Beyond Medical Treatment: Surgical Treatment of Gout.

PURPOSE OF REVIEW: Medical treatment with urate-lowering therapy (ULT) is efficacious. A recent publication suggested that surgery in gout is more prevalent than previously reported. This revelation led us to review what is known about surgical treatment of gout. RECENT FINDINGS: The Google Scholar database (January 1, 2014-January 1, 2020) found 104 publications with a total of 169 gout patients, with an average disease duration of 6.7 years. Most (68%) were not on ULT. The mean pre-operative serum urate levels were 9.19 mg/dL. One hundred thirteen patients underwent tophi excision, while in 33 patients, tophi were found during surgery. The majority of the surgeries were performed in Asia and Europe. Most patients were not taking ULT at the time of surgery, leading to hyperuricemia. This can result in tophi reformation post-surgery. The role of surgery should be a last-line treatment and until recently has only been demonstrated through case reports.

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.

Projected Health and Economic Burden of Comorbid Gout and Chronic Kidney Disease in a Virtual US Population: A Microsimulation Study.

INTRODUCTION: Gout, a common comorbidity of chronic kidney disease (CKD), is associated with high morbidity and healthcare utilization. However, a large proportion of gout remains undermanaged or untreated which may lead to worse patient outcomes and greater healthcare costs. This study estimates the present and future health and economic burden of controlled and uncontrolled gout in a virtual United States (US) CKD population. METHODS: A validated microsimulation model was used to project the burden of gout in patients with CKD in the USA through 2035. Databases were utilized to build a virtual CKD population of "individuals" with controlled or uncontrolled gout. Modelling assumptions were made on the basis of the literature, which was sparse in some cases. Health and economic outcomes with the current care (baseline) scenario were evaluated, along with potential benefits of urate-lowering intervention scenarios. RESULTS: The prevalence of comorbid gout and CKD in the USA was projected to increase by 29%, from 7.9 million in 2023 to 9.6 million in 2035 in the baseline scenario. Gout flares, tophi, and comorbidity development were also projected to increase markedly through 2035, with the economic burden of gout in the CKD population subsequently increasing from $38.9 billion in 2023 to $47.3 billion in 2035. An increased use of oral urate-lowering therapies in undermanaged patients, and pegloticase use in patients refractory to oral urate-lowering therapies were also project to result in 744,000 and 353,000 fewer uncontrolled gout cases, respectively, by 2035. Marked reductions in complications and costs ensued. CONCLUSIONS: This study projected a substantial increase in comorbid gout and CKD. However, improved use of urate-lowering interventions could mitigate this growth and reduce the health and economic burdens of gout.

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 2weeks)+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 Weeks 14, 24, and 52. Patients with paired baseline-Week 52 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 52weeks (5 MTX), 42weeks (1 PBO), and 6weeks (1 MTX, 1 PBO) of pegloticase therapy. Patients who prematurely discontinued pegloticase maintained SU<6mg/dL on allopurinol (n=2)/febuxostat (n=1). At Week 52, 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 during pegloticase therapy was observed with concomitant bone remodeling within 1year. Following pegloticase discontinuation, VMSU reduction slowed or stopped even when SU was maintained<6mg/dL with oral ULT. CLINICAL TRIAL REGISTRATION: NCT03994731.

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.

Skeletal muscle mass and quality in gout patients versus non-gout controls: A computed tomography imaging study.

OBJECTIVE: Patients with gout are at elevated risk of multiple vascular and metabolic comorbidities. Whether they are also at risk of sarcopenia, which is known to affect patients with other rheumatic diseases, has not been previously assessed. We examined whether patients with gout have decreased lumbar muscle quality and quantity, indicating an association between gout and sarcopenia. METHODS: Fifty gout subjects and 25 controls, ages 45-80, underwent computed tomography imaging of the lumbosacral spine. We measured muscle quantity (skeletal muscle area [SMA] and index [SMI]) and quality (skeletal muscle radiation attenuation [SMRA] and intermuscular adipose tissue [IMAT] area and index [IMATI]) of the psoas and erector spinae muscles at the L3 level. RESULTS: Seventy subjects (45 gout and 25 controls) were included in the analysis. Gout subjects had higher BMI, more kidney disease and hypertension, lower exercise frequency, and higher mean serum urate and creatinine vs. controls. Lumbar SMRA was significantly lower in gout subjects vs. controls, indicating reduced muscle quality. Lumbar IMAT area was significantly higher in gout subjects vs. controls, as was lumbar IMATI, indicating increased muscle adiposity. These differences persisted after adjusting for potential confounders. In contrast, there was no significant difference between gout and control groups in lumbar SMA or lumbar SMI, suggesting that muscle quantity may not be routinely affected by the diagnosis of gout. CONCLUSIONS: Gout patients exhibit decreased lumbar muscle quality compared with controls, consistent with an association between gout and sarcopenia.

Real-World Effectiveness of Pegloticase Associated With Use of Concomitant Immunomodulatory Therapy.

OBJECTIVE: The objective of this study was to ascertain pegloticase persistence and adverse events associated with concomitant immunomodulatory drug treatment in patients with gout. METHODS: We conducted a retrospective analysis of patients with gout using the American College of Rheumatology's Rheumatology Informatics System for Effectiveness registry from January 2016 through June 2020. The first pegloticase infusion defined the index date. Based on concomitant immunomodulatory drug treatment, we identified three exposure groups: (1) immunomodulatory drug initiators (patients initiating an immunomodulatory prescription ±60 days from the index date), (2) prevalent immunomodulatory drug recipients (patients receiving their first immunomodulatory drug prescription >60 days before the index date with at least one prescription within ±60 days of the index date), and (3) immunomodulatory nonrecipients (patients receiving pegloticase without concomitant immunomodulatory drugs). We calculated the proportion of patients who achieved serum urate levels ≤6 mg/dL and who had laboratory abnormalities (white blood cell count <3.4 x 109/L, platelet count <135,000, hematocrit level <30%, alanine aminotransferase or aspartate aminotransferase level ≥1.5 times the upper limit normal value) within 180 days after the index date. Cox regression analyzed time to pegloticase discontinuation, controlling for potential confounders. RESULTS: We identified 700 pegloticase recipients (91 immunomodulatory drug initiators, 33 prevalent immunomodulatory drug recipients, and 576 nonrecipients), with a median follow-up of 14 months. Immunomodulatory drug recipients were less likely to discontinue pegloticase. The adjusted hazard ratios of pegloticase discontinuation associated with concomitant immunomodulatory drug initiation and prevalent treatment were 0.52 (95% confidence interval [CI] 0.37-0.75) and 0.69 (95% CI 0.42-1.16), respectively. Laboratory abnormalities were uncommon (<5%) and were not higher in concomitant immunomodulatory drug treatment. CONCLUSION: Consistent with clinical trials, results from this large observational registry suggest that concomitant immunomodulatory drug treatment improves pegloticase persistence.

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.

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.

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.

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.

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.

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.

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.

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.

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).