Infliximab therapy increases body fat mass in early rheumatoid arthritis independently of changes in disease activity and levels of leptin and adiponectin: a randomised study over 21 months.

INTRODUCTION: Rheumatoid arthritis (RA) is associated with changes in body composition and bone mineral density (BMD). The purpose of the present study was to evaluate whether anti-TNF treatment in early RA has an impact on body composition and BMD besides that which could be achieved by intensive disease-modifying anti-rheumatic drug (DMARD) combination therapy. METHODS: Forty patients with early RA who failed treatment with methotrexate up to 20 mg/week for 3 months were randomised to addition of sulphasalazine and hydroxychloroquine (treatment A) or addition of infliximab (treatment B). At 3, 12 and 24 months, body composition and BMD were assessed by total-body dual-energy X-ray absorptiometry. At the same time points, leptin, adiponectin, apolipoproteins, insulin-like growth factor-1 (IGF-1) and markers of bone remodelling were analysed. Compliance to treatment was considered in the analyses. Data were analysed with a mixed, linear model. RESULTS: Patients treated with anti-TNF had a significant increase in fat mass at 2 years, 3.8 (1.6 to 5.9) kg, in contrast to patients in treatment A, 0.4 (-1.5 to 2.2) kg (P = 0.040), despite similar reduction in disease activity. Both treatment strategies prevented loss of muscle mass and bone. Leptin concentrations increased significantly in both groups at 2 years and adiponectin increased significantly at 2 years in treatment A and at 1 year in treatment B. There were no significant changes in apolipoproteins or IGF-1. The markers of bone resorption decreased at 12 months in both treatment groups with no significant difference between the treatment groups. CONCLUSIONS: Infliximab therapy increased body fat mass, an effect that was not achieved with the combination of DMARDs, despite a similar reduction in disease activity, and thus seemed to be drug specific. The increase of fat mass was not associated with an exacerbated atherogenic lipid profile. Leptin and adiponectin concentrations increased in both treatment groups. The increase of adiponectin may partially explain the reduced frequency of cardiovascular diseases found when disease activity is reduced in RA. TRIAL REGISTRATION: ISRCTN39045408.

Gonadal hormones in men with rheumatoid arthritis--from onset through 2 years.

OBJECTIVE: To evaluate changes over a 2-year course in the hypothalamic-pituitary-gonadal (HPG) axis in men with early rheumatoid arthritis (RA) from start of treatment with disease modifying antirheumatic drugs. METHODS: Forty-one men with early RA and with joint symptoms less than 1 year were studied. Mean age at inclusion was 53 years and mean disease duration 6 months. They were followed prospectively for 2 years for disease activity [Disease Activity Score 28 (DAS28)], physical impairment (Health Assessment Questionnaire), total serum testosterone, non-sex hormone-binding globulin-bound testosterone, and luteinizing hormone (LH). A group of 131 healthy, medicine-free men served as controls for baseline hormone concentrations. RESULTS: The men with RA already had mean testosterone levels lower than controls early in the disease course. Patients older than 50 years also had significantly lower LH levels compared with controls, consistent with mild hypogonadotropic hypogonadism. In patients who responded to treatment at the 2-year followup the testosterone levels increased significantly. A decrease in DAS28 during the 2 years correlated significantly with increased testosterone levels (r(s) = -0.46, p = 0.006). LH levels were low and stable and did not correlate with disease activity. CONCLUSION: In early RA, current inflammation seemed to affect the HPG axis, mainly at the gonadal rather than the hypothalamic-pituitary level. Prospective studies are indicated to determine if low HPG activity may be a cause rather than a consequence of a chronic inflammatory state.

Impact of low-dose prednisolone on bone synthesis and resorption in early rheumatoid arthritis: experiences from a two-year randomized study.

INTRODUCTION: Patients with rheumatoid arthritis (RA) have an increased frequency of osteoporosis, mainly because of increased bone resorption. Reduction of disease activity is suggested to reduce bone remodelling. It might also be possible that prednisolone treatment could cause this effect because prednisolone has been shown to arrest the development of joint destruction in early RA. Therefore, we examined the effects of low-dose prednisolone on serum concentrations of bone remodelling markers and insulin-like growth factor-1 (IGF-1) in RA patients in relation to bone mineral density. METHODS: One hundred and fifty patients, 67% women, with early RA, mean disease duration of six months (95% confidence interval (CI) = three to eight months), who had participated in the BARFOT (Better Anti-Rheumatic FarmacOTherapy) low-dose prednisolone study were included. They had been randomised to either the P-group, who were treated with 7.5 mg prednisolone daily (n = 70, mean age = 51 years, 95% CI 48 to 54 years), or the NoP-group, who received no prednisolone (n = 80, mean age 58 years, 95% CI 56 to 61 years), when they started their first disease-modifying anti-rheumatic drug (DMARD). Serum samples were analysed at baseline, 3 and 12 months for procollagen type I N-terminal propeptide (P1NP), a marker of bone formation, and the C-telopeptide crosslaps of type I collagen (CTX-1) and C-terminal telopeptide of type I collagen (1CTP), markers of bone degradation. IGF-1 was analysed at baseline and after 12 months. Bone mineral density at the lumbar spine and femoral neck was assessed by dual-energy X-ray absorptiometry at baseline and after 24 months. RESULTS: Levels of P1NP decreased rapidly in the P-group (p < 0.001). Levels of CTX-1 and 1CTP decreased in both treatment groups, but significantly more in the P-group (differences between groups p < 0.019 and p < 0.001, respectively). IGF-1 increased in the P-group (p < 0.001) but remained stable in the NoP-group. Bone mineral density decreased in the spine in both groups, significantly more in postmenopausal women from the P-group. Femur bone mineral density only decreased in the NoP-group. CONCLUSIONS: Low-dose prednisolone in early RA counteracts the negative impact of rheumatoid inflammation on bone tissue in the hip, a juxta-articular localisation. Thus bone mineral density was preserved in the femur in the P-group and 1CTP decreased rapidly. However, the systemic inflammatory consequences on bone could not be prevented in the lumbar spine, especially not in postmenopausal women, probably because of the combined effect of suppression of bone synthesis by prednisolone and the postmenopausal status.

The foot: still the most important reason for walking incapacity in rheumatoid arthritis: distribution of symptomatic joints in 1,000 RA patients.

BACKGROUND AND PURPOSE: Our knowledge of frequency of foot involvement in rheumatoid arthritis (RA) is still often based on a study from Finland in 1956. Great changes in the treatment of RA may have led to a different situation. We investigated the distribution of joint involvement in RA patients today, with special attention given to the feet and subjective walking ability. METHODS: 1,000 RA patients answered a questionnaire concerning joints affected, joint surgery, foot problems, and subjectively experienced reasons for walking incapacity. RESULTS: In 45% of the patients, the forefoot was involved at the start of the disease. In 17%, the hindfoot/ankle was involved at the start. Only hand symptoms were commoner. 80% of patients reported current foot problems, 86% in the forefoot and 52% in the hindfoot/ankle. Difficulty in walking due to the feet was reported by 71%. For 41% of patients, the foot was the most important part of the lower extremity causing reduced walking capacity, and for 32% it was the only part. INTERPRETATION: After the hand, the foot was the most frequently symptomatic joint complex at the start of the disease, but also during active medical treatment. The foot caused walking disability in three-quarters of the cases and-4 times as often as the knee or the hip-it was the only joint to subjectively impair gait.

Effects of protein-rich supplementation and nandrolone on bone tissue after a hip fracture.

BACKGROUND & AIMS: Osteoporosis is a major health problem worldwide. Low weight is a major risk factor for low bone mass and fractures. The aim of this study was to investigate the effects on bone tissue of protein-rich supplementation alone or in combination with nandrolone decanoate in lean elderly women after a hip fracture. METHODS: Sixty elderly women with BMI <24 kg/m(2) admitted to hospital due to a femoral neck fracture were randomised to a control group, to receive a protein-rich formula or to receive the same formula with an addition of nandrolone decanoate for 6 months. All patients received additional calcium and vitamin D. The effects after 6 and 12 months were measured by means of bone mineral density (BMD) using dual-energy X-ray absorptiometry (DXA), and with biochemical bone markers. Osteocalcin and C-terminal telopeptide of collagen-1 (CTX) were used to estimate bone formation and bone resorption, respectively. RESULTS: The analyses showed an increase in total body BMD at 6 and 12 months in patients who received protein-rich supplementation. Nandrolone decanoate did not appear to have any additional effect on BMD. Osteocalcin increased in all groups while no significant changes were found for CTX. CONCLUSION: The overall results of the study indicated that protein-rich supplementation given to lean elderly female hip fracture patients increased the total body BMD.

Increased DHEAS levels in patients with rheumatoid arthritis after treatment with tumor necrosis factor antagonists: evidence for improved adrenal function.

OBJECTIVE: To determine if major reduction of inflammation with longterm tumor necrosis factor (TNF) antagonist treatment has any influence on the adrenal and gonadal axes in patients with rheumatoid arthritis (RA). METHODS: Forty-eight patients with RA were treated with infliximab or etanercept for 2 years. Disease activity, clinical response, and physical function were evaluated and serum levels of high sensitivity C-reactive protein and interleukin 6 were analyzed before start of treatment and after 1 and 2 years. At the same timepoints adrenocorticotropic hormone (ACTH), cortisol, and dehydroepiandrosterone sulfate (DHEAS) were analyzed; luteinizing hormone (LH), estradiol, and testosterone were analyzed as well in 18 male patients. RESULTS: DHEAS increased (p

[TNF blockade in rheumatoid arthritis can cause severe fibrosing alveolitis. Six case reports]. / TNF-blockad vid reumatoid artrit kan ge svår fibrotiserande alveolit. Sex fallbeskrivningar.

TNF-blockade has been increasingly used in the treatment of rheumatoid arthritis (RA). However, the safety is unclear and an increased risk of both tuberculosis and other infections has been identified. Recently severe fibrosing alveolitis has also been reported in RA-patients treated with TNF-blockade. We report a further six RA patients, who during treatment with infliximab or etanercept developed fulminant lung fibrosis with alveolitis. For four of the patients, the fibrosing alveolitis was fatal. All patients were RF positive and above 60 years and five had mild fibrosis associated with RA before TNF-blockade treatment. Duration of TNF-blockade treatment was for three patients only two months and for the other three, 20-51 months. Age above 60 years and previous lung fibrosis appear to be risk factors for developing fibrosing alveolitis in RA patients treated with TNF-blockade.

Effects of protein-rich supplementation and nandrolone in lean elderly women with femoral neck fractures.

AIM: To evaluate the effects of a protein-rich liquid supplementation, alone or in combination with the anabolic steroid nandrolone decanoate, on body composition, activities of daily living (ADL) status and the health-related quality of life (HRQoL) after a femoral neck fracture. METHODS: Sixty women, aged 83 +/- 5 years (mean +/- SD), BMI < 24 kg/m2 (20.4 +/- 2 kg/m2 ) and capable of co-operating, with a femoral neck fracture treated with internal fixation, were randomised to open treatment during 6 months with a protein-rich liquid formula alone (PR, Fortimel, 200 ml/day, 20 g protein/day) or in combination with nandrolone decanoate (PR/N, Deca-Durabol 25 mg i.m./3 weeks) or to a control group (C). The patients were re-examined after 6 and 12 months regarding body weight (BW), lean body mass (LBM, DXA), ADL status according to Katz, HRQoL according to EQ 5-D and fracture healing. RESULTS: LBM decreased in the C (-1.2 +/- 2 kg) and PR groups (-1.2 +/- 1 kg) but remained the same in the PR/N group (0.3 +/- 1 kg) (P < 0.05 between groups). ADL remained at a high level in the two intervention groups but declined significantly in the C group (P < 0.005 between groups). The decline in HRQoL was least pronounced in the PR/N group at 6 months (P < 0.05 between groups). Patients with fracture healing complications lost more BW (P < 0.05) and LBM (P < 0.01) than patients with uneventful fracture healing. CONCLUSION: Protein-rich liquid supplementation in combination with nandrolone given for 6 months to lean elderly women after a femoral neck fracture may positively affect LBM, ADL and HRQoL.

The influence of sex on rheumatoid arthritis: a prospective study of onset and outcome after 2 years.

OBJECTIVE: This prospective study analyzed influence of patient's sex on early rheumatoid arthritis (RA) within one year of disease onset and after 2 years' followup. METHODS: A total of 844 consecutive patients, 538 women, with RA of less than 12 months were studied. Standardized clinical and radiographic assessments were performed at study entry and after 2 years. The association of several variables at study entry with the outcome variables Disease Activity Score (DAS28), functional disability measured by the Health Assessment Questionnaire (HAQ), and, in 390 patients, Larsen score at the 2-year followup were analyzed in men and women separately. RESULTS: At study entry the women were younger compared with the men and the sexes showed different age distributions. The women had higher DAS28 and HAQ scores. However, women below 50 years of age at study entry had milder disease than older women and close to that of men. At 2-year followup the women still had higher DAS28 and HAQ scores compared to men, who had achieved remission in a higher frequency. Larsen score showed no sex difference either at study entry or after 2 years. Presence of rheumatoid factor (RF) was associated with lower age at study entry and higher DAS28 at followup in men only. Higher DAS28 and HAQ scores at entry were more strongly correlated with severe disease at followup in women than in men. Presence of the "shared epitope" was not associated with age or the outcome variables DAS28 and Larsen score in either sex. CONCLUSION: The disease phenotype in early RA was significantly different between men and women, particularly concerning age, disease activity, and functional capacity. There were differences between the sexes concerning early disease characteristics associated with outcome at 2 years of followup.

Abnormal levels of serum dehydroepiandrosterone, estrone, and estradiol in men with rheumatoid arthritis: high correlation between serum estradiol and current degree of inflammation.

OBJECTIVE: Men with rheumatoid arthritis (RA) have a higher than normal frequency of low testosterone levels, but not much is known about other sex hormones. We investigated serum levels of estradiol, estrone, and the adrenal androgen dehydroepiandrosterone (DHEAS) in men with RA and evaluated the association of various disease variables with these sex hormones. METHODS: Inflammatory activity, measured as disease activity score including 28 joints (Disease Activity Score 28), and degree of disability, measured with the Health Assessment Questionnaire, were estimated in 101 men with RA. Presence of erosions, rheumatoid factor (RF), smoking habits, and body mass index were recorded. DHEAS (not measured in patients taking glucocorticoids), estradiol, and estrone were measured in patients and in healthy controls. RESULTS: DHEAS and estrone concentrations were lower and estradiol was higher in patients compared with healthy controls. DHEAS differed between RF positive and RF negative patients. Estrone did not correlate with any disease variable, whereas estradiol correlated strongly and positively with all measured indices of inflammation. CONCLUSION: Men with RA had aberrations in all sex hormones analyzed, although only estradiol consistently correlated with inflammation. The high levels of estradiol may have positive implications for bone health. The low levels of estrone and DHEAS may depend on a shift in the adrenal steroidogenesis towards the glucocorticoid pathway, whereas increased conversion of estrone to estradiol seemed to be the cause of the high estradiol levels.

Bone mineral density in men with rheumatoid arthritis is associated with erosive disease and sulfasalazine treatment but not with sex hormones.

OBJECTIVE: To quantify bone mineral density (BMD) in men with rheumatoid arthritis (RA) and to evaluate the influence of various disease-specific and non-disease-specific variables on bone mass. METHODS: Dual energy x-ray absorptiometry was performed in 104 male patients with RA and BMD was measured in lumbar spine, femoral neck, trochanter, and Ward's triangle. Inflammatory activity, measured as Disease Activity Score including 28 joints (DAS28), degree of functional impairment measured with the Health Assessment Questionnaire, and sex hormones (bioavailable testosterone, DHEAS, estradiol, and estrone) were estimated. Presence of erosions, rheumatoid factor, and current treatment as well as body mass index and smoking habits were recorded. Correlations were performed with nonparametric tests and multiple regression analyses. RESULTS: BMD was reduced in both spine and hip compared to an age matched reference population. Erosive disease was the variable with the strongest correlation with BMD. Treatment with sulfasalazine correlated positively with BMD at 3 of the 5 measured bone sites. However, in multivariate analysis significance was sustained only in the trochanter region. There were no correlations between the degree of inflammation, levels of sex hormones, treatment with corticosteroids, or smoking and BMD at any site measured. CONCLUSION: A large proportion of the men with RA had reduced bone mass. Sex hormone levels and treatment with corticosteroid did not influence BMD, nor did current degree of disease activity. Erosive disease was closely correlated with low BMD, whereas sulfasalazine was associated with high BMD at least in the trochanter region.