Adherence to dietary guidelines, and the risk of developing rheumatoid arthritis: results from a nested case-control study.

OBJECTIVES: To examine the relationship between adherence to dietary guidelines and the risk of developing RA. METHODS: Participants in the Malmö Diet and Cancer Study (MDCS) cohort diagnosed with RA were identified through register linkage and validated in a structured review. Four controls per case were selected, matched for sex, year of birth, and year of inclusion in the MDCS. Diet was assessed at baseline (1991-1996) using a validated diet history method. A Diet Quality Index (DQI) based on adherence to the Swedish dietary guidelines including intakes of fibre, vegetables and fruits, fish and shellfish, saturated fat, polyunsaturated fat, and sucrose, was used. The associations between the DQI and its components and the risk of RA were assessed using conditional logistic regression analysis, adjusting for total energy intake, smoking, leisure time physical activity and alcohol consumption. RESULTS: We identified 172 validated cases of incident RA in the cohort. Overall adherence to the dietary guidelines was not associated with the risk of RA. Adherence to recommended fibre intake was associated with decreased risk of RA in crude and multivariable-adjusted analyses, with odds ratios (ORs) 0.60 (95% CI 0.39, 0.93) and 0.51 (95% CI 0.29, 0.90), respectively, compared with subjects with non-adherence. CONCLUSIONS: Reaching the recommended intake level of dietary fibre, but not overall diet quality, was independently associated with decreased risk of RA. Further studies are needed to assess the role of different food sources of dietary fibre in relation to risk of RA and the underlying mechanisms.

Effects of Treatment with Adalimumab on Blood Lipid Levels and Atherosclerosis in Patients with Rheumatoid Arthritis.

BACKGROUND: Treatment with tumor necrosis factor inhibitors for rheumatoid arthritis has been associated with a decreased risk of cardiovascular disease in observational studies. There are conflicting data on the influence of tumor necrosis factor inhibitors on lipid levels. OBJECTIVES: To evaluate the effect of treatment with adalimumab on blood lipid levels, lipoproteins, and atherosclerosis of the carotid artery. METHODS: Fourteen patients with active rheumatoid arthritis (11 women and 3 men; mean age 63.7 years; median disease duration 9.0 years; and 78% rheumatoid factor positive) were treated with adalimumab 40 mg subcutaneously every 2 weeks and followed for 3 months. The patients had not been treated with adalimumab previously and had not received other tumor necrosis factor inhibitors within the past 3 months or moderate/high dose corticosteroids within the past 2 weeks. The intima-media thickness of the common carotid artery was assessed using B mode ultrasonography. Triglycerides, total cholesterol, LDL cholesterol, and HDL cholesterol levels were analyzed in fresh fasting blood samples, whereas apolipoprotein B and apolipoprotein A1 (apoA1) levels were determined in thawed plasma samples using standard turbidimetric immunoassays. RESULTS: Total cholesterol (mean = 5.36 vs 5.96 mmol/L; P = 0.005), LDL cholesterol (mean = 3.33 vs 3.77 mmol/L; P = .005), HDL cholesterol (mean = 1.43 vs 1.55 mmol/L; P = 0.048), apolipoprotein B (mean = 1.04 vs 1.13 g/L; P = .012), and apoA1 (mean = 1.42 vs 1.58 g/L; P = 0.005) all increased, but there were no major changes in the LDL to HDL cholesterol ratio (median = 2.56 vs 2.35; P = 0.27) or the apolipoprotein B to apoA1 ratio (mean = 0.76 vs 0.74; P = 0.46). There was no change in triglyceride levels (P = 0.55). Disease activity decreased significantly from baseline to the 3-month evaluation (disease activity score based on 28 joints mean = 5.6 vs 4.1; P = 0.007). An increase in apoA1 correlated with decreases in the patient global assessment of disease severity (r = 0.79; P = 0.001) and C-reactive protein level (r = 0.74; P = 0.003). Changes in the apoliprotein B to apoA1 ratio correlated with changes in erythrocyte sedimentation rate (r = 0.54; P = 0.046). There was no major change in the common carotid artery intima-media thickness (mean = 0.78 vs 0.80 mm; P = 0.48). CONCLUSIONS: Although these results suggest that control of inflammation could have a beneficial effect on the lipid profile through an increase in HDL cholesterol levels, the observed protective effect on cardiovascular disease events by tumor necrosis factor blockers is likely to be explained by other mechanisms than changes in lipid levels or short-term effects on atherosclerosis of the carotid artery.

A high body mass index is associated with reduced risk of rheumatoid arthritis in men, but not in women.

OBJECTIVE: To investigate the impact of overweight and obesity on the risk of RA. METHODS: From two large population-based health surveys (30 447 and 33 346 participants), individuals who developed RA after inclusion were identified by linkage to four different registers and a structured review of the medical records. Matched controls were selected from the corresponding health survey database. The impact of overweight or obesity (BMI > 25 kg/m(2)) compared with normal BMI (18.5-25 kg/m(2)) on the risk of RA was examined in conditional logistic regression models, stratified by sex. RESULTS: A total of 172 (36 men/136 women) and 290 (151 men/139 women) individuals were diagnosed with RA after inclusion in the two health surveys. The median time from inclusion to RA diagnosis was 5 years and 12 years, respectively. In men, being overweight or obese at inclusion in the health survey was associated with a reduced risk of subsequent development of RA in both cohorts [odds ratio (OR) = 0.33; 95% CI: 0.14, 0.76, and 0.60; 95% CI: 0.39, 0.91]. There was no such association in women (OR = 1.01; 95% CI: 0.65, 1.54, and 1.37; 95% CI: 0.86, 2.18). Estimates were similar in analyses adjusted for potential confounders, including smoking. CONCLUSION: A high BMI was associated with a reduced risk of future RA in men, but not in women. Factors related to adipose tissue may contribute to mechanisms that are protective from RA in men.

High serum cholesterol predicts rheumatoid arthritis in women, but not in men: a prospective study.

INTRODUCTION: Environmental exposures, including smoking, hormone-related factors, and metabolic factors, have been implicated in the etiology of rheumatoid arthritis (RA). A previous study has indicated that blood lipid levels may influence the development of RA. The objective of this study was to investigate the impact of serum total cholesterol and triglycerides on the risk of RA in a prospective study. METHODS: Among participants in a large population-based health survey (n = 33,346), individuals who subsequently developed RA were identified by linkage to four different registers and a structured review of the medical records. In a nested case-control study, with controls, matched for age, sex, and year of inclusion, from the health survey database, the relation between serum lipids (levels of total cholesterol and triglycerides) and future RA development was examined. RESULTS: In total, 290 individuals (151 men and 139 women) whose RA was diagnosed a median of 12 years (range of 1-28) after inclusion in the health survey were compared with 1160 controls. Women with a diagnosis of RA during the follow-up had higher total cholesterol levels at baseline compared with controls: odds ratio (OR) 1.54 per standard deviation; 95 % confidence interval (CI) 1.22-1.94. This association remained statistically significant in multivariate models adjusted for smoking and a history of early menopause and in analyses stratified by rheumatoid factor status and time to RA diagnosis. Total cholesterol had no significant impact on the risk of RA in men (OR 1.03; 95 % CI 0.83-1.26). Triglycerides did not predict RA in men or women. CONCLUSIONS: A high total cholesterol was a risk factor for RA in women but not in men. This suggests that sex-specific exposures modify the impact of lipids on the risk of RA. Hormone-related metabolic pathways may contribute to RA development.

Effects of adalimumab treatment on endothelial cell activation markers in the skeletal muscle of patients with rheumatoid arthritis.

OBJECTIVES: Patients with rheumatoid arthritis (RA), particularly those with severe disease, have increased risk of cardiovascular disease (CVD). Previous studies suggest that endothelial cell activation may contribute to this co-morbidity, and that treatment with tumour necrosis factor (TNF) inhibitors could reduce the risk of CVD in these patients. The aim of this study was to investigate endothelial cell activation markers in muscle tissue of patients after adalimumab treatment. METHODS: Patients with active RA who started treatment with adalimumab 40 mg every two weeks were included. Muscle biopsies taken before and 3 months after start of treatment were available from 11 patients (9 females, mean age 54.2 years, median disease duration 6.5 years, 91% anti-CCP positive, 7 on methotrexate [median dose 20 mg/week]). None of the patients had clinical signs of myopathy. IL-1α and HLA-DQ were investigated by immunohistochemistry. Quantification was performed by computer assisted image analysis. RESULTS: Disease activity, measured by DAS28 decreased (mean 5.5 vs. 4.1; p=0018). A good or moderate EULAR response was seen in 6/11 patients. HLA-DQ was mainly expressed in endothelial cells in capillaries, whereas IL-1α was mainly seen in larger vessels. HLA-DQ expression decreased significantly after treatment (p=0.041). There was a similar trend for IL-1α, in particlar in EULAR good/moderate responders. CONCLUSIONS: Adalimumab treatment was associated with decreased expression of endothelial markers previously associated with severe systemic inflammation in RA. Our findings indicate a reduced endothelial activation in patients treated with anti-TNF drugs, which might contribute to a lower risk of cardiovascular co-morbidity.

Association between testosterone levels and risk of future rheumatoid arthritis in men: a population-based case-control study.

OBJECTIVES: Rheumatoid arthritis (RA) is less common among men than women, and sex hormones have been suggested to play a part in the pathogenesis. Lower levels of testosterone have been demonstrated in men with RA, but it is not known if these changes precede the disease. METHODS: In a nested case-control study, using information and blood samples from a population-based health survey, we identified incident cases of RA by linking the cohort to local and national RA registers. Two controls for each validated case, matched for age, sex and year of screening, were selected from the health survey. Using stored blood samples, collected between 08:00 and 10:00 am after an overnight fast, we analysed levels of testosterone and other reproductive hormones. RESULTS: Serum was available from 104 cases (median time from screening to RA diagnosis 12.7 years (range 1-28); 73% rheumatoid factor (RF) positive at diagnosis or later) and 174 matched controls. In conditional logistic regression models, adjusted for smoking and body mass index, lower levels of testosterone were associated with subsequent development of RF-negative RA (OR 0.31 per SD, 95% CI 0.12 to 0.85), with a weaker association with RF-positive RA (OR 0.87 per SD; 95% CI 0.53 to 1.43). Levels of follicle-stimulating hormone were significantly increased in pre-RF-negative RA (p=0.02), but decreased in pre-RF-positive RA (p=0.02). CONCLUSIONS: Lower levels of testosterone were predictive of RF-negative RA, suggesting that hormonal changes precede the onset of RA and affect the disease phenotype.

Early menopause is an independent predictor of rheumatoid arthritis.

BACKGROUND: As rheumatoid arthritis (RA) occurs more often in women than in men, it has been suggested that reproductive hormones may play an important role in the pathogenesis. METHODS: Between 1991 and 1996, 30 447 subjects (18 326 women) were included in a community-based health survey. Information on female hormonal changes and stress-related factors was obtained using a self-administered questionnaire. This population was linked to four different local and national RA registers. The medical records for patients with a diagnosis of RA were subjected to a structured review and all women with incident RA according to the 1987 American College of Rheumatology criteria after inclusion in the health survey were included in a nested case-control study. Matched controls (1:4) were selected from the health survey population. RESULTS: Early age at menopause (≤45 years) was associated with the subsequent development of RA (OR 2.42, 95% CI 1.32 to 4.45). The effect of early menopause remained significant after adjusting for smoking, level of education and length of breastfeeding (OR 1.92, 95% CI 1.02 to 3.64) CONCLUSION: RA was predicted by an early age at menopause. This implicates an influence of hormonal changes during the fertile period on the development of RA in postmenopausal women.

Pulmonary dysfunction, smoking, socioeconomic status and the risk of developing rheumatoid arthritis.

OBJECTIVES: Environmental risk factors are of potential interest for both prevention and treatment of RA. The purpose of this study was to examine the effect of pulmonary function, smoking and socio-economic status on the future risk of RA. METHODS: Between 1974 and 1992, 22 444 men and 10 902 women were included in the Malmö Preventive Medicine Program (MPMP). Pulmonary function was assessed by a standard screening spirometry. Chronic obstructive pulmonary disease (COPD) and restrictive pulmonary dysfunction were defined based on pulmonary function tests. Individuals who developed RA were identified by linking the MPMP database to national and local RA registers. The patients were classified according to the 1987 ACR criteria for RA. Four matched controls for every case were selected. RESULTS: We identified 290 cases of incident RA (151 men/139 women; mean age at diagnosis 60 years). The median time from inclusion to diagnosis was 12 years. Forced vital capacity and forced expiratory volume within 1 s values were similar in cases and controls, overall and also in separate analysis of those screened ≤8 years before diagnosis. There was no association between COPD or restrictive pulmonary dysfunction and subsequent development of RA. Current smoking was a strong predictor for RA [odds ratio (OR) 1.79; 95% CI 1.32, 2.42]. Blue-collar workers had an increased risk of RA (OR 1.54; 95% CI 1.12, 2.10), independent of smoking. CONCLUSION: Pulmonary dysfunction did not predict RA, but smoking and low socio-economic status were independent risk factors for RA. Other effects of smoking may be important for RA susceptibility.

Increased cartilage turnover and circulating autoantibodies in different subsets before the clinical onset of rheumatoid arthritis.

BACKGROUND: Previous studies have indicated that autoantibodies may be detected years before the clinical onset of rheumatoid arthritis (RA). Cartilage biomarkers, such as cartilage oligomeric matrix protein (COMP), have not been studied previously in samples collected before the diagnosis of RA. METHODS: Between 1991 and 1996, 30 447 subjects were included in the Malmö Diet Cancer Study (MDCS). People who developed RA after inclusion were identified by linking the MDCS database to different Swedish registers. One matched control for each validated case was selected from the MDCS. IgG antibodies against cyclic citrullinated peptide (anti-CCP) and mutated citrullinated vimentin (anti-MCV) and IgM rheumatoid factor (IgM RF) were determined by ELISA. Serum COMP was measured with a sandwich ELISA. RESULTS: 172 incident cases of RA (median time from inclusion to diagnosis 5 years; range 1-13) were identified. Pre-RA cases were significantly more likely than controls to be positive for anti-CCP (21.9% vs 0.6%), anti-MCV (29.6% vs 3.0%) and IgM RF (18.9% vs 2.4%) (all p<0.001). Overall, mean serum COMP levels did not differ between cases and controls. Among pre-RA cases included 1-3 years before diagnosis, raised COMP (>12 U/l) was seen in a greater proportion of anti-CCP-negative than anti-CCP-positive subjects (50% vs 15%; p=0.04). CONCLUSIONS: Increased cartilage turnover, measured by COMP, and circulating RA-specific antibodies may be distinct processes in the preclinical phase of RA.