Faculty Bibliography

Kikuchi-Fujimoto's disease (KFD) and adult-onset Still's disease (AOSD) are rare idiopathic inflammatory conditions of unknown etiology. Ten prior instances of KFD and AOSD occurring together have been reported in the medical literature. These overlaps, together with certain distinguishing clinical and laboratory characteristics in these co-occurrences, offer insight into the pathophysiology of both of these rare disorders. Too, examination of these cases may help improve the diagnostic evaluation and care of patients afflicted with these rare diseases. We therefore report an additional patient with KFD and AOSD occurring in a middle-aged Hispanic female patient and perform a systematic literature review using the PubMed/MEDLINE and Embase databases to further analyze and compare prior identified cases. Our observations in our index case complement and expand previous reports, including new demographic and diagnostic features not seen in prior cases of overlap. Indeed ours is the first in a patient of Hispanic ethnicity, with retroperitoneal lymphadenopathy, as well as with a skin biopsy consistent with AOSD. Each of the reviewed cases of co-occurrence met the diagnostic criteria for both KFD and AOSD. This finding, in the setting of unique clinical and diagnostic manifestations that are not typically seen in either disease entity alone, suggests the presence of an overlap syndrome. Also, many of the shared clinical features and symptomatic responses to targeted therapies implies a similar, yet still poorly understood, pathophysiologic pathway for the two diseases.

PURPOSE OF REVIEW/OBJECTIVE:Calcium pyrophosphate deposition disease (CPPD) arises from calcium pyrophosphate deposition throughout the body, leading to different clinical syndromes that may be diagnosed using various imaging modalities. The purpose of this review is to highlight recent updates in the imaging of CPPD. RECENT FINDINGS/RESULTS:Conventional radiography remains the initial test when imaging CPPD; but musculoskeletal ultrasound and conventional computed tomography (CT) may also assist in diagnosing and characterizing CPP deposits, with increased sensitivity. Dual-energy CT is also being used to differentiate CPP crystals from other crystal deposition diseases. CPP discitis has been diagnosed with MRI, but MRI has lower sensitivity and specificity than the aforementioned imaging studies in CPPD diagnosis. Assorted imaging modalities are increasingly used to diagnose CPPD involving atypical joints, avoiding invasive procedures. Each modality has its advantages and disadvantages. Future imaging may be able to provide more utility than what is currently available.

Background/Purpose: Axial gout involvement was first reported in 1950 (1). Over 100 cases have subsequently been published. Reported cases have presented as acute back pain, cord compression, and/or neurologic symptoms, with diagnosis made by invasive procedure (surgical excision or biopsy). However, the true extent of MSU deposition in the spine of gout patients, including asymptomatic patients or those with non-specific symptoms, is unknown and likely higher. We used DECT to determine the extent of MSU deposition in the lumbosacral spines of patients with gout, with and without tophi, compared to controls without gout.
Method(s): We recruited controls, nontophaceous, and tophaceous gout patients, age 45-80. Individuals with CPPD disease, RA, spondyloarthropathy, active spinal malignancy, or on urate lowering treatment (ULT) >= 6 months were excluded. Gout subjects met 2015 ACR gout classification criteria, with entry serum urate (sU) of >6.8 mg/dL ( >6.0 mg/dL if on ULT for < 6 months). Demographics, gout history, Aberdeen back pain scale, sU, ESR, and CRP were collected. Subjects underwent DECT of the lumbosacral spine (LS) to assess for MSU deposition.
Result(s): 75 subjects were enrolled, and 72 completed the study (1 nontophaceous gout patient lost to follow-up prior to DECT, 2 tophaceous excluded after sU at time of DECT found to be < 6.0mg/dL). All groups were similar in age in years (controls 61.8+/-3.8, nontophaceous 64.0+/-6.1, tophaceous 60.4+/-11.0, p=0.81) but differed in BMI (controls 28.3+/-6.5 kg/m², nontophaceous 34.1+/-7.2 kg/m², tophaceous 29.5+/-4.5 kg/m², p=0.03) and creatinine (controls 1.0+/-0.2 mg/dL, nontophaceous 1.4+/-0.7 mg/dL, tophaceous 1.4+/-0.6 mg/dL, p< 0.05). Mean sU and ESR were higher in gout subjects (sU-controls 5.3+/-1 mg/dL, nontophaceous 8.5+/-1.7 mg/dL, tophaceous 8.5+/-1.6 mg/dL, p< 0.05; ESR-controls 13.7+/-13.8 mm/h, nontophaceous 26.5+/-19.4 mm/h, tophaceous 25.1+/-15.7 mm/h, p< 0.05). Using standard DECT settings for MSU visualization, gout patients had larger MSU volumes than controls (controls 2.2+/-1.2 cm3, all gout 5.23+/-6.9 cm3; p =0.03). Tophaceous patients had numerically greater MSU deposition compared with nontophaceous (6.0+/-8.9 cm3, vs 4.4+/-4.3 cm3, ns). Reanalysis of a subset of scans using highly specific settings to eliminate artifact reduced the number of subjects with MSU signal but confirmed greater prevalence of deposition among gout patients (n=29; controls with deposition 0/9, nontophaceous with deposition 1/11, tophaceous with deposition 2/9). Back pain was also more common among gout patients. No subject had frank tophi on spinal DECT.
Conclusion(s): Gout patients have significantly greater intercritical inflammation and LS MSU deposition than controls, and trend toward greater deposition among patients with tophi. Preliminary results using the most stringent DECT threshold settings suggests MSU differences are not artifact. The complete data set is currently undergoing evaluation and the full results will be presented

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.