Gender differences in patterns of cartilage loss: Data from the Osteoarthritis Initiative.

OBJECTIVE: Understanding gender-specific differences in patterns of cartilage loss can improve our knowledge of the pathogenesis of knee osteoarthritis (KOA) development and progression and may inform clinical trials of treatments for KOA. The goal of our observational study was to examine gender differences in patterns of cartilage loss in the central weight-bearing regions of the femur. METHODS: We measured cartilage volume change in the indexed knee of 700 subjects with Kellgren-Lawrence 1, 2, or 3 from the Osteoarthritis Initiative for four follow-up periods (baseline [BL] to 24 mo, BL to 48 mo, BL to 72 mo, and BL to 96 mo) using the local area cartilage segmentation (LACS) method. Briefly, the LACS method uses robust coordinate systems fixed to anatomical landmarks to measure patterns of change in cartilage volume in sub-regions using responsiveness heat maps. RESULTS: We observed a statistically significant gender difference in cartilage change in the medial femur (MF), lateral femur (LF), and medial tibia. The heat maps showed loss was primarily in the posterior central weight-bearing portion of the LF and more general in the LT and MF. Similar patterns were observed for each of the four follow-up periods. CONCLUSIONS: The LACS method was capable of illustrating gender-specific differences in patterns of cartilage loss that may offer insight into the variation of gender differences in the natural history of KOA and may be useful in evaluating the benefit of interventions for KOA.

Comparison of evaluation metrics of deep learning for imbalanced imaging data in osteoarthritis studies.

PURPOSE: To compare the evaluation metrics for deep learning methods that were developed using imbalanced imaging data in osteoarthritis studies. MATERIALS AND METHODS: This retrospective study utilized 2996 sagittal intermediate-weighted fat-suppressed knee MRIs with MRI Osteoarthritis Knee Score readings from 2467 participants in the Osteoarthritis Initiative study. We obtained probabilities of the presence of bone marrow lesions (BMLs) from MRIs in the testing dataset at the sub-region (15 sub-regions), compartment, and whole-knee levels based on the trained deep learning models. We compared different evaluation metrics (e.g., receiver operating characteristic (ROC) and precision-recall (PR) curves) in the testing dataset with various class ratios (presence of BMLs vs. absence of BMLs) at these three data levels to assess the model's performance. RESULTS: In a subregion with an extremely high imbalance ratio, the model achieved a ROC-AUC of 0.84, a PR-AUC of 0.10, a sensitivity of 0, and a specificity of 1. CONCLUSION: The commonly used ROC curve is not sufficiently informative, especially in the case of imbalanced data. We provide the following practical suggestions based on our data analysis: 1) ROC-AUC is recommended for balanced data, 2) PR-AUC should be used for moderately imbalanced data (i.e., when the proportion of the minor class is above 5% and less than 50%), and 3) for severely imbalanced data (i.e., when the proportion of the minor class is below 5%), it is not practical to apply a deep learning model, even with the application of techniques addressing imbalanced data issues.

Tanezumab for the treatment of osteoarthritis pain.

Tanezumab is a novel humanized IgG2 monoclonal antibody that works by selectively targeting, binding to and inhibiting nerve growth factor (NGF). NGF is upregulated in response to injury and inflammation, and preclinical data indicate it plays a role in pain signaling by inducing peripheral and central sensitization. Tanezumab potentially reduces sensitization and pain by blocking the interaction between NGF and the tropomyosin receptor kinase A (TrkA), and it has been studied extensively for the treatment of pain in patients with osteoarthritis (OA). In 2017, tanezumab was granted fast track designation in the U.S. for the treatment of chronic pain in patients with OA, as well as for the treatment of chronic low-back pain. This review discusses the mechanism of action, preclinical data and phase I, II and III studies of efficacy and safety of tanezumab in patients with OA.

Is There an Association Between a History of Running and Symptomatic Knee Osteoarthritis? A Cross-Sectional Study From the Osteoarthritis Initiative.

OBJECTIVE: Regular physical activity, including running, is recommended based on known cardiovascular and mortality benefits. However, controversy exists regarding whether running can be harmful to knees. The purpose of this study is to evaluate the relationship of running with knee pain, radiographic osteoarthritis (OA), and symptomatic OA. METHODS: This was a retrospective cross-sectional study of Osteoarthritis Initiative participants (2004-2014) with knee radiograph readings, symptom assessments, and completed lifetime physical activity surveys. Using logistic regression, we evaluated the association of history of leisure running with the outcomes of frequent knee pain, radiographic OA, and symptomatic OA. Symptomatic OA required at least 1 knee with both radiographic OA and pain. RESULTS: Of 2,637 participants, 55.8% were female, the mean ± SD age was 64.3 ± 8.9 years, and the mean ± SD body mass index was 28.5 ± 4.9 kg/m2 ; 29.5% of these participants ran at some time in their lives. Unadjusted odds ratios of pain, radiographic OA, and symptomatic OA for those prior runners and current runners compared to those who never ran were 0.83 and 0.71 (P for trend = 0.002), 0.83 and 0.78 (P for trend = 0.01), and 0.81 and 0.64 (P for trend = 0.0006), respectively. Adjusted models were similar, except radiographic OA results were attenuated. CONCLUSION: There is no increased risk of symptomatic knee OA among self-selected runners compared with nonrunners in a cohort recruited from the community. In those without OA, running does not appear to be detrimental to the knees.

Does a Patient-centered Educational Intervention Affect African-American Access to Knee Replacement? A Randomized Trial.

BACKGROUND: A TKA is the most effective and cost-effective surgical option for moderate to severe osteoarthritis (OA) of the knee. Yet, black patients are less willing to undergo knee replacement surgery than white patients. Decision aids help people understand treatment options and consider the personal importance of possible benefits and harms of treatments, including TKA. QUESTIONS/PURPOSES: We asked: (1) Does a patient-centered intervention consisting of a decision aid for knee OA and motivational interviewing improve the proportion of referrals of blacks with knee OA to orthopaedic surgery? (2) Does the intervention increase patients' willingness to undergo TKA? METHODS: Adults who self-identified as black who were at least 50 years old with moderate to severe knee OA were enrolled from urban primary care clinics in a two-group randomized, controlled trial. A total of 1253 patients were screened for eligibility, and 760 were excluded for not meeting inclusion criteria, declining to participate, or other reasons. Four hundred ninety-three patients were randomized and completed the intervention; three had missing referral data at followup. The mean age of the patients was 61 years, and 51% were women. The majority had an annual household income less than USD 15,000. Participants in the treatment group were shown a decision-aid video and had a brief session with a trained counselor in motivational interviewing. Participants in the control group received an educational booklet about OA that did not mention joint replacement. The two groups had comparable demographic and socioeconomic characteristics. The primary outcome was referral to orthopaedic surgery 12 months after treatment exposure. Receipt of referral was defined as the receipt of a recommendation or prescription from a primary care provider for orthopaedic evaluation. The secondary outcome was change in patient willingness to undergo TKA based on patient self-report. RESULTS: The odds of receiving a referral to orthopaedic surgery did not differ between the two study groups (36%, 90 of 253 of the control group; 32%, 76 of 240 of the treatment group; odds ratio [OR], 0.81; 95% CI, 0.56-1.18; p = 0.277). At 2 weeks followup, there was no difference between the treatment and the control groups in terms of increased willingness to consider TKA relative to baseline (34%, 67 of 200 patients in the treatment group; 33%, 68 of 208 patients in the control group; OR, 1.06; p = 0.779). At 12 months followup, the percent increase in willingness to undergo TKA still did not differ between patients in the treatment and control groups (29%, 49 of 174 in the treatment group; 27%, 51 of 191 in the control group; OR, 1.10; p = 0.679). CONCLUSION: A combination decision aid and motivational interviewing strategy was no better than an educational pamphlet in improving patients' preferences toward joint replacement surgery for knee OA. The type of intervention treatment also did not affect access to surgical evaluation. Other tools that target patient knowledge, beliefs, and attitudes regarding surgical treatments for OA may be further developed and tested in the future. LEVEL OF EVIDENCE: Level I, therapeutic study.

Semiquantitative Imaging Biomarkers of Knee Osteoarthritis Progression: Data From the Foundation for the National Institutes of Health Osteoarthritis Biomarkers Consortium.

OBJECTIVE: To determine the association between changes in semiquantitative magnetic resonance imaging (MRI) biomarkers over 24 months and radiographic and pain progression over 48 months in knees with mild-to-moderate osteoarthritis (OA). METHODS: We undertook a nested case-control study as part of the Foundation for the National Institutes of Health Biomarkers Consortium Project. We used multivariable logistic regression models to examine the association between change over 24 months in semiquantitative MRI markers and radiographic and pain progression in knee OA. MRIs were read according to the MRI OA Knee Score system. We focused on changes in cartilage, osteophytes, meniscus, bone marrow lesions, Hoffa-synovitis, and effusion-synovitis. RESULTS: The most parsimonious model included changes in cartilage thickness and surface area, effusion-synovitis, Hoffa-synovitis, and meniscal morphology (C statistic 0.740). Compared with no worsening, worsening in cartilage thickness in ≥3 subregions was associated with 2.8-fold (95% confidence interval [95% CI] 1.3-5.9) greater odds of being a case, and worsening in cartilage surface area in ≥3 subregions was associated with 2.4-fold (95% CI 1.3-4.4) greater odds of being a case. Worsening of meniscal morphology in any region was associated with 2.2-fold (95% CI 1.3-3.8) greater odds of being a case. Worsening effusion-synovitis and Hoffa-synovitis were also associated with a greater odds of being a case (odds ratios 2.7 and 2.0, respectively). CONCLUSION: Twenty-four-month changes in cartilage thickness, cartilage surface area, effusion-synovitis, Hoffa-synovitis, and meniscal morphology were independently associated with OA progression, suggesting that these factors may serve as efficacy biomarkers in clinical trials of disease-modifying interventions for knee OA.

Efficacy of periosteal stimulation for chronic pain associated with advanced knee osteoarthritis: a randomized, controlled clinical trial.

BACKGROUND: Because of morbidity associated with painful knee osteoarthritis (OA) and commonly prescribed analgesics, patients often pursue complementary and alternative modalities (eg, acupuncture). Clinical trials have demonstrated modest therapeutic efficacy of traditional Chinese acupuncture for knee OA pain, and patients with advanced disease have largely been excluded. We have previously demonstrated preliminary short-term tolerability and efficacy of periosteal stimulation therapy (PST) (ie, electrical stimulation of the periosteum facilitated by acupuncture needles) for older adults with advanced knee OA. OBJECTIVE: This study evaluated the sustained efficacy of PST and boosters for treating chronic pain with advanced knee OA. METHODS: One hundred ninety participants age >50 years with Kellgren-Lawrence grade 3 or 4 knee OA and chronic pain were randomized to (1) PST (once a week for 10 weeks) followed by PST boosters for 6 months (once every 2 weeks 2 times, then once a month), (2) control PST (ie, periosteal needles and brief electrical stimulation of control points) once a week for 10 weeks, or (3) PST for 10 weeks followed by control PST boosters for 6 months. Change in the Western Ontario and McMaster Universities Osteoarthritis Index pain score immediately after the 10-week intervention and at 6-month follow-up (9 months after baseline) was the primary outcome. OMERACT-OARSI (Outcome Measures in Rheumatology Clinical Trials-Osteoarthritis Research Society International) criteria also were evaluated. Secondary measures of outcome included (1) physical performance (Short Physical Performance Battery, gait speed, Timed Up and Go, and timed stair climb); (2) psychological factors (depressive symptoms measured with the Center for Epidemiologic Studies-Depression scale, coping measured with the catastrophizing subscale of the Coping Strategies Questionnaire, and self-efficacy measured with the Arthritis Self-Efficacy Scale); (3) health-related quality of life measured with the Medical Outcomes Study 36-Item Short-Form Health Survey; (4) rescue pain medication use tracked with diaries; and (5) health care utilization and interim physical activity were monitored via monthly telephone calls. RESULTS: After adjustment for pain at baseline, the PST and control booster did not differ from controls at 10 weeks (difference, 1.3; 95% CI, -0.10 to 2.8; P = 0.0683) or 9 months (difference, 1.1; 95% CI, -0.32 to 2.6; P = 0.13). The PST and PST booster group had similar improvement compared with controls at 10 weeks (baseline adjusted difference, 1.1; 95% CI, -0.34 to 2.5; P = 0.1369) but significantly more improvement at 9 months (baseline adjusted difference, 1.5; 95% CI, 0.069 to 3.0; P = 0.0401). Baseline depressive symptoms, low self-efficacy, higher difficulty performing daily activities, and greater knee stiffness predicted a lower likelihood of response. CONCLUSION: PST plus PST boosters in patients age >50 with advanced knee OA were well-tolerated and modestly reduced pain. ClinicalTrials.gov identifier: NCT00865046.

Willingness and access to joint replacement among African American patients with knee osteoarthritis: a randomized, controlled intervention.

OBJECTIVE: African American patients are significantly less likely to undergo knee replacement for the management of knee osteoarthritis (OA). Racial difference in preference (willingness) has emerged as a key factor. This study was undertaken to examine the efficacy of a patient-centered educational intervention on patient willingness and the likelihood of receiving a referral to an orthopedic clinic. METHODS: A total of 639 African American patients with moderate-to-severe knee OA from 3 Veterans Affairs primary care clinics were enrolled in a randomized, controlled trial with a 2 × 2 factorial design. Patients were shown a knee OA decision-aid video with or without brief counseling. The main outcome measures were change in patient willingness and receipt of a referral to an orthopedic clinic. Also assessed were whether patients discussed knee pain with their primary care provider or saw an orthopedic surgeon within 12 months of the intervention. RESULTS: At baseline, 67% of the participants were definitely/probably willing to consider knee replacement, with no difference among the groups. The intervention increased patient willingness (75%) in all groups at 1 month. For those who received the decision aid intervention alone, the gains were sustained for up to 3 months. By 12 months postintervention, patients who received any intervention were more likely to report engaging their provider in a discussion about knee pain (92% versus 85%), to receive a referral to an orthopedic surgeon (18% versus 13%), and for those with a referral, to attend an orthopedic consult (61% versus 50%). CONCLUSION: An educational intervention significantly increased the willingness of African American patients to consider knee replacement. It also improved the likelihood of patient-provider discussion about knee pain and access to surgical evaluation.

Baseline and longitudinal change in isometric muscle strength prior to radiographic progression in osteoarthritic and pre-osteoarthritic knees--data from the Osteoarthritis Initiative.

OBJECTIVE: To test whether cross-sectional or longitudinal measures of thigh muscle isometric strength differ between knees with and without subsequent radiographic progression of knee osteoarthritis (KOA), with particular focus on pre-osteoarthritic female knees (knees with risk factors but without definite radiographic KOA). METHODS: Of 4,796 Osteoarthritis Initiative participants, 2,835 knees with Kellgren Lawrence grade (KLG) 0-3 had central X-ray readings, annual quantitative joint space width (JSW) and isometric muscle strength measurements (Good strength chair). Separate slope analysis of covariance (ANCOVA) models were used to determine differences in strength between "progressor" and "non-progressor" knees, after adjusting for age, body mass index, and pain. RESULTS: 466 participant knees exceeded the smallest detectable JSW change during each of two observation intervals (year 2→4 and year 1→3) and were classified as progressors (213 women, 253 men; 128 KLG0/1, 330 KLG2/3); 946 participant knees did not exceed this threshold in either interval and were classified as non-progressors (588 women, 358 from men; 288KLG0/1, 658KLG2/3). Female progressor knees, including those with KLG0/1, tended to have lower extensor and flexor strength at year 2 and at baseline than those without progression, but the difference was not significant after adjusting for confounders. No significant difference was observed in longitudinal change of muscle strength (baseline→year 2) prior to radiographic progression. No significant differences were found for muscle strength in men, and none for change in strength concomitant with progression. CONCLUSION: This study provides no strong evidence that (changes in) isometric muscle strength precedes or is associated with structural (radiographic) progression of KOA.

Pattern of joint damage in persons with knee osteoarthritis and concomitant ACL tears.

Anterior cruciate ligament (ACL) tears are known to be a risk factor for incident knee osteoarthritis (OA). At the present time, it is unknown whether an incidental ACL tear in those with established knee OA alters the pattern of synovial joint damage. Therefore, our aim was to assess whether ACL tears in persons with knee OA are associated with specific patterns of cartilage loss, meniscal degeneration, and bone marrow lesion (BML) location. We included 160 participants from the progression subcohort of the Osteoarthritis Initiative (OAI) Study, an ongoing 4-year, multicenter study, focusing on knee OA. Regional cartilage morphometry measures including cartilage volume (mm(3)), denuded area, normalized cartilage volume, bone surface area, as well as location of meniscal pathology and BMLs in index knees on the same side were compared between those with and without ACL tears. Of the 160 subjects (51% women, age 62.1 (±9.9), BMI 30.3 (±4.7) kg/m(2)), 14.4% had an ACL tear. After adjusting for age, BMI and gender participants with ACL tears had significantly greater cartilage volume in the posterior lateral femur (P = 0.04) and the central medial tibia (0.001) compared to those without ACL tears. Normalized cartilage volume was not different between those with and without ACL tears. In addition, individuals with ACL tears had significantly larger bone surface areas in the medial tibia (P = 0,006), the central medial tibia (P = 0.008), the posterior lateral femur (P = 0.004), and the posterior medial femur (P = 0.04). Furthermore, participants with ACL tears showed significantly more meniscal derangement in the lateral posterior horn (P = 0.019) and significantly more BMLs in the lateral femur (P = 0.0025). We found clear evidence of predominant lateral tibiofemoral involvement, with OA-associated findings on MRI, including increased denuded area and bone surface area, BMLs, and meniscal derangement in knees of individuals with ACL tears compared to those without.

The association of osteoarthritis risk factors with localized, regional and diffuse knee pain.

OBJECTIVE: To identify determinants of different patterns of knee pain with a focus on risk factors for knee osteoarthritis (OA). DESIGN: The Knee Pain Map is an interviewer-administered assessment that asks subjects to characterize their knee pain as localized, regional, or diffuse. A total of 2677 participants from the Osteoarthritis Initiative were studied. We used multinomial logistic regression to examine the relationship between risk factors for OA and knee pain patterns. We examined the bivariate and multivariate relationships of knee pain pattern with age, body mass index (BMI), sex, race, family history of total joint replacement, knee injury, knee surgery, and hand OA. RESULTS: We compared 2462 knees with pain to 1805 knees without pain. In the bivariate analysis, age, sex, BMI, injury, surgery, and hand OA were associated with at least one pain pattern. In the multivariate model, all of these variables remained significantly associated with at least one pattern. When compared to knees without pain, higher BMI, injury, and surgery were associated with all patterns. BMI had its strongest association with diffuse pain. Older age was less likely to be associated with localized pain while female sex was associated with regional pain. CONCLUSIONS: We have shown that specific OA risk factors are associated with different knee pain patterns. Better understanding of the relationship between OA risk factors and knee pain patterns may help to characterize the heterogeneous subsets of knee OA.

The relation of femoral notch stenosis to ACL tears in persons with knee osteoarthritis.

OBJECTIVE: A significant risk factor for anterior cruciate ligament (ACL) tears in young athletes is a reduced femoral Notch Width Index (NWI). The purpose of this study was to test if persons with knee osteoarthritis (OA) and ACL tears have smaller NWI independent of prior joint injury and osteophyte volume. METHODS: We included 160 participants from the progression sub-cohort of the Osteoarthritis Initiative (OAI) Study, an ongoing 4-year, multi-center study, focusing on knee OA. The femoral notch width, the condylar notch width at 2/3 of the notch depth, and the intercondylar notch angle (beta) were measured on sagittal and coronal MR-images. NWI=notch width/condylar width at 2/3 of the notch depth, was calculated and outcome of ACL tear frequency was compared between two groups; NWI0.20. The NWI and beta were analyzed as continuous variables. RESULTS: Of the 160 subjects [51% female, age 62.1 (+/-9.9), BMI 30.3 (+/-4.7)kg/m(2)] 14.4% showed an ACL tear. Osteophyte bone volume was available for 150 participants, of which 13% had an ACL tear. The continuous measure of NWI on the coronal images was significantly (P=0.01) smaller in participants with ACL tear [0.246, 95% confidence interval (CI) 0.234-0.258] compared to those without (0.263, 95% CI 0.258-0.268). Adjustment for demographic variables still showed significant results (P=0.03, mean difference 0.015 95% CI -0.001-0.030) and adjustment for demographic variables and osteophyte bone volume were borderline significant (P=0.06, mean difference 0.015 95% CI 0.001-0.029). CONCLUSIONS: We identified a smaller NWI in participants with knee OA and ACL tears. Further longitudinal investigation is necessary to determine this as an independent risk factor.

Co-morbid medical and psychiatric illness and substance abuse in HCV-infected and uninfected veterans.

Comorbidities may affect the decision to treat chronic hepatitis C virus (HCV) infection. We undertook this study to determine the prevalence of these conditions in the HCV-infected persons compared with HCV-uninfected controls. Demographic and comorbidity data were retrieved for HCV-infected and -uninfected subjects from the VA National Patient Care Database using ICD-9 codes. Logistic regression was used to determine the odds of comorbid conditions in the HCV-infected subjects. HCV-uninfected controls were identified matched on age, race/ethnicity and sex. We identified 126 926 HCV-infected subjects and 126 926 controls. The HCV-infected subjects had a higher prevalence of diabetes, anaemia, hypertension, chronic obstructive pulmonary disease (COPD)/asthma, cirrhosis, hepatitis B and cancer, but had a lower prevalence of coronary artery disease and stroke. The prevalence of all psychiatric comorbidities and substance abuse was higher in the HCV-infected subjects. In the HCV-infected persons, the odds of being diagnosed with congestive heart failure, diabetes, anaemia, hypertension, COPD/asthma, cirrhosis, hepatitis B and cancer were higher, but lower for coronary artery disease and stroke. After adjusting for alcohol and drug abuse and dependence, the odds of psychiatric illness were not higher in the HCV-infected persons. The prevalence and patterns of comorbidities in HCV-infected veterans are different from those in HCV-uninfected controls. The association between HCV and psychiatric diagnoses is at least partly attributable to alcohol and drug abuse and dependence. These factors should be taken into account when evaluating patients for treatment and designing new intervention strategies.

Elderly hospitalized patients with diastolic heart failure: lack of gender and ethnic differences in 18-month mortality rates.

BACKGROUND: Racial and gender differences in mortality rates have been reported for patients with systolic heart failure. Relatively little is known regarding diastolic heart failure prognosis. METHODS: Our sample consisted of 1058 patients 65 years of age or older who were admitted to 30 hospitals in Northeastern Ohio with a principal diagnosis of heart failure and a left ventricular ejection fraction of >/=50% by echocardiogram. RESULTS: Of the 1058 patients with diastolic heart failure (13% African American and 87% white), African Americans and whites were comparable with respect to history of angina, stroke, being on dialysis, and alcohol use; the proportion of male patients was also comparable. The African American to white adjusted odds ratio for 18-month mortality (all cause) was 1.03 (0.66-1.59). For men versus women (30% vs 70%), the above-mentioned comorbidities were comparable, except women were more likely to have a do not resuscitate status (16% vs 7.3%; p =.000) and to be older (79.5 +/- 8 vs 77 +/- 7; p =.000). Men were more likely to have a history of tobacco use (30% vs 14%; p =.000) and alcohol use (36% vs 15%; p =.000), and a higher serum creatinine level (1.7 +/- 1.2 vs 1.4 +/- 1.1; p =.001). The men to women adjusted odds ratio for 18-month mortality (all cause) was 1.06 (0.76-1.46). CONCLUSION: In this cohort of elderly patients admitted with diastolic heart failure, there were no ethnic or gender differences in 18-month mortality rates.