New approach to testing treatments for osteoarthritis: FastOA.

Animal models of post traumatic osteoarthritis have shown many promising treatments for disease, but human trials have mostly failed to identify effective treatments. This viewpoint suggests that the frequent failure of drug and treatment development in osteoarthritis is due, in part, to the advanced stage of disease of patients in trials and suggests that mirroring the animal model approach might be more successful. It suggests a path forward by enriching trial enrollees with those likely to develop post traumatic OA quickly.

2023 EULAR classification criteria for hand osteoarthritis.

OBJECTIVES: The objective of this study is to develop classification criteria for overall hand osteoarthritis (OA), interphalangeal OA and thumb base OA based on self-reported data and radiographic features. METHODS: The classification criteria sets were developed in three phases. In phase 1, we identified criteria that discriminated hand OA from controls. In phase 2, we used a consensus-based decision analysis approach to derive a clinician-based evaluation of the relative importance of the criteria. In phase 3, we refined the scoring system, determined the cut-offs for disease classification and compared the sensitivity and specificity of the European Alliance of Associations for Rheumatology (EULAR) criteria with the 1990 American College of Rheumatology (ACR) criteria. RESULTS: In persons with hand symptoms and no other disease (including psoriasis) or acute injury that can explain the hand symptoms (mandatory criteria), hand OA can be classified based on age, duration of morning stiffness, number of joints with osteophytes and joint space narrowing, and concordance between symptoms and radiographic findings. Using a sum of scores based on each diagnostic element, overall hand OA can be classified if a person achieves 9 or more points on a 0-15 scale. The cut-off for interphalangeal OA and thumb base OA is 8 points. While the EULAR criteria demonstrated better sensitivity than the ACR criteria in the phase 1 data set, the performance of the two criteria sets was similar in two external cohorts. CONCLUSIONS: International experts developed the EULAR criteria to classify overall hand OA, interphalangeal OA and thumb base OA in clinical studies using a rigorous methodology.

Assessing the association of epigenetic age acceleration with osteoarthritis in the Multicenter Osteoarthritis Study (MOST).

PURPOSE: Advancing age is one of the strongest risk factors for osteoarthritis (OA). DNA methylation-based measures of epigenetic age acceleration may provide insights into mechanisms underlying OA. METHODS: We analyzed data from the Multicenter Osteoarthritis Study in a subset of 671 participants ages 45-69 years with no or mild radiographic knee OA. DNA methylation was assessed with the Illumina Infinium MethylationEPIC 850K array. We calculated predicted epigenetic age according to Hannum, Horvath, PhenoAge, and GrimAge epigenetic clocks, then regressed epigenetic age on chronological age to obtain the residuals. Associations between the residuals and knee, hand, and multi-joint OA were assessed using logistic regression, adjusted for chronological age, sex, clinical site, smoking status, and race. RESULTS: Twenty-three percent met criteria for radiographic hand OA, 25% met criteria for radiographic knee OA, and 8% met criteria for multi-joint OA. Mean chronological age (SD) was 58.4 (6.7) years. Mean predicted epigenetic age (SD) according to Horvath, Hannum, PhenoAge, and GrimAge epigenetic clocks was 64.9 (6.4), 68.6 (5.9), 50.5 (7.7), and 67.0 (6.2), respectively. Horvath epigenetic age acceleration was not associated with an increased odds of hand OA, odds ratio (95% confidence intervals) = 1.03 (0.99-1.08), with similar findings for knee and multi-joint OA. We found similar magnitudes of associations for Hannum epigenetic age, PhenoAge, and GrimAge acceleration compared to Horvath epigenetic age acceleration. CONCLUSIONS: Epigenetic age acceleration as measured by various well-validated epigenetic clocks based on DNA methylation was not associated with increased risk of knee, hand, or multi-joint OA independent of chronological age.

Survival analysis on subchondral bone length for total knee replacement.

OBJECTIVE: Use subchondral bone length (SBL), a new MRI-derived measure that reflects the extent of cartilage loss and bone flattening, to predict the risk of progression to total knee replacement (TKR). METHODS: We employed baseline MRI data from the Osteoarthritis Initiative (OAI), focusing on 760 men and 1214 women with bone marrow lesions (BMLs) and joint space narrowing (JSN) scores, to predict the progression to TKR. To minimize bias from analyzing both knees of a participant, only the knee with a higher Kellgren-Lawrence (KL) grade was considered, given its greater potential need for TKR. We utilized the Kaplan-Meier survival curves and Cox proportional hazards models, incorporating raw and normalized values of SBL, JSN, and BML as predictors. The study included subgroup analyses for different demographics and clinical characteristics, using models for raw and normalized SBL (merged, femoral, tibial), BML (merged, femoral, tibial), and JSN (medial and lateral compartments). Model performance was evaluated using the time-dependent area under the curve (AUC), Brier score, and Concordance index to gauge accuracy, calibration, and discriminatory power. Knee joint and region-level analyses were conducted to determine the effectiveness of SBL, JSN, and BML in predicting TKR risk. RESULTS: The SBL model, incorporating data from both the femur and tibia, demonstrated a predictive capacity for TKR that closely matched the performance of the BML score and the JSN grade. The Concordance index of the SBL model was 0.764, closely mirroring the BML's 0.759 and slightly below JSN's 0.788. The Brier score for the SBL model stood at 0.069, showing comparability with BML's 0.073 and a minor difference from JSN's 0.067. Regarding the AUC, the SBL model achieved 0.803, nearly identical to BML's 0.802 and slightly lower than JSN's 0.827. CONCLUSION: SBL's capacity to predict the risk of progression to TKR highlights its potential as an effective imaging biomarker for knee osteoarthritis.

American College of Rheumatology/EULAR remission criteria for rheumatoid arthritis: 2022 revision.

OBJECTIVE: In 2011, the American College of Rheumatology (ACR) and EULAR endorsed provisional criteria for remission in rheumatoid arthritis (RA), both Boolean-based and index-based. Based on recent studies indicating that a higher threshold for the patient global assessment (PtGA) may improve agreement between the two sets of criteria, our goals were to externally validate a revision of the Boolean remission criteria using a higher PtGA threshold and to validate the provisionally endorsed index-based criteria. METHODS: We used data from four randomised trials comparing biological disease-modifying antirheumatic drugs to methotrexate or placebo. We tested the higher proposed PtGA threshold of 2 cm (Boolean2.0) (range 0-10 cm) compared with the original threshold of 1 cm (Boolean1.0). We analysed agreement between the Boolean-based and index-based criteria (Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI)) for remission and examined how well each remission definition predicted later good physical function (Health Assessment Questionnaire (HAQ) score≤0.5) and radiographic non-progression. RESULTS: Data from 2048 trial participants, 1101 with early RA and 947 with established RA, were included. The proportion of patients with disease in remission at 6 months after treatment initiation increased when using Boolean2.0 compared with Boolean1.0, from 14.8% to 20.6% in early RA and 4.2% to 6.0% in established RA. Agreement between Boolean2.0 and the SDAI or CDAI remission criteria was better than for Boolean1.0, particularly in early disease. Boolean2.0, SDAI, and CDAI remission criteria had similar positive likelihood ratios (LRs) to predict radiographic nonprogression and a HAQ score of ≤0.5 (positive LR 3.8-4.3). The omission of PtGA (BooleanX) worsened the prediction of good functional outcomes. CONCLUSION: Using the Boolean 2.0 criteria classifies, more patients as achieving remission and increases the agreement with index-based remission criteria without jeopardising predictive value for radiographic or functional outcomes. This revised Boolean definition and the previously provisionally endorsed index-based criteria were endorsed by ACR and EULAR.

Increased risk of osteoarthritis in patients with atopic disease.

OBJECTIVES: To determine the incidence of osteoarthrits (OA) in patients with atopic disease compared with matched non-exposed patients. METHODS: We conducted a retrospective cohort study with propensity score matching using claims data from Optum's de-identified Clinformatics Data Mart (CDM) (January 2003 to June 2019) and electronic health record data from the Stanford Research Repository (STARR) (January 2010 to December 2020). We included adult patients without pre-existing OA or inflammatory arthritis who were exposed to atopic disease or who were non-exposed. The primary outcome was the development of incident OA. RESULTS: In Optum CDM, we identified 117 346 exposed patients with asthma or atopic dermatitis (mean age 52 years; 60% female) and 1 247 196 non-exposed patients (mean age 50 years; 48% female). After propensity score matching (n=1 09 899 per group), OA incidence was higher in patients with asthma or atopic dermatitis (26.9 per 1000 person-years) compared with non-exposed patients (19.1 per 1000 person-years), with an adjusted odds ratio (aOR) of 1.58 (95% CI 1.55 to 1.62) for developing OA. This effect was even more pronounced in patients with both asthma and atopic dermatitis compared with non-exposed patients (aOR=2.15; 95% CI 1.93 to 2.39) and in patients with asthma compared with patients with chronic obstructive pulmonary disease (aOR=1.83; 95% CI 1.73 to 1.95). We replicated our results in an independent dataset (STARR), which provided the added richness of body mass index data. The aOR of developing OA in patients with asthma or atopic dermatitis versus non-exposed patients in STARR was 1.42 (95% CI 1.36 to 1.48). CONCLUSIONS: This study demonstrates an increased incidence of OA in patients with atopic disease. Future interventional studies may consider targeting allergic pathways for the prevention or treatment of OA.

A clinician's perspective on the role of imaging in knee osteoarthritis in clinical practice.

Knee osteoarthritis (OA) is a highly prevalent and disabling disease. Most persons age 45 and over with chronic knee pain have OA and with characteristic history and physical findings, diagnostic imaging is usually not necessary. Further, treatment of chronic knee pain with or without evidence of OA is similar, so imaging does not usually alter therapy. The exception is atypical presentations, such as sudden onset of pain perhaps after trauma or evidence of arthritis in atypical locations elsewhere in the body. Imaging is also unnecessary to follow patients. Given the absence of treatments that slow progression, there is little rationale for acquiring repeated imaging. However, ultrasound or other knee imaging may be helpful in locating the joint when carrying out intraarticular corticosteroid injections. There is controversy as to whether imaging should be acquired before these injections, but recent studies suggest no increased risk of disease progression for most persons receiving these injections. While guidelines currently discourage imaging in the diagnosis or management of most persons with OA, this may change for individuals with identifiable correctible lesions, when effective treatments that alter progression emerge or when imaging is used to identify subtypes of disease that may respond to specific treatments.

Delayed timing of physical therapy initiation increases the risk of future opioid use in individuals with knee osteoarthritis: a real-world cohort study.

OBJECTIVE: We assessed whether late versus early initiation of physical therapy (PT) was related to greater risk of future opioid use in people with knee osteoarthritis (OA) who receive PT. METHODS: We used Commercial and Medicare Advantage claims data from 1999 to 2018 from American adults with incident knee OA referred for PT within 1 year of diagnosis. We categorised people as opioid naïve or opioid experienced based on prior prescriptions. We examined the association of timing of PT initiation with any and chronic opioid use over 1 year. RESULTS: Of the 67 245 individuals with incident knee OA, 35 899 were opioid naïve and 31 346 were opioid experienced. In the opioid naïve group, compared with PT within 1 month, PT 1 to <3, 3 to <6, 6 to <9, 9-12 months from diagnosis was associated with adjusted risk ratio (aRR (95% CIs)) for any opioid use of 1.18 (1.10 to 1.28), 1.49 (1.37 to 1.61), 1.73 (1.58 to 1.89) and 1.93 (1.76 to 2.12), respectively; aRRs (95% CIs) for chronic opioid use were 1.25 (1.01 to 1.54), 1.83 (1.48 to 2.26), 2.29 (1.82 to 2.89) and 2.50 (1.96 to 3.19). Results were similar among opioid experienced; aRRs (95% CIs) for any opioid use were 1.19 (1.14 to 1.24), 1.32 (1.26 to 1.37), 1.39 (1.32 to 1.45) and 1.54 (1.46 to 1.61); aRRs (95% CIs) for chronic opioid use were 1.25 (1.17 to1.34), 1.43 (1.33 to 1.54), 1.53 (1.41 to 1.66) and 1.65 (1.51 to 1.80). CONCLUSION: Compared with PT initiation within 1 month, delayed PT initiation was associated with higher risk of opioid use in people with incident knee OA. The longer the delay in PT initiation, the greater was the risk.

Gait, physical activity and tibiofemoral cartilage damage: a longitudinal machine learning analysis in the Multicenter Osteoarthritis Study.

OBJECTIVE: To (1) develop and evaluate a machine learning model incorporating gait and physical activity to predict medial tibiofemoral cartilage worsening over 2 years in individuals without advanced knee osteoarthritis and (2) identify influential predictors in the model and quantify their effect on cartilage worsening. DESIGN: An ensemble machine learning model was developed to predict worsened cartilage MRI Osteoarthritis Knee Score at follow-up from gait, physical activity, clinical and demographic data from the Multicenter Osteoarthritis Study. Model performance was evaluated in repeated cross-validations. The top 10 predictors of the outcome across 100 held-out test sets were identified by a variable importance measure. Their effect on the outcome was quantified by g-computation. RESULTS: Of 947 legs in the analysis, 14% experienced medial cartilage worsening at follow-up. The median (2.5-97.5th percentile) area under the receiver operating characteristic curve across the 100 held-out test sets was 0.73 (0.65-0.79). Baseline cartilage damage, higher Kellgren-Lawrence grade, greater pain during walking, higher lateral ground reaction force impulse, greater time spent lying and lower vertical ground reaction force unloading rate were associated with greater risk of cartilage worsening. Similar results were found for the subset of knees with baseline cartilage damage. CONCLUSIONS: A machine learning approach incorporating gait, physical activity and clinical/demographic features showed good performance for predicting cartilage worsening over 2 years. While identifying potential intervention targets from the model is challenging, lateral ground reaction force impulse, time spent lying and vertical ground reaction force unloading rate should be investigated further as potential early intervention targets to reduce medial tibiofemoral cartilage worsening.

Association of dietary fiber and risk of hip fracture in men from the Framingham Osteoporosis Study and the Concord Health and Ageing in Men Project.

BACKGROUND: Data in the Offspring Framingham Osteoporosis Study (FOS) suggested that higher intake of dietary fiber was modestly protective against loss of bone mineral density at the femoral neck in men but not in women. AIM: To examine the relationship of fiber intake with risk of hip fractures in men. METHODS: We included 367 men from the FOS Original cohort, 1730 men from the FOS Offspring cohort, and 782 men from the Concord Health and Ageing in Men Project (CHAMP) in the analysis. Incident fractures were defined as medically confirmed first occurrence of osteoporotic fractures at the proximal femur. Fiber intake was estimated via a validated food frequency questionnaire (FFQ) or diet history. Cox proportional hazards models were applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). A random-effects model was used to estimate the pooled relative risk in meta-analysis. RESULTS: Seventy-two incident hip fractures were identified, of which 24 occurred in the FOS Original cohort [mean (SD): age 75.3 (5.1) years; follow-up time: 8.5 (6.2) years; dietary fiber: 19 (8) (g/d)], 19 in the FOS Offspring cohort [58.8 (9.8) years; 11.0 (5.9) years; 19 (8) (g/d)], and 29 in CHAMP [81.4 (4.5) years; 5.2 (1.5) years; 28 (10) (g/d)]. We did not find significant associations within each cohort between fiber intake and risk of hip fractures. The pooled HR (95% CI) was 0.80 (0.39, 1.66) comparing energy-adjusted dietary fiber at tertile 3 vs. tertile 1 (I2 = 0, p = 0.56). CONCLUSION: These data suggested that dietary fiber was not associated with risk of incident hip fractures in men.

Genome-wide association of phenotypes based on clustering patterns of hand osteoarthritis identify WNT9A as novel osteoarthritis gene.

BACKGROUND: Despite recent advances in the understanding of the genetic architecture of osteoarthritis (OA), only two genetic loci have been identified for OA of the hand, in part explained by the complexity of the different hand joints and heterogeneity of OA pathology. METHODS: We used data from the Rotterdam Study (RSI, RSII and RSIII) to create three hand OA phenotypes based on clustering patterns of radiographic OA severity to increase power in our modest discovery genome-wide association studies in the RS (n=8700), and sought replication in an independent cohort, the Framingham Heart Study (n=1203). We used multiple approaches that leverage different levels of information and functional data to further investigate the underlying biological mechanisms and candidate genes for replicated loci. We also attempted to replicate known OA loci at other joint sites, including the hips and knees. RESULTS: We found two novel genome-wide significant loci for OA in the thumb joints. We identified WNT9A as a possible novel causal gene involved in OA pathogenesis. Furthermore, several previously identified genetic loci for OA seem to confer risk for OA across multiple joints: TGFa, RUNX2, COL27A1, ASTN2, IL11 and GDF5 loci. CONCLUSIONS: We identified a robust novel genetic locus for hand OA on chromosome 1, of which WNT9A is the most likely causal gene. In addition, multiple genetic loci were identified to be associated with OA across multiple joints. Our study confirms the potential for novel insight into the genetic architecture of OA by using biologically meaningful stratified phenotypes.

Which Chronic Low Back Pain Patients Respond Favorably to Yoga, Physical Therapy, and a Self-care Book? Responder Analyses from a Randomized Controlled Trial.

PURPOSE: To identify baseline characteristics of adults with chronic low back pain (cLBP) that predict response (i.e., a clinically important improvement) and/or modify treatment effect across three nonpharmacologic interventions. DESIGN: Secondary analysis of a randomized controlled trial. SETTING: Academic safety net hospital and seven federally qualified community health centers. SUBJECTS: Adults with cLBP (N = 299). METHODS: We report patient characteristics that were predictors of response and/or modified treatment effect across three 12-week treatments: yoga, physical therapy [PT], and a self-care book. Using preselected characteristics, we used logistic regression to identify predictors of "response," defined as a ≥30% improvement in the Roland Morris Disability Questionnaire. Then, using "response" as our outcome, we identified baseline characteristics that were treatment effect modifiers by testing for statistical interaction (P < 0.05) across two comparisons: 1) yoga-or-PT vs self-care and 2) yoga vs PT. RESULTS: Overall, 39% (116/299) of participants were responders, with more responders in the yoga-or-PT group (42%) than the self-care (23%) group. There was no difference in proportion responding to yoga (48%) vs PT (37%, odds ratio [OR] = 1.5, 95% confidence interval = 0.88 - 2.6). Predictors of response included having more than a high school education, a higher income, employment, few depressive symptoms, lower perceived stress, few work-related fear avoidance beliefs, high pain self-efficacy, and being a nonsmoker. Effect modifiers included use of pain medication and fear avoidance beliefs related to physical activity (both P = 0.02 for interaction). When comparing yoga or PT with self-care, a greater proportion were responders among those using pain meds (OR = 5.3), which differed from those not taking pain meds (OR = 0.94) at baseline. We also found greater treatment response among those with lower (OR = 7.0), but not high (OR = 1.3), fear avoidance beliefs around physical activity. CONCLUSIONS: Our findings revealed important subgroups for whom referral to yoga or PT may improve cLBP outcomes.

Knee osteoarthritis and time-to all-cause mortality in six community-based cohorts: an international meta-analysis of individual participant-level data.

BACKGROUND: Osteoarthritis (OA) is a chronic joint disease, with increasing global burden of disability and healthcare utilisation. Recent meta-analyses have shown a range of effects of OA on mortality, reflecting different OA definitions and study methods. We seek to overcome limitations introduced when using aggregate results by gathering individual participant-level data (IPD) from international observational studies and standardising methods to determine the association of knee OA with mortality in the general population. METHODS: Seven community-based cohorts were identified containing knee OA-related pain, radiographs, and time-to-mortality, six of which were available for analysis. A two-stage IPD meta-analysis framework was applied: (1) Cox proportional hazard models assessed time-to-mortality of participants with radiographic OA (ROA), OA-related pain (POA), and a combination of pain and ROA (PROA) against pain and ROA-free participants; (2) hazard ratios (HR) were then pooled using the Hartung-Knapp modification for random-effects meta-analysis. FINDINGS: 10,723 participants in six cohorts from four countries were included in the analyses. Multivariable models (adjusting for age, sex, race, BMI, smoking, alcohol consumption, cardiovascular disease, and diabetes) showed a pooled HR, compared to pain and ROA-free participants, of 1.03 (0.83, 1.28) for ROA, 1.35 (1.12, 1.63) for POA, and 1.37 (1.22, 1.54) for PROA. DISCUSSION: Participants with POA or PROA had a 35-37% increased association with reduced time-to-mortality, independent of confounders. ROA showed no association with mortality, suggesting that OA-related knee pain may be driving the association with time-to-mortality. FUNDING: Versus Arthritis Centre for Sport, Exercise and Osteoarthritis and Osteoarthritis Research Society International.

Intra-articular Corticosteroid Injections for the Treatment of Hip and Knee Osteoarthritis-related Pain: Considerations and Controversies with a Focus on Imaging-Radiology Scientific Expert Panel.

Current management of osteoarthritis (OA) is primarily focused on symptom control. Intra-articular corticosteroid (IACS) injections are often used for pain management of hip and knee OA in patients who have not responded to oral or topical analgesics. Recent case series suggested that negative structural outcomes including accelerated OA progression, subchondral insufficiency fracture, complications of pre-existing osteonecrosis, and rapid joint destruction (including bone loss) may be observed in patients who received IACS injections. This expert panel report reviews the current understanding of pain in OA, summarizes current international guidelines regarding indications for IACS injection, and considers preinterventional safety measures, including imaging. Potential profiles of those who would likely benefit from IACS injection and a suggestion for an updated patient consent form are presented. As of today, there is no established recommendation or consensus regarding imaging, clinical, or laboratory markers before an IACS injection to screen for OA-related imaging abnormalities. Repeating radiographs before each subsequent IACS injection remains controversial. The true cause and natural history of these complications are unclear and require further study. To determine the cause and natural history, large prospective studies evaluating the risk of accelerated OA or joint destruction after IACS injections are needed. However, given the relatively rare incidence of these adverse outcomes, any clinical trial would be challenging in design and a large number of patients would need to be included.

Does cartilage loss cause pain in osteoarthritis and if so, how much?

OBJECTIVES: Although treatment development in osteoarthritis (OA) focuses on chondroprotection, it is unclear how much preventing cartilage loss reduces joint pain. It is also unclear how nociceptive tissues may be involved. METHODS: Using data from the Osteoarthritis Initiative, we quantified the relation between cartilage loss and worsening knee pain after adjusting for bone marrow lesions (BMLs) and synovitis, and examined how much these factors mediated this association. 600 knee MRIs were scored at baseline, 12 months and 24 months for quantitative and semiquantitative measures of OA structural features. We focused on change in medial cartilage thickness using an amount similar to that seen in recent trials. Linear models calculated mean change in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score with cartilage loss, adjusted for baseline BMLs, synovitis and covariates. Mediation analysis tested whether change in synovitis or BMLs mediated the cartilage loss-pain association. We carried out a subanalysis for knees with non-zero baseline WOMAC pain scores and another for non-valgus knees. RESULTS: Cartilage thickness loss was significantly associated with a small degree of worsening in pain over 24 months. For example, a loss of 0.1 mm of cartilage thickness over 2 years was associated with a 0.32 increase in WOMAC pain (scale 0-20). The association of cartilage thickness loss with pain was mediated by synovitis change but not by BML change. Subanalysis results were similar. CONCLUSIONS: Cartilage thickness loss is associated with only a small amount of worsening knee pain, an association mediated in part by worsening synovitis. Demonstrating that chondroprotection reduces knee pain will be extremely challenging and is perhaps unachievable.

Testing different thresholds for patient global assessment in defining remission for rheumatoid arthritis: are the current ACR/EULAR Boolean criteria optimal?

OBJECTIVES: This study aimed to evaluate different patient global assessment (PGA) cut-offs required in the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean remission definition for their utility in rheumatoid arthritis (RA). METHODS: We used data from six randomised controlled trials in early and established RA. We increased the threshold for the 0-10 score for PGA gradually from 1 to 3 in steps of 0.5 (Boolean1.5 to Boolean3.0) and omitted PGA completely (BooleanX) at 6 and 12 months. Agreement with the index-based (Simplified Disease Activity Index (SDAI)) remission definition was analysed using kappa, recursive partitioning (classification and regression tree (CART)) and receiver operating characteristics. The impact of achieving each definition on functional and radiographic outcomes after 1 year was explored. RESULTS: Data from 1680 patients with early RA and 920 patients with established RA were included. The proportion of patients achieving Boolean remission increased with higher thresholds for PGA from 12.4% to 19.7% in early and 5.9% to 12.3% in established RA at 6 months. Best agreement with SDAI remission occurred at PGA cut-offs of 1.5 and 2.0, while agreement decreased with higher PGA (CART: optimal agreement at PGA≤1.6 cm; sensitivity of PGA≤1.5 95%). Changing PGA thresholds at 6 months did not affect radiographic progression at 12 months (mean ꙙsmTSS for Boolean, 1.5, 2.0, 2.5, 3.0, BooleanX: 0.35±5.4, 0.38±5.14, 0.41±5.1, 0.37±4.9, 0.34±4.9, 0.27±4.7). However, the proportion attaining HAQ≤0.5 was 90.2%, 87.9%, 85.2%, 81.1%, 80.7% and 73.1% for the respective Boolean definitions. CONCLUSION: Increasing the PGA cut-off to 1.5 cm would provide high consistency between Boolean with the index-based remission; the integer cut-off of 2.0 cm performed similarly.

Correction to: Assessment of knee pain from MR imaging using a convolutional Siamese network.

The original version of this article, published on 13 February 2020, unfortunately contained a mistake.

Assessment of knee pain from MR imaging using a convolutional Siamese network.

OBJECTIVES: It remains difficult to characterize the source of pain in knee joints either using radiographs or magnetic resonance imaging (MRI). We sought to determine if advanced machine learning methods such as deep neural networks could distinguish knees with pain from those without it and identify the structural features that are associated with knee pain. METHODS: We constructed a convolutional Siamese network to associate MRI scans obtained on subjects from the Osteoarthritis Initiative (OAI) with frequent unilateral knee pain comparing the knee with frequent pain to the contralateral knee without pain. The Siamese network architecture enabled pairwise learning of information from two-dimensional (2D) sagittal intermediate-weighted turbo spin echo slices obtained from similar locations on both knees. Class activation mapping (CAM) was utilized to create saliency maps, which highlighted the regions most associated with knee pain. The MRI scans and the CAMs of each subject were reviewed by an expert radiologist to identify the presence of abnormalities within the model-predicted regions of high association. RESULTS: Using 10-fold cross-validation, our model achieved an area under curve (AUC) value of 0.808. When individuals whose knee WOMAC pain scores were not discordant were excluded, model performance increased to 0.853. The radiologist review revealed that about 86% of the cases that were predicted correctly had effusion-synovitis within the regions that were most associated with pain. CONCLUSIONS: This study demonstrates a proof of principle that deep learning can be applied to assess knee pain from MRI scans. KEY POINTS: • Our article is the first to leverage a deep learning framework to associate MR images of the knee with knee pain. • We developed a convolutional Siamese network that had the ability to fuse information from multiple two-dimensional (2D) MRI slices from the knee with pain and the contralateral knee of the same individual without pain to predict unilateral knee pain. • Our model achieved an area under curve (AUC) value of 0.808. When individuals who had WOMAC pain scores that were not discordant for knees (pain discordance < 3) were excluded, model performance increased to 0.853.

Knee osteoarthritis has doubled in prevalence since the mid-20th century.

Knee osteoarthritis (OA) is believed to be highly prevalent today because of recent increases in life expectancy and body mass index (BMI), but this assumption has not been tested using long-term historical or evolutionary data. We analyzed long-term trends in knee OA prevalence in the United States using cadaver-derived skeletons of people aged ≥50 y whose BMI at death was documented and who lived during the early industrial era (1800s to early 1900s; n = 1,581) and the modern postindustrial era (late 1900s to early 2000s; n = 819). Knee OA among individuals estimated to be ≥50 y old was also assessed in archeologically derived skeletons of prehistoric hunter-gatherers and early farmers (6000-300 B.P.; n = 176). OA was diagnosed based on the presence of eburnation (polish from bone-on-bone contact). Overall, knee OA prevalence was found to be 16% among the postindustrial sample but only 6% and 8% among the early industrial and prehistoric samples, respectively. After controlling for age, BMI, and other variables, knee OA prevalence was 2.1-fold higher (95% confidence interval, 1.5-3.1) in the postindustrial sample than in the early industrial sample. Our results indicate that increases in longevity and BMI are insufficient to explain the approximate doubling of knee OA prevalence that has occurred in the United States since the mid-20th century. Knee OA is thus more preventable than is commonly assumed, but prevention will require research on additional independent risk factors that either arose or have become amplified in the postindustrial era.

Effect of Biomechanical Footwear on Knee Pain in People With Knee Osteoarthritis: The BIOTOK Randomized Clinical Trial.

IMPORTANCE: Individually calibrated biomechanical footwear therapy may improve pain and physical function in people with symptomatic knee osteoarthritis, but the benefits of this therapy are unclear. OBJECTIVE: To assess the effect of a biomechanical footwear therapy vs control footwear over 24 weeks of follow-up. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial conducted at a Swiss university hospital. Participants (N = 220) with symptomatic, radiologically confirmed knee osteoarthritis were recruited between April 20, 2015, and January 10, 2017. The last participant visit occurred on August 15, 2017. INTERVENTIONS: Participants were randomized to biomechanical footwear involving shoes with individually adjustable external convex pods attached to the outsole (n = 111) or to control footwear (n = 109) that had visible outsole pods that were not adjustable and did not create a convex walking surface. MAIN OUTCOMES AND MEASURES: The primary outcome was knee pain at 24 weeks of follow-up assessed with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscore standardized to range from 0 (no symptoms) to 10 (extreme symptoms). The secondary outcomes included WOMAC physical function and stiffness subscores and the WOMAC global score, all ranging from 0 (no symptoms) to 10 (extreme symptoms) at 24 weeks of follow-up, and serious adverse events. RESULTS: Among the 220 randomized participants (mean age, 65.2 years [SD, 9.3 years]; 104 women [47.3%]), 219 received the allocated treatment and 213 (96.8%) completed follow-up. At 24 weeks of follow-up, the mean standardized WOMAC pain subscore improved from 4.3 to 1.3 in the biomechanical footwear group and from 4.0 to 2.6 in the control footwear group (between-group difference in scores at 24 weeks of follow-up, -1.3 [95% CI, -1.8 to -0.9]; P < .001). The results were consistent for WOMAC physical function subscore (between-group difference, -1.1 [95% CI, -1.5 to -0.7]), WOMAC stiffness subscore (between-group difference, -1.4 [95% CI, -1.9 to -0.9]), and WOMAC global score (between-group difference, -1.2 [95% CI, -1.6 to -0.8]) at 24 weeks of follow-up. Three serious adverse events occurred in the biomechanical footwear group compared with 9 in the control footwear group (2.7% vs 8.3%, respectively); none were related to treatment. CONCLUSIONS AND RELEVANCE: Among participants with knee pain from osteoarthritis, use of biomechanical footwear compared with control footwear resulted in an improvement in pain at 24 weeks of follow-up that was statistically significant but of uncertain clinical importance. Further research would be needed to assess long-term efficacy and safety, as well as replication, before reaching conclusions about the clinical value of this device. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02363712.