The COMPARE head-to-head, randomized controlled trial of SEL-212 (pegadricase plus rapamycin-containing nanoparticle, ImmTOR™) versus pegloticase for refractory gout.

OBJECTIVES: Serum urate (SU) lowering with PEGylated uricases in gout can reduce flares and tophi. However, treatment-emergent anti-drug antibodies adversely affect safety and efficacy and the currently approved PEGylated uricase pegloticase requires twice-monthly infusions. Investigational SEL-212 therapy aims to promote uricase-specific tolerance via monthly sequential infusions of a proprietary rapamycin-containing nanoparticle (ImmTOR) and pegadricase. METHODS: COMPARE was a randomized, phase 2, open-label trial of SEL-212 vs pegloticase in adults with refractory gout. SEL-212 [ImmTOR (0.15 mg/kg) and pegadricase (0.2 mg/kg)] was infused monthly or pegloticase (8 mg) twice monthly for 6 months. The primary endpoint was the proportion of participants with SU <6 mg/dl for ≥80% of the time during 3 and 6 months. Secondary outcomes were mean SU, gout flares, number of tender and/or swollen joints and safety. RESULTS: During months 3 and 6 combined, numerically more participants achieved and maintained a SU <6 mg/dl for ≥80% of the time with SEL-212 vs pegloticase (53.0% vs 46.0%, P = 0.181). The percentage reductions in SU levels were statistically greater during months 3 and 6 with SEL-212 vs pegloticase (-73.79% and -47.96%, P = 0.0161). Reductions in gout flare incidence and number of tender and/or swollen joints were comparable between treatments. There were numerical differences between the most common treatment-related adverse events of interest with SEL-212 and pegloticase: gout flares (60.2% vs 50.6%), infections (25.3% vs 18.4%) and infusion-related reactions (15.7% vs 11.5%), respectively. Stomatitis (and related terms) was experienced by eight participants (9.6%) with SEL-212 and none with pegloticase. Stomatitis, a known event for rapamycin, was associated with ImmTOR only. CONCLUSIONS: SEL-212 efficacy and tolerability were comparable to pegloticase in refractory gout. This was associated with a substantial reduction in treatment burden with SEL-212 due to decreased infusion frequency vs pegloticase. CLINICAL TRIAL REGISTRATION: NCT03905512.

Pegloticase causes prolonged improvement in multiple disease parameters in patients with chronic refractory gout who maintain low serum urate levels.

OBJECTIVES: To assess the benefit of long-term urate-lowering with pegloticase. METHODS: The results from two, 6-month, randomised controlled trials (RCTs) and their 30-month open-label extension (OLE) were analysed. Efficacy was assessed in urate responders (patients with plasma urate <6.0 mg/dL for ≥80% of assessments around the 3- and 6-month time periods) to the approved regimen (8 mg every 2 weeks [q2w]) and responders to q4w treatment. Assessments included serum urate (sU), Patient Global Assessment (PtGA), tender and swollen joints (TJC and SJC), pain, Health Assessment Questionnaire Disability Index, bodily pain, the Arthritis-Specific Health Index, and reduction of target tophi. RESULTS: 34 responders to pegloticase in the RCTs were followed throughout the 2.5 years of the OLE. Of these, 20 received 8 mg pegloticase q2w and 14 q4w. The results for patients who received pegloticase q2w indicated significant improvements between RCT baseline and the final OLE evaluation for sU (p<0.0001), PtGA (p<0.0001), TJC (p=0.0001), and SJC (p=0.0014); 61.5%, had complete target tophus resolution. The results for patients treated monthly indicated significant improvements between RCT baseline and the final OLE evaluation for sU (p<0.001), PGA (p=0.0003), TJC (p=0.008), and SJC (p<0.0001);100% had complete target tophus resolution. CONCLUSIONS: There were significant sustained clinical benefits with long-term pegloticase treatment in patients with chronic refractory gout achieving a urate-lowering effect during the first 6 months of therapy and followed for up to 30 additional months.

Expert Opinion on Pegloticase with Concomitant Immunomodulatory Therapy in the Treatment of Uncontrolled Gout to Improve Efficacy, Safety, and Durability of Response.

PURPOSE OF REVIEW: Gout is a systemic disease from which some patients develop numerous painful tophi that adversely affect quality of life and functionality. Some patients treated with oral urate-lowering therapy are unable to maintain serum urate levels below 6 mg/dL, and these patients, thus classified as having refractory or uncontrolled gout, often require therapy with pegloticase to reduce symptoms and tophaceous burden. The objective of this expert opinion review is to summarize the available evidence supporting the use of concomitant immunomodulators with pegloticase to prevent development of anti-drug antibodies (ADAs) when treating patients with uncontrolled gout. RECENT FINDINGS: Emerging evidence suggests that adding an immunomodulator to pegloticase therapy can substantially increase response rates to double those observed in phase 3 randomized controlled trials. The combination of immunomodulation with pegloticase should be considered in routine clinical practice to improve durability of response, efficacy, and safety among patients with uncontrolled gout who otherwise have limited therapeutic options.

eConsults' Impact on Care Access and Wait Times in Rheumatology.

BACKGROUND/OBJECTIVE: A growing number of health systems have implemented eConsults to improve access to specialty advice, but few studies have described their use in rheumatology or impact on visit wait times. We evaluated the uptake of an eConsult program and its impact on wait times for in-person rheumatology visits. METHODS: In this quality improvement project, we analyzed electronic health record data from 4 intervention clinics and 4 comparison clinics, 12 months before and after implementation of an eConsult program. We compared median wait time for rheumatology appointments using a pre-post difference-in-differences analysis and quantile regression, adjusting for patient age, race, sex, clinic pair, and primary insurance payer. We also interviewed 11 primary care providers from the intervention clinics and conducted a rheumatology provider focus group (n = 4) to elucidate experiences with the program. RESULTS: Rheumatologists recommended management in primary care or referral to another specialty for 41% of eConsults, reducing initial demand for in-person visits. The median wait times dropped in the intervention and the comparison clinics (42 and 25 days, respectively). Intervention clinic median wait time dropped 17 days more than comparison clinics, and this was nonstatistically significant (p = 0.089). eConsults fit provider care tasks best for triage or initial workup for diagnosis, and less well when tests required interpretation, or when back and forth communication was needed to manage the patient's condition. CONCLUSIONS: Implementation of eConsults for rheumatology was associated with reduced wait times for rheumatology appointments and supported primary care providers in the triage and workup for a substantial portion of patients.

A Randomized, Phase II Study Evaluating the Efficacy and Safety of Anakinra in the Treatment of Gout Flares.

OBJECTIVE: To evaluate the efficacy and safety of anakinra compared to triamcinolone in the treatment of gout flares. METHODS: Patients for whom nonsteroidal antiinflammatory drugs and colchicine were not suitable treatments were enrolled in this multicenter, randomized, double-blind study with follow-up for up to 2 years. The study was designed to assess superiority of anakinra (100 or 200 mg/day for 5 days) over triamcinolone (40 mg in a single injection) for the primary end point of changed patient-assessed pain intensity in the most affected joint (scored on a visual analog scale of 0-100) from baseline to 24-72 hours. Secondary outcome measures included: safety, immunogenicity, and patient- and physician-assessed global response. RESULTS: One hundred sixty-five patients were randomized to receive anakinra (n = 110) or triamcinolone (n = 55). The median age was 55 years (range 25-83), 87% were men, the mean disease duration was 8.7 years, and the mean number of self-reported flares during the prior year was 4.5. A total of 301 flares were treated (214 with anakinra; 87 with triamcinolone). Anakinra in both doses and triamcinolone provided clinically meaningful reduction in patient-assessed pain intensity in the first and subsequent flares. For the first flare, the mean decline in pain intensity from baseline to 24-72 hours for total anakinra and triamcinolone was -41.2 and -39.4, respectively (P = 0.688). Anakinra performed better than triamcinolone for most secondary end points. There were no unexpected safety findings. The presence of antidrug antibodies was not associated with adverse events or altered pain reduction. CONCLUSION: Anakinra was not superior to triamcinolone for the primary end point, but had comparable efficacy in pain reduction and was favored for most secondary end points. Anakinra is an effective option for gout flares when conventional therapy is unsuitable.

The effect of immunomodulators on the efficacy and tolerability of pegloticase: a systematic review.

INTRODUCTION: Pegloticase is a recombinant PEGylated uricase that converts relatively insoluble urate to highly water-soluble allantoin, which is readily excreted by the kidneys. It is the first and only biologic treatment indicated for refractory or uncontrolled gout. Clinical trials showed a 6-month pegloticase responder rate of 42%, with the non-responder rate largely being attributed to the development of high-titer anti-drug antibodies (ADAs) against pegloticase. Immunomodulation attenuates ADA formation to biologics in a number of autoimmune conditions, but their use with pegloticase for uncontrolled gout is less established. This systematic review examined published cases of refractory gout patients treated with immunomodulation in combination with pegloticase. METHODS: Published cases of immunomodulation with pegloticase were identified in a PubMed search and in abstract databases of major rheumatology society meetings (2012-2020). Duplicate and review articles were excluded, as were those that did not include cases of pegloticase use with immunomodulation. Cases with off-label pegloticase administration schedules were also excluded. Pegloticase response was defined according to each study's specified standard. RESULTS: Ten publications describing 82 cases of pegloticase use in the setting of immunomodulation were identified. Overall pegloticase response rate was 82.9%. Patients co-treated with an individual immunomodulator had the following response rates: methotrexate: 87.5% (35 of 40 patients), mycophenolate mofetil: 86.4% (19 of 22 patients vs. pegloticase monotherapy [placebo]: 40% [4 of 10 patients]), azathioprine: 63.6% (7 of 11 patients), and leflunomide: 66.7% (4 of 6 patients). A single patient was co-treated with cyclosporin and was a responder. The two patients treated with more than one immunomodulator were both responders. CONCLUSION: Published reports suggest that immunomodulation co-therapy has the potential to markedly improve pegloticase responder rates in patients with uncontrolled gout.

SARILUMAB FOR RECALCITRANT CYSTOID MACULAR EDEMA IN NON-PARANEOPLASTIC AUTOIMMUNE RETINOPATHY.

PURPOSE: To demonstrate a rapid improvement of recalcitrant cystoid macular edema (CME) and perivascular leakage, in a patient with non-paraneoplastic autoimmune retinopathy and autoimmune optic neuropathy after treatment with sarilumab, a human anti-interleukin-6 (IL-6) receptor antibody. METHODS: Observational case report. RESULTS: A 29-year-old woman was diagnosed with non-paraneoplastic autoimmune retinopathy and autoimmune optic neuropathy and followed over 1.5 years. She had recalcitrant CME despite local corticosteroid and immunosuppressive therapy that included azathioprine and adalimumab. Subcutaneous sarilumab was initiated at a dose of 200 mg every 2 weeks. Cystoid macular edema significantly decreased after two injections and resolved after four injections with associated improvement in visual acuity and significant improvement in perivascular leakage on fluorescein angiography. There was a sustained visual and anatomical improvement at 6 months along with mild improvement in electroretinogram responses. The patient tolerated the medication with no side effects. CONCLUSION: Management of CME in non-paraneoplastic autoimmune retinopathy is challenging, and long-term immunosuppression is often employed with varying degrees of success. The improvement in refractory CME and perivascular leakage in this case supports the potential role of an IL-6 inhibitor to treat CME associated with non-paraneoplastic autoimmune retinopathy suggesting the role.

The biology of urate.

Urate is the end-product of the purine metabolism in humans. The dominant source of urate is endogenous purines and the remainder comes through diet. Approximately two thirds of urate is eliminated via the kidney with the rest excreted in the feces. While the transporter BCRP, encoded by ABCG2, has been found to play a role in both the gut and kidney, SLC22A12 and SLC2A9 encoding URAT1 and GLUT9, respectively, are the two transporters best characterized. Only 8-12% of the filtered urate is excreted by the kidney. Renal elimination of urate depends substantially on specific transporters, including URAT1, GLUT9 and BCRP. Studies that have assessed the biologic effects of urate have produced highly variable results. Although there is a suggestion that urate may have anti-oxidant properties in some circumstances, the majority of evidence indicates that urate is pro-inflammatory. Hyperuricemia can result in the formation of monosodium urate (MSU) crystals that may be recognized as danger signals by the immune system. This immune response results in the activation of the NLRP3 inflammasome and ultimately in the production and release of interleukin-1ß, and IL-18, that mediate both inflammation, pyroptotic cell death, and necroinflammation. It has also been demonstrated that soluble urate mediates effects on the kidney to induce hypertension and can induce long term epigenetic reprogramming in myeloid cells to induce "trained immunity." Together, these sequelae of urate are thought to mediate most of the physiological effects of hyperuricemia and gout, illustrating this biologically active molecule is more than just an "end-product" of purine metabolism.

Time to disease recurrence in noninfectious uveitis following long-acting injectable fluocinolone acetonide implant.

PURPOSE: To determine the time to disease recurrence with long-acting injectable fluocinolone acetonide implant (FAi) for noninfectious intermediate, posterior, and panuveitis. METHODS: This was a retrospective study of patients with at least 12 months of follow-up who had completed a 2-year prospective, investigational new drug study with 0.18-mg FAi. Time to uveitis recurrence or cystoid macular edema (CME) occurrence was recorded. RESULTS: Twelve eyes from 12 participants (mean age 43 years, range 25-64 years) were included. Patients were followed for a mean of 34.2 months (range, 12.0-56.9 months) after completion of the prospective trial. Five eyes (42%) did not have a documented uveitis recurrence or CME occurrence. Five eyes (42%) had a uveitis recurrence with the mean time to recurrence 36.1 months (range, 22.8-61.1 months) after FAi implantation. Two eyes (16%) had CME alone, the mean time to occurrence 36.9 months (range 36.1-42.1 months). On Kaplan-Meier analysis, the estimated probability of remaining recurrence-free 36 months after FAi implantation was 0.67 (95% confidence interval, 0.34-0.86). CONCLUSIONS: Data of study participants after completing a clinical trial suggest that the injectable FAi for noninfectious uveitis can provide control for 3 years on average. These long-term data support the use of FAi to control noninfectious uveitis.

RECONSTITUTION OF THE ELLIPSOID ZONE WITH TOCILIZUMAB IN AUTOIMMUNE RETINOPATHY.

PURPOSE: To demonstrate improvement and stabilization of retinal findings, including recalcitrant cystoid macular edema, in a patient with nonparaneoplastic autoimmune retinopathy after treatment with tocilizumab, a humanized monoclonal antibody against soluble and membrane-bound IL-6 receptor. METHODS: Observational case report. A 46-year-old woman was diagnosed with nonparaneoplastic autoimmune retinopathy and followed over 4 years on various immunosuppressive medications with worsening disease and recalcitrant cystoid macular edema. This report describes the rapid improvement and stabilization of her ocular disease once tocilizumab was initiated. RESULTS: Tocilizumab, a monoclonal antibody against the IL-6 receptor, was initiated at a dose of 8 mg/kg every 4 weeks. Cystoid macular edema was significantly decreased after just two infusions and nearly resolved after five infusions. Ellipsoid zone and outer retinal integrity also improved on optical coherence tomography. The patient tolerated the medication with limited side effects. CONCLUSION: Long-term immunosuppression is the cornerstone of treatment for nonparaneoplastic autoimmune retinopathy, although success is highly variable. We report a case treated with tocilizumab with dramatic improvement in refractory macular edema and reconstitution of the ellipsoid zone on optical coherence tomography in a patient with nonparaneoplastic autoimmune retinopathy. This case highlights the potential role of treatment with an IL-6 inhibitor in autoimmune retinopathy though further studies are needed.

Colorectal Cancer Among Gout Patients Undergoing Colonoscopy.

BACKGROUND/OBJECTIVE: The connection between gout and various cancers remains unclear. We assessed the relationship between gout and colorectal cancer in a population of veterans. METHODS: We reviewed the Computerized Patient Record System of the VA New York Harbor Health Care System to assess the 10-year occurrence of colorectal cancer in patients with gout undergoing colonoscopy, versus patients with osteoarthritis but no gout. RESULTS: Gout and osteoarthritis subjects were similar in age, ethnicity, body mass index, and smoking history. Among 581 gout and 598 osteoarthritis subjects with documented colonoscopies, the 10-year prevalence of colorectal cancer was significantly lower in gout (0.8%) versus osteoarthritis (3.7%) (p = 0.0008) patients. Differences in colorectal cancer rates remained significant after stratifying for nonsteroidal anti-inflammatory drug use. Among gout subjects, use of colchicine and/or allopurinol, as well as the presence/absence of concomitant osteoarthritis, did not influence colorectal cancer occurrence. On subanalysis, differences in colorectal cancer occurrence between gout and osteoarthritis subjects persisted among those who underwent diagnostic (0.5% in gout vs 4.6% in osteoarthritis subjects, p < 0.001) but not screening (0.9% in gout subjects vs 1% in osteoarthritis subjects, p = 1.0) colonoscopy. There was no significant difference in nonmalignant colorectal polyp occurrence between gout and osteoarthritis subjects. CONCLUSIONS: Subjects with gout had decreased colonoscopy-documented occurrence of colorectal cancer compared with osteoarthritis subjects, suggesting a possible protective effect.

Low-Dose Allopurinol Promotes Greater Serum Urate Lowering in Gout Patients with Chronic Kidney Disease Compared with Normal Kidney Function.

OBJECTIVES: Gout patients with chronic kidney disease (CKD) accumulate the active allopurinol metabolite oxypurinol, suggesting that allopurinol may promote greater serum urate (sU) lowering in CKD patients. METHODS: We identified all patientswith gout diagnoses on either 100 mg or 300 mg of allopurinol daily, with available pre- and on-treatment sU levels, in our system in a 1-year period. Mean sU decrement by dosing per CKD groups was determined by CKD stage. RESULTS: Of 1,288 subjects with gout, 180 met entry criteria, with 83 subjects receiving 100 mg and 97 receiving 300 mg allopurinol. Subjects with CKD stage 1 experienced less sU lowering with 100 mg than 300 mg of allopurinol. Subjects with stage 4 and 5 CKD had equivalent sU decreases across the 100 mg and 300 mg allopurinol groups. However, the 100 mg group started at a higher pre-treatment sU and ended at a higher final sU than the 300 mg group. CONCLUSIONS: The strategy of titrating allopurinol to sU in patients with kidney impairment may result in greater sU lowering at lower doses than in patients without CKD but may also pose a treatment challenge from a possible drug ceiling effect.

Moving the Needle: Improving the Care of the Gout Patient.

Gout is a the most common inflammatory arthritis in the United States. It is a significant cause of morbidity, disability, lost work days, and high healthcare utilization due to intermittent attacks, chronic inflammation, and joint damage. Despite our understanding of the prelude and pathophysiology of gout, hyperuricemia, it is still poorly misunderstood by patients and poorly managed by healthcare providers. Several parallel treatment paradigms have been developed by professional societies around the world based on the understanding of how hyperuricemia occurs, gout epidemiology, expert opinion, and clinical trials data in order to lower uric acid and eventually eliminate the patient's crystal burden. This review focuses on both the treatment of acute attacks, and more importantly, the long-term management of gout and the lowering of serum uric acid levels to a goal of < 6 mg/dl (0.360 mmol/l) or treating to target. Treating to a target serum uric acid goal is an opportunity to decrease morbidity and improve the quality of care of every gout patient.

Use of Pre-Infusion Serum Uric Acid Levels as a Biomarker for Infusion Reaction Risk in Patients on Pegloticase.

INTRODUCTION: The aim of this work is to evaluate the impact of the timing of pre-infusion serum uric acid (sUA) test results for use in applying stopping rules for pegloticase to identify patients at risk for infusion reactions (IRs) while on therapy. METHODS: Data from the phase 3 clinical trials of pegloticase were reviewed and individual uric acid levels of the 85 patients who received the approved regimen of biweekly infusions were examined in relation to the occurrence of IRs. RESULTS: Of the 22 patients (26%) who experienced an IR on pegloticase therapy without uric acid stopping rules, only seven (8%) would have had IRs if pegloticase therapy had been discontinued after two consecutive pre-infusion sUA levels above 6 mg/dl. If pegloticase therapy was stopped after a single pre-infusion sUA above 6 mg/dl, only two patients (2%) would have experienced IRs during the clinical studies. CONCLUSIONS: A pre-infusion sUA level functions as a highly accurate biomarker for identification of patients who are at risk of IRs while on pegloticase therapy. Stopping pegloticase in patients who have a rise in pre-infusion uric acid levels to above 6 mg/dl while on therapy would result in most IRs being avoided. FUNDING: Horizon Pharma.

Gout, Hyperuricemia, and Crystal-Associated Disease Network Consensus Statement Regarding Labels and Definitions for Disease Elements in Gout.

OBJECTIVE: The language currently used to describe gout lacks standardization. The aim of this project was to develop a consensus statement on the labels and definitions used to describe the basic disease elements of gout. METHODS: Experts in gout (n = 130) were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach consensus on the labeling and definitions for the basic disease elements of gout. Disease elements and labels in current use were derived from a content analysis of the contemporary medical literature, and the results of this analysis were used for item selection in the Delphi exercise and face-to-face consensus meeting. RESULTS: There were 51 respondents to the Delphi exercise and 30 attendees at the face-to-face meeting. Consensus agreement (≥80%) was achieved for the labels of 8 disease elements through the Delphi exercise; the remaining 3 labels reached consensus agreement through the face-to-face consensus meeting. The agreed labels were monosodium urate crystals, urate, hyperuric(a)emia, tophus, subcutaneous tophus, gout flare, intercritical gout, chronic gouty arthritis, imaging evidence of monosodium urate crystal deposition, gouty bone erosion, and podagra. Participants at the face-to-face meeting achieved consensus agreement for the definitions of all 11 elements and a recommendation that the label "chronic gout" should not be used. CONCLUSION: Consensus agreement was achieved for the labels and definitions of 11 elements representing the fundamental components of gout etiology, pathophysiology, and clinical presentation. The Gout, Hyperuricemia, and Crystal-Associated Disease Network recommends the use of these labels when describing the basic disease elements of gout.

PERIVASCULAR THICKENING ON OPTICAL COHERENCE TOMOGRAPHY AS A MARKER OF INFLAMMATION IN BIRDSHOT RETINOCHOROIDITIS.

PURPOSE: In this study, we hypothesized that thickening along the major arcade vessels is a noninvasive marker of inflammation in eyes with birdshot retinochoroiditis (BRC). METHODS: In this single-center retrospective study, patients with BRC were identified. Perivascular thickening was categorized as mild, moderate, or severe, based on a set of standard reference retinal thickness maps derived from representative spectral domain optical coherence tomography volume scans. The assigned perivascular severity thickness category was then compared with other inflammatory markers and optical coherence tomography measurements. These parameters were also examined in eyes with intermediate uveitis to assess the diagnostic specificity of perivascular thickening. RESULTS: In eyes with BRC, greater perivascular thickening was associated with increased vitreous haze (P = 0.009) and retinal vascular leakage on fluorescein angiography (P = 0.0001). Perivascular thickening was correlated with central subfield thickness and total macular volume on optical coherence tomography. Controlling for central subfield thickness and total macular volume, the odds of higher severity level of perivascular thickening were nine times greater in eyes with BRC than those with intermediate uveitis (P < 0.0001). Eyes with BRC and active inflammation were more likely to have moderate or severe perivascular thickening (P = 0.02). CONCLUSION: Perivascular thickening, determined by optical coherence tomography, may be a useful noninvasive biomarker of inflammation in eyes with BRC.