Association of Antibodies to Citrullinated Protein Antigens with Blood Pressure in First-Degree Relatives of Rheumatoid Arthritis Patients: The Studies of the Etiology of Rheumatoid Arthritis.

BACKGROUND: Hypertension is more common in patients with rheumatoid arthritis (RA) than in the general population. It is unknown whether hypertension is due to RA-related medications or the disease itself. Therefore, we sought to investigate associations between RA-related autoantibodies, specifically antibodies to citrullinated protein antigens (ACPA) and systolic blood pressure (SBP) and diastolic blood pressure (DBP) in first-degree relatives of RA patients, who were free of RA and RA-related medications. We hypothesized that a greater number of detectable ACPA would be associated with high SBP and DBP, independent of other risk factors in these first-degree relatives. METHODS: We evaluated associations between ACPA and SBP and DBP in a cross-sectional study of 72 first-degree relatives (defined as parent, child, or sibling) of RA patients. Fifteen ACPA were measured using a Bio-Plex bead-based assay; each was dichotomized as positive/negative based on pre-specified cut-points. Analysis of covariance was used to evaluate associations between ACPA positivity and SBP and DBP, adjusting for age, sex, race, body mass index (BMI), pack-years of smoking, high sensitivity C-reactive protein (hsCRP), and current use of anti-hypertensive medications. RESULTS: Average age was 51 and 69% were women. Mean SBP was 119 ± 18 and DBP was 74 ± 9 mm Hg. Thirty-three (46%) first-degree relatives were positive for ≥1 ACPA; and were younger, had lower BMI, more pack-years of smoking, and higher hsCRP concentrations compared to ACPA negative first-degree relatives. For each additional positive ACPA, SBP was 0.98 ± 0.5 mm Hg (p = 0.05) higher, and DBP was 0.66 ± 0.3 mm Hg (p = 0.04) higher. Anti-cit-fibrinogen A (211-230) positive and anti-cit-filaggrin positive first-degree relatives had 11.5 and 13.9 mm Hg higher SBP (p = 0.02) respectively. Anti-cit-clusterin, cit-filaggrin, and cit-vimentin positive first-degree relatives had 7-8 mm Hg higher DBP (p = 0.03, 0.05, 0.05 respectively), compared to being negative for these individual ACPA. Consistent with associations between ACPA, SBP, and DBP, anti-cyclic citrullinated peptides (anti-CCP2) positive first-degree relatives had 16.4± (p = 0.03) higher SBP and 12.1± mm Hg (p = 0.01) higher DBP than anti-CCP2 negative first-degree relatives. CONCLUSION: In first-degree relatives without RA, ACPA positivity is associated with higher SBP and DBP. Subclinical autoimmune processes and ACPA may play a role in the vascular changes potentially leading to hypertension prior to RA onset.

Urine Collagen Fragments and CKD Progression-The Cardiovascular Health Study.

Tubulointerstitial fibrosis is common with ageing and strongly prognostic for ESRD but is poorly captured by eGFR or urine albumin to creatinine ratio (ACR). Higher urine levels of procollagen type III N-terminal propeptide (PIIINP) mark the severity of tubulointerstitial fibrosis in biopsy studies, but the association of urine PIIINP with CKD progression is unknown. Among community-living persons aged ≥65 years, we measured PIIINP in spot urine specimens from the 1996 to 1997 Cardiovascular Health Study visit among individuals with CKD progression (30% decline in eGFR over 9 years, n=192) or incident ESRD (n=54) during follow-up, and in 958 randomly selected participants. We evaluated associations of urine PIIINP with CKD progression and incident ESRD. Associations of urine PIIINP with cardiovascular disease, heart failure, and death were evaluated as secondary end points. At baseline, mean age (±SD) was 78±5 years, mean eGFR was 63±18 ml/min per 1.73 m(2), and median urine PIIINP was 2.6 (interquartile range, 1.4-4.2) µg/L. In a case-control study (192 participants, 231 controls), each doubling of urine PIIINP associated with 22% higher odds of CKD progression (adjusted odds ratio, 1.22; 95% confidence interval, 1.00 to 1.49). Higher urine PIIINP level was also associated with incident ESRD, but results were not significant in fully adjusted models. In a prospective study among the 958 randomly selected participants, higher urine PIIINP was significantly associated with death, but not with incident cardiovascular disease or heart failure. These data suggest higher urine PIIINP levels associate with CKD progression independently of eGFR and ACR in older individuals.

The relationship between adiposity-associated inflammation and coronary artery and abdominal aortic calcium differs by strata of central adiposity: The Multi-Ethnic Study of Atherosclerosis (MESA).

Adipokines regulate metabolic processes linked to coronary artery (CAC) and abdominal aorta calcification (AAC). Because adipokine and other adiposity-associated inflammatory marker (AAIM) secretions differ between visceral and subcutaneous adipose tissue, we hypothesized that central adiposity modifies associations between AAIMs and CAC and AAC. We evaluated 1878 MESA participants with complete measures of AAIMs, anthropometry, CAC, and AAC. Associations of AAIMs with CAC and AAC prevalence and severity were analyzed per standard deviation of predictors (SD) using log binomial and linear regression models. The waist-to-hip ratio (WHR) was dichotomized at median WHR values based on sex/ethnicity. CAC and AAC prevalence were defined as any calcium (Agatston score >0). Severity was defined as ln (Agatston score). Analyses examined interactions with WHR and were adjusted for traditional cardiovascular disease risk factors. Each SD higher interleukin-6 (IL-6), fibrinogen and CRP was associated with 5% higher CAC prevalence; and each SD higher IL-6 and fibrinogen was associated with 4% higher AAC prevalence. Associations of IL-6 and fibrinogen with CAC severity, but not CAC prevalence, were significantly different among WHR strata. Median-and-above WHR: each SD higher IL-6 was associated with 24.8% higher CAC severity. Below-median WHR: no association (p interaction=0.012). Median-and-above WHR: each SD higher fibrinogen was associated with 19.6% higher CAC severity. Below-median WHR: no association (p interaction=0.034). Adiponectin, leptin, resistin, and tumor necrosis factor-alpha were not associated with CAC or AAC prevalence or severity. These results support findings that adiposity-associated inflammation is associated with arterial calcification, and further add that central adiposity may modify this association.

Performance of anti-cyclic citrullinated Peptide assays differs in subjects at increased risk of rheumatoid arthritis and subjects with established disease.

OBJECTIVE: To compare the diagnostic accuracy and agreement of commonly available assays for anti-citrullinated protein antibodies in patients with established rheumatoid arthritis (RA) and subjects at increased risk of RA. METHODS: Tests for anti-cyclic citrullinated peptide (anti-CCP) antibodies were performed using CCP2 IgG and CCP3.1 IgA/IgG enzyme-linked immunosorbent assays in the following groups: probands with established RA (n = 340) from the Studies of the Etiology of Rheumatoid Arthritis (SERA) cohort and their first-degree relatives (FDRs) without inflammatory arthritis (n = 681), Department of Defense Serum Repository (DoDSR) RA cases with pre-RA diagnosis samples (n = 83; 47 cases also had post-RA diagnosis samples), and blood donor and DoDSR control subjects (n = 283). RESULTS: In patients with established RA, the CCP2 assay was more specific (99.2% versus 93.1%; P < 0.01) but less sensitive (58.7% versus 67.4%; P = 0.01) than the CCP3.1 assay; the specificity of the CCP3.1 assay increased to 97.2% when cutoff levels ≥3-fold the standard level were considered. In all subjects, CCP3.1 assay positivity (using standard cutoff levels) was more prevalent. Among DoDSR cases, the CCP2 assay was more specific than the CCP3.1 for predicting a future diagnosis of RA, and higher CCP levels trended toward increasing specificity for the development of RA within 2 years. At standard cutoff levels, assay agreement was good in patients with established RA (κ = 0.76) but poor in FDRs without inflammatory arthritis (κ = 0.25). CONCLUSION: Anti-CCP assays differ to an extent that may be meaningful for diagnosing RA in patients with inflammatory arthritis and evaluating the natural history of RA development in subjects at risk of RA. The mechanisms underlying these differences in test performance need further investigation.

Relatives without rheumatoid arthritis show reactivity to anti-citrullinated protein/peptide antibodies that are associated with arthritis-related traits: studies of the etiology of rheumatoid arthritis.

OBJECTIVE: To examine reactivity to anti-citrullinated protein/peptide antibodies (ACPAs) and determine associations between ACPAs and other rheumatoid arthritis (RA)-related autoantibodies and clinically assessed swollen or tender joints in unaffected first-degree relatives of RA patients. METHODS: Serum samples were obtained from first-degree relatives without RA according to the 1987 American College of Rheumatology (ACR) and the 2010 ACR/European League Against Rheumatism classification criteria. A bead-based assay was used to measure 16 separate ACPAs in sera from 111 antibody-positive first-degree relatives who were positive on at least 1 visit for any of 5 RA-related autoantibodies (rheumatoid factor [RF], anti-cyclic citrullinated peptide 2 [anti-CCP-2], and RF isotypes), and sera from 99 antibody-negative first-degree relatives who were never autoantibody positive. Cutoffs for positivity for each ACPA were determined using receiver operating characteristic curves derived from data on 200 RA patients and 98 blood donor controls, in which positivity for ≥9 ACPAs had 92% specificity and 62% sensitivity for RA. In first-degree relatives, ACPA reactivity was assessed, and associations between ACPAs (number positive, and positivity for ≥9 ACPAs) and RA-related characteristics were examined. RESULTS: Fifty-seven percent of anti-CCP-2-positive first-degree relatives and 8% of anti-CCP-2- negative first-degree relatives were positive for ≥9 ACPAs. After adjusting for age, sex, ethnicity, and pack-years of smoking, an increasing number of ACPAs was directly associated with the presence of ≥1 tender joint on examination (odds ratio [OR] 1.18, 95% confidence interval [95% CI] 1.04-1.34), with the greatest risk of having ≥1 tender joint seen in first-degree relatives positive for ≥9 ACPAs (OR 5.00, 95% CI 1.37-18.18). CONCLUSION: RA-free first-degree relatives (even those negative for RF and anti-CCP-2) demonstrate reactivity to multiple ACPAs, and the presence of an increasing number of ACPAs may be associated with signs of joint inflammation. Prospective evaluation of the relationship between these findings and the progression of classifiable RA is warranted.

Multiple cytokines and chemokines are associated with rheumatoid arthritis-related autoimmunity in first-degree relatives without rheumatoid arthritis: Studies of the Aetiology of Rheumatoid Arthritis (SERA).

OBJECTIVE: We investigated whether rheumatoid arthritis (RA)-related autoantibodies were associated with systemic inflammation in a prospective cohort of first-degree relatives (FDRs) of RA probands, a population without RA but at increased risk for its future development. METHODS: We studied 44 autoantibody positive FDRs, of whom 29 were rheumatoid factor (RF) positive, 25 were positive for the high risk autoantibody profile (HRP), that is, positive for anti-cyclic citrullinated peptide and/or for at least two RF IgM, IgG or IgA isotypes, and nine FDRs who were positive for both; and 62 FDRs who were never autoantibody positive. Twenty-five cytokines/chemokines were measured using a bead-based assay in serum. As a comprehensive measure of inflammation, we calculated a Cytokine Score by summing all cytokine/chemokine levels, weighted by their regression coefficients for RA-autoantibody association. We compared C-reactive protein, individual cytokines/chemokines and Cytokine Score to the outcomes: positivity for RF and for the HRP using logistic regression. RESULTS: Adjusting for age, sex, ethnicity and ever smoking, the Cytokine Score and levels of IL-6 and IL-9 were associated with both RF and HRP. IL-2, granulocyte macrophage-colony stimulating factor (GM-CSF), and interferon (IFN)-γ were associated with HRP only. Associations between the Cytokine Score and RF and HRP positivity were replicated in an independent military personnel cohort. CONCLUSIONS: In first-degree relatives of patients with RA, RA-related autoimmunity is associated with inflammation, as evidenced by associations with multiple cytokines and chemokines.

Serum reactivity to citrullinated protein/peptide antigens and left ventricular structure and function in the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Antibodies to citrullinated protein antigens have been linked to altered left ventricular (LV) structure and function in patients with rheumatoid arthritis (RA). Serum reactivity to several citrullinated protein/peptide antigens has been identified in RA, which are detectable years before RA onset and in individuals who may never develop RA. Among community-living individuals without heart failure (HF) at baseline in the Multi-Ethnic Study of Atherosclerosis (MESA), we investigated associations between serum reactivity to citrullinated protein/peptide antigens, LV mass, LV ejection fraction (LVEF), and incident HF. METHODS: Among 1232 MESA participants, we measured serum reactivity to 28 different citrullinated proteins/peptides using a multiplex bead-based array. Each antibody was defined as having extremely high reactivity (EHR) if >95th percentile cut-off in MESA. Number of EHR antibody responses to citrullinated protein/peptide antigens were summed for each participant (range 0-28). LV mass(g) and LVEF(%) were measured on cardiac MRI. Associations between EHR antibodies and LV mass and LVEF were evaluated using linear regression. Cox proportional hazards models were used to evaluate associations between EHR antibodies and incident HF during 11 years of follow-up, adjusting for age, gender, race/ethnicity, smoking status, systolic blood pressure, use of anti-hypertensive medications, self-reported arthritis, IL-6, body surface area, and estimated glomerular filtration rate. RESULTS: Mean age was 65±10, 50% were female, 40% were White, 21% were Black, 26% were Hispanic/Latino, and 14% were Chinese. Twenty-seven percent of MESA participants had extremely high reactivity to ≥ 1 citrullinated protein/peptide antigen. In fully adjusted analysis, every additional EHR antibody was significantly associated with 0.1% lower LVEF (95% CI: -0.17%, -0.02%). No association was observed with LV mass (ß per additional EHR antibody) = 0.13±0.15 (p = 0.37)). Neither the presence nor number of EHR antibodies was associated with incident HF during follow-up (HR per additional EHR antibody = 1.008 (95% CI: 0.97, 1.05)). CONCLUSION: Greater number of extremely highly reactive antibodies was associated with lower LVEF, but not with LV mass or incident HF. Thus, serum reactivity to citrullinated protein/peptide antigens was associated with subtle subclinical changes in myocardial contractility, but the significance in relation to clinically apparent HF is uncertain.

The Association of Metabolic Syndrome and Obesity With Clinical Hip Osteoarthritis in the Study of Osteoporotic Fractures and the Osteoporotic Fractures in Men Study Cohorts.

OBJECTIVE: Metabolic dysregulation frequently co-occurs with obesity, which has been shown to be a risk factor for lower extremity osteoarthritis (OA). We evaluated the association between metabolic syndrome (MetS), alone and in combination with obesity, and hip OA. METHODS: In two parallel cross-sectional analyses, we studied 403 women from the Study of Osteoporotic Fractures (SOF) and 2354 men from the Osteoporotic Fractures in Men (MrOS) study. We used multivariable logistic regression to evaluate associations of obesity (body mass index ≥30 kg/m2 ) and/or MetS (three of five National Cholesterol Education Program Adult Treatment Panel III criteria) with clinical hip OA, defined as a modified Croft score of 2 or more or total hip replacement, and pain or limited range of motion. Our analysis adjusted for demographics. RESULTS: Approximately 3.5% of SOF women and 5.4% of MrOS men had clinical hip OA. Among women, obesity was not associated with hip OA, yet those with MetS had a 365% higher odds of hip OA (95% CI: 1.37-15.83). Among men, those who had obesity had a 115% higher odds of hip OA (95% CI: 1.39-3.32), yet MetS was not associated with hip OA. There was no interaction between MetS, obesity, and hip OA in either women or men. CONCLUSION: In women, but not in men, MetS was associated with hip OA. In men, but not in women, obesity was associated with hip OA. These findings suggest that mechanical effects of obesity may predominate in the pathogenesis of hip OA in men, whereas metabolic effects predominate in women.

A Simple and Versatile Test for Elbow Posterolateral Rotatory Instability.

BACKGROUND: Posterolateral rotatory instability (PLRI) results from lateral ulnar collateral ligament (LCL) deficiency. The lateral pivot shift test is used to diagnose PLRI but can be difficult to perform and is poorly tolerated. We present a new maneuver, the Posterior Radiocapitellar Subluxation Test (PRST), that we believe is easier to perform. The purpose of this study was to compare the efficacy and reproducibility of the PRST with the lateral pivot shift test. METHODS: We obtained 10 cadaveric upper extremity specimens, performed a Kocher approach on each, released the LCL origin in 5, then closed. The specimens were randomized, and 3 attending orthopedic surgeons and 1 resident blindly performed the PRST then the lateral pivot shift test after re-randomization and assessed presence or absence of PLRI. This process was repeated the following day. The data for each test were analyzed for sensitivity, specificity, and accuracy. RESULTS: For the blinded testing when comparing PRST with the pivot shift test, overall accuracy was 77.5%, compared with 67.5% (P = .03), sensitivity was 75.0%, compared with 50.0% (P = .003), and specificity was 80.0%, compared with 85.0% (P = .55). Conclusions: The PRST appears to be at least as accurate as the lateral pivot shift test, with comparable intraobserver and interobserver reliability.

Musculoskeletal injuries sustained at the California, USA: Baja California, Mexico border.

BACKGROUND: Individuals attempting to enter the USA from Mexico at non-authorized points along the border fence often sustain injuries requiring medical intervention. We evaluated characteristics of this patient population and their hospital care to better understand patient treatment needs. Given the high-velocity nature of these injuries, we hypothesized that higher pain scores would be associated with longer lengths of hospital stay. METHODS: In this cross-sectional study, we selected records of all patients from 2013 to 2019 who received care by the Orthopaedic Surgery department following an injury sustained at the California-Baja California border. We evaluated demographics, musculoskeletal injuries, procedures, length of hospital stay (LOS), follow-up, and pain scores via retrospective chart review. We used linear regression, adjusting for age and gender, to evaluate associations between pain scores and hospital LOS. RESULTS: Among all 168 patients, there were 248 total injuries comprised of 46% lower extremity, 15% upper extremity, 17% spine, and 4% pelvic injuries. Average age at injury was 33 ± 10, 74% were male, and 85% identified as Hispanic. Of this patient population, 68% underwent operative interventions, 26% sustained open injuries, and 21% required external fixation for initial injury stabilization. Thirteen percent were seen for follow-up after discharge. Spine (n = 42), pilon (n = 36), and calcaneus fractures (n = 25) were the three most common injury types. Average LOS for all patients was 7.8 ± 8.1 days. Pain scores were not significantly associated with LOS ( p = 0.08). However, for every surgical procedure performed, hospital LOS was increased by 5.16 ± 0.47 days (p < 0.001). CONCLUSION: Many injuries incurred by patients crossing the border were severe, requiring multiple surgical interventions and a prolonged LOS. The higher number of procedures was significantly associated with longer LOS in all operatively treated patients. Future studies are needed to determine how we can optimize care for this unique patient population and facilitate post-discharge care.

Density and Fat Fraction of the Psoas, Paraspinal, and Oblique Muscle Groups Are Associated With Lumbar Vertebral Bone Mineral Density in a Multi-Ethnic Community-Living Population: The Multi-Ethnic Study of Atherosclerosis.

Low vertebral bone mass is a major risk factor for vertebral compression fractures. Although sarcopenia has been shown to be associated with low bone mineral density (BMD), it is not known whether trunk musculature is directly associated with lumbar BMD, and whether exercise modifies this association. Using data from the Multi-Ethnic Study of Atherosclerosis (MESA), we sought to determine the association of muscle density and fat fraction of the psoas, paraspinal, and oblique muscle groups with L3 lumbar volumetric BMD, and whether these associations were modified by exercise. We obtained L3 vBMD measurements, and fat and muscle measurements (in Hounsfield units [HU]) from abdominal computed tomography (CT) scans spanning the L2 -L4 intervertebral disc spaces. Muscle density was defined as the mean HU value for a muscle group area. Fat fraction was calculated as the mean HU value for the muscle group fat area/total muscle group area (cm2 ). Exercise data were self-reported (MET-minute/week). We utilized multivariable linear regression to evaluate these associations, stratified by gender, and adjusting for demographics, body mass index (BMI), smoking status, impaired fasting glucose, and corticosteroid and anti-resorptive medication use. Among 1923 MESA participants, mean ± standard deviation (SD) age was 62 ± 10 years, 49% were female, 40% white, 21% black, 26% Hispanic/Latino, and 13% Chinese. In fully adjusted analysis, for every 1-SD higher psoas fat fraction, there was a 3.19-SD lower L3 vBMD in men and 4.3-SD lower L3 vBMD in women (p < 0.001). For every 1-SD higher psoas density, there was a 0.2-SD higher L3 vBMD (p < 0.001) in men and 0.19-SD higher L3 vBMD (p < 0.001) in women. Findings were similar for paraspinal and oblique muscles. Intentional exercise did not modify these associations. In men and women, trunk muscle density was positively associated with higher lumbar BMD, suggesting a local association. Future studies are warranted to determine the temporality of this association. © 2022 American Society for Bone and Mineral Research (ASBMR).

Surgical site peptidylarginine deaminase 4 (PAD4), a biomarker of NETosis, correlates with insulin resistance in total joint arthroplasty patients: A preliminary report.

While obesity and insulin resistance are known risk factors for wound complications after total joint arthroplasty (TJA), the biologic causes remain to be elucidated. Recently, neutrophil extracellular trap formation (NETosis) was identified as a mediator of delayed wound healing in insulin resistant states. Herein, we explored the relationship between obesity, insulin resistance and biomarkers of NET formation in TJA subjects. We enrolled 14 obese (body mass index [BMI]≥30 kg/m2), and 15 lean (BMI<30 kg/m2) subjects undergoing primary knee or hip TJA. On the day of surgery, skeletal muscle proximal to the operated joint and plasma were collected. Protein abundance of NETosis biomarkers, peptidylarginine deaminase 4 (PAD4) and neutrophil elastase (NE) were assessed in skeletal muscle by immunoblotting and metabolic parameters (glucose, insulin, triglycerides, free fatty acids) and cell-free double-stranded DNA (cf-dsDNA) were assessed in plasma and were correlated with obesity and insulin resistance (as measured by the homeostatic model assessment for insulin resistance). When comparing lean and obese subjects, there were no significant differences in plasma cf-dsDNA or skeletal muscle NE or PAD4 abundance. In contrast, skeletal muscle PAD4 abundance, but not NE or plasma cf-dsDNA, was positively correlated with insulin resistance. Compared to insulin sensitive subjects, insulin resistant TJA subjects have higher expression of PAD4 at the surgical site and therefore may have higher rates of NET formation, which may lead to delayed surgical site wound healing.

Regional variation in bone turnover at the iliac crest versus the greater trochanter.

BACKGROUND: Iliac crest bone biopsy with histomorphometry is the gold standard for diagnosis of abnormalities in bone turnover, yet fractures more frequently occur at the greater trochanter of the hip. Whether bone turnover is similar at these two anatomic sites within individuals is uncertain. METHODS: We collected bone biopsy samples from the ipsilateral iliac crest and greater trochanter in 9 deceased individuals undergoing autopsies at an academic medical center between March-August 2018. We measured 14 static bone histomorphometry parameters including osteoclast number (N.Oc/T.A), eroded surface (ES/BS), trabecular separation (Tb.Sp), osteoclast surface (Oc.S/BS) and osteoid volume (OV/BV) as markers of bone turnover, mineralization, and volume (TMV), and evaluated the correlation of these markers between the iliac crest and greater trochanter. RESULTS: Average age at time of death was 58 ± 15 years, 2 were women, and average time from death to autopsy was 2.9 ± 1.8 days. Overall, correlations of the markers of bone turnover across the two sites were poor, ranging from as low as 0 for Tb.Sp (p = 1.0) to as high as 0.583 for Oc.S/BS (p = 0.102). CONCLUSIONS: Static histomorphometric measures of bone turnover at the iliac crest may not provide reliable information about turnover at other anatomic sites.

Evaluating associations of joint swelling, joint stiffness and joint pain with physical activity in first-degree relatives of patients with rheumatoid arthritis: Studies of the Aetiology of Rheumatoid Arthritis (SERA), a prospective cohort study.

OBJECTIVE: Physical activity (PA) in preclinical rheumatoid arthritis (RA) is associated with lower RA risk and disease severity. As joint signs and symptoms of inflammatory arthritis serve as a barrier to PA in RA, it is important to consider whether they affect PA in the time prior to RA. Therefore, we investigated whether joint swelling, stiffness or pain were associated with PA in first-degree relatives (FDRs) of patients with RA, a population at higher risk for future RA. DESIGN: Prospective study design. SETTING: We recruited FDRs of patients with RA from academic centres, Veterans' hospitals and rheumatology clinics or through responses to advertising from six sites across the USA. PARTICIPANTS: We evaluated associations of joint stiffness, joint swelling and joint pain with PA time in 268 FDRs with ≥2 visits over an average 1.2 years. Clinicians confirmed joint swelling. Participants self-reported joint stiffness and/or pain. PRIMARY OUTCOME MEASURES: PA during a typical 24-hour day was quantified via questionnaire, weighted to reflect metabolic expenditure, where 24 hours was the minimum PA time. Linear mixed models evaluated associations between symptoms and change in PA over time, adjusting for age, sex, race, body mass index, smoking and RA-related autoantibodies. RESULTS: Average weighted PA time was 37±7 hours. In the cross-sectional analysis, PA time was 1.3±0.9 hours higher in FDRs reporting joint pain (p=0.15); and 0.8±1.6 and 0.4±1 hours lower in FDRs with joint swelling (p=0.60) and stiffness (p=0.69), respectively. Longitudinally, adjusting for baseline PA time, baseline symptoms were not significantly associated with changes in PA time. However, on average over time, joint stiffness and pain were associated with lower PA time (pinteraction=0.0002, pinteraction=0.002), and joint swelling was associated with higher PA time (pinteraction <0.0001). CONCLUSION: Baseline symptoms did not predict future PA time, but on average over time, joint symptoms influenced PA time.

Metabolic Syndrome Is Associated With Higher Risk of Wound Complications After Total Hip Arthroplasty.

BACKGROUND: Obesity is prevalent among patients undergoing total hip arthroplasty and has been associated with the risk of wound complications, particularly when an anterior approach is used. However, most studies have focused on obesity defined by the body mass index (BMI), without considering the metabolic effects of adiposity. Thus, in this study, we investigated the independent effects of the BMI and metabolic syndrome on wound complications after total hip arthroplasty. METHODS: Among 804 consecutive patients undergoing total hip arthroplasty between October 2013 and July 2016, we evaluated the associations between obesity (BMI ≥30 mg/kg2), metabolic syndrome (defined by the National Cholesterol Education Program Adult Treatment Panel III guidelines), and wound complication (defined as documented wound dehiscence, drainage, erythema, hematoma, infection, or seroma) over a 1-year follow-up period. We used Cox proportional hazards models adjusting for demographics, smoking status, and hospital length of stay. RESULTS: Patients' mean age at time of surgery was 62.0 ± 11.9 years. Forty-seven percent were male, 27.9% were obese, and 11.6% met the definition for metabolic syndrome. Metabolic syndrome was associated with a 4-fold higher risk of wound complication (95% confidence interval: 1.4-11.1) after adjusting for all covariates including the BMI. In unadjusted analysis, obesity was associated with a higher risk of wound complication (hazard ratio: 2.8, 95% confidence interval: 1.3-6.2). However, obesity was not associated with the risk of wound complication after adjusting for the metabolic syndrome (P = .16). CONCLUSIONS: Metabolic syndrome, but not obesity, defined by a BMI ≥30, was associated with wound complications, suggesting that metabolic effects of adiposity may represent a distinct risk factor in the development of wound complications from a higher BMI alone.

Biomarkers of Bone Turnover Identify Subsets of Chronic Kidney Disease Patients at Higher Risk for Fracture.

BACKGROUND: We sought to identify biomarkers that indicate low turnover on bone histomorphometry in chronic kidney disease (CKD) patients, and subsequently determined whether this panel identified differential risk for fractures in community-dwelling older adults. METHODS: Among CKD patients who underwent iliac crest bone biopsies and histomorphometry, we evaluated candidate biomarkers to differentiate low turnover from other bone disease. We applied this biomarker panel to 641 participants in the Health Aging and Body Composition Study (Health ABC) study with estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2 who were followed for fracture. Cox proportional hazards models evaluated the association of bone mineral density (BMD) with fracture risk and determined whether biomarker-defined low bone turnover modified fracture risk at any level of BMD. RESULTS: In 39 CKD patients age 64 ± 13 years, 85% female, with mean eGFR 37 ± 14 mL/min/1.73 m2 who underwent bone biopsy, lower fibroblast growth factor (FGF)-23, higher ɑ-Klotho, and lower parathyroid hormone (PTH) indicated low bone turnover in accordance with bone histomorphometry parameters (individual area under the curve = 0.62, 0.73, and 0.55 respectively; sensitivity = 22%, specificity = 100%). In Health ABC, 641 participants with CKD were age 75 ± 3 years , 49% female, with mean eGFR 48 ± 10 mL/min/1.73 m2. For every SD lower hip BMD at baseline, there was an 8-fold higher fracture risk in individuals with biomarker-defined low turnover (hazard ratio 8.10 [95% CI, 3.40-19.30]) vs a 2-fold higher risk in the remaining individuals (hazard ratio 2.28 [95% CI, 1.69-3.08]) (Pinteraction = .082). CONCLUSIONS: In CKD patients who underwent bone biopsy, lower FGF-23, higher ɑ-Klotho, and lower PTH together had high specificity for identifying low bone turnover. When applied to older individuals with CKD, BMD was more strongly associated with fracture risk in those with biomarker-defined low turnover.

Lumbar Muscle Structure Predicts Operational Postures in Active-Duty Marines.

Background The relationship between lumbar spine posture and muscle structure is not well understood. Objectives To investigate the predictive capacity of muscle structure on lumbar spine posture in active-duty Marines. Methods Forty-three Marines were scanned in this cross-sectional study, using an upright magnetic resonance imaging scanner while standing without load and standing, sitting, and prone on elbows with body armor. Cobb, horizontal, and sacral angles were measured. Marines were then scanned while unloaded in supine using a supine magnetic resonance imaging scanner. The imaging protocol consisted of T2 intervertebral disc mapping; high-resolution, anatomical, fat-water separation, and diffusion tensor imaging to quantify disc hydration and muscle volume, fat fraction, and restricted diffusion profiles in the lumbar muscles. A stepwise multiple linear regression model was used to identify physiological measures predictive of lumbar spine posture. Results The multiple regression model demonstrated that fractional anisotropy of the erector spinae was a significant predictor of lumbar posture for 7 of 18 dependent variables measured, and explained 20% to 35% of the variance in each model. Decreased fractional anisotropy of the erector spinae predicted decreased lordosis, lumbosacral extension, and anterior pelvic tilt. Conclusion Fractional anisotropy is inversely related with muscle fiber size, which is associated with the isometric force-generating capacity of a muscle fiber. This suggests that stronger erector spinae muscles predict decreased lordosis, lumbosacral extension, and anterior pelvic tilt in a highly trained population. J Orthop Sports Phys Ther 2018;48(8):613-621. Epub 17 May 2018. doi:10.2519/jospt.2018.7865.

Plasma adiponectin levels are associated with circulating inflammatory cytokines in autoantibody positive first-degree relatives of rheumatoid arthritis patients.

BACKGROUND: Extra-articular manifestations of rheumatoid arthritis (RA), potentially due to systemic inflammation, include cardiovascular disease and sarcopenic obesity. Adiponectin, an adipose-derived cytokine, has been implicated in inflammatory processes in RA, but little is known regarding its association with inflammation in a pre-clinical period. Therefore, we investigated whether adiponectin was associated with inflammatory markers in individuals at risk for RA, and whether RA-related autoimmunity modifies these associations. METHODS: We analyzed samples from 144 first-degree relatives (FDRs) of RA probands, of whom 23 were positive for anti-cyclic citrullinated peptide antibody and/or ≥ 2 rheumatoid factor isotypes (IgM, IgG or IgA). We called this phenotype the 'high risk autoantibody profile (HRP)' as it has been shown in prior work to be >96% specific for future RA. We measured adiponectin, cytokines, and high-sensitivity C-reactive protein (hsCRP). Using linear mixed effects models, we evaluated interaction between HRP positivity and adiponectin on inflammatory markers, adjusting for age, sex, ethnicity, body mass index, pack-years smoking, and use of cholesterol-lowering medications. RESULTS: In everyone, adiponectin concentration was inversely associated with hsCRP and IL-1ß in adjusted models, where a 1% higher adiponectin was associated with a 26% lower hsCRP (p = 0.04) and a 26% lower IL-1ß (p = 0.04). Significant interactions between HRP and adiponectin for associations with GM-CSF, IL-6, and IL-9 were detected in fully adjusted models (p = 0.0006, p = 0.006, p = 0.01, respectively). In HRP positive FDRs but not HRP negative FDRs, a 1% higher adiponectin was associated with 97% higher GM-CSF, 73% higher IL-6, and 54% higher IL-9 concentrations. CONCLUSIONS: Adiponectin associates with inflammatory markers, and these associations differ in individuals with a high-risk autoantibody profile compared with those without. The interaction between adiponectin and autoimmunity warrants further investigation into the potential systemic effects of RA-related autoantibodies and adiponectin on inflammation in the absence of clinically apparent RA.

The Relation of Serum Potassium Concentration with Cardiovascular Events and Mortality in Community-Living Individuals.

BACKGROUND AND OBJECTIVES: Hyperkalemia is associated with adverse outcomes in patients with CKD and in hospitalized patients with acute medical conditions. Little is known regarding hyperkalemia, cardiovascular disease (CVD), and mortality in community-living populations. In a pooled analysis of two large observational cohorts, we investigated associations between serum potassium concentrations and CVD events and mortality, and whether potassium-altering medications and eGFR<60 ml/min per 1.73 m2 modified these associations. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 9651 individuals from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS), who were free of CVD at baseline (2000-2002 in the MESA and 1989-1993 in the CHS), we investigated associations between serum potassium categories (<3.5, 3.5-3.9, 4.0-4.4, 4.5-4.9, and ≥5.0 mEq/L) and CVD events, mortality, and mortality subtypes (CVD versus non-CVD) using Cox proportional hazards models, adjusting for demographics, time-varying eGFR, traditional CVD risk factors, and use of potassium-altering medications. RESULTS: Compared with serum potassium concentrations between 4.0 and 4.4 mEq/L, those with concentrations ≥5.0 mEq/L were at higher risk for all-cause mortality (hazard ratio, 1.41; 95% confidence interval, 1.12 to 1.76), CVD death (hazard ratio, 1.50; 95% confidence interval, 1.00 to 2.26), and non-CVD death (hazard ratio, 1.40; 95% confidence interval, 1.07 to 1.83) in fully adjusted models. Associations of serum potassium with these end points differed among diuretic users (Pinteraction<0.02 for all), such that participants who had serum potassium ≥5.0 mEq/L and were concurrently using diuretics were at higher risk of each end point compared with those not using diuretics. CONCLUSIONS: Serum potassium concentration ≥5.0 mEq/L was associated with all-cause mortality, CVD death, and non-CVD death in community-living individuals; associations were stronger in diuretic users. Whether maintenance of potassium within the normal range may improve clinical outcomes requires future study.

Associations between cystatin C-based eGFR, ambulatory blood pressure parameters, and in-clinic versus ambulatory blood pressure agreement in older community-living adults.

OBJECTIVES: The objective of this study was to determine the relationship between chronic kidney disease [CKD; measured using cystatin C-based estimated glomerular filtration rate (eGFR)] and abnormal ambulatory blood pressure (including nocturnal dipping) in healthy older adults. Further, this study aimed to assess the agreement between clinic and ambulatory blood pressure monitoring. METHODS: Serum cystatin C levels were measured to calculate eGFR. Participants underwent clinic and 24-h ambulatory blood pressure measurements. Multiple linear regression was performed to examine the association between reduced cystatin C-based eGFR (CKDcys) and blood pressure parameters. Bland-Altman analysis was carried out to evaluate the agreement between clinic and ambulatory measurements. RESULTS: The average age was 72 years. There were 60 individuals with CKDcys (eGFR<60 ml/min/1.73 m). Compared with those without CKDcys, individuals with CKDcys were older, more likely to have hypertension, and less likely to have normal dipping patterns. On multivariate analysis, the presence of CKDcys was found to be significantly associated with a lower mean ambulatory diastolic blood pressure (-2 mmHg, P=0.048), but not with nocturnal dipping or other blood pressure parameters. Clinic systolic blood pressure (SBP) significantly overestimated the mean wake-time ambulatory SBP; the mean difference was 11 mmHg for those without CKDcys (95% limits of agreement -14 to 35 mmHg) and 14 mmHg for those with CKDcys (95% limits of agreement -13 to 41 mmHg); there was no statistically significant effect modification by CKD status. CONCLUSION: In older, seemingly healthy adults, mild CKD was associated with lower ambulatory diastolic blood pressure. The presence of CKD did not affect interpretation of clinic versus ambulatory blood pressure monitoring, although the accuracy of clinic SBP was poor.