Factors influencing mortality in rheumatoid arthritis

The prognosis in rheumatoid arthritis respecting mortality was studied in a consecutive series of 489 hospital patients over a period of 18 years. The relative risk of mortality was raised in both men (2.6; p less than 0.001) and women (3.4; p less than 0.001). In the women the relative risk was also influenced by prior duration of RA and was characterised by a diminution in risk 5-9 years after first presentation. Relative risks for men were more uniformly distributed over time. Annual excess mortality rates were strongly associated with age at first presentation in women, the rate increasing with increasing age in both the group seen within 5 years of onset of disease (chi 2(1) for trend = 30.4; p less than 0.001) and in the later referral group (chi 2(1) = 34.0; p less than 0.001). A similar but much less marked effect was observed in men in the early referral group (chi 2(1) = 13.7; p less than 0.001) only. These results suggest that initially women may have a milder form of disease and that hormonal status may affect prognosis. Future long-term therapeutic studies in RA should take into account the prognostic factors of age, sex and duration of disease.     

Mechanisms of bone loss in rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease in which destruction of bone in the joints causes major morbidity. Recent research has shed light on the cell and molecular mechanisms that lead to this osteolysis, all due directly or indirectly to the chronic inflammation. The aspects of this research covered in this review include the alteration of cell proliferation and survival that results in growth of the RA synovium. This process depends upon an increase in angiogenesis and local blood flow, which is also a feature of increased bone turnover. In addition, the inflammatory environment increases expression of chemokines, which are involved in the recruitment of monocytic osteoclast precursors. Chronic inflammation also promotes an overall catabolic state, with increased osteoclast differentiation and resorptive activity, driven by disregulation of receptor activator of NF-κB ligand (RANKL) and the synergistic activity of inflammatory cytokines such as tumor necrosis factor-α and interleukin-1. Osteoclast survival is increased in this environment, but osteoblast differentiation and survival are decreased, with a consequent reduction in bone formation and a net loss of bone. Recognition of these processes and the factors involved will enable more effective and targeted treatments for RA.     

Rapid periarticular bone loss in rheumatoid arthritis

For approximately 2 years, bone loss was measured in women with early stages of rheumatoid arthritis (RA) and in control subjects, using serial computed tomography and dual photon absorptiometry. Rapid trabecular bone loss from the distal radius was observed in the RA patients but not the controls. The bone loss correlated with initial plasma levels of parathyroid hormone and 1,25-dihydroxyvitamin D₃ (calcitriol) concentrations. It has been suggested that these humoral factors may interact with cytokines or other mediators produced in the adjacent wrist joint. Losses of the cortical bone of the radial midshaft and the lumbar spine were modest and were comparable in the 2 groups. Indices relating to both bone formation and bone resorption predicted bone loss at these 2 sites, but changes in the parathyroid hormone and calcitriol concentrations did not.     

Physical activity prevents bone loss in premenopausal women with rheumatoid arthritis: a cohort study

The aim of the study was to compare the bone loss and the influence of physical activity between premenopausal women with rheumatoid arthritis (RA) and healthy women. A total of 71 patients with RA and 29 healthy premenopausal women with the criteria of the American College of Rheumatology for RA were followed for 2 years. Of these 85% were Caucasian, aged 38 +/- 6.6 years and with a duration of disease of 88 +/- 50 months and 48 (71.8%) used GC, mean daily dose, 7.3 +/- 3.5 mg. There was a reduction in the T-score of the femoral neck (P = 0.04) and in the Ward region (P = 0.05) in RA. Through logistic regression, it was found that sedentarism was a risk factor for osteopenia in RA, with relative risk of 1.6 (IC = 1.238-1.734). Moderate physical activity reduced the risk of osteopenia by 50%. Sedentarism and low weight are the main factors associated with bone loss. Physical activity reduces bone loss. Early preventive and therapeutic measures must be encouraged.     

Mechanisms of bone loss in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease in which destruction of bone in the joints causes major morbidity. Recent research has shed light on the cell and molecular mechanisms that lead to this osteolysis, all due directly or indirectly to the chronic inflammation. The aspects of this research covered in this review include the alteration of cell proliferation and survival that results in growth of the RA synovium. This process depends upon an increase in angiogenesis and local blood flow, which is also a feature of increased bone turnover. In addition, the inflammatory environment increases expression of chemokines, which are involved in the recruitment of monocytic osteoclast precursors. Chronic inflammation also promotes an overall catabolic state, with increased osteoclast differentiation and resorptive activity, driven by disregulation of receptor activator of NF-κB ligand (RANKL) and the synergistic activity of inflammatory cytokines such as tumor necrosis factor-α and interleukin-1. Osteoclast survival is increased in this environment, but osteoblast differentiation and survival are decreased, with a consequent reduction in bone formation and a net loss of bone. Recognition of these processes and the factors involved will enable more effective and targeted treatments for RA.     

Measures of bone loss in rheumatoid arthritis

Patients with rheumatoid arthritis (RA) are prone to develop osteoporosis, especially women receiving steroid hormone therapy. Inhibition of bone formation and/or excessive bone resorption may be responsible. Bone gamma-carboxyglutamic acid-containing protein (BGP), the major noncollagen protein of bone and a plasma marker of bone formation, was measured in 81 consecutive RA patients and 79 age- and sex-matched control subjects, in addition to the hormone regulators of bone metabolism, calcitonin, parathyroid hormone, and 1,25-dihydroxyvitamin D. Mean (+/- SE) BGP levels (picomoles per milliliter) were lower for RA men (1.46 +/- 0.14) and women (1.52 +/- 0.2) compared with their respective controls (2.05 +/- 0.17 for men, 2.47 +/- 0.22 for women). Women taking steroids had the lowest levels (1.13 +/- 0.22) and, in contrast to men, this value was lower than the nonsteroid-treated group. Steroid treatment appears to be a major determinant of low BGP levels; the effect of RA itself is suspected but not proved in this study. Calcitonin levels were lower in RA men as well as in all women. Diminution of BGP in these subjects supports the view that "low-dose" corticosteroid treatment may suppress bone formation, especially in women. Prevention or remediation of osteopenia may be monitored by BGP, if further studies validate this hypothesis with other measures of skeletal mass.     

Effects of low dose corticosteroids on bone mass in rheumatoid arthritis: a longitudinal study.

Low dose corticosteroids are effective in suppressing synovitis in rheumatoid arthritis (RA), but there remains concern about their side effects, particularly osteoporosis. To examine the effects of low dose corticosteroids on bone loss in RA bone mineral density (BMD) was measured in the lumbar spine and hip for up to two years in 15 patients treated with these agents (mean dose prednis(ol)one 6.6 mg/day). 15 patients not receiving them, and 15 age matched controls. The initial BMD at both skeletal sites was significantly reduced in both patient groups compared with controls. The mean change in bone density was 0.2, 0.1, and -0.1% a year in the spine and -2.0, -1.9, and -1.0% a year in the hip respectively for the three groups. These rates of bone loss were not significantly different between groups at either site. These findings suggest that low dose corticosteroid treatment in RA is not associated with an increased risk of osteoporosis.     

Mortality of rheumatoid arthritis in Japan: a longitudinal cohort study

OBJECTIVE: To determine the mortality risk of Japanese patients with rheumatoid arthritis, taking into account lifestyle and physical factors, including comorbidity. METHODS: 91 individuals with rheumatoid arthritis were identified during screening a cohort of 16 119 Japanese atomic bomb survivors in the period 1958 to 1966. These individuals and the remainder of the cohort were followed for mortality until 1999. Mortality risk of the rheumatoid patients was estimated by the Cox proportional hazards model. In addition to age and sex, lifestyle and physical factors such as smoking status, alcohol consumption, blood pressure, and comorbidity were included as adjustment factors for the analysis of total mortality and for analysis of mortality from each cause of death. RESULTS: 83 of the rheumatoid patients (91.2%) and 8527 of the non-rheumatoid controls (52.9%) died during mean follow up periods of 17.8 and 28.0 years, respectively. The age and sex adjusted hazard ratio for mortality in the rheumatoid patients was 1.60 (95% confidence interval, 1.29 to 1.99), p < 0.001. Multiple adjustments, including for lifestyle and physical factors, resulted in a similar mortality hazard ratio of 1.57 (1.25 to 1.94), p < 0.001. Although mortality risk tended to be higher in male than in female rheumatoid patients, the difference was not significant. Pneumonia, tuberculosis, and liver disease were significantly increased as causes of death in rheumatoid patients. CONCLUSIONS: Rheumatoid arthritis is an independent risk factor for mortality. Infectious events are associated with increased mortality in rheumatoid arthritis.     

Depressive symptoms in early rheumatoid arthritis: a comparative longitudinal study

Our objective was to investigate symptoms of depression in early rheumatoid arthritis (eRA) patients, and follow them longitudinally during a 3-year prospective study of 73 Hungarian and 45 Austrian early rheumatoid arthritis patients. Compared to validated national population data, mild symptoms of depression were detected in Hungarian early rheumatoid arthritis patients, which were independent of corticosteroid use. In the Hungarian subgroup, the Beck Depression Inventory scores were found to be stable during follow-up. Except at the baseline visit, depressive symptoms and functional status, as measured by the Health Assessment Questionnaire, were correlated. Significant differences were detected between Austrian and Hungarian patients despite of their geographical and cultural proximity. The mean depression score was higher in the Hungarian when compared to the Austrian patients. Depression is an important feature of early rheumatoid arthritis. Studies assessing depression in rheumatoid arthritis patients must be based on validated national data of normal population.     

Determinants of axial bone loss in rheumatoid arthritis

To assess mechanisms that cause generalized osteoporosis in rheumatoid arthritis (RA), we measured bone mineral density (BMD) by dual photon absorptiometry in the lumbar spine and femoral neck of 111 patients with RA. BMD was significantly reduced at both sites in these patients. Physical activity correlated significantly with BMD in patients with RA, and was found, by multiple regression analysis, to be a significant predictor of femoral bone density in female patients. Multiparity exerted a protective effect on lumbar bone density. Prednisolone (mean dosage 8 mg/day) was not associated with significantly increased bone loss in women, whereas higher dosages in men (mean 10.3 mg/day) were associated with increased lumbar bone loss. Reduced physical activity leading to a form of disuse osteoporosis appears to be an important factor in axial bone loss in RA.     

Hand bone loss in early undifferentiated arthritis: evaluating bone mineral density loss before the development of rheumatoid arthritis

OBJECTIVES: (1) To examine the change in regional bone mineral density (BMD), including the hands, and assess its role as a predictor of outcome in patients presenting with an early undifferentiated inflammatory arthritis; (2) to examine for associations with the changes in hand BMD. METHODS: 74 patients with undifferentiated hand arthritis of less than 12 months' duration were examined at baseline and then at three, six, and 12 months follow up, including BMD measurement of the femoral neck, spine (L2-4), and the whole hands using dual energy absorptiometry (DXA). RESULTS: During the study, 13 patients were diagnosed as having rheumatoid arthritis, 19 as having inflammatory non-rheumatoid joint disorders, and 42 as having non-inflammatory joint disorders. At the femoral neck and lumbar spine no significant bone loss was seen in any of the three subgroups. At the 12 months follow up the mean (95% confidence interval) hand BMD loss in the patients with rheumatoid arthritis was -4.27% (-1.41 to -7.13); in the inflammatory non-rheumatoid group, -0.49% (-1.33 to +0.35); and in the non-inflammatory joint disorder group, -0.87% (-1.51 to -0.23). In a multivariate linear regression model (including age, rheumatoid factor, mean C reactive protein, mean HAQ score, and cumulative glucocorticoid dose), only mean C reactive protein (p<0.001) and rheumatoid factor (p = 0.04) were independently associated with change in hand BMD during follow up. CONCLUSIONS: Hand DXA provides a very sensitive tool for measuring bone loss in early rheumatoid arthritis and may be useful in identifying patients at high risk of developing progressive disease. Further studies are needed to evaluate the role of hand bone loss as a prognostic factor and outcome measure in rheumatoid arthritis.     

Self-efficacy and health status in rheumatoid arthritis: a two-year longitudinal observational study

OBJECTIVE: To investigate the relationship between baseline level of self-efficacy for pain and other symptoms and changes in measures for similar dimensions of health status over a period of 2 yr in patients with rheumatoid arthritis (RA). METHODS: Data collected from patients with RA enrolled in a county-based disease register in Oslo, Norway were analysed: 815 patients were examined by mail questionnaire in 1994 and again in 1996. Relationships of the baseline level of self-efficacy and demographic variables with 2-yr changes in health status measures were examined by bivariate and multiple regression analysis. The following health status measures were included: pain and fatigue on a visual analogue scale; the patient's global assessment of disease activity; the symptom and affect scales of the Arthritis Impact Measurement Scales (AIMS2); and the bodily pain, mental health, general health and vitality scales of the Short Form-36 (SF-36). RESULTS: For all health status measures, there was a significant correlation between the change over a 2-yr span and baseline self-efficacy, even after adjustment for demographic variables and for the baseline level of the health status measure. Favourable changes were associated with high self-efficacy scores. CONCLUSIONS: In patients with RA, the baseline levels of self-efficacy for pain and other symptoms seem to influence 2-yr changes in health status measures regarding these aspects.     

Hand bone densitometry in rheumatoid arthritis,a five year longitudinal study: an outcome measure and a prognostic marker

OBJECTIVE: To investigate whether hand bone mineral content (BMC) measurement is an outcome measure for RA and whether the early changes in hand BMC predict functional disability. METHODS: Tender and swollen joints in hands and body, HAQ score, Larsen score on hand radiographs, serum CRP, and hand BMC measurement by DXA were studied every six months for five years in 40 patients with early RA. At the final visit, patients completed the SF-36 and Duruoz hand function questionnaires. RESULTS: All patients completed two years and 29 completed five years' follow up. Hand BMC worsened over the first three years (percentage loss from baseline: mean (SD) -5.5 (7.2), -7.5 (8.4), -9.8 (9.4)) and stabilised over last two years (-9.9 (8.8), -10 (7.8)). Baseline disease activity and function correlated with hand BMC loss at five years (swollen joints in hands: r=-0.38, p=0.043; swollen joints in body: r=-0.47, p=0.01; HAQ: r=-0.52, p=0.004). Percentage change in hand BMC over five years correlated with SF-36 physical function (r=0.61, p<0.01), hand function (r=-0.64, p<0.01), HAQ score (r=-0.63, p<0.01) at five years. Relative risk of bad hand functional outcome at five years was significantly higher for patients with hand BMC loss of >/=1.17 g (smallest detectable difference) than for patients with less bone loss within the first six months (OR=6.9, 95% CI 1.3 to 34.5, p<0.02). CONCLUSION: Early loss of hand BMC in patients with RA is a composite marker of disease activity and functional status and can predict poor functional outcome.     

Factors influencing length of time taking methotrexate in rheumatoid arthritis

OBJECTIVE: Duration of therapy has been suggested to represent a measure of effectiveness. Life table analyses of therapy with methotrexate (MTX) in rheumatoid arthritis (RA) have indicated a longer duration than with other drugs. However, individual patients continue taking MTX for different periods of time. We assessed the influence of patient variables at treatment onset upon subsequent duration of MTX therapy. METHODS: Patients with RA (n = 437) from 8 North American databank centers beginning MTX therapy after January 1, 1988, were followed prospectively. Age at onset of MTX treatment, sex, years of education, age at onset of disease, years with disease, number of comorbid conditions, number of disease modifying antirheumatic drugs (DMARD) and nonsteroidal antiinflammatory drugs (NSAID) taken just prior to MTX. disability level, pain, and global assessment prior to starting MTX were used in univariate Kaplan-Meier analyses to predict number of months taking MTX alone. An index that divided the patients into risk strata for predicting duration of therapy was constructed to be clinically useful. RESULTS: The median number of months continuing MTX without addition of other DMARD was 41 months and the median for the total course taking MTX was 52 months. The retention rate was lowest for patients with the most negative initial health state. High level of initial pain, long duration of disease, and not using a DMARD just prior to MTX were associated with low retention rate and can be used to predict expected durations of MTX treatment ranging from 17 to 52 months. For practical guidance in clinical decisions an index was computed based on the predictor variables: level of initial pain, duration of disease, and number of DMARD; this index identifies subgroups with very different durations taking MTX alone. Disease duration at baseline was strongly related to time taking MTX alone and could therefore also be used as a simplified rule in clinical work. CONCLUSION: Expected duration of MTX treatment is influenced by clinical variables, and these may suggest those patients likely to have more or less satisfactory experiences with MTX. The time taking drug alone (therapeutic segment) may be a more logical and sensitive indicator of effectiveness than the total course on the medication.     

Prevention of postmenopausal bone loss in rheumatoid arthritis patients. A two-year prospective study

The effect of three different therapeutic regimens on bone mineral content at the radius and lumbar spine was studied in a group of 60 postmenopausal rheumatoid arthritis patients. Results were compared to those in a group of controls matched for sex, age, disease duration and menopausal state. Serum and urinary parameters of calcium metabolism were also evaluated in the three treatment groups. The three treatment regimens were: 1 alpha hydroxyvitamin D + calcium + placebo; 1 alpha hydroxyvitamin D + calcium + lynestrenol; and 1 alpha hydroxyvitamin D + calcium + sodium fluoride. In all treatment groups there was a positive effect of therapy compared to controls, though this was only significant in the 1 alpha hydroxyvitamin D + calcium + lynestrenol group at the axial skeleton after 1 and 2 years of treatment. Serum calcium rose significantly in the 1 alpha hydroxyvitamin D + calcium + placebo group and serum creatinin was raised in all the treatment groups during therapy. In the 1 alpha hydroxyvitamin D + calcium + lynestrenol group, serum alkaline phosphatase activity and urinary hydroxyproline excretion decreased significantly.     

Predicting erosive disease in rheumatoid arthritis. A longitudinal study of changes in bone density using digital X-ray radiogrammetry: a pilot study

OBJECTIVE: Periarticular osteoporosis is one of the first radiological signs of rheumatoid arthritis (RA). Osteoporosis is now quantified using dual-energy X-ray absorptiometry (DXA), although it was originally assessed by radiogrammetry. A new updated system of radiogrammetry has been developed: digitized X-ray radiogrammetry (DXR). We used this DXR system to identify whether changes seen in hand X-rays of RA patients can predict those who subsequently develop erosions. METHODS: We enrolled 24 patients with early RA and they attended for hand radiographs at baseline, 12, 24 and 48 months. The hand radiographs were analysed using a Pronosco X-Posure system which measures bone mineral density, and other parameters using DXR. DXA of the hand was also performed to measure bone mineral density. Sharp and Larsen radiographic scores were calculated and other disease activity markers were measured. RESULTS: DXR bone mineral density fell significantly throughout the study. The group of RA subjects were divided according to the change in erosive status. Change in DXR bone mineral density after 1 yr was very specific (100%) and highly sensitive (63%) in predicting those who either became erosive or whose erosions significantly worsened. In contrast, of the other disease activity markers, only baseline ESR (sensitivity 67%, specificity 80%) significantly predicted the erosive status of subjects at 4 yr. CONCLUSION: Computerized radiogrammetry from digitized images can predict at 1 yr those patients with RA who will become erosive at 4 yr. A larger prospective study is required to confirm these findings; however, these results show some promise as a method of targeting those patients who require more aggressive, expensive therapy.     

Postmenopausal bone loss in rheumatoid arthritis: effect of estrogens and androgens.

Osteoporosis is a frequent complication of rheumatoid arthritis (RA), especially in postmenopausal women, and may involve both juxtaarticular and generalized bone loss. To examine the effect of exogenous estrogens and endogenous androgens on bone loss in RA we determined rates of bone loss by serial bone density measurement for up to 4 years in 38 postmenopausal women with RA. Serum dehydroepiandosterone sulfate concentrations correlated significantly with the change in femoral neck bone but not in lumbar spine bone. Estrogen therapy prevented lumbar spine bone loss, but did not affect bone loss from the hip. These data suggest adrenal androgen status may influence bone loss in RA and that, although estrogen therapy can prevent bone loss from the spine, it may not prevent bone loss at sites near involved joints.