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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.

Background: We aimed to determine if composite structural measures of knee osteoarthritis (KOA) progression on magnetic resonance (MR) imaging can predict the radiographic onset of accelerated knee osteoarthritis., Methods: We used data from a nested case-control study among participants from the Osteoarthritis Initiative without radiographic KOA at baseline. Participants were separated into three groups based on radiographic disease progression over 4 years: 1) accelerated (Kellgren-Lawrence grades [KL] 0/1 to 3/4), 2) typical (increase in KL, excluding accelerated osteoarthritis), or 3) no KOA (no change in KL). We assessed tibiofemoral cartilage damage (four regions: medial/lateral tibia/femur), bone marrow lesion (BML) volume (four regions: medial/lateral tibia/femur), and whole knee effusion-synovitis volume on 3 T MR images with semi-automated programs. We calculated two MR-based composite scores. Cumulative damage was the sum of standardized cartilage damage. Disease activity was the sum of standardized volumes of effusion-synovitis and BMLs. We focused on annual images from 2 years before to 2 years after radiographic onset (or a matched time for those without knee osteoarthritis). To determine between group differences in the composite metrics at all time points, we used generalized linear mixed models with group (3 levels) and time (up to 5 levels). For our prognostic analysis, we used multinomial logistic regression models to determine if one-year worsening in each composite metric change associated with future accelerated knee osteoarthritis (odds ratios [OR] based on units of 1 standard deviation of change)., Results: Prior to disease onset, the accelerated KOA group had greater average disease activity compared to the typical and no KOA groups and this persisted up to 2 years after disease onset. During a pre-radiographic disease period, the odds of developing accelerated KOA were greater in people with worsening disease activity [versus typical KOA OR (95% confidence interval [CI]): 1.58 (1.08 to 2.33); versus no KOA: 2.39 (1.55 to 3.71)] or cumulative damage [versus typical KOA: 1.69 (1.14 to 2.51); versus no KOA: 2.11 (1.41 to 3.16)]., Conclusions: MR-based disease activity and cumulative damage metrics may be prognostic markers to help identify people at risk for accelerated onset and progression of knee osteoarthritis.

Background: Prior research on accelerated knee osteoarthritis (AKOA) was primarily confined to the Osteoarthritis Initiative, which was enriched with people with risk factors for knee osteoarthritis (KOA). It is unclear how often AKOA develops in a community-based cohort and whether we can replicate prior findings from the Osteoarthritis Initiative in another cohort. Hence, we determined the incidence and characteristics of AKOA among women in the Chingford Study, which is a prospective community-based cohort., Methods: The Chingford Study had 1003 women with quinquennial knee radiographs over 15 years. We divided the 15-year observation period into three consecutive 5-year phases. Within each 5-year phase, we selected 3 groups of participants among women who started a phase without KOA (Kellgren-Lawrence [KL] < 2): 1) incident AKOA developed KL grade ≥ 3, 2) typical KOA increased radiographic scoring (excluding AKOA), and 3) no KOA had the same KL grade over time. Study staff recorded each participant's age, body mass index (BMI), and blood pressure at baseline, 5-year, and 10-year study visits. We used multinomial logistic regression models to test the association between groups (outcome) and age, BMI, and blood pressure at the start of each phase. The cumulative incidences and odds ratios (OR) from each phase were pooled using a fixed-effect meta-analysis model., Results: The person-based cumulative incidence of AKOA was 3.9% over 5 years (pooled estimate across the three 5-year phases). Among incident cases of KOA, AKOA represented ~ 15% of women with incident KOA. Women with AKOA were older than those with typical (OR = 1.56, 95%CI = 1.16-2.11) or no KOA (OR = 1.84, 95%CI = 1.40-2.43). Women with AKOA had a greater BMI than those without KOA (OR = 1.52, 95%CI = 1.17-1.97). We observed no association between group and blood pressure., Conclusions: In a community-based cohort, > 1 in 7 women with incident KOA had AKOA. Like the Osteoarthritis Initiative, people with AKOA were more likely to have greater age and BMI.

Background: To determine if adults with incident accelerated knee osteoarthritis (KOA) are more likely to have degenerative knee ligaments or tendons compared to individuals with typical or no KOA., Methods: We identified 3 sex-matched groups among Osteoarthritis Initiative participants who had a knee without radiographic KOA at baseline (Kellgren-Lawrence [KL] < 2): 1) accelerated KOA: at least 1 knee had KL grade ≥ 3 in ≤48 months, 2) typical KOA: at least 1 knee increased in radiographic scoring within 48 months, 3) no KOA: both knees had the same KL grade at baseline and 48 months. We evaluated knee magnetic resonance images up to 2 years before and after a visit when the accelerated or typical KOA criteria were met (index visit). Radiologists reported degenerative signal changes for cruciate and collateral ligaments, and extensor mechanism and proximal gastrocnemius tendons. We used generalized linear mixed models with 2 independent variables: group and time., Results: Starting at least 2 years before onset, adults with accelerated KOA were twice as likely to have degenerative cruciate ligaments than no KOA (odds ratio = 2.10, 95% CI = 1.18, 3.74). A weaker association (not statistically significant) was detected for adults with accelerated versus typical KOA (OR = 1.72, 95%CI = 0.99, 3.02). Regardless of time, adults with accelerated (odds ratio = 2.13) or typical KOA (odds ratio = 2.16) were twice as likely to have a degenerative extensor mechanism than no KOA. No other structural features were statistically significant., Conclusions: Degenerative cruciate ligaments or extensor mechanism antedate radiographic onset of accelerated KOA. Hence, knee instability may precede accelerated KOA, which might help identify patients at high-risk for accelerated KOA and novel prevention strategies.

Background: Accelerated knee osteoarthritis (AKOA) is characterized by more pain, impaired physical function, and greater likelihood to receive a joint replacement compared to individuals who develop the typical gradual onset of disease. Prognostic tools are needed to determine which structural pathologies precede the development of AKOA compared to individuals without AKOA. Therefore, the purpose of this manuscript was to determine which pre-radiographic structural features precede the development of AKOA., Methods: The sample comprised participants in the Osteoarthritis Initiative (OAI) who had at least one radiographically normal knee at baseline (Kellgren-Lawrence [KL] grade < 1). Participants were classified into 2 groups based on radiographic progression from baseline to 48 months: AKOA (KL grade change from < 1 to > 3) and No AKOA. The index visit was the study visit when participants met criteria for AKOA or a matched timepoint for those who did not develop AKOA. Magnetic resonance (MR) images were assessed for 12 structural features at the OAI baseline, and 1 and 2 years prior to the index visit. Separate logistic regression models (i.e. OAI baseline, 1 and 2 years prior) were used to determine which pre-radiographic structural features were more likely to antedate the development of AKOA compared to individuals not developing AKOA., Results: At the OAI baseline visit, degenerative cruciate ligaments (Odds Ratio [OR] = 2.2, 95% Confidence Interval [CI] = 1.3,3.5), infrapatellar fat pad signal intensity alteration (OR = 2.0, 95%CI = 1.2,3.2), medial/lateral meniscal pathology (OR = 2.1/2.4, 95%CI = 1.3,3.4/1.5,3.8), and greater quantitative knee effusion-synovitis (OR = 2.2, 95%CI = 1.4,3.4) were more likely to antedate the development of AKOA when compared to those that did not develop AKOA. These results were similar at one and two years prior to disease onset. Additionally, medial meniscus extrusion at one year prior to disease onset (OR = 3.5, 95%CI = 2.1,6.0) increased the likelihood of developing AKOA., Conclusions: Early ligamentous degeneration, effusion/synovitis, and meniscal pathology precede the onset of AKOA and may be prognostic biomarkers.

Background: Greater age and body mass index are strong risk factors for osteoarthritis (OA). Older and overweight individuals may be more susceptible to OA because these factors alter tissue turnover in menisci, articular cartilage, and bone via altered glucose homeostasis and inflammation. Understanding the role of inflammation and glucose homeostasis on structural features of early-stage OA may help identify therapeutic targets to delay or prevent the onset of OA among subsets of adults with these features. We examined if serum concentrations of glucose homeostasis (glucose, glycated serum protein [GSP]) or inflammation (C-reactive protein [CRP]) were associated with prevalent knee bone marrow lesions (BMLs) or effusion among adults without knee OA., Methods: We conducted a cross-sectional study using baseline data from the Osteoarthritis Initiative. We selected participants who had no radiographic knee OA but were at high risk for knee OA. Blinded staff conducted assays for CRP, GSP, and glucose. Readers segmented BML volume and effusion using semi-automated programs. Our outcomes were prevalent BML (knee with a BML volume > 1 cm 3 ) and effusion (knee with an effusion volume > 7.5 cm 3 ). We used logistic regression models with CRP, GSP, or glucose concentrations as the predictors. We adjusted for age, sex, body mass index (BMI), and Physical Activity Scale for the Elderly (PASE) scores., Results: We included 343 participants: mean age = 59 ± 9 years, BMI = 27.9 ± 4.5 kg/m 2 , PASE score = 171 ± 82, and 64% female. Only CRP was associated with BML prevalence (odds ratio [OR] = 1.43, 95% confidence interval [CI] = 1.09 to 1.87). For effusion, we found an interaction between BMI and CRP: only among adults with a BMI <25 kg/m 2 was there a significant trend towards a positive association between CRP and effusion (OR = 1.40, 95% CI = 1.00 to 1.97). We detected a U-shaped relationship between GSP and effusion prevalence. Fasting glucose levels were not significantly associated with the presence of baseline effusion or BML., Conclusions: Among individuals without knee OA, CRP may be related to the presence of BMLs and effusion among normal weight individuals. Abnormal GSP may be associated with effusion. Future studies should explore whether inflammation and glucose homeostasis are predictive of symptomatic knee OA.

Background: Accelerated knee osteoarthritis may be a unique subset of knee osteoarthritis, which is associated with greater knee pain and disability. Identifying risk factors for accelerated knee osteoarthritis is vital to recognizing people who will develop accelerated knee osteoarthritis and initiating early interventions. The geometry of an articular surface (e.g., coronal tibial slope), which is a determinant of altered joint biomechanics, may be an important risk factor for incident accelerated knee osteoarthritis. We aimed to determine if baseline coronal tibial slope is associated with incident accelerated knee osteoarthritis or common knee osteoarthritis., Methods: We conducted a case-control study using data and images from baseline and the first 4 years of follow-up in the Osteoarthritis Initiative. We included three groups: 1) individuals with incident accelerated knee osteoarthritis, 2) individuals with common knee osteoarthritis progression, and 3) a control group with no knee osteoarthritis at any time. We did 1:1:1 matching for the 3 groups based on sex. Weight-bearing, fixed flexion posterior-anterior knee radiographs were obtained at each visit. One reader manually measured baseline coronal tibial slope on the radiographs. Baseline femorotibial angle was measured on the radiographs using a semi-automated program. To assess the relationship between slope (predictor) and incident accelerated knee osteoarthritis or common knee osteoarthritis (outcomes) compared with no knee osteoarthritis (reference outcome), we performed multinomial logistic regression analyses adjusted for sex., Results: The mean baseline slope for incident accelerated knee osteoarthritis, common knee osteoarthritis, and no knee osteoarthritis were 3.1(2.0), 2.7(2.1), and 2.6(1.9); respectively. A greater slope was associated with an increased risk of incident accelerated knee osteoarthritis (OR = 1.15 per degree, 95 % CI = 1.01 to 1.32) but not common knee osteoarthritis (OR = 1.04, 95 % CI = 0.91 to 1.19). These findings were similar when adjusted for recent injury. Among knees with varus malalignment a greater slope increases the odds of incident accelerated knee osteoarthritis; there is no significant relationship between slope and incident accelerated knee osteoarthritis among knees with normal alignment., Conclusions: Coronal tibial slope, particularly among knees with malalignment, may be an important risk factor for incident accelerated knee osteoarthritis.

Background: Cartilage morphometry based on magnetic resonance images (MRIs) is an emerging outcome measure for clinical trials among patients with knee osteoarthritis (KOA). However, current methods for cartilage morphometry take many hours per knee and require extensive training on the use of the associated software. In this study we tested the feasibility, reliability, and construct validity of a novel osteoarthritis cartilage damage quantification method (Cartilage Damage Index [CDI]) that utilizes informative locations on knee MRIs., Methods: We selected 102 knee MRIs from the Osteoarthritis Initiative that represented a range of KOA structural severity (Kellgren Lawrence [KL] Grade 0 - 4). We tested the intra- and inter-tester reliability of the CDI and compared the CDI scores against different measures of severity (radiographic joint space narrowing [JSN] grade, KL score, joint space width [JSW]) and static knee alignment, both cross-sectionally and longitudinally., Results: Determination of the CDI took on average14.4 minutes (s.d. 2.1) per knee pair (baseline and follow-up of one knee). Repeatability was good (intra- and inter-tester reliability: intraclass correlation coefficient >0.86). The mean CDI scores related to all four measures of osteoarthritis severity (JSN grade, KL score, JSW, and knee alignment; all p values < 0.05). Baseline JSN grade and knee alignment also predicted subsequent 24-month longitudinal change in the CDI (p trends <0.05). During 24 months, knees with worsening in JSN or KL grade (i.e. progressors) had greater change in CDI score., Conclusions: The CDI is a novel knee cartilage quantification method that is rapid, reliable, and has construct validity for assessment of medial tibiofemoral osteoarthritis structural severity and its progression. It has the potential to addresses the barriers inherent to studies requiring assessment of cartilage damage on large numbers of knees, and as a biomarker for knee osteoarthritis progression.

Background: In the knee, high-resolution magnetic resonance (MR) imaging has demonstrated that increased apparent bone volume fraction (trabecular bone volume per total volume; BV/TV) in the peri-articular proximal medial tibia is associated with joint space narrowing and the presence of bone marrow lesions. However, despite evidence of construct validity, MR-based apparent BV/TV has not yet been cross-validated in the proximal medial tibia by comparison with a gold standard (e.g., micro-computed tomography [microCT]). In this cadaveric validation study we explored the association between MR-based apparent BV/TV and microCT-based BV/TV in the proximal peri-articular medial tibia., Methods: Fresh cadaveric whole knee specimens were obtained from individuals 51 to 80 years of age with no knee pathology other than osteoarthritis. Ten knees were collected from five cadavers within 10 hours of death and underwent a 3-Tesla MR exam including a coronal-oblique 3-dimensional fast imaging with steady state precession (3D FISP) sequence within 36 hours of death. The specimens were placed in a 4% paraformaldehyde in phosphate buffer within 58 hours of death. After preservation, a subchondral region from the tibial plateau was collected and underwent microCT imaging with a voxel size of 9 μm x 9 μm x 9 μm. A single reader analyzed the microCT images in a similar volume of interest as selected in the MR measures. A different reader analyzed the MR-based trabecular morphometry using a custom analysis tool. To analyze the MR-based trabecular morphometry, a rectangular region of interest (ROI) was positioned on the 20 central images in the proximal medial tibial subchondral bone. The primary outcome measures were MR-based and microCT-based trabecular BV/TV in the proximal medial tibia., Results: The MR-based apparent BV/TV was strongly correlated with microCT-based BV/TV (r=0.83, confidence interval=0.42 to 0.96), despite the MR-based apparent BV/TV being systematically lower than measured using microCT., Conclusions: MR-based apparent BV/TV in the proximal peri-articular medial tibia has good construct validity and may represent an alternative for CT-based BV/TV.

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.

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.