Michael Stoltenberg

Magnetic resonance imaging-determined synovial membrane volume as a marker of disease activity and a predictor of progressive joint destruction in the wrists of patients with rheumatoid arthritis.

OBJECTIVE To evaluate the synovial membrane volume, determined by magnetic resonance imaging (MRI), as a marker of joint disease activity and a predictor of progressive joint destruction in rheumatoid arthritis (RA). METHODS Twenty-six patients with RA, randomized to receive disease-modifying antirheumatic drug (DMARD) therapy alone (11 patients) or DMARDs in combination with oral prednisolone (15 patients), were followed up for 1 year with contrast-enhanced MRI of the dominant wrist (months 0, 3, 6, and 12), conventional radiography (months 0 and 12), and clinical and biochemical examinations. Bone erosion (by MRI and radiography) and synovial membrane volumes (by MRI) were assessed. RESULTS Significant synovial membrane volume reductions were observed after 3 and 6 months in the DMARD + prednisolone group, and after 6 and 12 months in the DMARD-alone group (P < 0.01-0.02, by Wilcoxon-Pratt analysis). The rate of erosive progression on MRI was highly correlated with baseline scores and, particularly, with area under the curve (AUC) values of synovial membrane volume (Spearmans sigma = 0.69, P < 0.001), but not with baseline or AUC values of local or global clinical or biochemical parameters, or with prednisolone treatment. In none of 5 wrists with baseline volumes <5 cm3, but in 8 of 10 wrists with baseline volumes > or =10 cm3, erosive progression was found by MRI and/or radiography, indicating a predictive value of synovial membrane volumes. MRI was more sensitive than radiography for the detection of progressive bone destruction (22 versus 12 new bone erosions). CONCLUSION MRI-determined synovial membrane volumes are closely related to the rate of progressive joint destruction. Quantitative MRI assessment of synovitis may prove valuable as a marker of joint disease activity and a predictor of progressive joint destruction in RA.

Quantification of synovistis by MRI: correlation between dynamic and static gadolinium-enhanced magnetic resonance imaging and microscopic and macroscopic signs of synovial inflammation

Dynamic and static gadolinium-diethylenetriaminepentaacetic acid(Gd-DTPA)-enhanced magnetic resonance imaging (MRI) were evaluated as measures of joint inflammation in arthritis, by a comparison with macroscopic and microscopic signs of synovitis. Furthermore, the importance of the size of the evaluated synovial areas was investigated, as was the optimal time for enhancement measurements. Seventeen rheumatoid arthritis knees and 25 osteoarthritis knees, scheduled for arthroscopy or arthrotomy, were included. Macroscopic and microscopic synovial inflammation as well as nine histologic tissue characteristics were graded at four preselected biopsy sites. Preoperative T1-weighted dynamic fast low angle shot and static spin-echo Gd-enhanced MRI were performed. The dynamic enhancement rate and the static enhancement were measured in the entire synovial membrane of a preselected slice as well as at the four biopsy sites, and compared to synovial pathology. The rate of early enhancement of the total synovial membrane of the preselected slice, determined by dynamic MRI, was highly correlated with microscopic evidence of active inflammation (Spearman p = 0.73; p < 10(-7). Dynamic MRI could distinguish knees with and without synovial inflammation with a high predictive value (0.81-0.90). Moderate and severe inflammation could not be differentiated. The early enhancement rate was correlated with histologic features of active inflammation, particularly vessel proliferation and mononuclear leucocyte infiltration. Dynamic evaluation of small synovial sections at the biopsy sites and static spin-echo MRI resulted in considerably weaker correlations to histologic inflammation than dynamic evaluation of the total synovium. The optimal time for enhancement measurements was one-half to one minute after Gd injection, as the highest correlation coefficients to histologic inflammation were observed in this interval. Dynamic MRI can be used to determine synovial inflammation. Evaluation of large synovial areas one-half to one minute after Gd injection best reflects joint inflammation.

A randomised trial of differentiated prednisolone treatment in active rheumatoid arthritis. Clinical benefits and skeletal side effects.

OBJECTIVES To study benefits and skeletal side effects of carefully monitored prednisolone treatment in patients with active rheumatoid arthritis. METHODS One hundred and two patients with active rheumatoid arthritis were randomly allocated to treatment with disease modifying anti-inflammatory drug (DMARD) alone or DMARD and prednisolone in a one year follow up study. Prednisolone was given in a dose regimen adapted to the disease activity of the individual patient. The mean dose was 6 mg and the mean cumulated dose was 2160 mg. Patients were followed up with disease activity parameters, radiograph of the hands (Larsen score), and bone mineral density (BMD) of the lumbar spine, distal forearm and hand. At one year 26 patients had withdrawn from the investigation leaving 76 patients for evaluation. RESULTS The results showed that disease activity in the prednisolone treated group was reduced within two weeks. In the DMARD alone group disease activity was gradually reduced over months. At six months there was no difference between the groups as evaluated by an improvement score using a number of ACR criteria. Prednisolone in the present set up was not able to protect significantly against radiological disease progression, although there was a trend towards less progression in Larsen score in the prednisolone group, a matter that was further underlined in an intention to treat analysis. BMD data revealed a significant reduction in spinal BMD in the prednisolone group, whereas prednisolone seemed to have a protective effect against bone loss in the hand and distal forearm. CONCLUSIONS This study does not allow any firm conclusions for or against the treatment of rheumatoid arthritis with prednisolone. The data suggest that the beneficial effects of prednisolone are not as clear cut in established rheumatoid arthritis as in early disease. Furthermore the data indicate that treatment in the chosen relatively low dose does not provide sufficient control of disease. On the other hand the spinal bone loss observed in the prednisolone group does invite considerations about using higher doses.

Scoring of Synovial Membrane Hypertrophy and Bone Erosions by MR Imaging in Clinically Active and Inactive Rheumatoid Arthritis of the Wrist

MRI-scores of synovial membrane hypertrophy and bone erosions of the RA-wrist are introduced. Gadolinium-DTPA enhanced magnetic resonance imaging (MRI) and conventional radiography (CR) of the wrist were performed in 16 patients with rheumatoid arthritis (RA) and 3 healthy controls. A MRI-score of synovial membrane hypertrophy was obtained by summation of gradings of synovial hypertrophy in 6 regions of the wrist. The score was significantly higher in wrists with than in wrists without clinical signs of active arthritis. The score was 0 in all healthy controls. Each bone of the wrist was assessed by MRI and CR with respect to bone erosions. Bone erosions were detected by MRI in 14 wrists in contrast to only 6 wrists by CR. In all patients the erosions were more numerous on MRI. The introduced methods may be useful quantitative measures of synovitis and early joint destruction in RA.

YKL‐40 in giant cells and macrophages from patients with giant cell arteritis

OBJECTIVE YKL-40, a mammalian member of the family 18 glycosyl hydrolases, is secreted by activated macrophages at a late stage of differentiation. Macrophages are present in inflammation of the arterial wall and are thought to participate in the pathogenesis of giant cell arteritis (GCA). The aim of this study was to evaluate whether macrophages and giant cells of patients with GCA produce YKL-40, and whether serum YKL-40 concentrations are elevated in these patients. METHODS Serum YKL-40 was determined by radioimmunoassay in 19 patients with GCA and 8 patients with polymyalgia rheumatica (PMR) who were followed up prospectively during 1 year of treatment with prednisolone. Immunohistochemical staining for YKL-40 was performed in temporal artery biopsy samples that were obtained before treatment. RESULTS In the arteritic vessels of patients with GCA, positive staining for the YKL-40 antigen was found in CD68+ giant cells and mononuclear cells located in the media. Macrophages located in the adventitia and intima were negative for YKL-40. At the time of diagnosis, patients with GCA had an increased median serum level of YKL-40 (256 microg/liter; P<0.01) compared with healthy age-matched controls (median 118 microg/liter), and the serum level of YKL-40 decreased to normal levels during prednisolone treatment (-38% after 1 month; P<0.001). Most patients with PMR had normal serum YKL-40 levels (median 158 microg/liter) and had no changes in the serum YKL-40 levels during prednisolone treatment. The observed changes in serum YKL-40 did not always parallel the changes in serum C-reactive protein levels and erythrocyte sedimentation rate during the 1-year study period. CONCLUSION YKL-40 is found in CD68+ giant cells and mononuclear cells in the media of arteritic vessels of patients with GCA, and the concentration of serum YKL-40 may reflect the local activity of these cells in the inflamed artery.

Bone loss in rheumatoid arthritis : influence of disease activity, duration of the disease, functional capacity, and corticosteroid treatment

Axial and appendicular bone mass were studied in 95 patients with rheumatoid arthritis. The aims were to quantify bone mineral density (BMD) and to evaluate the importance of disease activity, duration of disease, functional capacity, and corticosteroid treatment for bone loss in patients with rheumatoid arthritis. The BMD in the lumbar spine (BMDSPINE) did not differ from age-matched healthy controls, but distal forearm BMD (BMDARM) and metacarpal BMD (BMDMCB) were significantly lower in the patients (p < 0.01 and p < 0.001, respectively). Neither BMDSPINE nor BMDMCB were related to the disease activity at the time of investigation. By contrast, BMDARM was decreased in patients with active disease. BMD in any of the three measured locations was not directly correlated to duration of the disease. However, the bone mass in the appendicular skeleton was already decreased within the first two years after the start of the disease. The overall functional capacity in terms of physical activity increased BMD in the axial skeleton. The local functional capacity in terms of grip strength was positively related to BMD in the appendicular skeleton. Patients with severe functional impairment had the lowest BMDARM. The decreased BMD in patients with rheumatoid arthritis seems primarily to be caused by an impaired physical activity which may be related to disease activity. Corticosteroids did not decrease BMD in neither the axial nor the appendicular skeleton. The antiinflammatory effect of steroids lead to clinical improvement, which may counteract the expected negative effect of these drugs on bone in rheumatoid arthritis.

Quantitative magnetic resonance imaging as marker of synovial membrane regeneration and recurrence of synovitis after arthroscopic knee joint synovectomy: a one year follow up study

OBJECTIVES By repeated magnetic resonance imaging (MRI) to study synovial membrane regeneration and recurrence of synovitis after arthroscopic knee joint synovectomy in patients with rheumatoid arthritis (RA) and other (non-RA) causes of persistent knee joint synovitis. METHODS Contrast enhanced MRI was performed in 15 knees (nine RA, six non-RA) before and one day, seven days, two months, and 12 months after arthroscopic synovectomy. Synovial membrane volumes, joint effusion volumes, and cartilage and bone destruction were assessed on each MRI set. Baseline microscopic and macroscopic assessments of synovitis and baseline and follow up standard clinical and biochemical examinations were available. RESULTS Synovial membrane and joint fluid volumes were significantly reduced two and 12 months after synovectomy. However, MRI signs of recurrent synovitis were already present in most knees at two months. No significant differences between volumes in RA and non-RA knees were seen. Synovial membrane volumes at two months were significantly inversely correlated with the duration of clinical remission, for all knees considered together (Spearmans correlationr s=−0.67; p<0.05), for RA knees (r s=−0.76; p<0.05), and for non-RA knees (r s=−0.83; p<0.05). Baseline volumes were not significantly correlated with clinical outcome. Only three knees (all RA) showed erosive progression. The rate of erosive progression was not correlated with MRI volumes or with clinical or biochemical parameters. CONCLUSION The synovial membrane had regenerated two months after arthroscopic knee joint synovectomy and despite significant volume reductions compared with baseline it often showed signs of recurrent synovitis. MRI seems to be valuable as a marker of inflammation, destruction and, perhaps, as a predictor of therapeutic outcome in arthritis.

Effect of Intraarticular Osmic Acid on Synovial Membrane Volume and Inflammation, Determined by Magnetic Resonance Imaging

The changes in MR-determined synovial membrane volume, early synovial enhancement, and cartilage and bone erosions after osmic acid knee synovectomy were studied. Gadolinium-DTPA enhanced magnetic resonance imaging (MRI) of 18 knees with persistent arthritis was performed before and 1 month after treatment. The synovial membrane volume was significantly reduced (median -52%) in all 9 patients brought into clinical remission (p < 0.01), while no significant change was found in patients with clinical relapse. The early synovial enhancement was not significantly changed. MRI revealed progressive erosive changes in 2 patients. The time of relapse was correlated to a MR-erosion score, but not to early synovial enhancement or volumes of synovium or effusion (Spearman tests). MRI-determined synovial membrane volumes and early synovial enhancement may be objective quantitative markers of inflammation. MR-scores of cartilage and bone erosions are sensitive to progressive changes occurring within a month.

The Accuracy of MRI-determined Synovial Membrane and Joint Effusion Volumes in Arthritis: A comparison of pre- and post-aspiration volumes

Magnetic resonance imaging (MRI) of 18 knees of patients with arthritis was performed before and immediately after arthrocentesis. Pre- and post-aspiration volumes were calculated by adding the outlined areas of synovium/effusion from a continuous series of gadolinium-DTPA-enhanced 5 mm transversal T1-weighted MR-images. The difference between MRI-determined and syringe-determined volumes of aspirated joint fluid was 0-7 ml, median 2 ml, corresponding to 0-18%, median 7%, of the pre-aspiration effusion volume. Synovial membrane volumes, determined before and after arthrocentesis varied 0-10 ml, median 3 ml (0-17%, median 7%). No significant systematic misinterpretation of the borderline between joint fluid and synovium was found. We conclude that effusion volumes and in all probability also synovial membrane volumes, can be determined by MRI with a maximal analytical error of approximately 20%. The acceptable accuracy of the method encourages further studies of the value of effusion and synovial membrane volumes as markers of the activity and/or severity of joint inflammation.

Intra-articular and circulating levels of type I and III collagen markers in inflammatory and degenerative joint disease

In a chronic inflammatory disease as rheumatoid arthritis, the local processes in the affected tissues lead to destruction of the joint. When estimating the inflammatory activity in rheumatic joint diseases, a major problem is the rather unspecific and indirect character of the biochemical and the crude character of the clinical measures used.