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Knee osteoarthritis (OA) is a heterogeneous disease associated with substantial effects on quality of life, and its clinical management is difficult. Among the several available guidelines for the management of knee OA, those from OARSI and ESCEO were updated in 2019. Here, we examine the similarities and differences between these two guidelines and provide a narrative to help guide health-care providers through the complexities of non-surgical management of knee OA. OARSI and ESCEO both recommend education, structured exercise and weight loss as core treatments, topical NSAIDs as first-line treatments and oral NSAIDs and intra-articular injections for persistent pain. Low-dose, short-term acetaminophen, pharmaceutical grade glucosamine and chondroitin sulfate are recommended by ESCEO whereas OARSI strongly recommends against their use (including all glucosamine and chondroitin formulations). Despite this difference, the two guidelines are consistent in the majority of their recommendations and provide useful treatment recommendations for individuals with OA and health-care providers.A working group including authors of the latest OARSI and ESCEO recommendations for the management of knee osteoarthritis and independent experts compare and contrast these guidelines, and provide insights into their differences that could help inform application of the recommendations.

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. Summary 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 Risk prediction algorithms increase understanding of which patients are at greatest risk of a harmful outcome. Our goal was to create a clinically useful prediction algorithm for structural progression of knee osteoarthritis (OA), using medial joint space loss as a proxy; and to quantify the benefit of including periarticular bone mineral density (BMD) in the algorithm. Methods Participants were from the Osteoarthritis Initiative (OAI) Progression Cohort, with X-ray readings of medial joint space at 36- and 48-month visits, and a 30- or 36-month medial-to-lateral tibial BMD ratio (M:L BMD ratio) value. Loss of medial joint space was the outcome and clinically available factors associated with OA progression were employed in the base prediction algorithm, with M:L BMD ratio added to an enhanced prediction algorithm. The benefit of adding M:L BMD ratio was evaluated by change in area under the ROC curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Results Five hundred thirty-three participants were included; 51 (14%) had medial joint space loss; 47% were female; the mean (SD) age was 64.6 (9.2) years and BMI was 29.6 (4.8) kg/m 2 . The base algorithm model included age, BMI, gender, recent injury, knee pain, and hand OA as predictors and had an AUC value of 0.65. The algorithm adding M:L BMD ratio had an AUC value of 0.73, and the AUC, NRI and IDI were all significantly improved ( p  ≤ 0.002). Conclusions This clinical prediction algorithm predicts structural progression in individuals with OA using only clinically available predictors supplemented by the M:L BMD ratio, a biomarker that could be made available at clinical sites.

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 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 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 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.

Osteoarthritis (OA), a chronic and often painful disease for which there is no cure, accounts for more mobility issues in older adults than any other disease. Cross-sectional studies have found that arthritis is the most common reason for older adults to use complementary and alternative medicine (CAM). Although previous research has profiled the sociodemographic and clinical characteristics of CAM users, few studies have provided information on variation in CAM use over time and most only considered use of any CAM, which was often a mixture of heterogeneous therapies. This study sought to describe the longitudinal patterns of CAM use among older adults with knee OA and to identify correlates and predictors of different commonly used CAM therapies. The Osteoarthritis Initiative included 1121 adults aged ≥65 years with radiographic tibiofemoral OA in one or both knees at baseline. Annual surveys captured current use of conventional therapies and 25 CAM modalities (grouped into 6 categories) for joint pain or arthritis at baseline and during the 4-year follow-up. We assessed longitudinal use of CAM modalities by summing the number of visits with participants reporting use of each modality. Correlates of CAM use under consideration included sociodemographic indicators, body mass index, overall measures of mental and physical well-being, and clinical indices of knee OA. Generalized estimation equations provided adjusted odds ratio estimates and 95% CIs. Nearly one-third of older adults reported using ≥1 CAM modality for treating OA at all assessments. With the exception of glucosamine and chondroitin (18%), few were persistent users of other CAM modalities. One in 5 of those using nonsteroidal anti-inflammatory drugs or glucosamine and/or chondroitin were using them concurrently. Adjusted models revealed the following: (1) adults aged ≥75 years were less likely to use dietary supplements than those between ages 65 and 75 years; (2) persons with more severe knee pain or stiffness reported more CAM use; (3) better knee-related physical function was correlated with more use of chiropractic care or massage; and (4) older adults with more comorbidities were less likely to report use of dietary supplements. Patterns of CAM use are, to some extent, inconsistent with current guidelines for OA treatment. Evaluating the potential risks and benefits in older adults from commonly used CAM modalities, with or without combination use of conventional analgesics, is warranted.

Despite the rapid proliferation of hyaluronate (HA) and corticosteroid (CO) injections and clinical guidelines regarding their use in osteoarthritis (OA), information on the characteristics of people receiving these injections is scarce. We describe the use of injections among adults with radiographically confirmed knee OA and identify factors associated with injection use. We used publicly available data from the Osteoarthritis Initiative (OAI), an international collaboration sponsored by the National Institutes of Health, and included participants with ≥1 radiographically confirmed knee OA (Kellgren-Lawrence grade ≥2 [definite osteophytes and possible joint space narrowing (JSN) on anteroposterior weight-bearing radiograph]) at baseline. We matched 415 participants who received at least 1 HA and/or CO injection during the 6-month interval before 1 of the first 7 annual follow-up assessments to 1841 injection nonusers by randomly selecting a study visit to match the distribution observed in the injection users. Multinomial logistic regression models were used for identifying factors associated with injection use, including sociodemographic and clinical/functional factors. Eighteen percent of the 2256 patients identified as having knee OA had received at least 1 injection (years 1–7, 16.9%, 13.7%, 16.6%, 13.5%, 15.9%, 13.5%, and 9.9%, respectively), most commonly with CO (68.4%). HA and CO were more commonly injected in those with a higher annual household income (adjusted odds ratio [aOR] [95% CI] with HA, US ≥$50,000 vs <$25,000, 3.63; [1.20–10.99]) and less commonly in black patients (HA, 0.19 [0.06–0.55]). Greater Kellgren-Lawrence grade (grade 4 vs 2) was associated with an increased likelihood (aOR [95% CI]) of having received HA (4.79 [2.47–9.30]), CO (1.56 [1.04–2.34]), or both (4.94 [1.99–12.27]). The receipt of HA or CO injection may be associated with higher socioeconomic positioning and indicators of greater disease severity in patients with knee OA.

Introduction Knee osteoarthritis (OA) is a common painful disorder. Intra-articular (IA) corticosteroid injections are frequently prescribed to treat knee pain. Lorecivivint (LOR), a novel IA cdc2-Like Kinase (CLK)/Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase (DYRK) inhibitor thought to modulate Wnt and inflammatory pathways, has appeared safe and demonstrated improved patient-reported outcomes compared with placebo. While LOR is proposed for stand-alone use, in clinical practice, providers might administer LOR in close time proximity to IA corticosteroid. This open-label, parallel-arm, healthy volunteer study assessed potential short-term safety, tolerability and pharmacokinetic (PK) interactions between IA LOR and triamcinolone acetonide (TCA) administered 7 days apart. Methods Healthy volunteers were randomized to Treatment Sequence 1 (IA 40 mg TCA followed by IA 0.07 mg LOR) or Treatment Sequence 2 (IA 0.07 mg LOR followed by IA 40 mg TCA). Treatment-emergent adverse events (TEAEs) were categorized by “epoch”, with epoch 1 spanning from first until second injection, and epoch 2 spanning from second injection until end of study. Plasma PK was assessed pre injection and out to 22 days after to assess PK treatment interaction. Results A total of 18 TEAEs were reported by 11 (27.5%) of 40 enrolled participants, and there were no serious adverse events. Thirteen TEAEs were reported in Treatment Sequence 1 and five in Treatment Sequence 2, similarly distributed between epochs 1 and 2. In all participants and at all time points, plasma LOR concentrations were below the limit of quantification (0.100 ng/mL). Geometric mean concentrations and PK parameters for TCA were similar between treatment sequences. Conclusion No safety signals were observed. There were no quantifiable plasma concentrations of LOR in either Treatment Sequence. The PK of TCA was unaffected by previous LOR injection. These results suggest that IA administration of LOR and TCA in close time proximity is unlikely to pose a safety concern. Trial Registration ClinicalTrials.gov identifier, NCT04598542. Plain Language Summary Knee osteoarthritis (OA) is a common disorder characterized by pain and loss of function. This clinical trial tested if two different treatments for OA injected into the same knee 1 week apart would impact the safety or exposure of either treatment. The treatments evaluated were an injection of a corticosteroid, triamcinolone acetonide, and a potential OA treatment in development, lorecivivint, a novel small molecule thought to inhibit inflammation and a biological pathway called the Wnt pathway. The amount of either treatment found in circulation was not different when injected before or after the other treatment. The order of injection did not change the safety profile for either agent, suggesting injection of the two agents 1 week apart is unlikely to pose a safety concern.