Single Injection AAV2-FGF18 Gene Therapy Reduces Cartilage Loss and Subchondral Bone Damage in a Mechanically Induced Model of Osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is a highly debilitating, degenerative pathology of cartilaginous joints affecting over 500 million people worldwide. The global economic burden of OA is estimated at $260-519 billion and growing, driven by aging global population and increasing rates of obesity. To date, only the multi-injection chondroanabolic treatment regimen of Fibroblast Growth Factor 18 (FGF18) has demonstrated clinically meaningful disease-modifying efficacy in placebo-controlled human trials. Our work focuses on the development of a novel single injection disease-modifying gene therapy, based on FGF18's chondroanabolic activity. METHODS: OA was induced in Sprague-Dawley rats using destabilization of the medial meniscus (DMM) (3 weeks), followed by intra-articular treatment with 3 dose levels of AAV2-FGF18, rh- FGF18 protein, and PBS. Durability, redosability, and biodistribution were measured by quantifying nLuc reporter bioluminescence. Transcriptomic analysis was performed by RNA-seq on cultured human chondrocytes and rat knee joints. Morphological analysis was performed on knee joints stained with Safranin O/Fast Green and anti-PRG antibody. RESULTS: Dose-dependent reductions in cartilage defect size were observed in the AAV2-FGF18- treated joints relative to the vehicle control. Total defect width was reduced by up to 76% and cartilage thickness in the thinnest zone was increased by up to 106%. Morphologically, the vehicle- treated joints exhibited pronounced degeneration, ranging from severe cartilage erosion and bone void formation, to subchondral bone remodeling and near-complete subchondral bone collapse. In contrast, AAV2-FGF18-treated joints appeared more anatomically normal, with only regional glycosaminoglycan loss and marginal cartilage erosion. While effective at reducing cartilage lesions, treatment with rhFGF18 injections resulted in significant joint swelling (19% increase in diameter), as well as a decrease in PRG4 staining uniformity and intensity. In contrast to early-timepoint in vitro RNA-seq analysis, which showed a high degree of concordance between protein- and gene therapy-treated chondrocytes, in vivo transcriptomic analysis, revealed few gene expression changes following protein treatment. On the other hand, the gene therapy treatment exhibited a high degree of durability and localization over the study period, upregulating several chondroanabolic genes while downregulating OA- and fibrocartilage-associated markers. CONCLUSION: FGF18 gene therapy treatment of OA joints can provide benefits to both cartilage and subchondral bone, with a high degree of localization and durability.

Associations of inflammatory and metabolic biomarkers with incident erosive hand osteoarthritis in the osteoarthritis initiative cohort.

OBJECTIVE: Erosive hand osteoarthritis (eHOA) is a subtype of hand osteoarthritis (OA) that develops in finger joints with pre-existing OA and is differentiated by clinical characteristics (hand pain/disability, inflammation, and erosions) that suggest inflammatory or metabolic processes. METHOD: This was a longitudinal nested case-cohort design among Osteoarthritis Initiative participants who had hand radiographs at baseline and 48-months, and biospecimens collected at baseline. We classified incident radiographic eHOA in individuals with ≥1 joint with Kellgren-Lawrence ≥2 and a central erosion present at 48-months but not at baseline. We used a random representative sample (n = 1282) for comparison. We measured serum biomarkers of inflammation, insulin resistance and dysglycemia, and adipokines using immunoassays and enzymatic colorimetric procedures, blinded to case status. RESULTS: Eighty-six participants developed incident radiographic eHOA. In the multivariate analyses adjusted for age, gender, race, smoking, and body mass index, and after adjustment for multiple analyses, incident radiographic eHOA was associated with elevated levels of interleukin-7 (risk ratio (RR) per SD = 1.30 [95% confidence interval (CI) 1.09, 1.55] p trend 0.01). CONCLUSION: This exploratory study suggests an association of elevated interleukin-7, an inflammatory cytokine, with incident eHOA, while other cytokines or biomarkers of metabolic inflammation were not associated. Interleukin-7 may mediate inflammation and tissue damage in susceptible osteoarthritic finger joints and participate in erosive progression.

Association of Weight Loss and Weight Gain With Structural Defects and Pain in Hand Osteoarthritis: Data From the Osteoarthritis Initiative.

OBJECTIVE: Our aim was to define the association of weight change (weight loss or weight gain) with the incidence and progression of hand osteoarthritis (OA), assessed either by radiography or by pain, using data from the Osteoarthritis Initiative. METHODS: Among the 4,796 participants, we selected 4,598 participants, excluding those with cancer or rheumatoid arthritis or a body mass index under 18.5 kg/m2. We investigated the association of weight change with incidence and progression of radiographic hand OA and the development and resolution of hand pain. Using multivariable logistic regression, we investigated the association of weight change from baseline to the 4-year follow-up with the incidence and progression of radiographic hand OA at the 4-year follow-up. Additionally, multivariable repeated-measure mixed-effects logistic regression analyzed the association of weight change with the development and resolution of hand pain across 2-year, 4-year, 6-year, and 8-year follow-ups. RESULTS: No statistically significant associations were observed between weight change and the investigated outcomes. Specifically, for each 5% weight loss, the odds ratios for the incidence and progression of radiographic hand OA were 0.90 (95% confidence interval [95% CI] 0.67-1.23) and 0.92 (95% CI 0.84-1.00), respectively. Similarly, for each 5% weight loss, the odds ratios for the development and resolution of hand pain at the 8-year follow-up were 1.00 (95% CI 0.92-1.09) and 1.07 (95% CI 0.91-1.25), respectively. CONCLUSION: Our study found no evidence of an association between weight change and the odds of incidence or progression of radiographic hand OA over 4 years, nor the development or resolution of hand pain over 8 years.

Novel Framework for Measuring Whole Knee Osteoarthritis Progression Using Magnetic Resonance Imaging.

OBJECTIVE: We developed and validated a set of composite scores that combine quantitative magnetic resonance imaging (MRI)-based measurements of hyaline cartilage damage, bone marrow lesions (BMLs), and effusion-synovitis into composite scores. METHODS: We selected 300 participants (n = 100 for development cohort; n = 200 for validation cohort) from the Osteoarthritis Initiative with complete clinical, radiographic, and MRI data at baseline and 24 months. We used semiautomated programs to quantify tibiofemoral and patellar cartilage damage, BML volume, and whole-knee effusion-synovitis volume. The candidate composite scores were formed by summing changes from baseline to 24 months based on prespecified methods. We evaluated the candidate composite scores for 1) the ability to differentiate groups with and without knee osteoarthritis progression (17 radiographic and patient-reported definitions), 2) sensitivity to change (standardized response means), and 3) relative performance relating to legacy outcome measures of knee osteoarthritis progression. RESULTS: Three of 13 developed composite scores qualified for testing in the validation cohort (ranked by sensitivity to change): whole-knee cumulative cartilage damage, unweighted total knee score, and BML plus effusion-synovitis volume. Change in cumulative cartilage damage associated with radiographic progression (Kellgren/Lawrence grade: odds ratio [OR] 1.84; joint space width progression: OR 2.11). Changes in the unweighted total knee score (OR 1.97) and BML plus effusion-synovitis score (OR 1.92) associated with Western Ontario and McMaster Universities Osteoarthritis Index knee pain progression. CONCLUSION: Two composite scores emerged, reflecting discrete domains of knee osteoarthritis progression. First, cumulative damage, which is measured by a whole-knee cartilage damage score, reflects the damage accrued over time. Second, dynamic disease activity, which is measured by a BML plus effusion-synovitis score, relates to changes in a patient's state of disease and symptoms.

Mobile health technologies for the management of rheumatic diseases: a systematic review of online stores in Brazil.

Rheumatic diseases are serious conditions with a low uptake of conservative treatments. Mobile health (mHealth) applications (apps) offer potential to assist the self-management of rheumatic diseases. Our goal was to perform a systematic review of available mHealth apps for rheumatic diseases in Brazil. We focused on the most prevalent rheumatic diseases: osteoarthritis, rheumatoid arthritis, fibromyalgia, systemic lupus erythematosus, osteoporosis, and axial spondylarthritis. Google Play Store and AppStore in Brazil were queried by two independent reviewers on September 2020, and the quality of eligible mHealth apps was assessed using the Mobile App Rating Scale (MARS). Of the 3173 mHealth apps found, five were eligible for inclusion. Two for fibromyalgia and two for axial spondylarthritis offered exercise, educational content, and tools to track patient-reported symptoms; and one for osteoporosis offered educational content and tracking tools only. The included apps scored moderately on the MARS quality scale, with a mean score (SD) of 3.1 (0.7) on a 0-5 scale. Most apps scored poorly based on credibility, user interface and experience, and engagement. There is growing interest in the development of mHealth technologies to support rheumatic diseases patients. Although the majority of the included apps came from non-profit organizations, they are still of poor quality and limited functionality. This study is a call for to the development of new user-centered mHealth apps that can empower rheumatic diseases patients in Brazil, especially in the area of osteoarthritis, rheumatoid arthritis, and lupus, since no apps were found.

Risk factors and the natural history of accelerated knee osteoarthritis: a narrative review.

BACKGROUND: Osteoarthritis is generally a slowly progressive disorder. However, at least 1 in 7 people with incident knee osteoarthritis develop an abrupt progression to advanced-stage radiographic disease, many within 12 months. We summarize what is known - primarily based on findings from the Osteoarthritis Initiative - about the risk factors and natural history of accelerated knee osteoarthritis (AKOA) - defined as a transition from no radiographic knee osteoarthritis to advanced-stage disease < 4 years - and put these findings in context with typical osteoarthritis (slowly progressing disease), aging, prior case reports/series, and relevant animal models. Risk factors in the 2 to 4 years before radiographic manifestation of AKOA (onset) include older age, higher body mass index, altered joint alignment, contralateral osteoarthritis, greater pre-radiographic disease burden (structural, symptoms, and function), or low fasting glucose. One to 2 years before AKOA onset people often exhibit rapid articular cartilage loss, larger bone marrow lesions and effusion-synovitis, more meniscal pathology, slower chair-stand or walking pace, and increased global impact of arthritis than adults with typical knee osteoarthritis. Increased joint symptoms predispose a person to new joint trauma, which for someone who develops AKOA is often characterized by a destabilizing meniscal tear (e.g., radial or root tear). One in 7 people with AKOA onset subsequently receive a knee replacement during a 9-year period. The median time from any increase in radiographic severity to knee replacement is only 2.3 years. Despite some similarities, AKOA is different than other rapidly progressive arthropathies and collapsing these phenomena together or extracting results from one type of osteoarthritis to another should be avoided until further research comparing these types of osteoarthritis is conducted. Animal models that induce meniscal damage in the presence of other risk factors or create an incongruent distribution of loading on joints create an accelerated form of osteoarthritis compared to other models and may offer insights into AKOA. CONCLUSION: Accelerated knee osteoarthritis is unique from typical knee osteoarthritis. The incidence of AKOA in the Osteoarthritis Initiative and Chingford Study is substantial. AKOA needs to be taken into account and studied in epidemiologic studies and clinical trials.

Adults With Incident Accelerated Knee Osteoarthritis Are More Likely to Use Pharmacological Treatment Options and Receive Arthroscopic Knee Surgery: Data From the Osteoarthritis Initiative.

OBJECTIVE: To determine if people with incident accelerated knee osteoarthritis (AKOA) were more likely to receive a pharmacological treatment or arthroscopic knee surgery than those with typical knee osteoarthritis (KOA) or no KOA. METHODS: We conducted a nested cohort study using data from baseline and the first 8 years of the Osteoarthritis Initiative. Eligible participants had no radiographic KOA at baseline (Kellgren-Lawrence [KL] < 2). We classified three groups using KL grades: 1) AKOA: knee progressed to advanced-stage KOA (KL 3/4) in 4 years or less, 2) typical KOA: knee increased in KL grade by 8 years (excluding AKOA), and 3) No KOA: no change in KL grade by 8 years. The outcome was self-reported arthroscopic knee surgery or a pharmacological treatment option: nonsteroidal anti-inflammatory drugs (NSAIDs), hyaluronic acid injections, intra-articular corticosteroid injections, or prescription analgesics. Between-group differences in therapeutic use were evaluated with Chi-square tests. RESULTS: Adults who developed AKOA (n = 92) were more likely to report arthroscopic knee surgery (AKOA: 32%, KOA [n = 380]: 8%, no KOA [n = 875]: 3%; P < 0.001), hyaluronic acid injections (AKOA: 10%, KOA: 4%, no KOA: 1%; P < 0.001), intra-articular corticosteroid injections (AKOA: 30%, KOA: 7%, no KOA: 4%; P < 0.001), and NSAID use (over the counter: AKOA: 65%, KOA: 48%, and no KOA: 46%; P = 0.003; prescription: AKOA: 61%, KOA: 43%, no KOA: 41%; P = 0.002). CONCLUSION: Adults with AKOA are more likely to receive pharmacological treatment or arthroscopic knee surgery than their peers. Adults with AKOA are an important patient population that is understudied in clinical research despite their use of greater health care resources.

Association Between Declining Walking Speed and Increasing Bone Marrow Lesion and Effusion Volume in Individuals with Accelerated Knee Osteoarthritis.

OBJECTIVE: To determine whether a decline in walking speed during the year prior to disease onset is associated with concurrent changes in cartilage, bone marrow lesions (BMLs), or effusion in adults who develop common knee osteoarthritis (OA), accelerated knee OA, or no knee OA. METHODS: We identified 3 groups from the Osteoarthritis Initiative based on annual radiographs from baseline to 48 months: accelerated knee OA, common knee OA, and no knee OA. We used the cartilage damage index (CDI) to assess tibiofemoral cartilage damage and used a semiautomated program to measure BML and effusion volume. Walking speed was assessed as an individual's habitual walking speed over 20 meters. One-year change in walking speed and structural measures were calculated as index visit measurements minus measurements from the year prior visit. Logistic regression models were used to determine whether change in walking speed (exposure) was associated with change in each structural measure (outcome) for the overall group and then separately for the accelerated knee OA, common knee OA, and no knee OA groups. RESULTS: Adults who slowed their walking speed were almost twice as likely to present with increased BML volume, with a significant association (odds ratio 3.04 [95% confidence interval (95% CI) 1.03-8.95]) among adults with accelerated knee OA. Adults with accelerated knee OA who slowed their walking speed were approximately 3.4 times (95% CI 1.10-10.49) more likely to present with increased effusion volume. Walking speed change was not significantly associated with CDI change. CONCLUSION: A change in an easily assessable clinical examination (i.e., 20-meter walk test) was associated with concurrent worsening in BML and effusion volume in adults who developed accelerated knee OA.

Accelerated Knee Osteoarthritis Is Characterized by Destabilizing Meniscal Tears and Preradiographic Structural Disease Burden.

OBJECTIVE: To determine whether accelerated knee osteoarthritis (KOA) is preceded by, and characterized over time by, destabilizing meniscal tears or other pathologic changes. METHODS: We selected 3 sex-matched groups of subjects from the first 48 months of the Osteoarthritis Initiative, comprising adults who had a knee without KOA (Kellgren/Lawrence [K/L] radiographic grade <2) at baseline. Subjects in the accelerated KOA group developed KOA of K/L grade ≥3, those with typical KOA showed increased K/L radiographic scores, and those with no KOA had the same K/L grade over time. An index visit was the visit when the radiographic criteria for accelerated KOA and typical KOA were met (the no KOA group was matched to the accelerated KOA group). The observation period was up to 2 years before and after an index visit. Radiologists reviewed magnetic resonance (MR) images of the index knee and identified destabilizing meniscal tears (root tears, radial tears, complex tears), miscellaneous pathologic features (acute ligamentous or tendinous injuries, attrition, subchondral insufficiency fractures, other incidental findings), and meniscal damage in >2 of 6 regions (3 regions per meniscus: anterior horn, body, posterior horn). In addition, bone marrow lesions (BMLs) and cartilage damage on MR images were quantified. Linear mixed regression models were performed to analyze the results. RESULTS: At 1 year before the index visit, >75% of adults with accelerated KOA had meniscal damage in ≥2 regions (odds ratio 3.19 [95% confidence interval 1.70-5.97] versus adults with typical KOA). By the index visit, meniscal damage in ≥2 regions was ubiquitous in adults with accelerated KOA, including 42% of subjects having evidence of a destabilizing meniscal tear (versus 14% of subjects with typical KOA). These changes corresponded to findings of larger BMLs and greater cartilage loss in the accelerated KOA group. CONCLUSION: Accelerated KOA is characterized by destabilizing meniscal tears in a knee compromised by meniscal damage in >2 regions, and also characterized by the presence of large BMLs and greater cartilage loss.

Bioluminescence and second harmonic generation imaging reveal dynamic changes in the inflammatory and collagen landscape in early osteoarthritis.

Osteoarthritis (OA) is a leading cause of chronic disability whose mechanism of pathogenesis is largely elusive. Local inflammation is thought to play a key role in OA progression, especially in injury-associated OA. While multiple inflammatory cytokines are detected, the timing and extent of overall inflammatory activities in early OA and the manner by which joint inflammation correlates with cartilage structural damage are still unclear. We induced OA via destabilization of the medial meniscus (DMM) in NFκB luciferase reporter mice, whose bioluminescent signal reflects the activity of NFκB, a central mediator of inflammation. Bioluminescence imaging data showed that DMM and sham control joints had a similar surge of inflammation at 1-week post-surgery, but the DMM joint exhibited a delay in resolution of inflammation in subsequent weeks. A similar trend was observed with synovitis, which we found to be mainly driven by synovial cell density and inflammatory infiltration rather than synovial lining thickness. Interestingly, an association between synovitis and collagen structural damage was observed in early OA. Using Second Harmonic Generation (SHG) imaging, we analyzed collagen fiber organization in articular cartilage. Zonal differences in collagen fiber thickness and organization were observed as soon as OA initiated after DMM surgery, and persisted over time. Even at 1-week post-surgery, the DMM joint showed a decrease in collagen fiber thickness in the deep zone and an increase in collagen fiber disorganization in the superficial zone. Since we were able detect and quantify collagen structural changes very early in OA development by SHG imaging, we concluded that SHG imaging is a highly sensitive tool to evaluate pathological changes in OA. In summary, this study uncovered a dynamic profile of inflammation and joint cartilage damage during OA initiation and development, providing novel insights into OA pathology.

Comparison of self-report and objective measures of physical activity in US adults with osteoarthritis.

To describe levels of daily physical activity and examine the extent of agreement between self-reported and objectively measured indices of physical activity, and characteristics associated with under or overestimated physical activity among persons with osteoarthritis (OA). Using cross-sectional data from the 2003-2006 National Health and Nutrition Examination Survey, we identified 533 adults ≥45 years of age with self-reported OA who completed physical activity questionnaires and had accelerometry data collected using Actigraph AM-7164. Average daily minutes of moderate to vigorous activity and 95 % confidence intervals (95 % CIs) using self-reported and objective measures were compared across sociodemographic and clinical subgroups and Spearman's rank correlations were calculated. Differences between self-reported and objectively measured moderate to vigorous activity across various personal characteristics were also estimated. Most persons with OA were non-Hispanic white (87.9 %) and women (68.9 %) with an average age of 65 years old. Self-reported measure of daily moderate to vigorous activity was on average 7 min higher compared to objective measure (17.9 vs. 10.8 min/day). Correlations between self-reported and objective measures across sociodemographic groups were mostly weak to moderate ranging from 0.01 to 0.48. Participants with higher education and better self-reported health status were more likely to over-estimate their moderate to vigorous activity using self-reported measures. Measurement methods and sociodemographic and health factors are associated with differences in reporting physical activity among persons with OA. Future research examining relationships between physical activity and health outcomes in OA should be aware of measurement issues and differences of reporting in subgroups.

Exploratory analysis of osteoarthritis progression among medication users: data from the Osteoarthritis Initiative.

BACKGROUND: We conducted an exploratory analysis of osteoarthritis progression among medication users in the Osteoarthritis Initiative to identify interventions or pathways that may be associated with disease modification and therefore of interest for future clinical trials. METHODS: We used participants from the Osteoarthritis Initiative with annual medication inventory data between the baseline and 36-month follow-up visit (n = 2938). Consistent medication users were defined for each medication classification as a participant reporting at all four annual visits that they were regularly using an oral prescription medication at the time of the visit. The exploratory analysis focused on medication classes with 40 or more users. The primary outcome measures were medial tibiofemoral joint space width change and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) knee pain score change (12-36-month visits). Within each knee, we explored eight comparisons between users and matched or unmatched nonusers (defined two ways). An effect size of each comparison was calculated. Medication classes had potential signals if (a) both knees had less progression among users compared with nonusers, or (b) there was less progression based on structure and symptoms in one knee. RESULTS: We screened 28 medication classes. Six medication classes had signals for fewer structural changes and better knee pain changes: alpha-adrenergic blockers, antilipemic (excluding statins and fibric acid), anticoagulants, selective serotonin reuptake inhibitors, antihistamines, and antineoplastic agents. Four medication classes had signals for structural changes alone: anti-estrogen (median effect size = 0.28; range = -0.41-0.64), angiotensin-converting enzyme inhibitors (median effect size = 0.13; range = -0.08-0.28), beta-adrenergic blockers (median effect size = 0.09; range = 0.01-0.30), and thyroid agents (median effect size = 0.04; range = -0.05-0.14). Thiazide diuretics had evidence for symptom modification (median effect size = -0.12; range = -0.24-0.04). CONCLUSIONS: Users of neurovascular, antilipemic, or hormonal interventions may have less disease progression compared with nonusers.

Magnetic Resonance Image Sequence Influences the Relationship between Bone Marrow Lesions Volume and Pain: Data from the Osteoarthritis Initiative.

Subchondral bone marrow lesions (BMLs) are related to structural and symptomatic osteoarthritis progression. However, it is unclear how sequence selection influences a quantitative BML measurement and its construct validity. We compared quantitative assessment of BMLs on intermediate-weighted fat suppressed (IW FS) turbo spin echo and 3-dimensional dual echo steady state (3D DESS) sequences. We used a customized software to measure 30 knees' (24- and 48-month MR images) BMLs on both sequences. The results showed that the IW FS sequences have much larger BML volumes (median: IW FS = 1840 mm(3); DESS = 191 mm(3)) and BML volume change (between 24 and 48 months) than DESS sequence and demonstrate more BML volume change. The 24-month BML volume on IW FS is correlated with BML volume on DESS (r s = 0.83). BML volume change on IW FS is not significantly correlated with change on DESS. The 24-month WOMAC pain is correlated with the 24-month BMLs on IW FS (r s = 0.39) but not DESS. The change in WOMAC pain is correlated with BML volume change on IW FS (r s = 0.37) but not DESS. Overall, BML quantification on IW FS offers better validity and statistical power than BML quantification on a 3D DESS sequence.

Evaluation of bone marrow lesion volume as a knee osteoarthritis biomarker--longitudinal relationships with pain and structural changes: data from the Osteoarthritis Initiative.

INTRODUCTION: Bone marrow lesion (BML) size may be an important imaging biomarker for osteoarthritis-related clinical trials and reducing BML size may be an important therapeutic goal. However, data on the interrelationships between BML size, pain, and structural progression are inconsistent and rarely examined in the same cohort. Therefore, we evaluated the cross-sectional and longitudinal associations of BML volume with knee pain and joint space narrowing (JSN). METHODS: A BML volume assessment was performed on magnetic resonance images of the knee collected at the 24- and 48-month Osteoarthritis Initiative visits from a convenience sample of 404 participants in the progression cohort. During the same visits, knee pain was assessed with WOMAC pain scores and knee radiographs were acquired and scored for JSN. BML volume was summed to generate a total knee volume and an index tibiofemoral compartment volume (compartment with greater baseline JSN). Primary analyses included multiple linear regressions (outcome = pain, predictor = total knee BML volume) and logistic regressions (outcome = JSN, predictor = index tibiofemoral compartment BML volume). RESULTS: This sample was 49% female with a mean age of 63 (9.2 standard deviation (SD)) years, and 71% had radiographic osteoarthritis in the study knee. Larger baseline BMLs were associated with greater baseline knee pain (P = 0.01), the presence of JSN at baseline (odds ratio (OR) = 1.50, 95% confidence interval (CI) = 1.23 to 1.83), and JSN progression (OR = 1.27, 95%CI = 1.11 to 1.46). Changes in total knee BML volume had a positive association with changes in knee pain severity (P = 0.004) and this association may be driven by knees that were progressing from no or small baseline BMLs to larger BMLs. In contrast, we found no linear positive relationship between BML volume change and JSN progression. Instead, regression of medial tibiofemoral BML volume was associated with JSN progression compared to knees with no or minimal changes in BML volume (OR = 3.36, 95%CI = 1.55 to 7.28). However, follow-up analyses indicated that the association between JSN progression and BML volume change may primarily be influenced by baseline BML volume. CONCLUSION: Large baseline BMLs are associated with greater baseline knee pain, the presence of JSN at baseline, and disease progression. Additionally, BML regression is associated with decreased knee pain but not a reduced risk of concurrent JSN progression.

Quantification of bone marrow lesion volume and volume change using semi-automated segmentation: data from the osteoarthritis initiative.

BACKGROUND: To determine the validity of a semi-automated segmentation of bone marrow lesions (BMLs) in the knee. METHODS: Construct validity of the semi-automated BML segmentation method was explored in two studies performed using sagittal intermediate weighted, turbo spine echo, fat-suppressed magnetic resonance imaging sequences obtained from the Osteoarthritis Initiative. The first study (n = 48) evaluated whether tibia BML volume was different across Boston Leeds Osteoarthritis Knee Scores (BLOKS) for tibia BMLs (semiquantitative grades 0 to 3). In the second study (n = 40), we evaluated whether BML volume change was associated with changes in cartilage parameters. The knees in both studies were segmented by one investigator. We performed Wilcoxon signed-rank tests to determine if tibia BML volume was different between adjacent BLOKS BML scores and calculated Spearman correlation coefficients to assess the relationship between 2-year BML volume change and 2-year cartilage morphometry change (significance was p ≤ 0.05). RESULTS: BML volume was significantly greater between BLOKS BML score 0 and 1 (z = 2.85, p = 0.004) and BLOKS BML scores 1 and 2 (z = 3.09, p = 0.002). There was no significant difference between BLOKS BML scores 2 and 3 (z = -0.30, p = 0.77). Increased tibia BML volume was significantly related to increased tibia denuded area (Spearman r = 0.42, p = 0.008), decreased tibia cartilage thickness (Spearman r = -0.46, p = 0.004), increased femur denuded area (Spearman r = 0.35, p = 0.03), and possibly decreased femur cartilage thickness (Spearman r = -0.30, p = 0.07) but this last finding was not statistically significant. CONCLUSION: The new, efficient, and reliable semi-automated BML segmentation method provides valid BML volume measurements that increase with greater BLOKS BML scores and confirms previous reports that BML size is associated with longitudinal cartilage loss.

Bone marrow lesion volume reduction is not associated with improvement of other periarticular bone measures: data from the Osteoarthritis Initiative.

INTRODUCTION: We evaluated the associations between bone marrow lesion (BML) volume change and changes in periarticular bone mineral density (paBMD) as well as subchondral sclerosis to determine whether BML change is associated with other local bone changes. METHODS: The convenience sample comprised participants in the Osteoarthritis Initiative (OAI) with weight-bearing posterior-anterior knee radiographs and magnetic resonance images (MRIs) at the 24- and 48-month visits and dual-energy x-ray absorptiometry (DXA) at the 30-/36-month and 48-month visits. The right knee was assessed unless contraindicated for MRI. We used knee DXA scans to measure medial tibia paBMD and medial/lateral paBMD ratio (M:L paBMD). Knee radiographs were scored for sclerosis (grades 0 to 3) in the medial tibia. Two raters determined BML volume on sagittal fat-suppressed MRI by using a semiautomated segmentation method. To focus on knees with only medial tibia BML changes, knees with lateral tibial BMLs were excluded. Medial tibial BML volume change was classified into three groups: BML regression (lowest quartile of medial tibial BML volume change), no-to-minimal change (middle two quartiles), and BML progression (highest quartile). We used proportional odds logistic regression models to evaluate the association between quartiles of changes in medial paBMD or M:L paBMD ratio, as outcomes, and BML volume change. RESULTS: The sample (n = 308) included 163 (53%) female subjects, 212 (69%) knees with radiographic osteoarthritis, and participants with a mean age of 63.8 ± 9.3 years and mean body mass index of 29.8 ± 4.7 kg/m(2). We found an association between greater increases in medial tibia paBMD and BML regression (OR = 1.7 (95% confidence interval (CI) = 1.1 to 2.8)) and a similar trend for BML progression (OR = 1.6 (95% CI = 1.0 to 2.6]). We also detected associations between greater increase in M:L paBMD and BML regression (OR = 1.6 (95% CI = 1.0 to 2.7]) and BML progression (OR = 1.8 (95% CI = 1.1 to 3.0)), although BML regression had borderline statistical significance. The frequency of sclerosis progression in the medial tibia (n = 14) was greater among knees with BML progression or regression compared with knees without BML change (P = 0.01 and P = 0.04, respectively). CONCLUSION: BML regression and BML progression are characterized by concurrent increases in paBMD and sclerosis, which are characteristic of increased radiographic osteoarthritis severity. At least during 24 months, BML regression is not representative of improvement in other periarticular bone measures.

Quantitative bone marrow lesion size in osteoarthritic knees correlates with cartilage damage and predicts longitudinal cartilage loss.

BACKGROUND: Bone marrow lesions (BMLs), common osteoarthritis-related magnetic resonance imaging findings, are associated with osteoarthritis progression and pain. However, there are no articles describing the use of 3-dimensional quantitative assessments to explore the longitudinal relationship between BMLs and hyaline cartilage loss. The purpose of this study was to assess the cross-sectional and longitudinal descriptive characteristics of BMLs with a simple measurement of approximate BML volume, and describe the cross-sectional and longitudinal relationships between BML size and the extent of hyaline cartilage damage. METHODS: 107 participants with baseline and 24-month follow-up magnetic resonance images from a clinical trial were included with symptomatic knee osteoarthritis. An 'index' compartment was identified for each knee defined as the tibiofemoral compartment with greater disease severity. Subsequently, each knee was evaluated in four regions: index femur, index tibia, non-index femur, and non-index tibia. Approximate BML volume, the product of three linear measurements, was calculated for each BML within a region. Cartilage parameters in the index tibia and femur were measured based on manual segmentation. RESULTS: BML volume changes by region were: index femur (median [95% confidence interval of the median]) 0.1 cm3 (-0.5 to 0.9 cm3), index tibia 0.5 cm3 (-0.3 to 1.7 cm3), non-index femur 0.4 cm3 (-0.2 to 1.6 cm3), and non-index tibia 0.2 cm3 (-0.1 to 1.2 cm3). Among 44 knees with full thickness cartilage loss, baseline tibia BML volume correlated with baseline tibia full thickness cartilage lesion area (r = 0.63, p< 0.002) and baseline femur BML volume with longitudinal change in femoral full thickness cartilage lesion area (r = 0.48 p< 0.002). CONCLUSIONS: Many regions had no or small longitudinal changes in approximate BML volume but some knees experienced large changes. Baseline BML size was associated to longitudinal changes in area of full thickness cartilage loss.

Is lipstick associated with the development of systemic lupus erythematosus (SLE)?

Lipstick use has been hypothesized to be a risk factor of developing systemic lupus erythematosus (SLE). The objective of this study was to investigate the association between lipstick use and risk of SLE. We performed an Internet-based case-control study of SLE with Google users searching on medical key terms as the source population. Cases were diagnosed within 5 years and met > or =4 ACR criteria for SLE by medical record review. Controls were matched to cases on age, gender, race, ethnicity, region of residence, reference year, education, and income using propensity score. Demographic characteristics and lifestyle factors were collected using an online questionnaire. Conditional logistic regression models were used for the analyses with smoking, alcohol consumption, permanent hair dye use, and chemical hair straightener use adjusted. The analysis included 124 cases and 248 matched controls of whom 96% were females and 81% were whites. The median of disease duration was 2 years (range 0-4 years). Using lipstick at least 3 days/week was significantly associated with increased risk of SLE (adjusted OR = 1.71, 95%CI = 1.04-2.82). There was a trend of greater risk with earlier age of initiation of lipstick use (<16 years vs. never use; OR = 1.95, 95%CI = 1.01-3.76, p trend = 0.02) and with increased frequency of use (7 days/week vs. never use; OR = 1.75, 95%CI = 0.89-3.44, p trend = 0.07). Biologic effects of chemicals present in lipsticks absorbed across the buccal mucosa and confounding from unmeasured lifestyle factors could be the explanation of this association. Epidemiologic studies of SLE should include this exposure in exploring its environmental triggers.

Association of periodontal disease and tooth loss with rheumatoid arthritis in the US population.

OBJECTIVE: To test for an association of periodontitis and tooth loss with rheumatoid arthritis (RA). METHODS: The third National Health and Nutrition Examination Survey (NHANES III) is a nationally representative cross-sectional survey of noninstitutionalized civilians. We included participants aged > or = 60 years who had undergone both musculoskeletal and dental examinations. RA was defined based on American College of Rheumatology criteria. Dental examinations quantified decayed and filled surfaces, missing teeth, and periodontitis. Periodontitis was defined as at least 1 site exhibiting both attachment loss and a probing depth of > or = 4 mm. We classified dental health status as (1) no periodontitis, (2) periodontitis, or (3) edentulous (i.e., complete tooth loss). We performed multivariate multinomial logistic regression models with dental health status as the dependent and RA as the independent variables. RESULTS: The sample consisted of 4461 participants, of whom 103 were classified as having RA. Participants with RA had more missing teeth (20 vs 16 teeth; p < 0.001), but less decay (2% vs 4%; p < 0.001) than participants without RA. After adjusting for age, sex, race/ethnicity, and smoking, subjects with RA were more likely to be edentulous [odds ratio (OR) 2.27, 95% confidence interval (CI) 1.56 3.31] and have periodontitis (OR 1.82, 95% CI 1.04 3.20) compared with non-RA subjects. In participants with seropositive RA there was a stronger association with dental health status, in particular with edentulism (OR 4.5, 95% CI 1.2 17). CONCLUSION: RA may be associated with tooth loss and periodontitis.