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.

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.

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.

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.

The role of cystoid macular edema as a marker in the progression of non-paraneoplastic autoimmune retinopathy.

PURPOSE: To determine the relationship between cystoid macular edema (CME) and disease severity and progression in non-paraneoplastic autoimmune retinopathy (npAIR). METHODS: A retrospective study was conducted on patients seen between 2008 and 2016 with npAIR as defined by electroretinogram (ERG) dysfunction, visual field changes, presence of antiretinal antibodies, a negative malignancy workup, and no other apparent cause for visual dysfunction. Optical coherence tomography (OCT) scans were reviewed for each patient. A minimum follow-up of 1 year was necessary for study inclusion. The presence or absence of CME and the length of the preserved EZ on the centermost line scan of the SD-OCT images was recorded at each visit. The main outcome measure assessed was the rate of EZ loss (EZ final - EZ initial / days follow-up) over time, a marker for disease progression. RESULTS: Thirty-two eyes (16 patients) were included with an average follow-up of 42 months. Twenty-one eyes (66%) had CME on initial presentation and final follow-up (group 1), eight eyes (25%) did not have CME on presentation or final follow-up (group 2), and three eyes (9%) did not have CME on presentation but developed CME during follow-up (group 3). Group 1 eyes had a lower maximal a-wave amplitude (59.0 vs. 220.9 mV, p = 0.012) and lower maximal b-wave amplitude (88.1 vs 256.9 mV, p = 0.017) on baseline ERG compared to Group 2 eyes. The rate of EZ loss over time was significantly greater for group 1 with CME compared to group 2 without CME both at 12 months (- 1.26 µm/day vs. - 0.26 µm/day, p = 0.022) and at final follow-up (- 1.03 µm/day vs. - 0.08 µm/day, p = 0.012). CONCLUSIONS: CME was associated with decreased ERG amplitudes and greater velocity of EZ loss, suggesting that CME is a useful biomarker of more severe and more progressive disease in npAIR.

An examination of the relationship between serum uric acid level, a clinical history of gout, and cardiovascular outcomes among patients with acute coronary syndrome.

BACKGROUND: Studies have suggested a relationship between higher baseline serum uric acid (sUA) levels and an elevated risk of subsequent ischemic cardiovascular outcomes among acute coronary syndrome (ACS) patients; this relationship may be modified by a clinical history of gout and has not been studied in large patient cohorts. We sought to understand the effect of sUA and gout on ACS outcomes. METHODS: Using PLATO and TRACER data on 27,959 ACS patients, we evaluated baseline sUA levels in relation to a composite of cardiovascular death, myocardial infarction (MI), or stroke. We assessed interaction terms to determine if a baseline clinical diagnosis of gout modified this putative relationship; 46% (n=12,882) had sUA levels elevated >6.0 mg/dL. RESULTS: Patients with elevated levels were more often male with a history of prior MI, diabetes, and heart failure compared with those with sUA <6.0 mg/dL. The unadjusted risk of the composite endpoint increased with corresponding elevations in sUA levels (per 1 mg/dL increase) (HR=1.23 [95% CI: 1.20-1.26]) above the statistical inflection point of 5.0 mg/dL. After adjustment, the association between sUA level and the composite outcome remained significant (HR=1.07 [95% CI: 1.04-1.10]), and baseline gout did not modify this relationship. CONCLUSIONS: In patients with ACS, increasing levels of sUA are associated with an elevated risk of cardiovascular events, regardless of a clinical diagnosis of gout. Further investigation is warranted to determine the mechanism behind this relationship and to delineate whether sUA is an appropriate therapeutic target to reduce cardiovascular risk.

Lesinurad in combination with allopurinol: a randomised, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR 2 study).

OBJECTIVES: Determine the efficacy and safety of daily lesinurad (200 or 400 mg orally) added to allopurinol in patients with serum uric acid (sUA) above target in a 12-month, randomised, phase III trial. METHODS: Patients on allopurinol ≥300 mg (≥200 mg in moderate renal impairment) had sUA level of ≥6.5 mg/dL (≥387 µmol/L) at screening and two or more gout flares in the prior year. Primary end point was the proportion of patients achieving sUA level of <6.0 mg/dL (<357 µmol/L) (month 6). Key secondary end points were mean gout flare rate requiring treatment (months 7 through 12) and proportions of patients with complete resolution of one or more target tophi (month 12). Safety assessments included adverse events and laboratory data. RESULTS: Patients (n=610) were predominantly male, with mean (±SD) age 51.2±10.90 years, gout duration 11.5±9.26 years and baseline sUA of 6.9±1.2 mg/dL (410±71 µmol/L). Lesinurad at 200 and 400 mg doses, added to allopurinol, significantly increased proportions of patients achieving sUA target versus allopurinol-alone therapy by month 6 (55.4%, 66.5% and 23.3%, respectively, p<0.0001 both lesinurad+allopurinol groups). In key secondary end points, there were no statistically significant treatment-group differences favouring lesinurad. Lesinurad was generally well tolerated; the 200 mg dose had a safety profile comparable with allopurinol-alone therapy. Renal-related adverse events occurred in 5.9% of lesinurad 200 mg+allopurinol, 15.0% of lesinurad 400 mg+allopurinol and 4.9% of allopurinol-alone groups, with serum creatinine elevation of ≥1.5× baseline in 5.9%, 15.0% and 3.4%, respectively. Serious treatment-emergent adverse events occurred in 4.4% of lesinurad 200 mg+allopurinol, in 9.5% of lesinurad 400 mg+allopurinol and in 3.9% of allopurinol-alone groups, respectively. CONCLUSION: Lesinurad added to allopurinol demonstrated superior sUA lowering versus allopurinol-alone therapy and lesinurad 200 mg was generally well tolerated in patients with gout warranting additional therapy. TRIAL REGISTRATION NUMBER: NCT01493531.

Injectable Fluocinolone Acetonide Long-Acting Implant for Noninfectious Intermediate Uveitis, Posterior Uveitis, and Panuveitis: Two-Year Results.

PURPOSE: To determine the effect of an injectable fluocinolone acetonide implant (FAi) in eyes with noninfectious intermediate uveitis, posterior uveitis, or panuveitis. DESIGN: Noncomparative, interventional, dose-randomized, dose-masked, prospective, individual, investigator-sponsored investigational new drug study. PARTICIPANTS: Eleven eyes of 11 participants with a history of recurrent noninfectious intermediate uveitis, posterior, or panuveitis. METHODS: Participants were randomized to receive either a low- or a high-dose FAi. Eyes were observed on day 0 (day the implant was injected) and then at regular intervals through 2 years. MAIN OUTCOME MEASURES: Ocular inflammation, visual acuity, anti-inflammatory medication use, and safety parameters before and after FAi implantation. RESULTS: All participants were followed up for 2 years. At baseline, mean study eye visual acuity was 0.56 logarithm of the minimum angle of resolution (logMAR; standard deviation [SD], 0.43 logMAR). These values improved significantly to +0.25 logMAR (SD, 0.14 logMAR) and +0.17 logMAR (SD, 0.14 logMAR) at 12 and 24 months after implantation, respectively (P = 0.041 and P = 0.016, respectively). The average number of inflammation recurrences in the 12 months before implantation was 1.54 episodes per eye. None of the study eyes experienced a recurrence during the follow-up period. Of the 6 participants who continued receiving systemic medication after implantation, the dosage was reduced in 4 participants. Five of 11 eyes received an average of 1.6 posterior sub-Tenon triamcinolone acetonide (PSTA) injections in the 12 months preceding implantation. None required a PSTA injection after FAi implantation. The most common adverse event was intraocular pressure (IOP) rise. At baseline, 1 study eye (9%) required pressure-lowering drops; 2 additional study eyes (18%) required them during the follow-up period. Filtering procedures were performed in 2 of these eyes (18.1%). No FAi explantations were required, nor were any participants lost to follow-up during the investigation. CONCLUSIONS: It is feasible to place a long-acting FAi in an outpatient setting, without prolonged adverse events attributed to the implant injection procedure. The FAi effectively controlled intraocular inflammation in all eyes in the study, and at the last follow-up, all implanted eyes demonstrated an improvement in visual acuity. Elevated IOP that occurred in 18% of FAi-implanted eyes was managed by standard means. The FAi implant is a promising approach for patients with noninfectious intermediate uveitis, posterior uveitis, or panuveitis who do not respond to, or are intolerant to, conventional therapy.

New and Pipeline Drugs for Gout.

Gout is the most common inflammatory arthropathy in the western world. Affecting millions and accounting for lost wages, increased health care costs, and significant disability, it remains a burden for those afflicted, their families, and the health care system. Despite the availability of a number of effective therapies, gout is often inadequately treated, and its impact on the patients overall health and well-being is underestimated by physicians and patients alike. For many decades, controlling acute flares was the priority in the management of gout. More recently, however, a deeper understanding of gout pathophysiology has resulted in a new appreciation that gout impacts the patient with consequences well beyond the episodes of acute inflammatory arthritis. Reflecting the chronic nature of the disease, gout treatment needs to be chronic as well, and aimed at reducing the underlying cause of gout-hyperuricemia-as well as the symptom of acute attacks. Therapy therefore requires both urate lowering and anti-inflammatory strategies. Unfortunately, the most commonly used urate lowering and anti-inflammatory treatments may be problematic in some gout patients, who often have multiple comorbidities that establish relative contraindications. Novel urate lowering therapies, and new medications to treat and prevent acute gouty flares, can not only improve care of the individual; they can also lead to a better discourse for the edification of those who manage and are managed for this underestimated disease. In this paper, we discuss new and pipeline drugs for acute gout, prophylactic anti-inflammatory therapies as well as urate lowering therapies.

Genetics of hyperuricemia and gout: implications for the present and future.

Gout is the most common inflammatory arthropathy and occurs in the setting of elevated serum urate levels. Gout is also known to be associated with multiple comorbidities including cardiovascular disease and the metabolic syndrome. Recent advances in research have increased our understanding and improved our knowledge of the pathophysiology of gout. Genome-wide association studies have permitted the identification of several new and common genetic factors that contribute to hyperuricemia and gout. Most of these are involved with the renal urate transport system (the uric acid transportasome), generally considered the most influential regulator of serum urate homeostasis. Thus far, SCL22A12, SCL2A9, and GLUT9 have been found to have the greatest variation and most influence on serum urate levels. However, genetics are only a part of the explanation in the development of hyperuricemia and gout. As results have been mixed, the role of known urate influential genes in gout's associated comorbidities remains unclear. Regardless, GWAS findings have expanded our understanding of the pathophysiology of hyperuricemia and gout, and will likely play a role in the development of future therapies and treatment of this ancient disease.

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 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.

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.

Unusual clinical presentations of gout.

PURPOSE OF REVIEW: The dogmatic description of gout is described as an inflammatory crystal-induced arthropathy that afflicts peripheral joints. This manuscript describes many recent cases and unusual clinical presentations of gout. Emphasis is placed on the ability of gout to cause diagnostic dilemmas that can impact patient treatment and care. RECENT FINDINGS: Various genetic mutations can predispose patients in developing early onset gout. Environmental exposures, medications, and certain patient populations can affect pathophysiology of uric acid, predisposing patients both typical and atypical manifestations of gout. Numerous reports have described gout deposition in unusual parts of the body, which can mimic unrelated disease processes. SUMMARY: Although classic gout is still most commonly seen, the disease can manifest as with a wide array of presentations. It is likely that such atypical presentations are a result of a complexity of reasons. When presented with a diagnostic challenge in a patient with gout, the clinician should be aware of unusual manifestations of gout and consider it in the differential.

Gout, hyperuricemia, and the risk of cardiovascular disease: cause and effect?

Gout and hyperuricemia have long been suspected to be risk factors for cardiovascular disease. However, studies have frequently failed to distinguish whether these entities have an independent effect on cardiovascular risk or serve as markers for other risk factors. In vitro and animal studies suggest that uric acid is a biologically active compound that can increase inflammatory mediators known to lead to vascular damage. In contrast, uric acid also has potentially protective effects as a strong antioxidant, approaching the potency of vitamin C. Large clinical trials demonstrate a consistent relationship between elevated serum uric acid and a variety of cardiovascular diseases, although the strength of association varies greatly. We review the evidence for and against an independent role for hyperuricemia and/or gout in cardiovascular pathology.

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.

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.