The coexistence of diabetes, hypertension and obesity is associated with worse pain outcomes following exercise for osteoarthritis: A cohort study on 80,893 patients.

OBJECTIVES: To investigate how the co-occurrence of diabetes, hypertension and overweight/obesity is associated with pain following an exercise intervention for knee and hip osteoarthritis (OA). METHODS: Register-based cohort study. We included people from the Swedish Osteoarthritis Register who underwent education and exercise for knee or hip OA. Diabetes and hypertension were defined using medical records and dispensation of medication. Body Mass Index (BMI) was used to identify people with overweight (≥25 to <30), and obesity (≥30). We used linear mixed-effect models with patients nested into clinics to estimate the associations between the exposures and pain (Numeric Rating Scale 0-10), adjusting for age, sex, education, and physical activity. RESULTS: We analysed 80,893 patients with knee or hip OA. The accumulation of metabolic conditions was associated with worse pain at baseline and follow-ups. When obesity, hypertension and diabetes coexisted, patients treated for knee OA reported more pain at baseline (adjusted mean pain difference 0.9 [95 %CI: 0.8; 1.0]), 3 months (1.0 [0.9; 1.1]) and 12 months (1.3 [1.1; 1.4]) compared to those without any of the conditions. Similar results were observed for patients treated for hip OA when obesity, hypertension and diabetes coexisted (baseline (0.7 [0.5; 0.8], 3 (0.8[0.6; 1.0]) and 12 months (1.1[0.8; 1.3]). CONCLUSIONS: When diabetes, hypertension and obesity coexist with OA, patients not only experience heightened baseline pain compared to metabolically healthy individuals, but the disparity increases after an education and exercise intervention suggesting that a one-size-fits-all approach may be inadequate in addressing the complex interplay between metabolic health and OA.

Risk factors for knee osteoarthritis after traumatic knee injury: a systematic review and meta-analysis of randomised controlled trials and cohort studies for the OPTIKNEE Consensus.

OBJECTIVE: To identify and quantify potential risk factors for osteoarthritis (OA) following traumatic knee injury. DESIGN: Systematic review and meta-analyses that estimated the odds of OA for individual risk factors assessed in more than four studies using random-effects models. Remaining risk factors underwent semiquantitative synthesis. The modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach for prognostic factors guided the assessment. DATA SOURCES: MEDLINE, EMBASE, CENTRAL, SPORTDiscus, CINAHL searched from inception to 2009-2021. ELIGIBILITY: Randomised controlled trials and cohort studies assessing risk factors for symptomatic or structural OA in persons with a traumatic knee injury, mean injury age ≤30 years and minimum 2-year follow-up. RESULTS: Across 66 included studies, 81 unique potential risk factors were identified. High risk of bias due to attrition or confounding was present in 64% and 49% of studies, respectively. Ten risk factors for structural OA underwent meta-analysis (sex, rehabilitation for anterior cruciate ligament (ACL) tear, ACL reconstruction (ACLR), ACLR age, ACLR body mass index, ACLR graft source, ACLR graft augmentation, ACLR+cartilage injury, ACLR+partial meniscectomy, ACLR+total medial meniscectomy). Very-low certainty evidence suggests increased odds of structural OA related to ACLR+cartilage injury (OR=2.31; 95% CI 1.35 to 3.94), ACLR+partial meniscectomy (OR=1.87; 1.45 to 2.42) and ACLR+total medial meniscectomy (OR=3.14; 2.20 to 4.48). Semiquantitative syntheses identified moderate-certainty evidence that cruciate ligament, collateral ligament, meniscal, chondral, patellar/tibiofemoral dislocation, fracture and multistructure injuries increase the odds of symptomatic OA. CONCLUSION: Moderate-certainty evidence suggests that various single and multistructure knee injuries (beyond ACL tears) increase the odds of symptomatic OA. Risk factor heterogeneity, high risk of bias, and inconsistency in risk factors and OA definition make identifying treatment targets for preventing post-traumatic knee OA challenging.

Variation in Patient-Reported Outcomes in Young and Old Patients Up to 4 to 6 Years After Arthroscopic Partial Meniscectomy.

OBJECTIVE: To assess the variation in changes in patient-reported outcomes 4 to 6 years after arthroscopic partial meniscectomy (APM). DESIGN: Prospective cohort study. SETTING: Orthopedic departments at public hospitals. PATIENTS: Patients (n = 447) from the Knee Arthroscopy Cohort Southern Denmark undergoing APM. INTERVENTIONS: All patients underwent APM. MAIN OUTCOME MEASURES: Change in KOOS4 scores from baseline before surgery to ∼5 years (range 4-6 years) after surgery. KOOS4 is the average aggregated score of 4 of 5 of the Knee injury and Osteoarthritis Outcome Score (KOOS) excluding the activities of daily living subscale (minimal clinical important improvement ∼10 points). A mixed linear model adjusted for sex and body mass index was used to assess change from baseline to ∼5-year follow-up. Change in KOOS4 was divided into 5 categories based on change from baseline to ∼5-year follow-up: <0 points, 0 to 9 points, 10 to 19 points, 20 to 29 points, and ≥30 points. RESULTS: On average, patient-reported outcomes continued to improve from baseline to ∼5-year follow-up (mean KOOS4 change: 26, 95% CI, 24-28). Proportions in the different response groups were <0 points (12%), 0 to 9 points (13%), 10 to 19 points (16%), 20 to 29 points (19%), and ≥30 points (40%), with no difference between younger (≤40 years, n = 75) and older (>40 years, n = 337) patients (P = 0.898). CONCLUSIONS: Patient-reported outcomes on average improved up to ∼5 years after APM; however, large variability was observed. The similar variability in younger and older patients questions the assumption that younger patients with traumatic injuries experience larger benefits from APM.

Does early anterior cruciate ligament reconstruction prevent development of meniscal damage? Results from a secondary analysis of a randomised controlled trial.

OBJECTIVES: To determine development of new and worsening meniscal damage over 5 years after acute anterior cruciate ligament (ACL) injury comparing rehabilitation plus early ACL reconstruction ('early-ACLR') versus rehabilitation with optional delayed ACL reconstruction ('optional-delayed-ACLR'). METHODS: We used knee MRIs from the only randomised controlled trial in the field including 121 young adults. One musculoskeletal radiologist read baseline and 5-year follow-up images using the Anterior Cruciate Ligament Osteoarthritis Score (ACLOAS). We defined development (ie, new and worsening) of meniscal damage both dichotomously and as a sum score representing severity (based on the reclassified ACLOAS meniscus grades). In the full analysis set, we analysed development of meniscal damage (yes/no) with logistic regression and severity with zero-inflated Poisson regression and adjusted for age, sex and baseline meniscal damage. RESULTS: Over 5 years, new or worsening meniscal damage developed in 45% of subjects with early-ACLR and in 53% of subjects with optional-delayed-ACLR. The relative risk for development of meniscal damage on knee level was 1.3 (95% CI 0.9 to 1.9) in optional-delayed-ACLR versus early-ACLR. For medial and lateral meniscal damage, respectively, the relative risks were 2.1 (95% CI 1.1 to 3.9) and 1.0 (95% CI 0.6 to 1.5). The mean severity score was 1.5 higher (more severe damage) on knee level in optional-delayed-ACLR versus early-ACLR (95% CI 1.1 to 1.9) among those with meniscal damage at 5 years. For medial and lateral meniscal damage, respectively, the corresponding scores were 1.7 (95% CI 1.2 to 2.5) and 1.1 (95% CI 0.8 to 1.4). CONCLUSION: A strategy of early-ACLR may reduce development of medial meniscal damage following acute ACL injury. For the lateral meniscus, ACLR seems neither to be protective nor to increase the risk of damage. TRIAL REGISTRATION NUMBER: ISRCTN 84752559.

Wild goose chase - no predictable patient subgroups benefit from meniscal surgery: patient-reported outcomes of 641 patients 1 year after surgery.

BACKGROUND: Despite absence of evidence of a clinical benefit of arthroscopic partial meniscectomy (APM), many surgeons claim that subgroups of patients benefit from APM. OBJECTIVE: We developed a prognostic model predicting change in patient-reported outcome 1 year following arthroscopic meniscal surgery to identify such subgroups. METHODS: We included 641 patients (age 48.7 years (SD 13), 56% men) undergoing arthroscopic meniscal surgery from the Knee Arthroscopy Cohort Southern Denmark. 18 preoperative factors identified from literature and/or orthopaedic surgeons (patient demographics, medical history, symptom onset and duration, knee-related symptoms, etc) were combined in a multivariable linear regression model. The outcome was change in Knee injury and Osteoarthritis Outcome Score (KOOS4) (average score of 4 of 5 KOOS subscales excluding the activities of daily living subscale) from presurgery to 52 weeks after surgery. A positive KOOS4 change score constitutes improvement. Prognostic performance was assessed using R2 statistics and calibration plots and was internally validated by adjusting for optimism using 1000 bootstrap samples. RESULTS: Patients improved on average 18.6 (SD 19.7, range -38.0 to 87.8) in KOOS4. The strongest prognostic factors for improvement were (1) no previous meniscal surgery on index knee and (2) more severe preoperative knee-related symptoms. The model's overall predictive performance was low (apparent R2=0.162, optimism adjusted R2=0.080) and it showed poor calibration (calibration-in-the-large=0.205, calibration slope=0.772). CONCLUSION: Despite combining a large number of preoperative factors presumed clinically relevant, change in patient-reported outcome 1 year following meniscal surgery was not predictable. This essentially quashes the existence of 'subgroups' with certain characteristics having a particularly favourable outcome after meniscal surgery. TRIAL REGISTRATION NUMBER: NCT01871272.

Structural effects of sprifermin in knee osteoarthritis: a post-hoc analysis on cartilage and non-cartilaginous tissue alterations in a randomized controlled trial.

BACKGROUND: A recent publication on efficacy of Sprifermin for knee osteoarthritis (OA) using quantitatively MRI-defined central medial tibio-femoral compartment cartilage thickness as the structural primary endpoint reported no statistically significant dose response. However, Sprifermin was associated with statistically significant, dose-dependent reductions in loss of total and lateral tibio-femoral cartilage thickness. Based on these preliminary promising data a post-hoc analysis of secondary assessment and endpoints was performed to evaluate potential effects of Sprifermin on semi-quantitatively evaluated structural MRI parameters. Aim of the present analysis was to determine effects of sprifermin on several knee joint tissues over a 12 month period. METHODS: 1.5 T or 3 T MRIs were acquired at baseline and 12 months follow-up using a standard protocol. MRIs were read according to the Whole-Organ Magnetic Resonance Imaging Score (WORMS) scoring system (in 14 articular subregions) by four muskuloskeletal radiologists independently. Analyses focused on semiquantitative changes in the 100 µg subgroup and matching placebo of multiple MRI-defined structural alterations. Analyses included a delta-subregional and delta-sum approach for the whole knee and the medial and lateral tibio-femoral (MTFJ, LTFJ), and patello-femoral (PFJ) compartments, taking into account number of subregions showing no change, improvement or worsening and changes in the sum of subregional scores. Mann-Whitney - Wilcoxon tests assessed differences between groups. RESULTS: Fifty-seven and 18 patients were included in the treatment and matched placebo subgroups. Less worsening of cartilage damage was observed from baseline to 12 months in the PFJ (0.02, 95 % confidence interval (CI) (-0.04, 0.08) vs. placebo 0.22, 95 % CI (-0.05, 0.49), p = 0.046). For bone marrow lesions (BMLs), more improvement was observed from 6 to 12 months for whole knee analyses (-0.14, 95 % CI (-0.48, 0.19) vs. placebo 0.44, 95 % CI (-0.15, 1.04), p = 0.042) although no significant effects were seen from the baseline visit, or in Hoffa-synovitis, effusion-synovitis, menisci and osteophytes. CONCLUSIONS: In this post-hoc analysis cartilage showed less worsening from baseline to 12 months in the PFJ, and BMLs showed more improvement from 6 to 12 months for the whole knee. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01033994 .

A missense mutation in the aggrecan C-type lectin domain disrupts extracellular matrix interactions and causes dominant familial osteochondritis dissecans.

Osteochondritis dissecans is a disorder in which fragments of articular cartilage and subchondral bone dislodge from the joint surface. We analyzed a five-generation family in which affected members had autosomal-dominant familial osteochondritis dissecans. A genome-wide linkage analysis identified aggrecan (ACAN) as a prime candidate gene for the disorder. Sequence analysis of ACAN revealed heterozygosity for a missense mutation (c.6907G > A) in affected individuals, resulting in a p.V2303M amino acid substitution in the aggrecan G3 domain C-type lectin, which mediates interactions with other proteins in the cartilage extracellular matrix. Binding studies with recombinant mutated and wild-type G3 proteins showed loss of fibulin-1, fibulin-2, and tenascin-R interactions for the V2303M protein. Mass spectrometric analyses of aggrecan purified from patient cartilage verified that V2303M aggrecan is produced and present in the tissue. Our results provide a molecular mechanism for the etiology of familial osteochondritis dissecans and show the importance of the aggrecan C-type lectin interactions for cartilage function in vivo.

Clinical trials in orthopaedics and the future direction of clinical investigations for femoroacetabular impingement.

Femoroacetabular impingement (FAI) represents a heterogeneous group of disorders that affect a diverse patient population. The natural history of the disease, the role of nonsurgical management, the indications for surgery, optimal surgical techniques, and the predictors of treatment outcomes need to be further defined. To date, clinical research reports have included primarily surgical case series. Future clinical investigations are needed to establish improved clinical evidence to guide patient care. Most urgent is the need to better understand the potential role of standardized nonsurgical treatment options for FAI and to define the predictors of surgical and nonsurgical outcomes. Future randomized controlled trials and large observational cohort studies targeted at these clinical research deficiencies will strengthen the evidence and improve informed decision making regarding the management of symptomatic FAI.

Smoking and secondary ACL rupture are detrimental to knee health post ACL injury-a Bayesian analysis.

PURPOSE: To identify potential prognostic factors for patient-reported outcomes in an Icelandic cohort of ACL injured subjects. METHODS: All knee MRI reports written in Iceland between the years 2001 to 2011 were read to identify individuals with a possible ACL injury. These individuals were contacted and asked to complete an online questionnaire regarding their injury and current knee related health. The questionnaire collected information on years since surgery, injury circumstance, brace use, physiotherapy, ACL surgery, second ACL injury and current smoking status. In addition, the baseline status of their meniscii were assessed from the original MRI report and medical records were used to identify any subsequent, non-ACL surgery. The patient-reported Knee Osteoarthritis and Injury Outcome Score (KOOS) was used assess current knee related health. A Bayesian proportional odds model was used to assess the effect of all potential prognostic factors above as well as age and sex on KOOS outcomes. RESULTS: A total of 408 subjects completed the questionnaire indicating that they did rupture their ACL. The following variables were associated with worse outcomes across all KOOS subscales: having a subsequent arthroscopy, reinjury to your ACL, and smoking. Having physiotherapy for 9 months was associated with worse KOOS pain scores than having 6 months of physiotherapy. Conversely KOOS pain score tended to be higher if you injured your knee during sports. CONCLUSION: Reinjuring your ACL, smoking and having subsequent (non-ACLR) surgery predict your knee related health following an ACL injury. Strategies should be implemented to reduce the risk of secondary ACL injury, and patients should be strongly advised not to smoke.

The appropriate use of non-steroidal anti-inflammatory drugs in rheumatic disease: opinions of a multidisciplinary European expert panel.

INTRODUCTION: Given the safety issues of non-steroidal anti-inflammatory drugs (NSAID) and the robustness of guidelines, making treatment choices in daily clinical practice is increasingly difficult. This study aimed systematically to analyse the opinions of a multidisciplinary European expert panel on the appropriateness of different NSAID, with or without the use of a proton pump inhibitor (PPI), in individual patients with chronic rheumatic disease. METHODS: /Using the Research and Development/University of California at Los Angeles appropriateness method, the appropriateness of five (non-)selective NSAID with or without a PPI was assessed for 144 hypothetical patient profiles, ie, unique combinations of cardiovascular and gastrointestinal risk factors. Appropriateness statements were calculated for all indications. RESULTS: All options without PPI were considered appropriate in patients with no gastrointestinal/cardiovascular risk factors. Cyclooxygenase-2 selective inhibitors (C2SI) alone and non-selective NSAID plus PPI were preferred for patients with elevated gastrointestinal risk and low cardiovascular risk. Naproxen plus PPI was favoured in patients with high cardiovascular risk. For the combination of high gastrointestinal/high cardiovascular risk the use of any NSAID was discouraged; if needed, naproxen plus PPI or a C2SI plus PPI could be considered. DISCUSSION: The panel results may support treatment considerations at the level of individual patients, according to their gastrointestinal/cardiovascular risk profile.

Efficacy and cost-effectiveness of Stem Cell injections for symptomatic relief and strUctural improvement in people with Tibiofemoral knee OsteoaRthritis: protocol for a randomised placebo-controlled trial (the SCUlpTOR trial).

INTRODUCTION: Knee osteoarthritis (KOA) is a highly prevalent disabling joint disease. Intra-articular stem cell therapy is increasingly being used for treating KOA with little high-quality evidence to support its use. The aim of this study is to investigate the efficacy, safety and cost-effectiveness of allogeneic mesenchymal stem cells (Cymerus MSCs) for treating symptomatic tibiofemoral KOA and improving knee structure over 24 months. METHODS AND ANALYSIS: The Stem Cell injections for symptomatic relief and strUctural improvement in people with Tibiofemoral knee OsteoaRthritis study is a phase III, multi-centre, parallel, superiority, randomised, double-blind, placebo-controlled trial, which will be conducted in Sydney and Hobart, Australia. 440 participants (220 per arm) aged over 40 years with painful KOA and mild to moderate structural change on X-ray (Kellgren and Lawrence grade 2 or 3) with medial minimum joint space width between 1 and 4 mm in the study knee will be recruited from the community and randomly allocated to receive either intra-articular MSCs or saline at baseline, week 3 and week 52. The coprimary outcomes will be the proportion of participants achieving patient-acceptable symptom state for knee pain at 24 months and quantitative central medial femorotibial compartment cartilage thickness change from baseline to 24 months. Main secondary outcomes include change in knee pain, Patient Global Assessment, physical function, quality of life and other structural changes. Additional data for cost-effectiveness analysis will also be recorded. Adverse events will be monitored throughout the study. The primary analysis will be conducted using modified intention-to-treat. ETHICS AND DISSEMINATION: This protocol has been approved by The University of Sydney (USYD) Human Research Ethics Committee (HREC) #: 2020/119 and The University of Tasmania (UTAS) HREC #: H0021868. All participants will be required to provide informed consent. Dissemination will occur through conferences, social media, and scientific publications. TRIAL REGISTRATION NUMBERS: Australian New Zealand Clinical Trials Registry (ACTRN12620000870954); U1111-1234-4897.

The association between hip fracture and hip osteoarthritis: a case-control study.

BACKGROUND: There have been reports both supporting and refuting an inverse relationship between hip fracture and hip osteoarthritis (OA). We explore this relationship using a case-control study design. METHODS: Exclusion criteria were previous hip fracture (same side or contralateral side), age younger than 60 years, foreign nationality, pathological fracture, rheumatoid arthritis and cases were radiographic examinations were not found in the archives. We studied all subjects with hip fracture that remained after the exclusion process that were treated at Akureyri University Hospital, Iceland 1990-2008, n = 562 (74% women). Hip fracture cases were compared with a cohort of subjects with colon radiographs, n = 803 (54% women) to determine expected population prevalence of hip OA. Presence of radiographic hip OA was defined as a minimum joint space of 2.5 mm or less on an anteroposterior radiograph, or Kellgren and Lawrence grade 2 or higher. Possible causes of secondary osteoporosis were identified by review of medical records. RESULTS: The age-adjusted odds ratio (OR) for subjects with hip fracture having radiographic hip OA was 0.30 (95% confidence interval [95% CI] 0.12-0.74) for men and 0.33 (95% CI 0.19-0.58) for women, compared to controls. The probability for subjects with hip fracture and hip OA having a secondary cause of osteoporosis was three times higher than for subjects with hip fracture without hip OA. CONCLUSION: The results of our study support an inverse relationship between hip fractures and hip OA.

Understanding the role of diabetes in the osteoarthritis disease and treatment process: a study protocol for the Swedish Osteoarthritis and Diabetes (SOAD) cohort.

INTRODUCTION: Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability worldwide. Metabolic comorbidities such as type II diabetes occur with a higher rate in people with OA than in the general population. Several factors including obesity, hyperglycaemia toxicity and physical inactivity have been suggested as potential links between diabetes and OA, and have been shown to negatively impact patients' health and quality of life. However, little is known on the role of diabetes in determining the outcome of non-surgical and surgical management of OA, and at the same time, how different OA interventions may affect diabetes control. Thus, the overall aim of this project is to explore (1) the impact of diabetes on the outcome of non-surgical and surgical OA treatments and (2) the impact of non-surgical and surgical OA treatments on diabetes control. METHODS AND ANALYSIS: The study cohort is based on prospectively ascertained register data on a national level in Sweden. Data from OA patients who received a first-line non-surgical intervention and are registered in the National Quality Register for Better Management of Patients with Osteoarthritis will be merged with data from the Swedish Knee and Hip Arthroplasty Registers and the National Diabetes Register. Additional variables regarding patients' use of prescribed drugs, comorbidities, socioeconomic status and cause of death will be obtained through other national health and population data registers. The linkage will be performed on an individual level using unique personal identity numbers. ETHICS AND DISSEMINATION: This study received ethical approval (2019-02570) from the Swedish Ethical Review Authority. Results from this cohort will be submitted to peer-reviewed scientific journals and reported at the leading national and international meetings in the field.