Multiple Joint Sites Research Articles

A Damaging COL6A3 Variant Alters the MIR31HG-Regulated Response of Chondrocytes in Neocartilage Organoids to Hyperphysiologic Mechanical Loading.

The pericellular matrix (PCM), with its hallmark proteins collagen type VI (COLVI) and fibronectin (FN), surrounds chondrocytes and is critical in transducing the biomechanical cues. To identify genetic variants that change protein function, exome sequencing is performed in a patient with symptomatic OA at multiple joint sites. A predicted damaging variant in COL6A3 is identified and introduced by CRISPR-Cas9 genome engineering in two established human induced pluripotent stem cell-derived in-vitro neocartilage organoid models. The downstream effects of the COL6A3 variant on the chondrocyte phenotypic state are studied by a multi-omics (mRNA and lncRNA) approach in interaction with hyper-physiological mechanical loading conditions. The damaging variant in COL6A3 results in significantly lower binding between the PCM proteins COLVI and FN and provokes an osteoarthritic chondrocyte state. By subsequently exposing the neocartilage organoids to hyperphysiological mechanical stress, it is demonstrated that the COL6A3 variant in chondrocytes abolishes the characteristic inflammatory signaling response after mechanical loading with PTGS2, PECAM1, and ADAMTS5, as central genes. Finally, by integrating epigenetic regulation, the lncRNA MIR31HG is identified as key regulator of the characteristic inflammatory signaling response to mechanical loading.

Assessment of Musculoskeletal Ultrasound of Rheumatoid Arthritis.

Musculoskeletal ultrasound (MSUS) is a valuable tool that is used in outpatient clinics or at the bedside to assess multiple joint sites, including small joints. It provides detailed images of structures commonly observed in rheumatoid arthritis (RA), such as synovitis, tenosynovitis, bone erosions, cartilage damage, and synovial fluid accumulation. MSUS is frequently used in the management of RA and provides more objective information for an early diagnosis and disease activity assessment through imaging findings.

Osteonecrosis is associated with APOL1 variants in African Americans with systemic lupus erythematosus

Background/purposeAfrican Americans (AA) with systemic lupus erythematosus (SLE) are at higher risk for both kidney disease and Osteonecrosis (ON). Two Apolipoprotein L1 (APOL1) risk variants (RV), G1 and G2, have been associated with chronic kidney disease (CKD), hypertension, and microvascular disease in AAs, which are independent risk factors for ON. Accordingly, we investigated the association between carriers of the APOL1 risk variants and the prevalence of ON in AA SLE patients.MethodsA cohort of 121 adult participants of self-reported AA ancestry and meeting at least four of the American College of Rheumatology (ACR) revised criteria for SLE were recruited from a high volume urban SLE clinical site. PCR/sequencing was used to stratify participants by APOL1 genotype. Medical records, including clinical notes and imaging reports, were retrospectively reviewed for documentation of ON. Association between the number of APOL1 risk variants with time to first ON was tested.ResultsIn our cohort, 18 individuals developed ON; across the APOL1 genotype groups, 2/37 0RV, 11/59 1RV, and 5/15 2RV participants were affected. The mean time to ON was 27 years, 22 years, and 18 years in 0RV, 1RV, and 2RV carriers, respectively. An adjusted Cox regression model showed that carrying the APOL1 risk variants associated with shorter ON free survival with hazard ratios (HR) of 3.1 (95% CI: 1.6–6.2) and 9.6 (95% CI 2.4–37.8) for 1RV and 2RV carriers, respectively. 2RV carriers more often exhibited multiple and bilateral joint sites affected by ON. Disease duration was longer in ON-affected participants at 20.5 years compared to 9.0 years in those unaffected (p < 0.001). In individuals who had received glucocorticoids, median cumulative prednisone equivalent dose was higher in ON-affected participants, though this did not reach statistical significance (18.7 g vs. 9.0 g; p-value = 0.3).ConclusionOur analysis suggests a higher risk of osteonecrosis among African American SLE patients who carry the APOL1 risk variants. In addition, disease duration increased the rate of ON. Given the high frequency of the APOL1 risk variants in African Americans, APOL1 high-risk genotype carriers may represent an ON-vulnerable subgroup within the AA population. Further work is necessary to uncover the mechanism of this association.

P118 Orthopaedic surgical interventions in a cohort of patients with hypermobility related disorders, compared with chronic pain syndrome patients in a tertiary referral centre

Abstract Background Mechanisms of pain associated with hypermobility are poorly understood and include nociceptive pain due to structural joint changes, neuropathic pain due to disrupted proprioception, muscle weakness and central sensitisation. The influence of anxiety and low mood is also unknown. There is limited published evidence regarding orthopaedic interventions in hypermobile patients particularly following the updated 2017 Ehlers-Danlos syndrome (EDS) classification criteria. We aimed to evaluate the characteristics of a hypermobility patient cohort who had received surgical interventions and compare these with a patient population with chronic pain syndromes. Methods A retrospective analysis of medical records was conducted of patients attending a tertiary referral centre (University College London Hospital) between January 2018 and December 2018. A hypermobility-related disorders cohort was compared with a cohort of patients with chronic pain syndrome, including fibromyalgia (but without any evidence of hypermobility). Results There were 350 patients (300 females, 50 males) in the hypermobility cohort with a mean age of 36 years (range 18-71 years) at time of clinic review. 63% had hypermobility spectrum disorder or hypermobility syndrome and 37% had EDS (hypermobile, classic, vascular and other rare types). 24% of hypermobile patients had undergone orthopaedic interventions. The Beighton score did not correlate with surgical procedures. 134 patients (121 females, 13 males) with chronic pain syndromes were identified, with a mean age of 51 years (range 26-85 years). 16% of chronic pain patients had received orthopaedic surgery. 76% of hypermobile patients who had orthopaedic interventions were under 50 years old, compared to 23% in the chronic pain cohort. The total number of surgical procedures in the hypermobility cohort was 227 (0.6485 interventions per patient) compared with 25 in the chronic pain cohort (0.1865 interventions per patient); relative risk 3.477 (95% CI 2.42-4.99; P < 0.0001, chi-squared test). 33% of hypermobile patients had surgery on two or more joint groups (including 8 patients who had surgery in four or more joint groups), whereas 95% of chronic patients had surgery on only one joint group. In the hypermobile group the knee (23%) and hips (24%) were the most common site of operative intervention; however in the chronic pain cohort the most common sites were the knee (32%), spine (20%) and shoulders (20%), with only 4% requiring hip surgery. Conclusion Patients with hypermobility have a greater number of surgical procedures at multiple joint sites and at a younger age than patients with chronic pain syndromes, suggesting that mechanical pathology (rather than pain alone) and anticipated surgical success may contribute to the need for surgical intervention. The Beighton score does not appear to be a reliable predictor of surgical intervention. Earlier diagnosis and a holistic, non-operative approach, including physiotherapy and pain management, may reduce the need for surgical procedures. Disclosures S. Wright None. P. Mehta None. A. Rahman None. H. Kazkaz None.

Health enhancing physical activity in patients with hip or knee osteoarthritis - an observational intervention study

BackgroundOsteoarthritis is one of the leading causes of inactivity worldwide. The recommended level of health enhancing physical activity (HEPA) is at least 150 min of moderate intensity physical activity per week. The purpose of this study was to explore how the proportion of patients, who reached the recommended level of HEPA, changed following a supported osteoarthritis self-management programme in primary care, and to explore how reaching the level of HEPA was influenced by body mass index (BMI), gender, age and comorbidity.MethodsAn observational study was conducted using data from a National Quality Registry in which 6810 patients in primary care with clinically verified hip or knee osteoarthritis with complete data at baseline, 3 and 12 months follow-up before December 31st 2013 were included. HEPA was defined as self-reported physical activity of at least moderate intensity either a) at least 30 min per day on four days or more per week, or b) at least 150 min per week. HEPA was assessed at baseline, and again at 3 and 12 months follow-up. Cochran’s Q test was used to determine change in physical activity over time. The association between reaching the level of HEPA and time, age, BMI, gender, and Charnley classification was investigated using the generalized estimation equation (GEE) model.ResultsThe proportion of patients who reached the level of HEPA increased by 345 patients, from 77 to 82%, from baseline to 3 months follow-up. At 12 months, the proportion of patients who reached the level of HEPA decreased to 76%. Not reaching the level of HEPA was associated with overweight, obesity, male gender and Charnley category C, i.e. osteoarthritis in multiple joint sites (hip and knee), or presence of any other disease that affects walking ability.ConclusionsFollowing the supported osteoarthritis self-management programme there was a significant increase in the proportion of patients who reached the recommended level of HEPA after 3 months. Improvements were lost after 12 months. To increase physical activity and reach long-lasting changes in levels of physical activity, more follow-up sessions might be needed.

Multidisciplinary approaches to managing osteoarthritis in multiple joint sites: a systematic review.

BackgroundThe National Institute for Health and Care Excellence’s Osteoarthritis (OA) guidelines recommended that future research should consider the benefits of combination therapies in people with OA across multiple joint sites. However, the clinical effectiveness of such approaches to OA management is unknown. This systematic review therefore aimed to identify the clinical and cost effectiveness of multidisciplinary approaches targeting multiple joint sites for OA in primary care.MethodsA systematic review of randomised controlled trials. Computerised bibliographic databases were searched (MEDLINE, EMBASE, CINAHL, PsychINFO, BNI, HBE, HMIC, AMED, Web of Science and Cochrane). Studies were included if they met the following criteria; a randomised controlled trial (RCT), a primary care population with OA across at least two different peripheral joint sites (multiple joint sites), and interventions undertaken by at least two different health disciplines (multidisciplinary). The Cochrane ‘Risk of Bias’ tool and PEDro were used for quality assessment of eligible studies. Clinical and cost effectiveness was determined by extracting and examining self-reported outcomes for pain, function, quality of life (QoL) and health care utilisation. The date range for the search was from database inception until August 2015.ResultsThe search identified 1148 individual titles of which four were included in the review. A narrative review was conducted due to the heterogeneity of the included trials. Each of the four trials used either educational or exercise interventions facilitated by a range of different health disciplines. Moderate clinical benefits on pain, function and QoL were reported across the studies. The beneficial effects of exercise generally decreased over time within all studies. Two studies were able to show a reduction in healthcare utilisation due to a reduction in visits to a physiotherapist or a reduction in x-rays and orthopaedic referrals. The intervention that showed the most promise used educational interventions delivered by GPs with reinforcement by practice nurses.ConclusionsThere are currently very few studies that target multidisciplinary approaches suitable for OA across multiple joint sites, in primary care. A more consistent approach to outcome measurement in future studies of this nature should be considered to allow for better comparison.

THU0219 Prevalence of Joint Pain and Self-Reported Osteoarthritis in British Columbia, Canada

BackgroundSurvey data provide important information on the prevalence of chronic conditions across different areas and population groups. In Canada, large national surveys routinely ask about physician-diagnosed arthritis. However, population data...

A gain of function mutation in TNFRSF11B encoding osteoprotegerin causes osteoarthritis with chondrocalcinosis

ObjectiveTo identify pathogenic mutations that reveal underlying biological mechanisms driving osteoarthritis (OA).MethodsExome sequencing was applied to two distant family members with dominantly inherited early onset primary OA at multiple joint...

Quadriceps muscle strength and its relationship to radiographic knee osteoarthritis

Quadriceps muscle strength and its relationship to radiographic knee osteoarthritis

Metabolic health in families enriched for longevity is associated with low prevalence of hand osteoarthritis and influences OA biomarker profiles

ObjectivesIndividual metabolic characteristics and age-related changes may affect osteoarthritis (OA) risk as well as levels of potential OA biomarkers such as serum cartilage oligomeric protein (sCOMP) and urinary cross-linked C-telopeptide...

Quantification of the whole-body burden of radiographic osteoarthritis using factor analysis

IntroductionAlthough osteoarthritis (OA) commonly involves multiple joints, no widely accepted method for quantifying whole-body OA burden exists. Therefore, our aim was to apply factor analytic methods to radiographic OA (rOA) grades across multiple joint sites, representing both presence and severity, to quantify the burden of rOA.MethodsWe used cross-sectional data from the Johnston County Osteoarthritis Project. The sample (n = 2092) had a mean age of 65 ± 11 years, body mass index (BMI) 31 ± 7 kg/m2, with 33% men and 34% African Americans. A single expert reader (intra-rater κ = 0.89) provided radiographic grades based on standard atlases for the hands (30 joints, including bilateral distal and proximal interphalangeal [IP], thumb IP, metacarpophalangeal [MCP] and carpometacarpal [CMC] joints), knees (patellofemoral and tibiofemoral, 4 joints), hips (2 joints), and spine (5 levels [L1/2 to L5/S1]). All grades were entered into an exploratory common factor analysis as continuous variables. Stratified factor analyses were used to look for differences by gender, race, age, and cohort subgroups.ResultsFour factors were identified as follows: IP/CMC factor (20 joints), MCP factor (8 joints), Knee factor (4 joints), Spine factor (5 levels). These factors had high internal consistency reliability (Cronbach's α range 0.80 to 0.95), were not collapsible into a single factor, and had moderate between-factor correlations (Pearson correlation coefficient r = 0.24 to 0.44). There were no major differences in factor structure when stratified by subgroup.ConclusionsThe 4 factors obtained in this analysis indicate that the variables contained within each factor share an underlying cause, but the 4 factors are distinct, suggesting that combining these joint sites into one overall measure is not appropriate. Using such factors to reflect multi-joint rOA in statistical models can reduce the number of variables needed and increase precision.

Positive association between increased popliteal artery vessel wall thickness and generalized osteoarthritis: is OA also part of the metabolic syndrome?

PurposeThe purpose of the study was to determine if a positive association exists between arterial vessel wall thickness and generalized osteoarthritis (OA). Our hypothesis is that generalized OA is another facet of the metabolic syndrome.Materials and methodsThe medical ethical review board of our institution approved the study. Written informed consent was obtained from each patient prior to the study. Magnetic resonance (MR) images of the knee were obtained in 42 patients who had been diagnosed with generalized OA at multiple joint sites. Another 27 MR images of the knee were obtained from a matched normal (non-OA) reference population. Vessel wall thickness of the popliteal artery was quantitatively measured by dedicated software. Linear regression models were used to investigate the association between vessel wall thickness and generalized OA. Adjustments were made for age, sex, and body mass index (BMI). Confidence intervals (CI) were computed at the 95% level and a significance level of α = 0.05 was used.ResultsPatients in the generalized OA population had a significant higher average vessel wall thickness than persons from the normal reference population (p ≤ α), even when correction was made for sex, age, and BMI. The average vessel wall thickness of the popliteal artery was 1.09 mm in patients with generalized OA, and 0.96 mm in the matched normal reference population.ConclusionThe association found between increased popliteal artery vessel wall thickness and generalized osteoarthritis suggests that generalized OA might be another facet of the metabolic syndrome.

The role of plasma cytokine levels, CRP and Selenoprotein S gene variation in OA

Investigating the association between plasma levels of cytokines and chemokines, Selenoprotein S (SELS) gene variation and osteoarthritis (OA) subtypes. The genetics of osteoarthritis and progression (GARP) study consists of 191 sibling pairs with symptomatic OA at multiple joint sites. We have measured plasma levels of 17 cytokines and chemokines and genetic variation at the SELS gene. Nine out of 17 serum markers could be assessed quantitatively, whereas eight markers were assessed qualitatively. Principal component analysis (PCA) on the quantitatively assessed markers and serum high sensitive C-reactive protein (S-HsCRP) revealed that three components underlie 61% of the total plasma variation. Three single nucleotide polymorphisms (SNPs) in the SELS gene revealed four common haplotypes, one of which, GAG (frequency 3.5%) showed significant association to an anti-inflammatory (P=0.019) and acute phase related (P=0.036) component. OA subtype analysis showed that one component (mainly representing chemokine variation) was significantly associated to hand OA and disc degeneration (P=0.029 and P=0.010 respectively) as well as a physical component score (PCS) (P=0.042). The CRP related component also showed a strong association to the PCS (P=0.007). SELS haplotypes showed no association to OA subtypes in the GARP study. Genetic variation in the SELS gene associates to components representing inflammatory signaling. Another component, representing chemokine variation, showed association to hand OA and disc degeneration in the GARP study indicating chemokines may contribute to OA pathogenesis.

258 PAIN AND FUNCTIONAL DISABILITY IN SYMPTOMATIC HAND OSTEOARTHRITIS DEPEND ON TYPE OF JOINT INVOLVEMENT

Purpose: Pain, a core outcome in osteoarthritis (OA) research, can be measured during physical examination by an articular index called the Doyle Index. The value of this pain score as an outcome measure in OA is not established. In the present study the reliability, validity and feasibility of this index will be determined. Methods: The Doyle Index includes 48 joints or joint groups, being hands, wrists, elbows, shoulders, acromioclavicular, sternoclavicular, hips, knees, ankles, feet and spine. Pain is assessed by pressure on the joint margin or by passive movement of the joint, scored on a four-point scale (0 = no pain, 1 = pain, 2 = pain and wincing, 3 = pain, wincing and withdrawal of the joint; range 0–144). The Doyle Index was performed by one observer in 90 patients with OA at multiple joint sites in the hands or with OA in two or more of the following joint sites: hand, knee, hip, cervical or lumbar spine. Reliability and feasibility were determined in a random sample of 18 patients, by examining these patients twice with a 90 minutes time interval, using four observers. Intraclass correlation coefficients (ICC) and their 95% confidence intervals (95%CI) were calculated, as well as the mean time it took each observer to perform the Doyle Index. Validity was assessed by correlating Doyle Index scores obtained in the whole population to the pain subscale scores of the Australian/Canadian Osteoarthritis Hand Index (AUSCAN) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), using Spearman rank coefficient. Results: The patient population consisted of 90 patients (82% women, mean age 65.0 years). The median Doyle Index score for the whole population was 9.5 (interquartile range (IQR) 4−16). The median score of all observations in the sample of 18 patients was 16.5 (IQR 8.25−29.75). Interobserver reliability was 0.88 (95% CI 0.77−0.94). Intraobserver reliabilities for the four observers ranged from 0.94 (95% CI 0.84−0.98) to 0.97 (95% CI 0.93−0.99). The mean time to perform the Doyle Index for a single patient was between 4.0 and 6.0 minutes. The Doyle Index scores correlated to the AUSCAN pain subscale (r = 0.48 (p< 0.001)) and to the WOMAC pain subscale (r = 0.45 (p< 0.001)). Conclusions: The Doyle Index showed to be a reliable, valid and feasible measure for the assessment of OA pain during physical examination. Based on the findings of the present study, the Doyle Index is a promising outcome measure for pain in OA, although further research on its clinimetric properties is advisable.

Bone marrow edema-like lesions change in volume in the majority of patients with osteoarthritis; associations with clinical features

It has been suggested that bone marrow edema-like (BME) lesions in the knee are associated with progression of osteoarthritis (OA). The purpose of our study in patients with OA was to evaluate prospectively changes of BME lesions over 2 years and their relationship with clinical features. Magnetic resonance (MR) images of the knee were obtained from 182 patients (20% male; aged 43–76 years; mean age 59 years) who had been diagnosed with familial symptomatic OA at multiple joint sites. MR images were made at baseline and at 2 years follow-up. BME lesions in 2 years were associated with clinical features assessed by Western Ontario and McMaster Universities Osteoarthritis (WOMAC) scores. A total of 327 BME lesions were recorded. Total size of BME lesions changed in 90 patients (66%). Size of individual lesions changed in 147 foci (45%): new lesions appeared in 69 (21%), existing lesions disappeared in 32 (10%), increased in size in 26 (8%) and decreased in size in 20 (6%) lesions. Increase or decrease of BME lesions, over a 2-year time period, was not associated with severity of WOMAC scores. BME lesions fluctuated in the majority of patients with OA over a 2-year time period. These changes were not associated with severity of WOMAC scores at the study end point.

Influence of familial factors on radiologic disease progression over two years in siblings with osteoarthritis at multiple sites: A prospective longitudinal cohort study

The contribution of genetics to osteoarthritis (OA) progression is not known. To gain more insight into whether familial factors play a role in disease progression of OA, we analyzed familial aggregation of radiologic OA progression in a study of sibling pairs (the Genetics, Arthrosis, and Progression [GARP] study). A total of 105 white probands and their 105 siblings with OA at multiple joint sites were included in a prospective cohort study. Radiologic progression of OA was defined as a 1-point score increase in total scores for severity of joint space narrowing (JSN) or osteophytes on standardized radiographs of the hands, knees, and hips obtained at baseline and after 2 years. Odds ratios were calculated for siblings and probands sharing radiologic disease progression. A total of 100 probands and 93 siblings were followed for 2 years (median age 60 years, 80% women). In 92 sibling pairs both the proband and sibling had complete radiographic followup. Radiologic progression of JSN and osteophytes was present in 47% and 42% of the probands and 34% and 37% of the siblings, respectively. The odds ratios (95% confidence intervals), adjusted for age, sex, and body mass index, of a sibling having radiologic progression if the proband had progression were 3.0 (1.2-7.8) for JSN progression and 1.5 (0.6-3.6) for osteophyte progression. A dose-response relationship was found between the amount of increase in JSN total scores among probands and the progression of JSN in siblings. Familial factors played a role in the radiologic progression of JSN over 2 years in patients with OA at multiple sites.

Osteoarthritis of the Knee: Association between Clinical Features and MR Imaging Findings

To prospectively evaluate the association between clinical features and structural abnormalities found at magnetic resonance (MR) imaging in patients with osteoarthritis (OA) of the knee. The study was approved by the institutional medical ethics review board. Written informed consent was obtained from each patient. MR images of the knee were obtained from 205 (42 [20%] men, 163 [80%] women; median age, 60 years; range, 43-77 years) patients in whom symptomatic OA at multiple joint sites was diagnosed. MR images were analyzed for various abnormalities of OA. All patients were interviewed concerning pain and stiffness in the knee that was imaged. Odds ratios (ORs) with 99% confidence intervals (CIs) were used to determine the association between the imaging findings and clinical features of OA. A large joint effusion was associated with pain (OR, 9.99; 99% CI: 1.28, 149) and stiffness (OR, 4.67; 99% CI: 1.26, 26.1). The presence of an osteophyte in the patellofemoral compartment (OR, 2.25; 99% CI: 1.06, 4.77) was associated with pain. All other imaging findings, including focal or diffuse cartilaginous abnormalities, subchondral cysts, bone marrow edema, subluxation of the meniscus, meniscal tears, or Baker cysts, were not associated with symptoms. Findings of this study indicate that only two associations exist between clinical symptoms and structural findings found on MR images in patients with OA of the knee.

Factors affecting radiographic progression of knee osteoarthritis.

To evaluate the prognostic significance of patient characteristics and radiographic features at the knee for outcome of knee osteoarthritis. This was a prospective observational study of 350 osteoarthritic knees. Clinical and radiographic data were obtained on 188 hospital referred patients (mean age 70, range 34-91 years). Median duration of follow up was two years (range 1-5 years). The majority of patients (48%) reported deterioration, but 23% experienced improvement in symptoms during the study period. Reported exercise tolerance remained unchanged in the majority (62%) and deteriorated in 35%. Change in at least one individual radiographic feature of osteoarthritis was seen in 252 (72%) knees: increase in joint space narrowing occurred in 52%, osteophyte in 32%, cysts in 19%, sclerosis in 14%, and attrition in 30%. Increase in Kellgren grade occurred in 137 (39%) knees. Knee effusion, osteoarthritis at multiple joint sites, and nodal change associated with change in Kellgren grade (odds ratios 1.03, 2.39, and 1.80; 95% confidence intervals (CI) 1.01 to 1.05, 1.16 to 4.93, and 1.02 to 3.17, respectively); warmth at the knee associated with change in any radiographic feature (odds ratio 2.22; 95% CI 1.19 to 4.14). Development of, or increase in, attrition and joint space narrowing associated with worsening symptoms and function and occurred with increased frequency in knees with effusions, clinical warmth and calcium pyrophosphate crystals in synovial fluid (p < 0.05). A high rate of change, radiographic more than clinical, was seen in osteoarthritic knees during this study. Poor clinical and radiographic outcome associated with calcium pyrophosphate crystal deposition and clinical inflammation as reflected by knee effusion and warmth.