Relationship of BK polyoma virus (BKV) in the urine with hemorrhagic cystitis and renal function in recipients of T Cell-depleted peripheral blood and cord blood stem cell transplantations.

Hematopoietic stem cell transplant (HSCT) recipients are at significant risk for BK virus (BKV) reactivation, hemorrhagic cystitis (HC), and renal dysfunction. We prospectively monitored 98 patients who had received HSCT by serial BKV PCR in the urine through day (D) +100 to analyze the relationship between BK viruria and HC, serum creatinine (Cr), and creatinine clearance (CrCl) through D +180 or death. Patients, median age 52 years (range, 20 to 73), received T cell-depleted (50%) or cord blood allografts (21%). Median pre-HSCT BKV IgG titers were 1:10,240. Incremental increase in BKV IgG titers correlated with developing BK viruria ≥ 10(7) copies/mL. By D +100, 53 (54%) patients had BK viruria. BKV load in the urine increased at engraftment and persisted throughout D +100. HC developed in 10 patients (10%); 7 of 10 with BK viruria. In competing risk analyses, BK viruria ≥ 10(7) copies/mL, older age, cytomegalovirus reactivation, and foscarnet use were risk factors for HC. Cr and CrCl at 2, 3, and 6 months after HSCT were similar between patients with and without BK viruria.

Associations of galectin-3 levels with measures of vascular disease in patients with rheumatoid arthritis.

OBJECTIVES: Galectin-3 is a beta-galactoside-binding lectin and is a marker of cardiovascular disease (CVD) in the general population. It may also play a role in joint inflammation. We asked whether serum galectin-3 is a useful marker of subclinical vascular disease in patients with rheumatoid arthritis (RA). METHODS: RA patients without clinical CVD underwent assessment of coronary artery calcium (CAC) score, aortic inflammation (using 18Fluorodeoxyglucose positron emission-computed tomography [FDG PET/CT]), and myocardial flow reserve (MFR). Aorta FDG uptake was measured as standardized uptake values (SUV). Generalized linear models were constructed to explore the associations of galectin-3 levels with CAC score, aortic SUV, and MFR. RESULTS: A total of 124 RA patients (mean age 57; 82 % women, 45 % Hispanic; median RA duration 6.8 years; 75 % seropositive; median CDAI 16; 33 % on prednisone; 89 % on DMARDs; median CAC score 0; median aorta SUV 2.59; mean MFR 2.86; median galectin-3 level 8.54 ng/mL) were analyzed. In univariable analysis, higher galectin-3 levels were associated with higher aortic SUV (p = 0.007) but CAC score and MFR were not. In multivariable analysis, higher galectin-3 level remained significantly associated with higher aortic SUV (ß Coefficient=0.1786, p value=0.002). CONCLUSION: In our cohort of RA patients without clinical CVD, higher serum galectin-3 levels were independently associated with higher levels of aortic inflammation, but not CAC score or MFR. This suggests that galectin-3 may be a biomarker for an inflammatory and potentially reversible stage, but not a later (calcified) stage, of atherosclerosis in patients with RA.

Ultrasound-Guided Injections of HYADD4 for Knee Osteoarthritis Improves Pain and Functional Outcomes at 3, 6, and 12 Months without Changes in Measured Synovial Fluid, Serum Collagen Biomarkers, or Most Synovial Fluid Biomarker Proteins at 3 Months.

BACKGROUND: Prior studies have demonstrated improved efficacy when intra-articular (IA) therapeutics are injected using ultrasound (US) guidance. The aim of this study was to determine if clinical improvement in pain and function after IA hyaluronic acid injections using US is associated with changes in SF volumes and biomarker proteins at 3 months. METHODS: 49 subjects with symptomatic knee OA, BMI < 40, and KL radiographic grade II or III participated. Subjects with adequate aspirated synovial fluid (SF) volumes received two US-guided IA-HA injections of HYADD4 (24 mg/3 mL) 7 days apart. Clinical evaluations at 3, 6, and 12 months included WOMAC, VAS, PCS scores, 6 MWD, and US-measured SF depth. SF and blood were collected at 3 months and analyzed for four serum OA biomarkers and fifteen SF proteins. RESULTS: Statistical differences were observed at 3, 6, and 12 months compared to baseline values, with improvements at 12 months for WOMAC scores (50%), VAS (54%), and PCS scores (24%). MMP10 levels were lower at 3 months without changes in SF volumes, serum levels of C2C, COMP, HA, CPII, or SF levels of IL-1 ra, IL-4, 6, 7, 8, 15, 18, ILGFBP-1, 3, and MMP 1, 2, 3, 8, 9. Baseline clinical features or SF biomarker protein levels did not predict responsiveness at 3 months. CONCLUSIONS: Clinical improvements were observed at 12 months using US needle guidance for IA HA, whereas only one SF protein biomarker protein was different at 3 months. Larger studies are needed to identify which SF biomarkers will predict which individual OA patients will receive the greatest benefit from IA therapeutics.

Prospective changes in diastolic function in patients with rheumatoid arthritis.

BACKGROUND: Diastolic dysfunction (DD) is more prevalent in patients with rheumatoid arthritis (RA) compared to the general population. However, its evolution over time and its significant clinical predictors remain uncharacterized. We report on baseline and prospective changes in diastolic function and its associated RA and cardiovascular (CV) predictors. METHODS: In this study, 158 RA patients without clinical CV disease (CVD) were enrolled and followed up at 4 to 6 years, undergoing baseline and follow-up echocardiography to assess for DD, as well as extensive characterization of RA disease activity and CV risk factors. Novel measures of myocardial inflammation and perfusion were obtained at baseline only. Using baseline and follow-up composite DD (E/e', Left Atrial Volume Index (LAVI) or peak tricuspid regurgitation (TR) velocity; ≥ 1 in top 25%) as the outcome, multivariable regression models were constructed to identify predictors of DD. RESULTS: DD was prevalent in RA patients without clinical heart failure (HF) (40.7% at baseline) and significantly progressed on follow-up (to 57.9%). Baseline composite DD was associated with baseline RA disease activity (Clinical Disease Activity Index; CDAI) (OR 1.39; 95% CI 1.02-1.90; p=0.034). Several individual diastolic parameters (baseline E/e' and LAVI) were associated with troponin-I and brain natriuretic peptide (BNP). Baseline and follow-up composite DD, however, were not associated with myocardial inflammation, myocardial microvascular dysfunction, or subclinical atherosclerosis. CONCLUSIONS: DD is prevalent in RA patients without clinical HF and increases to >50% over time. Higher RA disease activity at baseline predicted baseline composite DD. Future longitudinal studies should explore whether adverse changes in diastolic function lead to clinical HF and are attenuated by disease-modifying antirheumatic drugs (DMARDs).

Precision Medicine for Rheumatoid Arthritis: The Right Drug for the Right Patient-Companion Diagnostics.

Despite the growing number of biologic and JAK inhibitor therapeutic agents available to treat various systemic autoimmune illnesses, the lack of a validated companion diagnostic (CDx) to accurately predict drug responsiveness for an individual results in many patients being treated for years with expensive, ineffective, or toxic drugs. This review will focus primarily on rheumatoid arthritis (RA) therapeutics where the need is greatest due to poor patient outcomes if the optimum drug is delayed. We will review current FDA-approved biologic and small molecule drugs and why RA patients switch these medications. We will discuss the sampling of various tissues for potential CDx and review early results from studies investigating drug responsiveness utilizing advanced technologies including; multiplex testing of cytokines and proteins, autoantibody profiling, genomic analysis, proteomics, miRNA analysis, and metabolomics. By using these new technologies for CDx the goal is to improve RA patient outcomes and achieve similar successes like those seen in oncology using precision medicine guided therapeutics.

Duration of rheumatoid arthritis and the risk of developing interstitial lung disease.

Age of ILD onset is similar in patients with RA-UIP and RA-NSIP but duration of RA before ILD onset differs https://bit.ly/3lgjfDJ.

Coronavirus disease 2019: investigational therapies in the prevention and treatment of hyperinflammation.

Introduction: The mortality of coronavirus disease 2019 (COVID-19) is frequently driven by an injurious immune response characterized by the development of acute respiratory distress syndrome (ARDS), endotheliitis, coagulopathy, and multi-organ failure. This spectrum of hyperinflammation in COVID-19 is commonly referred to as cytokine storm syndrome (CSS). Areas covered: Medline and Google Scholar were searched up until 15th of August 2020 for relevant literature. Evidence supports a role of dysregulated immune responses in the immunopathogenesis of severe COVID-19. CSS associated with SARS-CoV-2 shows similarities to the exuberant cytokine production in some patients with viral infection (e.g.SARS-CoV-1) and may be confused with other syndromes of hyperinflammation like the cytokine release syndrome (CRS) in CAR-T cell therapy. Interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha have emerged as predictors of COVID-19 severity and in-hospital mortality. Expert opinion: Despite similarities, COVID-19-CSS appears to be distinct from HLH, MAS, and CRS, and the application of HLH diagnostic scores and criteria to COVID-19 is not supported by emerging data. While immunosuppressive therapy with glucocorticoids has shown a mortality benefit, cytokine inhibitors may hold promise as 'rescue therapies' in severe COVID-19. Given the arguably limited benefit in advanced disease, strategies to prevent the development of COVID-19-CSS are needed.

Trends in systemic sclerosis and systemic sclerosis-related pulmonary arterial hypertension mortality in the USA.

There are limited data nationwide on the burden of systemic sclerosis (SSc)-related mortality. We aimed to determine recent trends in SSc and SSc-related pulmonary arterial hypertension (PAH) mortality overall and across population subgroups. Using death certificate data from the National Center for Health Statistics, we computed the age-adjusted mortality rates of SSc and SSc-SSc-PAH, a lethal prevailing complication, across demographic groups, geographic regions and comorbid cardiorespiratory conditions, and used Joinpoint regression analysis to calculate the average annual percentage change (APC) in mortality. From 2003 to 2016, 25 175 death records contained a code for SSc. Decedents were predominantly female (81%) and white (73%), with an average age of 66±14 years. The age-adjusted mortality rate decreased by 3% per year from 6.6 in 2003 to 4.3 per 1 000 000 population in 2016. Also, a decreasing trend was found when SSc was stratified by age, sex, race and geographic region. The prevalence of PAH was 23%. The odds of PAH were highest in female and black decedents, and in decedents with concomitant pulmonary embolism, cardiomyopathy and interstitial lung disease (ILD). SSc-PAH mortality remained stable from 2003 to 2008 then decreased by 3% per year from 2008 to 2016. In decedents with SSc-PAH, among all concomitant comorbidities, the mortality rate associated with ILD had the highest increase (average APC 6%, 95% CI 2%-10%). The mortality rate from SSc decreased from 2003 to 2016. Decreases in mortality rates were similar across demographic groups and geographic regions. SSc-PAH-related mortality remained stable. The death rate for SSc-ILD and concomitant PAH increased during this period.

IgA Antibodies Directed Against Citrullinated Protein Antigens Are Elevated in Patients With Idiopathic Pulmonary Fibrosis.

BACKGROUND: The etiology of idiopathic pulmonary fibrosis (IPF) is unknown. Because it shares genetic, histopathologic, and radiographic features with the fibrosing interstitial lung disease seen in rheumatoid arthritis (RA), the goal of this study was to investigate RA-related autoantibodies in IPF. METHODS: The study included patients with IPF from two separate cohorts at National Jewish Health and Brigham Women's Hospital (n = 181), general population control subjects (n = 160), and control subjects with disease (n = 86 [40 with RA-usual interstitial pneumonia and 46 with hypersensitivity pneumonitis]). Serum was tested for RA-associated antibodies (including IgG and IgA) to citrullinated protein antigens (ACPA). Lung tissue in 11 patients with IPF was examined for ectopic lymphoid aggregates. RESULTS: An increased prevalence of ACPA positivity was found in two separate IPF cohorts. In particular, positivity for IgA-ACPA was increased in these two IPF cohorts compared with general population control subjects (21.3% and 24.8% vs 5.6%; P < .01). Patients with IPF were more likely to be IgA-ACPA-positive than IgG-ACPA-positive (23.2% vs 8.3%; P < .01), whereas patients with RA were more likely to be IgG-ACPA-positive than IgA-ACPA-positive (72.5% vs 52.5%; P = .04). There was a strong correlation between IgA-ACPA level and the number of ectopic lymphoid aggregates on lung histologic examination in IPF (r = 0.72; P = .01). CONCLUSIONS: In this study, IgA-ACPA was elevated in patients with IPF and correlated with lymphoid aggregates in the lung, supporting the theory that IgA-ACPA may play a role in lung disease pathogenesis in a subset of individuals with IPF. Future studies are needed to determine whether this subset of ACPA-positive patients with IPF is distinct from patients with IPF but without antibodies.

Current Perspectives On Emerging Biomarkers For Rheumatoid Arthritis-Associated Interstitial Lung Disease.

Rheumatoid arthritis (RA) is a common systemic autoimmune disease whose fibro-inflammatory manifestations may affect a number of tissues and organs, including the lungs. In fact, interstitial lung disease (ILD) is a leading cause of mortality among patients with RA. RA-related interstitial lung disease (RA-ILD) most often presents in an injury pattern called usual interstitial pneumonia (UIP), which portends a relatively worse prognosis than other less commonly occurring patterns of RA-ILD, like non-specific interstitial pneumonia (NSIP). Biomarkers from serum or bronchoalveolar lavage fluid could aid in the identification of patients at risk for RA-ILD, the detection of patients most likely to develop the UIP pattern of RA-ILD, and the prediction of disease behaviour over time. Notably, the use of highly sensitive serologic biomarkers, including rheumatoid factor (RF) and antibodies targeting cyclic citrullinated peptides, while somewhat specific for RA joint disease, have only limited utility as biomarkers for RA-ILD. Candidate biomarkers for RA-ILD include these and other autoantibodies as well as certain genes and molecules that hold promise as biomarkers in other forms of ILD. In this manuscript, we summarize the state of knowledge on biomarkers for the development and progression of RA-ILD.

Myocardial Microvascular Dysfunction in Rheumatoid ArthritisQuantitation by 13N-Ammonia Positron Emission Tomography/Computed Tomography.

BACKGROUND: The goal of this study was to assess the prevalence of myocardial microvascular dysfunction in rheumatoid arthritis (RA) patients without clinical cardiovascular disease and its association with RA characteristics and measures of cardiac structure and function. METHODS: Participants with RA underwent rest and vasodilator stress N-13 ammonia positron emission tomography and echocardiography. Global myocardial blood flow was quantified at rest and during peak hyperemia. Myocardial flow reserve (MFR) was calculated as peak stress myocardial blood flow/rest myocardial blood flow. A small number of asymptomatic and symptomatic non-RA controls were also evaluated. RESULTS: In RA patients, mean±SD MFR was 2.9±0.8, with 29% having reduced MFR (<2.5). Male sex and higher interleukin-6 were significantly associated with lower MFR, while the use of tumor necrosis factor inhibitors was associated with higher MFR. Lower MFR was associated with higher left ventricle mass index and higher left ventricle volumes but not with ejection fraction or diastolic dysfunction. RA and symptomatic controls had comparable MFR (mean±SD: 2.9±0.8 versus 2.55±0.6; P=0.48). In contrast, MFR was higher in the asymptomatic controls (mean±SD: 3.25±0.7) although not statistically different. CONCLUSIONS: Reduced MFR was observed in a third of RA patients without clinical cardiovascular disease and was associated with a measure of inflammation and with higher left ventricle mass and volumes. MFR in RA patients was similar to controls referred for clinical scans (symptomatic controls). Whether reduced MFR contributes to the increased risk for heart failure in RA remains unknown.

Myocardial Inflammation, Measured Using 18-Fluorodeoxyglucose Positron Emission Tomography With Computed Tomography, Is Associated With Disease Activity in Rheumatoid Arthritis.

OBJECTIVE: To determine the prevalence and correlates of subclinical myocardial inflammation in patients with rheumatoid arthritis (RA). METHODS: RA patients (n = 119) without known cardiovascular disease underwent cardiac 18-fluorodeoxyglucose (FDG) positron emission tomography with computed tomography (PET-CT). Myocardial FDG uptake was assessed visually and measured quantitatively as the standardized uptake value (SUV). Multivariable linear regression was used to assess the associations of patient characteristics with myocardial SUVs. A subset of RA patients who had to escalate their disease-modifying antirheumatic drug (DMARD) therapy (n = 8) underwent a second FDG PET-CT scan after 6 months, to assess treatment-associated changes in myocardial FDG uptake. RESULTS: Visually assessed FDG uptake was observed in 46 (39%) of the 119 RA patients, and 21 patients (18%) had abnormal quantitatively assessed myocardial FDG uptake (i.e., mean of the mean SUV [SUVmean ] ≥3.10 units; defined as 2 SD above the value in a reference group of 27 non-RA subjects). The SUVmean was 31% higher in patients with a Clinical Disease Activity Index (CDAI) score of ≥10 (moderate-to-high disease activity) as compared with those with lower CDAI scores (low disease activity or remission) (P = 0.005), after adjustment for potential confounders. The adjusted SUVmean was 26% lower among those treated with a non-tumor necrosis factor-targeted biologic agent compared with those treated with conventional (nonbiologic) DMARDs (P = 0.029). In the longitudinal substudy, the myocardial SUVmean decreased from 4.50 units to 2.30 units over 6 months, which paralleled the decrease in the mean CDAI from a score of 23 to a score of 12. CONCLUSION: Subclinical myocardial inflammation is frequent in patients with RA, is associated with RA disease activity, and may decrease with RA therapy. Future longitudinal studies will be required to assess whether reduction in myocardial inflammation will reduce heart failure risk in RA.

A Case of Docetaxel Induced Myositis and Review of the Literature.

In phase I and II trials taxane chemotherapeutic agents reported side effects, including myelosuppression, peripheral edema, and fluid retention. With further use of these agents, studies in the late 1980s and early 1990s began to report peripheral neuropathy and proximal muscle weakness as common complaints, the later with unexplained pathophysiology. We report a 65-year-old Hispanic woman with estrogen receptor (ER) and progesterone receptor (PR) positive invasive ductal breast carcinoma who presented with right thigh pain and swelling eight days after her third infusion of docetaxel (a taxane chemotherapeutic) and cyclophosphamide. Laboratory findings were notable for elevation in creatine phosphokinase (CPK), aldolase, and erythrocyte sedimentation rate (ESR); a magnetic resonance imaging (MRI) of her lower extremities showed evidence of bilateral muscle edema involving the anterior compartment muscles of the thighs. A workup to rule out other causes of myositis was negative. Docetaxel was not reintroduced and the patient improved with corticosteroids. Since 2005 this is, to our knowledge, the fifth reported case of docetaxel related inflammatory myositis. Taxanes have been noted to cause disabling but transient arthralgias and myalgias; it is important to consider the possibility of inflammatory myopathy as a possible complication in patients undergoing treatment with these agents.

Indicators of walking speed in rheumatoid arthritis: relative influence of articular, psychosocial, and body composition characteristics.

OBJECTIVE: To explore the contributions from and interactions between articular swelling and damage, psychosocial factors, and body composition characteristics on walking speed in rheumatoid arthritis (RA). METHODS: RA patients underwent the timed 400-meter long-corridor walk. Demographics, self-reported levels of depressive symptoms and fatigue, RA characteristics, and body composition (using whole-body dual X-ray absorptiometry, and abdominal and thigh computed tomography) were assessed and their associations with walking speed explored. RESULTS: A total of 132 RA patients had data for the 400-meter walk, among whom 107 (81%) completed the full 400 meters. Significant multivariable indicators of slower walking speed were older age, higher depression scores, higher reported pain and fatigue, higher swollen and replaced joint counts, higher cumulative prednisone exposure, nontreatment with disease-modifying antirheumatic drugs, and worse body composition. These features accounted for 60% of the modeled variability in walking speed. Among specific articular features, slower walking speed was primarily correlated with large/medium lower-extremity joint involvement. However, these articular features accounted for only 21% of the explainable variability in walking speed. Having any relevant articular characteristic was associated with a 20% lower walking speed among those with worse body composition (P < 0.001), compared with only a 6% lower speed among those with better body composition (P = 0.010 for interaction). CONCLUSION: Psychosocial factors and body composition are potentially reversible contributors to walking speed in RA. Relative to articular disease activity and damage, nonarticular indicators were collectively more potent indicators of an individual's mobility limitations.

Low skeletal muscle mass and risk of functional decline in elderly community-dwelling women: the prospective EPIDOS study.

OBJECTIVES: To assess relationships between low skeletal muscle mass (SMM) and functional decline in community-dwelling elderly women. DESIGN: Secondary analysis of data from EPIDOS, a French prospective observational multicenter cohort study of osteoporosis epidemiology. SETTING: One center in France between 1992 and 1994. PARTICIPANTS: Women aged 75 years or older without disability and with available baseline SMM measurements. MEASUREMENTS: SMM was assessed using dual-energy X-ray absorptiometry and functional decline was defined as loss of at least one Instrumental Activity of Daily Living component. Associations linking low SMM to functional decline were estimated using the Cox proportional hazards model. RESULTS: Of 975 women followed for 4 years, 452 (46.4%) experienced functional decline. Factors independently associated with functional decline were decreased SMM (adjusted hazard ratio [aHR] per SD decrease, 1.12; 95% confidence interval [95% CI], 1.01-1.24), older age (aHR per SD increase, 1.28; 95% CI, 1.17-1.39), one or more comorbidities (aHR, 1.65; 95%CI, 1.05-2.59), and impaired chair-stand test (aHR, 1.35; 95% CI, 1.01-1.82). The second SMM quartile was associated with functional decline (aHR, 1.39; 95% CI, 1.06-1.84) and the lowest quartile showed a nearly significant association (aHR, 1.29; 95% CI, 0.98-1.72). Factors negatively associated with functional decline were living alone (aHR, 0.76; 95% CI, 0.59-0.96), higher handgrip strength (aHR per SD increase, 0.88; 95% CI, 0.78-0.88), and walking speed (aHR per SD increase, 0.86; 95% CI, 0.77-0.96). CONCLUSION: Low SMM was independently associated with functional decline within 4 years after adjustment for age, muscle strength, physical performance, and comorbidities in community-dwelling elderly women.