Martyn Snow

Association of circulating miR-223 and miR-16 with disease activity in patients with early rheumatoid arthritis

Background Identification of parameters for early diagnosis and treatment response would be beneficial for patients with early rheumatoid arthritis (ERA) to prevent ongoing joint damage. miRNAs have features of potential biomarkers, and an altered expression of miRNAs was shown in established rheumatoid arthritis (RA). Objective To analyse RA associated miRNAs in the sera of patients with ERA to find markers of early disease, clinical activity or predictors of disease outcome. Methods Total RNA was isolated from whole sera in ERA patients (prior to and after 3 and 12 months of therapy with disease modifying antirheumatic drugs), in patients with established RA and in healthy controls (HC) using phenol–chloroform extraction. Expression of miR-146a, miR-155, miR-223, miR-16, miR-203, miR-132 and miR-124a was analysed by TaqMan Real Time PCR. Results From all analysed miRNAs, levels of miR-146a, miR-155 and miR-16 were decreased in the sera of ERA patients in comparison with established RA. A change in circulating miR-16 in the first 3 months of therapy was associated with a decrease in DAS28 in long term follow-up in ERA (p=0.002). Levels of circulating miR-223 in treatment naïve ERA correlated with C reactive protein (p=0.008), DAS28 (p=0.031) and change in DAS28 after 3 months (p=0.003) and 12 months (p=0.011) of follow-up. However, neither miR-16 nor miR-223 could distinguish ERA from HC. Conclusions Differential expression of circulating miR-146a, miR-155 and miR-16 in the sera of ERA patients may characterise an early stage of the disease. We suggest miR-223 as a marker of disease activity and miR-16 and miR-223 as possible predictors for disease outcome in ERA.

Slap Tears of the Glenoid Labrum in Contact Athletes

Objective:To describe the distribution and clinical presentation of labral injuries in rugby players and the time taken for them to return to sports. Design:Retrospective cohort study. Setting:Busy shoulder practice in the North West of England, treating a large number of professional athletes. Patients:A review of 51 shoulder arthroscopies performed on professional rugby players over a 35 month period. All patients diagnosed with a SLAP lesion at arthroscopy were identified. Eighteen patients had a documented SLAP tear; this group represented our study population. Interventions:Arthroscopic debridement and/or stabilization was carried out for all labral injuries using Panaloc anchors and No. 2 PDS via a 2 portal technique. Main Outcome Measurements:Classification of injury, Satisfaction, Time to return to play. Results:The incidence of SLAP tears in our study population was 35%. There were 11 isolated SLAP tears (61%), 3 SLAP tears associated with a Bankart lesion (17%), 2 SLAP tears associated with a posterior labral lesion (11%), and 2 SLAP tears associated with an anterior and posterior labral injuries (11%). Of the 18 SLAP tears, 14 (78%) were type 2, 3 (17%) were type 3, and 1 (5%) was type 4. None of the patients with a SLAP tear presented with symptoms of instability. MR Arthrogram had a 76% sensitivity for detecting SLAP tears. By 6 months postsurgery, 89% of patients were satisfied. Patients with isolated SLAP tears were the quickest to return to sports, at an average of 2.6 months postsurgery. Conclusions:SLAP tears are a common injury in rugby players. These can often be diagnosed with MR arthrography. Arthroscopic repair is associated with excellent results and early return to sports.

Posterior Arthroscopic Capsular Release in Frozen Shoulder

PURPOSE The aims of our study were to assess the overall effectiveness of arthroscopic capsular release and to determine if the addition of a posterior capsular release had any benefit, particularly in relation to internal rotation. METHODS Forty-eight consecutive patients with primary or secondary frozen shoulder in whom conservative physiotherapy had failed were included in the study. Arthroscopic capsular release was performed in all cases. Group 1 had an anterior and inferior release only; group 2 included a posterior release. All data were collected prospectively. Constant-Murley functional scores were used to assess outcome. Overall satisfaction and patient reported outcomes were also measured. RESULTS The mean patient age was 51 years (range, 28 to 65 years), with no difference between the 2 groups. There were 27 patients in group 1 and 21 patients in group 2. The mean follow-up was 5 months. Etiology of the frozen shoulder was primary (22), diabetic (7), post-traumatic (7), and postoperative (11). Overall across both groups, there was a highly significant improvement in Constant score (P < .001) postoperatively. A similar pattern was noted in the range of motion (P < .001). The mean satisfaction score was 7 of 10 postoperatively. The patients reported overall outcome as much better (24), better (15), the same (1), and worse (4). There was no significant difference in Constant score between the 2 groups, and no significant difference in the improvement of the range of motion, in particular internal rotation. CONCLUSIONS We have shown an overall rapid significant improvement following arthroscopic capsular release for primary and secondary frozen shoulder. There was no significant difference in the overall outcome with the addition of a posterior release. LEVEL OF EVIDENCE Level III, therapeutic, retrospective comparative study.

Expression of FcRL4 defines a pro-inflammatory, RANKL-producing B cell subset in rheumatoid arthritis

Objectives The success of B cell targeting therapies has highlighted the importance of B cells in rheumatoid arthritis pathogenesis. We have previously shown that B cells in the RA synovium are capable of producing pro-inflammatory and bone-destructive cytokines including RANKL. Here we sought to characterise the nature and functional relevance of the RANKL-producing B cell subset in the RA synovium. Methods Synovial fluid and peripheral blood B cells from patients with RA were analysed by flow cytometry for markers of B cell differentiation and activation and for chemokine receptors. FcRL4+ and FcRL4− B cells sorted from synovial fluid were analysed for cytokine expression using Taqman low-density arrays. Synovial tissue biopsies obtained from patients with RA were analysed by immunofluorescence for CD20, RANKL and FcRL4. FCRL4 mRNA expression was determined in synovial tissue of RA patients and non-inflammatory control subjects by real-time PCR. Results RANKL-producing B cells in RA synovial tissue and fluid were identified as belonging to a distinct subset of B cells defined by expression of the transmembrane protein FcRL4. FcRL4+ B cells express a distinct combination of cytokines and surface proteins indicating a function distinct from that of FcRL4− B cells. Notably, FcRL4+ B cells expressed high levels of TNF-α and RANKL mRNA. Conclusions We have identified a novel pro-inflammatory B cell population in the RA synovium which is defined by expression of FcRL4 and responsible for RANKL production. This B cell population expresses high levels of CD20, and its removal by rituximab may contribute to the anti-inflammatory effect of this drug.

Expression of chemokines CXCL4 and CXCL7 by synovial macrophages defines an early stage of rheumatoid arthritis

Background and objectives For our understanding of the pathogenesis of rheumatoid arthritis (RA), it is important to elucidate the mechanisms underlying early stages of synovitis. Here, synovial cytokine production was investigated in patients with very early arthritis. Methods Synovial biopsies were obtained from patients with at least one clinically swollen joint within 12 weeks of symptom onset. At an 18-month follow-up visit, patients who went on to develop RA, or whose arthritis spontaneously resolved, were identified. Biopsies were also obtained from patients with RA with longer symptom duration (>12 weeks) and individuals with no clinically apparent inflammation. Synovial mRNA expression of 117 cytokines was quantified using PCR techniques and analysed using standard and novel methods of data analysis. Synovial tissue sections were stained for CXCL4, CXCL7, CD41, CD68 and von Willebrand factor. Results A machine learning approach identified expression of mRNA for CXCL4 and CXCL7 as potentially important in the classification of early RA versus resolving arthritis. mRNA levels for these chemokines were significantly elevated in patients with early RA compared with uninflamed controls. Significantly increased CXCL4 and CXCL7 protein expression was observed in patients with early RA compared with those with resolving arthritis or longer established disease. CXCL4 and CXCL7 co-localised with blood vessels, platelets and CD68+ macrophages. Extravascular CXCL7 expression was significantly higher in patients with very early RA compared with longer duration RA or resolving arthritis Conclusions Taken together, these observations suggest a transient increase in synovial CXCL4 and CXCL7 levels in early RA.

Arthroscopic treatment options for irreparable rotator cuff tears of the shoulder.

The management of patients with irreparable rotator cuff tears remains a challenge for orthopaedic surgeons with the final treatment option in many algorithms being either a reverse shoulder arthroplasty or a tendon transfer. The long term results of these procedures are however still widely debated, especially in younger patients. A variety of arthroscopic treatment options have been proposed for patients with an irreparable rotator cuff tear without the presence of arthritis of the glenohumeral joint. These include a simple debridement with or without a biceps tenotomy, partial rotator cuff repair with or without an interval slide, tuberplasty, graft interposition of the rotator cuff, suprascapular nerve ablation, superior capsule reconstruction and insertion of a biodegradable spacer (Inspace) to depress the humeral head. These options should be considered as part of the treatment algorithm in patients with an irreparable rotator cuff and could be used as either as an interim procedure, delaying the need for more invasive surgery in the physiologically young and active, or as potential definitive procedures in the medically unfit. The aim of this review is to highlight and summarise arthroscopic procedures and the results thereof currently utilised in the management of these challenging patients.

Defining the Role of the Tibial Tubercle–Trochlear Groove and Tibial Tubercle–Posterior Cruciate Ligament Distances in the Work-up of Patients With Patellofemoral Disorders

Background: The radiological work-up of patients with patellofemoral disorders continues to be debated. The interchangeability of the tibial tubercle–trochlear groove (TT-TG) distance between computed tomography (CT) and magnetic resonance imaging (MRI) has recently been questioned. In addition, a new measurement—the tibial tubercle–posterior cruciate ligament (TT-PCL) distance—has shown that not all patients with a pathological TT-TG distance (>20 mm) have lateralization of the tibial tubercle. Another factor to consider when looking at the position of the tibial tubercle is the knee joint rotation, defined as the angle between the femoral dorsal condylar line and the tibial dorsal condylar line. Purpose: To determine, with a larger population, if the TT-TG measurements can be used interchangeably between CT and MRI and to confirm the correlation between the TT-PCL and TT-TG distances in determining tibial tubercle lateralization. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: Patients with patellofemoral disorders and MRI and CT scans of the same knee (n = 141) were identified. The TT-PCL, the knee joint rotation, and TT-TG were measured independently by 2 fellowship-trained orthopaedic surgeons. Thirty measurements were repeated on a separate occasion to allow for an assessment of the intrarater reliability. The intraclass correlation coefficient (ICC) was used to assess reliability of the measurements. Results: The mean TT-TG was 4.16 mm less on MRI (P < .05), with the mean TT-TG ± SD being 17.72 ± 5.15 mm on CT (range, 6.97-31.33 mm) and 13.56 ± 6.07 mm on MRI (range, 2-30.04 mm). The ICC for each rater comparing the 2 imaging modalities was only fair (0.54 and 0.48). The mean TT-PCL measurement was 20.32 ± 3.45 mm (range, 10.11-32.01 mm) with excellent interobserver and intraobserver reliability (>0.75). Based on the TT-TG and TT-PCL measurements, 4 groups of patients can be established. When knee joint rotation is compared among groups, an increased TT-TG may result from true lateralization of the tibial tubercle, an increased knee joint rotation, or both. Conclusion: Based on a statistically significant mean difference (4.11 mm) and only a fair ICC (0.54 and 0.48) for raters comparing the 2 modalities, the measurements for the TT-TG cannot be used interchangeably between CT and MRI. Therefore, currently accepted values for TT-TG based on CT scans should not be applied to an MRI scan. The TT-PCL measurement is a measure of true lateralization of the tibial tubercle, while the TT-TG is an amalgamated measure of true lateralization and knee joint rotation.

Rotator cuff repair: a review of surgical techniques, animal models, and new technologies under development

Rotator cuff tears are the most common musculoskeletal injury occurring in the shoulder. Current surgical repair fails to heal in 20% to 95% of patients, depending on age, size of the tear, smoking, time of repair, tendon quality, muscle quality, healing response, and surgical treatments. These problems are worsened by the limited healing potential of injured tendons attributed to the presence of degenerative changes and relatively poor vascularity of the cuff tendons. Development of new techniques to treat rotator cuff tears requires testing in animal models to assess safety and efficacy before clinical testing. Hence, it is important to evaluate appropriate animal models for rotator cuff research with degeneration of tendons, muscular atrophy, and fatty infiltration similar to humans. This report reviews current clinical treatments and preclinical approaches for rotator cuff tear repair. The review will focus on current clinical surgical treatments, new repair strategies under clinical and preclinical development, and will also describe different animal models available for rotator cuff research. These findings and future directions for rotator cuff tear repair will be discussed.

The Basic Science of Bone Marrow Aspirate Concentrate in Chondral Injuries.

There has been great interest in bone marrow aspirate concentrate (BMAC) as a cost effective method in delivering mesenchymal stem cells (MSCs) to aid in the repair and regeneration of cartilage defects. Alongside MSCs, BMAC contains a range of growth factors and cytokines to support cell growth following injury. However, there is paucity of information relating to the basic science underlying BMAC and its exact biological role in supporting the growth and regeneration of chondrocytes. The focus of this review is the basic science underlying BMAC in relation to chondral damage and regeneration.

An In Vitro Comparison of the Incorporation, Growth, and Chondrogenic Potential of Human Bone Marrow versus Adipose Tissue Mesenchymal Stem Cells in Clinically Relevant Cell Scaffolds Used for Cartilage Repair

Aim To compare the incorporation, growth, and chondrogenic potential of bone marrow (BM) and adipose tissue (AT) mesenchymal stem cells (MSCs) in scaffolds used for cartilage repair. Methods Human BM and AT MSCs were isolated, culture expanded, and characterised using standard protocols, then seeded into 2 different scaffolds, Chondro-Gide or Alpha Chondro Shield. Cell adhesion, incorporation, and viable cell growth were assessed microscopically and following calcein AM/ethidium homodimer (Live/Dead) staining. Cell-seeded scaffolds were treated with chondrogenic inducers for 28 days. Extracellular matrix deposition and soluble glycosaminoglycan (GAG) release into the culture medium was measured at day 28 by histology/immunohistochemistry and dimethylmethylene blue assay, respectively. Results A greater number of viable MSCs from either source adhered and incorporated into Chondro-Gide than into Alpha Chondro Shield. In both cell scaffolds, this incorporation represented less than 2% of the cells that were seeded. There was a marked proliferation of BM MSCs, but not AT MSCs, in Chondro-Gide. MSCs from both sources underwent chondrogenic differentiation following induction. However, cartilaginous extracellular matrix deposition was most marked in Chondro-Gide seeded with BM MSCs. Soluble GAG secretion increased in chondrogenic versus control conditions. There was no marked difference in GAG secretion by MSCs from either cell source. Conclusion Chondro-Gide and Alpha Chondro Shield were permissive to the incorporation and chondrogenic differentiation of human BM and AT MSCs. Chondro-Gide seeded with BM MSCs demonstrated the greatest increase in MSC number and deposition of a cartilaginous tissue.