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.

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.

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.

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.

Protirelin stimulation test and thyroid function during treatment of depression.

Thyroid levels were estimated in 15 patients with endogenous depressions. Before electroconvulsive treatment (ECT), serum thyroxine (T4) and free T4 index values were elevated (P less than .02). After recovery from depression, the levels were normal. Serum triiodothyronine (T3) and free T3 index were normal both before and after ECT. Serum thyrotropin (TSH) levels were also normal and not substantially altered by the ECT procedure. The mean maximal TSH response to protirelin (thyrotropin-releasing hormone) was diminished in the depressed patients and normal after recovery. In three patients, the increase in TSH response to protirelin after recovery did not occur and they relapsed within six months, while in seven patients with increased TSH response to protirelin after recovery only one relapse occurred. The disturbances in the free T4 index, T4, and the protirelin test may in some depressed patients resemble hyperthyroidism, but this condition can be excluded by means of serum, T3 and free T3 index.

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.

[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.

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.