Publications by authors named "Amanda E Nelson"

58 Publications

The Prevalence of Knee Symptoms, Radiographic, and Symptomatic Osteoarthritis at Four Time Points: The Johnston County Osteoarthritis Project, 1999-2018.

ACR Open Rheumatol 2021 Jul 10. Epub 2021 Jul 10.

University of North Carolina at Chapel Hill.

Objective: To describe point prevalence of knee symptoms, radiographic knee osteoarthritis (rKOA), severe rKOA, and symptomatic rKOA at four time points in the longitudinal, population-based Johnston County Osteoarthritis Project (JoCo OA).

Methods: Data were from 2573 JoCo OA participants with up to 18 years of follow-up (1999-2018) and standardized fixed-flexion knee radiographs read by a single, reliable expert musculoskeletal radiologist. The four outcomes were 1) self-reported knee symptoms, defined by "On most days, do you have pain, aching, or stiffness in your right/left knee?"; 2) rKOA, defined as a Kellgren-Lawrence grade (KLG) of 2 to 4); 3) severe rKOA, defined as a KLG of 3 or 4; and 4) symptomatic rKOA, defined as both symptoms and rKOA in the same joint. Weighted prevalence estimates and 95% confidence intervals (CIs) were generated overall and by age group, sex, race, and body mass index (BMI).

Results: Most recently (2017-2018, T4), the overall prevalence (percentage) of knee symptoms, rKOA, severe rKOA, and symptomatic rKOA was 41% (95% CI: 35-47%), 61% (95% CI: 56-67%), 35% (95% CI: 30-40%), and 30% (95% CI: 24-35%), respectively. From time point T1 to T4, prevalence increased for rKOA, severe rKOA, and symptomatic rKOA but not for knee symptoms. The prevalence of both severe rKOA (17-39%) and symptomatic rKOA (23-30%) was consistently higher among women. The prevalence of all outcomes was higher among those with higher BMI and among Black participants at all time points, particularly rKOA (35-69%) and severe rKOA (22-46%).

Conclusion: These updated estimates demonstrate a large and increasing burden of knee OA, particularly among women and Black individuals.
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http://dx.doi.org/10.1002/acr2.11295DOI Listing
July 2021

Associations between baseline and longitudinal semi-automated quantitative joint space width at the hip and incident hip osteoarthritis: Data from a community-based cohort.

Arthritis Care Res (Hoboken) 2021 Jul 5. Epub 2021 Jul 5.

Department of Radiology, Brigham and Women's Hospital, Boston, MA, USA.

Objective: To evaluate quantitative joint space width (qJSW, at 10-, 30-, and 50-degree locations) in relation to incident radiographic and symptomatic hip osteoarthritis (rHOA and sxHOA, respectively) in a community-based cohort.

Methods: Data were from Johnston County OA Project (JoCoOA) participants with supine hip radiographs at each of 4 timepoints; all had Kellgren-Lawrence grades (KLG) and qJSW. We assessed covariates (age, race, height, weight, body mass index [BMI]) associated with qJSW, and hip-level associations between qJSW and HOA, over time using sex-stratified and multivariable-adjusted linear mixed models. A cluster analysis with logistic regression estimated associations between qJSW trajectory groups and incident rHOA and sxHOA.

Results: At baseline, 397 participants (784 hips, 41% men, 24% Black, mean age=57 years) had a mean BMI=29 kilograms/meter . Over a mean of 18 years, 20% and 12% developed incident KLG-defined rHOA or sxHOA, respectively. QJSW was more sensitive to changes over time at 50 degrees. Values were stable among men but declined over time in women. Heavier women lost more qJSW; changes in qJSW were not significantly associated with race, education, or injury in women or men. In women only, loss of qJSW over time was associated with 2-3 times higher odds of rHOA and sxHOA; among women and men, narrower baseline qJSW was associated with these outcomes.

Conclusion: Hip qJSW demonstrates marked sex differences, with significant loss over time only in women. Loss of qJSW over time in women, and narrower baseline qJSW in men and women, was associated with incident rHOA and sxHOA.
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http://dx.doi.org/10.1002/acr.24742DOI Listing
July 2021

Associations of Comorbid Conditions and Transitions Across States of Knee Osteoarthritis in a Community-Based Cohort.

ACR Open Rheumatol 2021 Jul 1. Epub 2021 Jul 1.

University of North Carolina at Chapel Hill.

Objective: To examine relationships between knee osteoarthritis (KOA) and obesity, diabetes mellitus (DM), and cardiovascular disease (CVD).

Methods: Associations of time-dependent obesity, DM, and CVD with KOA transition states over approximately 18 years were examined among 4093 participants from a community-based cohort. Transition states were 1) no knee symptoms and no radiographic KOA (rKOA; Kellgren-Lawrence grade ≥2 in at least one knee), 2) asymptomatic rKOA, 3) knee symptoms only, 4) symptomatic rKOA (sxKOA; rKOA and symptoms in same knee). Markov multistate models estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for associations between comorbid conditions and transitions across states, adjusting for baseline age, sex, race, education, enrollment cohort, birth year, and time-dependent knee injury history.

Results: At baseline, 40% of participants had obesity, 13% had DM, and 22% had CVD (mean age = 61 years; 34% Black; 37% male). Compared with those without obesity, those with obesity had a higher hazard of worsening from no rKOA/no symptoms to asymptomatic rKOA (aHR = 1.7; 95% CI = 1.3-2.2) and from knee symptoms to sxKOA (aHR = 1.7; 95% CI = 1.3-2.3), as well as a lower hazard of symptom resolution from sxKOA to asymptomatic rKOA (aHR = 0.5 [95% = CI 0.4-0.7]). Compared with those without CVD, those with CVD had a higher hazard of worsening from no rKOA/symptoms to knee symptoms (aHR = 1.5; 95% CI = 1.1-2.1). DM was not associated with transitions of rKOA.

Conclusion: Prevention of obesity and CVD may limit the development or worsening of rKOA and symptoms.
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http://dx.doi.org/10.1002/acr2.11287DOI Listing
July 2021

How feasible is the stratification of osteoarthritis phenotypes by means of artificial intelligence?

Authors:
Amanda E Nelson

Expert Rev Precis Med Drug Dev 2021 23;6(2):83-85. Epub 2020 Nov 23.

Department of Medicine, Division of Rheumatology, Allergy, and Immunology, Director, Phenotyping and Precision Medicine Resource Core of the UNC Core Center for Clinical Research, University of North Carolina at Chapel Hill School of Medicine, 3300 Doc J. Thurston Building, Campus Box #7280, Chapel Hill, NC, USA, 27599-7280.

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http://dx.doi.org/10.1080/23808993.2021.1848424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009315PMC
November 2020

Incidence and progression of ankle osteoarthritis: The johnston county osteoarthritis project.

Semin Arthritis Rheum 2021 02 21;51(1):230-235. Epub 2020 Dec 21.

Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC, USA; Department and School of Medicine, University of North Carolina, Chapel Hill, NC, USA. Electronic address:

Objective: To determine the incidence and progression of ankle osteoarthritis (OA) and associated risk factors in a community-based cohort of African Americans and whites.

Methods: Data were from 541 participants who had standardized lateral and mortise radiography of the ankles in weight bearing at baseline (2013-2015) and follow-up (2017-2018). Incident radiographic ankle OA (rAOA) was defined as a Kellgren-Lawrence grade (KLG) ≥ 1 at follow-up among ankles with baseline KLG < 1; progressive rAOA was a ≥ 1 KLG increase at follow-up among ankles with KLG ≥ 1 at baseline. Symptoms were assessed using self-reported pain, aching, and stiffness (PAS) on most days and the Foot and Ankle Outcome Score (FAOS) symptoms subscale. Ankle-level logistic regression models were used to assess associations of ankle outcomes with covariates (age, sex, race, body mass index [BMI], smoking, number of symptomatic joints, comorbidities, prior ankle injury, and knee or foot OA).

Results: Among ankles without rAOA at baseline, 28% developed incident rAOA, 37% had worsening FAOS symptoms, and 7% had worsening PAS. Incident rAOA and worsening ankle symptoms were associated with higher BMI and symptoms in other joints. Among ankles with baseline rAOA, 4% had progressive rAOA, 35% had worsening of FAOS symptoms, and 9% had worsening PAS. rAOA progression was associated with ankle injury and concomitant knee or foot OA; worsening of symptoms was associated with higher BMI and other symptomatic joints.

Conclusions: Not all ankle OA is post-traumatic. Smoking prevention/cessation, a healthy weight, and injury prevention may be methods for reducing the incidence and progression of rAOA.
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http://dx.doi.org/10.1016/j.semarthrit.2020.10.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902450PMC
February 2021

Turning the Page in Osteoarthritis Assessment with the Use of Ultrasound.

Authors:
Amanda E Nelson

Curr Rheumatol Rep 2020 08 26;22(10):66. Epub 2020 Aug 26.

Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, 3300 Doc J. Thurston Building, Campus Box #7280, Chapel Hill, NC, 27599-7280, USA.

Purpose Of Review: This narrative review summarizes the last 5 years of published, peer-reviewed research on the use of musculoskeletal ultrasound (US) in osteoarthritis (OA).

Recent Findings: Multiple features relevant to OA can be visualized on US, including synovitis, erosion, enthesitis, osteophytes, cartilage damage, meniscal extrusion, and popliteal cysts. US can be used to confirm a diagnosis of OA or make an alternate diagnosis in the clinical setting. When a standardized protocol is used, US is a reliable modality for assessment of the features of OA. Findings on US can predict progression and response to therapy in OA of the hand and knee and can allow characterization of risk factors in a cost-effective, non-invasive, repeatable manner. US is becoming more widely used in OA imaging and has clear value in addition to radiography and clinical assessment. US will likely prove useful in defining phenotypes and providing treatment guidance in OA.
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http://dx.doi.org/10.1007/s11926-020-00949-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887707PMC
August 2020

Foot osteoarthritis frequency and associated factors in a community-based cross-sectional study of White and African American adults.

Arthritis Care Res (Hoboken) 2020 Aug 19. Epub 2020 Aug 19.

Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC, USA, Chapel Hill.

Objective: Few studies have explored foot osteoarthritis (OA) in the general population. The purpose of this study was to determine the frequency of foot OA and identify associated factors in a cross-sectional analysis of a large community-based cohort.

Methods: Data were from the 2013-2015 study visit of the Johnston County OA Project. Radiographic OA (rOA) of the foot was defined using the La Trobe radiographic atlas (≥2 osteophytes or joint space narrowing in at least one of five joints). Symptomatic OA (sxOA) of the foot was defined as foot rOA with pain, aching, or stiffness in the same foot. At the foot-level, separate logistic regression models with generalized estimating equations to account for intra-person correlations were performed to examine associations of foot rOA or sxOA with age, body mass index (BMI), sex, race, educational attainment, and previous foot injury.

Results: Of 864 participants with available data (mean age 71 years, mean BMI 30 kg/m , 68% women, 33% African American, 13% <12 years of schooling), 22% had foot rOA, 20% had foot symptoms, and 5% had foot sxOA. Radiographic, but not symptomatic, foot OA was more common in African Americans than Whites. Participants with obesity, compared to normal weight, had over 2 times the odds of rOA and over 5 times the odds of sxOA in adjusted models.

Conclusion: Foot rOA and foot symptoms were common in the sample, but both conditions simultaneously (i.e., sxOA) occurred infrequently. Notably, obesity was linked with foot sxOA, perhaps implicating metabolic or mechanical influences.
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http://dx.doi.org/10.1002/acr.24427DOI Listing
August 2020

Developing a Primary Care-Focused Intervention to Engage Patients With Osteoarthritis in Physical Activity: A Stakeholder Engagement Qualitative Study.

Health Promot Pract 2020 Aug 12:1524839920947690. Epub 2020 Aug 12.

Durham VA Healthcare System, Durham, NC, USA.

Physical activity (PA) is important for managing osteoarthritis (OA), but many patients are inactive. Research is needed on strategies to leverage clinical encounters to engage patients in PA. Guided by the socioecological model of health behavior, this study aimed to engage stakeholders in the process of refining an Osteoarthritis Physical Activity Care Pathway (OA-PCP). Six focus groups and seven individual interviews were conducted with key stakeholders. Focus groups were specific to stakeholder roles and included patients with OA, support partners, and clinic personnel ( = 6 focus groups). Interview participants were local and national PA program representatives ( = 7 interviews). Data were analyzed by thematic analysis. Themes identified in the data included ways the OA-PCP can help patients with OA address challenges to PA engagement, strategies for connecting patients with PA resources, methods for implementing OA-PCP into clinical settings and potential use of PA trackers in the OA-PCP program. Stakeholders' comments were summarized into key recommendations for OA-PCP. Some recommendations reinforced and led to refinements in planned aspects of OA-PCP, including tailoring to individual patients, involvement of a support partner, and addressing pain with PA. Other recommendations resulted in larger changes for OA-PCP, including the addition of three email- or mail-based contacts and not requiring use of a PA tracker. The refined OA-PCP program is being evaluated in an exploratory trial, with the ultimate goal of establishing a PA program for OA that can be successfully implemented in clinical settings.
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http://dx.doi.org/10.1177/1524839920947690DOI Listing
August 2020

A Standardized, Pragmatic Approach to Knee Ultrasound for Clinical Research in Osteoarthritis: The Johnston County Osteoarthritis Project.

ACR Open Rheumatol 2020 Jul 29;2(7):438-448. Epub 2020 Jun 29.

University of North Carolina at Chapel Hill.

Objective: This study sought to develop and employ a comprehensive and standardized ultrasound (US) protocol and scoring atlas for the evaluation of features relevant to knee osteoarthritis (KOA) in a community-based cohort in the United States, with the goals of demonstrating feasibility, reliability, and validity.

Methods: We utilized data from the fourth follow-up (2016-2018) of the Johnston County OA Project, which includes individuals with (~50%) and without radiographic KOA. All participants underwent standardized knee radiography and completed standard questionnaires including the Knee Injury and Osteoarthritis Outcome Score (KOOS). Bilateral knee US images were obtained by a trained sonographer using a standardized protocol and scored by trained rheumatologists using an atlas developed for this study. A total of 396 knees were each scored by two readers according to the atlas. Associations between US features, radiographic findings (graded by an expert radiologist), and KOOS scores were assessed.

Results: Overall interreader reliability for US scoring was fair to moderate. The strongest correlations between US and radiographic features were seen for osteophytes, and similarly strong correlations were seen between US osteophytes and overall radiographic Kellgren-Lawrence Grade, demonstrating criterion validity. Features of effusion/synovitis and osteophytes were most associated with KOOS pain and impaired function.

Conclusion: US is a feasible, reliable, and valid method to assess features relevant to KOA in clinical and research settings. The protocol and atlas developed in this study can be utilized to evaluate KOA in a standardized fashion in future clinical studies, enabling greater utilization of this valuable modality in osteoarthritis.
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http://dx.doi.org/10.1002/acr2.11159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368135PMC
July 2020

Osteoarthritis physical activity care pathway (OA-PCP): results of a feasibility trial.

BMC Musculoskelet Disord 2020 May 16;21(1):308. Epub 2020 May 16.

Department of Exercise and Sport Science and Thurston Arthritis Research Center, University of North Carolina, 3330 Thurston Bldg, CB #7280, Chapel Hill, NC, #7280, USA.

Background: To obtain information on feasibility and acceptability, as well as preliminary data on efficacy, of an Osteoarthritis Physical activity Care Pathway (OA-PCP).

Methods: This was a single group pilot study involving 60 participants with symptomatic, physician diagnosed knee or hip OA, recruited from primary care clinics. Participants self-reported completing less than 150 min per week of moderate-to-vigorous physical activity (MVPA) at baseline. The 3-month OA-PCP intervention involved 3 physical activity (PA) coaching calls (focused on goal setting), three check-in emails and linkage with community-based or online resources to support PA. Efficacy outcomes were collected at baseline and 4-month follow-up. The primary efficacy outcome was minutes of MVPA, assessed via accelerometer. Secondary outcomes included minutes of light intensity activity, sedentary minutes, step counts, and Western Ontario and McMaster Universities (WOMAC) pain and function subscales. Participants were also asked to rate the helpfulness of the OA-PCP intervention on a scale of 0-10. Differences in efficacy outcomes between baseline and 4-month follow-up were assessed using paired t-tests.

Results: Among participants beginning the study, 88% completed follow-up assessments and ≥ 90% completed each of the intervention calls. Average daily minutes of MVPA was 8.0 at baseline (standard deviation (SD) = 9.9) and 8.9 at follow-up (SD = 12.1, p = 0.515). There were no statistically significant changes in light intensity activity, sedentary time or step counts. The mean WOMAC pain score improved from 8.1 (SD = 3.6) at baseline to 6.2 (SD = 3.8) at follow-up (p < 0.001); the mean WOMAC function score improved from 26.2 (SD = 13.2) to 20.2 (SD = 12.5; p < 0.001). The mean rating of helpfulness was 7.6 (SD = 2.5).

Conclusions: Results supported the feasibility and acceptability of the study, and participants reported clinically relevant improvements in pain and function. PA metrics did not improve substantially. Based on these results and participant feedback, modifications including enhanced self-monitoring are being made to increase the impact of the OA-PCP intervention on PA behavior.

Trial Registration: NCT03780400, December 19, 2018.
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http://dx.doi.org/10.1186/s12891-020-03339-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229580PMC
May 2020

Precision Medicine Approach to Develop and Internally Validate Optimal Exercise and Weight-Loss Treatments for Overweight and Obese Adults With Knee Osteoarthritis: Data From a Single-Center Randomized Trial.

Arthritis Care Res (Hoboken) 2021 05;73(5):693-701

University of North Carolina, Chapel Hill.

Objective: To apply a precision medicine approach to determine the optimal treatment regime for participants in an exercise (E), dietary weight loss (D), and D + E trial for knee osteoarthritis that would maximize their expected outcomes.

Methods: Using data from 343 participants of the Intensive Diet and Exercise for Arthritis (IDEA) trial, we applied 24 machine-learning models to develop individualized treatment rules on 7 outcomes: Short Form 36 physical component score, weight loss, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain/function/stiffness scores, compressive force, and interleukin-6 level. The optimal model was selected based on jackknife value function estimates that indicate improvement in the outcomes if future participants follow the estimated decision rule compared to the optimal single, fixed treatment model.

Results: Multiple outcome random forest was the optimal model for the WOMAC outcomes. For the other outcomes, list-based models were optimal. For example, the estimated optimal decision rule for weight loss indicated assigning the D + E intervention to participants with baseline weight not exceeding 109.35 kg and waist circumference above 90.25 cm, and assigning D to all other participants except those with a history of a heart attack. If applied to future participants, the optimal rule for weight loss is estimated to increase average weight loss to 11.2 kg at 18 months, contrasted with 9.8 kg if all participants received D + E (P = 0.01).

Conclusion: The precision medicine models supported the overall findings from IDEA that the D + E intervention was optimal for most participants, but there was evidence that a subgroup of participants would likely benefit more from diet alone for 2 outcomes.
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http://dx.doi.org/10.1002/acr.24179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483572PMC
May 2021

Effects of Comorbid Cardiovascular Disease and Diabetes on Hand Osteoarthritis, Pain, and Functional State Transitions: The Johnston County Osteoarthritis Project.

J Rheumatol 2020 10 15;47(10):1541-1549. Epub 2020 Feb 15.

A.E. Nelson, MD, MSCR, Associate Professor of Medicine, Thurston Arthritis Research Center, and Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

Objective: The purpose of this study is to examine the course of hand osteoarthritis (HOA) and its relationship with cardiovascular disease (CVD) and diabetes (DM).

Methods: Data were collected at 3 timepoints from 845 Johnston County Osteoarthritis Project participants (two-thirds women, one-third African Americans, mean age 60 yrs) with and without HOA, CVD, or DM. A diagnosis of radiographic HOA (rHOA) required a Kellgren-Lawrence severity grade of ≥ 2 in at least 3 joints in each hand. A 4-state progressive model included transitions based on rHOA and pain or function as defined using the Australian/Canadian HOA Index (AUSCAN). Markov multistate models estimated HR (aHR) and 95% CI for associations between DM or CVD and specific state transitions, adjusting for baseline and time-varying covariates.

Results: Participants with DM (vs those without DM) were more likely to experience worsening pain with rHOA. Individuals who had or developed CVD (vs those who did not) were significantly less likely to experience symptomatic improvement, regardless of rHOA status. Those with DM or CVD (vs those without these comorbidities) were less likely to experience improvement in function, although this was statistically significant only for those with DM and no rHOA.

Conclusion: Overall, having or developing DM and/or CVD reduced the likelihood of symptomatic and functional improvement over time, suggesting an effect of comorbid CVD and DM on the clinical and radiographic course of HOA. Additional studies are needed to confirm these findings.
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http://dx.doi.org/10.3899/jrheum.191075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429254PMC
October 2020

Comorbid conditions and the transition among states of hip osteoarthritis and symptoms in a community-based study: a multi-state time-to-event model approach.

Arthritis Res Ther 2020 01 20;22(1):12. Epub 2020 Jan 20.

Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, 3300 Doc J. Thurston Building, Campus Box #7280, Chapel Hill, NC, 27599-7280, USA.

Background: We examined the association of three common chronic conditions (obesity, diabetes mellitus [DM], and cardiovascular disease [CVD]) with transitions among states of hip osteoarthritis (HOA).

Methods: This longitudinal analysis used data from the Johnston County Osteoarthritis Project (JoCo OA, n = 3857), a community-based study in North Carolina, USA, with 18.4 ± 1.5 years of follow-up. Transitions across the following states were modeled: development of radiographic HOA (rHOA; Kellgren-Lawrence grade [KLG] of< 2); development of hip symptoms (self-reported hip pain, aching, or stiffness on most days) or symptomatic HOA (sxHOA; rHOA and symptoms in the same hip), and resolution of symptoms. Obesity (body mass index ≥ 30 kg/m) and self-reported DM and CVD were the time-dependent comorbid conditions of interest. Markov multi-state models were used to estimate adjusted hazard ratios and 95% confidence intervals to describe the associations between the conditions and HOA states.

Results: The sample included 33% African Americans, 39% men, with a mean (SD) age of 62.2 (9.8) years; the frequencies of the comorbidities increased substantially over time. When considered individually, obesity was associated with incident hip symptoms, while CVD and DM were associated with reduced symptom resolution. For those with > 1 comorbidity, the likelihood of incident sxHOA increased, while that of symptom resolution significantly decreased. When stratified by sex, the association between obesity and incident symptoms was only seen in women; among men with DM versus men without, there was a significant (~ 75%) reduction in symptom resolution in those with rHOA. When stratified by race, African Americans with DM, versus those without, were much more likely to develop sxHOA.

Conclusions: Comorbid chronic conditions are common in individuals with OA, and these conditions have a significant impact on the persistence and progression of HOA. OA management decisions, both pharmacologic and non-pharmacologic, should include considerations of the inter-relationships between OA and common comorbidities such as DM and CVD.
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http://dx.doi.org/10.1186/s13075-020-2101-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972032PMC
January 2020

2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee.

Arthritis Rheumatol 2020 02 6;72(2):220-233. Epub 2020 Jan 6.

American College of Rheumatology, Atlanta, Georgia.

Objective: To develop an evidence-based guideline for the comprehensive management of osteoarthritis (OA) as a collaboration between the American College of Rheumatology (ACR) and the Arthritis Foundation, updating the 2012 ACR recommendations for the management of hand, hip, and knee OA.

Methods: We identified clinically relevant population, intervention, comparator, outcomes questions and critical outcomes in OA. A Literature Review Team performed a systematic literature review to summarize evidence supporting the benefits and harms of available educational, behavioral, psychosocial, physical, mind-body, and pharmacologic therapies for OA. Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of the evidence. A Voting Panel, including rheumatologists, an internist, physical and occupational therapists, and patients, achieved consensus on the recommendations.

Results: Based on the available evidence, either strong or conditional recommendations were made for or against the approaches evaluated. Strong recommendations were made for exercise, weight loss in patients with knee and/or hip OA who are overweight or obese, self-efficacy and self-management programs, tai chi, cane use, hand orthoses for first carpometacarpal (CMC) joint OA, tibiofemoral bracing for tibiofemoral knee OA, topical nonsteroidal antiinflammatory drugs (NSAIDs) for knee OA, oral NSAIDs, and intraarticular glucocorticoid injections for knee OA. Conditional recommendations were made for balance exercises, yoga, cognitive behavioral therapy, kinesiotaping for first CMC OA, orthoses for hand joints other than the first CMC joint, patellofemoral bracing for patellofemoral knee OA, acupuncture, thermal modalities, radiofrequency ablation for knee OA, topical NSAIDs, intraarticular steroid injections and chondroitin sulfate for hand OA, topical capsaicin for knee OA, acetaminophen, duloxetine, and tramadol.

Conclusion: This guideline provides direction for clinicians and patients making treatment decisions for the management of OA. Clinicians and patients should engage in shared decision-making that accounts for patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.
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http://dx.doi.org/10.1002/art.41142DOI Listing
February 2020

2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee.

Arthritis Care Res (Hoboken) 2020 02 6;72(2):149-162. Epub 2020 Jan 6.

American College of Rheumatology, Atlanta, Georgia.

Objective: To develop an evidence-based guideline for the comprehensive management of osteoarthritis (OA) as a collaboration between the American College of Rheumatology (ACR) and the Arthritis Foundation, updating the 2012 ACR recommendations for the management of hand, hip, and knee OA.

Methods: We identified clinically relevant population, intervention, comparator, outcomes questions and critical outcomes in OA. A Literature Review Team performed a systematic literature review to summarize evidence supporting the benefits and harms of available educational, behavioral, psychosocial, physical, mind-body, and pharmacologic therapies for OA. Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of the evidence. A Voting Panel, including rheumatologists, an internist, physical and occupational therapists, and patients, achieved consensus on the recommendations.

Results: Based on the available evidence, either strong or conditional recommendations were made for or against the approaches evaluated. Strong recommendations were made for exercise, weight loss in patients with knee and/or hip OA who are overweight or obese, self-efficacy and self-management programs, tai chi, cane use, hand orthoses for first carpometacarpal (CMC) joint OA, tibiofemoral bracing for tibiofemoral knee OA, topical nonsteroidal antiinflammatory drugs (NSAIDs) for knee OA, oral NSAIDs, and intraarticular glucocorticoid injections for knee OA. Conditional recommendations were made for balance exercises, yoga, cognitive behavioral therapy, kinesiotaping for first CMC OA, orthoses for hand joints other than the first CMC joint, patellofemoral bracing for patellofemoral knee OA, acupuncture, thermal modalities, radiofrequency ablation for knee OA, topical NSAIDs, intraarticular steroid injections and chondroitin sulfate for hand OA, topical capsaicin for knee OA, acetaminophen, duloxetine, and tramadol.

Conclusion: This guideline provides direction for clinicians and patients making treatment decisions for the management of OA. Clinicians and patients should engage in shared decision-making that accounts for patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.
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http://dx.doi.org/10.1002/acr.24131DOI Listing
February 2020

Polypharmacy and Incident Frailty in a Longitudinal Community-Based Cohort Study.

J Am Geriatr Soc 2019 12 24;67(12):2482-2489. Epub 2019 Oct 24.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Objectives: Polypharmacy may affect frailty, a common and costly condition among older adults. Frailty prevalence is elevated among racial/ethnic minorities and persons living in the US South, and research is needed to inform future pharmacologic interventions in these populations. Our aim was to quantify the prevalence of frailty and polypharmacy, and to estimate the association between polypharmacy and incident frailty.

Design: Prospective cohort study.

Setting: A community-based cohort study of adults residing in Johnston County, North Carolina.

Participants: White and African American adults aged 50 to 95 years (n=1697).

Measurements: At each study visit, all prescription and over-the-counter medications were recorded. We calculated annual polypharmacy (5-9 medications) and excessive polypharmacy (≥10 medications) prevalence at the 2006-2010 visit (n = 1697) and operationalized the Fried frailty phenotype to describe prevalent and incident frailty at two consecutive visits (2006-2010 and 2013-2015). We estimated risk ratios (RRs) and 95% confidence intervals (CIs) for the association between polypharmacy and incident frailty using weighted log-binomial regression to account for measured confounding and attrition using inverse probability of treatment and attrition weights, respectively.

Results: At the 2006-2010 visit, 678 (41%) and 260 (16%) participants were exposed to polypharmacy and excessive polypharmacy, respectively. Overall, 353 (21%) participants and 180 (21%) participants were frail at the 2006-2010 and 2013-2015 visits, respectively. Frailty was more common among participants identifying as white, women, and having less educational attainment relative to those without these characteristics. Incident frailty at the 2013-2015 visit was 15% (mean follow-up = 5.5 years). Our results suggest that polypharmacy is positively associated with incident frailty (weighted RR = 1.4; 95% CI = .9-2.0), yet estimates are imprecise and should be interpreted with caution.

Conclusion: Consistent with the current weight of evidence, our results suggest an association between polypharmacy and incident frailty. Prospective studies evaluating deprescribing interventions are needed to clarify whether reducing polypharmacy decreases frailty incidence. J Am Geriatr Soc 67:2482-2489, 2019.
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http://dx.doi.org/10.1111/jgs.16212DOI Listing
December 2019

Phenotypes of osteoarthritis: current state and future implications.

Clin Exp Rheumatol 2019 Sep-Oct;37 Suppl 120(5):64-72. Epub 2019 Oct 15.

Department of Medicine, University of North Carolina at Chapel Hill, and Thurston Arthritis Research Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA.

In the most recent years, an extraordinary research effort has emerged to disentangle osteoarthritis heterogeneity, opening new avenues for progressing with therapeutic development and unravelling the pathogenesis of this complex condition. Several phenotypes and endotypes have been proposed albeit none has been sufficiently validated for clinical or research use as yet. This review discusses the latest advances in OA phenotyping including how new modern statistical strategies based on machine learning and big data can help advance this field of research.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936212PMC
October 2019

Knee and hip osteoarthritis as predictors of premature death: a review of the evidence.

Clin Exp Rheumatol 2019 Sep-Oct;37 Suppl 120(5):24-30. Epub 2019 Oct 14.

Thurston Arthritis Research Center, Division of Rheumatology, Immunology, and Allergy, Dept. of Medicine, University of North Carolina at Chapel Hill, and Departments of Orthopaedics and Social Medicine, University of North Carolina, Chapel Hill, NC, USA.

Rheumatic and musculoskeletal diseases (RMDs) are common, with osteoarthritis (OA) being the most prevalent. RMDs, including OA, are associated with significant pain and functional limitations, as well as mortality rates up to 1.6-fold higher than in the general population. Most studies of OA and mortality have focused on knee and hip OA. Some, but not all, of these studies suggest an increased risk of death, however risks may differ by region. Reasons for discordant findings may be due to methodological considerations including definition of OA, study design, length of follow-up, and whether variables that can change and develop over time, such as measures of OA, body mass index (BMI) and comorbidities, were re-assessed during the follow-up period. Research has shown that the prognosis of OA is similar to that seen in rheumatoid arthritis (RA) patients, in many respects. In RA, disability and comorbidities are the most important predictors of mortality, although pain may be more prominent in the prognosis of OA mortality. The data suggest that addressing functional limitations and pain seen with OA could potentially reduce the increased mortality that has been observed in these individuals. Further study is needed concerning the potential excess mortality attributable to lower body OA, as well as associated disability, pain and comorbidities.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934074PMC
October 2019

Public Health Interventions for Osteoarthritis - updates on the Osteoarthritis Action Alliance's efforts to address the 2010 OA Public Health Agenda Recommendations.

Clin Exp Rheumatol 2019 Sep-Oct;37 Suppl 120(5):31-39. Epub 2019 Oct 14.

Osteoarthritis Action Alliance, Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, USA.

Osteoarthritis (OA) is a painful joint disease affecting more than 32.5 million adults in the US and over 350 million adults worldwide. The prevalence is expected to rise continually over the next several decades with significant impacts to societal health and economic costs as well as individuals' daily activities and quality of life. In 2008, the Centers for Disease Control and Prevention (CDC) and the Arthritis Foundation (AF) led a collaborative effort to address approaches to reduce the burden of OA via public health interventions, policies (systems and environmental), and communication strategies. This collaboration resulted in the National Public Health Agenda for OA (OA Agenda), which was vetted by more than 75 stakeholder organisations and released in 2010. The OA Agenda listed ten recommendations focused on public health interventions for OA including weight management, physical activity, self-management education, and injury prevention, and policies, systems, communication, research and evaluation. In 2011, the CDC and AF mobilised the OA Action Alliance (OAAA), a national coalition of organisations concerned with mitigating the public health impact of OA, to operationalise the recommendations set forth in the OA Agenda. Since then, the OAAA has grown to include more than 110 organisations that work collectively to increase awareness about the prevention and management of OA, provide educational resources, and expand access to evidence-based programmes for target audiences including individuals with OA, community-based organisations, healthcare systems and providers, and policymakers. This review highlights the OAAA's progress to date in addressing the OA Agenda recommendations; successes and challenges in delivery of effective communication, programmes, and resources; and future implications.
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October 2019

Joint hypermobility is not positively associated with prevalent multiple joint osteoarthritis: a cross-sectional study of older adults.

BMC Musculoskelet Disord 2019 Apr 11;20(1):165. Epub 2019 Apr 11.

Thurston Arthritis Research Center, University of North Carolina, 3300 Doc J. Thurston Building, Campus Box #7280, Chapel Hill, NC, 27599-7280, USA.

Background: This cross-sectional study evaluated associations of joint hypermobility and multiple joint osteoarthritis (MJOA) in a community-based cohort of adults 45+ years of age.

Methods: MJOA and joint hypermobility data were from 1677 participants (mean age 69 years, 68% women) who completed research clinic visits during 2003-2010. Prevalent MJOA was defined in four ways. Radiographic OA (rOA) was defined as Kellgren-Lawrence (KL) > 2 at any included study joint; symptomatic OA (sxOA) required both symptoms and rOA in a joint. Joint hypermobility was defined as a Beighton score of > 4. Separate logistic regression models were used to estimate odds ratios (OR) between joint hypermobility and each MJOA definition, adjusting for age, sex, race, body mass index, and baseline visit.

Results: In this cohort, 4% had Beighton score > 4 and 63% met any definition of MJOA. Joint hypermobility was associated with significantly lower odds of radiographic and symptomatic MJOA-1 (multiple joint OA-definition 1: involvement of > 1 IP (interphalangeal) nodes and > 2 sites of hip, knee, and spine; 74 and 58% lower, respectively). However, for the other MJOA definitions (i.e., MJOA-2:involvement of > 2 IP joints, > 1 carpometacarpal [CMC] joints, and knee or hip sites; MJOA-3: involvement of > 5 joint sites from among distal interphalangeal, proximal interphalangeal, CMC, hip, knee, or spine sites; and MJOA-4:involvement of > 2 lower body sites (hip, knee, or spine), there were no statistically significant associations. For associations between site-specific hypermobility and any MJOA definition, most adjusted ORs were less than one, but few were statistically significant.

Conclusions: Overall, joint hypermobility was not positively associated with any definition of prevalent MJOA in this cohort, and an inverse association existed with one definition of MJOA. Longitudinal studies are needed to determine the contribution of hypermobility to the incidence and progression of MJOA outcomes.
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http://dx.doi.org/10.1186/s12891-019-2550-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460832PMC
April 2019

Relationship of joint hypermobility with low Back pain and lumbar spine osteoarthritis.

BMC Musculoskelet Disord 2019 Apr 9;20(1):158. Epub 2019 Apr 9.

Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC, USA.

Background: Chronic low back pain (cLBP) affects millions of Americans and costs billions. Studies suggest a link between cLBP and joint hypermobility.

Methods: We conducted cross-sectional primary analyses of joint hypermobility and cLBP, lumbar spine osteoarthritis (OA), and lumbar facet joint OA (FOA) in 3 large studies-the Generalized Osteoarthritis Study, Genetics of Generalized Osteoarthritis Study, and Johnston County Osteoarthritis Project (total n = 5072). Associations of joint hypermobility and Beighton trunk flexion with cLBP and lumbar OA were estimated using separate adjusted logistic regression models. Adjusted pooled odds ratios (pORs) and 95% confidence intervals (CIs) were then summarized-using random effect univariate, multivariate crude, and adjusted models-and heterogeneity was determined (I statistic).

Results: In univariate models, hypermobility was associated with symptomatic FOA (pOR = 0.64 [95% CI 0.44, 0.93]) but this result was not found in the multivariate models. In multivariate adjusted models, hypermobility was not significantly associated with cLBP and lumbar OA, but trunk flexion was inversely associated with cLBP (pOR = 0.40 [95% 0.26, 0.62]), spine OA (pOR = 0.66 [95% CI 0.50, 0.87]), symptomatic spine OA (pOR = 0.39 [95% CI 0.28, 0.53]), and symptomatic FOA (pOR = 0.53 [95% CI 0.37, 0.77]). Generally, between-study heterogeneity was moderate-high.

Conclusions: Hypermobility was not associated with cLBP or lumbar OA. The inverse association of trunk flexion with cLBP and lumbar OA may indicate a role for a flexible spine in avoiding or managing these conditions.
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http://dx.doi.org/10.1186/s12891-019-2523-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456963PMC
April 2019

Application of Traditional and Emerging Methods for the Joint Analysis of Repeated Measurements With Time-to-Event Outcomes in Rheumatology.

Arthritis Care Res (Hoboken) 2020 05 8;72(5):615-621. Epub 2020 Apr 8.

University of North Carolina, Chapel Hill.

Objective: The goal of this paper is to describe approaches for the joint analysis of repeatedly measured data with time-to-event end points, first separately and then in the framework of a single comprehensive model, emphasizing the efficiency of the latter approach. Data from the Johnston County Osteoarthritis (JoCo OA) Project will be used as an example to investigate the relationship between the change in repeatedly measured body mass index (BMI) and the time-to-event end point of incident worsening of radiographic knee OA that was defined as an increased Kellgren/Lawrence grade in at least 1 knee over time.

Methods: First, we provide an overview of the methods for analyzing repeated measurements and time-to-event end points separately. Then, we describe traditional (Cox proportional hazards model [CoxPH]) and emerging (joint model [JM]) approaches, both of which allow combined analysis of repeated measures with a time-to-event end point in the framework of a single statistical model. Finally, we apply the models to JoCo OA data and interpret and compare the results from the different approaches.

Results: Applications of the JM (but not the CoxPH) showed that the risk of worsening radiographic OA is higher when BMI is higher or increasing, thus illustrating the advantages of the JM for analyzing such dynamic measures in a longitudinal study.

Conclusion: Joint models are preferable for simultaneous analyses of repeated measurement and time-to-event outcomes, particularly in the context of chronic disease, where dependency between the time-to-event end point and the longitudinal trajectory of repeated measurements is inherent.
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http://dx.doi.org/10.1002/acr.23881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761043PMC
May 2020

The importance of hip shape in predicting hip osteoarthritis.

Authors:
Amanda E Nelson

Curr Treatm Opt Rheumatol 2018 Jun 10;4(2):214-222. Epub 2018 Apr 10.

Purpose Of Review: This narrative review summarizes the evidence relating hip shape and risk of osteoarthritis at the hip, with a focus on the most recent body of work.

Recent Findings: Hip OA is a prevalent and potentially disabling condition with few effective non-surgical treatment options. Risk factors for hip OA appear to differ somewhat from those at other sites. Variations in hip morphology, whether assessed through standard geometric measures or statistical modeling methods, seem to increase hip OA risk and may provide a novel approach to interventions to reduce or prevent OA. Such variations have also led to focused surgical interventions to "correct" abnormal shape, although comparisons with non-surgical management are lacking.

Summary: There remains a lack of understanding regarding the optimal management, whether surgical, non-surgical, or a combination, for FAI syndrome. Even less is known regarding other potential morphologic variations that may contribute to OA risk. Additionally, many individuals who have shape variations that would seem to increase their risk will never develop hip OA. Questions remain regarding key risk factors for hip OA development, which individuals should be targeted for therapies, whether directed at symptoms, function, or prevention, and which therapies should be studied and offered. Trials are underway to help address some of these questions.
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http://dx.doi.org/10.1007/s40674-018-0096-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269115PMC
June 2018

Contributions of symptomatic osteoarthritis and physical function to incident cardiovascular disease.

BMC Musculoskelet Disord 2018 Nov 10;19(1):393. Epub 2018 Nov 10.

Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, 3300 Thurston Bldg., CB# 7280, Chapel Hill, NC, 27599, USA.

Background: Osteoarthritis (OA) is associated with worsening physical function and a high prevalence of comorbid health conditions. In particular, cardiovascular disease (CVD) risk is higher in individuals with OA than the general population. Limitations in physical function may be one pathway to the development of CVD among individuals with OA. This study evaluated associations of symptomatic knee OA (sxKOA), baseline physical function and worsening of function over time with self-reported incident CVD in a community-based cohort.

Methods: Our sample consisted of individuals from the Johnston County Osteoarthritis Project who did not report having CVD at baseline. Variables used to evaluate physical function were the Health Assessment Questionnaire (HAQ), time to complete 5 chair stands, and the 8-ft walk. Worsening function for these variables was defined based on previous literature and cutoffs from our sample. Logistic regression analyses examined associations of sxKOA, baseline function and worsening of function over time with self-reported incident CVD, unadjusted and adjusted for relevant demographic and clinical characteristics.

Results: Among 1709 participants included in these analyses, the mean age was 59.5 ± 9.5 years, 63.6% were women, 15% had sxKOA, and the follow up time was 5.9 ± 1.2 years. About a third of participants reported worsening HAQ score, about two-fifths had worsened chair stand time, half had worsened walking speed during the 8-ft walk, and 16% self-reported incident CVD. In unadjusted analyses, sxKOA, baseline function, and worsening function were all associated with self-reported incident CVD. In multivariable models including all of these variables, sxKOA was not associated with incident CVD, but worsening function was significantly associated with increased CVD risk, for all three functional measures: HAQ odds ratio (OR) = 2.49 (95% confidence interval (CI) 1.90-3.25), chair stands OR = 1.58 (95% CI 1.20-2.08), 8-ft walk OR = 1.53 (95%CI 1.15-2.04). These associations for worsening function remained in models additionally adjusted for demographic and clinical characteristics related to CVD risk.

Conclusions: The association between symptomatic knee osteoarthritis and cardiovascular disease risk was explained by measures of physical function. This highlights the importance of physical activity and other strategies to prevent functional loss among individuals with symptomatic knee osteoarthritis.
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http://dx.doi.org/10.1186/s12891-018-2311-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230250PMC
November 2018

Defining multiple joint osteoarthritis, its frequency and impact in a community-based cohort.

Semin Arthritis Rheum 2019 06 9;48(6):950-957. Epub 2018 Oct 9.

Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, 3300 Doc J. Thurston Building, Campus Box #7280, Chapel Hill, NC 27599-7280, United States; School of Medicine, University of North Carolina at Chapel Hill, 321 S Columbia St, Chapel Hill, NC 27516, United States. Electronic address:

Background/purpose: To update definitions of multiple joint osteoarthritis (MJOA), and to determine the frequency and impact of MJOA in a community-based cohort.

Methods: Following PRISMA guidelines and with the help of a professional research librarian, we performed a systematic review in Medline using the terms osteoarthritis, generalized, polyarticular, multiple joint, and multi-joint among others, to obtain articles related to MJOA. A total of 42 articles were included for data extraction based on multiple criteria including the requirement for a clearly stated definition of OA assessed at more than one body site. We assessed frequency of these definitions in the Johnston County OA Project (JoCo OA) cohort as well as outcomes related to general health and physical function.

Results: A total of 6 clearly stated definitions for MJOA were identified. These definitions were integrated with a list of 24 definitions from our previous systematic review and distilled down to produce 10 literature-derived, operationalized MJOA definitions. Based on these definitions, high frequencies of radiographic (4-74%) and symptomatic (2-52%) MJOA were found in the JoCo OA. Significant detrimental effects were seen on general health and physical function for most definitions.

Conclusions: We constructed a list of 10 summary MJOA definitions based in the literature that are frequent and associated with important clinical outcomes. These definitions capture some of the variability of MJOA phenotypes and provide a starting point for future analyses of both existing and newly initiated studies.
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http://dx.doi.org/10.1016/j.semarthrit.2018.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456431PMC
June 2019

Relationship of Joint Hypermobility with Ankle and Foot Radiographic Osteoarthritis and Symptoms in a Community-Based Cohort.

Arthritis Care Res (Hoboken) 2019 04;71(4):538-544

University of North Carolina, Chapel Hill.

Objective: To explore associations of joint hypermobility (a condition where range of motion is greater than normal) with ankle and foot radiographic osteoarthritis (OA) and symptoms in a large community-based cohort of African American and white adults ages 55-94 years old.

Methods: Ankle and foot radiographs and joint hypermobility data (Beighton score for joint hypermobility criteria) were available for 848 participants (from 2003 to 2010) in this cross-sectional study. General joint hypermobility was defined as a Beighton score ≥4 (range 0-9); knee hypermobility was defined as hyperextension of at least 1 knee. Standing anteroposterior and lateral foot radiographs were read with standard atlases for Kellgren-Lawrence grade, osteophytes, and joint space narrowing (JSN) at the tibiotalar joint, and for osteophytes and JSN to define OA at 5 foot joints. Ankle or foot symptoms were self-reported. Separate person-based logistic regression models were used to estimate associations of ankle and foot OA and symptom outcomes with hypermobility measures, adjusting for age, sex, race, body mass index, and history of ankle/foot injury.

Results: This sample cohort included 577 women (68%) and 280 African Americans (33%). The mean age of the participants was 71 years, with a mean body mass index of 31 kg/m . The general joint hypermobility of the participants was 7% and knee hypermobility was 4%. Having a history of ankle injury was 11.5%, and foot injury was 3.8%. Although general joint hypermobility was not associated with ankle and foot outcomes, knee hypermobility was associated with ankle symptoms, foot symptoms, and talonavicular OA (adjusted odds ratios of 4.4, 2.4, and 3.0, respectively).

Conclusion: Knee joint hypermobility may be related to talonavicular OA and to ankle and foot symptoms.
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http://dx.doi.org/10.1002/acr.23686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310667PMC
April 2019

A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments.

Nat Med 2018 08 25;24(8):1178-1191. Epub 2018 Jun 25.

Department of Pathology, University of California San Francisco, San Francisco, CA, USA.

Intratumoral stimulatory dendritic cells (SDCs) play an important role in stimulating cytotoxic T cells and driving immune responses against cancer. Understanding the mechanisms that regulate their abundance in the tumor microenvironment (TME) could unveil new therapeutic opportunities. We find that in human melanoma, SDC abundance is associated with intratumoral expression of the gene encoding the cytokine FLT3LG. FLT3LG is predominantly produced by lymphocytes, notably natural killer (NK) cells in mouse and human tumors. NK cells stably form conjugates with SDCs in the mouse TME, and genetic and cellular ablation of NK cells in mice demonstrates their importance in positively regulating SDC abundance in tumor through production of FLT3L. Although anti-PD-1 'checkpoint' immunotherapy for cancer largely targets T cells, we find that NK cell frequency correlates with protective SDCs in human cancers, with patient responsiveness to anti-PD-1 immunotherapy, and with increased overall survival. Our studies reveal that innate immune SDCs and NK cells cluster together as an excellent prognostic tool for T cell-directed immunotherapy and that these innate cells are necessary for enhanced T cell tumor responses, suggesting this axis as a target for new therapies.
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http://dx.doi.org/10.1038/s41591-018-0085-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475503PMC
August 2018

Association between general joint hypermobility and knee, hip, and lumbar spine osteoarthritis by race: a cross-sectional study.

Arthritis Res Ther 2018 04 18;20(1):76. Epub 2018 Apr 18.

Thurston Arthritis Research Center, University of North Carolina, 3300 Doc J. Thurston Bldg, CB#7280, Chapel Hill, 27599-7280, NC, USA.

Background: Osteoarthritis (OA) prevalence differs by race. General joint hypermobility (GJH) may be associated with OA, but differences by race are not known. This community-based study examined the frequency of GJH and its relationship with knee, hip, and lumbar spine OA by race (African American vs. Caucasian).

Methods: Data were from the Johnston County OA project, collected 2003-2010. GJH was defined as Beighton score ≥4. OA symptoms were defined as the presence of pain, aching, or stiffness on most days separately at the knee, hip, and lower back. Radiographic OA (rOA) of the knee or hip was defined as Kellgren-Lawrence grade 2-4. Lumbar spine rOA was disc space narrowing grade ≥1 and osteophyte grade ≥2 in ≥ 1 at the same lumbar level. Lumbar spine facet rOA was present in ≥ 1 lumbar levels. Separate logistic regression models stratified by race were used to examine the association between hypermobility and rOA or OA symptoms at each joint site, adjusting for age, sex, previous joint injury, and body mass index (BMI).

Results: Of 1987 participants, 1/3 were African-American and 2/3 were women (mean age 65 years, mean BMI 31 kg/m). Nearly 8% of Caucasians were hypermobile vs. 5% of African-Americans (p = 0.03). Hypermobility was associated with lower back symptoms in Caucasians (adjusted odds ratio (aOR) 1.54, 95% confidence interval (CI) 1.00, 2.39), but not in African-Americans (aOR 0.77, 95% CI 0.34, 1.72). Associations between hypermobility and other knee, hip, or lumbar spine/facet OA variables were not statistically significant.

Conclusions: General joint hypermobility was more common in Caucasians than African-Americans. Although there were no associations between hypermobility and rOA, the association between hypermobility and lower back symptoms may differ by race.
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http://dx.doi.org/10.1186/s13075-018-1570-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907300PMC
April 2018

Lower Extremity Osteoarthritis: Management and Challenges.

N C Med J 2017 Sep-Oct;78(5):332-336

assistant professor, Thurston Arthritis Research Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Osteoarthritis is the most common form of arthritis, a significant contributor to disability and the major cause for joint replacements, but treatment for the disease is still limited. Although no disease-modifying treatments exist, there are evidence-based algorithms and guidelines for the symptomatic treatment of the disease.
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http://dx.doi.org/10.18043/ncm.78.5.332DOI Listing
July 2018

Cross-sectional associations between variations in ankle shape by statistical shape modeling, injury history, and race: the Johnston County Osteoarthritis Project.

J Foot Ankle Res 2017 26;10:34. Epub 2017 Jul 26.

Arthritis and Musculoskeletal Medicine, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK.

Background: Injury is an important risk factor for osteoarthritis (OA), a highly prevalent and disabling joint disease. Joint shape is linked to OA, but the interplay of injury and joint shape and their combined role in OA, particularly at the ankle, is not well known. Therefore, we explored cross-sectional associations between ankle shape and injury in a large community-based cohort.

Methods: Ankles without radiographic OA were selected from the current data collection of the Johnston County OA Project. Ankles with self-reported prior injury were included as injury cases ( = 108) along with 1:1 randomly selected non-injured ankles. To define ankle shape, a 68 point model on weight-bearing lateral ankle radiographs was entered into a statistical shape model, producing a mean shape and a set of continuous variables (modes) representing variation in that shape. Nineteen modes, explaining 80% of shape variance, were simultaneously included in a logistic regression model with injury status as the dependent variable, adjusted for intra-person correlation, sex, race, body mass index (BMI), baseline OA radiographic grade, and baseline symptoms.

Results: A total of 194 participants (213 ankles) were included; mean age 71 years, BMI 30 kg/m, 67% white and 71% women. Injured ankles were more often symptomatic and from whites. In a model adjusted only for intra-person correlation, associations were seen between injury status and modes 1, 6, 13, and 19. In a fully adjusted model, race strongly affected the estimate for mode 1 (which was no longer statistically significant).

Conclusions: This study showed variations in ankle shape and history of injury as well as with race. These novel findings may indicate a change in ankle morphology following injury, or that ankle morphology predisposes to injury, and suggest that ankle shape is a potentially important factor in the development of ankle OA.
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http://dx.doi.org/10.1186/s13047-017-0216-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530536PMC
February 2018