Serum proteomic biomarkers diagnostic of knee osteoarthritis.

OBJECTIVE: To better understand the pathogenesis of knee osteoarthritis (OA) through identification of serum diagnostics. DESIGN: We conducted multiple reaction monitoring mass spectrometry analysis of 107 peptides in baseline sera of two cohorts: the Foundation for National Institutes of Health (NIH) (n = 596 Kellgren-Lawrence (KL) grade 1-3 knee OA participants); and the Johnston County Osteoarthritis Project (n = 127 multi-joint controls free of radiographic OA of the hands, hips, knees (bilateral KL=0), and spine). Data were split into (70%) training and (30%) testing sets. Diagnostic peptide and clinical data predictors were selected by random forest (RF); selection was based on association (p < 0.05) with OA status in multivariable logistic regression models. Model performance was based on area under the curve (AUC) of receiver operating characteristic (ROC) and precision-recall (PR) curves. RESULTS: RF selected 23 peptides (19 proteins) and body mass index (BMI) as diagnostic of OA. BMI weakly diagnosed OA (ROC-AUC 0.57, PR-AUC 0.812) and only symptomatic OA cases. ACTG was the strongest univariable predictor (ROC-AUC 0.705, PR-AUC 0.897). The final model (8 serum peptides) was highly diagnostic (ROC-AUC 0.833, 95% confidence interval [CI] 0.751, 0.905; PR-AUC 0.929, 95% CI 0.876, 0.973) in the testing set and equally diagnostic of non-symptomatic and symptomatic cases (AUCs 0.830-0.835), and not significantly improved with addition of BMI. The STRING database predicted multiple high confidence interactions of the 19 diagnostic OA proteins. CONCLUSIONS: No more than 8 serum protein biomarkers were required to discriminate knee OA from non-OA. These biomarkers lend strong support to the involvement and cross-talk of complement and coagulation pathways in the development of OA.

Arthritis Foundation/HSS Workshop on Hip Osteoarthritis, Part 1: Epidemiology, Early Development, and Cohorts From Around the World.

Far more publications are available for osteoarthritis of the knee than of the hip. Recognizing this research gap, the Arthritis Foundation, in partnership with the Hospital for Special Surgery, convened an in-person meeting of thought leaders to review the state of the science of and clinical approaches to hip osteoarthritis. This article summarizes the recommendations and clinical research gaps gleaned from 5 presentations given in the "how hip osteoarthritis begins" session of the 2023 Hip Osteoarthritis Clinical Studies Conference, which took place on February 17 and 18, 2023, in New York City.

Sociodemographic and Clinical Predictors of Prescription Opioid Use in a Longitudinal Community-Based Cohort Study of Middle-Aged and Older Adults.

OBJECTIVES: Identifying factors associated with opioid use in middle-aged and older adults is a fundamental step in the mitigation of potentially unnecessary opioid consumption and opioid-related harms. METHODS: Using longitudinal data on a community-based cohort of adults aged 50-90 years residing in Johnston County, North Carolina, we examined sociodemographic and clinical factors in non-opioid users (n = 786) at baseline (2006-2010) as predictors of opioid use at follow-up (2013-2015). Variables included age, sex, race, obesity, educational attainment, employment status, household poverty rate, marital status, depressive symptoms, social support, pain catastrophizing, pain sensitivity, insurance status, polypharmacy, and smoking status. RESULTS: At follow-up, 13% of participants were using prescription opioids. In the multivariable model, high pain catastrophizing (adjusted odds ratio; 95% confidence interval = 2.14; 1.33-3.46), polypharmacy (2.08; 1.23-3.53), and history of depressive symptoms (2.00; 1.19-3.38) were independent markers of opioid use. DISCUSSION: Findings support the assessment of these modifiable factors during clinical encounters in patients ≥ 50 years old with chronic pain.

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

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.

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

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.

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

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.

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

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.

Critical Role for CD103(+)/CD141(+) Dendritic Cells Bearing CCR7 for Tumor Antigen Trafficking and Priming of T Cell Immunity in Melanoma.

Intratumoral dendritic cells (DC) bearing CD103 in mice or CD141 in humans drive intratumoral CD8(+) T cell activation. Using multiple strategies, we identified a critical role for these DC in trafficking tumor antigen to lymph nodes (LN), resulting in both direct CD8(+) T cell stimulation and antigen hand-off to resident myeloid cells. These effects all required CCR7. Live imaging demonstrated direct presentation to T cells in LN, and CCR7 loss specifically in these cells resulted in defective LN T cell priming and increased tumor outgrowth. CCR7 expression levels in human tumors correlate with signatures of CD141(+) DC, intratumoral T cells, and better clinical outcomes. This work identifies an ongoing pathway to T cell priming, which should be harnessed for tumor therapies.

Racial differences in associations between baseline patterns of radiographic osteoarthritis and multiple definitions of progression of hip osteoarthritis: the Johnston County Osteoarthritis Project.

BACKGROUND: To identify baseline radiographic features that predict hip osteoarthritis (HOA) progression, and to explore differences in these associations by race. METHODS: Radiographs from the community-based Johnston County OA Project were scored using Kellgren-Lawrence (KL) grade and for presence and location of joint space narrowing (JSN), osteophytes, and subchondral changes. Associations between these features and HOA progression (increase of at least 1 KL grade, interval hip replacement, range of motion [ROM, a reduction of ≥10° in internal rotation], or disability [increase of ≥0.2 in Health Assessment Questionnaire scores], or Any of these) were assessed using logistic regression, adjusting for age, gender, race, hip injury, BMI, education, smoking and follow-up time, accounting for multiple comparisons. Race interactions were assessed and analyses stratified as indicated. RESULTS: The sample (n = 1,422) included 40 % men and 26 % African American (AA) participants, with mean age 61 years and BMI 29 kg/m(2). The baseline frequency of radiographic hip OA (RHOA) between Caucasians and AAs was similar (23 %), although some radiographic features differed. AAs were more likely to have progression defined by ROM or disability or Any progression; Caucasians were more likely to have RHOA progression. JSN, subchondral sclerosis, and medial osteophytes were associated with increased RHOA progression overall; JSN was associated with disability progression only in AAs, while lateral osteophytes were associated with ROM progression only in Caucasians. CONCLUSIONS: AAs and Caucasians exhibited differences in the radiographic presentation and progression patterns of HOA, with AAs reporting progressive pain and disability, while Caucasians had more RHOA progression.

The Prevalence of Neck and Shoulder Symptoms and Associations with Comorbidities and Disability: The Johnston County Osteoarthritis Project.

OBJECTIVES: Neck and shoulder pain are common but underreported by older people, raising important questions of frequency, medical comorbidities, gender and racial disparities and functional impact associated with neck and shoulder symptoms in elders, which we examined in this analysis. METHODS: We performed a cross-sectional analysis in the community-based Johnston County Osteoarthritis Project, a cohort that is representative of the U.S. population, utilizing data from 1672 participants with a mean age of 68 years; 69% were white and 68% were women. Trained staff obtained data on participant-reported: symptoms, comorbidities, depression, and functional status; and performance-based functional assessments. Regression models of neck and shoulder symptoms and functional measures were adjusted for age, sex, race, and body mass index, and additionally for other joint symptoms and comorbidities. RESULTS: Symptoms of neck (8%), shoulder (13%) or both (13%) were reported by participants. Neck symptoms were most frequently reported by White women; shoulder symptoms were evenly distributed among race and gender subgroups. Neck and shoulder symptoms were associated with cancer, diabetes mellitus, depression, and lung, cardiovascular, and other musculoskeletal problems, as well as pain, aching or stiffness at other sites, and independently with self-reported and performance -based functional measures. CONCLUSIONS: These findings suggest that primary health care providers should inquire about neck and shoulder symptoms and address potential underlying causes to improve functional status and decrease disability in older people.

Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity.

It is well understood that antigen-presenting cells (APCs) within tumors typically do not maintain cytotoxic T cell (CTL) function, despite engaging them. Across multiple mouse tumor models and human tumor biopsies, we have delineated the intratumoral dendritic cell (DC) populations as distinct from macrophage populations. Within these, CD103(+) DCs are extremely sparse and yet remarkably capable CTL stimulators. These are uniquely dependent on IRF8, Zbtb46, and Batf3 transcription factors and are generated by GM-CSF and FLT3L cytokines. Regressing tumors have higher proportions of these cells, T-cell-dependent immune clearance relies on them, and abundance of their transcripts in human tumors correlates with clinical outcome. This cell type presents opportunities for prognostic and therapeutic approaches across multiple cancer types.

Associations between biomarkers of joint metabolism, hand osteoarthritis, and hand pain and function: the Johnston County Osteoarthritis Project.

OBJECTIVE: To determine the associations between joint metabolism biomarkers and hand radiographic osteoarthritis [(rOA), based on Kellgren Lawrence (KL) grade ≥ 2], symptoms, and function. METHODS: Cross-sectional data were available for 663 participants (mean age 63 yrs, 63% white, 49% women). Three definitions of hand rOA were considered: (1) a composite measure involving at least 3 hand joints distributed bilaterally with 2 of 3 in the same joint group, including ≥ 1 distal interphalangeal joint, without metacarpophalangeal (MCP) swelling; (2) rOA in at least 1 joint of a group; and (3) number of joints with KL ≥ 2. We assessed hand symptoms and the 15-item Australian Canadian Hand Osteoarthritis Index (AUSCAN; Likert format). We measured serum cartilage oligomeric matrix protein (sCOMP), hyaluronic acid (sHA), carboxy-terminal propeptide of type II collagen, type II collagen degradation product, urinary C-terminal crosslinked telopeptide of type II collagen, and urinary N-terminal crosslinked telopeptide. Linear regression models were performed to assess associations between each biomarker with hand rOA, AUSCAN, and symptoms, adjusting for age, sex, race, current smoking/drinking status, body mass index, and hip and knee rOA. RESULTS: In adjusted analyses, MCP (p < 0.0001) and carpometacarpal rOA (p = 0.003), and a higher number of hand joints with rOA (p = 0.009), were associated with higher levels of sHA. Positive associations were seen between AUSCAN and hand symptoms and levels of sCOMP (p ≤ 0.003) and sHA (p ≤ 0.048). CONCLUSION: Hand symptoms and higher AUSCAN scores were independently associated with higher levels of both sCOMP and sHA; hand rOA was associated only with sHA levels.

A systematic review of recommendations and guidelines for the management of osteoarthritis: The chronic osteoarthritis management initiative of the U.S. bone and joint initiative.

PURPOSE: Although a number of osteoarthritis (OA) management guidelines exist, uptake has been suboptimal. Our aim was to review and critically evaluate existing OA management guidelines to better understand potential issues and barriers. METHODS: A systematic review of the literature in MEDLINE published from January 1, 2000 to April 1, 2013 was performed and supplemented by bibliographic reviews, following PRISMA guidelines and a written protocol. Following initial title and abstract screening, 2 authors independently reviewed full-text articles; a third settled disagreements. Two independent reviewers extracted data into a standardized form. Two authors independently assessed guideline quality using the AGREE II instrument; three generated summary recommendations based on the extracted guideline data. RESULTS: Overall, 16 articles were included in the final review. There was broad agreement on recommendations by the various organizations. For non-pharmacologic modalities, education/self-management, exercise, weight loss if overweight, walking aids as indicated, and thermal modalities were widely recommended. For appropriate patients, joint replacement was recommended; arthroscopy with debridement was not recommended for symptomatic knee OA. Pharmacologic modalities most recommended included acetaminophen/paracetamol (first line) and NSAIDs (topical or oral, second line). Intra-articular corticosteroids were generally recommended for hip and knee OA. Controversy remains about the use of acupuncture, knee braces, heel wedges, intra-articular hyaluronans, and glucosamine/chondroitin. CONCLUSIONS: The relative agreement on many OA management recommendations across organizations indicates a problem with dissemination and implementation rather than a lack of quality guidelines. Future efforts should focus on optimizing implementation in primary care settings, where the majority of OA care occurs.

Whole blood lead levels are associated with biomarkers of joint tissue metabolism in African American and white men and women: the Johnston County Osteoarthritis Project.

PURPOSE: To examine associations between biomarkers of joint tissue metabolism and whole blood lead (Pb), separately for men and women in an African American and Caucasian population, which may reflect an underlying pathology. METHODS: Participants in the Johnston County Osteoarthritis Project Metals Exposure Sub-Study (329 men and 342 women) underwent assessment of whole blood Pb and biochemical biomarkers of joint tissue metabolism. Urinary cross-linked N telopeptide of type I collagen (uNTX-I) and C-telopeptide fragments of type II collagen (uCTX-II), serum cleavage neoepitope of type II collagen (C2C), serum type II procollagen synthesis C-propeptide (CPII), and serum hyaluronic acid (HA) were measured using commercially available kits; the ratio of [C2C:CPII] was calculated. Serum cartilage oligomeric matrix protein (COMP) was measured by an in-house assay. Multiple linear regression models were used to examine associations between continuous blood Pb and biomarker outcomes, adjusted for age, race, current smoking status, and body mass index. Results are reported as estimated change in biomarker level for a 5-unit change in Pb level. RESULTS: The median Pb level among men and women was 2.2 and 1.9µg/dL, respectively. Correlations were noted between Pb levels and the biomarkers uNTX-I, uCTX-II, and COMP in women, and between Pb and uCTX-II, COMP, CPII, and the ratio [C2C:CPII] in men. In adjusted models among women, a 5-unit increase in blood Pb level was associated with a 28% increase in uCTX-II and a 45% increase in uNTX-I levels (uCTX-II: 1.28 [95% CI: 1.04-1.58], uNTX-I: 1.45 [95% CI:1.21-1.74]). Among men, levels of Pb and COMP showed a borderline positive association (8% increase in COMP for a 5-unit change in Pb: 1.08 [95% CI: 1.00-1.18]); no other associations were significant after adjustment. CONCLUSIONS: Based upon known biomarker origins, the novel associations between blood Pb and biomarkers appear to be primarily reflective of relationships to bone and calcified cartilage turnover among women and cartilage metabolism among men, suggesting a potential gender-specific effect of Pb on joint tissue metabolism that may be relevant to osteoarthritis.

Whole blood lead levels are associated with radiographic and symptomatic knee osteoarthritis: a cross-sectional analysis in the Johnston County Osteoarthritis Project.

INTRODUCTION: Lead (Pb) is known to affect bone, and recent evidence suggests that it has effects on cartilage as well. As osteoarthritis (OA) is a highly prevalent disease affecting bone and cartilage, we undertook the present analysis to determine whether whole blood Pb levels are associated with radiographic and symptomatic OA (rOA and sxOA, respectively) of the knee. METHODS: The analysis was conducted using cross-sectional data from the Johnston County Osteoarthritis Project, a rural, population-based study, including whole blood Pb levels, bilateral posteroanterior weight-bearing knee radiography and knee symptom data. rOA assessment included joint-based presence (Kellgren-Lawrence (K-L) grade 2 or higher) and severity (none, K-L grade 0 or 1; mild, K-L grade 2; moderate or severe, K-L grade 3 or 4), as well as person-based laterality (unilateral or bilateral). SxOA was deemed present (joint-based) in a knee on the basis of K-L grade 2 or higher with symptoms, with symptoms rated based on severity (0, rOA without symptoms; 1, rOA with mild symptoms; 2, rOA with moderate or severe symptoms) and in person-based analyses was either unilateral or bilateral. Generalized logit or proportional odds regression models were used to examine associations between the knee OA status variables and natural log-transformed blood Pb (ln Pb), continuously and in quartiles, controlling for age, race, sex, body mass index (BMI), smoking and alcohol drinking. RESULTS: Those individuals with whole blood Pb data (N = 1,669) had a mean (±SD) age of 65.4 (±11.0) years and a mean BMI of 31.2 (±7.1) kg/m2, including 66.6% women and 35.4% African-Americans, with a median blood Pb level of 1.8 µg/dl (range, 0.3 to 42.0 µg/dl). In joint-based analyses, for every 1-U increase in ln Pb, the odds of prevalent knee rOA were 20% higher (aOR, 1.20; 95% CI, 1.01 to 1.44), while the odds of more severe rOA were 26% higher (aOR, 1.26; 95% CI, 1.05 to 1.50, under proportional odds). In person-based analyses, the odds of bilateral rOA were 32% higher for each 1-U increase in ln Pb (aOR, 1.32; 95% CI, 1.03 to 1.70). Similarly for knee sxOA, for each 1-U increase in ln Pb, the odds of having sxOA were 16% higher, the odds of having more severe symptoms were 17% higher and the odds of having bilateral knee symptoms were 25% higher. Similar findings were obtained with regard to ln Pb in quartiles. CONCLUSIONS: Increases in the prevalence and severity measures for both radiographically and symptomatically confirmed knee OA (although statistically significant only for rOA) were observed with increasing levels of blood Pb, suggesting that Pb may be a potentially modifiable environmental risk factor for OA.

Characterization of individual radiographic features of hip osteoarthritis in African American and White women and men: the Johnston County Osteoarthritis Project.

OBJECTIVE: To describe differences in radiographic features of hip osteoarthritis (OA) between African American and white men and women. METHODS: We conducted a cross-sectional analysis of radiographic hip OA using baseline data from the Johnston County Osteoarthritis Project, using Kellgren/Lawrence (K/L) grade, and the presence, location, and severity of 4 individual radiographic features (joint space narrowing [JSN], subchondral cysts, sclerosis, and osteophytes). Sex-specific logistic regression was used to evaluate associations between race and individual radiographic features, adjusting for age, body mass index, education, and prior hip injury. Robust variance estimators via generalized estimating equations were used to account for correlation between hips from the same individual. RESULTS: The sample (n = 2,739) comprised 57% women and 31% African American participants. Among women, African Americans and whites had a similar prevalence of hip OA, defined as K/L grade > or =2 (23% versus 22%), but African American women were significantly more likely to have superior or medial JSN, moderate or severe axial JSN, medial or lateral osteophytes, and subchondral cysts. Among men, 21% of African Americans and 17% of whites had hip OA; African American men were more likely to have superior or medial JSN and lateral osteophytes, but were less likely to have axial JSN. CONCLUSION: Individual radiographic features and patterns of hip OA differed by race among women and men, suggesting the possibility of anatomic and/or developmental variation in the hip joint. African Americans have an increased frequency of features that have been predictive of hip replacement in other populations, a finding worthy of further study.