L (-12.8,0.0); and ESR: -4.0 mm/hr (-13.0,0.0). Therapy post-discontinuation included oral ULTs (86.0%), restarting pegloticase (4.5%), and no documentation of ULT (9.5%), excluding patients with multiple same-day prescriptions (n = 17). Oral ULTs following pegloticase were: 62.7% allopurinol, 34.1% febuxostat. The median (IQR) time to starting/restarting ULT was 92.0 days (55.0,173.0). Following ULT prescribing (≥ 30 days), only 51.0% of patients had SU < 6 mg/dL. Patients restarting pegloticase achieved a median SU of 0.9 mg/dL (IQR:0.2,9.7) and 58.3% had an SU < 6 mg/dL. CONCLUSION: Pegloticase treats uncontrolled gout in patients with failed response to xanthine oxidase inhibitors, but among patients who discontinue, optimal treatment is unclear. Based on this analysis, only half of those starting another ULT achieved target SU. Close follow-up is needed to optimize outcomes after pegloticase discontinuation.

Examination of monosodium urate crystal depletion and bone erosion remodeling during pegloticase treatment in patients with uncontrolled gout: exploratory dual-energy computed tomography findings from MIRROR RCT.

OBJECTIVE: Monosodium-urate (MSU) crystal deposits can be visualized and quantified with dual-energy CT (DECT). Pegloticase lowers serum urate (SU) in uncontrolled gout patients, with methotrexate (MTX) co-therapy recommended to increase SU-lowering response rate and decrease infusion reaction risk. The literature on serial DECT-imaging during pegloticase+MTX co-therapy is sparse, with only 2 prior cases of rapid MSU deposition depletion with subsequent bone-erosion remodeling reported from a small open-label trial. Here, we report DECT findings during pegloticase treatment in a larger number of patients from a randomized controlled trial to confirm bone-erosion remodeling that follows MSU depletion with pegloticase. The influence of length-of-therapy is also explored. METHODS: Patients received pegloticase (8mg every 2-weeks)+MTX (15mg/week orally) or pegloticase+placebo (PBO) during the MIRROR RCT trial. A subset underwent DECT-imaging on Day1 (first pegloticase infusion) and at Week 14, 24, and 52. Patients with paired baseline-Week52 images were included. Imaged regions with baseline MSU-crystal volume (VMSU) <0.5cm3 were excluded to minimize artifact contributions. VMSU and bone erosion remodeling were assessed. RESULTS: Eight patients (6 MTX, 2 PBO) were included. Included patients had received 52-weeks (5 MTX), 42-weeks (1 PBO), and 6-weeks (1 MTX, 1 PBO) of pegloticase therapy. Patients who prematurely discontinued pegloticase maintained SU <6mg/dL on allopurinol (n=2)/febuxostat (n=1). At Week52, VMSU had markedly decreased in both the pegloticase+MTX and pegloticase+PBO treatment groups, with faster depletion during pegloticase therapy. Bone-erosion remodeling was observed in 29/42 (69%) evaluated erosions: 29 (69%) size decrease, 4 (9.5%) recortication, 3 (7.1%) new bone formation. CONCLUSION: Rapid VMSU depletion pegloticase therapy was observed with concomitant bone remodeling within 1-year. Following pegloticase discontinuation, VMSU reduction slowed or stopped even when SU was maintained <6mg/dL with oral ULT. CLINICAL TRIAL REGISTRATION: NCT03994731.

Intensive urate-lowering with pegloticase plus methotrexate co-therapy in uncontrolled gout patients with and without chronic kidney disease: A retrospective case series.

Chronic kidney disease (CKD) and gout commonly co-occur. Pegloticase lowers serum urate (SU) in uncontrolled gout patients but antidrug antibodies limit urate-lowering response and increase infusion reaction (IR) risk. Methotrexate (MTX) co-administration increases pegloticase response rate and mitigates IR risk but CKD limits MTX use. This pooled case series examined pegloticase + MTX co-therapy in uncontrolled gout patients with and without CKD. Cases of pegloticase + MTX co-therapy in existing datasets were retrospectively examined. Baseline eGFR classified patients as CKD (eGFR < 60 mL/min/1.73 m2) or non-CKD (eGFR ≥ 60 mL/min/1.73 m2). Patient characteristics, treatment parameters, laboratory values, urate-lowering response rate (≥12 pegloticase infusions received and SU < 6 mg/dL just before infusion 12), and AEs were examined. Fifteen CKD (eGFR: 43.2 ±â€…11.3 mL/min/1.73 m2; SU: 8.6 ±â€…2.2 mg/dL), 27 non-CKD (eGFR: 82.9 ±â€…19.0 mL/min/1.73 m2; SU: 9.5 ±â€…1.7 mg/dL) patients were included. Comorbidity profiles were similar, but CKD patients were older (72.0 ±â€…9.9 vs 52.3 ±â€…14.3 years) and more often female (33.3% vs 7.4%). Treatment parameters were similar with 4-week MTX Run-in followed by mean of 14.7 ±â€…8.1 [CKD] vs 14.1 ±â€…7.1 [non-CKD] pegloticase infusions. However, CKD patients had lower MTX dose (14.8 ±â€…5.8 vs 19.3 ±â€…4.9 mg/week). Urate-lowering response was similar (92% vs 86%). eGFR increased during treatment in 60% of CKD (+11.5 ±â€…20.9 mL/min/1.73 m2, 87% stable/improved CKD-stage) and 44% of non-CKD (+4.2 ±â€…15.0 mL/min/1.73 m2) patients. AEs were similar (≥1 AE CKD: 53%, non-CKD: 67%; gout flare most-reported). One case each of pancytopenia and IR (mild) occurred in non-CKD patients. These real-world data show similar pegloticase + MTX efficacy in CKD and non-CKD patients. No new safety signals were identified, with most CKD patients showing renal function stability or improvement during therapy.

Social Listening in Gout: Impact of Proactive vs. Reactive Management on Self-Reported Emotional States.

INTRODUCTION: This study aimed to characterize patient-reported outcomes from social media conversations in the gout community. The impact of management strategy differences on the community's emotional states was explored. METHODS: We analyzed two social media sources using a variety of natural language processing techniques. We isolated conversations with a high probability of discussing disease management (score > 0.99). These conversations were stratified by management type: proactive or reactive. The polarity (positivity/negativity) of language and emotions conveyed in statements shared by community members was assessed by management type. RESULTS: Among the statements related to management, reactive management (e.g., urgent care) was mentioned in 0.5% of statements, and proactive management (e.g., primary care) was mentioned in 0.6% of statements. Reactive management statements had a significantly larger proportion of negative words (59%) than did proactive management statements (44%); "fear" occurred more frequently with reactive statements, whereas "trust" predominated in proactive statements. Allopurinol was the most common medication in proactive management statements, whereas reactive management had significantly higher counts of prednisone/steroid mentions. CONCLUSIONS: A unique aspect of examining gout-related social media conversations is the ability to better understand the intersection of clinical management and emotional impacts in the gout community. The effect of social media statements was significantly stratified by management type for gout community members, where proactive management statements were characterized by more positive language than reactive management statements. These results suggest that proactive disease management may result in more positive mental and emotional experiences in patients with gout.

Economic and Health Care Resource Use Burden of Systemic Sclerosis.

OBJECTIVE: To describe the health care resource use (HCRU) and costs of patients with systemic sclerosis (SSc) prior to and after diagnosis. METHODS: This retrospective study used a claims data set (Merative MarketScan; 2015-2019). Eligible patients with SSc were identified by diagnosis codes and required at least 24 months of enrollment without an SSc diagnosis before their first SSc claim and at least 12 months of enrollment thereafter. Total HCRU and costs were reported for three intervals: 2 years and 1 year before and 1 year after index diagnosis. A general population cohort without SSc was matched 1:1 to the SSC cohort on age and sex for comparison. RESULTS: Eligibility criteria identified 902 patients with SSc (mean age: 54 years old; 85% female). Mean per-member per year costs increased each year from $22,383 to $29,708 to $47,095, 2 years before, 1 year before, and 1 year after index diagnosis versus $10,232 to $9656 to $9714 in the general population cohort. Outpatient settings represented the largest proportion of cost 1 year after SSc diagnosis ($16,392), followed by prescription drugs ($10,692), physician office ($10,523), and inpatient ($9448) settings. CONCLUSION: Patients with SSC accrued greater costs and required more services than a general population cohort. These elevated expenditures and HCRU were observed at least 2 years before an SSc diagnosis and increased over time, reflecting both the progressive, multisystem nature of SSc and potential challenges in diagnosis. These findings suggest that SSc poses a substantial burden on the US health care system and highlights the need for early diagnosis and effective therapies.

Human cardiovascular disease model predicts xanthine oxidase inhibitor cardiovascular risk.

Some health concerns are often not identified until late into clinical development of drugs, which can place participants and patients at significant risk. For example, the United States Food and Drug Administration (FDA) labeled the xanthine oxidase inhibitor febuxostat with a"boxed" warning regarding an increased risk of cardiovascular death, and this safety risk was only identified during Phase 3b clinical trials after its approval. Thus, better preclinical assessment of drug efficacy and safety are needed to accurately evaluate candidate drug risk earlier in discovery and development. This study explored whether an in vitro vascular model incorporating human vascular cells and hemodynamics could be used to differentiate the potential cardiovascular risk associated with molecules that have similar on-target mechanisms of action. We compared the transcriptomic responses induced by febuxostat and other xanthine oxidase inhibitors to a database of 111 different compounds profiled in the human vascular model. Of the 111 compounds in the database, 107 are clinical-stage and 33 are FDA-labelled for increased cardiovascular risk. Febuxostat induces pathway-level regulation that has high similarity to the set of drugs FDA-labelled for increased cardiovascular risk. These results were replicated with a febuxostat analog, but not another structurally distinct xanthine oxidase inhibitor that does not confer cardiovascular risk. Together, these data suggest that the FDA warning for febuxostat stems from the chemical structure of the medication itself, rather than the target, xanthine oxidase. Importantly, these data indicate that cardiovascular risk can be evaluated in this in vitro human vascular model, which may facilitate understanding the drug candidate safety profile earlier in discovery and development.

Pegloticase co-administered with high MW polyethylene glycol effectively reduces PEG-immunogenicity and restores prolonged circulation in mouse.

The interactions between polymers and the immune system remains poorly controlled. In some instances, the immune system can produce antibodies specific to polymer constituents. Indeed, roughly half of pegloticase patients without immunomodulation develop high titers of anti-PEG antibodies (APA) to the PEG polymers on pegloticase, which then quickly clear the drug from circulation and render the gout treatment ineffective. Here, using pegloticase as a model drug, we show that addition of high molecular weight (MW) free (unconjugated) PEG to pegloticase allows us to control the immunogenicity and mitigates APA induction in mice. Compared to pegloticase mixed with saline, mice repeatedly dosed with pegloticase containing different MW or amount of free PEG possessed 4- to 12- fold lower anti-PEG IgG, and 6- to 10- fold lower anti-PEG IgM, after 3 rounds of pegloticase dosed every 2 weeks. The markedly reduced APA levels, together with competitive inhibition by free PEG, restored the prolonged circulation of pegloticase to levels observed in APA-naïve animals. In contrast, mice with pegloticase-induced APA eliminated nearly all pegloticase from the circulation within just four hours post-injection. These results support the growing literature demonstrating free PEG may effectively suppress drug-induced APA, which in turn may offer sustained therapeutic benefits without requiring broad immunomodulation. We also showed free PEG effectively blocked the PEGylated protein from binding with cells expressing PEG-specific B cell receptors. It provides a template of how we may be able to tune the interactions and immunogenicity of other polymer-modified therapeutics. STATEMENT OF SIGNIFICANCE: A major challenge with engineering materials for drug delivery is their interactions with the immune system. For instance, our body can produce high levels of anti-PEG antibodies (APA). Unfortunately, the field currently lack tools to limit immunostimulation or overcome pre-existing anti-PEG antibodies, without using broad immunosuppression. Here, we showed that simply introducing free PEG into a clinical formulation of PEG-uricase can effectively limit induction of anti-PEG antibodies, and restore their prolonged circulation upon repeated dosing. Our work offers a readily translatable method to safely and effectively restore the use PEG-drugs in patients with PEG-immunity, and provides a template to use unconjugated polymers with low immunogenicity to regulate interactions with the immune system for other polymer-modified therapeutics.

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.

OBJECTIVE: To assess 12-month safety and efficacy of pegloticase + methotrexate (MTX) versus pegloticase + placebo (PBO) cotherapy in a PBO-controlled, double-blind trial (A randomized, double-blind, placebo-controlled, multicenter, efficacy and safety study of methotrexate to increase response rates in patients with uncontrolled gout receiving pegloticase [MIRROR RCT]). METHODS: Patients with uncontrolled gout (serum urate level [SU] ≥7 mg/dl, oral urate-lowering therapy failure or intolerance, and presence of one or more gout symptoms [one or more tophi, two or more flares in 12 months, gouty arthropathy]) were randomized 2:1 to receive pegloticase (8-mg infusion every 2 weeks) with blinded MTX (oral 15 mg/week) or PBO for 52 weeks. Efficacy end points included proportion of responders (SU level <6 mg/dl for ≥80% of examined month) in the intent-to-treat population (ITT) (all randomized patients) during month 6 (primary end point), month 9, and month 12; proportion with resolution of one or more tophi (ITT); mean SU reduction (ITT); and time to SU-monitoring pegloticase discontinuation. Safety was evaluated via adverse event reporting and laboratory values. RESULTS: Month 12 response rate was significantly higher in patients cotreated with MTX (60.0% [60 of 100] vs. 30.8% [16 of 52]; difference: 29.1% [95% confidence interval (CI): 13.2%-44.9%], P = 0.0003), with fewer SU discontinuations (22.9% [22 of 96] vs. 63.3% [31 of 49]). Complete resolution of one or more tophi occurred in 53.8% (28 of 52) versus 31.0% (9 of 29) of MTX versus PBO patients at week 52 (difference: 22.8% [95% CI: 1.2%-44.4%], P = 0.048), more than at week 24 (34.6% [18 of 52] vs. 13.8% [4 of 29]). Consistent with observations through month 6, pharmacokinetic and immunogenicity findings showed increased exposure and lower immunogenicity of pegloticase when administered with MTX, with an otherwise similar safety profile. No infusion reactions occurred after 24 weeks. CONCLUSION: Twelve-month MIRROR RCT data further support MTX cotherapy with pegloticase. Tophi resolution continued to increase through week 52, suggesting continued therapeutic benefit beyond month 6 for a favorable treatment effect.

Comparison Between Early-Onset and Common Gout: A Systematic Literature Review.

INTRODUCTION: Gout is an inflammatory, metabolic disease associated with a high comorbidity burden including cardiovascular disease, hypertension, type 2 diabetes, hyperlipidemia, renal disease, and metabolic syndrome. Approximately 9.2 million Americans have gout, making prognosis and treatment outcome predictors highly important. About 600,000 Americans have early-onset gout (EOG), generally defined as first gout attack at ≤ 40 years of age. However, data on EOG clinical features, comorbidity profile, and treatment response are sparse; this systematic literature review provides insight. METHODS: PubMed and American College of Rheumatology (ACR)/European Alliance of the Associations for Rheumatology (EULAR) abstract archives were searched for early-onset gout, "early onset gout," and ("gout" AND "age of onset"). Duplicate, foreign language, single case report, older (before 2016), and irrelevant/data insufficient publications were excluded. The age of diagnosis categorized patients as having common gout (CG, generally > 40 years) or EOG (generally ≤ 40 years). Applicable publications were extensively reviewed/discussed among authors for inclusion/exclusion consensus. RESULTS: A total of 283 publications were identified, with 46 (35 articles, 10 abstracts) reviewed and 17 (12 articles, 5 abstracts) ultimately included. Eleven reported clinical characteristics, with 6 EOG-CG retrospective/cross-sectional comparisons. Gout diagnosis preceded cardiometabolic comorbidity and renal comorbidities were less prevalent in EOG than CG patients. EOG patients had more severe disease (more gout flares, polyarticular disease), higher pre-therapy serum urate (SU), and worse oral urate-lowering therapy response. Genetics-focused publications reported higher incidences of dysfunctional urate transporter mutations in EOG patients. CONCLUSIONS: This review suggests that EOG is more recalcitrant to urate-lowering therapy, is associated with urate transporter defects, and carries heavy disease burden. Therefore, early rheumatology referral and urate-lowering in a treat-to-target fashion may benefit EOG patients. Interestingly, EOG patients had fewer cardiometabolic comorbidities at diagnosis than CG patients, presenting a potential "window of opportunity" to attenuate cardiometabolic comorbidity development with SU control. Preventing gout-related suffering and health burden is particularly important in these young EOG patients who will live with gout and its sequelae for decades.

Gout, an inflammatory arthritis caused by high urate levels in the blood (SU), is associated with medical issues, including heart disease, high blood pressure, type 2 diabetes, and kidney disease. Millions of Americans have gout, with some having early-onset gout (EOG), generally the first gout attack at or before 40 years of age. Little information on EOG has been published; this literature review provides insight. More recent articles and major rheumatology meeting presentations (2016 to August 2022) on EOG were reviewed. Publications that were duplicates, not in English, on a single patient, or were not relevant/did contain enough information were excluded. The age at gout diagnosis determined if patients had common gout (CG) or EOG. Of the 283 publications identified, 17 were included in this review. Gout-associated medical issues (heart, metabolic, and kidney-related) were less common in EOG than CG patients and occurred after gout diagnosis in EOG patients. Compared to CG patients, EOG patients more often had severe gout (more gout attacks and affected joints), higher SU, and worse response to oral SU-lowering medications. Genetics-focused publications showed that mutations affecting how urate is removed from the body are more common in EOG patients. Overall, the literature suggests that EOG may be difficult to treat, has a genetic component, and has a heavy disease burden. Therefore, early rheumatology referral and gout management may benefit EOG patients due to a potential "window of opportunity" where proper SU control may prevent gout-related suffering and health burden in young EOG patients who will live with gout and its consequences for decades.

Gout Prevalence, Practice Patterns, and Associations with Outcomes in North American Dialysis Patients.

INTRODUCTION: Gout occurs frequently in patients with kidney disease and can lead to a significant burden on quality of life. Gout prevalence, and its association with outcomes in hemodialysis (HD) and peritoneal dialysis (PD) populations located in North America, is unknown. METHODS: We used data from North America cohorts of 70,297 HD patients (DOPPS, 2012-2020) and 5117 PD patients (PDOPPS, 2014-2020). We used three definitions of gout for this analysis: (1) having an active prescription for colchicine or febuxostat; (2) having an active prescription for colchicine, febuxostat, or allopurinol; or (3) having an active prescription for colchicine, febuxostat, or allopurinol, or prior diagnosis of gout. Propensity score matching was used to compare outcomes among patients with versus without gout. Outcomes included erythropoietin resistance index (ERI=erythropoiesis stimulating agent dose per week/(hemoglobin×weight)), all-cause mortality, hospitalization, and patient-reported outcomes (PROs). RESULTS: The gout prevalence was 13% in HD and 21% in PD; it was highest among incident dialysis patients. Description of previous history of gout was rare, and identification of gout defined by colchicine (2%-3%) or febuxostat (1%) prescription was less frequent than by allopurinol (9%-12%). Both HD and PD patients with gout (versus no gout) were older, were more likely male, had higher body mass index, and had higher prevalence of cardiovascular comorbidities. About half of patients with a gout history were prescribed urate-lowering therapy. After propensity score matching, mean ERI was 3%-6% higher for gout versus non-gout patients while there was minimal evidence of association with clinical outcomes or PROs. CONCLUSION: In a large cohort of PD and HD patients in North America, we found that gout occurs frequently and is likely under-reported. Gout was not associated with adverse clinical or PROs.

A Randomized, Placebo-Controlled Study of Methotrexate to Increase Response Rates in Patients with Uncontrolled Gout Receiving Pegloticase: Primary Efficacy and Safety Findings.

OBJECTIVE: To assess efficacy, safety, pharmacokinetics, and immunogenicity of pegloticase plus methotrexate (MTX) versus pegloticase plus placebo cotreatment for uncontrolled gout in a randomized, placebo-controlled, double-blind trial. METHODS: This study included adults with uncontrolled gout, defined as serum urate ≥7 mg/dl, oral urate-lowering therapy failure or intolerance, and presence of ongoing gout symptoms including ≥1 tophus, ≥2 flares in the past 12 months, or gouty arthritis. Key exclusion criteria included MTX contraindication, current immunosuppressant use, G6PDH deficiency, and estimated glomerular filtration rate <40 ml/minute/1.73 m2 . Patients were randomized 2:1 to 52 weeks of pegloticase (8 mg biweekly) with either oral MTX (15 mg/week) or placebo. The primary end point was the proportion of treatment responders during month 6 (defined as serum urate <6 mg/dl for ≥80% of visits during weeks 20-24). Efficacy was evaluated in all randomized patients (intent-to-treat population), and safety was evaluated in all patients receiving ≥1 blinded MTX or placebo dose. RESULTS: A total of 152 patients were randomized, 100 to receive pegloticase plus MTX, 52 to receive pegloticase plus placebo. Significantly higher treatment response occurred during month 6 in the MTX group versus the placebo group (71.0% [71 of 100 patients] versus 38.5% [20 of 52 patients], respectively; between-group difference 32.3% [95% confidence interval 16.3%, 48.3%]) (P < 0.0001 for between-group difference). During the first 6 months of pegloticase plus MTX or pegloticase plus placebo treatment, 78 (81.3%) of 96 MTX patients versus 47 (95.9%) of 49 placebo patients experienced ≥1 adverse event (AE), most commonly gout flare (64 [66.7%] of 96 MTX patients and 34 [69.4%] of 49 placebo patients). Reports of AEs and serious AEs were comparable between groups, but the infusion reaction rate was considerably lower with MTX cotherapy (4.2% [4 of 96 MTX patients, including 1 patient who had anaphylaxis]) than with placebo cotherapy (30.6% [15 of 49 placebo patients, 0 who had anaphylaxis]) (P < 0.001). Antidrug antibody positivity was also lower in the MTX group. CONCLUSION: MTX cotherapy markedly increased pegloticase response rate over placebo (71.0% versus 38.5%) during month 6 with no new safety signals. These findings verify higher treatment response rate, lower infusion reaction incidence, and lower immunogenicity when pegloticase is coadministered with MTX.

Improved joint and patient-reported health assessments with pegloticase plus methotrexate co-therapy in patients with uncontrolled gout: 12-month exploratory outcomes of the MIRROR open-label trial.

BACKGROUND: Uncontrolled/refractory gout patients are recalcitrant/intolerant to oral urate-lowering therapies (ULTs), experiencing frequent gout flares, functionally limiting tophi, and low quality of life. Pegloticase lowers urate, but anti-pegloticase antibodies limit urate-lowering efficacy and increase infusion reaction (IR) risk. Immunomodulator + pegloticase co-administration may improve treatment response rates, with 79% of MIRROR open-label trial (MIRROR-OL, pegloticase + oral methotrexate) participants meeting 6-month response criteria. Exploratory outcomes from MIRROR-OL are described here. METHODS: Adults with uncontrolled gout (serum urate [SU] ≥ 6 mg/dL and ULT-intolerance/recalcitrance or functionally limiting tophi) were included. Oral methotrexate (15 mg/week) was administered 4 weeks before and during pegloticase treatment (biweekly 8 mg infusion, ≤ 52 weeks). Exploratory outcomes included change from baseline (CFB) in number of affected joints, Health Assessment Questionnaires (HAQs), and Gout Global Assessments. RESULTS: Fourteen patients received ≥ 1 pegloticase infusion, with 13 included in 52-week analyses (1 enrolled before treatment-extension amendment, exited at 24 weeks). Three patients prematurely exited due to SU rise; 10 completed 52-week evaluations (8 completed 52 weeks of co-therapy, 2 completed 24 weeks [met treatment goals]). At 52 weeks, SU averaged 1.1 ± 2.5 mg/dL, with improvements in HAQ pain and health (CFB: - 33.6 and - 0.7, respectively), Patient and Physician Global Assessments (CFB: - 4.6 and - 5.7, respectively), and joint involvement (CFB: - 5.6, - 8.4, - 6.0 tender, swollen, tophi-affected joints, respectively). Two patients underwent dual-energy computed tomography, showing concomitant monosodium urate volume reductions. All patients had ≥ 1 AE, with 92.9% experiencing acute flare. One mild IR ("cough") occurred and no new safety signals were identified. CONCLUSION: Pegloticase + methotrexate co-therapy resulted in sustained SU-lowering with meaningful improvements in clinical measures, urate burden, and patient-reported outcomes. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03635957).

Community Practice Experiences with a Variety of Immunomodulatory Agents Co-Administered with Pegloticase for the Treatment of Uncontrolled Gout.

OBJECTIVE: Patients with uncontrolled/refractory gout have heavy disease burden, but few treatment options. Pegloticase lowers serum urate (SU), but anti-drug antibodies can limit treatment efficacy. Evidence supports immunomodulator-pegloticase co-administration to increase sustained urate-lowering rates, but published cases are limited. This study investigated experience with pegloticase-immunomodulation co-therapy at two community rheumatology practices. METHODS: Patients initiating pegloticase with immunomodulation in 2017 or later were included. Patient/treatment characteristics and proportion of responders (≥ 12 pegloticase infusions, SU < 6 mg/dl at infusion-12) were examined. Patients on therapy at data collection with < 12 infusions were excluded from response analyses. eGFR before and after therapy was examined. RESULTS: Thirty-four patients (79% male, 62.4 ± 16.3 years) with uncontrolled gout (SU = 9.1 ± 2.0 mg/dl, 91% tophaceous) were included. Most-reported comorbidities were hypertension (76%), obesity (71%), osteoarthritis (68%), and CKD (47%). Pre-therapy eGFR was 65.4 ± 25.2 ml/min/1.73 m2 (41% eGFR < 60 ml/min/1.73 m2). All patients initiated immunomodulation before (5.3 ± 3.0 weeks, n = 32) or at (n = 2) first pegloticase infusion. Subcutaneous methotrexate (15.4 ± 4.9 mg/week, n = 20), oral methotrexate (15.3 ± 3.6 mg/week, n = 9), mycophenolate mofetil (1000 mg/day, n = 3), and azathioprine (100 mg/day, n = 2) were administered. Patients received 14.6 ± 7.1 infusions over 28.5 ± 14.9 weeks. Overall response rate was 89%, ranging among immunomodulators (subcutaneous methotrexate: 93%, oral methotrexate: 89%, mycophenolate mofetil: 100%, azathioprine: 50%). On average, eGFR increased during therapy (+ 10.3 ± 16.9 ml/min/1.73 m2), with CKD stability/improvement in 85%. Nineteen patients (56%) experienced gout flares. No infusion reactions or infections were noted. No new safety concerns were identified. CONCLUSIONS: These real-world findings provide further support for increased pegloticase response rates when co-treatment with immunomodulating therapy is used.

Patients with gout that does not respond to oral urate-lowering therapies have heavy disease burden and few treatment options. Pegloticase lowers serum urate levels (SU) and resolves tophi, but anti-drug antibodies can limit urate-lowering efficacy duration. Evidence increasingly supports co-administering an immunomodulator with pegloticase to increase the proportion of patients with sustained urate-lowering response. However, there are few published cases from real-world clinical practice. This study examined treatment with pegloticase + immunomodulation at two community rheumatology practices. Patients who began treatment with pegloticase and an immunomodulator in 2017 or later were included. The proportion of patients with sustained urate-lowering response (≥ 12 infusions received, SU < 6 mg/dl at infusion 12) was investigated. Renal function before and after therapy was also examined. Thirty-four patients were included. Before treatment, SU averaged 9.1 mg/dl and most-reported comorbidities were hypertension (76%), obesity (71%), osteoarthritis (68%), and chronic kidney disease (47%). All patients began using an immunomodulator before or at first pegloticase infusion (subcutaneous methotrexate [20 patients], oral methotrexate [9 patients], mycophenolate mofetil [3 patients], and azathioprine [2 patients]). On average, 14.6 infusions were administered over 28.5 weeks and overall response rate was 89%. Response rate varied among different immunomodulators: subcutaneous methotrexate: 93%, oral methotrexate: 89%, mycophenolate mofetil: 100%, azathioprine: 50%. On average, kidney function improved, with chronic kidney disease stage stability/improvement in 85% of patients. Nineteen patients (56%) experienced gout flares. No infusion reactions or infections were noted and no new safety concerns were identified. These real-world findings provide further support for administering immunomodulation as co-therapy to pegloticase.

A multicentre, efficacy and safety study of methotrexate to increase response rates in patients with uncontrolled gout receiving pegloticase (MIRROR): 12-month efficacy, safety, immunogenicity, and pharmacokinetic findings during long-term extension of an open-label study.

BACKGROUND: Publications suggest immunomodulation co-therapy improves responder rates in uncontrolled/refractory gout patients undergoing pegloticase treatment. The MIRROR open-label trial showed a 6-month pegloticase + methotrexate co-therapy responder rate of 79%, compared to an established 42% pegloticase monotherapy responder rate. Longer-term efficacy/safety data are presented here. METHODS: Uncontrolled gout patients (serum urate [SU] ≥ 6 mg/dL and SU ≥ 6 mg/dL despite urate-lowering therapy [ULT], ULT intolerance, or functionally-limiting tophi) were included. Patients with immunocompromised status, G6PD deficiency, severe kidney disease, or methotrexate contraindication were excluded. Oral methotrexate (15 mg/week) and folic acid (1 mg/day) were administered 4 weeks before and during pegloticase therapy. Twelve-month responder rate (SU < 6 mg/dL for ≥ 80% during month 12), 52-week change from baseline in SU, and extended safety were examined. Efficacy analyses were performed for patients receiving ≥ 1 pegloticase infusion. Pharmacokinetics (PK)/anti-drug antibodies (ADAs) were examined and related to efficacy/safety findings. RESULTS: Fourteen patients were included (all male, 49.3 ± 8.7 years, 13.8 ± 7.4-year gout history, pre-therapy SU 9.2 ± 2.5 mg/dL). Three patients were non-responders and discontinued study treatment before 24 weeks, one patient exited the study per protocol at 24 weeks (enrolled prior to treatment extension amendment), and 10 remained in the study through week 52. Of the 10, 8 completed 52 weeks of pegloticase + methotrexate and were 12-month responders. The remaining two discontinued pegloticase + methotrexate at week 24 (met treatment goals) and stayed in the study under observation (allopurinol prescribed at physicians' discretion); one remained a responder at 12 months. At 52 weeks, change from baseline in SU was - 8.2 ± 4.1 mg/dL (SU 1.1 ± 2.4 mg/dL, n = 10). Gout flares were common early in treatment but progressively decreased while on therapy (weeks 1-12, 13/14 [92.9%]; weeks 36-52, 2/8 [25.0%]). One patient recovered from sepsis (serious AE). Two non-responders developed high ADA titers; fewer patients had trough concentrations (Cmin) below the quantitation limit (BQL), and the median Cmin was higher (1.03 µg/mL vs. BQL) than pegloticase monotherapy trials. CONCLUSIONS: Pegloticase + methotrexate co-therapy was well-tolerated over 12 months, with sustained SU lowering, progressive gout flare reduction, and no new safety concerns. Antibody/PK findings suggest methotrexate attenuates ADA formation, coincident with higher treatment response rates. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03635957 . Registered on 17 August 2018.

Enhancing the Response Rate to Recombinant Uricases in Patients with Gout.

Refractory, or uncontrolled, gout is a chronic, progressive, inflammatory arthropathy resulting from continued urate deposition after failed attempts to lower serum uric acid below the therapeutic threshold with oral urate-lowering therapies such as allopurinol and febuxostat. Recombinant uricase is increasingly being used to treat refractory gout; however, the immunogenicity of uricase-based therapies has limited the use of these biologic therapies. Antidrug antibodies against biologic therapies, including uricase and PEGylated uricase, can lead to loss of urate-lowering response, increased risk of infusion reactions, and subsequent treatment failure. However, co-therapy with an immunomodulator can attenuate antidrug antibody development, potentially increasing the likelihood of sustained urate lowering, therapy course completion, and successful treatment outcomes. This review summarizes evidence surrounding the use of immunomodulation as co-therapy with recombinant uricases.

Effect of Leflunomide on Pegloticase Response Rate in Patients with Uncontrolled Gout: A Retrospective Study.

BACKGROUND: Pegloticase, a PEGylated uricase for uncontrolled gout, rapidly lowers serum urate (SU). Not all patients complete a full-therapy course because anti-pegloticase antibodies can develop, causing efficacy loss and infusion reactions. The literature and clinical trial data indicate that methotrexate co-administration markedly improves pegloticase response rates from the established monotherapy response rate of 42%. Unfortunately, methotrexate use is restricted by kidney disease, which is often present in uncontrolled gout patients. Leflunomide is less restricted in patients with renal dysfunction. This study examined the treatment response rate of pegloticase co-administered with leflunomide. METHODS: Patients co-treated with pegloticase (8 mg biweekly infusion) and oral leflunomide (20 mg/day) were included. Patient/treatment characteristics and safety parameters (adverse events [AEs], laboratory parameters) were examined. Pre-infusion prophylaxis was administered (day of infusion: IV solumedrol, night before and morning of infusion: oral fexofenadine or diphenhydramine). Patients were considered treatment responders if ≥ 12 pegloticase infusions were administered and pre-infusion SU < 6 mg/dl at infusion-12. RESULTS: Ten patients (five male, 72.7 ± 12.5 years) were included. The most common comorbidities were chronic kidney disease (90%), hypertension (70%), diabetes mellitus (60%), obesity (60%), and congestive heart failure (50%). Baseline SU was 7.1 ± 2.4 mg/dl and nine patients (90%) had subcutaneous tophi noted. Seven patients (70%) met responder criteria, receiving 26.6 ± 14.0 infusions (range 13-55) with a pre-infusion-12 SU of 0.9 ± 1.5 mg/dl. The three non-responders received < 12 infusions because of unrelated AEs or loss of follow-up. Three patients (30%) experienced AEs. One had unrelated cardiac disease worsening and three gout flares, one had a pre-infusion solumedrol reaction (wooziness/loss of consciousness), and one had two mild, transient increases in liver enzymes. CONCLUSIONS: This study supports leflunomide as co-therapy to pegloticase in uncontrolled gout patients. Heterogeneity and high comorbidity burden in uncontrolled gout patients makes having a variety of immunomodulators options important.

Comparison of Rates of Lower Extremity Amputation in Patients With and Without Gout in the US Department of Veterans Affairs Health System.

Importance: Cardiometabolic and other risk factors could render patients with gout more likely to undergo lower extremity amputation (LEA). Objective: To examine the rate of and factors associated with LEA in patients with gout. Design, Setting, and Participants: In this matched cohort study using national administrative data, multivariable Cox proportional hazards regression models were used to examine the associations of gout with LEA. In analyses limited to patients with gout, attributes of serum urate control and treatment with urate-lowering therapy were examined as factors associated with LEA. This study included patients who used US Department of Veterans Affairs services from January 1, 2000, to July 31, 2015. Patients with gout were identified using diagnostic codes and matched with up to 10 controls by age, sex, and year of benefit enrollment. Data analysis was performed from January 26, 2021, to September 3, 2021. Exposures: Gout classification served as the primary independent variable of interest. In analyses limited to patients with gout, factors associated with serum urate control and urate-lowering therapy were examined. Main Outcomes and Measures: Overall LEA, as well as toe, transmetatarsal, below-the-knee, and above-the-knee amputation. Results: This cohort study included 5 924 918 patients, 556 521 with gout (mean [SD] age, 67 [12] years; 550 963 (99.0%) male; 88 853 [16.0%] Black non-Hispanic; 16 981 [4.3%] Hispanic/Latinx; 345 818 [62.1%] White non-Hispanic; 80 929 [14.5%] with race and ethnicity data missing; and 23 940 [4.3%] classified as other) and 5 368 397 without gout (mean [SD] age, 67 [12] years; 5 314 344 [99.0%] male; 558 464 [10.4%] Black non-Hispanic; 204 291 [3.0%] Hispanic/Latinx; 3 188 504 [59.4%] White non-Hispanic; 1 257 739 [23.4%)] with race and ethnicity data missing; and 159 399 [3.0%] classified as other). Compared with patients without gout, patients with gout were more likely to undergo amputation, an increased rate that remained after adjustment (adjusted hazard ratio, 1.20; 95% CI, 1.16-1.24) and was highest for below-the-knee amputation (adjusted hazard ratio, 1.59; 95% CI, 1.39-1.81). In those with gout, poor serum urate control (mean >7 mg/dL during the preceding year) was associated with a 25% to 37% increase in the rate of amputation. In contrast, treatment with urate-lowering therapy was not associated with the LEA rate. Conclusions and Relevance: In this matched cohort study, patients with gout were more likely to undergo LEA. This increase was independent of other comorbidities that have been associated with amputation, including diabetes and peripheral vascular disease. Serum urate control was independently associated with the LEA rate, suggesting the possibility that lower extremity amputation may be preventable in some patients.

High MW polyethylene glycol prolongs circulation of pegloticase in mice with anti-PEG antibodies.

Pegloticase is an enzyme used to reduce serum uric acid levels in patients with chronic, treatment-refractory gout. Clinically, about 40% of patients develop high titers of anti-PEG antibodies (APA) after initial treatment, which in turn quickly eliminate subsequent doses of pegloticase from the systemic circulation and render the treatment ineffective. We previously found that pre-infusion with high MW free PEG (40 kDa) can serve as a decoy to saturate circulating APA, preventing binding to a subsequently administered dose of PEG-liposomes and restoring their prolonged circulation in mice, without any detectible toxicity. Here, we investigated the use of 40 kDa free PEG to restore the circulation of radio-labeled pegloticase in mice using longitudinal Positron Emission Tomography (PET) imaging over 4 days. Mice injected with pegloticase developed appreciable APA titers by Day 9, which further increased through Day 14. Compared to naïve mice, mice with pegloticase-induced APA rapidly cleared 89Zr-labeled pegloticase, with ~75% lower pegloticase concentrations in the circulation at four hours after treatment. The 96-h AUC in APA+ mice was less than 30% of the AUC in naïve mice. In contrast, pre-infusion of free PEG into PEG-sensitized mice restored the AUC of pegloticase to ~80% of that seen in naïve mice, resulting in a similar biodistribution to pegloticase in naïve mice over time. These results suggest that pre-infusion of free PEG may be a promising strategy to enable the safe and efficacious use of pegloticase and other PEGylated drugs in patients that have previously failed therapy due to induced APA.