Laura A. Rhodes

Mode of action of abatacept in rheumatoid arthritis patients having failed tumour necrosis factor blockade: a histological, gene expression and dynamic magnetic resonance imaging pilot study.

Objectives: Abatacept is the only agent currently approved to treat rheumatoid arthritis (RA) that targets the co-stimulatory signal required for full T-cell activation. No studies have been conducted on its effect on the synovium, the primary site of pathology. The aim of this study was to determine the synovial effect of abatacept in patients with RA and an inadequate response to tumour necrosis factor alpha (TNFα) blocking therapy. Methods: This first mechanistic study incorporated both dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and arthroscopy-acquired synovial biopsies before and 16 weeks after therapy, providing tissue for immunohistochemistry and quantitative real-time PCR analyses. Results: Sixteen patients (13 women) were studied; all had previously failed TNFα-blocking therapy. Fifteen patients completed the study. Synovial biopsies showed a small reduction in cellular content, which was significant only for B cells. The quantitative PCR showed a reduction in expression for most inflammatory genes (Wald statistic of p<0.01 indicating a significant treatment effect), with particular reduction in IFNγ of −52% (95% CI −73 to −15, p<0.05); this correlated well with MRI improvements. In addition, favourable changes in the osteoprotegerin and receptor activator of nuclear factor kappa B levels were noted. DCE–MRI showed a reduction of 15–40% in MRI parameters. Conclusion: These results indicate that abatacept reduces the inflammatory status of the synovium without disrupting cellular homeostasis. The reductions in gene expression influence bone positively and suggest a basis for the recently demonstrated radiological improvements that have been seen with abatacept treatment in patients with RA.

Magnetic resonance imaging in the assessment of metacarpophalangeal joint disease in early psoriatic and rheumatoid arthritis

Objectives: The aim of this study was to determine whether magnetic resonance imaging (MRI)‐related entheseal changes including osteitis and extracapsular oedema could be used to differentiate between metacarpophalangeal (MCP) joint involvement in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Methods: Twenty patients (10 each with early RA and PsA) had dynamic contrast‐enhanced MRI (DCE‐MRI) of swollen MCP joints. Synovitis and tenosynovitis was calculated using quantitative analysis including the degree and kinetics of enhancement of gadolinium diethylenetriaminepentaacetic acid (Gd‐DTPA). Periarticular bone erosion and bone oedema were scored using the Outcome Measures in Rheumatology Clinical Trials (OMERACT) proposals. Entheseal‐related features including extracapsular soft tissue enhancement or regions of diffuse bone oedema were also evaluated. Results: MRI was not able to differentiate at the group level between both cohorts on the basis of entheseal‐related disease but a subgroup of PsA patients had diffuse extracapsular enhancement (30%) or diffuse bone oedema (20%). The RA patient group had a greater degree of MCP synovitis (p<0.0001) and tenosynovitis than PsA patients (p<0.0001). There were no significant differences in either the total number of erosions (p = 0.315) or the presence of periarticular bone oedema (p = 0.105) between the groups. Conclusion: Although conventional MRI shows evidence of an enthesitis‐associated pathology in the MCP joints in PsA, this is not sufficiently common to be of diagnostic utility.

Efficacy of infliximab on MRI-determined bone oedema in psoriatic arthritis

Background: Psoriatic arthritis (PsA) is commonly associated with bone pathology, including entheseal new bone formation and osteolysis. On MRI, areas of active clinical involvement are represented by bone oedema and synovitis. Aim: To assess the impact of infliximab on bone oedema in PsA as shown by MRI. Methods: 18 patients with joint swelling, psoriasis and seronegativity for rheumatoid factor received four infusions of infliximab, 3 mg/kg, in combination with methotrexate. MRI of the affected hand (12 patients) or knee joints (6 patients) was performed before and after treatment. The primary outcome was the assessment of bone oedema and synovitis at 20 weeks as shown by MRI. Secondary outcomes included the American College of Rheumatology (ACR) response criteria, psoriasis skin scores (Psoriasis Area and Severity Index (PASI)) and a quality of life measure (Psoriatic Arthritis Quality of Life (PsAQoL)). Results: At baseline, bone oedema was seen in 50% of patients (seven hands and two knees) in 30% of scanned joints, and this improved or resolved in all cases in the hand joints (p = 0.018) and in one knee joint at 20 weeks. Synovitis was found to be reduced in 90% of cases on MRI. Likewise, a significant improvement in all clinical outcomes, including PASI (p = 0.003) and PsAQoL (p = 0.006) was seen at week 20. 65% (n = 11) of the patients achieved an ACR response, of whom 45% had ACR70 or above and 54% had ACR20 or ACR50. Conclusions: Infliximab treatment is associated with dramatic improvements in MRI-determined bone oedema in PsA in the short term. It remains to be determined whether infliiximib treatment is the cause for prevention of new bone formation, bone fusion or osteolysis in PsA as shown by radiography.

Quantifying peri-meniscal synovitis and its relationship to meniscal pathology in osteoarthritis of the knee

Abstract The objectives of this study were to validate a semiquantitative scoring system for estimating perimeniscal synovitis in osteoarthritic (OA) knees and to examine the relationship between the extent of synovitis and the degree of meniscal pathology using gadolinium-enhanced magnetic resonance imaging (MRI). Forty-three subjects with clinically diagnosed OA knee were assessed for peri-meniscal synovitis using gadolinium-enhanced MRI. Quantitative measurements of synovitis were made by summing areas in consecutive slices within generated regions of interest, and the synovitis was also scored semi-quantitatively using a 0–3 scale. Meniscal pathology (extrusion, degeneration and tearing) was also scored semiquantitatively. Establishment of a correlative relationship was undertaken using Spearman’s rho (ρ). A total of 86 sites were assessed. The semi-quantitative synovitis score correlated well with the quantitative synovitis score (ρ>0.9). A moderate association between medial meniscal extrusion and synovitis was demonstrated (ρ=0.762, P<0.000), although this association was not as strong in the lateral compartment (ρ=0.524, P<0..000). The results suggest the semiquantitative scoring system is valid for assessing perimeniscal synovitis. The relationship between meniscal pathology and adjacent synovitis requires further study.

In vivo precision of dual-energy X-ray absorptiometry-derived hip structural analysis in adults.

Precision is integral to the monitoring of bone mineral density (BMD) change using dual-energy X-ray absorptiometry (DXA). Hip structural analysis (HSA) is a relatively recent method of assessing cross-sectional geometrical strength from the 2-dimensional images produced by DXA scans. By performing serial scans, we evaluated the in vivo precision of DXA-derived HSA in adults using a GE Lunar iDXA absorptiometer (GE Medical Systems, Madison, WI) in males and females (n=42), mean age of 34.5 (standard deviation [SD]: 8.5; range: 19.3-52.6)yr with a heterogeneous sample. Two consecutive intelligent DXA (iDXA) scans with repositioning of both femurs were conducted for each participant. The coefficient of variation, root-mean-square (RMS) averages of SD, and hence the least significant change (95%) were calculated. We found a high level of precision for BMD measurements of both the total hip and femoral neck, with RMS-SD=0.006 and 0.010 g/cm(2) and percent coefficient of variation (%CV)=0.52% and 0.94%, respectively. We also found good precision for HSA-derived geometrical properties, including sectional modulus, cross-sectional moment of inertia, and cross-sectional area, with %CV (average of the left and right sides) at 4.48%, 3.78%, and 3.13%, respectively. Precision was poorer for buckling ratio and femoral strength index with %CV 28.5% and 9.25%, respectively. The iDXA provides high precision for BMD measurements and with varying levels of precision for HSA geometrical properties.

Cross-calibration of a GE iDXA and Prodigy for Total and Regional Body Bone Parameters: The Importance of Using Cross-calibration Equations for Longitudinal Monitoring After a System Upgrade

We aimed to determine if cross-calibration equations could be applied to convert GE Lunar Prodigy total and regional bone measurements to the GE iDXA model to support longitudinal monitoring of subjects. The cross-calibration group comprised 63 adults (age 45.1 [12.8] yr; body mass index: 25.6 [3.7] kg/m(2)) and the validation group comprised 25 adults (age 40.5 [11.5] yr; body mass index: 25.7 [3.5] kg/m(2)). The parameters reported were total and regional bone mineral density (BMD), bone mineral content, and bone area. There were significant differences between densitometers for all anatomical regions and reported bone parameters (p < 0.0001); iDXA reported lower BMD than the Prodigy apart from the ribs. Linear regression indicated good agreement for all measurements. Bland-Altman analyses indicated significant bias for all measurements and that cross-calibration equations were required. The derived cross-calibration equations were effective in reducing differences between predicted and measured results for each parameter and at each region apart from leg BMD, where the difference remained significant (0.013 g/cm(2); p < 0.05). Our results indicate that cross-calibration is important to maintain comparability of total body-derived regional bone measurements between the Lunar Prodigy and iDXA.

High Resolution Magnetic Resonance Imaging of Excised Atherosclerotic Carotid Tissue: The Effects of Specimen Temperature on Image Contrast

Previous Magnetic Resonance (MR) studies of carotid endarterectomy (CEA) specimens have been directed at interpreting image contrast to determine plaque composition and stability. Such studies may give misleading results since it is believed that the acquired MR data is affected by the conditions used to store the excised tissue. This has been investigated in a high-resolution imaging study of the changes in contrast occurring with a change in specimen temperature. MR images were acquired from 20 CEA specimens. The initial MR examination was made within four hours of excision in tissue maintained and imaged at body temperature. Specimens were subsequently cooled and then re-examined at different times. The MR data was interpreted by comparison with histology obtained from equivalent sections. With the exception of signals arising from blood, changes in MR image contrast occurring in the 24-hour period after the CEA were relatively slight. Plaque lipid T2-weighted image intensity was initially relatively hyperintense in some samples and decreased with time on cooling reflecting a decrease in the lipid transverse (T2) relaxation time. High-resolution imaging allowed a detailed description of plaque calcification and showed that clot retraction was probably responsible for the marked change in the distribution of signals assigned to intraluminal blood. The use of high-resolution MR imaging to examine freshly excised specimens at body temperature showed previously unreported image features. This is important in the design of in vivo MR studies directed at assessing plaque stability by identifying the composition of the atheromatous tissue.

The body composition monitor: a flexible tool for routine fluid management across the haemodialysis population

Bioimpedance measurements with the Body Composition Monitor (BCM) have been shown to improve fluid management in haemodialysis. However, there is a lack of a sufficiently robust evidence-base for use of the BCM outside of standard protocols. This study aims to characterise BCM measurement variation to allow users to make measurements and interpret the results with confidence in a range of clinical scenarios. BCM measurements were made in 48 healthy controls and in 48 stable haemodialysis patients before and immediately after dialysis. The effect of utilising alternative measurement paths was assessed using mixed effects models and the effect of measuring post-dialysis was assessed by comparing changes in BCM-measured overhydration (OH) with weight changes over dialysis. The data from healthy controls suggest that there is no difference in BCM-measured OH between all the whole-body paths other than the foot-to-foot measurement. Dialysis patients showed similar results other than having higher BCM-measured OH when measured across the site of a vascular access. There was good agreement between BCM-measured OH and change in weight, suggesting post-dialysis measurements can be utilised. These results suggest BCM protocols can be flexible regarding measurement paths and timing of measurement to ensure as many patients as possible can benefit from the technology.

Resonant cavity perturbation: a promising new method for the assessment of total body water in children.

The accurate measurement of total body water (TBW) in children has important clinical and nutritional applications. Resonant cavity perturbation (RCP) is a new method for estimating TBW. This method measures the dielectric properties of the body which are related to body water. For RCP measurements, each subject lay supine on a bed inside a screened room which acts as a resonant cavity. A network analyser measures the frequencies of two low-order cavity resonances of the room, with electric-field vectors that were respectively vertical and horizontal, the resonant frequency shifts relative to the empty room are then derived. These frequency shifts correlates with TBW. The aims of this present study were to (a) develop TBW(RCP) predictive equations for children using TBWdil as the criterion method, (b) cross-validate the derived equations, (c) determine precision of the TBW(RCP) method, and (d) compare the criterion method TBWdil with three methods of estimating TBW: RCP, MFBIS and anthropometry.Predictive equations, independent of sex, were developed with linear regression in a group of 36 children. The relationship between combined RCP frequency shifts and TBWdilution had an r2  =  0.90 and standard error of the estimate (SEE)  =1.42 kg. Multiple regression analysis, that included a term for body mass index, only had a small effect on r2  =  0.93 and SEE  =  1.25 kg. In vivo TBW precision for the vertical, horizontal and combined frequency modes ranged from 0.7 to 3.4%. Bland-Altman analysis indicated close agreement between the criterion method TBWdil and the three other methods of TBW estimation. Mean differences were TBW(RCP(2))  =  0.01  ±  /-  1.34 kg, TBW(MFBIS)  =  0.45  ±  /-  1.35 kg, TBWAnthropometry  =  0.29  ±  /-  1.29 kg.Currently the RCP method does not significantly improve the prediction of TBW compared to MFBIS and anthropometry in this initial study. However the derived equation was independent of sex and body size had only a small effect.