Differentiation between early rheumatoid arthritis patients and healthy persons by conventional and dynamic contrast-enhanced magnetic resonance imaging.

OBJECTIVES: To identify the magnetic resonance imaging (MRI) parameter that best differentiates healthy persons and patients with early rheumatoid arthritis (RA), and to investigated responsiveness to treatment of various MRI parameters. METHOD: Conventional MRI and dynamic contrast-enhanced (DCE)-MRI of the hand were performed once for 26 healthy persons, and before and after 6 and 12 months of disease-modifying anti-rheumatic drug (DMARD) treatment for 14 early RA patients, using a 1.0-T MRI unit. One-slice DCE-MRI was analysed using Dynamika version 4.2. The number of enhancing voxels (Nvoxel), the initial rate of enhancement (IRE), the maximum enhancement (ME), ME×Nvoxel, and IRE×Nvoxel were calculated for wrist and 2nd-5th metacarpophalangeal (MCP) joints. Conventional MR images were evaluated using the RA MRI scoring system (RAMRIS) synovitis score. RESULTS: Using DCE-MRI, enhancement was demonstrated in 61.5% of healthy persons and in 91.7% of RA patients at baseline, with a median Nvoxel of 3 and 362, respectively. At baseline, all parameters were higher for patients than for healthy persons (all p ≤ 0.003). Only one patient had a baseline RAMRIS synovitis score below the 95th percentile of the healthy persons. The corresponding number of patients was 3 for Nvoxel, ME×Nvoxel and IRE×Nvoxel, and 10 for IRE and ME. The RAMRIS synovitis score and IRE showed the highest responsiveness, with a standardized response mean (SRM) of -1.00 and -0.88, respectively. CONCLUSIONS: The RAMRIS synovitis scoring of conventional MRI, and to a lesser extent the one-slice DCE-MRI parameters of synovial volume, differentiated early RA patients and healthy persons. The decrease in RAMRIS synovitis score, Nvoxel, and IRE showed sensitivity to change during treatment.

Upregulated baseline plasma CCL19 and CCR7 cell-surface expression on monocytes in early rheumatoid arthritis normalized during treatment and CCL19 correlated with radiographic progression.

OBJECTIVES: The aim of this study was to measure, in early rheumatoid arthritis (RA) patients, the concentration of CC-chemokine ligand 19 (CCL19) in plasma and the cell-surface expression of CC-chemokine receptor 7 (CCR7) on circulating monocytes and CD4+ T lymphocytes and to analyse correlations with disease activity and 5-year radiographic progression. METHOD: In disease-modifying anti-rheumatic drug (DMARD)-naïve RA patients (disease duration < 6 months), we measured plasma CCL19 by enzyme-linked immunosorbent assay (ELISA) (n = 160) and CCR7 cell-surface expression on monocytes and CD4+ T lymphocytes by flow cytometry (n = 40) at baseline and after 1 year of treatment with methotrexate (MTX) or methotrexate+cyclosporin A (MTX/CyA). Radiographic progression was scored by the van der Heijde-modified Total Sharp Score (TSS) from 0 to 5 years. RESULTS: Increased baseline CCL19 (median 85 pg/mL, range 31-1008 pg/mL, p = 0.01) decreased after 1 year (median 31 pg/mL, range 31-1030 pg/mL, p < 0.001) and 5 years (median 31 pg/mL, range 31-247 pg/mL, p < 0.001) to a level below the controls (n = 45) (median 60 pg/mL, range 31-152 pg/mL). Baseline plasma CCL19 levels [p = 0.011, 95% confidence interval (CI) 0.0030-0.0176], anti-cyclic citrullinated peptide (anti-CCP) antibody status (p = 0.002, 95% CI 0.61-2.38), and TSS > 0 at baseline (p < 0.001, 95% CI 1.21-3.16) were independent predictors of 5-year radiographic progression evaluated by multiple logistic regression in contrast to never smoked, C-reactive protein (CRP), gender, age, number of tender (NTJ) and swollen joints (NSJ), and 28-joint Disease Activity Score (DAS28). Increased CCR7 expression on monocytes (p = 0.008) correlated to CRP (p = 0.006, r = 0.52) and normalized (n = 15) after 1 year (p = 0.02). CONCLUSIONS: In DMARD-naïve RA patients, CCL19 plasma level and CCR7 surface expression on monocytes were upregulated and normalized after 1 year of treatment. Increased baseline plasma CCL19 level, anti-CCP antibody status, and TSS > 0 at baseline correlated independently with 5-year radiographic progression.

Periarticular and generalised bone loss in patients with early rheumatoid arthritis: influence of alendronate and intra-articular glucocorticoid treatment. Post hoc analyses from the CIMESTRA trial.

OBJECTIVES: The aims of this study were to investigate the influence of alendronate and intra-articular betamethasone treatment on bone mineral density (BMD) changes in hand, lumbar spine and femoral neck during 1 year of a treat-to-target study (Cyclosporine, Methotrexate, Steroid in RA (CIMESTRA)). PATIENTS AND METHODS: A hundred and sixty patients with early, active rheumatoid arthritis (RA) received methotrexate, intra-articular betamethasone and ciclosporin /placebo-ciclosporin. Patients with Z-score ≤0 also started alendronate 10 mg/day. BMD of the hand (digital x-ray radiogrammetry (DXR-BMDhand)), BMD of lumbar spine and femoral neck (dual x-ray absorptiometry (DXA-BMDlumbar spine and DXA-BMDfemoral neck)) and x-rays of hands, wrists and forefeet (modified Sharp-van der Heijde score) were measured at baseline and 1 year, with complete data available in 107 patients. RESULTS: The change in BMD in hand, lumbar spine and femoral neck was negatively associated with the dose of intra-articular betamethasone (p<0.01 for all), but the bone loss in hand was modest and in the axial skeleton comparable with that of healthy individuals. Alendronate did not influence changes in DXR-BMDhand, which averaged -2.8%, whereas significant changes were observed in DXA-BMDlumbar spine and DXA-BMDfemoral neck in alendronate-treated patients (1.8% and 0.8%) compared with untreated patients (-1.8% and -2.2%) (p<0.01 and 0.02). Alendronate did not affect the radiographic progression (alendronate-treated patients: 0 (range 0-19), non-alendronate: 0 (0-18)). CONCLUSIONS: In early active RA, intra-articular betamethasone injections added to disease-modifying antirheumatic drug (DMARD) treatment led to minimal loss of hip and lumbar BMD, and the loss could be prevented by treatment with alendronate. Alendronate treatment did not affect radiographic progression.

Aggressive combination therapy with intra-articular glucocorticoid injections and conventional disease-modifying anti-rheumatic drugs in early rheumatoid arthritis: second-year clinical and radiographic results from the CIMESTRA study.

OBJECTIVE: To investigate whether clinical and radiographic disease control can be achieved and maintained in patients with early, active rheumatoid arthritis (RA) during the second year of aggressive treatment with conventional disease-modifying antirheumatic drugs (DMARDs) and intra-articular corticosteroid. This paper presents the results of the second year of the randomised, controlled double-blind CIMESTRA (Ciclosporine, Methotrexate, Steroid in RA) study. METHODS: 160 patients with early RA (duration <6 months) were randomised to receive intra-articular betamethasone in any swollen joint in combination with step-up treatment with either methotrexate and placebo-ciclosporine (monotherapy) or methotrexate plus ciclosporine (combination therapy) during the first 76 weeks. At week 68 hydroxychlorochine 200 mg daily was added. From week 76-104 ciclosporine/placebo-ciclosporine was tapered to zero. RESULTS: American College of Rheumatology 20% improvement (ACR20), ACR50 and ACR70 levels were achieved in 88%, 79% and 59% of patients in the combination vs 72%, 62% and 54% in the monotherapy group (p = 0.03, 0.02 and 0.6 between groups). The patients globally declined from 50 to 12 vs 52 to 9, with 51% and 50% in Disease Activity Score (DAS) remission, respectively. Mean (SD) progressions in total Sharp-van der Heijde scores were 1.42 (3.52) and 2.03 (5.86) in combination and monotherapy groups, respectively (not significant). Serum creatinine levels increased by 7% in the combination group (4% in monotherapy), but hypertension was not more prevalent. CONCLUSION: Continuous methotrexate and intra-articular corticosteroid treatment resulted in excellent clinical response and disease control at 2 years, and the radiographic erosive progression was minimal. Addition of ciclosporine during the first 76 weeks resulted in significantly better ACR20 and ACR50 responses, but did not have any additional effect on remission rate and radiographic outcome.

Effects of silicone breast prostheses on the assessment of body composition by dual-energy X-ray absorptiometry.

We examined the influence of silicone breast prostheses on body composition as assessed by dual-energy X-ray absorptiometry (DXA). Eighteen women were measured with and without a pair of silicone breast prostheses placed on the upper part of the trunk simulating endogenous implants. Bone area, bone mineral content (BMC), areal bone mineral density (BMD), lean tissue mass (LTM) and fat tissue mass (FTM) of the total body and of the subregions of the body, i.e. the head, trunk, arms and legs, were measured by a Norland XR-36 DXA scanner. After application of the silicone prostheses, bone area, BMC and BMD of the total body significantly increased by an average of 3.7, 6.6 and 3.4% (P<0.0001), respectively. Total body LTM and FTM were not affected. In the trunk region, changes were more pronounced. Trunk BMC, for example, was overestimated by 17.9% (P<0. 0001). The prostheses also influenced measurements of truncal soft tissue composition, with a small but statistically significant overestimation of both LTM (1.1%) and FTM (2.1%) (P<0.05). No changes in bone mass and soft tissue composition were seen in the head, arms and legs. Activation of a high-density detection software utility provided by the manufacturer had no influence on any of the measurements. We conclude that silicone breast prostheses affect the assessment of body composition by DXA.

Quadriceps strength in women with a previous hip fracture: relationships to physical ability and bone mass.

Associations between physical ability, level of current physical activity and bone mass were examined in 47 elderly women (mean age 80 years) who had suffered from a hip fracture 3-36 months (mean 17 months) previously. Measures of physical ability included isokinetic quadriceps strength of both the non-fractured and fractured leg, and walking and stair climbing speed. An estimate of current physical activity was made using the Northwick Park activity index questionnaire specifically designed for hip fracture patients. Bone mineral density of the spine and hip (Ward's triangle, femoral neck and trochanter) was assessed by dual energy X-ray absorptiometry. Relationships between the measured parameters were analysed using multiple regression analyses, taking into account the confounding effects of age, height, weight and months since fracture. Quadriceps strength of the fractured leg was on average 18% lower than that of the contralateral leg (p < 0.001). Quadriceps strength of the fractured leg proved to be the most robust predictor of walking speed (Rpartial = 0.69, p < 0.0001), stair climbing speed (Rpartial = 0.46, p < 0.001) and the activity index (Rpartial = 0.56, p < 0.0001). Bone mineral density was independently predicted only by body weight (Rpartial range: 0.45-0.72, p < 0.001), not by any of the parameters of physical ability or by the Northwick Park activity index. In conclusion, quadriceps strength is markedly affected in women with a previous hip fracture and is associated with walking ability and level of physical activity. This study showed that bone mass is linked to body weight, not to physical ability and activity. Thus, the main benefit of muscle strengthening exercises in these women may be to promote mobility.

Influence of orthopaedic metal and high-density detection on body composition as assessed by dual-energy X-ray absorptiometry.

We examined the influence of orthopaedic material and computerized high-density detection (HDD) on analysis of bone mass and soft tissue composition performed by dual-energy X-ray absorptiometry (DXA). Measurements of total and regional bone area, bone mineral content (BMC), areal bone mineral density (BMD), lean tissue mass (LTM) and fat tissue mass (FTM) were made using a Norland XR-26 DXA scanner with dynamically changing samarium filtration. Twenty-one subjects who were free of metal implants were measured without and with a Biomet femoral prosthesis (titanium) placed on the proximal part of the femoral region. Twenty-one women with an endogenous prosthesis in the proximal femur were measured once. Analyses of tissue composition were performed without and with HDD using software provided by the manufacturer. Measurements were considerably affected by exogenous metal with overestimation of LTM and underestimation of FTM and bone area. BMC and BMD were over- or underestimated depending on the anatomical region. Enabling the HDD mode, values of bone area and tissue mass came closer to the expected values (-metal/-HDD) but were in general still significantly different from these. For the total body, the following significant changes were found after application of metal (+metal/-HDD vs. +metal/+HDD, mean values): bone area -19.8% vs. -6.9%, BMC +1.1% vs. -2.1%, BMD +26.5% vs. +4.7%, LTM +12.4% vs. +3.7%, FTM -15.8% vs. -7.0%. A similar pattern of change in tissue composition and bone area was found for the subregions of the body. Changes in tissue composition after HDD were similar in subjects with exogenous and endogenous metal, indicating that the experimental model was appropriate. In conclusion, measurements of tissue composition were substantially influenced by orthopaedic metal. HDD partly corrected for the artefacts induced by the metal.

Muscle strength and soft tissue composition as measured by dual energy x-ray absorptiometry in women aged 18-87 years.

Dual energy x-ray absorptiometry (DEXA) offers the possibility of assessing regional soft tissue composition, i.e. lean mass (LM) and fat mass: LM may be considered a measure of muscle mass. We examined age-related differences in LM, percentage fat (%fat) and muscle strength in 100 healthy non-athletic women aged 18-87 years. Relationships between muscle strength and leg LM in 20 elite female weight lifters and in 18 inactive women with previous hip fractures were also studied. The LM and %fat of the whole body, trunk, arms and legs were derived from a whole body DEXA scan. Isokinetic knee extensor strength (KES) and flexor strength (KFS) at 30 degrees.s-1 were assessed using an isokinetic dynamometer. The women aged 71-87 years had 35% lower KES and KFS than the women aged 18-40 years (P < 0.0001). Differences in LM were less pronounced. The LM of the legs, for instance, was 15% lower in the old than in the young women (P < 0.0001). In a multiple regression analysis with age, body mass, height and leg LM or KES as independent variables and KES or leg LM as the dependent variable, age was the most important predictor of KES (r(partial) = -0.74, P < 0.0001). The same applied to KFS. Body mass, not age, was the most important predictor of leg LM (r(partial) = 0.65, P < 0.0001) and of LM at all other measurement sites. The LM measured at different regions decreased equally with increasing age. The KES:leg LM ratio was negatively correlated with age (r = -0.70, P < 0.0001). The weight lifters had significantly higher KES:leg LM ratios than age-matched controls (+ 12%, P < 0.0001) and vice versa for the women with previous hip fractures (-36%, P < 0.0001). In conclusion, from our study it would seem that in healthy nonathletic women, age is a more important determinant of muscle strength than is LM as measured by DEXA. Muscle strengthening exercises and inactivity seem to have a considerably stronger influence on muscle strength than on LM.

Knee extensor and flexor strength in elderly women after recent hip fracture: assessment by the Cybex 6000 dynamometer of intra-rater inter-test reliability.

The reliability of knee extensor and flexor strength measurements was assessed in 20 women (aged 68-88 years) who had experienced a hip fracture two to four weeks before but who were otherwise healthy. Using the Cybex 6000 isokinetic dynamometer, isokinetic knee extensor and flexor strength (peak torque, total work and power) at 30 and 120 degree/second and isometric knee extensor and flexor strength (peak torque) were measured by the same examiner in both legs, successively, on four separate days within one week. Compared with the non-involved leg, the median reduction in peak extensor and flexor torque of the involved leg was 50% (p <0.001). With the protocol used, no significant change in muscle strength occurred during the test period Individual coefficients of variation (CVs) were calculated for each muscle strength variable. Depending on whether torque, work or power were measured, the median CVs of extensor and flexor strength measurements of the non-involved leg ranged from 5.6-14.6% and 10.8-28.6%, respectively. The corresponding CVs for the involved leg were 10.9-22.1% and 13.0-35.2%. Substantial variability between individual CVs were found for all strength variables. In conclusion, although muscle strength measurements may be applicable when comparing larger groups of hip fracture patients, the large CVs may be a limitation in monitoring individual patients. This finding should be taken into consideration when planning individual training programmes.

[Rehabilitation after trochanteric femoral fractures]. / Rehabilitering efter hoftenaer femurfraktur.

Hip fractures constitute an increasing problem due to the associated lengthy hospitalization, pressure on orthopaedic units and the frequently serious consequences for the health and social function of the patients. The outcome of rehabilitation following hip fractures depends on several prefracture risk factors with only limited possibilities for intervention. Modern surgical techniques permit early mobilisation and possible changes in surgical procedures will probably not essentially influence the outcome of rehabilitation. Foreign experiences, however, suggest that early transfer to a specialized unit for rehabilitative aftercare involves more effective rehabilitation with reduced consumption of resources.

Effects of nonselective and beta-1-selective blockade on glucose metabolism and hormone responses during insulin-induced hypoglycemia in normal man.

The effects of nonselective beta-blockade (propranolol) and beta-1-selective blockade (atenolol) on glucose metabolism during insulin-induced hypoglycemia were studied in eight normal subjects during constant infusion of 3-[3H]glucose. Propranolol and to a lesser extent atenolol prolonged the hypoglycemic response to insulin. After maximal hypoglycemia a significant increase in glucose uptake rate was seen after propranolol and a corresponding trend was found in the atenolol experiments. The two beta-blockers did not influence glucose production rate after insulin administration. FFA concentration declined rapidly after insulin. Propranolol delayed the subsequent normalization of FFA whereas atenolol had no significant effect. Propranolol increased epinephrine and GH responses to hypoglycemia, whereas atenolol had no effect. Neither of the two beta-blockers influenced the concentrations of glucagon, norepinephrine, and PRL. It is concluded that nonselective beta-blockade prolongs the hypoglycemic response to insulin through an increased tissue uptake of glucose which is not counteracted by an increased glucose production. It is suggested that nonselective beta-blockade increases muscle glucose uptake by lowering FFA concentrations. beta-Blocker inhibition of the antiinsulin effect of epinephrine on glucose uptake in muscle can, however, not be excluded.

Oesophageal varices as a late complication to neonatal umbilical vein catheterization.

Three recent cases are presented. Haematemesis in children with splenomegalia and a history of neonatal umbilical vein catheterization should involve careful examination for oesophageal varices due to portal hypertension.

Thyrotrophin-releasing hormone (TRH) stimulation test in manic-depressive illness.

The thyrotrophin (TSH) response to thyrotrophin-releasing hormone (TRH 200 microgram intravenously was studied in 19 patients with unipolar depression, 12 with bipolar depression, 14 with mania, and 5 with mixed manic-depressive illness. The TSH responses were decreased in all of these affective disorders compared to those found in 10 patients with reactive depression, 5 with reactive paranoid psychosis, 14 with neurotic depression, and 60 controls. The decrease of the TSH response in manics could not be accounted for by the effects of neuroleptic drugs. The TSH response in the groups with reactive depression, reactive paranoid psychosis, and neurotic depression, respectively, did not differ significantly from that found in controls. With the exception of a decrease in serum T3 level and free T3 index in the manics, no significant differences in serum T3 level or in free T3 and T4 indexes were found between the groups. Changes found in serum T4 level were due to changes in the thyroxine-binding proteins.

Intravenous and peroral TRH stimulation in sporadic atoxic goitre.

Thyrotrophin releasing hormone (TRH) stimulation test with 200 microng iv was performed in 35 patients with atoxic sporadic goitre. In 23 patients with diffuse goitre 7 showed a lack of increase in serum thyrotrophin (TSH) at a significantly increased frequency compared to controls (P = 0.0028). In 4 patients with solitary nodules 2 showed no significant response to TRH (negative), while 3 of the 8 patients with multinodular goitres had negative TRH test. Only 6 of the 12 TRH negative patients also had non-suppressible 131I uptake following T3. No significant difference in age and thyroid parameters was found between the TRH negative and TRH positive patients. In 7 TRH negative patients the test was repeated with 400 microng TRH but all remained negative. Five of these patients were given TRH perorally 80 mg daily for 2 weeks resulting in a significant increase in serum T4 and T3. No detectable increase in TSH was found. The response to iv bovine TSH in 4 TRH negative patients was found to be normal, suggesting that there was normal thyroid sensitivity to TSH. Our findings suggest that patients with TRH negative atoxic goitre can release biological active TSH following prolonged TRH stimulation. The high frequency of a negative standard TRH test in atoxic goitre seems to diminish the diagnostic value of the standard TRH test.