Faculty Bibliography

OBJECTIVE:To evaluate anakinra efficacy and safety compared to triamcinolone in the treatment of gout flares. METHODS:Patients unsuitable for NSAIDs and colchicine were enrolled in this multi-center, randomized, double-blind study lasting for up to 2 years (NCT03002974). The design was to show superiority of anakinra (100 or 200 mg/day for 5 days) over triamcinolone (40 mg single injection) for primary endpoint of changed patient-assessed pain intensity from baseline to 24-72 hours in the most affected joint measured on visual analogue scale (0-100). Secondary outcomes included: safety, immunogenicity, and patient's and physician's global response assessments. RESULTS:flare, the mean pain intensity decline from baseline to 24-72 hours for total anakinra and triamcinolone was -41.2 and -39.4, respectively (p=0.688). Most secondary endpoints favored anakinra. No unexpected safety findings were identified. Presence of anti-drug antibodies was not associated with adverse events or altered pain reduction. CONCLUSIONS:Anakinra was not superior to triamcinolone for the primary endpoint, but had comparable efficacy in pain reduction, and was favored for most secondary endpoints. Anakinra is an effective option for gout flares when conventional therapy is unsuitable.

BACKGROUND:Evidence suggests a role for excessive inflammation in COVID-19 complications. Colchicine is an oral anti-inflammatory medication beneficial in gout, pericarditis, and coronary disease. We aimed to investigate the effect of colchicine on the composite of COVID-19-related death or hospital admission. METHODS:The present study is a phase 3, randomised, double-blind, adaptive, placebo-controlled, multicentre trial. The study was done in Brazil, Canada, Greece, South Africa, Spain, and the USA, and was led by the Montreal Heart Institute. Patients with COVID-19 diagnosed by PCR testing or clinical criteria who were not being treated in hospital were eligible if they were at least 40 years old and had at least one high-risk characteristic. The randomisation list was computer-generated by an unmasked biostatistician, and masked randomisation was centralised and done electronically through an automated interactive web-response system. The allocation sequence was unstratified and used a 1:1 ratio with a blocking schema and block sizes of six. Patients were randomly assigned to receive orally administered colchicine (0·5 mg twice per day for 3 days and then once per day for 27 days thereafter) or matching placebo. The primary efficacy endpoint was the composite of death or hospital admission for COVID-19. Vital status at the end of the study was available for 97·9% of patients. The analyses were done according to the intention-to-treat principle. The COLCORONA trial is registered with ClinicalTrials.gov (NCT04322682) and is now closed to new participants. FINDINGS/RESULTS:Trial enrolment began in March 23, 2020, and was completed in Dec 22, 2020. A total of 4488 patients (53·9% women; median age 54·0 years, IQR 47·0-61·0) were enrolled and 2235 patients were randomly assigned to colchicine and 2253 to placebo. The primary endpoint occurred in 104 (4·7%) of 2235 patients in the colchicine group and 131 (5·8%) of 2253 patients in the placebo group (odds ratio [OR] 0·79, 95·1% CI 0·61-1·03; p=0·081). Among the 4159 patients with PCR-confirmed COVID-19, the primary endpoint occurred in 96 (4·6%) of 2075 patients in the colchicine group and 126 (6·0%) of 2084 patients in the placebo group (OR 0·75, 0·57-0·99; p=0·042). Serious adverse events were reported in 108 (4·9%) of 2195 patients in the colchicine group and 139 (6·3%) of 2217 patients in the placebo group (p=0·051); pneumonia occurred in 63 (2·9%) of 2195 patients in the colchicine group and 92 (4·1%) of 2217 patients in the placebo group (p=0·021). Diarrhoea was reported in 300 (13·7%) of 2195 patients in the colchicine group and 161 (7·3%) of 2217 patients in the placebo group (p<0·0001). INTERPRETATION/CONCLUSIONS:In community-treated patients including those without a mandatory diagnostic test, the effect of colchicine on COVID-19-related clinical events was not statistically significant. Among patients with PCR-confirmed COVID-19, colchicine led to a lower rate of the composite of death or hospital admission than placebo. Given the absence of orally administered therapies to prevent COVID-19 complications in community-treated patients and the benefit of colchicine in patients with PCR-proven COVID-19, this safe and inexpensive anti-inflammatory agent could be considered for use in those at risk of complications. Notwithstanding these considerations, replication in other studies of PCR-positive community-treated patients is recommended. FUNDING/BACKGROUND:The Government of Quebec, the Bill & Melinda Gates Foundation, the National Heart, Lung, and Blood Institute of the US National Institutes of Health, the Montreal Heart Institute Foundation, the NYU Grossman School of Medicine, the Rudin Family Foundation, and philanthropist Sophie Desmarais.

BACKGROUND:A systemic inflammatory response is observed in coronavirus disease 2019 (COVID-19). Elevated serum levels of C-reactive protein (CRP), a marker of systemic inflammation, are associated with severe disease in bacterial or viral infections. We aimed to explore associations between CRP concentration at initial hospital presentation and clinical outcomes in patients with COVID-19. METHODS AND RESULTS/RESULTS:Consecutive adults aged ≥18 years with COVID-19 admitted to a large New York healthcare system between 1 March and 8 April 2020 were identified. Patients with measurement of CRP were included. Venous thrombo-embolism (VTE), acute kidney injury (AKI), critical illness, and in-hospital mortality were determined for all patients. Among 2782 patients hospitalized with COVID-19, 2601 (93.5%) had a CRP measurement [median 108 mg/L, interquartile range (IQR) 53-169]. CRP concentrations above the median value were associated with VTE [8.3% vs. 3.4%; adjusted odds ratio (aOR) 2.33, 95% confidence interval (CI) 1.61-3.36], AKI (43.0% vs. 28.4%; aOR 2.11, 95% CI 1.76-2.52), critical illness (47.6% vs. 25.9%; aOR 2.83, 95% CI 2.37-3.37), and mortality (32.2% vs. 17.8%; aOR 2.59, 95% CI 2.11-3.18), compared with CRP below the median. A dose response was observed between CRP concentration and adverse outcomes. While the associations between CRP and adverse outcomes were consistent among patients with low and high D-dimer levels, patients with high D-dimer and high CRP have the greatest risk of adverse outcomes. CONCLUSIONS:Systemic inflammation, as measured by CRP, is strongly associated with VTE, AKI, critical illness, and mortality in COVID-19. CRP-based approaches to risk stratification and treatment should be tested.

Background: Gout affecting the spine is reported as a rare event presenting with neuropathy, spinal compression and acute back pain (1). Cases are often diagnosed by tissue confirmation of monosodium urate (MSU) deposition. The frequency of gout involving the spine asymptomatically or with milder, non-specific symptoms is likely higher than reported.
Objective(s): Using dual-energy CT (DECT), we are determining prevalence/ extent of MSU deposition in the lumbosacral spines of patients with gout and tophaceous gout, compared to non-gout controls.
Method(s): We are recruiting 25 controls, 25 non-tophaceous and 25 tophaceous gout patients, 45-80 years old. Exclusion criteria include CPPD disease, RA, spondyloarthropathy or spinal malignancy. All gout subjects meet ACR gout classification criteria with entry serum urate (sU) of >6.8 mg/dL, or sU >6.0 mg/dL on ULT for <6 months. Demographics, gout history, Aberdeen back pain scale, sU, ESR, and CRP are collected. DECT of the lumbosacral spine is used to assess MSU deposition and osteoarthritic changes.
Result(s): 63 subjects are enrolled and analyzed to date (25 control, 23 non-tophaceous and 15 tophaceous gout). Control, non-tophaceous gout, and tophaceous gout subjects have similar mean age in years (controls 61.8+/-3.8, non-tophaceous 64.0+/-6.2, tophaceous 63.5+/-9.2, p=0.45), but differ in BMI (controls 28.3+/-6.5 kg/ m2, non-tophaceous 32.1+/-6.7 kg/m², tophaceous 29.1+/-4.3 kg/m², p=0.01) and creatinine (controls 1.0+/-0.2 mg/dL, non-tophaceous 1.4+/-0.6 mg/dL, tophaceous 1.7+/-0.9 mg/dL, p=0.048). Mean sU and ESR are higher in gout subjects (sU-controls 5.3+/-1 mg/dL, non-tophaceous 8.3+/-1.4 mg/dL, tophaceous 8.4+/-2.0 mg/ dL, p<0.05; ESR-controls 13.7+/-13.8 mm/h, non-tophaceous 25.2+/-18.7 mm/h, tophaceous 22.5+/-15.1 mm/h, p<0.05). Using default threshold settings for MSU visualization, greater MSU deposition is observed in the spine of gout patients (controls 2.2+/-1.2 cm³, non-tophaceous 4.5+/-4.3 cm³, tophaceous 8.5+/-12.5 cm³, p<0.05; Table 1). Reanalysis of several scans using narrower threshold settings to limit possible artifact confirms increased MSU signal among gout patients. Although many subjects in each group do not have excessive MSU deposition, deposition is more common in both gout groups. No subject demonstrated a frank spinal tophus.
Conclusion(s): Based on preliminary results, gout patients have higher inflammatory markers and greater spinal MSU deposition than controls. Preliminary analyes with more stringent DECT threshold settings suggests these differences are not artifact, but analysis is ongoing. These data suggest that MSU deposition in the spine occurs in a subset of gout patients

The search for effective COVID-19 management strategies continues to evolve. Current understanding of SARS-CoV-2 mechanisms suggests a central role for exaggerated activation of the innate immune system as an important contributor to COVID-19 adverse outcomes. The actions of colchicine, one of the oldest anti-inflammatory therapeutics, target multiple mechanisms associated with COVID-19 excessive inflammation. While many COVID-19 trials have sought to manipulate SARS-CoV-2 or dampen the inflammatory response once patients are hospitalised, few examine therapeutics to prevent the need for hospitalisation. Colchicine is easily administered, generally well tolerated and inexpensive, and holds particular promise to reduce the risk of hospitalisation and mortality due to COVID-19 in the outpatient setting. Successful outpatient treatment of COVID-19 could greatly reduce morbidity, mortality and the demand for rare or expensive care resources (front-line healthcare workers, hospital beds, ventilators, biological therapies), to the benefit of both resource-replete and resource-poor regions.

OBJECTIVE:Disagreement exists between rheumatology and primary care societies regarding gout management. This paper describes a formal process for gathering input from stakeholders in the planning of a trial to compare gout management strategies. METHODS:We recruited patients, nurses, physician assistants, primary care clinicians, and rheumatologists to participate in a modified Delphi panel (mDP) to provide input on design of a trial focused on optimal management for primary care patients with gout. The 16 panelists received a plain-language briefing document that discussed the rationale for the trial, key clinical issues in gout, and aspects of trial design. The panelists also received information and considerations on nine voting questions (VQs), judged to be the key design questions. Cognitive interviews with panelists ensured that the VQs were understood by the range of panelists involved in the mDP. Panelists were asked to score all VQs from 1 (definitely no) to 9 (definitely yes). Two voting rounds were conducted-round 1 by email and round 2 by video conference. RESULTS:The VQs were modified through the cognitive interviews. The round 1 voting resulted in consensus on eight items, with consensus defined as median voting score in the same tercile (1-3, 4-6 or 7-9). Re-voting at the meeting (round 2) reached consensus on the remaining item. CONCLUSION/CONCLUSIONS:An mDP with various stakeholders facilitated consensus on the design of a trial of different management strategies for chronic gout. This method may be useful for designing trials of clinical questions with substantial disagreement across stakeholders.

PURPOSE OF REVIEW/OBJECTIVE:Although gout is a common, well-recognized, and extensively researched rheumatologic disease, it continues to be underappreciated and undertreated. Although the prevalence of gout has been rising over the past several decades, adherence to urate lowering therapy continues to be suboptimal. Recent studies have underscored the potential success of guideline-directed therapy. RECENT FINDINGS/RESULTS:Adherence to gout treatment continues to be suboptimal according to multinational metaanalyses. Moreover, studies measuring adherence are prone to overestimation and each methodologic approach has intrinsic limitations. Adherence may be analyzed from the perspective of patient adherence to taking a medication, or provider adherence to treatment guidelines. In addition to considering traditional risk factors, adherence should be viewed through the lens of healthcare disparities. The RAmP-Up trail and Nottingham Gout Treatment trial demonstrate the success of protocolized gout treatment using existing guidelines for reference. SUMMARY/CONCLUSIONS:Standardized gout treatment protocols should be established for all primary care and specialty practices. Two successful methods of improving adherence include using nonphysician providers to coordinate urate lowering therapy titration and monitoring serum urate. Having more frequent outpatient visits to focus on direct patient care and education has also been successful.

INTRODUCTION/BACKGROUND: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/CONCLUSIONS:Published reports suggest that immunomodulation co-therapy has the potential to markedly improve pegloticase responder rates in patients with uncontrolled gout.