Which MR sequences should we use for the reliable detection and localization of bone marrow edema in spondyloarthritis?

OBJECTIVES: To assess the diagnostic confidence in detecting and localizing areas of bone marrow edema in the sacroiliac joint of patients with suspected spondyloarthritis using a single-plane method and comparing it with multiplanar unenhanced and enhanced methods. MATERIALS AND METHODS: Patients with clinical suspicion of spondyloarthritis undergoing an MRI of the sacroiliac joint were included in this retrospective study. To assess sacroiliitis, three methods were applied: single-plane (i.e., para-coronal STIR alone), multiplanar unenhanced (i.e., para-coronal STIR and para-axial PD-fs), and multiplanar enhanced method (i.e., para-coronal and para-axial post-contrast T1-fs). Two 4-point scales were used to evaluate, respectively, the diagnostic confidence in detection and localization of bone marrow edema. The distribution of certain and uncertain rating according to signal intensity and size of the lesions was also calculated. RESULTS: Seventy-four patients met the inclusion criteria. Both multiplanar methods increased the diagnostic confidence in detection (p < 0.001) and localization (p < 0.001) of sacroiliitis; no significant difference occurred between the multiplanar unenhanced and enhanced methods (p = 0.405 and p = 1.00, respectively, for detection and localization). A statistically significant difference between the distributions of certain and uncertain rating for detection based on the size and signal intensity of each lesion emerged (p = 0.006 and p < 0.001, respectively), whereas no statistically significant difference occurred for the confidence of localization (p = 0.452 and p = 0.694, respectively). CONCLUSIONS: The multiplanar methods increased the diagnostic confidence in detection and localization of sacroiliitis. The absence of a significant difference between the proposed unenhanced and enhanced methods suggests that contrast medium is not mandatory for the detection of sacroiliitis.

Contrast-enhanced MR imaging of hand and finger joints in patients with early rheumatoid arthritis: do we really need a full dose of gadobenate dimeglumine for assessing synovial enhancement at 3 T?

PURPOSE: To investigate the diagnostic value of a half dose compared with a full dose of gadobenate dimeglumine in the assessment of synovitis or tenosynovitis in the wrist and finger joints in patients with early rheumatoid arthritis (RA) and a disease activity score greater than 3.2. MATERIALS AND METHODS: With institutional review board approval and informed consent, 57 patients with early RA underwent 3-T magnetic resonance (MR) imaging with two different doses of contrast media. The contrast enhancement was measured in inflamed synovial tissue at half dose (0.05 mmol per kilogram of body weight) and at full dose (0.1 mmol/kg) by using T1-weighted sequences with fat saturation. The differences and the correlation of signal intensities (SIs) at half- and full-dose sequences were compared by using the paired t test and Pearson correlations. Image quality, Rheumatoid Arthritis MRI Score (RAMRIS), and tenosynovitis score on half- and full-dose images were compared by two observers using the Wilcoxon test. Interrater agreement was assessed by using κ statistics. RESULTS: A significant difference in SI was found between half-dose and full-dose gadobenate dimeglumine-enhanced synovial tissue (mean: 914.35 ± 251.1 vs 1022 ± 244.5, P < .001). Because the SI showed high correlation between the ratio at half dose and full dose (r = 0.875), the formula, ratio of synovial enhancement to saline syringe at full dose = 0.337 + 1.070 × ratio of synovial enhancement to saline syringe at half dose, can be used to convert the normalized value of half dose to full dose. However, no difference in RAMRIS (score 0 in 490 of 1026 joints; score 1 in 344; score 2 in 158; and score 3 in 34) or tenosynovitis scores in grading synovitis or tenosynovitis in image quality and in assessment of synovial enhancement was detected between half-dose and full-dose images (P = 1). CONCLUSION: Postcontrast synovial SIs showed high correlation between half dose and full dose, and image quality was rated identically. Therefore, half-dose gadobenate dimeglumine at 3-T MR imaging may be sufficient for assessing synovitis or tenosynovitis in early RA.

Value of self-performed joint counts in rheumatoid arthritis patients near remission.

INTRODUCTION: To determine the validity and reliability of patients' self-performed joint counts compared to joint counts by professional assessors in rheumatoid arthritis (RA) patients in different disease activity states. METHODS: In patients with established RA we determined the inter-rater reliability of joint counts performed by an independent evaluator and the patient using intraclass correlation (ICC), and agreement on activity in individual joints by kappa statistics. We also performed longitudinal analyses to assess consistency of assessments over time. Finally, we investigated the concordance of joint counts of different assessors in patients with different levels of disease activity. RESULTS: The reliability of patient self-performed joint counts was high when compared to independent objective assessment (ICC; 95%confidence interval (CI)) for the assessment of swelling (0.32; 0.15 to 0.46) and tenderness (0.75; 0.66 to 0.81), with higher agreement for larger joints (kappa: 0.57 and 0.45, respectively) compared to smaller joints (metacarpo-phalangeal joint (MCPs): 0.31 and 0.45; and proximal interphalangeal joint (PIPs): 0.22 and 0.47, for swelling and tenderness, respectively).Patients in remission according to the Simplified Disease Activity Index (SDAI ≤ 3.3) showed better concordance of the joint counts (swollen joint count (SJC) ties 25/37, tender joint count (TJC) ties 26/37) compared to moderate/high disease activity states (SDAI > 11; MDA/HDA: SJC ties 9/72, TJC ties 21/72). Positive and negative predictive values regarding the presence of SDAI remission were reasonably good (0.86 and 0.95, respectively). A separate training session for patients did not improve the reliability of joint assessment. The results were consistent in the longitudinal analyses. CONCLUSIONS: Self-performed joint counts are particularly useful for monitoring in patients having attained remission, as these patients seem able to detect state of remission.

Endothelial progenitor cells in cardiovascular disease and chronic inflammation: from biomarker to therapeutic agent.

The discovery of endothelial progenitor cells in the 1990s challenged the paradigm of angiogenesis by showing that cells derived from hematopoietic stem cells are capable of forming new blood vessels even in the absence of a pre-existing vessel network, a process termed vasculogenesis. Since then, the majority of studies in the field have found a strong association between circulating endothelial progenitor cells and cardiovascular risk. Several studies have also reported that inflammation influences the mobilization and differentiation of endothelial progenitor cells. In this review, we discuss the emerging role of endothelial progenitor cells as biomarkers of cardiovascular disease as well as the interplay between inflammation and endothelial progenitor cell biology. We will also review the challenges in the field of endothelial progenitor cell-based therapy.

Estimation of a numerical value for joint damage-related physical disability in rheumatoid arthritis clinical trials.

BACKGROUND: Joint damage is an important outcome in trials of rheumatoid arthritis (RA), usually assessed by Total Sharp Score (TSS). It is currently unknown how it translates numerically into disability by the Health Assessment Questionnaire (HAQ). OBJECTIVE: To determine the units of HAQ score corresponding to one TSS unit. METHODS: A short-term observational trial of glucocorticoids in RA (the 'BEst LIfe with Rheumatoid Arthritis' (BELIRA) trial) was evaluated, using randomised controlled clinical trial (RCT) data for confirmation. For each trial arm HAQ, TSS and the Simplified Disease Activity Index (SDAI) were assessed. Based on the hypothesis that short-term HAQ changes will mostly be due to changes of disease activity, activity HAQ (ACT-HAQ) at end point (EP) was determined and remaining disability defined as damage related (DAM-HAQ). Using TSS at EP, the HAQ units corresponding to a TSS unit were estimated. RESULTS: In BELIRA, one TSS unit corresponded to a mean of 0.017 HAQ units; to account for other causes of irreversible disability, the 25th percentile was used: 0.011 HAQ units/TSS unit. In RCT trial arms, the HAQ/TSS were similar (0.013 and 0.015 in established and early RA, respectively; 25th percentile: 0.010). The correlation between DAM-HAQ(EP) and TSS was r=0.829. Over 5 years, damage would amount to an increase of irreversible HAQ of 0.33 on placebo, 0.13 on disease-modifying antirheumatic drugs (DMARDs) and 0.03 on TNF inhibitors+methotrexate (MTX). CONCLUSION: An approach to estimate the numerical relationship between HAQ and damage as 0.01 HAQ points/TSS unit is presented, although the linear relationship may not be generally valid. This allows the assessment of functional correlates of radiographic changes in trials.

Quantification of synovitis in rheumatoid arthritis: do we really need quantitative measurement of contrast-enhanced ultrasound?

OBJECTIVE: The quantification of synovitis is of great significance for adequate therapy management and follow-up in patients with Rheumatoid Arthritis (RA). The purpose of this study was to validate a semi-quantitative Power Doppler (PD) scoring system by comparing the PD scores to the objective measurement of the synovial inflammation using dynamic contrast-enhanced Pulse-Inversion Harmonic Imaging (PIHI). MATERIALS AND METHODS: In 27 patients with RA, two radiologists performed semi-quantitative scoring of a PD examination, using a four-point scale from 0 to 3, in the metacarpophalangeal joints, proximal interphalangeal joints, and the wrists. The scores were compared to the area under the time-echo intensity curves obtained by contrast-enhanced PIHI examination. The interobserver agreement for PD scoring was evaluated using the Cohen's kappa test. RESULTS: Preliminary results showed that the area under the curve of dynamic measurements of PIHI tended to correlate with PD scores. The interobserver agreement for PD scoring was good (kappa=0.768). DISCUSSION: Based on comparisons with dynamic contrast-enhanced PIHI, semi-quantitative PD scoring might meet the criteria for a reliable, reproducible, and practical scoring system. Although further studies that would include a larger study population are required, our preliminary results show that PIHI may not provide a real benefit for quantification of synovitis in day-to-day practice.

The need for prognosticators in rheumatoid arthritis. Biological and clinical markers: where are we now?

Rheumatoid arthritis is a heterogeneous disease with respect to clinical manifestations, serologic abnormalities, joint damage and functional impairment. Predicting outcome in a reliable way to allow for strategic therapeutic decision-making as well as for prediction of the response to the various therapeutic modalities available today, especially biological agents, would provide means for optimization of care. In the present article, the current information on biological and clinical markers related to disease activity and joint damage as well as for predictive purposes is reviewed. It will be shown that the relationship of many biomarkers with disease characteristics is confounded by factors unrelated to the disease, and that only few biomarkers exist with some predictive value. Moreover, clinical markers appear of equal value as biomarkers for this purpose, although they likewise have limited capacity in these regards. The analysis suggests the search for better markers to predict outcomes and therapeutic responsiveness in rheumatoid arthritis needs to be intensified.

Endothelial progenitor cells in active rheumatoid arthritis: effects of tumour necrosis factor and glucocorticoid therapy.

OBJECTIVES: To study the effects of short-term intermediate dose glucocorticoid (GC) therapy in patients with active rheumatoid arthritis (RA) on circulating endothelial progenitor cells (EPC), which are known to influence cardiovascular risk, and to elucidate mechanisms potentially responsible for the reduction of EPCs in patients with active RA. METHODS: EPCs were quantified in 29 patients with active RA by flow cytometry, colony forming unit (CFU) and circulating angiogenic cell (CAC) assays before and after 7 days of intermediate dose GC therapy. CFU from patients with RA and from healthy referents (HR) were cultured in vitro in the absence or presence of dexamethasone (Dex) and/or TNF. RESULTS: After 1 week of GC therapy, EPC increased from 0.026 (SD 0.003)% to 0.053 (SD 0.010)% (p<0.01), and from 12 (SD 4) to 27 (SD 7) CFU/well (p<0.02); CAC also increased from 7 (SD 2) to 29 (SD 8) cells/high power field (p<0.05). In parallel, disease activity decreased significantly after GC treatment. TNF serum levels also decreased from 36 (SD 10) to 14 (SD 6) pg/ml (p<0.0001). Addition of Dex to the RA CFU led to a significant increase of mean CFU counts, whereas addition of TNF induced a decrease of CFU. CONCLUSIONS: Our data indicate that TNF may be at least partly responsible for the reduction of EPC seen in patients with RA. Intermediate doses of GCs for a short period of time, apart from reducing disease activity, significantly increase circulating EPC.

Endothelial progenitor cells in kidney transplant recipients.

BACKGROUND: Lower concentrations of endothelial progenitor cells (EPCs) may be associated with increased cardiovascular risk. EPC counts and their correlates have not yet been studied in kidney transplant recipients (KTR). METHODS: We cross-sectionally studied EPC counts in 105 middle-aged KTR (mean estimated glomerular filtration rate 45.2 ml/min/1.73 m; range: 5.4 to 117.5). Using univariate and multivariate linear regression assuming a gamma distribution of the outcome, we examined the associations between counts of cultured EPCs and traditional cardiovascular disease risk factors (hypertension, diabetes, hyperlipidemia, smoking), kidney function, and immunosuppressive agents, amongst others. RESULTS: The median count of cultured EPCs was 34 cells per high-power field (interquartile range: 19 to 64), comparable to healthy individuals. From multivariate analyses, we found independent inverse associations between counts of cultured EPCs and body mass index, mean arterial pressure, and history of cardiovascular disease. Statin use was associated with greater EPC counts, whereas patients receiving azathioprine or angiotensin II receptor treatment had lower EPC counts (all P<0.01). CONCLUSIONS: This study suggests negative associations in KTR between EPC counts and body mass index, and blood pressure, whereas statin use was associated with greater EPC counts. These findings raise the hypothesis whether EPCs are responsible, at least in part, for the well established associations between these factors and cardiovascular outcomes in KTR.

History of cardiovascular disease is associated with endothelial progenitor cells in peritoneal dialysis patients.

BACKGROUND: It is unknown whether traditional cardiovascular disease risk factors influence the number of endothelial progenitor cells (EPCs) and whether numbers of EPCs correlate with endothelial function in patients with end-stage renal disease. METHODS: In a cross-sectional study of 38 peritoneal dialysis patients, we examined numbers of circulating CD34+/KDR+/CD133+ cells, CD34+ hematopoietic stem cells, and EPCs cultured from peripheral blood. We also assessed conventional cardiovascular disease risk factors, such as history of vascular disease, diabetes, hypercholesterolemia, hypertension, and smoking. We determined endothelial function by measurement of endothelium-dependent and endothelium-independent reactivity of forearm resistance arteries by using strain-gauge plethysmography. RESULTS: Numbers of EPCs cultured from peripheral blood and forearm blood flow reactivity did not differ between erythropoietin-treated peritoneal dialysis patients and healthy individuals. A history of vascular disease was associated with number of cultured EPCs, but other cardiovascular disease risk factors showed no association. Furthermore, there was no association of endothelial-dependent and endothelial-independent forearm blood flow reactivity with EPCs in peritoneal dialysis patients. CONCLUSION: In this first study of EPCs in peritoneal dialysis patients, we found an association between history of vascular disease and EPCs, but no association of EPCs with endothelial function or other cardiovascular disease risk factors.

The active metabolite of leflunomide, A77 1726, interferes with dendritic cell function.

Leflunomide, a potent disease-modifying antirheumatic drug used in the treatment of rheumatoid arthritis (RA), exhibits anti-inflammatory, antiproliferative and immunosuppressive effects. Although most of the beneficial effects of leflunomide have been attributed to its antimetabolite activity, mainly in T cells, other targets accounting for its potency might still exist. Because of mounting evidence for a prominent role of dendritic cells (DCs) in the initiation and maintenance of the immune response in RA, we analyzed the effect of the active metabolite of leflunomide (A77 1726; LEF-M) on phenotype and function of human myleloid DCs at several stages in their life cycle. Importantly, DCs differentiated in the presence of LEF-M exhibited an altered phenotype, with largely reduced surface expression of the critical co-stimulatory molecules CD40 and CD80. Furthermore, treatment of DCs during the differentiation or maturation phase with LEF-M aborted successful DC maturation. Exogenous addition of uridine revealed that DC modulation by LEF-M was independent of its proposed ability as an antimetabolite. In addition, the ability of DCs to initiate T-cell proliferation and to produce the proinflammatory cytokines IL-12 and tumour necrosis factor-alpha was markedly impaired by LEF-M treatment. As a molecular mechanism, transactivation of nuclear factor-kappaB, an transcription factor essential for proper DC function, was completely suppressed in DCs treated with LEF-M. These data indicate that interference with several aspects of DC function could significantly contribute to the beneficial effects of leflunomide in inflammatory diseases, including RA.

Depletion of endothelial progenitor cells in the peripheral blood of patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is characterized by increased cardiovascular morbidity and mortality that cannot be explained solely by traditional cardiovascular risk factors. Cardiovascular morbidity is related to disease activity and can be normalized by effective therapy. Because the quantity of endothelial progenitor cells (EPCs) in the peripheral blood is correlated inversely with cardiovascular risk, we studied whether such abnormalities could also be observed in patients with RA. METHODS AND RESULTS: EPCs were determined in 52 RA patients and in 16 healthy referents (HRs) by fluorescence-activated cell-sorting (FACS) analysis. Patients were divided into groups characterized by active disease (n=36) and low disease activity (n=16). Cells that were positive by flow cytometry for CD34/KDR/AC133 within the lymphocyte population were characterized as EPCs. Furthermore, in subgroups of patients, circulating EPCs were also quantified by a colony-forming unit (CFU) and a circulating angiogenic cell (CAC) assay. EPCs were significantly decreased in RA patients suffering from active disease compared with those from HRs, as measured by FACS analysis (0.026+/-0.002% versus 0.045+/-0.008%, respectively, P<0.05), CFU assay (mean of 5+/-2 versus 18+/-5 CFU/well in HRs, P<0.05), and CAC assay (mean of 7+/-2 versus 52+/-16 positive cells/high-power field, P<0.005). In contrast, the frequency of circulating EPCs from patients with low disease activity was comparable to that of healthy individuals (0.052+/-0.006% by FACS analysis), CFU assay (10+/-5 CFU/well), and CAC assay (mean of 25+/-5 positive cells). Moreover, EPC quantities in peripheral blood were correlated inversely with disease activity as assessed by the disease activity score (r=-0.38, P<0.01). CONCLUSIONS: Our observations indicate that active RA is associated with a depletion of circulating EPCs. This might be one of several factors contributing to the increased cardiovascular risk in RA.

Ankylosing spondylitis, psoriatic arthritis, and reactive arthritis show increased bone resorption, but differ with regard to bone formation.

OBJECTIVE: To test if markers of bone metabolism are altered in patients with seronegative spondyloarthropathies (SSpA). METHODS: We studied biochemical markers of bone resorption and bone formation, osteoprotegerin (OPG), and bone mineral density (BMD) in patients with psoriatic arthritis (PsA), ankylosing spondylitis (AS), and reactive arthritis (ReA) and healthy volunteers. RESULTS: The bone resorption markers urinary deoxypyridinoline and crosslinked telopeptide of collagen-I were significantly increased in patients with AS, PsA, and ReA; in PsA they correlated with the acute phase response (C-reactive protein and erythrocyte sedimentation rate). The bone formation markers were divergent: bone-specific alkaline phosphatase was increased in PsA, but not in AS or ReA. Osteocalcin levels were only elevated in AS. Serum levels of OPG were significantly increased in both AS and PsA. Dual energy x-ray absorptiometry (DEXA) measurements of lumbar spine and femoral neck revealed osteopenia in patients with AS, whereas the DEXA distribution was within normal range in PsA. CONCLUSION: Our data indicate high and, particularly in AS, unbalanced bone turnover in SSpA, consistent with the decrease in BMD found in patients with AS.