Association of FCGR3A and FCGR3B haplotypes with rheumatoid arthritis and primary Sjögren's syndrome [POSTER PRESENTATION]

Background Rheumatoid arthritis (RA) is an autoimmune disease that is thought to arise from a complex interaction between multiple genetic factors and environmental triggers. We have previously demonstrated an association between a Fc gamma receptor (FcγR) haplotype and RA in a cross-sectional cohort of RA patients. We have sought to confirm this association in an inception cohort of RA patients and matched controls. We also extended our study to investigate a second autoanti-body associated rheumatic disease, primary Sjögren's syndrome (PSS). Methods The FCGR3A-158F/V and FCGR3B-NA1/NA2 functional polymorphisms were examined for association in an inception cohort of RA patients (n = 448), and a well-characterised PSS cohort (n = 83) from the United Kingdom. Pairwise disequilibrium coefficients (D') were calculated in 267 Blood Service healthy controls. The EHPlus program was used to estimate haplotype frequencies for patients and controls and to determine whether significant linkage disequilibrium was present. A likelihood ratio test is performed to test for differences between the haplotype frequencies in cases and controls. A permutation procedure implemented in this program enabled 1000 permutations to be performed on all haplotype associations to assess significance. Results There was significant linkage disequilibrium between FCGR3A and FCGR3B (D' = -0.445, P = 0.001). There was no significant difference in the FCGR3A or FCGR3B allele or genotype frequencies in the RA or PSS patients compared with controls. However, there was a significant difference in the FCGR3A-FCGR3B haplotype distributions with increased homozygosity for the FCGR3A-FCGR3B 158V-NA2 haplotype in both our inception RA cohort (odds ratio = 2.15, 95% confidence interval = 1.1–4.2 P = 0.027) and PSS (odds ratio = 2.83, 95% confidence interval = 1.0–8.2, P = 0.047) compared with controls. The reference group for these analyses comprised individuals who did not possess a copy of the FCGR3A-FCGR3B 158V-NA2 haplotype. Conclusions We have confirmed our original findings of association between the FCGR3A-FCGR3B 158V-NA2 haplotype and RA in a new inception cohort of RA patients. This suggests that there may be an RA-susceptibility gene at this locus. The significant increased frequency of an identical haplotype in PSS suggests the FcγR genetic locus may contribute to the pathogenesis of diverse autoantibody-mediated rheumatic diseases

3-dimensional bone shape and knee osteoarthritis: What have we learned?

The concept that multiple joint tissues are involved in the osteoarthritis (OA) disease process is now widely accepted. There have been significant and important insights over the past two decades in the understanding of bone as a tissue undergoing pathological changes in OA. The specific bony changes of osteophyte growth and “bone attrition” associated with OA have been recognized for many years with several semi-quantitative radiographic and magnetic resonance imaging (MRI) grading systems designed to capture the magnitude of these changes. Over the past decade, there has been significant and important progress in the quantitative measurement of these changes. Manual methods for measuring bone area from 3D MR images have been improved with automation which offers both superior precision and a more responsive measurement that has been applied in several DMOAD randomized controlled trials. Measurement of true 3D bone shape, as opposed to simple geometric measures such as curvature and length, depends on automated methods of segmentation. In this field, important developments have taken place in the statistical parameterization of shape and the construction of OA vs non-OA shape metrics. Work has demonstrated that bone shape may provide an indication of OA status, may predict future OA onset, and is associated with clinical markers of OA such as pain, function and total joint replacement (TKR). Thus, bone shape may be a useful imaging biomarker for OA

Synovial and systemic pharmacokinetics (PK) of triamcinolone acetonide (TA) following intra-articular (IA) injection of an extended-release microsphere-based formulation (FX006) or standard crystalline suspension in patients with knee osteoarthritis (OA)

Objective: Intra-articular (IA) corticosteroids relieve osteoarthritis (OA) pain, but rapid absorption into systemic circulation may limit efficacy and produce untoward effects. We compared the pharmacokinetics of IA triamcinolone acetonide (TA) delivered as an extended-release, microsphere-based formulation (FX006) vs a crystalline suspension (TAcs) in knee OA patients. Method: This Phase 2 open-label study sequentially enrolled 81 patients who received a single IA injection of FX006 (5 mL, 32mg delivered dose, N=63) or TAcs (1 mL, 40mg, N=18). Synovial fluid (SF) aspiration was attempted in each patient at baseline and one post-IA-injection visit (FX006: Week1, Week6, Week12, Week16 or Week20; TAcs: Week6). Blood was collected at baseline and multiple post-injection times. TA concentrations (validated LC-MS/MS, geometric means), pharmacokinetics (non-compartmental analysis models), and adverse events (AEs) were assessed. Results: SF TA concentrations following FX006 were quantifiable through Week12 (pg/mL: 231,328.9 at Week1; 3590.0 at Week6; 290.6 at Week12); post-TAcs, only 2 of 8 patients had quantifiable SF TA at Week6 (7.7 pg/mL). Following FX006, plasma TA gradually increased to peak (836.4 pg/mL) over 24 hours and slowly declined to <110 pg/mL over Weeks12-20; following TAcs, plasma TA peaked at 4 hours (9,628.8 pg/mL), decreased to 4,991.1 pg/mL at 24 hours, and was 149.4 pg/mL at Week6, the last post-treatment time point assessed. AEs were similar between groups. Conclusion: In knee OA patients, microsphere-based TA delivery via a single IA injection prolonged SF joint residency, diminished peak plasma levels, and thus reduced systemic TA exposure relative to TAcs

Targeting the TRPV1 pain pathway in osteoarthritis of the knee

Introduction: The growing prevalence and lack of effective pain therapies for knee osteoarthritis (KOA) results in a substantial unmet need for novel analgesic therapies. The transient receptor potential vanilloid 1 (TRPV1) receptor is expressed in subsets of nociceptive sensory neurons and has major roles in pain transmission and regulation. In the structures of the knee joint, nociceptors are present in abundance. Areas covered: TRPV1-expressing nociceptors in the knee represent a rational target to modulate activity at the origin of the pain pathway in KOA and may avoid systemic side effects seen with currently available analgesics. TRPV1 antagonists can induce analgesia, but hyperthermia and thermal hypesthesia side effects have limited their utility. Clinical development of TRPV1 agonists for pain management has progressed further than that of TRPV1 antagonists. Capsaicin and resiniferatoxin have provided proof-of-concept for the modulation of TRPV1 activity in KOA. Expert opinion: Intra-articular administration of TRPV1 agonists enables direct delivery to target nerve terminals in the knee, offering a potentially transformative approach for the management of pain associated with KOA. Here, we explore the advances in understanding innervation of the knee joint in KOA, the role of TRPV1-expressing neurons and progress in developing TRPV1 modulators for KOA

3D bone shape from CT-scans provides an objective measure of osteoarthritis severity: Data from the IMI-APPROACH study

Decisions regarding total knee arthroplasty are usually made using a patient's own assessment of pain and the structural disposition of the joint as seen on plain film radiographs. Pain severity can fluctuate, and radiographs can be misleading, with the apparent joint status affected by anatomical orientation. An important component of the surgical management of knee osteoarthritis (OA) is the timing of surgical intervention: knee arthroplasty performed too early in the course of the disease may increase the need for revision surgery. Femoral 3D bone shape (B-score) from MR images is an objective measure of OA severity and has been correlated with current and future risk of pain. We aimed to derive the B-score from CT images and compare it against the B-score derived from MR images. We used baseline and 24-month image data from the IMI-APPROACH 2-year prospective cohort study, comprising pairs of CT and MR images taken for each subject-timepoint. The femur was automatically segmented in both CT and MR modalities using an active appearance model, a machine-learning method, to measure the B-score. Linear regression was used to test for correlation between measures. Limits of agreement and bias were tested using Bland-Altman analysis. CT-MR pairs of the same knee were available from 424 participants (78 % women). B-scores from CT and MR were strongly correlated (CCC = 0.980) with negligible bias of 0.0106 (95 % CI: −0. 0281, +0.0493). The strong correlation and small B-score bias suggests that B-scores may be measured reliably using CT images. Since CT images are used in planning robot-assisted knee arthroplasty, with further study B-scores derived from CT surgical planning images could in principle provide a useful objective input to deciding the appropriateness, timing and type of knee arthroplasty

Shoulder Symptom Trajectories Over Four Years: Data From a Longitudinal Study on Osteoarthritis

Objective Limited data exist on the natural history of shoulder symptoms. We aimed to describe longitudinal patterns of shoulder symptoms and determine risk factors for incidence and persistence. Methods Data from Osteoarthritis Initiative participants observed annually for four years were used to describe shoulder symptom (yes/no, side) incidence and prevalence using descriptive analyses. Regression analyses investigated the association among three shoulder symptoms outcomes (persistent, incident, and intermittent) and clinical factors. Latent class growth analysis (LCGA) identified trajectories in those reporting pain at one or more time point. Results In total, 4,796 participants (58% women, mean age 61.2 years) were included. Baseline shoulder symptom prevalence was 22%; 32% of these reported bilateral symptoms. In those reporting right symptoms, 260 of 1,886 (14%) had persistent symptoms. Those with persistent symptoms had worse baseline and four-year clinical status (poorer function, mental health, and quality of life). In regression analysis, persistent symptoms were associated with sleep disturbance (adjusted odds ratio [aOR] 1.97, 95% confidence interval [95% CI] 1.49–2.62), work absenteeism (aOR 2.16, 95% CI 1.38–2.62), lower limb weakness (aOR 1.76, 95% CI 1.37–2.27), multiple-site joint symptoms (≥3 joints excluding shoulders) (aOR 4.90, 95% CI 2.79–8.58) and White race (aOR 1.39, 95% CI 1.04–1.88). Lower limb weakness was also associated with incident symptoms; no variables were associated with intermittent symptoms. LCGA identified two trajectories: the trajectory with high probability for symptoms (9% of LCGA analysis cohort) showed similar relationships to clinical variables as in the persistent symptoms group. Conclusion In this large, four-year study, persistent shoulder symptoms were common and associated with worse clinical outcomes. At least one risk factor for incident symptoms is modifiable

Effectiveness and safety of polyacrylamide hydrogel injection for knee osteoarthritis: results from a 12-month follow up of an open-label study

Objective: There are few effective osteoarthritis (OA) therapies. A novel injectable polyacrylamide hydrogel (iPAAG) previously demonstrated efficacy and safety up to week 26 in an open-label study of knee OA. Here we report longer-term effectiveness and safety data. Methods: This multi-centre, open-label study included patients with symptomatic and radiographic knee OA. Primary outcome was WOMAC pain (0–100 scale) at 13 weeks, and patients continued to 26 weeks before entering a further 26-week extension phase. Secondary efficacy outcomes included WOMAC stiffness and function subscales, Patient Global Assessment (PGA) and proportion of OMERACT-OARSI responders. Safety outcomes were adverse events (AEs). Results: 49 participants (31 women, mean age 70) received an ultrasound-guided, intra-articular injection of 6 ml iPAAG; 46 completed the extension phase to 52 weeks. There was a significant reduction in the WOMAC pain score from baseline to 52 weeks (− 17.7 points (95% CI − 23.1; − 12.4); p < 0.0001). Similar sustained improvements were observed for WOMAC stiffness (11.0 points; 95% CI − 17.0; − 4.9), physical function (18.0 points; 95% CI − 19.1; − 10.6), and PGA (16.3 points; 95% CI − 23.1; − 9.4). At 52 weeks 62.2% of patients were OMERACT-OARSI responders. From 26 to 52 weeks, 8 adverse effects (AE), including 1 serious AE (cerebrovascular accident) were reported in 5 subjects. None of the new adverse events were thought to be device related. Conclusion: This open-label study suggests persistent benefits and safety of iPAAG through 52 weeks after a single injection. Trial registration: Clinicaltrials.gov NCT04179552

Primary care prediction of hip and knee replacement 1-5 years in advance using temporal graph-based convolutional neural networks (TG-CNNs)

Objective This study aimed to predict the risk of requiring a primary hip or knee replacement 1 and 5-years in advance, using Clinical Codes. Methods Primary care clinical codes, sourced from ResearchOne Electronic Health Records (EHRs) between 1999–2014, were used to represent patient pathways prior to hip or knee replacement. Patient records were used to train and test models for hip or knee replacement, 1 and 5-years in advance. Temporal graphs were constructed from clinical codes to predict hip and knee replacement risk, where nodes are clinical codes, and edges are the time between primary care visits. Hip and knee replacement cases were matched to controls by age, sex, and Index of Multiple Deprivation (IMD). The model was validated on unseen data, with performance measured using area under the receiver operator curve (AUROC), calibration, and area under the precision recall curve (AUPRC), recalibrating for class imbalance. Results For knee replacement prediction, AUROC was 0.915 (95% CI: 0.914, 0.916) (1-year) and 0.955 (95% CI: 0.954, 0.956), (5-year) with AUPRCs of 0.353 (95% CI: 0.302, 0.403) and 0.442 (95% CI: 0.382, 0.503), respectively. For hip replacement prediction, AUROC was 0.919 (95% CI: 0.918, 0.920) (1-year) and 0.967 (95% CI: 0.966, 0.968) (5-year), with AUPRCs of 0.409 (95% CI: 0.366, 0.451) and 0.879 (95% CI: 0.833, 0.924), respectively. Conclusion Hip and knee replacement risk can be predicted up to 5-years in advance, with a temporal-graph based artificial intelligence (AI) model achieving the best performance. This may be used for planning preventative treatment or triaging patients

A comparison of quantitative and semi-quantitative methods for assessing cartilage status and change over time; data from the osteoarthritis initiative

Introduction The aim of this study was to compare the cross-sectional relationship and longitudinal responsiveness of the semi-quantitative MRI Osteoarthritis Knee Score (MOAKS) with automated quantitative cartilage thickness measures. Methods Images and MOAKS scores from 297 participants with evidence of radiographic progression (groups 1 and 2) from the OAI FNIH sub-cohort were included. To facilitate direct comparison, novel quantitative measures of cartilage loss (termed Q-MOAKS) were matched to MOAKS regions. Mean normative cartilage thickness was computed for each subregion using OAI non-OA controls. The Q-MOAKS thickness loss score was based on the proportion of cartilage thickness over a subregion that was < 95% normative thickness, the denudation score was based on < 5% normative thickness. Q-MOAKS area proportions were categorised into scores as for MOAKS. Quantitative cartilage thickness (ThCtAB) was also measured in MOAKS subregions. We compared MOAKS against Q-MOAKS and ThCtAB cross-sectionally using Spearman’s rank correlation and descriptive statistics including proportions and boxplots. Longitudinally, responsiveness was assessed at 1 and 2 years using standardised response means (SRM). Results Cross-sectionally, there was a poor correlation between MOAKS and Q-MOAKS thickness loss and denudation scores in all regions except central medial femur (cMF) and tibia (cMT) with moderate correlation for thickness loss scores: cMF, ρ = 0.59, (95%CI:0.51, 0.66) cMT, ρ = 0.58, (0.50, 0.65). In cMF, despite the broad range for the MOAKS thickness loss score = 2 (10–75% region surface area), only 56% (89/159) of knees were Q-MOAKS = 2 and 23% of MOAKS denudation = 2 were represented in Q-MOAKS = 2. In cMT, the results for similar comparisons were 61% and 66% respectively. MOAKS appeared to overestimate grades 2 and 3. Over 2-year follow-up MOAKS thickness loss and denudation scores were less responsive than Q-MOAKS in most subregions. MOAKS thickness loss was most responsive in cMT (SRM = 0.47, (95%CI:0.41, 0.54)). ThCtAB was substantially more responsive: SRM=-0.84, (-0.96, -0.73) in this region. Conclusion Though MOAKS status scores showed reasonable correlation with quantitative measures of thickness in medial compartments, concordance between MOAKS and quantitative cartilage area loss was poor. Quantitative measures of thickness loss were substantially more responsive then MOAKS scores over a 1 and 2-year period