[Show abstract][Hide abstract] ABSTRACT: Gelatinous Heberden's nodes (HNs), also termed synovial cysts, are a common form of generalised osteoarthritis (OA). We sought to determine if HN cases at clinical presentation contained multipotential stromal cells (MSCs), and to explore whether such cells were more closely related to bone marrow (BM) or synovial fluid (SF) MSCs by transcriptional analysis.
Arthritis research & therapy. 06/2014; 16(3):R119.
[Show abstract][Hide abstract] ABSTRACT: The aims of this study were to investigate the extent of MRI-determined joint disease (erosion and synovitis) in SLE and to link this to autoantibody profiles known to be relevant to SLE, including ACPA, RF and anti-RA33 antibodies.
[Show abstract][Hide abstract] ABSTRACT: To monitor progression to inflammatory arthritis (IA) in individuals with non-specific musculoskeletal (MSK) symptoms and positive anticyclic citrullinated peptide (anti-CCP) antibodies. To develop a pragmatic model to predict development of IA in this patient group.
In this prospective observational cohort, patients with new non-specific MSK symptoms and positive anti-CCP were recruited from regional primary care and secondary care referrals. Clinical, imaging and serological parameters were assessed at baseline. Cox regression analysis was performed to identify predictors of progression to IA and develop a risk score to stratify patients at presentation.
100 consecutive patients (73 women, mean age 51 years) were followed up for median 19.8 months (range 0.1-69.0); 50 developed IA after a median 7.9 months (range 0.1-52.4), 34 within 12 months. The majority (43/50) fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism criteria for rheumatoid arthritis. A model for progression to IA was devised using four variables: tenderness of hand or foot joints, early morning stiffness ≥30 min, high-positive autoantibodies, and positive ultrasonographic power Doppler signal. None of the five individuals at low risk (score 0) progressed to IA, compared with 31% of 29 at moderate risk (1-2) and 62% of 66 at high risk (≥3). Adding shared epitope increased the number at low risk (score 0-1; 0/11 progressed).
In patients presenting with non-specific MSK symptoms and anti-CCP, the risk of progression to IA could be quantified using data available in clinical practice. The proposed risk score may be used to stratify patients for early therapeutic intervention.
NCT02012764 at ClinicalTrials.gov.
Annals of the rheumatic diseases 04/2014; · 8.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aim: To enumerate and characterize multipotential stromal cells (MSCs) in a cellular bone allograft and compare with fresh age-matched iliac crest bone and bone marrow (BM) aspirate. Materials & methods: MSC characterization used functional assays, confocal/scanning electron microscopy and whole-genome microarrays. Resident MSCs were enumerated by flow cytometry following enzymatic extraction. Results: Allograft material contained live osteocytes and proliferative bone-lining cells defined as MSCs by phenotypic and functional capacities. Without cultivation/expansion, the allograft displayed an 'osteoinductive' molecular signature and the presence of CD45(-)CD271(+)CD73(+)CD90(+)CD105(+) MSCs; with a purity over 100-fold that of iliac crest bone. In comparison with BM, MSC numbers enzymatically released from one gram of cellular allograft were equivalent to approximately 45 ml of BM aspirate. Conclusion: Cellular allograft bone represents a unique nonimmune material rich in MSCs and osteocytes. This osteoinductive graft represents an attractive alternative to autograft bone or composite/synthetic grafts in orthopedics and broader regenerative medicine settings.
Regenerative Medicine 03/2014; · 3.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The vast majority of literature pertaining to mesenchymal stem cells (MSC) immunomodulation has focussed on bone marrow derived MSC that are systemically infused to alleviate inflammatory conditions. Rheumatoid arthritis (RA) is the commonest autoimmune joint disease that has witnessed significant therapeutic advances in the past decade, but remains stubbornly difficult to treat in a subset of cases. Preclinical research has demonstrated that bone marrow, adipose, synovial and umbilical cord derived MSC all suppress the functions of different immune cells thus raising the possibility of new therapies for autoimmune diseases including RA. Indeed, preliminary evidence for MSC efficacy has been reported in some cases of RA and Systemic Lupus Erythromatosis (SLE). The potential use of BM-MSC for RA therapy is emerging but the use of synovial MSC (S-MSC) to suppress the exaggerated immune response within the inflamed joints remains rudimentary. Synovial fibroblasts that are likely derived from S-MSCs, also give rise to a cell cultured progeny termed fibroblast like synoviocytes (FLS), which are key players in the perpetuation of joint inflammation and destruction. A better understanding of the link between these cells and their biology could be a key to developing novel MSC based strategies for therapy. The review briefly focuses on BM-MSC and gives particular attention to joint niche synovial MSC and FLS with respect to immunoregulatory potential therapy roles.
QJM: monthly journal of the Association of Physicians 02/2014; · 2.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hypervascularization in finger clubbing is recognized, but its microanatomical basis remains unclear. This pilot descriptive study used magnetic resonance imaging (MRI) to explore this further.
High-resolution MRI acquired with contrast agent was carried out in 4 patients with finger clubbing and 4 healthy volunteers. The anatomy of the nail bed, capsular structures, and bony changes were described.
Marked nail bed thickening and contrast enhancement was noted in all clubbed fingers, with bone edema in 3 of the 4 patients. None of the healthy subjects had similar abnormalities.
This confirms that hypervascularization of the nail bed observed in the microanatomy on high-resolution MRI is associated with clubbed appearances of the nails.
The Journal of Rheumatology 01/2014; · 3.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
This study explored posterior cruciate ligament (PCL) synovio-entheseal complex (SEC) microanatomy to determine whether it may participate in the early osteoarthritis (OA) disease process.
SEC microanatomy and OA features were evaluated in 14 non-arthritic cadaveric knees (mean age=69.9) using magnetic resonance imaging (MRI) and histology. MRI images of 49 subjects selected from the progression cohort of the Osteoarthritis Initiative were evaluated by a musculoskeletal radiologist using an original semi-quantitative method for features associated with OA at the PCL tibial enthesis. Statistical analysis was performed using chi-square and Wilcoxon signed-rank tests to evaluate associations between SEC configuration and OA features.
The PCL formed a SEC-like structure encompassing bone- and ligament-lining intra-articular cartilages to which the posterior root of the medial meniscus contributed. Degenerative features at the PCL-SEC included: neovascularisation (44%), enthesis chondrocyte clustering (44%), collagen matrix fissuring at the enthesis (56%) and in the PCL itself (67%), tidemark duplication (44%), bone remodelling (44%) and microscopic inflammatory changes (33%). In the OAI cohort, SEC-related pathology included BMLs (69%) and osteophytosis (94%) at locations that corresponded to SEC-related cartilages. Posterior joint recess effusion (49%) was linked to MRI abnormalities at PCL-SEC cartilages (χ2 =7.27, p = 0.007).
The PCL has a prominent SEC configuration that is associated with microscopic OA changes in aged clinically non-diseased joints. MRI determined knee OA commonly exhibited pathological features at this site which was associated with adjacent joint effusion. Thus, the PCL-SEC could play a hitherto unappreciated role in the early OA disease process.
Osteoarthritis and Cartilage 01/2014; · 4.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this work was to test whether normal peri-entheseal vascular anatomy at anterior and posterior cruciate ligaments (ACL and PCL) was associated with distribution of peri-entheseal bone erosion/bone marrow lesions (BMLs) in inflammatory arthritis (IA) and osteoarthritis (OA).
Normal microanatomy was defined histologically in mice and by 3 T MRI and histology in 21 cadaveric knees. MRI of 89 patients from the Osteoarthritis Initiative and 27 patients with IA was evaluated for BMLs at ACL and PCL entheses. Antigen-induced arthritis (AIA) in mice was evaluated to ascertain whether putative peri-entheseal vascular regions influenced osteitis and bone erosion.
Vascular channels penetrating cortical bone were identified in knees of non-arthritic mice adjacent to the cruciate ligaments. On MRI of normal cadavers, vascular channels adjacent to the ACL (64% of cases) and PCL (71%) entheses were observed. Histology of 10 macroscopically normal cadaveric specimens confirmed the location of vascular channels and associated subclinical changes including subchondral bone damage (80% of cases) and micro-cyst formation (50%). In the AIA model, vascular channels clearly provided a site for inflammatory tissue entry and osteoclast activation. MRI showed BMLs in the same topographic locations in both patients with early OA (41% ACL, 59% PCL) and IA (44%, 33%).
The findings show that normal ACL and PCL entheses have immediately adjacent vascular channels which are common sites of subtle bone marrow pathology in non-arthritic joints. These channels appear to be key determinants in bone damage in inflammatory and degenerative arthritis.
Annals of the rheumatic diseases 10/2013; · 8.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aim: To enumerate and characterize mesenchymal stem cells (MSCs) and endothelial cells (ECs) in umbilical cord (UC) tissue digests. Materials & methods: Cultured UC cells were characterized phenotypically, and functionally by using 48-gene arrays. Native MSCs and ECs were enumerated using flow cytometry. Results: Compared with bone marrow (BM) MSCs, UC MSCs displayed significantly lower (range 4-240-fold) basal levels of bone-related transcripts, but their phenotypes were similar (CD73(+), CD105(+), CD90(+), CD45(-) and CD31(-)). UC MSCs responded well to osteogenic induction, but day 21 postinduction levels remained below those achieved by BM MSCs. The total yield of native UC MSCs (CD90(+), CD45(-) and CD235α(-)) and ECs (CD31(+), CD45(-) and CD235α(-)) exceeded 150 and 15 million cells/donation, respectively. Both UC MSCs and ECs expressed CD146. Conclusion: While BM MSCs are more predisposed to osteogenesis, UC tissue harbors large numbers of MSCs and ECs; such minimally manipulated 'off-the-shelf' cellular mixtures can be used for regenerating bone in patients with compromised vascular supply.
Regenerative Medicine 09/2013; 8(5):569-81. · 3.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
To determine the prevalence, on magnetic resonance imaging (MRI), of bone marrow edema lesions in symptomatic axial psoriatic arthritis (PsA), and to compare this prevalence with that in nonradiographic axial spondyloarthritis (SpA) and ankylosing spondylitis (AS) and its relationship to HLA–B27 status. Methods
We performed a cross-sectional audit of MRI scans of lumbar spine (L-spine) and sacroiliac (SI) joints. Using the semiquantitative Leeds Scoring System in which bone marrow edema is graded from 0 to 3 according to severity of the lesions, MRI scans were scored independently by 2 expert readers who were blinded to the clinical characteristics of the patients. Concordant data from the 2 readers were used to report on definite lesions. ResultsMRIs from 76 patients with comparable age ranges were categorized into 3 groups: those from PsA patients, those from patients with nonradiographic axial SpA, and those from AS patients. HLA–B27 positivity was similar in PsA patients (10 of 33) and patients with nonradiographic axial SpA (10 of 24) and higher in AS patients (18 of 19). Total MRI scores (L-spine plus SI joints) were higher in AS patients than in PsA patients (P = 0.025) or in patients with nonradiographic axial SpA (P = 0.007). A relationship was seen between the severity and extent of disease and HLA–B27 positivity in PsA patients, which was comparable to that in AS patients. HLA–B27–negative PsA patients had lower MRI scores than HLA–B27–positive PsA patients (P = 0.03) and AS patients (P = 0.006), whereas scores were similar in HLA–B27–positive PsA patients and AS patients. Similarly, MRI scores of HLA–B27–negative patients with nonradiographic axial SpA were lower than those of AS patients (P = 0.01). ConclusionHLA–B27 positivity defines a group of patients with more severe axial bone marrow edema that is likely related to the classic AS phenotype. Clinically, HLA–B27–negative PsA is more likely to be reported as a “negative” MRI examination result.
[Show abstract][Hide abstract] ABSTRACT: Ultrasonography (US) and magnetic resonance imaging (MRI) are increasingly used imaging techniques for visualising entheses, however few studies have made a direct comparison of each. This study aimed to compare each technique for the detection of enthesitis in patients with spondyloarthritis (SpA) related knee swelling in order to make a lesion by lesion comparison.
Consecutive SpA patients with knee synovitis were recruited: each had clinical assessment for enthesitis at 8 sites in the involved knee joint followed by US and MRI examinations. Inflammatory and structural changes at tendon and ligament insertions were scored and a lesion by lesion comparison was made.
21 patients were recruited. Clinically defined involved knee joint enthesitis was evident in 18 of 21 (86%) patients in 61 of 168 (36%) evaluated sites. Clinical enthesitis was associated with more hypoechogenicity (16 vs. 4%, p=0.007) and thickening (16 vs. 6%, p=0.03) by US compared to non-tender sites. Considering all MRI findings only increased signal in the surrounding tissues was higher at tender sites (41 vs. 20%, p=0.01) and the insertions points themselves showed little abnormality. The positive agreements between individual lesions by both methods was very low (10-26%) with low kappa values (0.06-0.18) with no correlations between the MRI and US scores (r²= 0.059).
The difficulty in procuring 'gold standard' histological validation is synovial joints makes the assessment of enthesitis using clinical and current imaging protocols of limited utility for diagnostic purposes.
Clinical and experimental rheumatology 08/2013; · 2.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Psoriatic nail disease is increasingly recognised to be of major clinical and research relevance. Clinical assessment remains the current gold standard for its evaluation. Objective: We compared optical coherence tomography (OCT) and ultrasound (US) for nail disease assessment in psoriatic disease. Methods: 18 patients with at least one involved nail and 12 healthy controls were scanned using OCT; psoriatic patients also had an US scan (using a linear probe at 9-14 MHz). Nail and contour abnormalities were documented. Clinical onychopathy was scored independently using the modified Nail Psoriasis Severity Index. Results: Among 180 nails, 67.8% had clinical findings whereas 33.9% were abnormal by US and 44.4% had abnormalities on OCT. A positive OCT had a sensitivity and specificity of 44.4 and 95.8%, respectively, with a positive likelihood ratio of 10.7 for nail disease. OCT demonstrated 76.3% absolute agreement compared with clinical assessment and 65% with US. OCT detected subtle abnormalities in 12 clinically normal nails and in 41 nails with normal US findings. Conclusion: These findings show that OCT has a potential for the systematic characterisation of psoriatic nail changes and could be useful in diagnosis and more objective assessment of treatment response.
[Show abstract][Hide abstract] ABSTRACT: Surgically induced periosteal membrane holds great potential for the treatment of large bone defects representing a simple alternative to combinations of exogenous stem cells, scaffolds and growth factors. The purpose of this study was to explore the biological basis for this novel regenerative medicine strategy in man.
Eight patients with critical size defects were treated with the induced membrane (IM) technique. After membrane formation 1cm(2) biopsy was taken together with matched, healthy diaphyseal periosteum (P) for comparative analysis. Morphological characteristics, cell composition and growth factor expression were compared. Functional and molecular evaluation of mesenchymal stromal cell (MSC) activity was performed.
Both tissues shared similar morphology although IM was significantly thicker than P (p=0.032). The frequency of lymphocytes, pericytes (CD45(-)CD34(-)CD146(+)) and cells expressing markers consistent with bone marrow MSCs (CD45(-/low)CD271(bright)) were 31. 3 and 15.5-fold higher respectively in IM (all p=0.043). IM contained 3-fold more cells/gram of tissue with a similar proportion of endothelial cells (CD45(-)CD31(+)). Both expressed bone morphogenic protein 2, vascular endothelial growth factor and stromal derived factor 1 (SDF-1); key tissue regeneration mediators. Adherent expanded cells from both tissues had molecular profiles similar to bone marrow MSCs but cells from IM expressed greater than 2 fold relative abundance of SDF-1transcript compared to P (p=0.043).
The IM is a thick, vascularized structure that resembles periosteum with a cellular composition and molecular profile facilitating large defect repair and therefore may be described as an "induced-periosteum". This tissue offers a powerful example of in situ tissue engineering.
[Show abstract][Hide abstract] ABSTRACT: With increasing life expectancies and the desire to maintain active lifestyles well into old age, the impact of the debilitating disease osteoarthritis (OA) and its burden on healthcare services is mounting. Emerging regenerative therapies could deliver significant advances in the effective treatment of OA but rely upon the ability to identify the initial signs of tissue damage and will also benefit from quantitative assessment of tissue repair in vivo. Continued development in the field of quantitative MRI in recent years has seen the emergence of techniques able to probe the earliest biochemical changes linked with the onset of OA. Quantitative MRI measurements including T(1), T(2) and T(1ρ) relaxometry, diffusion weighted imaging and magnetisation transfer have been studied and linked to the macromolecular structure of cartilage. Delayed gadolinium-enhanced MRI of cartilage, sodium MRI and glycosaminoglycan chemical exchange saturation transfer techniques are sensitive to depletion of cartilage glycosaminoglycans and may allow detection of the earliest stages of OA. We review these current and emerging techniques for the diagnosis of early OA, evaluate the progress that has been made towards their implementation in the clinic and identify future challenges in the field.
The British journal of radiology 03/2013; 86(1023):20120163. · 2.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Skin involvement is of major prognostic value in systemic sclerosis (SSc) and often the primary outcome in clinical trials. Nevertheless, an objective, validated biomarker of skin fibrosis is lacking. Optical coherence tomography (OCT) is an imaging technology providing high-contrast images with 4 μm resolution, comparable with microscopy ('virtual biopsy'). The present study evaluated OCT to detect and quantify skin fibrosis in SSc. METHODS: We performed 458 OCT scans of hands and forearms on 21 SSc patients and 22 healthy controls. We compared the findings with histology from three skin biopsies and by correlation with clinical assessment of the skin. We calculated the optical density (OD) of the OCT images employing Matlab software and performed statistical analysis of the results, including intraobserver/interobserver reliability, employing SPSS software. RESULTS: Comparison of OCT images with skin histology indicated a progressive loss of visualisation of the dermal-epidermal junction associated with dermal fibrosis. Furthermore, SSc affected skin showed a consistent decrease of OD in the papillary dermis, progressively worse in patients with worse modified Rodnan skin score (p<0.0001). Additionally, clinically unaffected skin was also distinguishable from healthy skin for its specific pattern of OD decrease in the reticular dermis (p<0.001). The technique showed an excellent intraobserver and interobserver reliability (intraclass correlation coefficient >0.8). CONCLUSIONS: OCT of the skin could offer a feasible and reliable quantitative outcome measure in SSc. Studies determining OCT sensitivity to change over time and its role in defining skin vasculopathy may pave the way to defining OCT as a valuable imaging biomarker in SSc.
Annals of the rheumatic diseases 02/2013; · 8.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective. This study used high-resolution PET to explore the pattern of DIP joint bone metabolism to test the hypothesis that the nail was functionally integrated with the bone, based on patterns of distal phalange (DP) bone metabolism in PsA compared with OA and normal joints.Methods. A total of 234 DIP joints were scanned in 30 subjects (10 PsA, 10 OA, 10 healthy control) with [(18)F]fluoride using the quad-high-density avalanche chamber nano PET scanner. The images were assessed blinded to diagnosis and symptoms for site and intensity of increased [(18)F]fluoride uptake.Results. [(18)F]fluoride uptake in the DP was strong relative to the intermediate phalange in both PsA and OA. In PsA there was a trend for uptake to occur in a diffuse pattern involving the entire DP. There was also greater uptake at the enthesis, the periosteum and at the tufts of the DP of PsA compared with OA. In OA, uptake was greatest in the subchondral region adjacent to known sites of osteophytosis and erosions. Both PsA and OA joints with uptake at the subchondral or periosteal bone are likely to be more symptomatic.Conclusion. This exploratory study suggested diffuse increased bone metabolism involving the entire DP, periosteum and entheses, especially in PsA. The subchondral bone and periosteum at the DP have large concentrations of enthesis attachments, including attachments from the nail, supporting the concept of an integrated nail and joint apparatus leading to a wide area of abnormal bone metabolism in PsA.